guide for

HIV/AIDS 

Clinical Care

U.S. Department of Health and Human Services

Health Resources and Services Administration

HIV/AIDS Bureau

April 2014
The publication was produced for the U.S. Department of Health and Human 

Services (HHS), Health Resources and Services Administration (HRSA) by the AIDS 

Education and Training Centers National Resource Center under contract number 

HHSH250201400001P. The Government has unlimited rights in this publication to 

use, disclose, reproduce, prepare derivative works, distribute copies to the public, and 

perform publicly and display publicly, in any manner and for any purpose, and to have 

or permit others to do so.

Guide for HIV/AIDS Clinical Care – 2014 Edition is not copyrighted. Readers are free to 

duplicate and use all or part of the information contained in this publication; however, 

some of the images are copyrighted and may not be used without permission. Sources 

are listed directly under the images. 

Pursuant to 42 U.S.C. § 1320b-10, this publication may not be reproduced, reprinted, or 

redistributed for a fee without specific written authorization from HHS. 

This publication lists non-federal resources in order to provide additional information 

to consumers. The views and content in these resources have not been formally 

approved by HHS or HRSA. Neither HHS nor HRSA endorses the products or services 

of the listed resources.

Suggested Citation:

U.S. Department of Health and Human Services, Health Resources and Services 

Administration, Guide for HIV/AIDS Clinical Care – 2014 Edition. Rockville, MD: U.S. 

Department of Health and Human Services, 2014
Table of Contents | iii

Table of Contents

Table of Contents

Contributors

Contributors . . . . . . . . . . . . . . . . . . vi

Introduction

Introduction . . . . . . . . . . . . . . . . . . vii

Abbreviations

for Dosing Terminology . . . . . . . . . . . viii

Section 1: The HIV Clinic: Providing 

Quality Care

Supporting Patients in Care . . . . . . . . . . 1

Clinic Management . . . . . . . . . . . . . . 9

Quality Improvement . . . . . . . . . . . . . 27

Health Resources and Services Administration 

HIV/AIDS Bureau Performance Measures . . . 41

HIV Care in Correctional Settings. . . . . . . . 45

Patient Education . . . . . . . . . . . . . . . 57

Section 2: Testing and Assessment

Initial History. . . . . . . . . . . . . . . . . . 61

Initial Physical Examination. . . . . . . . . . . 73

Initial and Interim Laboratory and Other Tests 79

Interim History and Physical Examination. . . . 91

HIV Classification: CDC and 

WHO Staging Systems . . . . . . . . . . . . 95

CD4 and Viral Load Monitoring. . . . . . . . . 99

Risk of HIV Progression/Indications for ART. . 103

Early HIV Infection. . . . . . . . . . . . . . 109

Expedited HIV Testing . . . . . . . . . . . .113

Resistance Testing . . . . . . . . . . . . . .121

Karnofsky Performance Scale. . . . . . . . . 127

Section 3: Health Care Maintenance 

and Disease Prevention

Occupational Postexposure Prophylaxis . . . 129

Nonoccupational Postexposure Prophylaxis . 137

Preventing HIV Transmission/Prevention 

with Positives . . . . . . . . . . . . . . . . 143

Immunizations for HIV-Infected Adults and 

Adolescents . . . . . . . . . . . . . . . . .157

Preventing Exposure to Opportunistic 

and Other Infections. . . . . . . . . . . . . 163

Opportunistic Infection Prophylaxis . . . . . 173

Latent Tuberculosis Infection. . . . . . . . . 181

Smoking Cessation . . . . . . . . . . . . . 189

Nutrition. . . . . . . . . . . . . . . . . . . 197

Section 4: HIV Treatment

Antiretroviral Therapy . . . . . . . . . . . .207

Reducing Perinatal HIV Transmission . . . . .221

Care of HIV-Infected Pregnant Women . . . .239

Health Care of HIV-Infected Women 

Through the Life Cycle . . . . . . . . . . . .253

Palliative Care and HIV . . . . . . . . . . . .263

Adherence . . . . . . . . . . . . . . . . . . 273
iv | Guide for HIV/AIDS Clinical Care

Table of Contents

Section 5: Common Complaints

Diarrhea. . . . . . . . . . . . . . . . . . . 281

Ear, Nose, Sinus, Mouth. . . . . . . . . . . . 287

Esophageal Problems . . . . . . . . . . . . 293

Eye Problems . . . . . . . . . . . . . . . . 297

Fatigue . . . . . . . . . . . . . . . . . . . 301

Fever . . . . . . . . . . . . . . . . . . . . 305

Headache . . . . . . . . . . . . . . . . . .309

Lymphadenopathy. . . . . . . . . . . . . . 313

Nausea and Vomiting . . . . . . . . . . . . 317

Neurologic Symptoms . . . . . . . . . . . .321

Pulmonary Symptoms . . . . . . . . . . . .325

Vaginitis/Vaginosis. . . . . . . . . . . . . . 329

Section 6: Comorbidities, Coinfections, 

and Complications

Abnormalities of Body-Fat Distribution. . . . 333

Dyslipidemia. . . . . . . . . . . . . . . . . 339

Insulin Resistance, Hyperglycemia, and 

Diabetes on Antiretroviral Therapy. . . . . . 351

Coronary Heart Disease Risk . . . . . . . . .357

Renal Disease . . . . . . . . . . . . . . . .361

Immune Reconstitution 

Inflammatory Syndrome. . . . . . . . . . . 375

Anal Dysplasia. . . . . . . . . . . . . . . . 383

Candidiasis, Oral and Esophageal. . . . . . . 389

Candidiasis, Vulvovaginal. . . . . . . . . . . 393

Cervical Dysplasia . . . . . . . . . . . . . .397

Cryptococcal Disease. . . . . . . . . . . . . 403

Cryptosporidiosis . . . . . . . . . . . . . . 409

Cytomegalovirus Disease. . . . . . . . . . . 413

Gonorrhea and Chlamydia . . . . . . . . . .419

Hepatitis B Infection . . . . . . . . . . . . .425

Hepatitis C Infection. . . . . . . . . . . . . 435

Herpes Simplex, Mucocutaneous. . . . . . . 447

Herpes Zoster/Shingles . . . . . . . . . . . 451

Histoplasmosis. . . . . . . . . . . . . . . . 455

Kaposi Sarcoma . . . . . . . . . . . . . . .461

Molluscum Contagiosum. . . . . . . . . . . 465

Mycobacterium avium Complex Disease. . . . 469

Mycobacterium tuberculosis . . . . . . . . . 475

Pelvic Inflammatory Disease . . . . . . . . .491

Pneumocystis Pneumonia . . . . . . . . . . 497

Progressive Multifocal Leukoencephalopathy. 503

Seborrheic Dermatitis . . . . . . . . . . . .507

Sinusitis . . . . . . . . . . . . . . . . . . .511

Syphilis . . . . . . . . . . . . . . . . . . . 515

Toxoplasmosis. . . . . . . . . . . . . . . . 523

Section 7: ARV Interactions 

and Adverse Events

Adverse Reactions to HIV Medications . . . . 527

Drug-Drug Interactions with HIV-Related 

Medications . . . . . . . . . . . . . . . . .535

Antiretroviral Medications and Hormonal 

Contraceptive Agents . . . . . . . . . . . . 541
Table of Contents | v

Table of Contents

Section 8: Neuropsychiatric Disorders

Pain Syndrome and Peripheral Neuropathy. . 547

HIV-Associated Neurocognitive Disorders. . . 557

Major Depression and Other 

Depressive Disorders. . . . . . . . . . . . . 567

Suicide Risk . . . . . . . . . . . . . . . . .577

Anxiety Disorders . . . . . . . . . . . . . .581

Panic Disorder. . . . . . . . . . . . . . . . 587

Posttraumatic Stress Disorder . . . . . . . . 591

Insomnia. . . . . . . . . . . . . . . . . . . 597

Section 9: Oral Health

Oral Health. . . . . . . . . . . . . . . . . . 603

Oral Ulceration. . . . . . . . . . . . . . . . 609

Oral Warts. . . . . . . . . . . . . . . . . . 613

Oral Hairy Leukoplakia. . . . . . . . . . . . 615

Necrotizing Ulcerative Periodontitis 

and Gingivitis . . . . . . . . . . . . . . . . 617

Section 10: Resources and References

Web-Based Resources . . . . . . . . . . . .619

Sulfa Desensitization. . . . . . . . . . . . . 623

Antiretrovirals Available in the 

United States and Mexico . . . . . . . . . . 627

Antiretroviral Reference Tables. . . . . . . . 629
vi | Guide for HIV/AIDS Clinical Care

Contributors

Contributing Authors

• Bruce D. Agins, MD, MPH;

AIDS Institute/New York State 

Department of Health

• Oliver Bacon, MD; University 

of California San Francisco

• Kirsten Balano, PharmD; San 

Francisco AETC; University of 

California San Francisco

• Julie Barroso, PhD, ANP, 

APRN, BC, FAAN; Duke 

University

• Robin Bidwell, RNC, BSN, 

CCRC; Christiana Care Health 

Services

• Carolyn K. Burr, EdD, RN;

AETC National Resource 

Center; Rutgers University

• Diane L. Casdorph, RPh, 

PharmD, BCPS, AAHIVE

• Susa Coffey, MD; AETC 

National Resource Center; 

University of California San 

Francisco

• Jonathan Allen Cohn, MD, 

MS, FACP; Midwest AETC, 

Michigan Local Performance 

Site

• Francine Cournos, MD;

New York/New Jersey AETC

• Ross D. Cranston, MD;

University of Pittsburgh 

Medical Center

• Dena Dillon, PharmD;

Midwest AETC

• Minda Dwyer, ANP-C;

New York/New Jersey AETC, 

Upstate Local Performance 

Site and Regional Resource for 

Corrections; Albany Medical 

College

• Douglas G. Fish, MD;

New York/New Jersey AETC, 

Upstate Local Performance 

Site and Regional Resource for 

Corrections; Albany Medical 

College

• Rena K. Fox, MD; University 

of California San Francisco

• Rebecca Fry, MSN, APN;

formerly AETC National 

Resource Center

• Abigail V. Gallucci, BS;

New York/New Jersey AETC, 

Upstate Local Performance 

Site and Regional Resource for 

Corrections; Albany Medical 

College

• Marshall Glesby, MD, PhD;

New York/New Jersey AETC, 

Cornell Clinical Trials Unit 

• Katherine Grieco, MD;

University of California San 

Francisco

• Elaine Gross, MS, RN, APNC;

formerly AETC National 

Resource Center

• Geeta Gupta, MD;

Pacific AETC

• Lois Hall, ARNP, MSN;

Florida/Caribbean AETC

• Bethsheba Johnson, MSN;

Midwest AETC

• Marta Kochanska, MD;

University of California San 

Francisco

• Jeffery Kwong, MS, MPH, 

ANP, ACRN; formerly

Mountain Plains AETC

• Annie Luetkemeyer, MD;

University of California San 

Francisco

• Mary Monastesse, NP;

Texas/Oklahoma AETC

• John Nelson, PhD, CPNP; 

AETC National Resource 

Center; Rutgers University

• Tonia Poteet, PA; Southeast 

AETC

• David Reznik, DDS; 

Southeast AETC

• Susan Richardson, MN, MPH, 

FNP-BC; Southeast AETC

• Barbara Scott, MPH, RD;

Pacific AETC

• Suzan Stringari-Murray, 

RN, MS, ANP; University of 

California San Francisco

• Alfredo Tiu, DO, FACP, FASN; 

University of California San 

Diego

• Milton Wainberg, MD;

New York/New Jersey AETC

• Sarah J. Walker, MS;

New York/New Jersey AETC, 

Upstate Local Performance 

Site and Regional Resource for 

Corrections; Albany Medical 

College

• Dianne Weyer, RN, MS, 

CFNP; formerly Southeast 

AETC

• Sophie Wong, MD;

University of California San 

Francisco; Asian Health 

Services

Editor: Susa Coffey, MD
Introduction | vii

Introduction

Introduction 

HIV/AIDS clinical care has improved 

dramatically over the decades, given the 

availability of new medications and a 

better understanding of how best to use 

antiretrovirals and deliver primary care 

to persons living with HIV/AIDS. Positive 

change on such a massive scale, however, 

brings with it new demands on clinicians. 

Along with innovations in HIV drug 

therapies, HIV/AIDS care has become more 

complex than ever before due to increasing 

comorbidities that are attributable to HIV 

treatment and the aging of the HIV-infected 

population in the United States. Patient needs 

also have expanded across a broad spectrum of 

medical, psychological, behavioral, and social 

issues. Notably, significant numbers of infected 

individuals are identified and enter care late in 

the course of their HIV disease, confronting 

clinicians with complex and immediate care 

challenges.

Since the early days of the epidemic, clinicians 

have received training in HIV/AIDS clinical 

care through the AIDS Education and 

Training Centers (AETCs) Program – the 

clinical training arm of the Ryan White HIV/

AIDS Program that is administered by the 

Health Resources and Services Administration 

(HRSA) and its HIV/AIDS Bureau (HAB). The 

AETC network conducts more than 14,000 

training events each year with approximately 

143,000 health care providers in attendance. 

The Guide for HIV/AIDS Clinical Care is a 

pillar of the Ryan White HIV/AIDS Program’s 

mission to continuously improve HIV/AIDS 

clinical care. The Guide was first published in 

1993 as a collaborative effort of several regional 

AETCs. It was subsequently updated and 

expanded in 2006 and 2011. The version before 

you incorporates many new insights, but the 

time-tested format has been retained – easy 

access to crucial facts for a busy clinician. 

The developers of the Guide strive to be 

responsive to how HIV/AIDS clinical care is 

provided today. 

• With more routine HIV testing in medical 

settings, a large number of individuals are 

entering care via primary care sites that have 

relatively limited experience managing HIV/

AIDS disease.

• A notable proportion of HIV/AIDS primary 

care in the United States is provided by 

advanced practice nurses and physician 

assistants. 

• Shortages in the health care work force are 

worsening. Experienced staff members are 

aging and retiring, a limited number of new 

clinicians are entering primary care and 

specializing in HIV/AIDS care, and fewer 

clinicians are available in geographic areas 

with limited resources. 

As a result, front line primary care providers 

may be less familiar with management of HIV/

AIDS disease, as outlined in U.S. Department 

of Health and Human Services treatment 

guidelines (available at aidsinfo.nih.gov) and 

clinical practices presented in this Guide. 

By presenting best practices in the clinical 

management of HIV/AIDS disease, the Guide

can help us continue the remarkable advances 

in HIV/AIDS care that have made the Ryan 

White HIV/AIDS Program a model for health 

care delivery for our Nation and for the world. 

— Laura W. Cheever, MD, ScM

Associate Administrator

HIV/AIDS Bureau

U.S. Department of Health

and Human Services

Health Resources and Services 

Administration (HRSA)
viii | Guide for HIV/AIDS Clinical Care

Dosing Abbreviations

Abbreviations

for Dosing Terminology

BID = twice daily

BIW = twice weekly

IM = intramuscular (injection), intramuscularly

IV = intravenous (injection), intravenously

PO = oral, orally

Q2H, Q4H, etc. = every 2 hours, every 4 hours, etc.

QAM = every morning

QH = every hour

QHS = every night at bedtime

QID = four times daily

QOD = every other day

QPM = every evening

TID = three times daily

TIW = three times weekly

Important Notice

The U.S. Department of Health and Human Services (HHS) HIV/AIDS Bureau is 

committed to providing accurate information on the care of HIV-infected persons. It 

is important to be aware that management options and protocols change over time. 

Forthcoming HHS guidance on certain topics may differ from recommendations 

contained in this Guide. Readers are encouraged to check for updates to treatment 

guidelines at AIDS Info (aidsinfo.nih.gov) and for updates to drug information at 

Drugs@FDA (www.accessdata.fda.gov/scripts/cder/drugsatfda).
Supporting Patients in Care | 1

Section 1: The HIV Clinic: 

Providing Quality Care

Supporting Patients in Care

Robin Bidwell, RNC*

* Based on Sheffield and Casale, see “References.”

Background 

Patients infected with HIV face a complex array of medical, psychological, and social challenges. 

A strong provider-patient relationship, the assistance of a multidisciplinary care team, and 

frequent office visits are key aspects of care. Through both the specific services they provide and 

their overall approach to patients, clinics can have a substantial impact on the quality of care for 

HIV-infected persons. For example, a patient-centered clinic environment in which education 

and supportive interventions are emphasized will greatly enhance patients’ knowledge about HIV 

infection. Improving patients’ skills in self-management will increase their participation in making 

health care decisions and provide a stimulus for more active involvement in their own care.

Special Challenges of Caring 

for HIV-Infected Patients

Providers need to be mindful of several special 

issues, including the following:

• Many medical, psychological, and social 

challenges confront persons living with HIV. 

The delivery of effective care usually requires 

a strong provider-patient relationship, a 

multidisciplinary approach, and frequent 

office visits.

• The stigma associated with HIV places a 

major psychosocial burden on patients. 

Stigma and discrimination must be 

addressed through strong confidentiality 

protections, emotional support, and cultural 

sensitivity. It is important to inform all 

patients of their rights and responsibilities in 

a language or manner that is respectful and 

understandable.

• Underserved racial and ethnic groups are 

overrepresented among people with HIV. 

Efforts to understand and acknowledge 

the beliefs of patients from a variety 

of cultural backgrounds are necessary 

to establish trust between providers 

and patients. Cultural competency is 

imperative in the field of HIV care.

• Providers play a key role in the public health 

system’s HIV prevention strategy. Disease 

reporting, partner notification, and risk 

assessment are important aspects of care. 

Patients may see this as threatening and 

may need education and emotional support 

in order to participate in this process. 

Patients need to be informed of their rights 

under the Health Insurance Portability 

and Accountability Act (HIPAA) and 

understand the public health implications 

of HIV.

• Many patients have inaccurate information 

about HIV infection that can heighten their 

anxiety, sabotage treatment adherence, 

and interfere with prevention behaviors. 

Patients need assurance that HIV is a 

treatable disease and that, with successful 

treatment, they can experience a normal life 

expectancy. They also need to hear explicitly 

that HIV may be transmitted through sexual 

contact, injection drug use and other blood 

contact, and perinatal exposure, and that 

they can take specific measures to prevent 

transmission to others.

• Many patients need the support that only a 

peer can provide. Peer educators should be 

available to help patients navigate difficult 

health care systems, medication regimens, 

and lifestyle changes.
2 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

• HIV-infected patients need to have an active 

voice in their health care. Patient advisory 

groups can provide valuable program 

evaluation, which can be used to promote 

the patient-centered focus of the health care 

system.

These issues are discussed further in the 

sections that follow.

Components of HIV Care 

and Ways to Enhance Care

Important Components of HIV Care

A first step in ensuring that patients are 

“engaged in care” is the establishment 

of systems that include mechanisms for 

coordination and communication of care.

• Clinics must offer a nonjudgmental and 

supportive environment, because of the 

sensitive nature of issues that must be 

discussed.

• A multidisciplinary approach, utilizing 

the special skills of nurses, pharmacists, 

nutritionists, social workers, case managers, 

patient navigators, and others is highly 

desirable to help address patient needs 

regarding housing, medical insurance, 

emotional support, financial benefits, mental 

health and substance abuse counseling, and 

legal issues.

• Providers and other clinic staff members 

should be prepared to conduct appropriate 

interventions and make timely referrals to 

community resources and institutions.

• The primary provider should coordinate the 

various aspects of health care, with close 

communication among providers across 

disciplines.

• Individual office visits should be long 

enough to allow time for thorough 

evaluation.

• Providers must be able to see patients as 

frequently as their medical and psychosocial 

needs require, and clinic scheduling should 

be flexible so that patients with acute 

problems can be seen quickly and new 

patients can receive and access care in a 

timely manner.

• A range of medical resources, including 

providers with subspecialty and laboratory 

expertise, needs to be established. Colocating services within testing and 

counseling sites or within HIV clinics is an 

excellent way to enhance patient compliance 

(see chapter Clinic Management).

• Patient education is a vital aspect of care 

that begins during the initial evaluation and 

continues throughout the course of care (see 

chapter Patient Education).

Taking Steps to Enhance Care

Providing comprehensive care for HIVinfected patients requires a patient-centered 

focus, a multidisciplinary team, and a 

willingness to spend time on building 

relationships with patients. Providers should 

do the following:

• With the help of case management agencies, 

counseling and testing centers, and patientcare navigators, provide quick and easy 

access to care to those newly diagnosed and 

entering into treatment.

• Front-end staff members need to be 

knowledgeable, compassionate and 

efficient with the initial patient contact in 

order to establish a warm and welcoming 

environment of care for the new patient.

• Make available self-management education 

to help patients identify problems, teach 

decision making techniques, and support 

patients to take appropriate actions to make 

necessary changes in their lives.

• Offer care in a patient-centered environment 

that allows the patient to actively participate 

in care decisions and provides patientspecific education.

• Encourage patients to learn all they can 

about their condition.

• Give accurate information regarding 

prognosis and antiretroviral therapy.
Supporting Patients in Care | 3

Section 1: The HIV Clinic: 

Providing Quality Care

• Foster an atmosphere of nonjudgment, trust, 

and openness.

• Anticipate that significant time will be 

required for patient education.

• Outline the range of clinic operations and 

state the expectations for provider-patient 

communication. Outline how appointments 

are scheduled and how prescription refill 

requests are managed.

• Arrange to see patients with acute problems 

quickly. Establish a triage system to provide 

efficient service delivery.

• Ensure that there are open lines of 

communication with all patients to receive 

and answer questions, assess treatment 

effectiveness, and manage side effects.

• Provide safe and secure access for patients 

to communicate with staff. Patient portals 

can provide quick and direct access to 

nonemergent information and can provide 

accurate answers to questions that arise 

between visits.

Helping Patients Cope with 

Emotional Issues

Patients coming to terms with HIV infection 

often experience a range of emotions, 

including anger, fear, shock, disbelief, 

sadness, and depression. Loss is a major 

issue for patients with HIV because health, 

employment, income, relationships with 

friends, lovers, and family, and hope all may be 

threatened. Many patients feel overwhelmed, 

and even patients who seem to be adjusting 

reasonably well can find it difficult to keep 

all of the many appointments that may be 

scheduled as they initiate care. Providers 

need to recognize that patients’ emotional 

states affect their ability to solve problems and 

attend to important medical or social issues. 

Providers can do the following:

• Assess each patient’s emotional state and 

the availability of friends and family for 

emotional support. Some patients will need 

counseling to help them decide whether to 

disclose their diagnosis to friends, family, or 

employers as well as support in dealing with 

HIV infection. Patients often feel hesitant 

about seeking emotional and practical 

support.

• Deliver important information in easily 

understood terms and in small amounts. 

Reassess patient understanding of crucial 

information at subsequent visits, and repeat 

important information as necessary. Realize 

that many visits may be required before 

patients are comfortable with their care and 

the navigation of the health care system.

• Screen for anxiety, depression (including 

suicidal ideation), and substance use.

• Refer patients to community resources for 

crisis counseling, support groups, and, if 

appropriate, psychiatric treatment to help 

them achieve emotional stability.

• Assist patients in finding a case manager or 

patient navigator who can help them learn to 

navigate the health care system and reduce 

anxiety about keeping their lives in order.

• Assist patients in linking to social work 

services to assist with enrollment into 

medical insurance and to meet other social 

service needs, such as housing, food, child 

care, and substance abuse treatment.

Helping Patients Develop SelfManagement Skills

Self-management support is defined by 

the Institute of Medicine as the systematic 

provision of education and supportive 

interventions by health care staff to increase 

patients’ skills and confidence in managing 

their health problems, including regular 

assessment of progress and setbacks, goal 

setting, and problem solving.

It can be viewed as a portfolio of techniques 

and tools to help patients choose healthy 

behaviors, and as a fundamental shift of 

the provider-patient relationship toward a 

collaborative partnership.
4 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

After patients have come to terms with their 

HIV infection, they are ready to embark 

upon the lifelong process of caring for 

themselves. Patient self-management involves 

adopting new health behaviors and requires 

changes that will occur as a progression of 

motivational skills. Motivation is defined as 

the “probability” that a person will enter into, 

continue, and adhere to a specific change 

strategy. Patients will feel empowered as they 

gain the skills and confidence to be active 

participants in their care.

The following practices should be adopted to 

foster patient self-management:

• Train staff at all levels on patient selfmanagement concepts and how to 

incorporate them into care.

• Create an atmosphere conducive to learning 

these self-management skills, including but 

not limited to the following areas: 

• Problem solving

• Medication issues

• Working with the health care team

• Planning for the future

• Goal setting

• Dealing with difficult emotions

• Healthy eating

• Advance directives

• Sex, intimacy, and disclosure

• Adopt a team approach to health care 

with the patient as the central team player 

(patient-centered care).

• Incorporate problem-solving skills into all 

education efforts.

• Allow the patient time to set small obtainable 

goals as “first steps” in self-management.

• Realize that many appointments with 

multiple members of the health care team 

may be necessary before a patient has all the 

necessary skills.

Helping Patients Make Positive 

Changes in Health Care Behaviors

Regardless of whether a patient is new to care 

or has been in care for many years, the burden 

of a chronic disease is wearing. Positive change 

in behavior needs to be an ongoing focus of 

patient-centered care. After patients have selfmanagement skills, they still need help setting 

action plans for their health care. The provider 

needs to help patients adopt realistic action 

plans by:

• Realizing that new health behaviors require 

motivation and occur as a progression of 

learned skills

• Bolstering patients’ self-confidence by 

adopting action plans that: 

• Are realistic

• Are something that patients find of value 

(i.e., something they want to do)

• Are reasonable (it is better to underestimate and exceed the goal than to 

overestimate and fail)

• Are action-specific, with 

small, obtainable goals

Peer Educators and Patient 

Advisory Groups

Patients need to be active participants in 

making decisions regarding their health care. 

Peer educators and patient advisory groups can 

help patients become more involved in their 

care.

In order to best support patients, it is helpful 

to have peer educators available for them 

during initial and subsequent visits. This helps 

to decrease patient anxiety and promotes a 

patient-centered atmosphere. Providers need 

to realize that peer educators are HIV-infected 

individuals who:

• Provide a unique approach 

to client-centered care

• May attend clinical sessions with patients 

and provide them with referrals for one-onone counseling and support
Supporting Patients in Care | 5

Section 1: The HIV Clinic: 

Providing Quality Care

• Are “seasoned clients” who have a desire to 

help patients in their care

• Work under the same confidentiality 

guidelines as all other staff members

Another valuable tool for patient-centered 

care is the use of a patient advisory group 

(PAG). The PAG is the voice of the people 

that the clinic serves. The HIV program will 

listen to this group’s suggestions and use them 

to improve patient satisfaction and clinic 

functionality. The PAG’s role could involve 

identifying clinic problems, recommending 

changes in the care delivery system, and 

discussing new treatment approaches. A 

successful PAG does the following:

• Provides comprehensive, individualized 

client-based education to all active patients

• Encourages clients to actively participate in 

treatment decisions and to involve family 

members and others who comprise their 

support system

• Designates members who facilitate meetings, 

promote upcoming meetings, coordinate 

speakers, and provide feedback to clinic staff 

and management

• Allows members to serve as cofacilitators, 

choose topics of discussion, set meeting 

guidelines, and invite new members

• Fulfills requirements of grants and other 

funding streams to have enhanced patient 

involvement

Stigma and Discrimination

Stigma is founded on fear and misinformation. 

Theodore de Bruyn observed that stigma 

is associated with HIV because, “It is a 

life-threatening disease; people are afraid 

of contracting HIV; it is associated with 

behaviors that are considered deviant; a 

belief that HIV has been contracted due to 

unacceptable lifestyle choices; and, some 

believe it is the result of a moral fault which 

deserves punishment.”

Stigma can adversely affect how patients 

are perceived by others and how they view 

themselves. The stigma associated with HIV/

AIDS is such that individuals known to be 

or suspected of being infected with HIV may 

be excluded from community activities and 

suffer isolation or abandonment. Some patients 

may feel ambivalent about seeking medical 

care if, by doing so, they risk disclosing their 

condition. Others may have learned from 

experience to expect rejection and therefore 

may not trust care providers. It is essential for 

providers to be supportive of patients who are 

dealing with the burden of stigma.

Stigma of Fear of Contagion

Unfortunately, patients and their families are 

often unaware that routine household contact 

with a person with HIV poses no risk of 

contagion. They should be educated about that, 

and also taught what to do in situations that do 

pose risk, such as when bleeding occurs. Clinic 

staff members must model behavior in this 

area. For example, gloves should be worn only 

as appropriate during physical examinations 

and as consistent with universal precautions. 

There should not be separate facilities or 

special procedures for HIV-infected patients.

Stigma Associated with Being Gay, 

Lesbian, Bisexual, or Transgender

Demonstrating respect and providing 

excellent care to patients with various cultural 

backgrounds, beliefs, and sexual orientations 

are central to medical professionalism. 

Providers should approach patients in an open 

and nonjudgmental fashion and be familiar 

with medical management issues unique 

to these populations, such as appropriate 

screening for sexually transmitted diseases 

for men who have sex with men (MSM) and 

hormonal treatment for transgender patients. 

Clinic staff members also must be respectful 

and supportive; having a staff that is familiar 

with lesbian, gay, bisexual, and transgender 

(LGBT) cultures is a natural way to create 

a welcoming environment. Providers and 

social workers should be aware of community 
6 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

agencies with resources available to people who 

are lesbian, gay, or transgender. In addition, 

providers and clinic staff members should 

be aware of special legal issues that affect 

these populations. For example, designating a 

durable power of attorney for medical decision 

making can be particularly important in states 

that do not recognize same-sex partners or 

spouses as legal next of kin.

Other Special Cultural Issues

African-Americans, Hispanics, and some 

immigrant groups are disproportionately 

affected by HIV, and many people of color 

with HIV infection have major socioeconomic 

problems such as poverty, homelessness, lack 

of medical insurance, lack of acculturation, 

and undocumented immigration status. 

Many young people with HIV face similar 

issues. All these obstacles can make accessing 

health care difficult and attending to health 

problems less of a priority for the individual. 

A patient’s cultural background influences 

health-related beliefs and behaviors, and 

personal or historical adverse experiences may 

make some patients distrustful of medical 

care. In addition, some patients’ distrust of 

medical research can impede their willingness 

to access new drug therapies. Culturally 

competent communication between provider 

and patient may substantially affect adherence 

with therapies. For all these reasons, providers 

should do the following:

• Carefully explore what each patient believes 

about his or her health, what would be 

appropriate treatment, and who should be 

involved in medical decision making.

• Use professional interpreters to help 

overcome language barriers.

• Use case managers and peer educators to 

help bridge social barriers. The team of 

peer educators should be culturally diverse 

in order to be effective with all minority 

groups.

Confidentiality and Disclosure

Confidentiality of medical information 

is always mandatory, but the stakes are 

particularly high for patients infected with 

HIV, who risk losing medical insurance, 

employment, and the support of friends 

or family if their diagnosis is disclosed 

inappropriately. Although people with HIV 

infection are protected against discrimination 

under provisions of the Americans with 

Disabilities Act, discrimination can be difficult 

to prove, and there are strict time limits after 

which charges of discrimination can no longer 

be made.

Protecting Patient Confidentiality

Adherence to the HIPAA regulations is 

an important aspect of protecting patient 

confidentiality. Personnel policies should 

reinforce measures such as requirements 

that papers and computer screens containing 

patient-identifying information not be left 

unattended and should include provisions for 

documenting whether phone messages can be 

left for the patient, and if so, with whom.

Helping Patients Disclose 

Their HIV Status

Patients who have a support network function 

better than those who are isolated. However, 

patients’ fears of disclosure are often well 

founded, and providers must find a balance 

between accepting patients’ unwillingness 

to disclose their HIV status and the need to 

develop support networks. Patients may find 

support groups or individual psychotherapy 

sessions beneficial in deciding when to 

disclose, and to whom.

The sex and needle-sharing partners of 

people with HIV need to be informed about 

their possible exposure to HIV. Local health 

departments can either assist patients 

in making these disclosures or provide 

anonymous partner notification for them.

A patient-centered clinic staff can help patients 

with disclosure. For example, staff members 
Supporting Patients in Care | 7

Section 1: The HIV Clinic: 

Providing Quality Care

could encourage patients to bring their 

partners to one of their clinic or counselor 

appointments in order to disclose their HIV 

serostatus in the context of the clinic visit. 

This could allow the health care professional 

to answer the partners’ questions and would 

provide a neutral environment for the 

disclosure discussion. Risk of intimate-partner 

violence should be assessed.

Public Health Role of 

Providers in the HIV Epidemic

Primary care providers must consider their 

public health role in curbing the spread 

of HIV. The incidence of HIV remains 

unacceptably high, and may be increasing in 

some populations, especially in communities 

with relaxed adherence to safer sex 

recommendations.

All AIDS diagnoses and, in some states, all 

positive HIV test results must be reported to 

the state health department. State laws vary 

in reporting requirements and subsequent 

notification of potentially exposed individuals 

(see the National HIV/AIDS Clinicians’ 

Consultation Center Compendium of State 

HIV Testing Laws at www.nccc.ucsf.edu), 

but the name of the source contact is never 

divulged to the person being notified. Providers 

should become familiar with the laws of 

their jurisdiction by contacting their health 

department. (The Association of State and 

Territorial Health Officers provides links to all 

state health departments at www.astho.org.) 

Providers are required to do the following:

• Inform patients that their AIDS diagnosis or 

positive HIV status (depending on individual 

state requirements) must be reported to 

the state health department, tell them 

whether partner notification is required, 

and explain what they should expect 

regarding efforts that must be made by the 

patient, provider, or health department 

to notify sex partners or individuals who 

may have been exposed to HIV through 

their needle sharing. Assure them that 

their names are always kept confidential 

and are never given to potentially exposed 

individuals by the health department.

• Carefully assess patients’ risk-taking 

behaviors, educate them regarding HIV 

transmission, and perform screening for 

sexually transmitted diseases. (See chapters 

Preventing HIV Transmission/Prevention 

with Positives, Initial History, Initial Physical 

Examination, and Initial and Interim 

Laboratory and Other Tests.)

• Provide counseling to encourage safer 

sexual practices and make referrals to drug 

rehabilitation or needle exchange centers 

as indicated. (See chapter Preventing HIV 

Transmission/Prevention with Positives.)

• Provide information about the role of 

antiretroviral therapy in reducing the risk of 

HIV transmission.

References

• de Bruyn T. HIV/AIDS and Discrimination: 

A Discussion Paper. Montreal: Canadian 

HIV/AIDS Legal Network and Canadian 

AIDS Society; 1998. Available at www.

aidslaw.ca/newsite/?p=330. Accessed 

December 1, 2013.

• Institute of Medicine. Crossing the Quality 

Chasm: A New Health System for the 

21st Century. Washington, DC: National 

Academy Press; 2001. Available at www.

nap.edu/openbook.php?ibsn=0309072808. 

Accessed December 1, 2013.

• Rollnick S, Miller WR. What is motivational 

interviewing? Behav Cogn Psychother. 

1995;23:325-334.

• Sheffield JVL, Casale GA. Approach to the 

Patient. In: A Guide to Primary Care of 

People with HIV/AIDS, 2004 Edition. Bartlett 

JG, Cheever LW, Johnson MP, et al., eds. 

Rockville, MD: U.S. Department of Health 

and Human Services; 2004:5-11.

Clinic Management | 9

Section 1: The HIV Clinic: 

Providing Quality Care

Clinic Management

Jonathan A. Cohn, MD

Background

HIV outpatient care is unique in that it combines two very different approaches to patient care: 

long-term health care for individuals with a chronic condition, and the vital public health service 

of reducing transmission of an infectious disease. Thus, chronic treatment and retention in care are 

important both for individual patients and for public health.

HIV services often are provided to persons who have challenges in regard to participation in 

their own health because of discrimination, poverty, active substance use, or mental health 

disorders. The context of HIV care still is one of persistent stigma regarding HIV infection itself 

and discrimination against racial, ethnic, and sexual minorities who constitute the groups with 

the highest HIV prevalence and incidence. At the same time, funding streams from federal, state, 

and local governments have created opportunities for treatment of uninsured and underinsured 

individuals and provide resources for creating innovative, effective programs. The Affordable 

Care Act creates new opportunities to provide care for previously uninsured persons through 

two insurance mechanisms and other benefits described below. Treatment guidelines, operations 

research data, and technical support are available to assist in designing, operating, and improving 

service programs. 

Patient Recruitment 

into Clinic

The persons who were easy to recruit and 

retain in care are already enrolled; the more 

challenging patients await recruitment. 

The U.S. Centers for Disease Control and 

Prevention (CDC) estimates that up to 25% of 

HIV-infected persons in the United States are 

not aware of their HIV infection (Branson, 

2006), so there is still much work to be done 

to diagnose those individuals and link them 

to care. For newly diagnosed patients, studies 

show that there often is a substantial delay 

in attendance at an initial HIV care visit, 

with only 20-40% of them accessing care 

within 6 months of diagnosis (Mugavero, 

2008). However, for the clinics, the number 

of newly diagnosed patients who present 

for care is substantial. A recent survey of 15 

HIV programs across the country (median of 

1,300 active patients each year) showed that 

a median of 250 (range 60-730) new patients 

were enrolled in each clinic each year (Yehia, 

2008).

To facilitate linkage to care, every HIV clinic 

should 1) be linked to agencies that provide 

HIV testing and services for persons with HIV, 

and 2) make clinic access easy and comfortable 

for the clients of those outside services. Many 

HIV clinics establish referral linkages with 

community HIV counseling and testing 

services (CTS), AIDS service organizations 

(ASOs), sexually transmitted disease (STD) 

treatment facilities, family planning agencies, 

drug treatment facilities, local health 

departments, regional HIV hotlines, and local 

hospitals and emergency rooms. Many clinics 

also offer free confidential or anonymous CTS 

using state or federal funding.

Clinic personnel should build personal 

relationships with agencies that may provide 

referrals, invite staff of community agencies to 

visit the clinic, or hold open houses. Providers 

from ASOs, such as case managers, can be 

invited to accompany patients on clinic visits. 

Referring agencies must know what services 

the clinic provides and which patients it serves, 

as well as those it cannot serve.
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Section 1: The HIV Clinic: 

Providing Quality Care

Various approaches may help facilitate the 

patient’s entry into care. A randomized 

study showed that using case managers to 

increase linkage of newly diagnosed persons 

to care can be effective: 78% of patients who 

had “strength-based” case management that 

promoted patient empowerment and selfefficacy kept an appointment within 6 months, 

whereas only 60% of patients without case 

management kept an appointment in the time 

frame (Mugavero, 2008).

Frequently, there is a delay of several weeks 

for a new appointment with an HIV clinician. 

Model programs have been established 

nationwide to improve linkage to HIV 

care. For example, the HIV clinic at the 

University of Alabama at Birmingham offers 

new patients an orientation visit in the HIV 

program within 5 days of their request for 

a new patient appointment. In this clinic, 

an HIV program staff member initiates a 

welcoming interaction during the patient’s 

first phone call requesting an appointment 

and invites the patient to an orientation visit. 

During that visit, a psychosocial assessment is 

performed, specimens are taken for baseline 

laboratory tests, any immediate health issues 

are addressed, and referrals for mental health 

or substance use disorder care are initiated, if 

indicated. The orientation visit is used to give 

patients information on how to use the clinic 

effectively, provide other on-site nonmedical 

services, and start processes to access health 

insurance or AIDS Drug Assistance Program 

(ADAP) services as needed. The full initial 

medical visit is scheduled for a later date. In a 

nonrandomized comparison, the no-show rate 

at that clinic dropped from 31% to 19% with 

that approach (Mugavero, 2008).

Success in linking newly diagnosed persons 

to care may be enhanced through the 

participation of HIV-infected consumers as 

peer advocates and peer navigators (see chapter 

Supporting Patients in Care). Either volunteer 

or paid peer advocates can meet newly 

diagnosed patients who have been referred to 

the clinic, help familiarize them with the clinic 

services and staff, and help them adjust to both 

the fact of their HIV infection and their role 

as a chronic care patient. Groups for newly 

diagnosed persons co-led by a peer advocate 

and a professional as well as one-on-one 

interactions with patients within or outside the 

clinic (e.g., through a buddy system) can help 

newly diagnosed persons succeed in the clinic. 

In clinics that use peers, particular attention 

must be paid to confidentiality issues. The peers 

must be trained and supervised (see below), 

and the patients must agree to participate 

with peers, either individually or in groups.

Clinics differ in terms of the characteristics 

of people living in their catchment area and 

in regard to the levels of expertise of clinic 

staff members. Some successful clinics target 

a narrow but underserved population and 

concentrate on meeting the needs of that 

population. The environment and services 

offered by the clinic may be tailored to the 

patient population. For example, a youthfriendly clinic may differ in these respects 

from one targeting the working poor.

Retaining Patients in Care

Retaining patients in care is an ongoing 

challenge (see chapter Supporting Patients in 

Care). Among the 15 surveyed HIV clinics 

mentioned above, the median no-show rate 

for appointments was 28% (range 8-40%). For 

new patients, the range was 5-54% and for 

returning patients it was 2-40%. Across all 

the clinics there was a median annual loss-tofollow-up rate of 15% (range 5-25%) (Yehia, 

2008). A number of approaches may help 

patients maintain continuous care in the clinic. 

An AIDS Education and Training Centers 

(AETC) working group is creating a toolkit 

for clinics to assist them in applying evidencebased methods to retention in care; this is 

available from the National Resource Center 

(NRC) of the AETC (see resources below).
Clinic Management | 11

Section 1: The HIV Clinic: 

Providing Quality Care

Respect and cultural competence:

Respecting patients and providing them 

with effective care builds trust and keeps 

them coming back. New clinic attendees may 

have strong feelings related to HIV infection 

(e.g., fear of death) or how they acquired it 

(e.g., issues of shame or of secrecy). They 

may lack trust in medical care (from prior 

personal experiences or from historic events 

such as the Tuskegee syphilis experiments) 

or in current treatments (e.g., “Everyone I 

knew who took AZT died ...”). Some patients 

believe that HIV was created in government 

laboratories to target African-Americans and 

may or may not believe that the clinic staff 

is part of the conspiracy. It is important that 

all staff members be trained to anticipate, 

recognize, and work with issues such as 

these.

Patients may experience obstacles to care 

when there are cultural differences or 

language barriers between themselves and 

the staff members. Diversity among health 

care staff can further improve the experience 

of racial, ethnic, and sexual minority 

patients.

Welcoming staff attitude:

Providers must know the target population 

and build a system that will make patients 

feel welcome. Patients always should be made 

to feel that they came to the right place (even 

in cases in which they must be referred on to 

another provider or clinic). Patients should 

receive understanding and support, even if 

they arrive at the clinic without the required 

managed care referral form (at least for the first 

few visits). 

Welcoming environment:

Physically comfortable waiting and 

examination areas, with linguistically and 

culturally appropriate decoration and reading 

material, are important for patient retention. 

A clinic that serves parents or children should 

make available toys or children’s books.

Orientation to clinic 

systems and rules:

New patients need a brief description of clinic 

staff and services, routine and emergency 

procedures, prescription refill procedures, and 

after-hours follow-up. They must understand 

requirements for referrals from managed care 

providers, and new patients may need help 

with fulfilling such requirements. Patients 

also must be oriented to what is expected 

of them (e.g., arriving on time, calling to 

cancel or reschedule appointments) and 

the consequences of not fulfilling their 

responsibilities (e.g., clinic rules regarding 

late arrivals). A handout or pamphlet with 

this information can be very helpful. Patients 

need to know how to determine the insurance 

coverage and other benefits for which they may 

qualify, and how to find out their options if 

their insurance coverage changes.

Peer support:

Many programs have HIV-infected staff 

members who provide specific peer-support 

services. Patients who have had unpleasant 

experiences seeking medical care in the past, 

or those who are not used to engaging in 

medical care, may get better support from 

another consumer than from a nonpeer 

staff member. Youth especially may trust 

information from peers more so than from 

adult professional staff members. 

Peer advocates or peer navigators may 

work in this role part time or full time, as 

either volunteers or paid staff. Often they 

work specifically to make new or recently 

returned patients comfortable in the clinic. 

Some programs designate consumers as peer 

navigators, emphasizing their role in helping 

new patients, or patients returning after being 

lost to care, in finding their way through the 

health care system and support systems. Peer 

advocates also can help patients ask questions 

or make their needs known to the clinic staff. 

Advocates or peer-support persons can be 

instrumental in helping patients build self-
12 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

esteem and acquire new habits that will enable 

them to use health care services in a proactive 

manner. Peers are especially helpful when 

they model good health behaviors, including 

adherence with appointments and medications 

and with avoiding unsafe sex or other HIV 

transmission activities. In some cases, peers 

have been the basis of a successful program, 

but in other cases peers model poor health 

behaviors and themselves become ill. Peers 

need to adhere to confidentiality rules and 

good work habits and need to provide accurate 

information to other clinic staff. Effective 

selection, training, and supervision of peers 

are extremely important.

Systems to support attendance:

Clinics should provide feedback and 

encouragement to patients about the 

importance of attending scheduled visits. This 

can be done through written materials such 

as posters and pamphlets, as well as through 

comments made by providers during clinic 

visits. These very inexpensive interventions 

have been shown to improve clinic attendance 

(Gardner, 2012).

Patients should receive appointment reminders 

about 48 hours before each appointment. 

Reminders typically are given by phone or 

mail, although text messaging or other forms 

of electronic communication may be more 

useful in some settings. It also may be effective 

to have a staff member contact patients who 

have missed appointments to find out what 

prevented them from attending, offer to 

reschedule, and try to eliminate barriers to 

clinic attendance. 

Factors such as child care needs, work 

schedules, and transportation problems can 

be substantial barriers to attending clinic 

appointments. Addressing these and other 

challenges may require coordinated efforts by 

the clinic staff, case manager, and others. In 

some instances, AIDS service organizations 

and other community organizations may have 

funding available to assist with these efforts.

Some programs have a policy detailing their 

interventions following one or more missed 

visits: usually one or more phone calls comes 

first, then a letter to the last known address, 

and as a last measure, some programs will 

dispatch personnel to visit the last known 

address in an attempt to reconnect with a 

patient who is lost to follow-up. These efforts 

are more successful when patients are asked 

for current telephone, address, and other 

contact information at every clinic visit. 

Staff members must know to whom a patient 

has disclosed his or her status; in verbal and 

written correspondence, staff members must 

avoid unintended disclosure of the patient’s 

HIV infection.

It is important to document movement 

of patients to other locations (including 

correctional facilities) or other care providers 

whenever the information is known so that 

these patients are considered transferred rather 

than lost. Some states provide public lists of 

incarcerated persons; larger programs may 

use those lists to find patients who have been 

missing for some time.
Clinic Management | 13

Section 1: The HIV Clinic: 

Providing Quality Care

HIV programs can be aggressive in trying 

to connect with patients who are missing, 

but also must respect explicit decisions by 

competent persons to change providers or to 

forgo medical care.

Outreach encounters to promote 

participation in care:

A study of seven sites across the United States, 

funded by the Health Resources and Services 

Administration (HRSA), found that outreach 

by health care professionals increased clinic 

attendance and that frequent outreach by any 

program staff member increased adherence 

with antiretroviral therapy (see “References,” 

below). Outreach by medical professionals 

included efforts by physicians, nurses, or 

physician assistants to meet patients outside 

the HIV clinic setting, often in another part 

of a medical facility such as an inpatient unit. 

These encounters were the most expensive type 

of outreach, but the most effective in engaging 

new patients in care. Encounters with medical 

professionals did not increase adherence with 

medications, however. Other types of outreach, 

either face-to-face or otherwise (by phone, 

email, or postal service), by professional, 

nonprofessional, or paraprofessional 

staff members, increased adherence with 

medications, but not with clinic attendance. 

More frequent encounters of this type were 

associated with greater improvements in 

adherence. The results of the study suggest 

that initial face-to-face contact with medical 

providers is important for establishing trust 

that enables new patients to engage in care, 

and that frequent encounters with other staff 

members is important for maintaining patients 

on medications.

Special Population: Women of Color

A 2008 report commissioned by HRSA 

collected data from the published literature, 

key informant interviews, and a consultation 

meeting with Ryan White Care Act (RWCA)-

funded providers to provide information on 

barriers and effective interventions to assist 

women of color in succeeding with HIV care. 

Three central themes were extracted from 

these varied inputs:

1. Development of a responsive care 

environment that incorporates respect, 

cultural competency, and flexibility to meet 

women’s needs;

2. Incorporation of peers into the care system 

as trained and paid participants in the care 

teams; and

3. Addressing women’s needs through care 

coordination, flexibility, health system 

navigation, and better coordination and 

communication between medical and 

social service providers.

HRSA funded a number of clinical sites to 

test different methodologies applying these 

principles through the Special Programs 

of National Significance mechanism; these 

projects are ongoing and results are not yet 

available.

Models of Care

Chronic Care Model

Popular in recent years, the chronic care model 

refers to a mechanism for providing patientcentered care using a variety of staff personnel 

and interventions to maximize desired health 

outcomes. This approach has been most 

highly developed for diabetes care, but it can 

apply equally well to a wide range of chronic 

illnesses. In this model, patient training in 

self-care is key. In contrast to the tradition of 

teaching patients the pathophysiology of their 

health condition in lay terms, with this model, 

training involves focused skills building so 

that patients can better monitor their health 

status, use their discretionary medications, 

and know when and how to contact the 

professionals for assistance. Frequent contact 
14 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

between patient and clinical staff, both face-toface and through other means, both in clinics 

and in the community, usually are involved. 

Care is directed toward panels of patients, 

not just individual patients. Program-wide 

monitoring of process and outcome variables, 

such as frequency and results of CD4 cell 

counts and plasma HIV RNA levels, informs 

the practice as a whole as well as the quality of 

care for individuals. These interventions have 

been shown to improve outcomes, but do not 

necessarily reduce costs because the staff time 

required can be substantial.

Patient-Centered Medical Home

The chronic care model concept has been 

merged with the concept of a home to 

coordinate care and medical records for 

children to create the current model of the 

Patient-Centered Medical Home or PCMH. 

This concept usually is applied to primary care 

providers and practices; however, it potentially 

applies to a specialist who cares for the most 

prominent or demanding of a patient’s health 

problems as well as other primary care issues. 

The chronic care model is limited to treatment 

of one health condition whereas the medical 

home model supplements such targeted care 

(e.g., HIV-specific care) with coordination 

of the other health services the patient may 

need. HIV programs often act as the primary 

care provider, especially for patients who 

do not have insurance and therefore have 

limited access to other providers, whether 

the practice is otherwise a primary care or 

specialty clinic. Many HIV clinics have the 

capacity to organize and implement a chronic 

care approach and to coordinate services 

across other specialties and providers in 

order to be a true medical home. Several 

national organizations provide certification 

of PCMH status to clinicians and practices. 

One organization is the National Center for 

Quality Assurance or NCQA (see details on 

its PCMH certification process on its website 

(www.ncqa.org). NCQA will certify individual 

providers and practices even when they are 

located within larger institutions. Another 

organization is the Joint Commission (www.

jointcommission.org), which usually certifies 

PCMH status within an organization that 

has Joint Commission accreditation for 

other purposes. General information about 

the concept and other agencies that provide 

certification is available online at the National 

Center for Medical Home Implementation 

(www.medicalhomeinfo.org). In some states 

or localities, insurers such as Blue Cross and 

Aetna have their own certification process. 

Some health plans provide additional payment 

to primary care clinicians and practices that 

are certified as medical home providers, to 

support the health informatics infrastructure, 

care coordination, teaching and skill building, 

and follow-up outside of office visits that 

are required to manage panels of patients in 

a proactive manner. The PCMH approach 

also will provide financial opportunities for 

practices that become involved in Accountable 

Care Organizations (ACO), as pay-forperformance models of reimbursement are 

implemented across the United States. HRSA 

provides technical assistance to Ryan White 

grantees interested in being certified as a 

medical home, and to those interested in 

learning the lessons of this process even if not 

seeking certification. Additional information 

regarding training, resources, and webinars is 

available on the HRSA Target Center website 

(careacttarget.org).

PCMH Neighbor

This is a concept for specialty practices who do 

not wish to or are not able to take up full care 

coordination for a patient, or who may not be 

eligible as specialists to become certified as a 

PCMH (see “References,” below). With this 

concept, a specialist participates in timely and 

thorough sharing of information and care 

coordination with a patient’s primary care 

medical home, so that the full array of PCMH 

services is available without duplication but 
Clinic Management | 15

Section 1: The HIV Clinic: 

Providing Quality Care

with the added expertise of the specialty 

practice. At this time, there is no additional 

reimbursement for this status. However, 

implementing this enhanced level of care 

coordination with the patient centeredness, 

proactive approach, and skill building that 

characterize a PCMH, is expected to improve 

outcomes and may create opportunities for 

enhanced reimbursement in the future. This 

coordination also will be useful for specialist 

participation in ACOs.

Clinical Services 

Needed for HIV Care

Optimal array of services provided 

by an HIV clinic

At a minimum, HIV medical care providers 

need to offer confirmation of HIV infection, 

education, recommendations, and 

management regarding antiretroviral therapy; 

prevention, diagnosis, and management 

of HIV-related opportunistic diseases and 

treatment-related complications; screening 

and referral for common comorbidities, and 

linkages to other general health services. Most 

patients will need additional primary care and 

specialty health care and support services; it 

is often more effective and more convenient 

when these are available on-site rather than 

by referral. For health interventions to be 

successful, many patients will need assistance 

with health behavior change.

The services ideally provided by the HIV clinic 

include those on the list that follows. Detailed 

information on most of these topics is available 

in other chapters in this manual. These 

standards are derived from the primary care 

guidelines of the HIV Medicine Association 

of the Infectious Diseases Society of America 

(HIVMA/IDSA), the HHS Guidelines for 

the Use of Antiretroviral Agents in HIV-1-

Infected Adults and Adolescents, the HHS 

Guidelines for the Prevention and Treatment 

of Opportunistic Infections in HIV-Infected 

Adults and Adolescents, the CDC guidelines on 

prevention services in HIV care programs, as 

well as U.S. Public Health Service Prevention 

Task Force and American Cancer Society 

recommendations (see “References,” below).

• Age-appropriate immunizations including 

HIV-specific indications for some, including 

pneumococcal vaccine, influenza vaccine, 

hepatitis A and B vaccines, quadrivalent 

human papillomavirus vaccine in 

appropriate age groups (see chapter 

Immunizations for HIV-Infected Adults and 

Adolescents).

• Screening for STDs (syphilis, gonorrhea, 

chlamydia, trichomonas in women, hepatitis 

B and C) at enrollment and periodically. 

After the initial screening, new standards 

promote periodic screening for acquisition 

of hepatitis C in persons at risk.

• Assessment of ongoing sexual or drug-use 

behaviors associated with HIV transmission, 

and counseling or other interventions 

to reduce transmission behaviors. 

Interventions regarding sexual transmission 

behaviors should be linked with family 

planning.

• General health screening for hypertension, 

diabetes, dyslipidemia, and cardiovascular 

risks, and cervical, breast, and colon cancer. 

The role of anal cytology in screening for 

anal cancer remains uncertain because of 

limited data on effective management of 

anal dysplasia.

• Care of common general medical illnesses 

including hypertension, dyslipidemia, 

uncomplicated diabetes, obesity, asthma, 

and chronic obstructive pulmonary disease. 

Care of a wider range of disorders, such as 

congestive heart failure and chronic kidney 

disease, will vary by practice.

• Evaluation and care of common 

comorbidities including hepatitis B and C 

infection and latent and active tuberculosis 

(TB). Treatment of active TB, including 
16 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

directly observed therapy, often is provided 

by public health agencies; treatment of 

hepatitis may require referral to a specialist 

(though increasingly HIV providers are 

likely to manage treatment of HCV in 

coinfected patients as additional directacting antivirals for hepatitis C become 

licensed, with their improved efficacy and 

lower side-effect profile).

• Provision or linkage to oral health care, 

nutritional services, and other medical 

specialties including ophthalmology, 

dermatology, and oncology.

• Provision or linkage to HIV care for 

pregnant women, adolescents, and infected 

or perinatally exposed infants.

• Behavior change for general health issues 

including smoking cessation and other 

unhealthy substance use, diet for weight 

control, and exercise.

• Behavioral health services for adaptation 

to the illness, mental health disorders, and 

substance-use disorders including unhealthy 

alcohol use.

• Provision or linkage to social support 

services, including community-based case 

management.

• Additionally, clinics should have a system in 

place to protect the safety of their employees 

in regard to occupational HIV exposure 

(see chapter Occupational Postexposure 

Prophylaxis).

Resources required in providing 

comprehensive HIV care

Patient access is maximized in clinics that 

can accept Medicare, Medicaid (including 

Medicaid managed care), and county 

insurance programs. Clinics with access to 

Ryan White Treatment Extension Act funding 

must accept patients regardless of health 

insurance status or ability to pay. Federally 

qualified health centers also can accept 

uninsured patients and have an important 

role in expanding access to care. Every state 

receives Ryan White Part B funds for an 

ADAP to pay for antiretroviral agents and 

often other drugs for the uninsured or other 

eligible persons with HIV. Details vary by state 

and are available at each state’s HIV hotline 

(for phone numbers, see hab.hrsa.gov/gethelp/

statehotlines.htm). Clinics should assist 

appropriate patients to enroll in the ADAP, 

and to access the drug coverage or other 

clinical services that vary by state.

Within designated metropolitan areas, Ryan 

White HIV/AIDS Program Part A funding 

may be available. Clinics planning to serve 

a moderate-to-high volume of HIV patients 

can apply for a Ryan White Part C planning 

grant. Clinics serving women, pregnant 

women, youth, and families are eligible 

to apply for Ryan White Part D funding. 

Clinics may collaborate with other agencies 

in seeking Ryan White funding. Smaller 

programs may become satellites of larger Ryan 

White-funded programs. Other individual 

providers or small clinics may be eligible for 

Part B reimbursement for medical care of 

uninsured persons, by working with local case 

management agencies.

The ACA created online insurance 

marketplaces or exchanges, at which persons 

and families with incomes between 100% 

and 400% of the Federal Poverty Level (FPL) 

can purchase affordable insurance using 

tax rebates (for 250-400% of FPL) and other 

subsidies (for 100-250% of FPL). In addition, 
Clinic Management | 17

Section 1: The HIV Clinic: 

Providing Quality Care

many states are expanding Medicaid eligibility, 

for example to persons and families with 

annual incomes up to 138% of FPL. Another 

benefit of the ACA for persons with HIV is 

the requirement that core health benefits, 

including evidence-based preventive services, 

are provided by all health plans. HIV patients 

will benefit from the fact that preexisting 

conditions no longer disqualify persons from 

obtaining individual health insurance at 

competitive rates, and that more employers 

are now expected to provide health insurance 

for employees. Ryan White Part B Drug 

Assistance Program (DAP) funds may be used 

to assist patients with the costs of health plans 

if doing so is less expensive than providing 

direct benefits to DAP beneficiaries. Details 

about the plans available on the exchanges, 

their costs and benefits, the role of DAP, 

and Medicaid eligibility vary by state. HIV 

provider organizations will need to contract 

with some of the new plans available on their 

state exchanges, and providers will need to 

educate themselves on details of their plans. 

Local organizations have been designated as 

Certified Application Counselors (CACs), 

which allows trained staff to assist patients 

with enrollment on the exchanges and to 

certify that hardcopy documentation provided 

by patients, if needed in the course of online 

enrollment, is accurate. Other help may be 

provided by ACA navigators, who can assist 

clients with enrollment decisions but are not 

able to certify clients’ documentation. Specific 

details and mechanisms for this interaction 

between ACA insurance benefits and Ryan 

White benefits are still evolving. Updated 

information on the benefits of the ACA for 

persons with HIV is available on the HRSA 

Target Center website (careacttarget.org).

Personnel:

For patients who are self-sufficient or 

can access community-based services on 

their own, a lone provider potentially can 

deliver comprehensive HIV care. In most 

circumstances, however, patient care needs 

are met more effectively when multiple team 

members are available at the clinical site.

Facilities:

In addition to the usual office layout, other 

facilities are useful. An examination room 

suitable for gynecologic examinations is 

important. An apparatus for pulse oximetry 

is very useful in assessing patients with 

respiratory symptoms. Easy access to facilities 

for collecting venous blood, urine, and stool 

specimens should be available. On-site access 

to rapid tests that do not require Clinical 

Laboratory Improvement Amendments (CLIA) 

certification may be useful, such as urine 

pregnancy tests, fingerstick blood glucose 

tests, and perhaps the rapid HIV antibody 

screening tests. Laboratory certification to 

perform urine analysis and microscopic 

examination of vaginal fluid specimens is very 

useful. Refrigeration to maintain vaccines 

and material for tuberculin skin testing is 

necessary. Refrigeration also enables the clinic 

to provide patients with on-site injection of 

medications required once a week or less 

frequently.

Training and technical assistance:

Patients look to nontechnical staff to 

corroborate information given by physicians 

and midlevel providers. Further, patients 

expect the same accepting attitude from all 

staff members. Thus, all clinic personnel 

need training in both technical and cultural 

matters. One important resource is the 

AETC NRC (www.aidsetc.org) and the local 

performance sites of the AETCs funded by 

HRSA to provide training and technical 

assistance to clinics. The NRC, local AETCs, 

and the website of the National HIV/AIDS 

Clinicians’ Consultation Center (www.nccc.
18 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

ucsf.edu) provide detailed and patient-specific 

education to assist clinicians in making 

treatment decisions. Written educational 

materials for staff, such as national and 

regional treatment guidelines, may be obtained 

free of charge via the Internet and are updated 

regularly. Many regional and national 

meetings provide training in both clinical care 

and prevention. Assistance with enhancing 

and implementing systems of care, including 

instituting a quality management program, 

also is available from the AETCs. See chapter 

Web-Based Resources for other resources 

for training and information. The National 

HIV/AIDS Clinicians’ Consultation Center’s 

Warmline provides expert clinical advice 

on HIV/AIDS management for health care 

providers. This telephone consultation service 

is available Monday through Friday, 9 a.m. to 8 

p.m. eastern time, at 800-933-3413.

Implementing interdisciplinary 

care in the clinic

It is not enough to have staff members from 

many disciplines on the payroll; rather, 

systems that allow staff members to function as 

a team must be created. Training with followup by supervisors is essential. Specific tasks 

for each staff member need to be assigned (see 

Table 1). Ideally, members of the staff can meet 

for a few minutes prior to each clinic session to 

anticipate special needs and allocate personnel 

resources. Some clinics place a checklist on 

each chart at each visit to indicate which team 

members a patient is meant to see that day and 

to confirm that all intended interactions have 

occurred.

The team’s potential can be best utilized if 

there is a regular opportunity to meet and 

discuss patients outside clinic sessions, 

in multidisciplinary team meetings. 

When all members participate, the 

discussions can range from the selection 

of antiretroviral regimens for a patient to 

addressing the patient’s adherence issues 

or chronic mental illness. Services for 

infected and affected family members also 

can be coordinated at these meetings.

Table 1. Clinic Personnel 

Responsibilities

Tasks prior to a clinic visit

• Remind every patient of appointments via 

phone call or mail.

• Review charts to list items to address during 

the visit.

Tasks during a clinic visit

• Verify patient’s current contact information 

and current insurance status. 

• Orient new patients.

• Assist with insurance gaps (e.g., teaching 

about need for referrals, help with insurance 

application or ADAP).

• Assess other barriers to care 

and psychosocial needs.

• Assess medication adherence.

• Teach and provide behavior change 

counseling about medications and self-care.

• Assess ongoing transmission behaviors.

• Teach and provide behavior change 

counseling about transmission behaviors.

• Educate about clinical trial 

opportunities (if applicable).

• Make referrals for psychosocial services.

• Make referrals/appointments for medical, 

dental, mental health care

Tasks following clinic sessions

• Make follow-up calls regarding new 

medication regimens or referrals.

• Call or mail correspondence to patients who 

missed their visits.

• Help patients overcome barriers to clinic 

attendance.

• Extract patient data and enter it into the 

information system, or upload data from an 

electronic medical record into reporting or 

data management software.
Clinic Management | 19

Section 1: The HIV Clinic: 

Providing Quality Care

Support Services and 

Linkages Needed for HIV Care

Case management and support 

services enhance clinical care

Case managers assist patients in accessing the 

range of services and entitlements that can 

help them succeed in treatment. This may 

include helping patients apply for insurance; 

access support groups; access supplemental 

food, housing, homemaker, and other 

concrete services; and access mental health 

and substance abuse services. Excellent case 

managers also help motivate patients.

Traditionally, case managers should perform 

periodic assessments of clients’ needs and 

update their comprehensive care plans at least 

every 6 months. Home visits can be very useful 

as part of the assessment. Some case managers 

or their agencies will provide certain direct 

services themselves; these may include shortterm counseling, transportation for clinic 

visits, accompanying patients to clinic visits, 

and providing financial assistance for specific 

emergencies.

In many localities, HIV case management has 

been a service provided by community-based 

agencies. With the evolution of the PCMH 

concept, and a stronger need to have health 

care coordination for patients with multiple 

complex medical conditions, the approach 

to HIV case management is evolving. A 

new, and perhaps more useful, model is one 

in which community-based case managers 

provide linkage and follow-up for communitybased services such as health insurance, 

transportation, housing, food security, 

income, and psychosocial support generally. 

These case managers often have training in 

a psychosocial discipline. At the same time, 

medical case managers, usually nurses, provide 

coordination of medical care services, with 

support for appointment and medication 

adherence, side-effect management, self-care, 

and clinical monitoring between office visits. 

Close coordination between clinic staff and 

case management is important for avoiding 

duplication of efforts and services. Periodic 

case conferences between clinic staff and case 

managers are ideal. Written communication, 

for example, when sharing case management 

care plans, can be useful. Case management 

agencies and clinical sites need to obtain 

written consent from patients to share the 

information that allows coordination.

Creating useful linkages with 

community-based services

Clinics can develop relationships with 

community-based case managers or directly 

with providers of specific services, such as 

mental health, substance abuse, or housing 

services. Personal contact between staff 

members of clinics and outside agencies is 

important for establishing the relationship, 

and ongoing contacts are necessary for 

coordination. Community organizations 

often are pleased to give in-service 

education to clinic staff personnel in order 

to streamline the referral process. Clinics 

should make their expectations clear to 

community-based agencies. Clinics can 

function as advocates to ensure that their 

patients receive the attention and services 

for which they were referred. Periodic 

interdisciplinary meetings of clinic staff with 

representatives of community-based agencies, 

including case managers, are very useful.

Consumer involvement in HIV 

clinical care

Many clinics have created patient (consumer) 

advisory groups to participate in planning 

and quality management. The role these 

groups take depends on the specific clinic; 

some advisory boards educate themselves 

about clinic issues and provide expert input 

to clinic processes. Other boards act more as 

social event or support groups. See chapter 

Supporting Patients in Care for further 

information.
20 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Enhancements to increase the HIV 

clinic’s effectiveness: information 

and support

Clinics can enable patients to better care 

for themselves by providing them with 

information about HIV and by helping to 

build a community among them.

Much information is available for patients, 

including publications on medications, side 

effects, and adherence. Many clinics display 

HIV-related education materials, including 

information on safer sex practices and birth 

control; many also provide male and female 

condoms with instructions about their use. In 

some clinics, a separate area for educational 

materials may help clients maintain 

confidentiality. Free educational materials are 

available from federal and state HIV websites, 

and the pharmaceutical industry also produces 

some appropriate materials.

Many ASOs and clinics host support groups 

for interested patients. Participation must 

be voluntary, and only patients who are 

comfortable with revealing their status to 

other patients will be willing to participate. 

Some support groups target specific 

populations. Groups may be more effective 

if an experienced counselor or mental health 

provider leads them.

Some clinics hold classes on HIV and 

adherence. Other clinics provide periodic 

symposia to keep patients up to date on 

treatment advances. Clinics serving pregnant 

women and parents may include classes on 

birth preparation and parenting. For clinics 

that have a community advisory board, the 

board can be the organizing force for these 

community updates. Both public grants and 

funds from the pharmaceutical industry may 

be used to support these events.

Some youth-oriented clinics arrange social 

events and outings for their patients. Programs 

for children or mothers may provide support 

services for both infected and affected 

children, ranging from formal psychological 

care to supportive recreational activities after 

school or during school breaks.

Medical Information Systems: Tools 

for Enhancing Care

Medical information systems may include 

Practice Management Software (PMS), 

Electronic Health Records (EHRs), and 

Personal Health Records (PHRs). These three 

types of software may be available as a suite 

or as separate products that can be linked, 

although the linkage of separate products 

sometimes is challenging. Software products 

may be designed to run on one desktop 

computer in a small practice or on a computer 

server that can be accessed by many users 

simultaneously, or they may be based on the 

Internet and managed by the vendor. In all 

instances, backup of the data and maintenance 

of confidentiality and compliance with Health 

Insurance Portability and Accountability Act

(HIPAA) rules and other laws are necessary.

PMS refers to software used principally for 

scheduling and billing; it includes information 

on patient demographics, insurance or payer, 

attendance with appointments, diagnoses, 

and sometimes other information. This is 

very useful in tracking clinic productivity 

and patient adherence with visits, and in 

developing an overview of a patient population 

and understanding the finances of a practice. 

PMS software can provide data regarding 

some quality measures, because services such 

as vaccinations and procedures performed 

within the practice can be tracked easily.

EHR refers to software used for clinical care, 

as a substitute for or supplement to a paper 

medical record. Providers enter their notes 

into these systems, and clinic staff document 

procedures and interventions performed in 

the office. With many systems, prescriptions 

may be written within the system and sent 

to pharmacies electronically or by fax, 
Clinic Management | 21

Section 1: The HIV Clinic: 

Providing Quality Care

diagnostic tests may be ordered, and test 

results may be sent electronically into the 

EHR for clinician review and action. Paper 

documents often can be scanned into the 

system so that hard copies of outside reports 

can be included in the medical record. EHRs 

that substitute for paper records can reduce 

issues of storage, retrieval, and access to 

paper charts once the transition is complete.

EHR refers to software that the patients can 

access to see part or all of their medical record. 

These systems are designed to empower 

patients as members of their health care team, 

to provide detailed information to them, and 

to promote interaction between the consumer 

and provider.

Potential advantages of EHRs

In an era of transformation of the U.S. health 

care system, much is said about the potential of 

these software products to increase efficiency 

and reduce errors. While this potential is real, 

substantial effort and investment is required to 

deploy and maintain systems that are useful to 

clinicians, administrators, and payers. An EHR 

for a small office or one that is deployed only in 

an HIV program can be managed fairly easily, 

and some products developed specifically 

for HIV care are available. An EHR for a 

large organization, such as a multispecialty 

group, is more complex and requires much 

more planning, training, maintenance, and 

sometimes customization to meet the needs of 

all the users.

Success in EHR implementation is greater 

when the users are involved in the selection 

and implementation of the system. 

Commercially available systems run on servers 

for large organizations may provide options 

for customization; however, customization 

greatly increases the cost and complexity of 

installing the software updates that are likely 

to be required.

EHRs may be text based (such as the system 

used by the Veterans Health Administration) 

or data based. Text-based systems are often 

quicker to learn; however data-based systems 

may provide more information for quality 

and program management and reporting 

needs and may be more useful for billing 

functions. Some EHR software packages are 

available at no cost (such as the Veterans 

Health Administration system and other opensource software) whereas others are available 

commercially and are maintained by vendors.

Once fully implemented, EHRs are expected to 

improve quality by improving communication 

and coordination among clinicians, reminding 

clinicians about standards of care and the 

timing of health maintenance or monitoring, 

avoiding errors associated with handwritten 

notes or prescriptions, documenting 

prescriptions, and providing warnings 

on potential drug interactions or hazards 

associated with specific diagnoses. EHRs 

are expected to lower costs by reducing the 

expense of maintaining paper records and by 

reducing duplication by sharing prescriptions, 

test orders, and test results among all 

users. EHRs can provide both process and 

outcome data for monitoring and for quality 

improvement activities (see chapter Quality 

Improvement), and data for Ryan White 

grantee reports. They also may make it easier 

for practices to fulfill and document adherence 

with the standards of payers.

Medicare and other payers are currently 

offering incentives for specific uses of EHRs, 

for example when at least 75% of prescriptions 

are sent electronically (because this is thought 

to reduce prescription errors) and for other 

types of “meaningful use” that are thought 

to improve the organization of care and 

adherence with clinical care standards.
22 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Cautions

These software packages are complex entities 

that require substantial staff time and effort, 

hardware purchase and maintenance, training, 

and modifications in workflow. EHRs are 

not simply replacements for paper records; 

effective use involves changes in the work 

habits of clinicians. Successful implementation 

of an EHR system requires working with the 

end users as the system is developed so that 

reasonable compromises and accommodations 

can be made. Choices must be made regarding 

both the software and the hardware to be 

used (e.g., a laptop computer used by a single 

clinician in multiple examination rooms versus 

a fixed desktop computer in each room). An 

EHR system that must share data with another 

system such as a hospital EHR or a laboratory 

reporting system can be very complex and 

require substantial investment of time and 

money, even when the different software 

systems use compatible data standards. 

Effective implementation often occurs over 

the course of years. Implementation of EHR 

systems is not a panacea and will not solve all 

health care system problems, but use of EHRs 

is likely to be a necessity for functioning in the 

evolving systems of health care finance and 

reimbursement, as well as an essential tool for 

monitoring and assuring quality of care for the 

individual patient and at a population level.

Ensuring that patients 

receive necessary services 

at clinics without EHRs

At clinics in which paper charts are in 

use, forms, checklists, and flow sheets can 

be designed to remind providers of care 

standards, simplify data collection, and 

serve other purposes as well. Sample forms 

for initial and follow-up visits are posted on 

the HRSA HIV/AIDS Bureau (HAB) website 

(www.hab.hrsa.gov). They include reminders 

regarding clinical standards, reminders of 

services required for billing levels, checklists 

built around definitions used by Ryan White 

HIV/AIDS Program grantees for reporting to 

HRSA, and other data for quality management. 

These instruments often can be used to 

generate reports to individual providers. Staff 

members may find it challenging to adjust to 

using new forms; however, using checklists 

often saves time by listing required elements 

of the visit and by reducing the amount of 

writing. Including representatives from 

clinical, data, and quality management staffs 

in the process of designing forms increases the 

acceptability of new forms or procedures.

Effective Management 

of HIV Programs

Managing a program with all the components 

described in this chapter is challenging. For 

enhancing communication and advancing 

the clinic’s objectives, staff meetings are 

important. Smaller organizations may include 

the entire staff at monthly meetings, whereas 

larger organizations may have staff meetings 

less often, such as on a quarterly basis. Some 

larger organizations find it useful to have a 

monthly interdisciplinary meeting of program 

leadership, with representation of the different 

disciplines or program components, such as 

nursing or clinical care, psychosocial support, 

data and quality management, behavioral 

health, research, finance, administration, 

satellite services, and consumers. These 

coordinating meetings provide an opportunity 

for personnel from each discipline to update 

others on current activities, challenges, 

successes, and initiatives. They also provide 

a regular forum for updates on fulfilling 

grant-related work plan tasks and reviews of 

financial reports. Minutes of the meetings, 

which include decisions taken and assignments 

made, should be prepared and circulated to 

participants; minutes should be reviewed at the 

subsequent meeting and reports on assigned 

tasks should be delivered.
Section 1: The HIV Clinic: 

Providing Quality Care

Clinic Management | 23

These larger organizations also may have 

monthly meetings by discipline, for example, 

comprising the nursing or clinical staff, to 

transmit information from the larger meeting 

and to coordinate the discipline-specific 

activities. In smaller programs, quality 

management may be part of monthly staff 

meetings whereas in larger programs it is 

more practical to have a separate quality 

management committee (see chapter Quality 

Improvement).

HIV programs often are contained within 

larger health organizations, and may be 

outliers with regard to the patients they 

serve and other features. It is important for 

program leadership to build and maintain 

support within the host institution. Where 

applicable, this may involve reminding the 

host institution of the grant or other funding 

the program generates. HIV programs often 

are on the forefront of innovative health care 

delivery, for example, in adopting quality 

management approaches and using other data 

to assist program management, incorporating 

EMR and PHR systems, implementing 

interdisciplinary care that integrates medical 

care with behavioral health, using a chronic 

care model or providing a medical home 

for patients, and linking with communitybased programs. An important task for 

HIV program leadership is making the host 

institution feel proud and supportive of the 

HIV program itself.

Suggested Resources

• National Resource Center of the AIDS 

Education and Training Centers 

(www.aidsetc.org)

• National HIV/AIDS Clinicians’ Consultation 

Center (www.nccc.ucsf.edu)

(free and confidential advice from a 

multidisciplinary team): 

• National HIV/AIDS Telephone 

Consultation Service (Warmline):

800-933-3413 (Monday-Friday, 

9 a.m. to 8 p.m. eastern time)

• National Clinicians’ Post-Exposure 

Prophylaxis Hotline (PEPline):

888-448-4911 (9 a.m. to 2 a.m. 

eastern time/7 days a week)

• National Perinatal HIV Consultation 

and Referral Service (Perinatal 

Hotline): 888-448-8765 (24 

hours a day/7 days a week)

• New York State AIDS Institute guidelines 

(www.hivguidelines.org)

• HRSA Target Center website 

(careacttarget.org)
24 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

References

• Aberg JA, Gallant JE, Ghanem KG, et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• American College of Physicians. The patientcentered medical home neighbor, the interface 

of the patient-centered medical home with 

specialty/subspecialty practices. American 

College of Physicians Position Paper 2010. 

Available at www.acponline.org/advocacy/

current_policy_papers/assets/pcmh_

neighbors.pdf. Accessed December 1, 2013.

• Branson BM, Handsfield HH, Lampe MA, 

et al.; Centers for Disease Control and 

Prevention. Revised recommendations 

for HIV testing of adults, adolescents, 

and pregnant women in health-care 

settings. MMWR Recomm Rep. 

2006 Sep 22;55(RR-14):1-17.

• Centers for Disease Control and Prevention. 

Incorporating HIV prevention into the medical 

care of persons living with HIV: Recommendations 

from CDC, the Health Resources and Services 

Administration, the National Institutes of Health, 

and the HIV Medicine Association of the Infectious 

Disease Society of America. MMWR 2003;52: 

(RR-12)1-17. 

• Gallant JE, Adimora AA, Carmichael JK, 

et al. Essential components of effective HIV 

care: a policy paper of the HIV Medicine 

Association of the Infectious Diseases Society 

of America and the Ryan White Medical 

Providers Coalition. Clin Infect Dis. 2011 

Dec;53(11):1043-50.

• Gardner LI, Marks G, Craw JA, et al.; 

Retention in Care Study Group. A low-effort, 

clinic wide intervention improves attendance 

for HIV primary care. Clin Infect Dis. 2012 

Oct;55(8):1124-34.

• Mugavero MJ. Improving engagement in HIV 

care: what can we do? Top HIV Med. 2008 

Dec;16(5):156-61.

• Naar-King S, Outlaw A, Green-Jones M, 

et al. Motivational interviewing by peer 

outreach workers: a pilot randomized clinical 

trial to retain adolescents and young adults in 

HIV care. AIDS Care. 2009 Jul;21(7):868-73.

• Naar-King S, Parsons JT, Murphy DA, et al. 

Improving health outcomes for youth living 

with the human immunodeficiency virus: a 

multisite randomized trial of a motivational 

intervention targeting multiple risk 

behaviors. Arch Pediatr Adolesc Med. 2009 

Dec;163(12):1092-8.

• National Committee of Quality Assurance. 

Patient-centered specialty practice recognition. 2013 White Paper. Available at www.

ncqa.org/Programs/Recognition/PatientCenteredSpecialtyPracticeRecognition.aspx. 

Accessed December 1, 2013.

• Outlaw AY, Naar-King S, Parsons JT, et al. Using 

motivational interviewing in HIV field outreach 

with young African American men who have 

sex with men: a randomized clinical trial. Am J 

Public Health. 2010 Apr 1;100 Suppl 1:S146-51.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
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Providing Quality Care

Clinic Management| 25

• Rollnick S, Miller WR, Butler CC. 

Motivational Interviewing in Health Care: 

Helping Patients Change Behavior. New 

York: Guilford Press; 2008.

• Saag MS. Ryan White: An unintentional home 

builder. AIDS Read. 2009 May;19(5):166-8.

• Thompson MA, Mugavero MJ, Amico KR, 

et al. Guidelines for improving entry into and 

retention in care and antiretroviral adherence 

for persons with HIV: evidence-based 

recommendations from an International 

Association of Physicians in HIV care panel.

Ann Intern Med 2012;156(11),817-833.

• U.S Department of Health and Human 

Resources, Health Resources and Services 

Administration, HIV/AIDS Bureau.

The Utilization and Role of Peers in HIV 

Interdisciplinary Teams. Consultation 

Meeting Proceedings. October 2009. 

Available at hab.hrsa.gov/newspublications/

peersmeetingsummary.pdf. Accessed 

December 1, 2013.

• U.S. Department of Health and Human 

Services, Health Resources and Services 

Administration, HIV/AIDS Bureau, Special 

Projects of National Significance. The 

Costs and Effects of Outreach Strategies 

That Engage and Retain People with HIV in 

Medical Care. March 2010. 

• Yehia BR, Gebo KA, Hicks PB, et al.; HIV 

Research Network. Structures of care in the 

clinics of the HIV Research Network. AIDS 

Patient Care STDS. 2008 Dec;22(12):1007-13.

Quality Improvement | 27

Section 1: The HIV Clinic: 

Providing Quality Care

Quality Improvement

Bruce D. Agins, MD, MPH

Improving Systems of Care: 

“Every system is perfectly designed to achieve 

exactly the results that it achieves.”

Quality improvement (QI) is an important strategy to 

improve systems and reduce variation in delivery of 

care and services so that patients receive the right care 

every time they visit clinic, increasing the likelihood 

of their achieving the expected benefits and outcomes 

of care. As we move forward to end AIDS in the 

United States and meet the goals of the National HIV/

AIDS Strategy, QI becomes an even more important 

methodology to implement in local systems through 

evidence-based interventions that can improve care, 

linkage, and retention. 

Quality improvement has become a fundamental 

component of the HIV service delivery system 

whether care is provided in dedicated or integrated 

delivery models. Clinical quality management is 

a legislative requirement for Ryan White-funded 

programs. Many clinicians have learned the basics of 

quality management, which are reinforced through 

Maintenance of Certification programs directed 

through medical and specialty boards. Many 

clinicians not only are participating actively in QI 

activities, but also are leading improvement efforts in their clinics. Moving beyond the basics, 

however, remains a challenge for clinicians who have limited time to participate in activities not 

related to direct patient care. Yet, focusing on quality can reveal important phenomena in the 

operational processes and delivery systems of the clinic of which the leadership is unaware and 

may reveal factors that explain why intended outcomes are not always being realized. Additionally, 

the participation of clinicians in clinic-wide QI improvement activities is often a critical ingredient 

for their success.

Increasingly, QI work in the HIV field is directed toward achieving important health outcomes 

such as HIV viral load suppression, retention in care, and reductions in readmissions and 

emergency department utilization. Simple subanalyses of basic performance data also may reveal 

disparities in how care is being provided to different patient groups in the clinic, for example, 

according to age, gender, or race/ethnicity. Careful assessment of the social determinants of health 

also may show which patients need to be targeted in improvement activities. At the same time, 

advances in health information technology have made it easier to generate data for performance 

measurement and to produce simple reports that can be used for improvement activities.

This chapter will review the basics of QI; an appendix at the end of the chapter illustrates 

concepts with examples of more advanced improvement work. The Health Resources and Services 

“Quality of care is the degree to which 

health services for individuals and 

populations increase the likelihood 

of desired health outcomes and are 

consistent with current professional 

knowledge.”

(Institute of Medicine, 1990) 

“All health care organizations, 

professional groups, and private and 

public purchasers should pursue six 

major aims; specifically, health care 

should be safe, effective, patientcentered, timely, efficient, and 

equitable.”

(Institute of Medicine, 2001)

“Health care interventions that are 

known to work and save lives are not 

being implemented for every patient 

every time.”

(Salzburg Seminar Statement, 2013)
28 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Administration HIV/AIDS Bureau Performance Measures chapter in this manual presents a 

national quality initiative developed by the U.S. Health Resources and Services Administration 

(HRSA) HIV/AIDS Bureau (HAB) for Ryan White HIV/AIDS Program-funded clinics; HRSA’s 

Performance Measures can be incorporated into the quality improvement programs of local 

clinics.

The fundamental concepts of QI have evolved over the past century to include the following:

• QI provides an opportunity to solve problems that are part of 

the system and do not depend on one individual.

• Reducing variation in performance will allow consistent delivery of the best possible care. 

• Improving processes within the health care delivery system 

will lead to improvements in outcomes.

• Data are the key to identifying problems and measuring change.

• Focusing on performance measurement and improvement usually 

stimulates employees to maximize their performance.

• Team-based problem-solving techniques lead to better care 

and promote a positive working environment.

• Testing changes will identify solutions that work and eliminate 

putting ineffective solutions into practice.

• Consumers play a pivotal role in providing the “end-user” perception of the quality 

of the services delivered; their active participation in the quality management 

program strengthens improvement work and leads to better results.

In addition, documentation of QI activities helps to demonstrate institution-wide compliance 

with accreditation responsibilities and funding requirements. Data generated from the clinic’s 

QI program showing improvements over time demonstrate to constituents that the program is 

successful and help to justify its funding. These data also build the evidence base for determining 

which interventions are successful and can be disseminated to achieve large scale change. 

Finally, quality management systems that are dependent on single individuals will not last when 

these key players leave the clinic or are absent for long periods, whereas a fully functioning QI 

program that involves staff working in teams with a clearly defined infrastructure will keep going 

when even the most dynamic individuals depart.

This chapter will articulate the core principles of QI and describe activities that can be easily adapted 

into the HIV ambulatory care setting to implement a sustainable quality management program. 

Introduction to Quality 

Improvement 

QI includes regular measurement of processes 

and outcomes to analyze the performance of 

the system of care with the ultimate goal of 

reducing variation in care delivery. It involves 

the implementation of solutions to improve 

care and the monitoring of their effectiveness 

in achieving optimal health outcomes for 

patients. Ongoing cycles of change and 

remeasurement are implemented to test 

and try different ideas to determine which 

practices result in improved care. QI activities 

in clinics can range from a single team 

focusing on improving one aspect of care to a 
Quality Improvement | 29

Section 1: The HIV Clinic: 

Providing Quality Care

comprehensive QI program with many teams 

working on a wide variety of improvement 

projects, with a well-established plan and an 

oversight committee.

The methods of QI are based on core principles 

that are readily translated into a practical 

approach and integrated into the clinical 

care delivery system (see Table 1). Successful 

implementation of QI involves actions at two 

levels: the QI activities and the HIV program 

processes that provide the structural backbone 

for them.

Table 1. Core Principles of Quality 

Improvement

• Emphasis on systems of care: improve 

processes that link to desired outcomes

• Focus on the customer: understanding 

patients’ experience in the clinic will identify 

areas that are important for improving care 

• Measurement: collect and use data to 

improve care

• Involvement of participants: encourage direct 

participation in teams by those individuals who 

implement the processes being evaluated

Measurement and Management 

Are Not Sufficient

Although it is the bedrock for improving care, 

measurement alone is not sufficient to improve 

quality. A common pitfall in implementing QI 

programs is to rely solely upon performance 

data, the medical or program director’s 

interpretation of it, and one person’s decisions 

about how to make changes. Successful 

improvements occur most often when staff 

members from the systems being assessed 

work together in teams. When they are 

engaged in the process, staff members are more 

likely to generate ideas for improvement and 

to accept changes. Staff review of improvement 

charts (e.g., see Figure 1, below) generates 

pride and a sense of accomplishment based on 

members’ participation in the QI work. These 

charts may be posted on bulletin boards in 

common areas of clinics so that everyone can 

view them.

QI Personnel 

The size of the clinic will determine who 

participates in quality-of-care activities. 

In small HIV clinics with a primary care 

provider, case manager, nurse, and support 

staff, most of the staff members are involved 

in all aspects of QI work. Larger institutions 

usually establish an HIV Quality Committee 

that includes senior management of the HIV 

clinic, designated QI staff members if there 

are any, and other key players who work in the 

clinic. A member of this committee represents 

the group in the agency-wide QI committee. 

The Quality Committee identifies the priorities 

for improvement or agrees to pursue the 

priorities identified by staff members or 

patients in the clinic. The Quality Committee 

also charters improvement teams and identifies 

potential members who are key stakeholders 

in the process under investigation. In a small 

clinic that has only a handful of staff members, 

all clinic personnel may participate in the 

quality management program and in QI 

activities, although perhaps in a less formal 

way than in larger clinics. 

Team Membership and 

Responsibilities

Teams are formed to address the specific 

care processes or systems that are targeted 

for improvement. Team members should be 

selected to represent the different functions 

involved in these processes or to represent the 

components of the system under focus. The 

size of a team varies according to the size of 

the clinic and the process under study. In small 

clinics, the few dedicated HIV program staff 

members may constitute the project teams, 

with added representation from different 

departments as needed (such as from the 

laboratory, or from other medical disciplines). 

In larger clinics, teams often include 6-10 

members. Membership should include 

representatives from the different groups in the 

clinic who are involved in the care process. In 
30 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

addition to the clinical and case management 

staff, scheduling clerks and medical records 

personnel are often important participants, 

especially when follow-up appointments and 

documentation are components of the care 

process or have been identified as areas that 

need to be improved.

Teams sometimes struggle with engaging 

physicians in their QI activities. Increasingly, 

physicians have overcome their reluctance to 

join process improvement teams, especially 

since more sophisticated data systems and 

comparative reports have become available 

to focus interest on improving care that 

does not meet standards or falls below mean 

performance rates. Moreover, physicians are 

now required to directly engage in practicebased learning and improvement to satisfy 

requirements for maintenance of professional 

certification. Studies of physician performance 

have demonstrated that participation in QI 

activities enhances job satisfaction and reduces 

work-life stress. 

Involving consumers in QI project teams 

enhances the work of the team. Consumers 

who are involved in the clinic’s community 

advisory board often are natural leaders and 

have a good grasp of clinic processes. Their 

feedback on the experience of care delivery 

can reveal areas that need improvement. 

They know the bottlenecks and can inform 

the staff how long a clinic visit lasts, whether 

assessments truly occurred, and whether 

behavioral interventions are effective. Their 

ideas about what improves care often diverge 

significantly from those generated by providers 

and may not even be recognized unless 

consumers participate directly in discussions 

about the system.

Teams are expected to analyze clinical 

processes, identify areas of change, 

implement tests of the changes, review data 

assessing the change, and ultimately make 

recommendations about which improvements 

should be adopted in the clinic.

Data Collection

Selecting Measures

Evaluating measurable aspects of care can help 

in determining the extent to which a facility 

provides a certain element of care. Quality 

measures should be based on standards or 

guidelines, meet the primary goals of QI, and 

reflect priorities specific to the community and 

the clinic. In addition, they should represent 

processes where changes are feasible. For 

example, in HIV clinics where the population 

consists of a large number of women, 

indicators may include rates of routine cervical 

cancer screening, rates of preconception 

counseling, or other aspects of care specific 

to women. In clinics that care for a high 

volume of patients who have been treated 

with antiretroviral therapy (ART) for a long 

time, measures may focus on rates of virologic 

suppression, screening for adverse effects of 

antiretroviral medications, and resistance 

testing. As we focus on our strategies to 

maximize community viral suppression, 

measures of linkage to care, engagement, and 

retention in care become priorities. 

Some measures should be selected by soliciting 

input from patients who attend the clinic 

(see Table 2). Staff members also often know 

what aspects of care would benefit from being 

measured and improved, and they should be 

consulted to determine priorities. If routine 

data collection systems already exist in the 

clinic, data should be reviewed to determine 

which components of care would be prime 

candidates for improvement.

Table 2. Methods for Obtaining Input 

from Patients

• Suggestion box

• Surveys

• Exit interviews

• Focus groups

• Consumer advisory 

board

• Participation 

on QI teams 

• Membership on 

the QI Committee
Quality Improvement | 31

Section 1: The HIV Clinic: 

Providing Quality Care

On a national level, the HRSA HIV/AIDS 

Bureau (HAB) has developed HIV/AIDS 

Performance Measures for monitoring the 

quality of care provided in Ryan White HIV/

AIDS Program-funded clinics. These measures 

emphasize important areas of HIV care that 

are linked to the goals of the National HIV/

AIDS Strategy and that are also endorsed by 

the National Quality Forum, which confers 

eligibility for inclusion in Meaningful 

Use criteria and other provisions of the 

Accountable Care Act that are important 

for both measuring care and are linked to 

enhanced reimbursement programs. They 

form a core package of priority indicators that 

can be enhanced by those that are identified 

through analysis of local data, or identified 

by local stakeholders. See chapter Health 

Resources and Services Administration HIV/

AIDS Bureau Performance Measures for these.

Ideally, a balanced set of measures should be 

selected. Different ways to categorize measures 

might include the following:

• Structure/process/outcome

• Treatment/care (non-ART)/prevention/

nonclinical service

• Provider/consumer/funder driven

• Aspects representing overutilization, 

underutilization, or misutilization of 

services

Developing and Quantifying 

Quality Measures

Three major activities constitute the process of 

developing performance measures:

• Defining the measurement population

• Defining the measures

• Developing the data collection plan

The measurement population is defined by 

determining factors such as the location of 

care being studied, whether both men and 

women are eligible, the applicability of the 

measure to various age groups, whether any 

clinical conditions are necessary to determine 

the applicability of the measure, the number of 

clinic visits by the patient, and amount of time 

the patient has been in care.

After the population is defined, the measure 

needs to be defined. The measure should 

be objective and should address specific 

aspects of quality care. It also should have 

a straightforward, dichotomous answer. 

For each measure, specific criteria must be 

developed to define the “yes” response and the 

“no” response (see Table 3). This often involves 

deciding the time period during which an 

activity has been performed. For example, a 

measure that evaluates viral load monitoring 

must include the frequency with which that 

test should be performed. One simple way to 

construct this measure would be to ask, “Was 

viral load measured within the past 6 months?”

Table 3. Examples of Specific Measures 

with Definitions of Responses 

Measure

Definition of 

Measure Yes/No Response

HIV Viral 

Load 

Monitoring

Was HIV 

viral load 

measured 

in the past 6 

months? 

Yes: Viral load testing 

was performed

No: Viral load testing 

was not performed 

(or the test was done 

but results were not 

documented)

HIV Viral 

Load 

Suppression

Was the HIV 

viral load 

<200 copies/

mL at the 

most recent 

test during 

the past year?

Yes: Viral load was 

<200 copies/mL

No: Viral load was 

>200 copies/mL

Several elements of care should be measured 

simultaneously, whether abstracted from medical 

records or analyzed through administrative 

databases. Measures reflecting aspects of patient 

management should be selected, as should 

those involving different populations. Measures 

also should be selected to evaluate various 

components of the health care system, such as 

the components of the chronic disease model. 
32 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Clinical measures should include those that affect 

a large proportion of the patient population, 

such as whether comprehensive mental health 

screening has been performed.

The data collection plan includes 

determining the source of information 

(e.g., whether medical records or an 

electronic database will be used), how 

the data will be recorded, who will 

record the data, and how a data sample 

will be selected. A representative 

sample will allow inferences to 

be made about the overall clinic 

population based on observations 

of the smaller sample. Some form of 

random sampling should be used, 

either by using a random numbers 

table or by selecting every nth record 

from the list of eligible patients.

If electronic health records (EHRs) are 

used, sampling will not be necessary. 

Careful planning is required, however, to ensure 

that the measures are included in the electronic 

system, and that the EHR database is constructed 

to contain the elements required in the reports 

generated by the quality evaluation queries.

A common pitfall at this point is to think of 

the measurement sample as a research project. 

For the purposes of QI, a sample needs only 

to be current, representative, and readily 

obtained (i.e., sample size calculations and the 

achievement of statistically significant results 

are not necessary).

Analyzing and Displaying Data

Data should be reviewed and distributed to all 

members of the team and others involved in the 

care process under evaluation. When possible, 

data should be displayed in graphic format. After 

data from multiple time periods have been collected (e.g., percentage of patients with HIV suppression), a simple line graph (run chart) can be 

constructed with each point representing a performance rate (percentage) for a given period of 

time. This usually is the simplest and most effective way to show performance data (see Figure 1).

Identifying Targets and 

Implementing Improvements 

After the project team has reviewed the 

data, it must decide where opportunities for 

improvement exist. The first step in this process 

is to investigate the care process in greater detail. 

Several techniques are used to accomplish this 

goal. The simplest is brainstorming, in which key 

stakeholders offer their suggestions as to which 

processes are the best candidates for change. 

Another easy method is flowcharting, in which 

the group breaks down the process into its 

components to identify how it is coordinated and 

how its parts fit together. A fishbone diagram, or 

cause-and-effect diagram, may aid in exploring 

and displaying the causes of a particular problem 

(Figures 2 and 3). It often helps for staff members 

to consider factors potentially influencing a 

process that are not obvious, and to help sort 

out those factors that are external to the clinic 

and those that are internal. A driver diagram is 

a visual tool to help understand and prioritize 

factors that drive desired outcomes, which are 

called the “primary outcome.” Primary drivers

are the factors that drive the primary outcome. 

Secondary drivers are subsets of factors that 

influence the primary drivers.

Adapted from Measuring Clinical Performance: A Guide for HIV Health Care Providers.

New York: New York State Department of Health AIDS Institute. April 2002.

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Figure 1. Percentage of Patients with HIV 

Viral Load Suppression, by Month
Quality Improvement | 33

Section 1: The HIV Clinic: 

Providing Quality Care

LOW

COLLECTION

OF RACE AND 

ETHNICITY

EQUIPMENT PATIENTS

PROCEDURES STAFF

Hardware

Can’t read forms

Don’t like asking

Need script and 

training Patients cannot ll out 

screening forms

Clerks also 

answer phones

HIPPA – need for 

auditory privacy

Race/Ethnicity 

classication too 

complicated Time

Computer

Not used to using

No time for extra questions

Don’t like taking up pts time

Materials

Limited access to translators

Stigma–don’t want family to know

Don’t like to be asked race

Don’t return for eligibility appts

Patients come too late to appts

Can’t read signs/yers

Literacy/English preferences

$$$–afraid data will 

be used for billing

Hard to enter data

Too easy to create new classes

Program–Labtracker

Computer stations 

xed—can’t move 

them

Causes

Main Cause 1 Main Cause 2

Main Cause 3 Main Cause 4

Problem 

Statement

Eect

Figure 2. Sample Fishbone Diagram 

Figure 3. Fishbone Diagram: Low Collection Rates of Race and Ethnicity Patient Data 

Used with permission from Kathleen A. Clanon, MD; Low-Income Health Program of Alameda County.
34 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

The driver diagram, which can be generated 

through discussion with stakeholders, is 

a particularly effective strategy to identify 

processes that may be key areas to target for 

improvement goals that will affect the ultimate 

outcome. For example, if retention in care is 

the desired outcome, housing status may be 

a primary driver that, in turn, is affected by 

access to factors such as entitlements, mental 

illness, substance use, or health literacy, 

which then are secondary drivers that, when 

addressed through QI activities, will affect 

the primary driver and ultimate outcome. 

Framing this larger picture of the system that 

is being improved may be extremely useful 

for participants at different levels who may be 

involved in only one aspect of the QI initiative, 

as well as for those only involved at the macro 

level who do not recognize the role of the 

processes being prioritized for ground-level 

work. An example of a driver diagram focusing 

on viral load suppression is shown in Figure 4. 

Figure 4. Driver Diagram: Viral Load 

Suppression

Increase the viral load

suppression rate by

10% at all clinics over a

10 month period

Patient

retention

AVR

adherence

Directly observed

therapy

ARV education and 

support

Health literacy

Housing

Substance use 

treatment

Mental health

Sta attitude

Transportation

Continuity of care

Primary Outcome Primary Driver Secondary Driver

Psychosocial

health

Then, the areas that would be most likely to 

benefit from improvement are selected for 

change (see Figure 5) and tested in the PlanDo-Study-Act (PDSA) cycle (see Figure 6). See 

“Appendix,” below, for examples of QI projects 

conducted in HIV clinics.

Figure 5. Sample Flow Chart

Patient arrives at

front desk.

Medical nurse

takes patient into the

exam room.

Patient in system?

Nurse asks for patient’s 

name and searches 

the database for 

his/her le.

Nurse asks patient to 

complete paperwork for 

new clients and return it 

to the front desk.

Ask patient to be 

seated in the waiting 

room.

Etc.

YES

NO

Oval shape shows 

beginning to ending 

step in a process.

Rectangle depicts 

particular step or 

task.

Arrow shows 

direction of process 

ow.

Diamond indicates a 

decision point.

Flowchart Symbols

Source: U.S. Department of Health and Human Services, Health 

Resources and Services Administration, HIV/AIDS Bureau. A Guide 

to Primary Care of People with HIV/AIDS. Bartlett JG, Cheever LW, 

Johnson MP, Paauw DS, eds. Rockville, MD: U.S. Department of 

Health and Human Services; 2004:145. 
Quality Improvement | 35

Section 1: The HIV Clinic: 

Providing Quality Care

Figure 6. Plan-Do-Study-Act Cycle

Act Plan

Study Do

Plan: Plan the change and collect baseline data

Do: Test the change and collect data

Study: Analyze the data

Act: If the change did not improve the process, 

try another idea. If the change resulted in 

improvement, adopt the change, monitor the 

process periodically, and spread the change 

throughout the clinic

Source: U.S. Department of Health and Human Services, Health 

Resources and Services Administration, HIV/AIDS Bureau. A Guide 

to Primary Care of People with HIV/AIDS. Bartlett JG, Cheever LW, 

Johnson MP, Paauw DS, eds. Rockville, MD: U.S. Department of 

Health and Human Services; 2004:145.

Even if evidence-based criteria on how to 

improve desired outcomes exist, how they 

are implemented varies according to the local 

context. Thinking through the “hows” of an 

intervention – who will do it, when during 

the care process it will be done, where it will 

be done – are important questions to ask as 

the test of the intervention is planned. After a 

change has been selected, a test of the change 

can be quickly implemented and evaluated. 

A limited implementation of the proposed 

change can be tested – perhaps with just a 

few subsequent patients, or those attending 

on the following day, or those seen by a 

particular clinician. If the small change does 

not work, another change can be selected and 

implemented quickly. If the change is feasible 

and improvement is noted, it can be adopted 

more widely, before formal remeasurement 

occurs, and a regular period of remeasurement 

can be adopted. If the change was not 

successful, then another one can be chosen and 

tested. Occasionally, multiple changes may be 

tested simultaneously or on different days of 

the week.

Many different approaches to QI exist and 

can be implemented successfully. However, 

sometimes just stepping back to refocus on 

the three basic questions of the model for 

improvement presented by Langley et al. (see 

“Suggested Resources,” below) can effectively 

guide QI activities. These are as follows:

• What do we want to accomplish?

• How do we know that a change will result 

in an improvement – in other words what 

measure will we use to demonstrate whether 

our improvements worked?

• What kinds of changes can we test that will 

result in an improvement?

Establishing Systems 

to Support QI

The key to sustaining QI in the clinic is 

development of an infrastructure that supports 

ongoing QI activities. The central components 

of this infrastructure include the following: 

• A QI plan with goals and a process to 

prioritize these goals

• A work plan that clearly defines steps, sets 

timeframes for completion, and identifies 

responsible parties

• An organizational framework that displays 

clear lines of accountability for QI in the 

organization

• Commitment of senior management staff to 

support the program, allocate resources, and 

celebrate its successes

• Creation of a culture that supports quality 

in the program and that values the activities 

of QI as part of the regular work of the clinic 

(see Table 4)
36 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Table 4. Tips for Promoting a 

Culture of Quality Improvement: 

Integration of Quality into the 

Regular Work of the Clinic

• Educate staff members about QI and 

provide them with the skills to participate 

in QI activities.

• Consistently articulate the values of QI in 

staff meetings.

• Display QI data and storyboards (simple 

statements and visual representations 

that describe a problem, the evaluation 

process, the proposed changes, and their 

implementation, and display the results).

• Celebrate successes.

• Provide opportunities for all staff members 

to participate in QI teams.

• Reward staff members through 

performance evaluation for their 

contributions to the QI program.

• Participate in activities with peers to discuss 

QI activities, share data and learn about 

successful strategies to improve care.

• Patient participation, to share experiential 

knowledge and inform QI program 

development

• Establishment of a formal QI committee 

to oversee quality activities, monitor the 

quality plan, and evaluate its effectiveness

The regular, ongoing work of the QI 

committee, supported by the clinic leadership, 

constitutes the backbone of the infrastructure 

that supports ongoing QI activities. The 

committee oversees the dynamic process of 

planning, implementation, and evaluation that 

involves the following: 

• Analysis of data from the QI projects

• Solicitation of feedback from participating 

staff members and from patients

• Decision-making based on the information 

from its analysis

These contribute to sustaining the QI program 

and its activities in the clinic.

Sustaining Improvements

Sustainability is probably the biggest challenge 

that clinics face in the field of QI. All too often, 

improvements do not last after initial projects 

are completed, because the structure and 

culture to support QI are not present or are 

not supported. The challenge of sustainability 

therefore is twofold: to maintain the successes 

of QI work and its clinical outcomes, and to 

maintain the systems of QI and keep the QI 

program vital. By asking questions about 

how care systems can be improved and how 

QI activities are progressing, clinicians play 

an important role in both catalyzing and 

supporting QI activities.

Appendix: Case 

Examples of Quality 

Management Initiatives

Using QI to Improve ART 

Management and Virologic 

Suppression

In one community health center, nearly 10% 

of patients on antiretroviral therapy (ART) 

were not virologically suppressed. The clinic 

had adopted a strategy of developing a specific 

ART management plan for each patient being 

treated. Review of the charts of the 45 patients 

not suppressed showed that only 40% had a 

plan in the chart. Only 20% had a plan that 

was executed. Improvement goals were set 

for each step, to increase from 40% to 90% 

for documentation of an ART management 

plan and from 20% to 75% for execution of the 

plan. Over the course of a 4-month period, 

clinicians and support staff were educated 

about the plan and decision-support tools 

were created, including an algorithm showing 

key decision points for plan development and 

execution with corresponding prompts in 

the clinic database. Visit forms were revised 

to incorporate data fields specific to the ART 

plans. Reminders also were created. All 
Quality Improvement | 37

Section 1: The HIV Clinic: 

Providing Quality Care

changes were implemented through small tests 

of change with formal remeasurement in 6 

months; this showed that 100% of patients had 

a plan in their charts and that 71% of them had 

it executed. Continued monitoring showed 

a dip in performance 4 months later to 88% 

and 60%, respectively, but with gains restored 

3 months subsequently to 100% and 65%, 

respectively. Vigilance and reaffirmation of 

the main steps have been keys to maintaining 

performance. The fields are now being added 

to the new clinic electronic medical record 

(EMR) system with automatic prompts based 

on changes in viral load values.

Another clinic focused QI efforts directly on 

improving rates of virologic suppression. Data 

on the HIV viral loads of each specific provider 

were generated to show comparative rates as 

a stimulus for improved performance on the 

part of individual providers. ART regimens 

were reviewed for their appropriateness, and 

renewed education about antiretroviral drug 

combinations and resistance monitoring was 

introduced. The clinicians reviewed their 

own patient lists each day. Patients who were 

not virologically controlled were contacted 

by phone by the clinician or a nurse. Nurses 

eventually were assigned directly to the 

primary care team to facilitate communication 

with patients and ensure that specific issues 

raised during phone conversations were 

addressed during clinic visits. Adherence 

problems were particularly common, and 

were addressed through these multiple 

contacts. Reasons for adherence lapses were 

identified, which allowed for more effective 

targeting of service interventions with specific 

patients, including substance use and mental 

health service referrals, regimen switching, 

and targeted adherence interventions. The 

individual providers improved their patients’ 

rates of virologic suppression from 45% to 

62%. Review of suppression rates also showed 

that a subset of patients remained controlled 

and did not require quarterly monitoring. A 

decrease in visit frequency was possible for this 

group, reducing overutilization of services and 

unnecessary costs.

Another federally qualified health center with 

multiple sites struggled with its rates of viral 

load suppression that ranged from 0% at one 

small clinic to 47% at another. The medical 

director was new to the clinic and undertook 

a thorough investigation of the problem with 

his team. First, they reviewed the results and 

matched them with their clinical data and 

knowledge of the patients. Based on that 

step, they sent specimens to another lab and 

found that there had been a major error in the 

processing of specimens. Once this special 

cause of their findings was corrected, their 

rates increased to a range of 50-67%. Then, the 

team undertook a more thorough investigation 

of their system and implemented a package of 

changes based on their analysis and discussions 

with their patients. Among the improvements 

the team introduced were the development 

of a group of adherence educators among 

their staff, case conferencing together with 

the patient to discuss the results and identify 

particular issues and concerns that could 

then be addressed (managed problem-solving), 

biweekly team case conferencing, home visits 

and phone calls as needed in between visits 

and preparing provider-specific data results 

to generate additional incentives for providers 

to intensify their efforts to work with their 

patients to decrease viral load. Rates have 

steadily improved up to the 70-80% range in 

the short run as the clinic team awaits ongoing 

measurement results to determine whether it 

can hold its gains and improve further. 

Using QI to Eliminate Disparities

The quality committee in another clinic 

wanted to determine whether the clinic’s 

performance was consistent across all patient 

groups and arranged to have the clinic’s patient 

data sorted by race, ethnicity, and primary 

language spoken. This revealed that data 

about race, ethnicity, and language spoken 

were not recorded in a high proportion of 
38 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

patient records. The team invited patients from 

their community advisory board to attend 

a staff meeting where a fishbone diagram 

was developed to identify potential causes 

of the poor collection rates of these patient 

data. Potential reasons were identified in all 

categories: equipment, patients, procedures, 

and staff (see Figure 3). A flow chart was 

developed to identify the sequential steps 

of data collection. A training program for 

intake staff was developed, resulting in an 

improvement in collection of these data to 85%.

Subsequent analysis showed that only 54% of 

African-American patients and 68% of Latino 

patients had suppressed HIV RNA whereas 

white patients had a suppression rate of 75%. 

A focus group with Spanish-speaking patients 

revealed that these patients were not getting 

enough information about medication and its 

side effects. The QI team decided to aim for an 

improvement in virologic suppression rates to 

75%. A number of changes were implemented 

and tested throughout the clinic including 

the addition of peer adherence counseling, 

using teach-back by nonphysician staff to 

facilitate adherence problem-solving, along 

with medication reconciliation. With these 

new interventions, virologic suppression rates 

improved to 71% for African-Americans, 

80% for Latinos, and 81% for whites. With 

ongoing QI activities, suppression rates have 

subsequently increased for all groups and the 

gaps between groups has narrowed. Ongoing 

changes aim to narrow these gaps even further.

Finally, in another clinic, analysis showed that 

major differences in viral load suppression 

were noted among patients who were stably 

housed and those who were not. To tackle 

their low rates, this agency intensified its 

relationship with their local housing agency 

and began to investigate other resources in 

their community to provide transitional 

housing services.

Suggested Resources

• Chassin and Loeb. The Ongoing 

Quality Improvement Journey: 

Next Stop, High Reliability. Heatlh 

Affairs. 2011 30, no. 4:559-568.

• Langley GJ, Nolan KM, Norman CL, et 

al. The Improvement Guide: A Practical 

Approach to Enhancing Organizational 

Performance. San Francisco: Jossey-Bass; 1996.

• McGlynn EA, Asch SM. Developing a 

clinical performance measure. Am J Prev 

Med. 1998 Apr;14(3 Suppl):14-21.

• New York State Department of Health 

AIDS Institute. HIVQUAL Group Learning 

Guide: Interactive Quality Improvement 

Exercises for HIV Healthcare Providers.

May 2002, revised 2006. Available at www.

hivguidelines.org/quality-of-care/qualityimprovement-resources.

• Quinn M, et. al. The Relationship Between 

Perceived Practice Quality and Quality 

Improvement Activities and Physician 

Practice Dissatisfaction, Professional 

Isolation and Work-Life Stress. Med Care 

2009;47: 924–928.

• Scholtes PR, Joiner BL, Streibel BJ. The Team 

Handbook (3rd Edition). Madison, WI: 

Oriel; 2003.
Quality Improvement | 39

Section 1: The HIV Clinic: 

Providing Quality Care

Websites 

HIV-Specific

• National Quality Center (NQC)

(www.nationalqualitycenter.org) Provides 

no-cost, state-of-the-art technical assistance 

to all Ryan White Program-funded 

grantees to improve the quality of HIV 

care nationwide. Website includes training 

and technical assistance materials

• The HRSA HIV/AIDS Program: Quality 

of Care (hab.hrsa.gov/deliverhivaidscare/

qualitycare.html)

• HIV Clinical Resources (HIVGuidelines.

org) Quality of Care Section (NY AIDS 

Institute) (www.hivguidelines.org/quality-ofcare)

• Health Care Improvement Project: 

HIV/AIDS (USAID) (www.hciproject.org/

improvement_topics/HIVAIDS) 

General QI Websites

• Institute for Healthcare Improvement 

(www.ihi.org/Pages/default.aspx)

• International Society for Quality in Health 

Care (www.isqua.org)

• American Society for Quality (ASQ)

(asq.org/index.aspx)

• My Tapestry! (www.mytapestry.com/qlinks.

html) (See the “Quality Links” page for 

extensive resource listing) 

• Agency for Healthcare Research and 

Quality (www.ahrq.gov)

• National Association for Healthcare 

Quality (www.nahq.org)

• Medical University of South Carolina 

(academicdepartments.musc.edu/fm_

ruralclerkship/curriculum/cqi.htm)

• Health Quality Ontario (www.hqontario.ca/

quality-improvement)

• The Health Foundation: Quality 

Improvement Made Simple (www.health.org.

uk/publications/quality-improvement-madesimple)

• USAID Applying Science to Strengthen 

and Improve Systems (ASSIST) Project 

(www.usaidassist.org)

• 1000 Lives Plus QI Guide 

(www.1000livesplus.wales.nhs.uk/qi-guide)

• NHS Scotland Quality Improvement Hub 

(www.qihub.scot.nhs.uk/knowledge-centre.

aspx)
40 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

References

• Institute for Healthcare Improvement. HIV/

AIDS Bureau Collaborations: Improving 

Care for People Living with HIV/AIDS 

Disease. Boston: Institute for Healthcare 

Improvement; 2002.

• Institute of Medicine. Medicare: A 

Strategy for Quality Assurance, Volume 1.

Washington: National Academies Press; 

1990.

• Institute of Medicine. Crossing the Quality 

Chasm. Washington: National Academies 

Press; 2001.

• Institute of Medicine. Measuring 

What Matters: Allocation, Planning, 

and Quality Assessment for the Ryan 

White CARE Act. Washington: 

National Academies Press; 2004.

• New York State Department of Health 

AIDS Institute. HIVQUAL Group Learning 

Guide: Interactive Quality Improvement 

Exercises for HIV Healthcare Providers.

May 2002, revised 2006. Available at www.

hivguidelines.org/quality-of-care. Accessed 

December 1, 2013.

• New York State Department of Health AIDS 

Institute. HIVQUAL Workbook. September 

2006. Available at www.hivguidelines.org/

quality-of-care. Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services, Health Resources and Services 

Administration, HIV/AIDS Bureau. Case 

Studies in QI in 9 Community Health 

Centers. Rockville, MD: U.S. Department 

of Health and Human Services; year of 

publication unknown.
HRSA HIV/AIDS Bureau Performance Measures | 41

Section 1: The HIV Clinic: 

Providing Quality Care

Health Resources and Services 

Administration HIV/AIDS Bureau 

Performance Measures

Overview

The HIV/AIDS Bureau has revised its performance measure portfolio. The updated portfolio is 

more focused on critical areas of HIV care and treatment, and, as of November 6, 2013, it contains 

fewer performance measures. The revisions include:

• Identifying core performance measures that 

are most critical to the care and treatment of 

people living with HIV

• Combining measures to address people of all 

ages living with HIV

• Aligning measures with U.S. Department 

of Health and Human Services (HHS) 

priorities, guidelines, and initiatives

• Promoting relevant performance measures 

used in other federal programs

• Archiving performance measures

Unlike the previous version wherein the 

portfolio included three groups of core 

measures intended for various levels of 

programs’ ability to implement, the updated 

portfolio features a set of Core Clinical 

Performance Measures and consolidates 

several of the previous clinical measures into 

four categories: All-Age Clinical Performance 

Measures, Adult and Adolescent Clinical 

Performance Measures, HIV-Exposed 

Children, and HIV-Infected Children. The 

Core performance measures emphasize the 

essential aspects of HIV care and treatment 

and align with the milestones along the 

HIV care continuum (hab.hrsa.gov/data/

reports/continuumofcare/index.html).

The Medical Case Management Performance 

Measures target all clients, and focus on 

two key issues: care plans and medical 

visits. Medical case management programs 

are encouraged to utilize the Core clinical 

performance measures as appropriate.

The Oral Health Performance Measures

target all clients. The measures are 

intended for use by programs providing 

direct oral health services.

The AIDS Drug Assistance Program (ADAP)

Measures are intended for use by the ADAP. 

Four measures are included and target all 

clients, regardless of age.

The Systems-Level Performance Measures

address aspects of access and entry to care and 

may be utilized by any system or network.

Two sets of measures not reproduced here 

(HIV-Exposed Children and HIV-Infected 

Children) address a range of clinical, social, and 

system issues for programs that serve pediatric 

clients. In addition, the archived performance 

measures are available for reference on 

the HRSA HAB website at hab.hrsa.gov/

deliverhivaidscare/habperformmeasures.html.

The HIV/AIDS Bureau encourages all 

organizations providing HIV services to use 

the Bureau’s revised performance measures, 

including the Core performance measures, and 

select the appropriate measures for their own 

portfolio. Measure selection is based on the 

services that are provided, prominent clinical 

issues, and patient demographics. The HIV/

AIDS Bureau does not promote using every 

performance measure available because the 

activities needed to implement performance 

measurement (e.g., collecting, analyzing, and 
42 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

reviewing data) can be costly. Individual programs are recommended to consider having some 

measures that are collected and analyzed more frequently (e.g., every 2 months or quarterly) and 

others that are collected and reviewed less frequently (e.g., every 6 months or annually). Grantees are 

not required to use all performance measures. Given the emphasis on using performance measures 

to improve patient health, grantees may trend performance measures over time and analyze 

performance measures for disparities in care.

Core Clinical Performance Measures

Measure Definition

HIV Viral Load 

Suppression

Percentage of patients, regardless of age, with a diagnosis of HIV with an HIV viral 

load of <200 copies/mL at last HIV viral load test during the measurement year

Prescription of HIV 

Antiretroviral Therapy

Percentage of patients, regardless of age, with a diagnosis of HIV who were 

prescribed antiretroviral therapy for the treatment of HIV infection during the 

measurement year

HIV Medical Visit 

Frequency

Percentage of patients, regardless of age, with a diagnosis of HIV who had at least 

one medical visit in each 6-month period of the 24-month measurement period 

with a minimum of 60 days between medical visits

Gap in HIV Medical Visits Percentage of patients, regardless of age, with a diagnosis of HIV who did not 

have a medical visit in the last 6 months of the measurement year

Pneumocystis jiroveci 

Pneumonia (PCP) 

Prophylaxis

Percentage of patients, aged 6 weeks or older with a diagnosis of HIV/AIDS, who 

were prescribed Pneumocystis jiroveci pneumonia (PCP) prophylaxis

All-Age Clinical Performance Measures

Measure Definition

CD4 Cell Count Percentage of patients, aged 6 months and older with a diagnosis of HIV/

AIDS, with at least two CD4 cell counts or percentages performed during the 

measurement year at least 3 months apart

HIV Drug Resistance 

Testing Before Initiation 

of Therapy

Percentage of patients, regardless of age, with a diagnosis of HIV who had an HIV 

drug resistance test performed before initiation of HIV antiretroviral therapy if 

therapy started during the measurement year

Influenza Immunization Percentage of patients, aged 6 months and older seen for a visit between 

October 1 and March 31, who received an influenza immunization OR who 

reported previous receipt of an influenza immunization 

Lipid Screening Percentage of patients, regardless of age, with a diagnosis of HIV who were 

prescribed HIV antiretroviral therapy and who had a fasting lipid panel during the 

measurement year

Tuberculosis Screening Percentage of patients aged 3 months and older with a diagnosis of HIV/AIDS, 

for whom there was documentation that a tuberculosis screening test was 

performed and results interpreted (for tuberculin skin tests) at least once since 

the diagnosis of HIV infection

Viral Load Monitoring Percentage of patients, regardless of age, with a diagnosis of HIV with a viral load 

test performed at least every 6 months during the measurement year
HRSA HIV/AIDS Bureau Performance Measures | 43

Section 1: The HIV Clinic: 

Providing Quality Care

Adult and Adolescent Clinical Performance Measures

Measure Definition

Cervical Cancer 

Screening

Percentage of female patients with a diagnosis of HIV who have a Pap screening 

in the measurement year

Chlamydia Screening Percentage of patients with a diagnosis of HIV at risk of sexually transmitted 

infections who had a test for chlamydia within the measurement year

Gonorrhea Screening Percentage of patients with a diagnosis of HIV at risk of sexually transmitted 

infections who had a test for gonorrhea within the measurement year

Hepatitis B Screening Percentage of patients, regardless of age, for whom hepatitis B screening was 

performed at least once since the diagnosis of HIV/AIDS or for whom there is 

documented infection or immunity

Hepatitis B Vaccination Percentage of patients with a diagnosis of HIV who completed the vaccination 

series for hepatitis B

Hepatitis C Screening Percentage of patients for whom hepatitis C screening was performed at least 

once since the diagnosis of HIV

HIV Risk Counseling Percentage of patients with a diagnosis of HIV who received HIV risk counseling 

in the measurement year

Oral Exam Percentage of patients with a diagnosis of HIV who received an oral exam by a 

dentist at least once during the measurement year

Pneumococcal 

Vaccination

Percentage of patients with a diagnosis of HIV who ever received pneumococcal 

vaccine

Preventive Care and 

Screening: Screening for 

Clinical Depression and 

Follow-Up Plan

Percentage of patients aged 12 years and older screened for clinical depression 

on the date of the encounter using an age-appropriate standardized depression 

screening tool AND, if positive, a follow-up plan is documented on the date of the 

positive screen

Preventive Care and 

Screening: Tobacco 

Use – Screening and 

Cessation Intervention

Percentage of patients aged 18 years and older who were screened for tobacco 

use one or more times within 24 months AND who received cessation counseling 

intervention if identified as a tobacco user

Substance Abuse 

Screening

Percentage of new patients with a diagnosis of HIV who have been screened for 

substance use (alcohol and drugs) in the measurement year

Syphilis Screening Percentage of adult patients with a diagnosis of HIV who had a test for syphilis 

performed within the measurement year

Medical Case Management Performance Measures

Measure Definition

Care Plan Percentage of medical case management patients, regardless of age, with a 

diagnosis of HIV who had a medical case management care plan developed and/or 

updated two or more times in the measurement year

Gap in HIV Medical Visits Percentage of medical case management patients, regardless of age, with a 

diagnosis of HIV who did not have a medical visit in the last 6 months of the 

measurement year (that is documented in the medical case management record)

HIV Medical Visit 

Frequency

Percentage of medical case management patients, regardless of age, with a 

diagnosis of HIV who had at least one medical visit in each 6-month period of the 

24-month measurement period with a minimum of 60 days between medical visits
44 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Oral Health Services Performance Measures

Measure Definition

Dental and Medical 

History 

Percentage of HIV-infected oral health patients who had a dental and medical 

health history (initial or updated) at least once in the measurement year

Dental Treatment Plan Percentage of HIV-infected oral health patients who had a dental treatment plan 

developed and/or updated at least once in the measurement year

Oral Health Education Percentage of HIV-infected oral health patients who received oral health education 

at least once in the measurement year

Periodontal Screening 

or Examination

Percentage of HIV-infected oral health patients who had a periodontal screen or 

examination at least once in the measurement year

Phase 1 Treatment 

Plan Completion

Percentage of HIV-infected oral health patients with a Phase 1 treatment plan that 

is completed within 12 months

AIDS Drug Assistance Program Performance Measures

Measure Definition

Application 

Determination 

Percent of ADAP applications approved or denied for new ADAP enrollment within 

14 days (2 weeks) of ADAP receiving a complete application in the measurement year

Eligibility 

Recertification 

Percentage of ADAP enrollees who are reviewed for continued ADAP eligibility two 

or more times in the measurement year

Formulary Percentage of new antiretroviral classes that are included in the ADAP formulary 

within 90 days of the date of inclusion of new antiretroviral classes in the HHS 

Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents

during the measurement year

Inappropriate 

Antiretroviral Regimen 

Components Resolved 

by ADAP 

Percent of identified inappropriate antiretroviral regimen components 

prescriptions that are resolved by the ADAP program during the measurement year

Systems-Level Performance Measures

Indicator Definition

Waiting Time for Initial 

Access to Outpatient/

Ambulatory Medical 

Care

Percentage of Ryan White Program-funded outpatient/ambulatory care 

organizations in the system/network with a waiting time of 15 or fewer business 

days for a Ryan White Program-eligible patient to receive an appointment to enroll 

in outpatient/ambulatory medical care

HIV Test Results for 

PLWHA

Percentage of individuals who test positive for HIV who are given their HIVantibody test results in the measurement year

HIV Positivity Percentage of HIV positive tests in the measurement year

Late HIV Diagnosis Percentage of patients with a diagnosis of Stage 3 HIV (AIDS) within 3 months of 

diagnosis of HIV

Linkage to HIV 

Medical Care

Percentage of patients who attended a routine HIV medical care visit within 3 

months of HIV diagnosis

Housing Status Percentage of patients with HIV diagnosis who were homeless or unstably housed 

in the 12-month measurement period

References

• U.S. Department of Health and Human Services HIV/AIDS Program. HAB HIV Performance Measures. 

Available at hab.hrsa.gov/deliverhivaidscare/habperformmeasures.html. Accessed December 1, 2013.
HIV Care in Correctional Settings | 45

Section 1: The HIV Clinic: 

Providing Quality Care

HIV Care in Correctional Settings

Minda Dwyer, ANP-C; Douglas G. Fish, MD; Abigail V. Gallucci, BS; and Sarah J. Walker, MS

Background

Caring for HIV-infected patients who are incarcerated is a complex and challenging task. For many 

of these patients, the prison health service provides their first opportunity for access to consistent 

health care. This chapter will discuss some of the issues relevant to the HIV-infected population in 

correctional settings.

Jail vs. Prison Settings

It is important to note the distinction between 

“jail” and “prison” custodial settings. These 

terms are often used interchangeably, but 

doing so can create confusion for health care 

providers, as the services that an inmate 

receives while incarcerated may differ greatly 

according to the type of facility (NYSDOH, 

2008).

Jails are locally operated, or managed, 

institutions that detain individuals who 

typically are serving short sentences of 1 year 

or less. They also hold individuals who are 

awaiting arraignment, trial, or sentencing, 

or those who have violated terms of their 

parole (Harrison and Beck, 2006). Because 

inmates who are detained in jail settings have 

shorter confinement terms, providers often 

face time constraints in establishing longerterm treatment plans for chronic conditions 

such as HIV/AIDS, and for substance use and 

mental health problems. Opportunities for 

inmate education also may be more limited. 

In addition, because jail inmates often are 

released within days, weeks, or months after 

initial confinement, establishing continuity of 

health care may be challenging for providers 

and administrators (Okie, 2007).

Prisons, in contrast, are operated by state 

governments or the Federal Bureau of 

Prisons. Prisons generally detain people 

who have been convicted of state or federal 

felonies and are sentenced to terms of longer 

than 1 year (Harrison and Beck, 2006). The 

nature of a person’s crime, namely a state 

or federal offense, will dictate the type of 

prison in which he or she will be detained. 

The length of sentences for inmates in state 

or federal custody is longer than those for 

persons serving time in jail, and prison 

inmates typically have a firm release date in 

advance. As a result, HIV-infected inmates 

released from prison may be more likely to 

have treatment and discharge plans in place 

(NYSDOH, 2008).

Note that these characteristics may differ from 

prison to prison and jail to jail.

Epidemiology

Inmates continue to be disproportionately 

affected by the epidemic, with the estimated 

overall rate of AIDS among prison inmates 

at more than 2.5 times the rate in the United 

States general population. In 2006, there were 

21,980 HIV-infected inmates in federal or 

state prisons, according to a report from the 

Bureau of Justice Statistics, and there are many 

more in jails. With the advent of effective 

combination antiretroviral therapy (ART), 

AIDS-related mortality as a percent of total 

deaths in state prisons decreased significantly 

between 1995 and 2006, from 34.2% to 4.6% 

(Maruschak, 2006).

Inmates who have drug- or sex-related illegal 

behaviors that lead to incarceration often are 

at high risk of becoming infected with HIV, 
46 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

hepatitis C virus (HCV), and other pathogens 

through these behaviors. Their risk factors 

may include unsafe substance use behaviors, 

such as sharing syringes and other injection 

equipment, and high-risk sexual practices, 

such as having multiple sex partners or 

unprotected sex. Many inmates also may 

have conditions that increase the risk of HIV 

transmission or acquisition, such as untreated 

sexually transmitted diseases (STDs).

The prevalences of chronic viral hepatitis 

and tuberculosis are much higher among 

incarcerated persons than among the general 

public. Depending on the prison system, 13% 

to 54% of inmates are infected with HCV 

(Cassidy, 2003). The incidence is 10 times 

higher among inmates than among noninmates and is 33% higher among women 

than among men (Nerenberg et al., 2002). The 

Centers for Disease Control and Prevention 

(CDC) recommends that all incoming inmates 

be screened for HCV, and those who are 

infected should be evaluated for liver damage 

and the need for treatment (Cassidy, 2003). 

Chronic hepatitis B virus (HBV) infection 

and tuberculosis also are substantially more 

common among the incarcerated population 

than among the general public. The presence 

of any of these conditions should prompt HIV 

testing (Nicodemus and Paris, 2002).

Incarcerated Women

Women account for almost 7% of the prison 

population in the United States (West and 

Sobol, 2009). The HIV epidemic in the United 

States increasingly affects women of color, 

and this trend is reflected in HIV rates among 

the incarcerated. In terms of total numbers, 

there are more males than females with HIV/

AIDS in state and federal prisons nationally 

(19,809 and 2,135, respectively). However, the 

percentage of female inmates with known HIV 

infection in these settings is higher than that 

for incarcerated males (2.4% and 1.6 percent, 

respectively) (Maruschak, 2006).

In many cases, incarcerated women are 

low-income and have limited education and 

sporadic employment histories. Compared 

with men, they are less likely to be incarcerated 

for a violent crime, and more likely to be 

incarcerated for a drug or property offense. 

Women’s property crimes often are the 

result of poverty and substance-use histories 

(National Institute of Corrections, 2003). 

Numerous studies have shown that the 

behaviors that lead to incarceration also put 

women at increased risk of HIV infection. 

Risk factors that are present in abundance 

among female inmates include the following 

(Hammett and Drachman-Jones, 2006):

• History of childhood sexual abuse and 

neglect

• History of sex work, with increased 

frequency of forced, unprotected sex

• High rates of STDs

• High rates of mental illness

• History of injection drug use (IDU) or sex 

partners with IDU history

• Poverty

Among all women entering a correctional 

facility, 10% are pregnant (De Groot and Cu 

Uvin, 2005). These women should be offered 

HIV testing, and HIV-infected pregnant 

women should be offered combination 

ART immediately to prevent perinatal HIV 

transmission. Many incarcerated women 

will receive their first gynecologic care in 

prison. Because the incidence of cervical 

cancer is higher among women with HIV, 

referrals for colposcopy should be made for 

any HIV-infected woman with an abnormal 

Papanicolaou test result.

Testing and Prevention

The correctional facility is an ideal location 

for identifying individuals already infected 

with HIV, HCV, or HBV, and for education 
HIV Care in Correctional Settings | 47

Section 1: The HIV Clinic: 

Providing Quality Care

interventions that are geared to prevent 

infection among those at highest risk of these 

acquiring diseases. For many adults, the 

prison or jail setting is a rare potential point of 

contact with the health care system, making 

it an important avenue for HIV testing and 

linkage to care. It also may be an effective 

setting in which to initiate and maintain 

individuals on ART.

Inmates commonly are hesitant to be tested 

for HIV because they fear a positive diagnosis 

and because of the potential stigma involved. 

They often lack accurate information about 

HIV, including awareness of behaviors that 

may have put them at risk and knowledge 

of means for protecting themselves from 

becoming infected. Health care providers in 

correctional settings are in a key position to 

evaluate inmates for HIV risk factors, to offer 

HIV testing, and to educate and counsel this 

high-risk group about HIV.

HIV testing policies in correctional facilities 

vary from state to state and among local, state, 

and federal penal institutions. Depending 

on the setting, policies may require testing 

of inmates upon entry, upon release, or both, 

but as of 2010 more than 50% of state prison 

systems did not require HIV testing at any 

point. Some prisons may do HIV testing based 

on clinical indication or risk exposure during 

incarceration, and this may be voluntary or 

mandatory. Most prison systems do provide 

HIV testing for inmates who request it. See 

Table 1 for an overview of the circumstances 

under which inmates in state prisons were 

tested for HIV in 2006 (Maruschak, 2006).

In high-risk settings such as correctional 

facilities, routine, voluntary HIV testing 

has been shown to be cost-effective and 

clinically advantageous (Paltiel et al., 2005). 

The CDC supports universal opt-out HIV 

screening in prisons and jails and has 

produced the HIV Testing Implementation 

Guidance for Correctional Settings (www.cdc.

gov/correctional health/default.htm). This 

document serves as a guide for individual 

institutions in determining and establishing 

the most appropriate testing strategy for their 

settings, presents the components of such a 

testing program, and explains obstacles that 

may be encountered in the implementation 

process. It also provides information regarding 

the following:

• Background statistics on HIV in 

correctional facilities

• Inmate privacy and confidentiality

• Opt-out HIV screening in correctional 

medical clinics

• HIV testing procedures

• HIV case reporting

Testing inmates for HIV prior to their release 

is a critical aspect not only of individuals’ 

own health care needs but also of preventing 

transmission of HIV to others. Knowledge 

of their HIV status affects people’s HIV risk 

behaviors: Studies have shown that, after 

learning they are infected with HIV, many 

persons take measures to reduce the risk of 

transmitting HIV to others.

Risk-Reduction Education

Given the high HIV seroprevalence among 

inmates, the reentry of inmates into the 

community presents a danger of spreading 

HIV and other infectious diseases, and it is 

a public health concern. Thus, inmates need 

adequate HIV prevention counseling before 

release, both to protect themselves and to 

decrease the likelihood of infecting others in 

their communities with HIV (Gaiter and Doll, 

1996). The World Health Organization (WHO) 

has stated: “All inmates and correctional staff 

and officers should be provided with education 

concerning transmission, prevention, 

treatment, and management of HIV infection. 

For inmates, this information should be 

provided at intake and updated regularly 

thereafter.”
48 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Risk-reduction counseling addresses specific 

ways the inmate can reduce the risk of 

becoming infected with HIV. If an inmate is 

already HIV infected, the goal of counseling 

is to reduce the risk of infecting others or 

becoming infected with a drug-resistant strain 

of HIV.

Education should include information about 

the efficacy of ART in decreasing risk of HIV 

transmission. In addition, it should focus on 

the use of latex barriers with all sexual activity. 

Condoms and dental dams are not available 

in most jails and prisons; nonetheless, the 

inmate should receive education regarding 

their proper use. The state prisons systems 

that provide condoms to inmates are those 

of Vermont and Mississippi. The larger 

metropolitan jails in New York City, such as 

Rikers Island, as well as those in Los Angeles, 

San Francisco, Philadelphia, and Washington, 

also provide condoms. Within the systems that 

allow condoms, inmates’ ability to obtain them 

may be restricted (e.g., limited to one per week 

or available only via medical prescriptions or 

dispensing machines) (Sylla, 2007); see chapter 

Preventing HIV Transmission/Prevention with 

Positives.

No correctional system in the United States 

provides clean injection needles as a part of a 

prevention program (Sylla, 2007). However, 

inmates with a history of IDU should be 

educated about the risks of sharing needles 

and injection equipment, specifically the high 

risk of transmitting or acquiring HIV, HCV, 

and HBV. Inmates also should be counseled 

about the risks of sharing needles and other 

“sharps,” such as those used for tattooing or 

body piercing. Substance abuse treatment 

should be provided when appropriate. 

Recovery from addiction often is a chronic 

process and relapses are common. In addition 

to substance abuse treatment, risk-reduction 

strategies should include planning for support 

after release from the correctional setting. 

For example, prior to release, inmates should 

be provided with information about syringe 

exchange or clean needle access programs 

in their communities. These programs have 

proved to be quite effective in decreasing the 

rate of parenteral HIV transmission (CDC, 

1999).

Furthermore, overdose prevention should be 

discussed with inmates leaving correctional 

systems. Using heroin after a period of 

abstinence, such as during incarceration, 

hospitalization, or drug treatment, is a major 

risk factor for overdose. Former inmates 

are at highest risk of overdose within the 

first 2 weeks after release (NYSDOH, 2008). 

Overdose risk is heightened when someone 

has a significant medical condition, such 

as HIV infection (Catania, 2007). The 

literature documents an increased number of 

correctional systems that consider including 

naloxone (Narcan) prescriptions in prerelease 

planning for inmates with a history of opiate 

addiction (Wakeman et al., 2009). Naloxone 

is a prescription medicine that reverses an 

overdose by blocking heroin (or other opioids) 

in the brain for 30-90 minutes (NYSDOH, 

2008).

Antiretroviral Therapy in 

Correctional Facilities

In correctional facilities, as in any setting, a 

consideration of HIV treatment must begin 

with educating the patient about the benefits 

and risks of treatment and the need to fully 

adhere to the entire regimen, and with an 

assessment of the patient’s motivation to take 

ART (see chapter Antiretroviral Therapy). 

Correctional facilities have two main 

methodologies for dispensing medications to 

those who are on ART. Each has advantages 

and disadvantages that can impact treatment 

adherence. These are directly observed therapy 

(DOT) and keep-on-person (KOP).
HIV Care in Correctional Settings | 49

Section 1: The HIV Clinic: 

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Directly Observed Therapy

DOT is the system in which the inmate 

goes to the medical unit or pharmacy for all 

medication doses; dosing is observed by staff 

members. This system offers the advantage of 

more frequent interaction between the patient 

and the health care team, allowing for earlier 

identification of side effects and other issues. 

In general, patients have better medication 

adherence in this system, resulting in better 

control of HIV. For some inmates, however, the 

need for frequent visits to the medical unit or 

pharmacy may be a barrier to receiving proper 

treatment, particularly if they are housed at 

a distance from the medical unit. Another 

disadvantage of DOT is the potential loss of 

confidentiality, as many inmates feel that the 

frequency of dosing and the large number of 

pills they may take will reveal clues that they 

are HIV infected. In addition, this system puts 

inmates in a passive role in terms of medication 

treatment and does not foster self-sufficiency.

Keep-on-Person

KOP is the system that allows inmates to keep 

their medications in their cells and take them 

independently. Monthly supplies are obtained 

at the medical unit or pharmacy. This system 

offers greater privacy and confidentiality 

regarding HIV status. It also allows inmates 

to develop self-sufficiency in managing 

medications, which may facilitate improved 

adherence upon release. However, as the KOP 

system involves less interaction with medical 

staff, problems with adherence can be more 

difficult to identify (Ruby, 2000). Problems 

with refills also can occur. For example, 

inmates usually must initiate the process for 

obtaining a refill. They may be told that a refill 

request was made too early or too late, which 

can result in delays in dispensing medications, 

and ultimately, treatment interruptions. In 

addition, many facilities do not have on-site 

pharmacies, but rely on local pharmacies, or a 

regional or central pharmacy in the state; this 

may further delay refills (NYSDOH, 2008).

In a study comparing DOT in HIV-infected 

inmates with KOP in nonincarcerated HIVInfected patients receiving ART as part of 

a clinical trial, a higher percentage of DOT 

patients achieved undetectable viral loads 

compared with the KOP patients (85% vs. 50%) 

over a 48-week period (Fischl, 2001).

Adherence

Adherence is one of the most important 

factors in determining the success or failure 

of ART. For the HIV-infected inmate 

starting ART, a number of issues can affect 

medication adherence. These include patientrelated factors, factors related to systems of 

care (including the medication dispensing 

systems described above), and medicationrelated factors. The following are suggestions 

for supporting adherence to ART. (Also see 

chapter Adherence.)

Patient-Related Factors

• Correct misconceptions about HIV and 

ART that are common among inmates and 

could affect adherence adversely. Inmates 

should be educated about the disease process 

and the role of the medications, along with 

the benefits and risks of taking ART.

• Use teaching tools that are appropriate 

in terms of language and reading level. 

Illiteracy and low-level reading ability are 

common among inmates. Diagrams and 

videos may be more effective than readingintensive material in some cases. Basic HIV 

education prior to initiation of ART should 

include the following topics: 

• How the medications work

• Potential benefits in terms of personal 

health and reducing transmission risk

• Consequences of nonadherence
50 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

• Names and dosages of all medications

• Potential side effects and strategies for 

managing them

• Encourage participation in peer support 

groups. These can be effective ways to foster 

self-esteem, empower inmates to come to 

terms with a positive diagnosis, allay fears 

and correct misconceptions about HIV 

disease, and aid adherence. Upon release, 

telephone hotlines may be available to 

provide follow-up support and linkages to 

community services. To the extent possible, 

family and friends should be included in the 

education process.

• Provide alcohol and substance abuse 

treatment before, or while, initiating ART. 

Without appropriate treatment during 

incarceration, linkages to supports, and 

follow-up treatment upon discharge, 

inmates are more likely to resume highrisk behaviors that may interfere with 

adherence to ART. In 2004, nearly one third 

of inmates in state facilities and one fourth 

of inmates in the federal system committed 

their offenses under the influence of drugs 

(Mumola and Karberg, 2006).

• Use mental health consultation to identify 

inmates with psychiatric needs. Treatment 

for underlying mental health disorders 

should precede or take place concurrently 

with the initiation of ART to ensure 

successful adherence. Depression and other 

psychiatric illnesses are more prevalent 

among inmates than among the general 

population (James and Glaze, 2006).

Factors Related to 

Systems of Care

• Educate the facility’s security staff about the 

importance of timely medication dosing, 

and communicate with other facilities in 

advance of a transfer; this can eliminate or 

reduce the frequency of missed doses.

• Schedule frequent follow-up medical visits in 

the early weeks after ART is initiated; these 

can make the difference in whether or not 

patients “stay the course.”

• Consult with an HIV specialist, if possible. 

If a facility’s medical provider lacks 

experience in treating patients with HIV, 

the results may be undertreatment of side 

effects or errors in prescribing medications. 

Because caring for HIV-infected patients is 

complicated, HIV specialists can provide 

assurance that patients are receiving proper 

care. Of particular concern are patients 

whose current ART regimens are failing, 

those who are declining clinically, and those 

who are coinfected with other diseases such 

as tuberculosis, HCV, and HBV.

Medication-Related Factors

• Aggressively monitor and treat side effects. 

The most common barrier to proper 

adherence to ART is side effects from the 

medications. Inmates should be educated 

in advance about potential adverse events 

and urged to observe and report them. 

In the first weeks after starting a new 

ART regimen, patients should be assessed 

frequently for side effects. For treating 

gastrointestinal toxicities, antiemetics and 

antidiarrheals should be available on an 

as-needed basis. As with all patients on ART, 

inmates should have appropriate laboratory 

monitoring.

• Be aware of food requirements. Various food 

requirements must be considered carefully 

when administering ART. That can be 

especially challenging in the correctional 

environment, particularly in facilities that 

do not allow inmates to self-administer 

medications. Make arrangements with 

prison authorities to provide food when 

inmates are taking medications that require 

administration with food.

• Avoid complex regimens and regimens 
HIV Care in Correctional Settings | 51

Section 1: The HIV Clinic: 

Providing Quality Care

with large pill burdens, if possible. Simple 

regimens with fewer pills appear to help 

improve adherence.

• Avoid drug-drug interactions. Some 

antiretroviral medications have clinically 

significant interactions with other drugs 

(e.g., methadone, oral contraceptives, 

cardiac medications, antacids). These 

interactions may cause failure of either the 

antiretroviral drug or the other medication, 

or they may cause additional toxicity. 

Consult an HIV specialist or pharmacist for 

information on drug interactions.

• Question patients about medication 

adherence at each appointment.

• ART regimens need to fit into each patient’s 

schedule and lifestyle. This becomes a 

bigger issue when an inmate is close to 

release. Education about HIV management, 

including ART adherence, should begin well 

before the inmate is discharged back to the 

community.

Transition to Community Care

It is estimated that 630,000 individuals are 

released from jails and prisons in the United 

States each year (Bonczar, 2003; Travis, 

2005), and many of these individuals are HIV 

infected. Many will have difficulty managing 

even the most basic elements for successful 

reintegration into their communities. Inmates 

living with HIV face many challenges when 

reentering the community, such as finding 

stable housing, employment, adequate 

medication supply, follow-up medical care, 

and psychiatric and substance use treatment 

services (Hammett et al., 1997).

Ideally, the discharge process at the 

correctional facility will maximize the 

likelihood that the person being released will 

have continuous medical care. At the time of 

discharge from the correctional facility, all 

HIV-infected inmates should have a discharge 

plan that addresses the following:

• Housing

• Health insurance

• 30-day supply of HIV medications

• Follow-up appointments for medical care 

and, if necessary, psychiatric and substance 

abuse care

As discussed, inmates in prisons generally 

serve longer sentences than do those 

incarcerated in jails, and they have a release 

date that is known in advance. Thus, HIVinfected inmates in prisons may be more likely 

than HIV-infected inmates in jails to have 

treatment and discharge plans in place before 

their release. However, because the extent of 

discharge planning resources varies among 

correctional systems of care, it is important for 

care providers to discuss the scope of services 

their clients received while incarcerated to 

learn of any service gaps upon reentry to the 

community (NYSDOH, 2008).

The need to find housing often is the greatest 

challenge for an HIV-infected inmate leaving 

a correctional facility. In many correctional 

systems, inmates must document a physical 

address at which they intend to reside in 

order to be released. However, problems with 

housing availability, stability, and location can 

create significant stressors for an HIV-infected 

person being released and can compromise 

the likelihood that he or she will access HIV 

health care and adhere to an HIV medication 

regimen (NYSDOH, 2008).

Medication Continuity Issues

HIV-infected individuals leaving correctional 

settings have a variety of experiences 

with ARV medication continuity. A short 

confinement period, for example, can prevent 

the development of a solid transition plan. 

Jail inmates may be released without their 

medications and have no choice but to call 

or walk into community health centers or 

clinics for their medications and ongoing 
52 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

care. Being released from jail after business 

hours, such as on a Friday night, can result 

in treatment interruptions over the weekend 

(NYSDOH, 2008). Depending on the state 

system, HIV-infected inmates leaving prison 

are more likely than jail releasees to have a 

medication supply in hand when they reenter 

the community. For example, in the New York 

State Department of Correctional Services, 

inmates will leave prison with a 30-day supply 

of HIV medications as well as a prescription 

for another 30-day supply (NYSDOH, 2008).

For some individuals, interruptions in 

treatment occur during their time in jail or 

prison. For example, many inmates choose 

not to disclose their HIV infection while they 

are incarcerated. Particularly if the sentence 

is short, an inmate may feel it better not 

to mention HIV status and instead plan to 

resume taking medications upon release. Such 

treatment interruptions can result in adverse 

health outcomes (NYSDOH, 2008).

It is important that clinic staff and 

community-based organizations develop the 

capacity to work with clients in real time as 

they present for care in order to help them 

maintain continuity with their medications.

Strategies for Supporting 

Inmates upon Release

• A clear way to support clients is to intervene 

immediately and directly upon their release, 

such as by meeting them as they step off a 

bus or exit a facility.

• Engage clients by: 

• Hearing their stories; listening to 

concerns, wishes, history, perceptions, 

feelings, and so forth

• Asking open-ended questions, affirming 

strengths, listening reflectively, and 

summarizing discussions and plans

• Understanding their backgrounds, goals, 

and motivations (understand “where they 

are coming from”)

• Avoiding getting caught up in issues about 

the crimes they committed

• Identifying perceived needs by asking how 

services can be beneficial to them

• Acting honestly by providing a full 

disclosure of one’s role as a provider (e.g., 

what you can or cannot do)

• Provide material assistance by giving clients 

something tangible such as a meal ticket, 

condoms, bleach kit, or hygiene kit.

• Provide information and referrals to shortterm and survival services for clients to help 

improve their immediate situation.

• If possible, accompany clients to support 

them in obtaining short-term and survival 

services such as health care, food, shelter, 

and clothing.

• Respond to emergency situations.

• Support clients in meeting parole 

or probation requirements to avoid 

reincarceration. Based on their individual 

histories, anticipate circumstances that may 

result in them breaking parole. For example, 

if a client confides that he or she has anxiety 

regarding meeting the parole officer, initiate 

and practice role plays to better prepare the 

client for this encounter.

• Be culturally competent.

• Link to services (e.g., medical care, mental 

health, substance use, domestic violence).

• Diversify clinic staffing, and use a 

multidisciplinary approach, including peer 

support.

• Think outside the box! (NYSDOH, 2008)

A number of HIV education resources for 

inmates and correctional health care providers 

are cited on the Albany Medical College 

website at www.amc.edu/Patient/services/HIV/

index.cfm (go to the section on correctional 

education).
HIV Care in Correctional Settings | 53

Section 1: The HIV Clinic: 

Providing Quality Care

Table 1. HIV Testing in Prisons: Circumstances Under Which Prison 

Inmates Were Tested for HIV (by Jurisdiction)

Jurisdiction

All Inmates

EnteringRandomHigh-riskInmate requestCourt orderClinical indicationInvolvement in incidentOther

In 

Custody

Upon 

Release

Federal X X X X X

Northeast

Connecticut X X X X X

Maine X X X

Massachusetts X X

New Hampshire X X X

New Jersey X X X X

New York X X X X X X

Pennsylvania X X X X

Rhode Island X X X X X

Vermont X X X

Midwest

Illinois X X X X X X

Indiana X X X X X X

Iowa X X X X X X

Kansas X X X X X X

Michigan X X X X

Minnesota X X X X X

Missouri X X X X X X X

Nebraska X X X X X

North Dakota X X X X X X

Ohio X X X X X

South Dakota X X X X X

Wisconsin X X X X X
54 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Jurisdiction

All Inmates

EnteringRandomHigh-riskInmate requestCourt orderClinical indicationInvolvement in incidentOther

In 

Custody

Upon 

Release

South

Alabama X X X X X X X X

Arkansas X X X X X X X X X

Delaware X X X X

Florida X X X X X

Georgia X X X X

Kentucky X X X

Louisiana X X X X

Maryland X X X X X X

Mississippi X X X X X X

North Carolina X X X X

Oklahoma X X X X X X

South Carolina X X X X X X

Tennessee X X X X X

Texas X X X X X X X

Virginia X X X X X

West Virginia X

West

Alaska X X X X

Arizona X X X X

California X X X X

Colorado X X X X X

Hawaii X X X

Idaho X X X X X X X

Montana X X X X

Nevada X X X X X X X

New Mexico X X

Oregon X X

Utah X X X X

Washington X X X X X X

Wyoming X X X

Adapted from Maruschak L. HIV in Prisons, 2006. Bureau of Justice Statistics Bulletin. Washington: U.S. Department of Justice, Office of 

Justice Programs; revised April 2008. Publication NCJ 222179.
HIV Care in Correctional Settings | 55

Section 1: The HIV Clinic: 

Providing Quality Care

References

• Bloom B, Owen B, Covington S. Gender 

Responsive Strategies: Research, Practice, 

and Guiding Principles for Women 

Offenders. Washington: National Institute of 

Corrections; 2003. 

• Bonczar TP. Prevalence of Imprisonment in 

the U.S. Population, 1974-2001. Bureau of 

Justice Statistics special report. Washington: 

U.S. Department of Justice, Office of Justice 

Programs; 2003.

• Cassidy W. Hepatitis C Infection in Prisons. 

Available at www.hcvadvocate.org/

hcsp%5Carticles/cassidy-1.html. Accessed 

December 1, 2013.

• Catania H. Drug Dependence Treatment in 

Prison and upon Release. Presented at the 

18th International Conference to Reduce 

Drug-Related Harm (Satellite on HIV/AIDS 

in Prison Settings); May 13, 2007; Warsaw.

• Centers for Disease Control and Prevention. 

Drug Use, HIV, and the Criminal Justice 

System. Available at www.cdc.gov/

correctionalhealth/rec-guide.html. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

HIV Testing Implementation Guidance 

for Correctional Settings. January 2009. 

Available at www.cdc.gov/hiv/pdf/risk_

Correctional_Settings_Guidelines.pdf. 

Accessed December 1, 2013.

• De Groot A, Cu Uvin S. HIV Infection 

among Women in Prison: Considerations 

for Care. Infectious Diseases in Corrections 

Report. Vol. 8, Issues 5 & 6; 2005. 

• Fischl M, Castro J, Monroid R, et al. Impact 

of directly observed therapy on long-term 

outcomes in HIV clinical trials. In: Program 

and abstracts of the 8th Conference on 

Retroviruses and Opportunistic Infections; 

February 4-8, 2001; Chicago, IL. Abstract 528.

• Gaiter J, Doll LS. Improving HIV/AIDS 

prevention in prisons is good public 

health policy. Am J Public Health. 1996 

Sep;86(9):1201-3.

• Hammett TM, Drachman-Jones A. HIV/

AIDS, sexually transmitted diseases, and 

incarceration among women: national and 

southern perspectives. Sex Transm Dis. 2006 

Jul;33(7 Suppl):S17-22.

• Hammett TM, Harmon MP, Rhodes W. The 

burden of infectious disease among inmates of 

and releasees from U.S. correctional facilities, 

1997. Am J Public Health. 2002;92:1789-

1794.

• Harrison P, Beck A. Prison and Jail Inmates 

at Midyear 2005. Bureau of Justice Statistics 

Bulletin. Washington: U.S. Department 

of Justice, Office of Justice Programs; May 

2006. Publication NCJ213133.

• James D, Glaze L. Mental Health Problems 

of Prison and Jail Inmates. Bureau of 

Justice Statistics Bulletin. Washington: U.S. 

Department of Justice, Office of Justice 

Programs; September 2006. Publication NCJ 

213600.

• Maruschak L. HIV in Prisons, 2006. Bureau 

of Justice Statistics Bulletin. Washington: 

U.S. Department of Justice, Office of Justice 

Programs; revised April 2008. Publication 

NCJ 222179.

• Mumola J, Karberg J. Drug Use and 

Dependence, State and Federal Prisoners. 

Bureau of Justice Statistics Bulletin.

Washington: U.S. Department of Justice, 

Office of Justice Programs; October 2006. 

Publication NCJ 213530.

• Nerenberg R, Wong M, DeGroot A. HCV in 

corrections: Front line or backwater? HEPP 

News. Vol 5 (4); 2002. 

• New York State Department of Health AIDS 

Institute HIV Education and Training 

Programs, Office of the Medical Director 
56 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

and Bureau of Community Based Services, 

Division of HIV Prevention. Improving 

Health Outcomes for HIV-Positive Individuals 

Transitioning from Correctional Settings to the 

Community (Trainer Manual). March 2008.

• Nicodemus M, Paris P. Bridging the 

Communicable Disease Gap: Identifying, 

Treating and Counseling High Risk Inmates. 

HIV Education Prison Project; August/

September 2001.

• Okie S. Sex, drugs, prisons and HIV. N Engl J 

Med. 2007 Jan 11;356(2):105-8.

• Paltiel AD, Weinstein MC, Kimmel AD, et 

al. Expanded screening for HIV in the United 

States – an analysis of cost-effectiveness. N Engl 

J Med. 2005 Feb 10;352(6):586-95.

• Ruby W, Tripoli L, Bartlett J, et al. HIV in 

Corrections. In: Medical Management of HIV 

Infection. Philadelphia: Lippincott, Williams & 

Wilkins; 2000.

• Sylla, M. Prevention in Practice: Prisoner 

Access to Condoms – The California 

Experience. Infectious Disease in Corrections 

Report (IDCR); 2007 Oct/Nov 9;20:2-3.

• Travis J. But They All Come Back: Facing the 

Challenges of Prisoner Reentry. Washington: 

Urban Institute Press, 2005: 21-38.

• Wakeman SE, Bowman SE, McKenzie M, 

et al. Preventing death among the recently 

incarcerated: an argument for naloxone 

prescription before release. J Addict Dis. 

2009;28(2):124-9.

• West H, Sabol W. Prison Inmates at 

Midyear 2008-Statistical Tables. Bureau 

of Justice Statistics Bulletin. Washington: 

U.S. Department of Justice, Office of Justice 

Programs; March 2009. Publication NCJ 

225619.
Patient Education | 57

Section 1: The HIV Clinic: 

Providing Quality Care

Patient Education

Background

Informed and empowered patients are better able to achieve healthy outcomes as a result of 

improved communication and development of trust with their care providers. HIV patient 

education provides patients with knowledge about HIV infection, including prevention, treatment, 

and other aspects of care, along with tools that enable them to participate more actively in 

decisions regarding their medical care. Given the complexity and the rapid evolution of HIV 

information, education and skills-building should be an ongoing activity and a key aspect of 

the clinical care of HIV patients. This chapter provides a brief review of the areas that should be 

addressed in patient education and discusses some strategies for integrating patient education 

into HIV care; additional information on patient education is found in many other chapters, 

particularly Supporting Patients in Care, Preventing HIV Transmission/Prevention with Positives, 

Smoking Cessation, and Adherence, as well as in the “Patient Education” sections found at the end 

of most of the clinical chapters.

S: Subjective

A newly diagnosed patient presents to clinic 

after being referred from a testing center in the 

community. The patient received the positive 

HIV test results more than a year ago, but has 

not been ready to seek care until now. The 

patient feared hearing that he/she was “going 

to die.” Now, he/she is ready to consider facing 

this “terminal” illness. The patient received 

some information about HIV infection at the 

testing center, but that was months ago.

O: Objective

See chapters Initial History, Initial Physical 

Examination, and Initial and Interim 

Laboratory and Other Tests for information on 

the initial clinic evaluation.

A/P: Assessment and Plan

The patient will need extensive information 

and education about HIV infection in general, 

his/her individual health status and prognosis, 

and the support and care systems that are 

available. Below are some suggestions about 

specific areas to review with a new patient.
58 | Guide for HIV/AIDS Clinical Care

Section 1: The HIV Clinic: 

Providing Quality Care

Topics for Patient Education

Patient education should cover 

the following topics:

• What is HIV?

• How is HIV transmitted?

• Progression of HIV; prognosis

• Interpretation of laboratory results

• Treatment information 

• General information regarding the 

benefits of treatment

• Indications for treatment, goals of 

treatment

• General information regarding potential 

side effects and risks of treatment

• Access to medication

• Insurance information

• Treatment options

• Prevention for positives

• Support services and support groups 

available to the patient

Patient Educators

In most clinics, a number of different 

personnel may take on the responsibilities 

of providing health education to patients. 

They may include primary care providers, 

nurses, social workers, case managers, and 

pharmacists. Some clinics have designated 

health educators whose role is to provide 

this type of support for patients. Even when 

a formal health educator is available, a 

collaborative, multidisciplinary approach to 

patient education serves both patients and 

providers optimally. However, it is important 

to ensure that patient education messages are 

coordinated and that patients are receiving 

consistent information.

Patient education must be provided in a 

language and at a literacy level appropriate 

for the patient. Patient education should be 

conducted in the patient’s primary language, 

if possible; otherwise, skilled medical 

interpreters should be involved.
Patient Education | 59

Section 1: The HIV Clinic: 

Providing Quality Care

Conducting Patient Education

Rarely are patients able to absorb all of the 

necessary information in a single session. 

Attention and comprehension levels are 

optimal during the first 15-20 minutes of 

a visit, after which an individual’s ability 

to absorb and retain information declines. 

Therefore, clinics should consider strategies 

to integrate brief patient education messages 

throughout the course of patient care and 

to engage patients in this process. Support 

groups, case managers, and peer educators can 

be invaluable in this process of engagement.

It is important to keep the medical information 

specific to the patient. Although there are 

some areas of education that should be 

considered for all patients (see above), patients 

should not be required to have a high level of 

understanding in each area. Patients should 

be given the opportunity to learn as much 

about an area as they would like, and should 

be encouraged to gain a working knowledge of 

the information that is necessary to keep them 

healthy and safe. Patients vary widely in terms 

of their interest level in mastering the details of 

their illness. For example, in the area of “What 

is HIV?” there may be some patients who 

want to know details about the basic science 

and immunologic impact of HIV. With this 

information, these patients might then want 

to take the lead in making treatment and care 

decisions for themselves, in consultation with 

their care providers. Other patients, however, 

would feel overwhelmed by this volume of 

information and involvement and may be 

best engaged in participating in their care by 

knowing how HIV is transmitted, how to keep 

themselves healthy, and how to access more 

information if they want it. Some patients 

would prefer for their care providers to “just 

tell them what to do” rather than take the lead 

in making their own treatment decisions.

There are a number of websites that provide 

HIV information for patients (see chapter 

Web-Based Resources). Many patients may 

prefer this form of self-education. Encourage 

patients to convey any information they 

discover to their care providers for further 

discussion. Reminding patients that they can 

be teachers as well as students can be a useful 

strategy for engaging patients in this process. 

In addition, patients may learn of novel tools 

and information sources that could be useful 

to others.

The following are some useful suggestions that 

providers can convey to their patients:

• Define your goals for each visit; please let 

your provider know your concerns and what 

you hope to learn in the course of the visit.

• Write down questions and concerns as they 

arise, and take that list with you to your 

appointments.

• Meet all the members of your care team and 

learn their areas of expertise and what they 

might be able to offer you.

• Ask about support groups and other peer 

groups that might be able to provide 

support/education.

• Review brochures and websites that provide 

additional information.

• Ask supportive friends or family 

members to accompany you to clinic 

visits. They may be able to obtain 

information that is helpful for their role 

in supporting your health or reminding 

you of information discussed at visits.

Initial History | 61

Section 2: Testing 

and Assessment

Initial History

Background 

Conducting a thorough initial history and physical 

examination is important even if previous medical 

records are available. This is the best opportunity to get 

a complete picture of the patient’s HIV disease status, 

comorbid conditions, and his or her physical and emotional 

condition, as well as to establish the basis for an ongoing 

relationship with the patient. Many of the conditions that 

put immunocompromised patients at risk of disease can be 

detected early, by means of a thorough assessment.

The information gathered through the initial history 

and physical examination will provide a comprehensive 

standardized database for the assessment and treatment 

of HIV-related problems, including acute intervention and 

ongoing prevention services and supportive care.

This chapter includes essential topics to cover during the 

clinic intake and examples of questions that can be used 

to elicit important information (the questions should be 

tailored to the individual patient). This can be completed 

during the initial visit or divided over the course of two 

or three early visits. For essential aspects of the physical 

examination to cover in an initial clinic intake visit, see 

chapter Initial Physical Examination.

HRSA HAB Performance 

Measures

Percentage of patients with a 

diagnosis of HIV who had at 

least one medical visit in each 

6-month period of the 24-month 

measurement period with a 

minimum of 60 days between 

medical visits

(Core measure)

Percentage of patients with a 

diagnosis of HIV who received HIV 

risk counseling in the measurement 

year

(Adult and Adolescent measure)

Percentage of new patients with 

a diagnosis of HIV who have been 

screened for substance use (alcohol 

and drugs) in the measurement year

(Adult and Adolescent measure)

Percentage of patients aged 12 

years and older screened for clinical 

depression on the date of the 

encounter using an age-appropriate 

standardized depression screening 

tool AND, if positive, a follow-up 

plan is documented on the date of 

the positive screen

(Adult and Adolescent measure)

S: Subjective

Initial History

Category / Topics 

to Cover Sample Questions 

History of Present Illness

HIV Testing • What was the date of your first positive HIV test?

• Did you have a previous HIV test? If so, when was the last negative result?

Treatment Status • Where do you usually receive 

your health care?

• Have you ever received care for HIV?

• What was the date of your 

last HIV care visit?

• What is your current CD4 

(T-cell) count?

• Do you know what your first CD4 

count was?

• What was your lowest CD4 count?

• What was your highest CD4 count?

• Do you know what your first viral load 

count was?

• What is your current viral load count?
62 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Category/Topic

to Cover Sample Questions 

History of Present Illness (continued)

HIV-Related 

Illnesses

• What opportunistic infection(s) 

have you had, if any? (PCP, MAC, 

cryptococcal meningitis, TB, etc.)

• What year(s) were you diagnosed with 

these infections?

• Have you had cancer(s)?

• What other HIV-related illnesses 

have you had? Have you had zoster 

(shingles), oral thrush, pneumonia?

Active TB and TB 

Testing History

• Have you ever had tuberculosis (TB)?

• When was your last TB test?

• Was it a TB skin test (TST) or interferon-gamma release assay (IGRA)?

• What were the results of this test?

• Have you ever had a positive TB result?

• What year and what health care setting?

• What medications did you take and for how long?

Antiretroviral 

Therapy (ART) 

History

• Are you taking HIV medications now?

• If so, please name them or describe 

them, and tell me how many 

times a day you take them.

• How many doses have you missed in 

the past 3 days?

• The past week?

• The past month? 

• What side effects, if any, do you have 

now? In the past?

• What HIV medicines have you taken in 

the past (names or descriptions)?

• When did you start and stop taking 

them (dates)?

• Do you know why you stopped taking 

these medications?

• Do you know what your HIV viral load 

or your CD4 counts were while you 

were taking your medications?

• Have you ever had a resistance test? 

• Did you have any side effects 

to past HIV medications?

Past Medical and Surgical History

Chronic Diseases Do you have any chronic conditions, such as the following? 

• Diabetes 

• High blood pressure 

• Heart disease

• Cholesterol problems 

• Asthma or emphysema 

• Sickle cell disease 

• Ulcers, acid reflux, or irritable 

bowel syndrome 

• Thyroid disorders 

• Kidney or liver problems

• Mental health disorders

If so, do you receive medical care for these conditions? 

Previous Illnesses • Have you had any hospitalizations? Where, when, and for what reason?

• Have you had any surgeries? When and where?

• Have you had any major illnesses, including mental health conditions?

Hepatitis • Have you ever had hepatitis? What type (A, B, C)?

• Do you have chronic hepatitis?

• Do you know whether you are immune to hepatitis A or hepatitis B? 

Have you been vaccinated?
Initial History | 63

Section 2: Testing 

and Assessment

Category/Topic

to Cover Sample Questions 

Past Medical and Surgical History (continued)

Gynecologic and 

Women’s Health

• When was your last cervical Papanicolaou (Pap) test?

• What were the results?

• Have you ever had an abnormal Pap test?

• When was your last menstrual period?

• What is the usual length of your cycle? Is it regular or irregular?

• Have you noticed changes in your menstrual cycle?

• When was your most recent breast examination?

• Have you had a mammogram? When?

• Have you ever had an abnormal breast examination or mammogram?

• Do you get yeast infections? How often?

• Do you get urinary infections?

• Have you ever had kidney stones?

Obstetric • How many pregnancies have you had?

• How many live births? Ages of children now?

• How many miscarriages or therapeutic abortions?

• Were you tested for HIV during any pregnancy? What year?

• Did you deliver an infant while you were HIV infected?

• Was HIV medication given during pregnancy and delivery?

• Do you have children? What is their HIV status?

• Do you intend to become pregnant?

Anorectal History • Have you ever had an anal Pap test?

• What were the results?

• Have you had anal warts? Other abnormalities?

Urologic History Have you ever had:

• Kidney stones

• Urinary tract Infections

• Prostate infection or enlargement

• Have you had a prostate-specific antigen (PSA) test? (What were the results?)

Sexually 

Transmitted 

Diseases

Have you ever had any of the following infections? If yes, when was last episode?

• Syphilis (If yes, ask about 

stage, treatment and date of 

treatment, titer follow-up, and 

date and result of last titer.)

• Vaginitis

• Genital herpes

• Nongonococcal urethritis (NGU)

• Gonorrhea (If yes, ask about sites of 

infection: oral, anal, urethral, vaginal.)

• Chlamydia (If yes, ask about sites of 

infection: oral, anal, urethral, vaginal.)

• Genital warts (HPV)

• Proctitis

• Pelvic inflammatory disease (PID)

• Trichomoniasis
64 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Category/Topic

to Cover Sample Questions 

Past Medical and Surgical History (continued)

Dental/Oral Care • When was your last oral health examination?

• Do you have all your natural teeth?

• Do you have partials or dentures?

Eye Care • When was your last vision examination?

• When was your last dilated retinal examination?

• Do you wear glasses or corrective lenses?

Medications • What (non-ARV) medications do you take?

• What herbs, vitamins, nutritional supplements, or over-the-counter (OTC) 

medications, do you take?

Allergies; 

Medication 

Intolerance

• Have you had an allergic reaction to any medications? 

What type of reaction, how severe?

• Have you had allergic reactions to other types of exposures?

• Have you had severe side effects from any medications?

Immunizations When was your last vaccination for the following:

• Streptococcal pneumonia (Pneumovax; PPV23, PCV13)

• Tetanus/Pertussis (Tdap)

• Influenza

• Hepatitis A

• Hepatitis B

Did you have chickenpox as a child, or were you vaccinated against chickenpox? 

What about measles, mumps, and rubella?

Health-Related 

Behaviors

Tobacco use: 

• Do you smoke? How many cigarettes 

per day? How long have you smoked? 

How much have you have smoked in 

the past?

• Besides tobacco, what do you smoke?

• Do you chew tobacco?

Alcohol use:

• How often do you have a drink 

containing alcohol? How many drinks 

do you have on a typical day? How 

many per week?

• Have you ever had a problem fulfilling 

work, social, or school obligations 

because of alcohol use?

• Have you ever sought treatment for 

alcohol-related problems?

Drug use: 

• Do you use any recreational or street 

drugs we haven’t covered in earlier 

questions? Any prescription drugs or 

medications that were not prescribed 

to you?

• If so, what drugs and how do you use 

them (inject, smoke, inhale, etc.)?

Drug use (continued): 

• How often do you use substances?

• Have you shared drug-use equipment 

with another person?

• What pain relievers do you use on a 

regular basis?

• Are you interested in treatment for 

alcohol or drug use?

• Have you ever sought treatment?

Exercise:

• What kind of exercise do you 

participate in? How frequently?

Diet:

• What do you eat during a typical day?

• Do you consume raw (unpasteurized) 

milk, raw eggs, raw or rare meat, deli 

meats, soft cheeses, or raw fish?

• How much water do you drink during 

a typical day?

• What is your source of water?

• How much caffeine do you drink 

during a typical day?
Initial History | 65

Section 2: Testing 

and Assessment

Category/Topic

to Cover Sample Questions 

Sensitive Sexual and Gender History Questions

Gender Identity • Do you consider yourself male or female?

• Have you had or considered treatment for sex change?

• Are you presently taking hormone therapy?

• Have you had hormone therapy in the past?

• Have you had any gender confirmation (sex reassignment) surgery?

General Sexual • Do you have sex with men, women, or both?

• In the past, have you had sex with men, women, or both?

• In the past 2 months, how many sex partners have you had?

• In the past 12 months, how many sex partners have you had?

Sexual Practices • Do you have anal sex? Vaginal? Oral?

• How do you protect yourself from sexually transmitted diseases, or HIV reinfection?

• For men who have sex with men: 

• Are you the receptive or insertive partner, or both?

• How often do you use alcohol or drugs before or during sex?

HIV Prevention • Do you know the HIV status of your partner(s)?

• Do you take measures to protect your partners from HIV? What measures?

• In what situations do you or your partner use condoms or some other barrier?

• Are there situations in which you do not use barrier protection?

Sex Trading • Have you ever exchanged sex for food, shelter, drugs, or money?

Contraception • What birth control measures do you use, if any?

• How often do you use condoms or other latex barriers?

• Do you have plans for you or your partner to become pregnant?

Family History

Do you have a family history of:

• Heart disease? Heart attacks or strokes?

• Cholesterol problems? Diabetes?

• Cancer?

• Mental health conditions (e.g., depression, bipolar disorder, anxiety, phobias)?

• Addictions?

Which family member(s), and what is their health status currently?

Social History

Relationship 

Situation

• What is your relationship status (single, married, partnered, divorced, widowed)?

• Do you have children?

• Does your partner (and/or children) know about your HIV status?

Living Situation • Do you live alone or with others? With whom?

• How long have you lived in your residence?

Support System • Who knows about your HIV status?

• Which individual has been the most supportive since your HIV diagnosis?

• Who has been the least supportive?

• Have you used any community services such as support groups?
66 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Category/Topic

to Cover Sample Questions 

Social History (continued)

Employment • Are you currently employed?

• Where do you work?

• Describe your job task(s).

• What setting do you work 

in on a daily basis?

• Does your employer provide 

health insurance?

• Does your employer know 

of your HIV status?

• If on disability: How long have 

you been on disability?

• What medical condition has 

made you disabled?

Incarceration 

History

• Have you ever been incarcerated? When was the last time?

Pets • What kind of pets do you have, and who cleans up after them?

Travel • Where have you traveled outside the United States?

• When did travel take place?

Mental Health

Coping • How do you handle your problems/stresses?

• What do you do to relax?

History • Have ever been diagnosed with depression, anxiety, panic, bipolar disorder, 

schizophrenia, etc.?

• Have you taken or are you taking any medications for these conditions?

• Are you seeing a therapist or mental health professional?

• Have you had any previous counseling or mental health problems?

• Have you ever been hospitalized for a psychiatric condition?

• Have you ever thought about hurting yourself? (If yes, probe for previous suicide 

attempts: Are you feeling that way now?) (See chapter Suicide Risk and prepare for 

immediate referral if necessary.)

Violence • Have you ever been sexually abused, assaulted, or raped?

• Has an intimate partner ever forced you to do something you did not want to do?

• Has a partner, family member, or other person ever physically hurt you?

• Have you lived in any situation with physical violence or intimidation?

• When has this occurred?

• Are you afraid for your safety now?

• (If yes) Did you seek legal help, therapy, or other type of assistance? 

Childhood Trauma • Was there any alcoholism or drug abuse in your household when you were a child?

• Did you experience or observe violence; physical, 

sexual, or emotional abuse; or neglect?
Initial History | 67

Section 2: Testing 

and Assessment

Review of Systems 

For each positive answer, ask about location, characteristics, duration of symptoms, exacerbating and 

alleviating factors, previous diagnostic workup, and treatments tried.

General • Do you ever wake up feeling tired?

Fever • Do you have fevers? How high, and for how long? How often?

Night Sweats • Do you ever sweat so much at night that it soaks your sheets and nightclothes?

Anorexia • How is your appetite?

Weight • What was your weight 1 year ago?

• What is a normal weight for you?

• Have you lost or gained weight unintentionally?

Body Changes • Have you noticed any changes in the shape of your body (describe)? For example, 

has there been an increase in your waist, collar, or breast size or a decrease in your 

arm, leg, or buttocks size?

• Have you noticed increased visibility of veins in your arms and legs?

• Have you noticed thinning of your face, especially around the cheeks?

Head, Ears, Eyes, Nose, and Throat

Vision • Have you noticed any changes in your vision, especially blurred vision or vision loss, 

double vision, new “floaters” or flashes of light?

• Have you noticed this problem in one or both eyes?

• When did you first notice these changes?

Mouth, Ears, Nose, 

Throat

• Have you noticed any white spots in your mouth or a white coating on your tongue 

(thrush, oral hairy leukoplakia)?

• Do you ever get sores in your mouth or the back of your throat? Gum problems?

• Any nosebleeds?

• Do you ever experience hearing loss, ringing in your ears, or ear pain?

Cardiovascular

Cardiac • Any chest pain or pressure? Palpitations?

• Any shortness of breath during activities or while you are lying down?

• How far can you walk or run before you get short of breath?

• Any swelling in your feet or legs?

Pulmonary

Cough • Do you have a cough?

• Can you describe it? Dry or productive, amount, color, odor, presence of blood in 

sputum? When is it the worst?

Dyspnea • Do you ever feel short of breath?

• Does that happen when you are sitting still, lying down, or moving around?

• How severe is your shortness of breath?

• What does it prevent you from doing?

• Do you ever wheeze??
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Section 2: Testing 

and Assessment

Gastrointestinal

Dysphagia • Do you have any problems with food sticking in your throat or being difficult to 

swallow?

• Do you gag or get nauseated when trying to eat?

• Do you notice it is easier to swallow liquids or solids?

• Do you have difficulty swallowing pills?

Odynophagia • Do you have pain in your throat, esophagus, or behind 

your breastbone when you swallow?

Dyspepsia/Reflux • Do you ever have heartburn (or a burning feeling rising from the stomach to 

behind the breastbone)?

• When does it happen – after eating, lying down, on an empty stomach?

• Do you get the taste of stomach acid in your mouth?

Nausea/Vomiting • Do you have nausea or vomiting?

• When? Are there specific things that cause this?

Diarrhea • Do you have diarrhea, or more than 3-5 unformed stools a day?

• Stool characteristics: bloody, pus, mucus?

• Pain or cramping with diarrhea? Tenesmus?

Bowel Habits • How frequently do you have bowel movements?

• Do you have problems with constipation, blood in the stools, or other?

• Do you have problems with flatulence or belching after eating?

Genitourinary

Genital • Do you have any lesions or sores on your genital area now, or have you in the past?

• Have you ever had genital herpes? If yes, how often do you have outbreaks?

• When was the most recent outbreak?

Women • Have you had any lower abdominal pain?

• Have you noticed a vaginal discharge or odor?

• Do you have any burning or pain on urination?

• Frequent urination?

• Do you lose control of your urine or have problems getting to the bathroom before 

you start to urinate?

Men • Have you noticed any swelling or testicular pain?

• Do you have difficulty starting your stream of urine?

• Are you getting up at night to urinate?

• Have you had burning or pain on urination?

• Do you lose control of your urine or have problems getting to the bathroom before 

you start to urinate?

• Do you have any difficulty developing or maintaining an erection?

• Any discharge from your penis?
Initial History | 69

Section 2: Testing 

and Assessment

Musculoskeletal

• Do you have any muscle aches or pains? Joint pain or swelling?

• Back pain?

• Have you ever broken any bones?

• Do you have chronic pain?

• Describe the pain – location, duration, rating (scale of 1-10), alleviating factors.

Skin

Skin Lesions • Have you noticed any rash or skin problems? If so, where?

• Have you noticed any new moles, bruises, or bumps on your skin?

• Do you have any moles that have changed shape, size, or color?

Tinea • Do you have fungal infections on your skin, especially 

groin, fingernails, toenails, or feet?

Folliculitis • Do you have any itchy bumps on your face, back, or chest?

Seborrhea • Do you have flaking or itching on your skin or scalp?

Neurologic

Headache • How often do you get headaches?

• Describe the headaches – location, timing, duration, 

alleviating or aggravating factors.

• Do they cause nausea or vomiting?

• Does sensitivity to light lead to headaches?

Neuropathy • Do you have any numbness, tingling, burning, or pain in your hands or feet?

Weakness • Do you have or have you had any weakness in your arms or legs?

Gait • Have you noticed any changes in the way you walk?

Memory • Do you have difficulty with your memory or ability to concentrate? If so, describe. 

Seizures • Have you ever had a seizure or “fit”?

• If so, describe the seizure – When? How long did it last? Did you experience loss of 

consciousness? Did you receive medical care?

Endocrine

Diabetes • Have you had any increase in thirst, hunger, or urination?

Thyroid • Have you noticed changes in your energy level?

• Do you have intolerance to heat or cold?

• Have you noticed changes in your hair (thinning, coarse texture)?

Sex Steroids • Have you noticed any changes in your libido? In your energy level, mood?

Hematologic/Lymphatic

Adenopathy • Do you have swollen glands?

• If so, describe – location, pain, size.

Bruising or 

Bleeding

• Have you noticed easy bruising or prolonged bleeding after injury?

• Nosebleeds or bleeding gums?
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Section 2: Testing 

and Assessment

Psychiatric

Mood • Depression screening: Have you experienced a decrease in your interest or pleasure 

in your activities? Have you felt depressed, down, or hopeless?

• Do you feel more angry, sad, depressed, numb, irritable, or anxious than usual?

• Have any major life events have occurred to cause you to feel sad or depressed?

• When did these events occur?

Sleep • How is your sleep?

• How many hours do you sleep each night?

• What is your sleeping schedule – time to bed and time to rise?

• Do you take naps?

HIV Research 

Sample Questions

• Have you participated in any research protocols? What studies, and when?

• Would you be interested in participating in research studies (if available)? 

O: Objective

• Conduct a physical examination, focusing 

on subjective findings elicited in the history. 

(See chapter Initial Physical Examination.) 

Note: If significant time has elapsed between 

the review of symptoms (ROS) and the 

physical examination, perform another ROS.

A/P: Assessment and Plan

• Arrange for baseline/intake laboratory work. 

(See chapter Initial and Interim Laboratory 

and Other Tests.)

• Compose a problem list. Initiate a 

medication list (if appropriate).

• Refer the patient to social services, mental 

health care, local health department partner 

services, community and other resources, or 

other clinic services as needed.

During the current visit or a future visit:

• Perform immunizations for pneumonia 

(Pneumovax), influenza (as appropriate), 

and other immunizations as indicated. (See 

chapter Immunizations for HIV-Infected 

Adults and Adolescents.)

• Provide counseling on prevention of HIV 

transmission (e.g., safer sex and injection 

practices), as appropriate. See chapter 

Preventing HIV Transmission/Prevention 

with Positives.

Patient Education

A very important aspect of caring for HIVinfected individuals is educating patients about 

HIV infection, including goals of care and 

ways of achieving those goals.

Review the following with each patient:

HIV disease

• Disease course

• Significance of CD4 cell count and HIV viral 

load

• Possible treatment approaches, including 

initial discussion about the importance of 

ART for the patient’s own health and for 

reducing risk of HIV transmission

• Disclosure (e.g., whom the patient may 

need to tell about HIV status, relevant legal 

requirements, approaches to disclosure)
Initial History | 71

Section 2: Testing 

and Assessment

HIV transmission prevention and risk 

reduction for HIV-infected individuals

(see chapter Preventing HIV Transmission/

Prevention with Positives)

• Strategies to prevent transmission of HIV 

to uninfected partners and to prevent 

acquisition of sexually transmitted diseases, 

hepatitis, and other infections

• Safer-sex approaches, including the use of 

condoms or other latex barriers during sexual 

contacts

• Safer use of recreational drugs

Nutrition

• Maintaining a healthy weight

• Nutritional support resources, if appropriate

• Importance of including a nutritionist in 

medical care

Mental health

• Stress reduction

• Rest and exercise to enhance a healthy 

mental state

Adherence

• Importance of keeping medical appointments

• Need for adhering to any medication regimen 

and the consequences of missed HIV 

medication doses

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency virus: 

2013 update by the HIV Medicine Association 

of the Infectious Diseases Society of America. 

Clin Infect Dis. 2014 Jan;58(1):e1-e34.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.

gov/guidelines. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment of 

opportunistic infections in HIV-infected adults 

and adolescents: recommendations from the 

Centers for Disease Control and Prevention, 

the National Institutes of Health, and the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• U.S. Department of Health and Human 

Services. Guide to Clinical Preventive Services, 

2012: Recommendations of the U.S. Preventive 

Services Task Force. Available at www.ahrq.

gov/professionals/clinicians-providers/

guidelines-recommendations/guide/

index.html. Accessed December 1, 2013.

Initial Physical Examination | 73

Section 2: Testing 

and Assessment

Initial Physical Examination

Background 

Many of the conditions that put immunocompromised 

patients at risk of disease can be detected early, by 

means of a thorough history and physical evaluation. 

S: Subjective 

See chapter Initial History.

O: Objective

Assess the patient’s general appearance, affect 

and demeanor in answering questions, body 

language, and other relevant characteristics. 

Measure vital signs; perform a physical 

examination. 

HRSA HAB Performance Measures

Percentage of female patients with a 

diagnosis of HIV who have a Pap screening

in the measurement year

(Adult and Adolescent measure)

Table 1. Vital Signs 

(These measurements establish a baseline against which future measurements can be compared.).)

Vital Sign Recommendation/Notes

• Height • Should be measured at baseline and annually.

• Weight • Record at each visit.

• Temperature • Record at each visit.

• Blood pressure • Record at each visit. The BP cuff size should be 

appropriate for the patient’s arm circumference.

• Heart rate • Record at each visit.

• Respiratory rate • Record at each visit.

• Oxygen saturation • Record at each visit.

• Waist, hip 

circumferences

• Waist and hip circumference should be measured at baseline for 

comparison in case the patient later develops obesity or lipoaccumulation 

related to antiretroviral therapy (ART); repeat as indicated.

Abdominal circumference:

>102 cm (39”) in men = abdominal obesity

>88 cm (35”) in women = abdominal obesity

Waist-hip ratios: 

>0.95 in men = increased risk of coronary heart disease (CHD)

>0.85 in women = increased risk of CHD
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and Assessment

Body mass index (BMI) BMI can be helpful in assessing underweight or overweight conditions, HIV/AIDSrelated weight loss, and ART-related weight gain. Perform at baseline and upon 

changes in weight. 

BMI calculation:

(weight in pounds) x 703

(height in inches) x (height in inches)

or,

(weight in kilograms)

(height in meters) x (height in meters)

BMI: 

<18.5 = underweight 

18.5-24.9 = normal range

25-29.9 = overweight

≥30 = obese

Table 2. Physical Examination 

Regions Recommendation/Notes

General • State of nourishment, physical appearance, well or ill appearing

Eyes • Examine visual acuity by Snellen chart, visual fields by confrontation.

• Test extraocular movements and pupillary size and reactivity.

• Perform funduscopic examination, with or without mydriatics. Note any retinal lesions, 

white or yellow retinal discoloration, infiltrates, or hemorrhages (could indicate 

cytomegalovirus retinitis, retinal necrosis, or ocular toxoplasmosis).

• Referral to ophthalmologist for retinal examination every 6 months if the CD4 count is 

<50 cells/μL. 

• Refer immediately if the patient has retinal lesions or new visual disturbances.

Ears/Nose • Examine ear canals and tympanic membranes.

• Visualize nasal turbinates.

• Palpate frontal and maxillary facial sinuses.

Oral Cavity • Good lighting is essential for this examination.

• Examine: 

• Gingiva and teeth (note loss of teeth, decay, or inflammation)

• Mucosal surfaces (with dentures removed) (note any lesions or discolorations)

• Posterior tongue

• Tonsils (note absence or presence; any abnormality in tonsil size)

• Pharynx (note lesions or exudate)

• Refer to oral health specialist for examination.

Endocrine • Check thyroid for enlargement, tenderness, nodules, and asymmetry.

Lymph Nodes • Document site and characteristics of each palpable node.

Node Sites:

• Posterior cervical 

chain

• Anterior cervical 

chain

• Submandibular

• Supraclavicular

• Submental

• Axillary

• Epitrochlear

• Inguinal

• Femoral

Characteristics:

• Size (two dimensions, in millimeters)

• Consistency (hard, fluctuant, soft)

• Tenderness

• Mobility

• Definition (discrete, matted)

• Symmetry
Initial Physical Examination | 75

Section 2: Testing 

and Assessment

Table 2. Physical Examination (continued)

Regions Recommendation/Notes

Lungs • Inspect, auscultate, and percuss.

• Note any abnormal sounds including crackles or wheezes (e.g., signs of infections, 

asthma, and congestive heart failure).

• Note any absence of air movement (e.g., pneumothorax, pleural effusion).

Heart • Examine for jugular venous distention (JVD).

• Palpate for point of maximal impulse (PMI).

• Note rate and rhythm, heart sounds, murmurs, extra heart sounds.

Breasts • Palpate for breast masses in both men and women.

• Check for symmetry, nipple discharge, dimpling, and masses.

Abdomen • View: examine for distention, obesity, 

undernutrition, vascular prominence, 

petechiae.

• Auscultate; note bowel sounds.

• Percuss; record liver size.

• Palpate for hepatomegaly, 

splenomegaly, masses, tenderness or 

rebound tenderness.

Genitals / 

Rectum

• Inspect the genitalia and perirectal area; note lesions, warts, etc.

• Look for discharges, ulcerative lesions, vesicles, or crusted lesions; take samples for 

diagnostic studies (e.g., for chlamydia, gonorrhea, herpes simplex virus, syphilis, 

chancroid, as appropriate).

Female Patients • Perform speculum examination; note any lesions on vaginal walls or cervix.

• Obtain a Papanicolaou (Pap) test.

• Obtain endocervical swab for gonorrhea and chlamydia, and a posterior pool swab for 

wet mount evaluation for trichomoniasis, candidiasis, and bacterial vaginosis.

• Consider anal Pap test, especially if the patient has a history of an abnormal cervical 

Pap test or genital warts (perform before introduction of lubricant).*

• Bimanual examination; note size of uterus and ovaries, shape, and any tenderness or 

pelvic pain.

• Rectal examination (e.g., for anorectal lesions, warts) and evaluation of posterior 

uterine abnormalities.

Male Patients • Examine external genitalia; note whether patient is circumcised; note any lesions, 

discharge, or other abnormalities, as above. Perform testicular examination for 

masses, tenderness.

• Consider anal Pap test (perform before introduction of lubricant).*

• Digital rectal examination to evaluate rectal tone, discharge or tenderness, masses, or 

lesions; perform prostate examination if appropriate.

Extremities / 

Musculoskeletal

• Joints; note any enlargement, swelling, or tenderness.

• Muscles; for the major muscle groups, evaluate muscle bulk (normal or decreased), 

tenderness, or weakness.

• Look for evidence of peripheral fat atrophy.

• Consider measuring baseline arm, thigh, and chest circumferences for later 

comparison.

• Note nail changes (clubbing, cyanosis, thickening, discoloration).

• Assess for pedal or leg edema.

Habitus • Look carefully for signs of lipoatrophy or lipohypertrophy, wasting, or obesity.

• Subcutaneous fat loss (face, extremities, buttocks).

• Central fat accumulation (neck, dorsocervical area, breasts, abdomen).
76 | Guide for HIV/AIDS Clinical Care

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Table 2. Physical Examination (continued)

Regions Recommendation/Notes

Skin • Examine the entire body, including scalp, axillae, palms, soles of feet, and pubic and 

perianal areas.

• Describe all lesions (e.g., size, borders, color, symmetry/asymmetry, distribution, 

raised/flat, induration, and encrustation).

• Note evidence of folliculitis, seborrheic dermatitis, psoriasis, Kaposi sarcoma, fungal 

infections, prurigo nodularis, etc.

• Note any tattoos or body piercings.

Neurologic Assess the following:

• Mental status, including orientation, 

registration, recent and remote 

memory, and ability to calculate (serial 

subtraction)

• Cranial nerves

• Peripheral sensory examination, 

including pinprick, temperature, and 

vibratory stimuli

• Extremity strength and gait to discern 

myopathy, neuropathy, and cerebellar 

disease

• Fine motor skills such as rapid 

alternating movements (often 

abnormal in dementia)

• Deep tendon and plantar reflexes

Psychiatric • Assess the patient’s general mood (e.g., 

depressed, anxious, hypertalkative).

• Note verbal content (e.g., whether 

the patient answers questions 

appropriately; unusual or odd content).

• Note inappropriate or unusual behavior, 

such as extremes of denial, hostility, or 

compulsiveness.

• See section Neuropsychiatric Disorders

for more complete information on 

common pathologies.

• If the possibility of an emergency 

situation exists (e.g., potential suicide 

or violence), refer to crisis mental health 

services for immediate evaluation.

* Anal Pap test: Consider this test if follow-up evaluation of an abnormal Pap test result is available. Rates of anal dysplasia and anal 

cancer are higher in HIV-infected women and men than in HIV-uninfected individuals; see chapter Anal Dysplasia.
Initial Physical Examination | 77

Section 2: Testing 

and Assessment

A/P: Assessment and Plan

After completing the initial history and 

physical examination, do the following: 

• Enter the information garnered through the 

history and physical examination into the 

patient’s chart or database.

• Continue to develop the problem list, 

assessment, and plan for patient care.

• Complete follow-up or laboratory studies 

suggested by the history and physical 

examination. (See chapter Initial and Interim 

Laboratory and Other Tests.)

• Prescribe opportunistic infection 

prophylaxis as appropriate. (See chapter 

Opportunistic Infection Prophylaxis.)

• Arrange for any appropriate vaccinations. 

(See chapter Immunizations for HIV-Infected 

Adults and Adolescents.)

• Refer for dental, nutrition, and social 

services, as well as case management and 

mental health care, as appropriate.

• Refer for any additional specialty care 

needs identified in the history or physical 

examination.

• Make follow-up appointment with health 

care provider.

• Answer the patient’s questions.

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency virus: 

2013 update by the HIV Medicine Association 

of the Infectious Diseases Society of America. 

Clin Infect Dis. 2014 Jan;58(1):e1-e34.

• Hollander H. Initiating Routine Care 

for the HIV-Infected Adult. In: Sande 

MA, Volberding PA, eds. The Medical 

Management of AIDS, 5th Edition. 

Philadelphia: WB Saunders; 1997:107-112.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

Initial and Interim Laboratory and Other Tests | 79

Section 2: Testing 

and Assessment

Initial and Interim Laboratory 

and Other Tests

Background 

This chapter discusses the laboratory tests and other monitoring that should be performed 

for HIV-infected individuals. This involves testing for staging HIV infection, screening for 

comorbidities, establishing baselines before treatment with antiretroviral (ARV) medications, and 

monitoring responses to ARV therapy (ART).

Note that documentation of HIV infection by laboratory testing is essential for each patient, and it 

should be included in the patient’s chart. 

HRSA HAB Performance Measures

Percentage of patients, aged 

6 months and older with a 

diagnosis of HIV/AIDS, with 

at least two CD4 cell counts 

or percentages performed 

during the measurement year 

at least 3 months apart

(All-Age measure)

Percentage of patients, 

regardless of age, with a 

diagnosis of HIV who had an 

HIV drug resistance test

performed before initiation 

of HIV antiretroviral therapy 

if therapy started during the 

measurement year

(All-Age measure)

Percentage of patients, 

regardless of age, with a 

diagnosis of HIV with a viral 

load test performed at least 

every 6 months during the 

measurement year

(All-Age measure)

Percentage of patients 

aged 3 months and older 

with a diagnosis of HIV/

AIDS, for whom there was 

documentation that a 

tuberculosis screening test 

was performed and results 

interpreted (for tuberculin skin 

tests) at lease once since the 

diagnosis of HIV infection

(All-Age measure)

Percentage of patients for 

whom hepatitis C screening

was performed at least once 

since the diagnosis of HIV

(Adult and Adolescent measure)

Percentage of patients, 

regardless of age, for whom 

hepatitis B screening was 

performed at least once since 

the diagnosis of HIV/AIDS or 

for whom there is documented infection or immunity

(Adult and Adolescent measure)

Percentage of patients, 

regardless of age, with a 

diagnosis of HIV who were 

prescribed HIV antiretroviral 

therapy and who had a 

fasting lipid panel during the 

measurement year

(All-Age measure)

Percentage of adult patients 

with a diagnosis of HIV 

who had a test for syphilis

performed within the 

measurement year

(Adult and Adolescent measure)

Percentage of patients with 

a diagnosis of HIV at risk of 

sexually transmitted infections 

who had a test for gonorrhea

within the measurement year

(Adult and Adolescent measure)

Percentage of female patients 

with a diagnosis of HIV who 

have a Pap screening in the 

measurement year

(Adult and Adolescent measure)
80 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

O: Objective 

Table 1. Laboratory Evaluations for HIV-Infected Patients 

Test Rationale Result Frequency and Comments

HIV Confirmation, Staging and ART Monitoring

HIV Antibody • Confirm diagnosis, if not 

documented previously

• At entry to care

CD4 Count • For HIV staging and 

prognosis

• Helps guide urgency of 

ART initiation

Indicates risk of 

opportunistic illnesses 

and guides initiation of 

prophylaxis against 

opportunistic infections

• Used to monitor immune 

reconstitution during ART

• Reported in cells/μL • Perform at baseline 

(twice).

• Repeat every 3-6 months 

for stable patients on or 

off ART; may repeat every 

6-12 months if stable and 

suppressed viral load.

• Repeat if results are 

inconsistent with the 

clinical picture or with 

previous trends.

• See chapter CD4 and Viral 

Load Monitoring. 

CD4 

Percentage

• Used in addition to the 

absolute CD4 count 

for monitoring trends; 

may be discrepant with 

absolute CD4 

• Pneumocystis pneumonia

prophylaxis is indicated 

for CD4 percentage <14% 

regardless of absolute 

count

CD4 

Count 

(cells/μL)

Expected 

CD4 

Percentage

• Usually obtained with 

absolute CD4 count.

>500 >29%

200-500 14%-28%

<200 <14%

Quantitative 

Plasma HIV 

RNA (HIV Viral 

Load)

• Estimates level of HIV 

replication

• Used to monitor effect 

of ART

• May be used to identify 

acute HIV infection; has 

high sensitivity in setting 

of acute infection, when 

antibody may be negative

• Reported in copies/mL

• In untreated patients, 

detectable (with 

rare exceptions) and 

measured to the upper

limit of detection 

(usually >500,000 

copies/mL)

• For patients taking

ART, ideally suppressed

to undetectable levels 

(usually <40 or <75 

copies/mL)

• Perform at baseline 

(twice).

• For patients on new or 

modified ART regimen: 

perform 2-8 weeks after 

initiation or change 

in ART, then every 4-8 

weeks until viral load is 

suppressed.

• For patients on stable 

ART: perform every 3-4 

months (if stable and viral 

load suppressed >2-3 

years, consider every 6 

months).

• For patients not taking 

ART: perform every 3-6 

months; more frequently 

if CD4 count is low.

Factors that may temporarily 

increase viral load:

• Immunizations

• Active infections

•
Initial and Interim Laboratory and Other Tests | 81

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Predicting Safety and Efficacy of ARVs

Drug 

Resistance 

Testing 

(Genotype, 

Phenotype)

• To assess whether the 

patient’s HIV virus is likely 

to be resistant to specific 

ARV medications

• Genotype: detects 

specific mutations to 

ARV medications 

• Phenotype: measures 

HIV viral replication in 

the presence of ARVs 

• Genotype is 

recommended for all 

ARV-naive patients. For 

greatest accuracy, should 

be done as early as 

possible in the course of 

HIV infection. 

• Acute or primary 

infection: recommended 

(genotype). 

• Chronic infection 

and treatment naive: 

recommended before 

initiation of ART. 

(genotype). If resistance 

test was performed at 

entry, consider repeat 

testing. 

• Pregnancy: 

recommended before 

initiation of ART (repeat 

if done earlier) or for 

patients with detectable 

HIV RNA while taking ART. 

• Virologic failure: 

recommended. 

• Obtain genotype for 

integrase mutations 

if integrase inhibitor 

resistance is a concern. 

(See chapter Resistance 

Testing for more information.) 

Coreceptor 

Tropism Test

• Determine coreceptor 

tropism

• If CXCR4-tropic (or 

dual/mixed tropic) 

virus is detected, 

CCR5 antagonist 

is not likely to be 

effective and should 

not be used

• Test before making 

decision to treat with 

CCR5 antagonist, or 

if virologic failure 

occurs while on a CCR5 

antagonist (phenotypic 

assay preferred). 

• For standard assay, HIV 

RNA must be >1,000 

copies/mL (a proviral 

DNA test is available for 

samples with HIV RNA 

below limits of detection; 

has not been clinically 

validated).

HLA-B*5701 • Establish risk of 

hypersensitivity reaction 

to abacavir

• If positive, high 

risk of abacavir 

hypersensitivity 

reaction; abacavir 

should not be used

• Test before starting 

treatment with abacavir.
82 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Baseline and Subsequent Hematologic, Renal, Hepatic, and Metabolic Screening

Complete 

Blood Count 

(CBC) with 

Differential 

and Platelets

• Detects anemia, 

thrombocytopenia, 

leukopenia

• Normal • Perform at baseline.

• Repeat every 3-6 months.

• Abnormal • Requires follow-up 

evaluation as indicated; 

may influence choice of 

ARVs. 

• Repeat more frequently 

if the patient’s results are 

abnormal or if the patient 

is taking bone marrow 

suppressive drugs 

(including zidovudine).

Chemistry 

Profile 

Electrolytes, 

Creatinine, 

eGFR 

(Estimated 

Glomerular 

Filtration Rate), 

Blood Urea 

Nitrogen

Liver 

Transaminases, 

Bilirubin (Total 

and Direct)

• Detects electrolyte 

abnormalities, kidney 

disease, liver disease

• Normal/abnormal • Perform at baseline; 

before starting ART.

• Repeat 2-8 weeks after 

starting or modifying 

ART, then every 3-6 

months if stable.

• May influence ARV 

selection.

• May be useful in 

monitoring drug 

toxicities.

• Abnormalities should 

prompt evaluation of 

cause.

Urinalysis with 

Urine Protein 

and Creatinine

• Used to screen for 

kidney disease

• Normal/abnormal Screen at baseline and before 

initiation or change of ART 

regimen.

Repeat every 12 months.

Repeat every 6 months for 

patients on tenofovir, more 

frequently if indicated.

Abnormalities should prompt 

evaluation of cause.

See chapter Renal Disease. 
Initial and Interim Laboratory and Other Tests | 83

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Baseline and Subsequent Hematologic, Renal, Hepatic, and Metabolic Screening (continued)

Lipid Profile 

(Total 

Cholesterol, 

LDL, HDL, 

Triglycerides); 

fasting

• Detects dyslipidemia, 

identifies risk factors for 

cardiovascular disease

• Normal/abnormal • Baseline; before starting 

ART.

• Consider repeating 4-8 

weeks months after 

starting or changing ART.

• Repeat annually if normal 

(on or off ART), or more 

frequently (e.g., every 

6 months) if abnormal 

or risk of cardiovascular 

disease.

• May influence ARV 

selection.

• May be useful in 

monitoring drug 

toxicities.

See chapter Dyslipidemia.

Glucose 

(preferably 

fasting) or 

hemoglobin 

A1C

• Detects diabetes and 

hyperglycemia

• Normal/abnormal • Baseline; before starting 

ART.

• Repeat every 3-6 months 

if abnormal, every 6 

months if normal on 

ART; every 12 months if 

normal and not on ART.

• May influence ARV 

selection.

• May be useful in 

monitoring drug 

toxicities.

See chapter Insulin Resistance, 

Hyperglycemia, and Diabetes 

on Antiretroviral Therapy.

Hepatitis A, B, and C Screening

Hepatitis A Serology

Hepatitis A 

Antibody 

(HAV IgG)

• Screen for immunity to 

hepatitis A; vaccinate 

those not immune

• Negative • Offer hepatitis A vaccine 

if indicated. (See chapter 

Immunizations for HIVInfected Adults and 

Adolescents.)

• Positive • Immune; no vaccine 

necessary.
84 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Hepatitis A, B, and C Screening (continued)

Hepatitis B Serology (See chapter Hepatitis B Infection.)

Hepatitis 

B Surface 

Antigen 

(HBsAg)

• Indicates active hepatitis B • sAg negative • Most likely, no chronic 

infection (may be falsely 

negative). 

• Vaccinate if HBsAb 

negative (not immune).

• sAg positive • Indicates chronic 

or acute hepatitis B 

infection; requires further 

evaluation (check HBV 

DNA). (See chapter 

Hepatitis B Infection.)

Hepatitis B 

Core Antibody 

(Anti-HBc, IgG)

• Indicates past infection or 

ongoing infection

• Anti-HBc negative • The patient most likely 

has not been infected 

with hepatitis B; consider 

vaccination if HBsAb 

negative and HBsAg 

negative.

• Anti-HBc positive • The patient most likely 

has been infected with 

hepatitis B; this test alone 

does not distinguish 

past exposure and active 

infection.

• In rare cases, may be 

falsely negative in some 

patients with chronic 

infection.

• If sAb negative and sAg 

negative, check HBV 

DNA to rule out active 

infection; vaccinate if HBV 

DNA is not detected.

• If sAb is positive, patient 

is immune.

Hepatitis 

B Surface 

Antibody 

(Anti-HBs)

• Indicates immunity status • Anti-HBs negative • The patient is not 

immune to hepatitis B; 

consider vaccination, 

unless patient has active 

hepatitis (sAg positive or 

HBV DNA positive).

• Anti-HBs positive • The patient is immune 

to hepatitis B either by 

previous infection or 

by immunization; may 

be negative in acute 

hepatitis B infection.
Initial and Interim Laboratory and Other Tests | 85

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Hepatitis A, B, and C Screening (continued)

Hepatitis C Serology (See chapter Hepatitis C Infection.)

Hepatitis C 

Antibody 

(HCV IgG)

• Hepatitis C status • HCV negative • Patient is not infected 

with hepatitis C.

• Screen at baseline; 

consider annual 

screening for high-risk 

patients, and if clinically 

indicated.

• HCV positive • Patient has chronic 

hepatitis C infection 

or past infection with 

spontaneous clearance 

(no protective immunity); 

confirm positive results 

with HCV RNA.

Other Opportunistic Infection Screening Tests

Toxoplasma 

gondii IgG

• Detects past exposure; 

if positive, patient 

has increased risk 

of developing CNS 

toxoplasmosis if CD4 

count <100 cells/μL

• Negative • Repeat if patient 

becomes symptomatic or 

when CD4 count drops to 

≤100 cells/μL.

• Positive • Note as baseline 

information. 

• Start toxoplasmosis 

prophylaxis if CD4 count 

drops to ≤100 cells/μL.

Tuberculosis 

(TB) Screening 

TST (Tuberculin 

Skin Test) 

or IGRA 

(InterferonGamma 

Release Assay) 

(if no history of 

TB or positive 

TB screening 

test in the past) 

• Detects latent TB 

infection (LTBI)

• Normal • Repeat every 12 months 

if high risk of repeated or 

ongoing exposure.

• Repeat if CD4 count was 

<200 cells/μL on initial 

test but increases to >200 

cells/μL on ART.

• Abnormal (TST 

induration ≥5 mm or 

positive IGRA)

• Evaluate for active TB. 

(See chapter Latent 

Tuberculosis Infection.)

Chest X-Ray 

(if pulmonary 

symptoms 

are present or 

positive LTBI 

test)

• Detects latent or 

active diseases

• Normal • Repeat as indicated for 

pulmonary symptoms or 

positive LTBI test.

• Abnormal • Evaluate for TB, PCP, or 

other pathology.
86 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Other Opportunistic Infection Screening Tests (continued)

Papanicolaou 

Test (cervical 

for women; 

consider anal 

for women 

and men)

• Detects abnormal cell 

changes, dysplasia

• Normal • Cervical: Repeat in 6 

months, then annually if 

negative on two tests and 

no ongoing risk factors. 

• Anal: No national 

guidelines; consider 

screen at baseline. 

Follow-up interval has 

not been determined; 

consider same as in 

cervical Pap screening.

• Abnormal • Perform workup, treat 

(see chapters Cervical 

Dysplasia and Anal 

Dysplasia) and follow up 

as indicated by condition.

Pregnancy Screening

Pregnancy Test • Indicates pregnancy 

status

• Positive/negative • Perform before starting 

efavirenz (given risk of 

teratogenicity).

• If positive, consider 

ART initiation; avoid 

efavirenz in first trimester 

(see chapters Reducing 

Perinatal HIV Transmission

and Care of HIV-Infected 

Pregnant Women).

Sexually Transmitted Disease Testing

Serum VDRL 

(Venereal 

Disease 

Research 

Laboratory) 

or RPR (Rapid 

Plasma Reagin)

(some centers 

screen using 

a treponemal 

test)

• Screen for syphilis at 

least annually in sexually 

active persons who are 

at risk; for men who have 

sex with men (MSM) with 

multiple partners: every 

3-6 months

• Negative/nonreactive • Counsel about safer sex 

and avoiding STDs.

• Repeat every 3-12 

months, depending on 

risk factors.

• Positive/reactive: 

confirm with 

treponemal test

• Treat patient; refer 

partner(s) for evaluation 

and treatment; counsel 

about safer sex. (See 

chapter Syphilis.)

• Perform serial testing 

if monitoring active 

disease. (See chapter 

Syphilis.)
Initial and Interim Laboratory and Other Tests | 87

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Women

Gonorrhea (GC) 

and Chlamydia 

(CT) Testing

Screen for STDs in sexually 

active women at risk 

according to CDC and USPSTF 

guidelines; screen all ≤25 

years of age at baseline 

and at least annually; more 

frequently if risk factors

Screen all sites of possible 

exposures: 

• Pharynx (recommended 

for GC screening)

• Cervix/vagina

• Rectum

• Negative • Counsel about safer sex 

and avoiding STDs. 

• Repeat every 6-12 

months; more frequently 

if at high risk (e.g., 

adolescents).

• Positive • Treat patient; refer 

partner(s) of previous 60 

days for evaluation and 

treatment; counsel about 

safer sex.

• Retest at 3 months.

Trichomoniasis 

Testing

• Wet mount (insensitive), 

culture or nucleic acid 

amplification test (NAAT) 

of vaginal secretions

• Screen HIV-infected 

women annually

• Negative • Counsel about safer sex 

and avoiding STDs.

• Repeat every 12 months.

• Positive • Treat patient; refer 

partner(s) for evaluation 

and treatment; counsel 

about safer sex.

• Retest at 3 months.

Men

Gonorrhea (GC) 

and Chlamydia 

(CT) Testing

• Screen for STDs in 

sexually active men who 

are at risk according to 

CDC guidelines, especially 

MSM

• Screen all MSM at baseline 

and at least annually; 

frequency of subsequent 

testing depends on risk 

factors

• Screen sites of possible 

exposures: 

• Pharynx, if 

receptive oral sex 

(recommended for GC 

screening)

• Rectum, if receptive 

anal sex

• Urethra for MSM, 

if insertive oral 

or anal sex

• Negative • Counsel about safer sex 

and avoiding STDs.

• Retest every 3-12 months, 

depending on risk 

factors.

• Positive • Treat; refer partner(s) 

of previous 60 days 

for evaluation and 

treatment; counsel about 

safer sex.

• Retest at 3 months.
88 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Test Rationale Result Frequency and Comments

Consider/Optional

G6PD Level • Prevent hemolytic reactions 

to certain medications 

by screening higherrisk patients (African, 

Mediterranean, Asian, 

Sephardic Jewish descent); 

some would recommend 

screening all patients

• Normal range • No intervention is 

necessary beyond 

documentation.

• Abnormal range • Avoid oxidant drugs such 

as dapsone, primaquine, 

and sulfonamides, if 

possible.

Cytomegalovirus (CMV) Antibody (anti-CMV 

IgG) (for those 

at low risk of 

CMV, especially 

those who are 

not MSM or 

injection drug 

users)

• Detects exposure; may 

reveal future disease risk

• Negative • Avoid exposure by 

practicing safer sex. 

• If blood transfusion 

is required, use CMVnegative or leukocytereduced blood.

• Positive • Be aware of disease risk in 

advanced HIV infection, 

when CD4 count is <50 

cells/μL.

Varicella zoster 

(Varicella IgG) 

(for those 

without history 

of chickenpox 

or shingles)

• Detects exposure • Negative • Consider vaccination, if 

CD4 count is >200 cells/μL.

• Positive • No intervention is 

necessary.

Dilated Retinal 

Examination 

• Detects CMV, ophthalmic 

toxoplasmosis, or HIV 

retinopathy

• Normal • If CD4 count is >100 cells/

μL, repeat annually. 

• If CD4 count is <50 cells/

μL or symptoms of retinal 

changes are present, 

repeat every 6 months.

• Abnormal • Follow up immediately 

with ophthalmologist.
Initial and Interim Laboratory and Other Tests | 89

Section 2: Testing 

and Assessment

Patient Education

• Discuss safer sex (review specifics 

appropriate to the patient’s sexual practices 

and infections) to prevent the patient’s 

exposure to herpes, hepatitis B, hepatitis 

C, and other STDs, and to prevent the 

patient from exposing others to HIV or 

other pathogens. In addition, remind the 

patient that safer sex practices will limit the 

risk of reinfection with HIV. (See chapters 

Preventing HIV Transmission/Prevention 

with Positives and Preventing Exposure to 

Opportunistic and Other Infections.)

• If Toxoplasma IgG test result is negative, 

see chapter Preventing Exposure to 

Opportunistic and Other Infections.

• If CMV test result is negative, counsel the 

patient that CMV is shed in semen, vaginal 

and cervical secretions, saliva, and urine 

of infected people. Latex condoms will 

help reduce risk. For women considering 

childbearing, CMV should be avoided to 

prevent severe disease and even death of the 

neonate. (See chapter Preventing Exposure to 

Opportunistic and Other Infections.)

• For patients who are hepatitis C negative 

and are using injection drugs, offer referral 

to a drug treatment program or a clean 

needle exchange program. (See chapters 

Preventing HIV Transmission/Prevention 

with Positives and Preventing Exposure to 

Opportunistic and Other Infections.)

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency 

virus: 2013 update by the HIV Medicine 

Association of the Infectious Diseases 

Society of America. Clin Infect Dis. 2014 

Jan;58(1):e1-e34.

• Bartlett JG, Cheever L. A Guide to Primary 

Care of People with HIV/AIDS, 2004 Edition.

Rockville, MD: Department of Health and 

Human Services, HIV/AIDS Bureau. 2004.

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 17; 59 

(No. RR-12):1-110. 

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines 

for the use of antiretroviral agents in 

HIV-1-infected adults and adolescents. 

Department of Health and Human Services. 

Available at aidsinfo.nih.gov/guidelines/

AdultandAdolescentGL.pdf. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.

Interim History and Physical Examination | 91

Section 2: Testing 

and Assessment

Interim History and 

Physical Examination

Background

This chapter shows the suggested frequency 

and follow-up intervals of the history and 

physical examination for monitoring HIVinfected patients, as well as specific areas 

to assess in an ongoing manner. With 

this information, the clinician can track 

disease progression and formulate and 

maintain an appropriate care plan. Note 

that information gathered in the history or 

physical examination may indicate a need for 

additional directed explorations.

It is important to document new or ongoing 

symptoms and functional limitations at 

each visit. This information is particularly 

useful when outside agencies must determine 

the patient’s disability status. (See chapter 

Karnofsky Performance Scale.)

See chapter Initial and Interim Laboratory and 

Other Tests for recommended screening tests.

HRSA HAB Performance Measures

Percentage of patients, regardless of age, 

with a diagnosis of HIV who had at least one 

medical visit in each 6-month period of 

the 24-month measurement period with a 

minimum of 60 days between medical visits

(Core measure)

Percentage of female patients with a 

diagnosis of HIV who have a Pap screening 

in the measurement yearr

(Adult and Adolescent measure)

Percentage of patients with a diagnosis of 

HIV who received HIV risk counseling in 

the measurement year

(Adult and Adolescent measure)

Percentage of new patients with a 

diagnosis of HIV who have been screened 

for substance use (alcohol and drugs) in 

the measurement year

(Adult and Adolescent measure)

Percentage of patients aged 12 years and 

older screened for clinical depression

on the date of the encounter using an 

age-appropriate standardized depression 

screening tool AND, if positive, a followup plan is documented on the date of the 

positive screen

(Adult and Adolescent measure)
92 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Table 1. History and Physical Examinations

History Physical Examination

Every visit (at least every 3-4 months)

• New symptoms

• Medications 

• HIV-related medications

• Medications for other conditions

• Over-the-counter medications

• Herbs or vitamins

• Adherence to medications and clinical care visits

• Antiretroviral (ARV) doses missed in the past 3 

days, in the past month

• Knowledge of HIV regimen

• HIV transmission risk behaviors and risk reduction 

methods

• Sexual history (risk factors for STDs)

• Mood

• Alcohol and recreational drug use

• Tobacco use

• Allergies

• Pain

• Social supports

• Housing

• Insurance

• Intimate partner violence

• Vital signs (temperature, blood pressure, heart 

rate, respiratory rate, and oxygen saturation)

• Weight

• General appearance and body habitus (including 

evaluation for lipodystrophy)

• Skin

• Oropharynx

• Lymph nodes

• Heart and lungs

• Abdomen

• Neurologic

• Psychiatric (e.g., mood, affect, and attention)

Every 6 months

As above As above, plus: 

• Vision and funduscopic examination (if CD4 

count <100 cells/μL)

• Ears/nose

Every 6 months (twice), and, if both are normal, annually thereafter

(see chapters Cervical Dysplasia and Anal Dysplasia) 

As above • Women: pelvic examination; cervical 

Papanicolaou (Pap) test; consider anorectal 

examination, anal Pap test

• Men: consider anal examination, anal Pap test

Annually

Update initial history: HIV-related symptoms, 

hospitalizations, major illnesses, and family history

Complete physical to include: 

• Genitorectal examination

• Testicular examination

• Prostate examination

• Breast examination
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References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency 

virus: 2013 update by the HIV Medicine 

Association of the Infectious Diseases 

Society of America. Clin Infect Dis. 2014 

Jan;58(1):e1-e34.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

HIV Classification: CDC and WHO Staging Systems | 95

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HIV Classification: CDC and 

WHO Staging Systems

Background 

HIV disease staging and classification systems are critical tools for tracking and monitoring the 

HIV epidemic and for providing clinicians and patients with important information about HIV 

disease stage and clinical management. Two major classification systems currently are in use: the 

U.S. Centers for Disease Control and Prevention (CDC) classification system and the World Health 

Organization (WHO) Clinical Staging and Disease Classification System.

The CDC disease staging system (most recently revised in 1993) assesses the severity of HIV 

disease by CD4 cell counts and by the presence of specific HIV-related conditions. The definition of 

AIDS includes all HIV-infected individuals with CD4 counts of <200 cells/μL (or CD4 percentage 

<14%) as well as those with certain HIV-related conditions and symptoms. Although the fine 

points of the classification system rarely are used in the routine clinical management of HIVinfected patients, a working knowledge of the staging criteria (in particular, the definition of 

AIDS) is useful in patient care. In addition, the CDC system is used in clinical and epidemiologic 

research.

In contrast to the CDC system, the WHO Clinical Staging and Disease Classification System 

(revised in 2007) can be used readily in resource-constrained settings without access to CD4 

cell count measurements or other diagnostic and laboratory testing methods. The WHO system 

classifies HIV disease on the basis of clinical manifestations that can be recognized and treated 

by clinicians in diverse settings, including resource-constrained settings, and by clinicians with 

varying levels of HIV expertise and training.

S: Subjective

When a patient presents with a diagnosis of 

HIV infection, review the patient’s history to 

elicit and document any HIV-related illnesses 

or symptoms (see chapter Initial History).

O: Objective

Perform a complete physical examination and 

appropriate laboratory studies (see chapters 

Initial Physical Examination and Initial and 

Interim Laboratory and Other Tests).

A: Assessment

Confirm HIV infection and perform staging.

P: Plan

Evaluate symptoms, history, physical 

examination results, and laboratory results, 

and make a staging classification according to 

the CDC or WHO criteria (see below). 

CDC Classification System 

for HIV Infection

The CDC categorization of HIV/AIDS 

is based on the lowest documented CD4 

cell count and on previously diagnosed 

HIV-related conditions (see Table 1). For 

example, if a patient had a condition that 

once met the criteria for category B but now 

is asymptomatic, the patient would remain 

in category B. Additionally, categorization 

is based on specific conditions, as indicated 

below. Patients in categories A3, B3, and C1-C3 

are considered to have AIDS.
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Table 1. CDC Classification System for HIV-Infected Adults and Adolescents

CD4 Cell Count 

Categories

Clinical Categories

A 

Asymptomatic, Acute 

HIV, or PGL

B*

Symptomatic 

Conditions, not A or C

C#

AIDS-Indicator 

Conditions

(1) ≥500 cells/μL A1 B1 C1

(2) 200-499 cells/μL A2 B2 C2

(3) <200 cells/μL A3 B3 C3

Abbreviations: PGL = persistent generalized lymphadenopathy

* Category B Symptomatic Conditions

Category B symptomatic conditions are 

defined as symptomatic conditions occurring 

in an HIV-infected adolescent or adult that 

meet at least one of the following criteria:

• They are attributed to HIV infection or 

indicate a defect in cell-mediated immunity.

• They are considered to have a clinical course 

or management that is complicated by HIV 

infection.

Examples include, but are not limited to, the 

following:

• Bacillary angiomatosis

• Oropharyngeal candidiasis (thrush)

• Vulvovaginal candidiasis, persistent or 

resistant

• Pelvic inflammatory disease (PID)

• Cervical dysplasia (moderate or severe)/

cervical carcinoma in situ

• Hairy leukoplakia, oral

• Herpes zoster (shingles), involving two or 

more episodes or at least one dermatome

• Idiopathic thrombocytopenic purpura

• Constitutional symptoms, such as fever 

(>38.5oC) or diarrhea lasting >1 month

• Peripheral neuropathy

# Category C AIDS-Indicator Conditions

• Bacterial pneumonia, recurrent (two or 

more episodes in 12 months)

• Candidiasis of the bronchi, trachea, or lungs

• Candidiasis, esophageal

• Cervical carcinoma, invasive, confirmed by 

biopsy

• Coccidioidomycosis, disseminated or 

extrapulmonary

• Cryptococcosis, extrapulmonary

• Cryptosporidiosis, chronic intestinal (>1 

month in duration)

• Cytomegalovirus disease (other than liver, 

spleen, or nodes)

• Encephalopathy, HIV-related

• Herpes simplex: chronic ulcers (>1 month 

in duration), or bronchitis, pneumonitis, or 

esophagitis

• Histoplasmosis, disseminated or 

extrapulmonary

• Isosporiasis, chronic intestinal (>1-month in 

duration)

• Kaposi sarcoma

• Lymphoma, Burkitt, immunoblastic, or 

primary central nervous system

• Mycobacterium avium complex (MAC) or 

Mycobacterium kansasii, disseminated or 

extrapulmonary
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• Mycobacterium tuberculosis, pulmonary or 

extrapulmonary 

• Mycobacterium, other species or 

unidentified species, disseminated or 

extrapulmonary

• Pneumocystis jiroveci (formerly carinii) 

pneumonia (PCP)

• Progressive multifocal leukoencephalopathy 

(PML)

• Salmonella septicemia, recurrent 

(nontyphoid)

• Toxoplasmosis of brain

• Wasting syndrome caused by HIV 

(involuntary weight loss >10% of baseline 

body weight) associated with either chronic 

diarrhea (two or more loose stools per day 

for ≥1 month) or chronic weakness and 

documented fever for ≥1 month

WHO Clinical Staging of HIV/

AIDS and Case Definition

The clinical staging and case definition of 

HIV for resource-constrained settings were 

developed by the WHO in 1990 and revised 

in 2007. Staging is based on clinical findings 

that guide the diagnosis, evaluation, and 

management of HIV/AIDS, and it does not 

require a CD4 cell count. This staging system is 

used in many countries to determine eligibility 

for antiretroviral therapy, particularly in 

settings in which CD4 testing is not available. 

Clinical stages are categorized as 1 through 4, 

progressing from primary HIV infection to 

advanced HIV/AIDS (see Table 2). These stages 

are defined by specific clinical conditions 

or symptoms. For the purpose of the WHO 

staging system, adolescents and adults are 

defined as individuals aged ≥15 years.

Table 2. WHO Clinical Staging of HIV/AIDS for Adults and Adolescents

Primary HIV Infection

• Asymptomatic • Acute retroviral syndrome

Clinical Stage 1

• Asymptomatic • Persistent generalized lymphadenopathy

Clinical Stage 2

• Moderate unexplained weight loss (<10% of 

presumed or measured body weight)

• Recurrent respiratory infections (sinusitis, 

tonsillitis, otitis media, and pharyngitis)

• Herpes zoster 

• Angular cheilitis 

• Recurrent oral ulceration

• Papular pruritic eruptions

• Seborrheic dermatitis

• Fungal nail infections

Clinical Stage 3

• Unexplained severe weight loss (>10% of 

presumed or measured body weight)

• Unexplained chronic diarrhea for >1 month

• Unexplained persistent fever for >1 month 

(>37.6oC, intermittent or constant)

• Persistent oral candidiasis (thrush)

• Oral hairy leukoplakia

• Pulmonary tuberculosis (current) 

• Severe presumed bacterial infections (e.g., 

pneumonia, empyema, pyomyositis, bone 

or joint infection, meningitis, bacteremia)

• Acute necrotizing ulcerative stomatitis, 

gingivitis, or periodontitis

• Unexplained anemia (hemoglobin <8 g/dL)

• Neutropenia (neutrophils <500 cells/μL)

• Chronic thrombocytopenia 

(platelets <50,000 cells/μL)
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Clinical Stage 4

• HIV wasting syndrome, as defined by the CDC 

(see Table 1, above)

• Pneumocystis pneumonia

• Recurrent severe bacterial pneumonia

• Chronic herpes simplex infection (orolabial, 

genital, or anorectal site for >1 month or visceral 

herpes at any site)

• Esophageal candidiasis (or candidiasis of trachea, 

bronchi, or lungs)

• Extrapulmonary tuberculosis

• Kaposi sarcoma

• Cytomegalovirus infection (retinitis or infection 

of other organs)

• Central nervous system toxoplasmosis

• HIV encephalopathy

• Cryptococcosis, extrapulmonary (including 

meningitis)

• Disseminated nontuberculosis mycobacteria 

infection

• Progressive multifocal leukoencephalopathy

• Candida of the trachea, bronchi, or lungs

• Chronic cryptosporidiosis (with diarrhea)

• Chronic isosporiasis

• Disseminated mycosis (e.g., histoplasmosis, 

coccidioidomycosis, penicilliosis)

• Recurrent nontyphoidal Salmonella bacteremia

• Lymphoma (cerebral or B-cell non-Hodgkin)

• Invasive cervical carcinoma

• Atypical disseminated leishmaniasis

• Symptomatic HIV-associated nephropathy

• Symptomatic HIV-associated cardiomyopathy

• Reactivation of American trypanosomiasis 

(meningoencephalitis or myocarditis)

References 

• Centers for Disease Control and Prevention. 

1993 revised classification system for HIV 

infection and expanded surveillance case 

definition for AIDS among adolescents and 

adults. MMWR Recomm Rep. 1992 Dec 

18;41(RR-17):1-19. Available at www.cdc.gov/

mmwr/preview/mmwrhtml/00018871.htm. 

Accessed December 1, 2013.

• Centers for Disease Control and 

Prevention. Guidelines for national 

human immunodeficiency virus case 

surveillance, including monitoring for 

human immunodeficiency virus infection 

and acquired immunodeficiency syndrome.

MMWR Recomm Rep. 1999 Dec 10;48(RR13):1-27, 29-31. Available at www.cdc.gov/

mmwr/preview/mmwrhtml/rr4813a1.htm. 

Accessed December 1, 2013.

• World Health Organization. WHO Case 

Definitions of HIV for Surveillance and 

Revised Clinical Staging and Immunological 

Classification of HIV-Related Disease in 

Adults and Children; 2007.
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CD4 and Viral Load Monitoring

Background 

The CD4 cell count and HIV viral 

load (RNA level) are closely linked to 

HIV-related illness and mortality. They 

give prognostic information on HIV 

progression and on response to therapy.

CD4 Monitoring

CD4 lymphocyte cells (also called T-cells 

or T-helper cells) are the primary targets of 

HIV. The CD4 count and the CD4 percentage 

mark the degree of immunocompromise. The 

CD4 count is the number of CD4 cells per 

microliter (μL) of blood. It is used to stage 

the patient’s disease, determine the risk of 

opportunistic illnesses, assess prognosis, and 

guide decisions about the urgency of starting 

antiretroviral therapy (ART) (see chapters Risk 

of HIV Progression/Indications for ART and 

Antiretroviral Therapy). The CD4 percentage is 

the percentage of the lymphocyte population 

that is CD4+; it is measured directly by flow 

cytometry. A CD4 percentage of <14% is 

considered to correspond to the same degree of 

immunosuppression as an absolute CD4 count 

of <200 cells/μL. The absolute CD4 count is 

calculated from the CD4 cell percentage and 

the total white blood cell count. 

The normal values for CD4 count vary 

considerably among different laboratories. 

The mean normal value for most laboratories 

is approximately 500-1,300 cells/μL. This 

calculated value is subject to more fluctuations 

than the CD4 cell percentage. Illness, 

vaccination, diurnal variation, laboratory 

error, and some medications can result in 

transient CD4 cell count changes, whereas 

the CD4 percentage remains more stable. 

Because CD4 counts may vary, treatment 

decisions generally should not be made on the 

basis of a single CD4 value. When results are 

inconsistent with previous trends, tests should 

be repeated, and treatment decisions usually 

should be based on two or more similar 

values. A change between two test results is 

considered significant if it is a 30% change 

in absolute CD4 count or 3 percentage point 

change in CD4 percentage.

In persons with untreated HIV infection, the 

CD4 count declines by approximately 50-80 

cells/μL per year, on average. The pattern of 

decline may be slow and steady, or the CD4 

count may level off for an extended period of 

time (as in long-term nonprogressors) and then 

decrease. Although it takes an average of 10 

years for a newly infected person to progress to 

AIDS, there is great variation among patients. 

For some patients, disease progression occurs 

within a year or two. For others, it takes more 

than 20 years, and a small number of patients 

appear to maintain high CD4 counts and 

undetectable HIV RNA levels without ART 

(aviremic or “elite” controllers).

Among asymptomatic individuals, the CD4 

count until recent years was the major factor 

that guided the decision to initiate therapy, 

and it remains so in resource-limited areas of 

HRSA HAB Performance Measures

Percentage of patients, aged 6 months and older with a 

diagnosis of HIV/AIDS, with at least two CD4 cell counts or 

percentages performed during the measurement year at 

least 3 months apart

(All-Age measure)

Percentage of patients, regardless of age, with a diagnosis 

of HIV with a viral load test performed at least every 6 

months during the measurement year

(All-Age measure)
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the world. Current United States guidelines 

recommend treatment for all HIV-infected 

individuals regardless of CD4 count. The CD4 

count, though, can help clinicians and patients 

decide how quickly to start therapy. Clinical 

status, viral load, pregnancy, comorbidities, 

patient adherence to medications, and risk of 

HIV transmission are among the other factors 

that should be taken into consideration (see 

chapters Risk of HIV Progression/Indications 

for ART and Antiretroviral Therapy). 

Prophylaxis against opportunistic infections 

is based on CD4 count, and sometimes on 

CD4 percentage. For example, a CD4 count 

of <200 cells/μL or a CD4 percentage of 

<14% is an indication for prophylaxis against 

Pneumocystis jiroveci pneumonia; a CD4 

count of <50 cells/μL is an indication for 

prophylaxis against Mycobacterium avium

complex. (See chapters Opportunistic Infection 

Prophylaxis and Risk of HIV Progression/

Indications for ART.) The CD4 count also 

guides decision making in determining when 

to stop prophylaxis against opportunistic 

infections with patients whose CD4 counts rise 

in response to ART.

Effective ART typically results in CD4 count 

increases of >50 cells/μL within weeks after 

viral suppression, and increases of 50-100 

cells/μL per year thereafter. For some patients, 

CD4 counts may not increase that quickly 

or steadily, even with durable viral load 

suppression. Patients who are older (age >50) 

and those with lower baseline CD4 cell counts 

are more likely to have blunted CD4 count 

responses. For monitoring purposes, the CD4 

count should be repeated approximately every 

3-6 months both in stable untreated patients 

and in patients on ART. For patients on ART 

with persistently suppressed HIV RNA and 

CD4 counts solidly above thresholds for 

opportunistic infection risk, current guidelines 

suggest monitoring every 6-12 months, and 

some data demonstrate that even less frequent 

CD4 checks in such patients is safe. The CD4 

count should be checked more often if clinically 

indicated (e.g., switching therapy, ART failure, 

rapidly declining CD4 count) (see Table 1).

Viral Load Monitoring

The HIV-1 viral load measurement indicates 

the number of copies of HIV-1 RNA 

per milliliter of plasma. Although HIV 

ultimately resides within cells, the plasma 

measurement is an accurate reflection of the 

burden of infection and the magnitude of 

viral replication. It is used to assess the risk 

of disease progression and can help guide 

initiation of therapy. It is critical in monitoring 

virologic response to ART.

There are several commercially available HIV1 viral load assays and numerous institutionspecific assays. The range of detectable virus 

differs somewhat with each test, but the lowest 

level of detection generally is 20-75 copies/

mL. A viral load below this “undetectable” 

level indicates the inability of the assay to 

detect HIV in the plasma, but does not indicate 

absence or clearance of the virus from the 

body. The highest levels of detection of the 

viral load assays typically are between 500,000 

copies/mL and 750,000 copies/mL. Viral 

loads higher than these levels are reported, for 

example, as >500,000 copies/mL. Note that 

commercially available assays may not detect 

HIV-2, and they do not accurately quantify it.

After initial infection with HIV, the viral 

load quickly peaks to very high levels, usually 

>100,000 copies/mL (see chapter Early HIV 

Infection). During the period of acute infection, 

when HIV antibody testing may indicate 

negative results, the viral load test may be used 

to detect HIV infection. Generally, 3-6 months 

after primary infection, the viral load declines 

and then levels off, remaining in a steady state. 

Among patients who are not taking ARV 

medications, a small number maintain a low or 

even undetectable viral load (aviremic or “elite” 

controllers), but the vast majority of those 

patients have relatively high HIV RNA levels.
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Higher plasma viral loads are associated with 

more rapid declines in CD4 cells and with 

increased risk of progression to symptomatic 

disease and AIDS; they also are associated 

with higher risk of HIV transmission (see 

chapter Risk of HIV Progression/Indications 

for ART). In untreated persons, the CD4 

cell count is more useful in determining the 

urgency of ART initiation, but once a patient 

has started ART, the viral load is used to 

monitor the response to therapy. A key goal 

of ART is to achieve a viral load that is below 

the level of quantitation (e.g., <40 copies/

mL). Because CD4 and clinical responses 

may lag behind changes in viral load, viral 

load testing is essential for detecting virologic 

failure in a timely manner. With an effective 

ARV regimen, a decline of at least 10-fold 

(1 logarithm) is expected within the first 

month, and suppression to undetectable 

levels should be achieved within 3-6 months 

after initiation of therapy. Isolated low-level 

elevations (typically <400 copies/mL) in viral 

load may occur in patients on ART; these 

“blips” generally do not predict subsequent 

virologic failure. (Additionally, some viral load 

assays appear to produce low-level positive 

results [<200 copies/mL] more commonly 

than others; as with blips, these do not in 

general appear to increase the risk of virologic 

failure.) To avoid confusing virologic failure 

with blips or test variability, current guidelines 

define virologic failure as repeated HIV RNA 

levels >200 copies/mL. If the viral load does 

not reduce to an undetectable level (or at 

least <200 copies/mL), or if it rebounds after 

suppression, virologic failure has occurred, 

and possible causes should be investigated 

(e.g., poor ARV adherence, resistance to 

ARVs, or reduced drug exposure).

The HIV viral load should be checked at 

least twice at baseline, before the patient 

starts an ART regimen. Follow-up viral load 

measurement should be performed at regular 

intervals, depending on the patient’s clinical 

situation (see Table 1). For stable patients, 

viral load usually should be monitored every 

3-4 months; for highly adherent and stable 

patients with suppressed viral loads for at 

least several years, monitoring every 6 months 

is adequate. With new therapy or changes in 

therapy, significant change in viral load or 

CD4 count, or declining clinical status, the 

viral load should be measured at more frequent 

intervals.

Table 1. CD4 and HIV Viral Load Monitoring Schedule

Baseline

Follow-Up 

Before ART 

Initiation

At ART 

Initiation or 

Switch

After ART 

Initiation or 

Switch

Follow-Up 

on Effective 

ART

Treatment 

Failure or 

Clinical 

Indications

CD4 Count √ Every 3-6 

months

√ 3-6 months Every 3-6 

months*

√

HIV Viral 

Load

√ Every 3-6 

months

√ 2-8 weeks, 

then every 

4-8 weeks 

until HIV 

RNA is 

undetectable

Every 3-4 

months**

√

* Clinically stable patients on ART with sustained viral suppression and CD4 counts above threshold for opportunistic infection risk: may 

monitor every 6-12 months.

**Adherent patients on stable ART with viral suppression and stable immunologic status for >2-3 years: can consider monitoring every 

6 months.

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected 

adults and adolescents. Department of Health and Human Services. Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.
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Viral loads, like CD4 counts, are affected 

by laboratory variation, assay fluctuations, 

and patient variables such as acute illness 

and recent vaccinations. Variations of 

<0.5 log10 copies/mL (threefold) usually 

are not clinically significant. Viral load 

results that are inconsistent with previous 

trends should be repeated, and treatment 

decisions usually should be based on two 

or more similar values. Recent illnesses or 

vaccinations can transiently increase viral 

load. If a patient has had a recent illness or 

vaccination, the viral load measurement 

should be deferred for 4 weeks, if possible.

Patient Education

• The CD4 cell count is the best indicator for 

gauging the strength of the immune system 

and for determining whether a person is at 

risk of infection with certain organisms. 

The higher the CD4 count, the stronger the 

immune system.

• CD4 counts are variable. Caution patients 

not to pin emotions and hopes to a single 

laboratory result. A change of <30% may not 

be significant.

• The HIV viral load is the best indicator of 

the level of HIV activity in the patient’s 

body.

• The CD4 count and HIV viral load may 

be used to help determine how urgently 

therapy is needed (note, though, that current 

guidelines recommend ART for all persons 

with HIV infection, regardless of CD4 or 

viral load).

• A key goal of therapy is to suppress the viral 

load to below the level of detectability by 

laboratory tests. An undetectable viral load 

does not mean HIV has been completely 

eradicated or that the patient is not 

infectious to others.

• For most patients on effective ART, the CD4 

count will rise as the virus is suppressed. 

This indicates an improvement in the 

immune system.

• In stable patients on ART, the CD4 count 

and HIV viral load usually should be 

monitored every 3-6 months.

References

• Hogg RS, Yip B, Chan KJ, et al. Rates 

of disease progression by baseline 

CD4 cell count and viral load after 

initiating triple-drug therapy. JAMA. 

2001 Nov 28;286(20):2568-77.

• Palella FJ, Deloria-Knoll M, Chmiel JS, et al. 

Survival benefit of initiating antiretroviral 

therapy in HIV-infected persons in different 

CD4+ cell strata. Ann Intern Med. 2003 Apr 

15;138(8):620-6.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Schacker TW, Hughes JP, Shea T, et al. 

Biological and virologic characteristics of 

primary HIV infection. Ann Intern Med. 

1998 Apr 15; 128(8):613-20.
Risk of HIV Progression/Indications for ART | 103

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Risk of HIV Progression/

Indications for ART

Background 

The CD4 cell count and HIV viral load (RNA level) are closely linked to HIV-related illness 

and mortality, and are the laboratory measures that are followed in clinical practice. They are 

the primary markers that give prognostic information on disease progression and on response 

to antiretroviral therapy (ART) (see chapter CD4 and Viral Load Monitoring). However, it is 

increasingly recognized that a number of other factors are involved in HIV disease progression. 

These include individual HIV-specific immune responses, immune activation, viral factors, 

host genetics, and age. The role of these factors and their interplay is complex and incompletely 

understood.

CD4 Count

The CD4 count (and CD4 percentage) marks 

the degree of immunocompromise. The 

CD4 count is used to stage the patient’s 

disease progression, determine the risk of 

opportunistic illnesses, and assess prognosis 

(see chapter CD4 and Viral Load Monitoring). 

The CD4 count also helps to determine the 

urgency and the timing of ART initiation, and 

the need for prophylaxis against opportunistic 

infections. It also helps in formulating 

differential diagnoses for symptomatic patients 

(see Table 1, Figure 1, and chapters CD4 and 

Viral Load Monitoring and Opportunistic 

Infection Prophylaxis).

Persons with HIV infection are at increased 

risk of complications at lower CD4 counts. 

A CD4 count of <200 cells/μL (or CD4 

percentage of <14%) indicates severe 

immunosuppression, and is an AIDS-defining 

condition. Persons with CD4 counts below 

this level are at greater risk of a number of 

opportunistic illnesses and death, increasingly 

so at lower CD4 counts (see Table 1).
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Table 1. Correlation Between CD4 Cell Counts and Complications of HIV Infection

CD4 

Count* 

(cells/μL) Infectious Complications Noninfectious Complications#

>500 • Acute retroviral syndrome

• Candidal vaginitis

• Persistent generalized lymphadenopathy (PGL)

• Guillain-Barré syndrome

• Myopathy

• Aseptic meningitis

200-500 • Pneumococcal and other bacterial 

pneumonias

• Pulmonary tuberculosis

• Herpes zoster

• Oropharyngeal candidiasis (thrush)

• Cryptosporidiosis (self-limited)

• Kaposi sarcoma (cutaneous)

• Oral hairy leukoplakia

• Herpes simplex (oral/genital)

• Cervical intraepithelial neoplasia

• Cervical cancer

• B-cell lymphoma

• Anemia

• Mononeuropathy multiplex

• Idiopathic thrombocytopenic purpura

• Hodgkin lymphoma

• Lymphocytic interstitial pneumonitis

• Fatigue

<200 • Pneumocystis jiroveci pneumonia (PCP)

• Disseminated histoplasmosis and 

coccidioidomycosis

• Miliary/extrapulmonary tuberculosis

• Progressive multifocal 

leukoencephalopathy (PML)

• Wasting

• Peripheral neuropathy

• HIV-associated dementia

• Cardiomyopathy

• Vacuolar myelopathy

• Progressive polyradiculopathy

• Non-Hodgkin lymphoma

<100 • Disseminated herpes simplex virus

• Toxoplasmosis

• Cryptococcosis

• Cryptosporidiosis, chronic

• Microsporidiosis

• Candidal esophagitis

• Kaposi sarcoma (visceral/pulmonary)

<50 • Disseminated cytomegalovirus (CMV)

• Disseminated Mycobacterium avium

complex (MAC)

• Central nervous system (CNS) lymphoma

* Most complications occur with increasing frequency at lower CD4 cell counts.

# Some conditions listed as “noninfectious” are associated with transmissible microbes. Examples include lymphoma (Epstein-Barr 

virus) and anal and cervical cancers (human papillomavirus).

Adapted from Bartlett JG, Gallant JE, Pham P. 2012 Medical Management of HIV Infection. Baltimore: Johns Hopkins University School of 

Medicine; 2012. Used with permission.

Increasing evidence suggests that the risk of 

complications from HIV infection occurs 

across a broad spectrum of CD4 counts, 

and that patients with relatively high counts 

(those with counts of >350 cells/μL and even 

those with counts of >500 cells/μL) also have 

increased rates of morbidities compared with 

HIV-uninfected persons. The complications 

in persons with higher CD4 counts typically 

are not the classic AIDS-related opportunistic 

illnesses but are “non-AIDS” illnesses such as 

cardiovascular disease, neurocognitive decline, 

and non-AIDS-associated cancers.

In asymptomatic individuals, CD4 count has been 

used as the main indicator of need for ART. It is 

well established that ART is extremely effective 
Risk of HIV Progression/Indications for ART | 105

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at reducing HIV-related illness in persons with 

lower CD4 counts. In recent years, accumulating 

data have suggested that ART also is beneficial for 

persons with high pretreatment CD4 counts. 

Randomized trials have shown that starting 

ART for asymptomatic patients with 

pretreatment CD4 counts of 200-350 cells/μL 

results in decreased morbidity and mortality 

compared with starting therapy for persons 

with CD4 counts of <200 cells/μL. For 

patients with pretreatment CD4 counts of 

>350 cells/μL, data from several randomized 

controlled studies and cohort studies have 

found decreased rates of complications and 

death among persons who initiated ART at 

CD4 counts of ≥350 cells/μL, compared with 

persons who initiated treatment at lower CD4 

counts. Additionally, some (though not all) 

observational evidence suggests a mortality 

benefit of ART even among persons with 

pretreatment CD4 counts of >500 cells/μL. 

These cohort studies are complemented by a 

number of investigations that demonstrate 

ongoing and adverse effects of HIV and 

associated inflammation on various organ 

systems. A randomized controlled trial to 

evaluate the strategy of starting treatment at 

CD4 counts >500 cells/μL is under way.

These lines of evidence, along with studies 

showing a substantial impact of ART in 

decreasing HIV transmission, and the 

availability of ARVs that generally are safe, 

tolerable, and effective, support the rationale for 

earlier initiation of treatment. The current U.S. 

Department of Health and Human Services 

(HHS) adult and adolescent treatment guidelines 

recommend starting ART for all HIV-infected 

persons regardless of CD4 count, both to 

enhance the health of the infected individual and 

to prevent transmission of HIV. The strength 

of this recommendation is greater if the CD4 

count is lower or the clinical status is poorer, and 

according to transmission risk groups (see Table 

2 and chapter Antiretroviral Therapy).

Table 2. HHS Recommendations on Initiation of Antiretroviral Therapy

The HHS guidelines state that, ”Antiretroviral therapy (ART) is recommended for all HIV-infected 

individuals to reduce the risk of disease progression.” The strength and evidence for this 

recommendation vary by pretreatment CD4 cell count, as follows:

 CD4 Criteria Strength of Recommendation*

• CD4 count <350 cells/μL

• CD4 count 350-500 cells/μL

• CD4 count >500 cells/μL

• Strongly recommended (AI)

• Strongly recommended (AII)

• Moderately recommended (BIII)

Additionally, the guidelines state that, “ART also is recommended for HIV-infected individuals for 

the prevention of transmission of HIV.” The strength and evidence for this recommendation vary by 

transmission risk, as follows:

Transmission Risk Group Strength of Recommendation*

• Perinatal transmission

• Heterosexual transmission 

• Other transmission risk groups

• Strongly recommended (AI)

• Strongly recommended (AI)

• Strongly recommended (AIII)

 * Rating of recommendation: A = strong; B = moderate; C = optional

Rating of evidence: I = data from randomized controlled trials; II = data from well-designed 

nonrandomized trials or observational cohort studies; III = expert opinion

Considerations

Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks 

of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on 

a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected 

adults and adolescents. Department of Health and Human Services. Available at aidsinfo. nih.gov/guidelines. Accessed December 1, 

2013.
106 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

A number of factors and coexisting conditions signal the need for speedier initiation 

of therapy, if possible. According to the HHS 

guidelines, these include the following:

• Pregnancy 

• History of AIDS-defining illness 

• Acute opportunistic infection

• Lower CD4 cell count 

• Acute/recent HIV infection 

• HIV-associated nephropathy 

• Hepatitis B coinfection 

• Hepatitis C coinfection 

• Rapidly declining CD4 counts (e.g., >100 

cells/μL per year) 

• Higher HIV RNA (e.g., >100,000 copies/mL)

HIV Viral Load

Whereas the CD4 count is an indicator of 

immune system function, the HIV viral load 

(RNA level) gives prognostic information 

on how quickly the CD4 count is likely to 

decline and, consequently, the risk of disease 

progression. Patients with high HIV viral 

loads generally demonstrate a faster decline 

in CD4 count and progression to AIDSrelated illnesses; they also may have a higher 

rate of non-AIDS-related events even with 

relatively high CD4 counts (e.g., >350 cells/

μL). Those with low viral loads usually have 

higher CD4 counts and remain asymptomatic 

for prolonged periods. A small percentage of 

persons with HIV infection may have very 

low or undetectable viral loads for extended 

periods of time.

By themselves, CD4 count and HIV viral load 

are useful, albeit rough, prognostic indicators. 

When considered together, they constitute a 

finer tool to estimate the risk of progression 

(see Figure 1).

Figure 1. Prognosis According to CD4 Cell 

Count and Viral Load in the Pre-ART and 

ART Eras: Kaplan-Meier Estimates of the 

Probability of AIDS at 3 Years

Abbreviations: HAART = highly active antiretroviral therapy

Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, 

Costagliola D, D’Arminio Monforte A, de Wolf F, Reiss P, Lundgren 

JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, 

Salzberger B, Sterne JA; ART Cohort Collaboration. Prognosis of 

HIV-1-infected patients starting highly active antiretroviral therapy: 

a collaborative analysis of prospective studies. Lancet. 2002 Jul 

13;360(9327):119-29. Reprinted with permission from Elsevier.

Other Factors Associated 

with HIV Progression

Although the CD4 count and HIV viral load 

are the most important predictors of HIV 

progression, it is increasingly recognized that 

a number of other factors, and likely others 

that remain unknown, contribute to disease 

progression in HIV infection.

Viral factors

Variations in the HIV genome have been 

associated with an altered rate of disease 

progression. For example, deletions in the 

nef gene have been associated with a slow 

rate of progression. On the other hand, 

virus that uses the CXCR4 protein as a 

coreceptor for entry (termed X4 virus or 

syncytia-inducing virus) has been associated 

with accelerated progression. As another 

example, drug-resistance mutations may 

100

80

60

40

20

0 >55 20–55 7–20 1.5–7 <1.5

HIV-1 RNA concentration (X10 copies/mL) 3

Pre-HAART era

3-year probability of AIDS (%)

<200 201–350

351–500

>750

CD4 count

(cells/ųL) 501–750

100

80

60

40

20

0 >55 20–55 7–20 1.5–7 <1.5

HIV-1 RNA concentration (X10 copies/mL) 3

Pre-HAART era

<200 201–350

351–500

>750

CD4 count

(cells/ųL) 501–750
Risk of HIV Progression/Indications for ART | 107

Section 2: Testing 

and Assessment

affect how efficiently the virus replicates 

(viral fitness). Patients who have virus with 

decreased fitness have slower immune 

deterioration than those with wild-type virus.

Host immune factors

Host genetic factors have been shown to alter 

the rate of HIV progression. Various human 

leukocyte antigen (HLA) alleles have been 

associated with faster or slower progression 

rates. Genetic polymorphisms also play a role. 

For example, CCR5 is a chemokine receptor 

that can serve as a coreceptor for HIV entry 

into the CD4 cell. A naturally occurring variant 

allele for CCR5 has a 32 base pair deletion. 

Individuals who are heterozygous for this allele 

have slower progression of HIV disease.

Increased immune activation and elevated 

markers of inflammation, such as IL-6 and 

D-dimer, also have been associated with risk 

of disease progression and death. They also 

may be involved in the ongoing damage seen 

in a number of end organs. Although T-cell 

activation and levels of inflammation decrease 

with ART, they often do not return to normal.

Age

Several studies have shown a higher risk of 

morbidity and mortality in older patients. 

When followed from seroconversion, older 

patients demonstrate faster disease progression 

compared with younger patients (see Table 

3). Older patients also are found to have a less 

robust increase in the CD4 count in response 

to ART and may have a higher rate of nonAIDS-related morbidities. 

Table 3. Median Survival and Time to 

AIDS by Age at Seroconversion

Age at 

Seroconversion 

(years)

Median

(95% CI) 

Survival 

(years)

Median

(95% CI) 

Time to AIDS 

(years)

15-24 12.5 (12.1-12.9) 11.0 (10.7-11.7)

25-34 10.9 (10.6-11.3) 9.8 (9.5-10.1)

35-44 9.1 (8.7-9.5) 8.6 (8.2-9.0)

45-54 7.9 (7.4-8.5) 7.7 (7.1-8.6)

55-64 6.1 (5.5-7.0) 6.3 (5.5-7.2)

≥65 4.0 (3.4-4.6) 5.0 (4.0-6.2)

Adapted from Concerted Action on SeroConversion to AIDS and 

Death in Europe. Time from HIV-1 seroconversion to AIDS and death 

before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Collaborative Group on AIDS Incubation and 

HIV Survival including the CASCADE EU Concerted Action. Lancet. 

2000 Apr 1;355(9210):1131-7.

Patient Education

• The CD4 cell count and HIV viral load are 

the two markers that provide information on 

the degree of current immunocompromise 

and the risk of disease progression.

• The lower the CD4 count, the higher the risk 

of AIDS-related illness.

• Current United States guidelines 

recommend ART for all HIV-infected 

individuals. In areas where treatment 

resources are limited, the CD4 count is the 

major indicator for initiation of ART.

• A low HIV viral load is associated with 

slower immune deterioration; a high viral 

load is associated with quicker immune 

deterioration.

• Older individuals may have a poorer 

response to therapy; earlier initiation of 

therapy may be considered for older patients.
108 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

References

• Cohen MS, Chen YQ, McCauley M, et al.; 

HPTN 052 Study Team. Prevention of HIV-1 

infection with early antiretroviral therapy. N 

Engl J Med. 2011 Aug 11;365(6):493-505.

• Collaboration of Observational HIV 

Epidemiological Research Europe 

(COHERE) Study Group. Response to 

combination antiretroviral therapy: variation 

by age. AIDS. 2008 Jul 31;22(12):1463-73.

• Concerted Action on Sero-Conversion to 

AIDS and Death in Europe. Time from HIV1 seroconversion to AIDS and death before 

widespread use of highly-active antiretroviral 

therapy: a collaborative re-analysis. 

Collaborative Group on AIDS Incubation 

and HIV Survival including the CASCADE 

EU Concerted Action. Lancet. 2000 Apr 

1;355(9210):1131-7.

• Connor RI, Sheridan KE, Ceradini D, et 

al. Change in coreceptor use coreceptor use 

correlates with disease progression in HIV1-infected individuals. J Exp Med. 1997 Feb 

17;185(4):621-8.

• Deeks SG, Wrin T, Liegler T, et al. 

Virologic and immunologic consequences 

of discontinuing combination antiretroviral 

drug therapy in HIV-infected patients with 

detectable viremia. N Engl J Med. 2001 Feb 

15;344(7):472-80.

• Egger M, May M, Chêne G, et al. Prognosis 

of HIV-1-infected patients starting highly 

active antiretroviral therapy: a collaborative 

analysis of prospective studies. Lancet. 2002 

Jul 13;360(9327):119-29.

• European AIDS Clinical Society. Clinical 

Management and Treatment of HIV-Infected 

Adults in Europe. English Version 5; 

November 2009.

• Kirchhoff F, Greenough TC, Brettler DB, 

et al. Brief report: absence of intact nef 

sequences in a long-term survivor with 

nonprogressive HIV-1 infection. N Engl J 

Med. 1995 Jan 26;332(4):228-32.

• Kuller L, SMART Study Group. Elevated levels of 

interleukin-6 and D-dimer are associated with an 

increased risk of death in patients with HIV. In: 

Program and Abstracts of the 15th Conference 

on Retroviruses and Opportunistic Infections; 

Boston; February 3-6, 2008. Abstract 139.

• Lederman MM, Rodriquez B, Sieg S. 

Immunopathogenesis of HIV Infection. 

In: Coffey S, Volberding PA, eds. 

HIV InSite Knowledge Base [online 

textbook]. San Francisco: UCSF 

Center for HIV Information; January 

2006. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-02-01-04. 

Accessed December 1, 2013.

• Mellors JW, Rinaldo CR Jr, Gupta P, et al. 

Prognosis in HIV-1 infection predicted by 

the quantity of virus in plasma. Science. 

1996;272:1167-70.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Reekie J, Gatell JM, Yust I, et al.; EuroSIDA 

in EuroCoord. Fatal and nonfatal AIDS 

and non-AIDS events in HIV-1-positive 

individuals with high CD4 cell counts 

according to viral load strata. AIDS. 2011 

Nov 28;25(18):2259-68.

• Rodríguez B, Sethi AK, Cheruvu VK, 

et al. Predictive value of plasma HIV 

RNA level on rate of CD4 T-cell decline 

in untreated HIV infection. JAMA. 

2006 Sep 27;296(12):1498-506.

• Sterne JA, May M, Costagliola D, et al; When 

to Start Consortium. Timing of initiation of 

antiretroviral therapy in AIDS-free HIV-1-

infected patients: a collaborative analysis 

of 18 HIV cohort studies. Lancet. 2009 Apr 

18;373(9672):1352-63.
Early HIV Infection | 109

Section 2: Testing 

and Assessment

Early HIV Infection

Background 

Acute HIV infection refers to the very early stages of HIV infection, or the interval from initial 

infection to the time that antibody to HIV is detectable; early HIV infection usually includes 

the first 6 months of infection. During the acute stage of HIV infection, patients typically have 

symptoms of acute retroviral illness, very high HIV RNA levels (>100,000 copies/mL) and 

detectable p24 antigen, and negative or indeterminate HIV antibody test results.

Diagnosing patients with acute HIV infection is a clinical challenge. The symptoms of acute HIV 

are nonspecific, and although many patients seek medical care for symptoms of acute retroviral 

syndrome, the diagnosis commonly is missed at initial presentation. The difficulties involve 

recognizing the clinical presentation of acute HIV infection and testing patients appropriately. In 

HIV treatment facilities, clinicians generally do not see patients with primary HIV infection unless 

they are referred with the diagnosis already established. In other health care settings, clinicians 

may not be familiar with the signs and symptoms of acute HIV infection and often do not consider 

this diagnosis. Despite the difficulties, recognizing early HIV infection in symptomatic patients is 

essential. Early diagnosis provides an opportunity for early linkage to HIV care and treatment and 

may decrease future HIV transmission by newly identified patients, who are particularly infectious 

during early untreated HIV infection.

After infection with HIV, it takes a median of about 25 days before the HIV antibodies are 

detectable in most people; in some individuals, it may be several months before seroconversion 

occurs. HIV RNA may be detectable within 10 days of infection and p24 antigen in about 15-20 

days. Persons with known exposures to HIV, whether occupational or not, should be monitored 

closely beginning at about 3 weeks after exposure (routine monitoring at 6 weeks, 3 months, and 

6 months after exposure to HIV is likely to result in delayed diagnosis of HIV infection). For 

information on postexposure prophylaxis, see chapters Nonoccupational Postexposure Prophylaxis 

and Occupational Postexposure Prophylaxis.

S: Subjective

Approximately two thirds of patients infected 

with HIV develop symptoms of acute HIV 

infection, a condition known as acute 

retroviral syndrome. Symptoms typically 

appear 2-6 weeks after exposure to HIV and 

generally include several of the following: 

• Fever (present in 80-90%)

• Rash, often erythematous and 

maculopapular

• Fatigue

• Pharyngitis (with or without exudate)

• Generalized lymphadenopathy

• Urticaria

• Myalgia/arthralgia

• Anorexia

• Mucocutaneous ulceration

• Headache, retroorbital pain

• Neurologic symptoms (e.g., aseptic 

meningitis, radiculitis, myelitis, cranial 

nerve palsies)

This symptomatic phase usually persists for 

2-4 weeks or less, although lymphadenopathy 

may last longer. Symptoms and signs are 

similar to those of many other illnesses, 

including other viral syndromes, influenza, 

and mononucleosis. However, generalized 

lymphadenopathy, rash, thrush, and mucosal 

ulceration are sufficiently uncommon in most 

adult febrile illnesses that, when present, they 
110 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

should trigger suspicion of acute HIV infection. 

It is important to obtain a history of recent risk 

behaviors from all patients who present with 

symptoms consistent with acute HIV infection 

and to have a low threshold for testing for acute 

HIV infection. Common laboratory findings 

include leukopenia, thrombocytopenia, and 

mild transaminase elevations. 

O: Objective

The 3rd-generation assays may detect HIV 

infection within 4 weeks, but new 4thgeneration HIV antigen/antibody tests 

usually show positive results within 2-3 

weeks after an infection occurs. During the 

symptomatic phase of HIV seroconversion, 

HIV antibody tests may still indicate 

negative or indeterminate serostatus. For 

patients who have negative or indeterminate 

antibody results but symptoms consistent 

with seroconversion illness and a recent 

risk history for HIV exposure, an HIV 

RNA (viral load) test should be performed. 

Patients with negative or indeterminate 

antibody test results but detectable HIV 

viral loads (particularly >10,000 copies/

mL) can be considered to be infected with 

HIV, although the antibody test should be 

repeated later to confirm seroconversion. 

A low viral load (<10,000 copies/mL) may 

indicate a false-positive result, because viral 

loads typically run very high (i.e., >100,000 

copies/mL and, often, millions of copies/

mL) during the acute infection stage. For 

patients who have negative or indeterminate 

HIV antibody test results and low positive 

HIV viral loads, the HIV RNA test should 

be repeated on a different blood specimen.

The 4th-generation HIV tests do not 

distinguish between antigen positivity and 

antibody positivity. Patients with a positive 

result should be retested with an antibody 

test; if the result is negative or indeterminate 

and acute HIV is suspected, an HIV RNA test 

should be sent, as above (see chapter Expedited 

HIV Testing).

A/P: Assessment/Plan

Patients with early HIV infection will need 

additional medical evaluation, baseline 

laboratory testing, and intensive support, 

counseling, and education about HIV 

infection. See chapters Initial History, Initial 

Physical Examination, and Initial and Interim 

Laboratory and Other Tests for detailed 

information on the initial evaluation of HIVinfected patients.

Laboratory

The initial laboratory work should include the 

following: 

• CD4 cell count and HIV viral load.

• A baseline HIV genotype test for all patients 

with early HIV infection, even those 

who do not choose to start antiretroviral 

treatment (ART). In some cities in the 

United States and Europe, 6-16% of infected 

individuals have acquired HIV virus strains 

with mutations that confer resistance to 

antiretroviral medications. These resistance 

mutations may be identified by early 

resistance testing, but may not be detectable 

later. (See chapter Resistance Testing.)

• Patients diagnosed on the basis of HIV RNA 

should have an HIV antibody test repeated 

in 3-6 months to document seroconversion.

Treatment

ART is recommended for all persons with 

HIV, including those with early HIV infection. 

Some limited evidence suggests that treatment 

initiated during primary HIV infection may 

have particular benefits, including preserving 

HIV-specific immune function that would 

otherwise be lost as the infection progresses, 

limiting the size of the HIV viral reservoir, 

and decreasing the loss of gastrointestinal 

lymphoid tissue. In addition, early treatment is 

expected to decrease rates of HIV transmission 

during a time of heightened infectiousness. 

The potential advantages of ART for 

primary infection must be weighed against 
Early HIV Infection | 111

Section 2: Testing 

and Assessment

the possibility of short- and long-term 

toxicities, the possibility of developing drug 

resistance, and the adherence challenges 

associated with starting ART quickly for 

newly diagnosed patients. Issues concerning 

the possible treatment of primary HIV 

infection are reviewed in the U.S. Department 

of Health and Human Services Guidelines 

for the Use of Antiretroviral Agents in 

HIV-1-Infected Adults and Adolescents

(available at aidsinfo.nih.gov/guidelines). 

For pregnant women with acute or recent 

HIV, the risk of perinatal HIV transmission 

is very high; thus, ART should be started as 

early as possible to try to prevent infection of 

the infant (see chapter Reducing Perinatal HIV 

Transmission).

For patients who opt to start therapy during 

primary HIV infection, the choice of agents 

and the recommendations for monitoring are 

the same as those for the treatment of patients 

with chronic HIV infection (see chapter 

Antiretroviral Therapy). The initial goal of 

therapy in primary HIV infection is to suppress 

the HIV viral load to undetectable levels.

Patient Education

• Patients with early HIV infection need 

support and counseling, as do all newly 

diagnosed patients.

• Intensive education about HIV infection, 

the course of disease progression, prognosis, 

and the benefits and risks of ART must be 

undertaken.

• Counseling patients about safer sex and 

drug injection techniques, as indicated, is 

especially important because these patients 

may have ongoing high-risk behaviors for 

HIV transmission and because they may 

be highly infectious during the primary 

infection period. (See chapter Preventing 

HIV Transmission/Prevention with Positives 

for more information about patient support 

and counseling in these areas.)

References

• Grijsen ML, Steingrover R, Wit FW, et al.; 

Primo-SHM Study Group. No treatment 

versus 24 or 60 weeks of antiretroviral 

treatment during primary HIV infection: the 

randomized Primo-SHM trial. PLoS Med. 

2012;9(3):e1001196.

• Hogan CM, Degruttola V, Sun X, et al.; 

A5217 Study Team. The setpoint study 

(ACTG A5217): effect of immediate 

versus deferred antiretroviral therapy 

on virologic set point in recently HIV-1-

infected individuals. J Infect Dis. 2012 Jan 

1;205(1):87-96. 

• Kassutto S, Rosenberg ES. Primary HIV 

type 1 infection. Clin Infect Dis. 2004 May 

15;38(10):1447-53.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Pilcher CD, Tien HC, Eron JJ Jr, et al.; Quest 

Study; Duke-UNC-Emory Acute HIV 

Consortium. Brief but efficient: acute HIV 

infection and the sexual transmission of HIV. 

J Infect Dis. 2004 May 15;189(10):1785-92.

• Schacker T, Collier AC, Hughes J, et al. 

Clinical and epidemiologic features of 

primary HIV infection. Ann Intern Med. 

1996 Aug 15;125(4):257-64.

Expedited HIV Testing | 113

Section 2: Testing 

and Assessment

Expedited HIV Testing

John Nelson, PhD, CPNP

Background

According to the U.S. Centers for Disease Control and Prevention (CDC), about 1.15 million 

people are living with HIV in the United States, and it has been estimated that about 18% of these 

individuals are unaware of their HIV serostatus. Additionally, it is estimated that 50,000 new HIV 

infections occur in the United States each year. It is important to identify persons who are infected 

with HIV as soon as possible after infection, in order both to link them to health care services and 

to reduce the risk that they will unknowingly transmit HIV to others.

In order to identify those with HIV infection, the CDC recommends routine voluntary HIV 

screening for all adults, adolescents, and pregnant women. Nevertheless, many people are reluctant 

to be tested, and many clinics do not offer routine testing. With expedited HIV testing, clients can 

be tested and receive their preliminary results during a single visit. The goals of expedited testing 

are to identify HIV infection as early as possible after initial infection and to do so in as little 

time as possible (negative results, indeterminate results, and confirmed positive test results are 

available during the same visit that testing is done). This makes it possible to link persons testing 

HIV positive to HIV medical care and other supports as quickly as possible. Expedited testing 

also allows for the efficient management of clients in need of urgent medical treatment (such as 

pregnant women) and situations requiring quick clinical decision making (such as assessment for 

postexposure prophylaxis).

Expedited HIV tests include both traditional nonlaboratory-performed rapid tests and antigen/

antibody (Ag/Ab) laboratory-based tests. The Ag/Ab 4th-generation tests detect both HIV p24 

antigen and anti-HIV antibodies (for HIV-1 and/or HIV-2). The 4th-generation tests are more 

sensitive during the acute phase of HIV infection than are the previous-generation screening 

immunoassay tests (including nonlaboratory-based rapid tests), so they are capable of diagnosing 

HIV infection at an earlier stage (as early as 2-3 weeks after infection). One laboratory-based 4thgeneration test is capable of delivering the preliminary results within 1 hour. 

Because of the greater sensitivity of 4th-generation laboratory-based immunoassays in identifying 

HIV at earlier stages of infection, it is now recommended that these tests be done whenever possible 

for HIV screening. Interestingly, 4th-generation testing is less expensive per test than the point-ofcare (POC) rapid tests in the United States.

Clients and Settings for 

Expedited Testing

Expedited HIV testing is important in settings 

in which the availability of HIV test results 

would influence medical care immediately, 

or in routine screening in settings where HIV 

prevalence is high or clients are not likely to 

return for the test results. Settings in which 

the use of highly sensitive 4th-generation HIV 

Ag/Ab testing from a laboratory is preferable 

include labor and delivery facilities (where 

identification of HIV infection is critical in 

preventing perinatal transmission), prenatal 

care facilities, hospital emergency departments, 

urgent care and acute care clinics, sexually 

transmitted disease clinics, drug treatment 

clinics, hospitals, and other clinical care 

or testing sites in communities with a high 

prevalence of HIV. In high-risk jurisdiction 

settings such as jails and mobile health service 

vans, and in community outreach programs 

where access to an on-site laboratory does not 

exist, nonlaboratory-based rapid testing is still 

recommended. 
114 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

Expedited HIV Tests

The U.S. Food and Drug Administration 

(FDA) has approved three 4th-generation HIV 

Ag/Ab tests for use in the United States (see 

Table 1). Federal regulations under the Clinical 

Laboratory Improvement Amendments (CLIA) 

program categorize tests as waived, moderate 

complexity, or high complexity. Many rapid 

tests are approved as CLIA-waived tests (see 

Table 2), meaning that they may be performed 

at the POC after appropriate staff training and 

with procedures in place to ensure quality 

control. These tests use whole blood or oral 

fluid and require a few simple steps to perform. 

Other rapid tests are “nonwaived” tests and 

must be performed in laboratories. Results for 

rapid tests performed at the POC are available 

in less than 30 minutes; results for expedited 

tests done in a laboratory should be available 

within 1 hour. 

As mentioned above, 4th-generation 

laboratory-based tests are recommended 

for HIV screening. In cases wherein 

laboratory-based 4th-generation HIV testing 

is not available, then 2nd- or 3rd-generation 

antibody POC rapid testing may be done with 

the knowledge that a person in seroconversion 

may test falsely negative. 

Table 1. FDA-Approved 4th-Generation HIV Tests for Laboratory 

Use Only (CLIA Moderate- or High-Complexity Tests) 

Test Name

Time to 

Test 

Result

Target Analyte

(Test 

Generation)

Sensitivity for 

Established 

HIV-1 Infection 

& Sensitivity for 

HIV-2Infection 

(%) (95% Confidence Interval)

Specificity for 

Established 

HIV-1 

Infection (%)

(95% 

Confidence 

Interval)

Approved 

Specimen 

Types & 

Volume

Assay 

Format

Abbott Architect HIV 

Ag/Ab Combo Assay 

(fully automated 

CLIA moderatecomplexity assay)

(Expedited)

<30 min HIV-1 p24 

antigen and 

antibodies to 

HIV-1/2

(4th generation)

Plasma/Serum 

HIV-1 p24: 100 

(94.3-100)/HIV-1: 

100 (99.63-100) 

HIV-2: 100 (98.2-

100)

Plasma/

Serum

99.8

(99.6-99.9)

Plasma/

Serum

150 μL

Chemiluminescent 

microparticle 

immunoassay

Bio-Rad GS HIV 

Combo Ag/Ab EIA 

(manual or semiautomated CLIA 

high-complexity 

assay)

>3 hours HIV-1 p24 

antigen and 

antibodies to 

HIV-1/2 

(4th generation)

Plasma/Serum

HIV-1: 100 

(99.7-100);

HIV-2: 100

(98.1-100)

Plasma/

Serum

99.87

(99.76-99.93)

Plasma/

Serum

75 μL

Enzyme 

immunoassay microwell format

Alere Determine 

HIV-1/2 Ag/

Ab Combo

20 

minutes

HIV p24 antigen 

and antibodies 

to HIV-1 and/or 

HIV-2 

(4th generation)

Whole Blood

99.9 

(99.4-100) 

Whole Blood

99.6 

(99.2-99.8) 

Plasma/

Serum

Whole 

Blood

Immunoassay

MultiSpot

HIV-1/HIV-2

Rapid Test

15 

minutes

Antibodies to 

HIV-1 and HIV-2 

(detection and 

differentiation) 

(3rd generation)

100% (99.9-100) 99.9%

(99.8-100)

Plasma/

Serum

Immunoassay

Adapted from U.S. Food and Drug Administration. Complete List of Donor Screening Assays for Infectious Agents and HIV Diagnostic Assays.

September 17, 2013.
Expedited HIV Testing | 115

Section 2: Testing 

and Assessment

Table 2. FDA-Approved HIV Rapid Screening Assays for Point-of-Care Testing 

Test Name

Time 

to Test 

Result

Target Analyte 

(Test Generation)

Sensitivity for 

Established

HIV-1 

Infection & 

Sensitivity 

for HIV-2 

Infection (%)

(95% 

Confidence 

Interval)

Specificity for 

Established

HIV-1 

Infection (%)

(95% 

Confidence 

Interval)

Approved 

Specimen Types 

Assay 

Format

SURE CHECK 

HIV 1/2 ASSAY

(Clearview 

Complete 

HIV 1/2)

<15 

minutes

Antibodies to HIV1 and/or HIV-2; 

point-of-care test

99.7

(98.9-100)

99.9

(99.6-100)

Fingerstick & 

Whole Blood 

(Venipuncture, 

Fingerstick)

Rapid 

Immunoassay

Clearview

HIV 1/2

STAT-PAK 

ASSAY

15 

minutes

Antibodies to HIV1 and/or HIV-2; 

point-of-care test

99.7

(98.9-100)

99.9

(99.6-100)

Fingerstick & 

Whole Blood 

(Venipuncture, 

Fingerstick)

Rapid

Immunoassay

OraQuick 

ADVANCE 

Rapid HIV-1/2 

Antibody Test

20 

minutes

Antibodies to HIV1 and/or HIV-2; 

point-of-care test

99.3

(98.4-99.7)

Oral Fluid

99.6

(98.5-99.9) 

Whole Blood

99.8

(99.6-99.9)

Oral Fluid

100

(99.7-100)

Whole Blood

Oral Fluid, 

Whole Blood 

(Venipuncture, 

Fingerstick)

Rapid

Immunoassay

Chembio DPP 

HIV 1/2 Assay

<40 

minutes

Antibodies to HIV1 and/or HIV-2; 

point-of-care test

98.9 

(98-99.4)

Oral Fluid

99.8 

(99.2-99.9)

Fingerstick 

Whole Blood

99.9 (99.7-99.9) 

Oral Fluid

100 (99.8-100) 

Fingerstick 

Whole Blood

Oral Fluid, 

Whole Blood 

(Venipuncture, 

Fingerstick)

Rapid 

Immunochromatographic 

Assay

Uni-Gold 

Recombigen 

HIV-1/2

10 

minutes

Antibodies to HIV1 and/or HIV-2; 

point-of-care test

100 (99.5-100) 99.7

(99.0-100)

Whole Blood 

(Venipuncture, 

Fingerstick)

Rapid EIA

bioLytical INSTI

HIV-1 Ab Test

60 

seconds

Antibodies to 

HIV-1; pointof-care test

99.8

(99.3-99.9)

100

(99.7-100) 

Whole Blood 

(Fingerstick)

Rapid 

FlowThrough 

Immunoassay

Adapted from U.S. Food and Drug Administration. Complete List of Donor Screening Assays for Infectious Agents and HIV Diagnostic Assays.

September 17, 2013.
116 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

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Interpreting Test Results

All FDA-approved tests are highly sensitive 

and specific. As previously mentioned, 4thgeneration HIV Ag/Ab tests have significantly 

greater sensitivity to very recent (acute) HIV 

infection. The negative predictive value of 

all rapid and expedited HIV tests is close 

to 100%. That means a client who receives a 

negative rapid test result almost assuredly 

is not infected, barring recent exposures 

(e.g., sexual contact or needle sharing with 

an infected person within the past 1-3 

months, depending on the test used). 

For clients who test reactive (positive) 

on a rapid or expedited test, the result 

is considered preliminary and must be 

confirmed. Traditionally, confirmation has 

been done by use of either a Western blot 

(WB) or immunofluorescence assay (IFA). 

However, neither of these confirmatory 

tests is expedited, and neither is able to 

differentiate HIV-1 and HIV-2 infections 

simultaneously. The confirmatory test 

currently recommended by the CDC is 

one that is able to differentiate HIV-1 and 

HIV-2 antibodies and is expedited (e.g., 

MultiSpot HIV-1/HIV-2 Rapid Test). If 

the confirmatory test result is positive, 

the client is considered to be infected 

with HIV. If the confirmatory test result 

is negative (no HIV Ab bands with a 

WB test or no visible reaction on the 

MultiSpot in the HIV-1 and/or HIV-2 Ab 

areas) or indeterminate (with the WB test, 

greater than 0 bands but too few bands to be 

considered positive), then an HIV RNA-1 test 

should be done immediately to check for early 

infection (Figure 1). In this case, a detectable 

HIV RNA (unless very low) will indicate 

early HIV infection – the client is most likely 

HIV infected and is seroconverting from 

antibody negative to positive status. The 

HIV-1 RNA test should be done regardless 

of the original HIV screening test (4thgeneration Ag/Ab or earlier-generation 

Ab). With detectable HIV RNA, the client 

should be considered infected, but an HIV 

confirmatory (WB or IFA) antibody test 

should be repeated in roughly 2-4 weeks to 

determine HIV antibody status. In the case 

of possible HIV-2 infection, consultation 

with an HIV specialist is recommended.

The positive predictive value of a single 

positive rapid or expedited HIV test result 

depends on the specificity of the test and 

the HIV prevalence in the community. 

The high specificity of the rapid or 

expedited tests means that, if a test result 

is positive, the likelihood that a client is 

truly HIV infected depends on the local 

HIV prevalence. In a population with a 

high HIV prevalence, a positive test result 

is likely a true positive, but in a population 

with a low HIV prevalence, that result has 

a greater chance of being a false positive.

Figure 3. 4th-Generation HIV Testing Algorithm

Centers for Disease Control and Prevention. Detection of acute 

HIV infection in two evaluations of a new HIV diagnostic testing 

algorithm – United States, 2011-2013. MMWR Morb Mortal Wkly 

Rep. 2013 Jun 21;62(24):489-94.

4th generation HIV-1/2 immunoassay

HIV-1/HIV-2 antibody dierentiation immunoassay

HIV-1 (-) HIV-1 (-) or indeterminate

HIV-1 (+) HIV-1 (+)

RNA (+)

(+)

HIV-2 (-) HIV-2 (+) HIV-2 (+) HIV-2 (-)

RNA (-)

(-)

RNA

Negative for HIV-1 and HIV-2

antibodies and p24 Ag

HIV-1 antibodies

detected

HIV-2 antibodies

detected

*Additional testing required to rule out dual infection

HIV antibodies

detected*
Expedited HIV Testing | 117

Section 2: Testing 

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Information for the Client

Educating the Client Before Testing

It is important to offer expedited HIV testing 

as part of a broader health screening, to 

educate clients about HIV infection and about 

the test, and to give them an opportunity 

to ask questions and to decline testing. The 

provider should emphasize that a second test 

is always performed in order to confirm a 

positive preliminary screening (laboratory or 

POC) test result. When possible, expedited 

or rapid testing should be made available 

during a regular visit so that clients do not 

face additional waiting time, and so that HIV 

infection can be detected as early as possible. 

Giving Reactive (Preliminary 

Positive) Rapid Test Results

Example of simple language to use

outside labor and delivery settings 

The following wording is suggested when the 

client’s rapid (nonconfirmed) test result is 

positive (or the expedited confirmatory testing 

is negative [and therefore the final result is 

“indeterminate”]):

“Your preliminary screening test result was 

positive, but we won’t know for sure if you are 

infected with HIV until we get the results from 

your confirmatory test. In the meantime, you 

should take precautions to avoid transmitting 

the virus. This means protecting all sex partners from possible exposure (using condoms, 

for example), not sharing needles or syringes 

for any purpose, and not sharing razors.”

Emphasize the importance of a confirmatory 

test, arrange for the confirmatory test to be done 

immediately. If an expedited, confirmatory test 

is available (MultiSpot Rapid), the client should 

not leave until that test has been completed and 

the result given. If an expedited confirmatory 

test is not available, then schedule a return 

visit for the client to receive the test result. It is 

important to develop a plan for follow-up with 

this client during this waiting period (by phone 

or in-person) and to reinforce the importance of 

following up. (Be sure to have the client’s contact 

information in case he or she does not return for 

confirmatory results.) 

Example of language to use in 

labor and delivery settings

The following wording is suggested when the 

client’s nonconfirmed expedited or rapid test 

result is positive: 

“Your preliminary HIV screening result was 

positive. You may have HIV infection. We 

need to do confirmatory tests to verify this first 

result, but it is important to start medication 

immediately to reduce the risk of passing HIV 

to your baby while we wait for the result. It 

is important to delay breast-feeding until we 

have the confirmatory test results.”

Follow-Up for Results of 

Confirmatory Tests

Clinical sites that offer expedited or rapid HIV 

testing should have a protocol for conveying 

the results of preliminary and confirmatory 

positive HIV test results to clients. With 

rapid tests and expedited laboratorybased testing, the client may be given the 

confirmatory results on the same day tested. 

If expedited laboratory-based confirmatory 

testing (MultiSpot Rapid), is not available, 

blood for confirmatory WB or IFA must be 

collected. In this case, results generally will 

not be available the same day, but appropriate 

specimen collection and test ordering should 

be done before the client leaves on the day the 

preliminary positive result is given. 

If the confirmatory result is negative or 

indeterminate (after a positive preliminary 

result), testing for HIV-1 RNA must be done.

Sites should either provide confirmatory 

notification services in-house or have 

mechanisms in place for notifying clients of 
118 | Guide for HIV/AIDS Clinical Care

Section 2: Testing 

and Assessment

their test results. All clients with confirmed 

positive HIV test results should be referred 

immediately for HIV care, community-based 

HIV services, or health department disease 

intervention specialists (who are trained 

to link people to care). Testing sites should 

establish reliable referral pathways to qualified 

HIV care providers with follow-up policies and 

procedures in place to make sure that linkage 

to care actually occurred.

Client Education

In general settings and in situations not 

involving labor and delivery, advise clients of 

the following: 

• Expedited laboratory and rapid 

nonlaboratory HIV testing is an important 

component of health screening. Learning 

early that they have HIV infection can help 

clients better maintain their health.

• Knowing that they have HIV infection 

can help clients start treatment as soon as 

possible, and to take precautions to prevent 

transmission of HIV to others.

• Clients can refuse an HIV test, and it will 

not affect the care they receive.

• The results from expedited or rapid tests are 

available at the same visit, usually in less 

than 1 hour.

• The expedited 4th-generation Ag/Ab 

tests are very accurate and are better at 

identifying newly infected persons than 

the 2nd- and 3rd-generation rapid and 

laboratory screening tests.

• If the expedited or rapid test result is 

positive, a second, confirmatory test always 

is done in order to provide assurance that 

the screening test result was accurate; and, 

if the confirmatory test is either negative or 

indeterminate, a third test (HIV viral load) 

needs to be done to determine whether the 

client is infected.

• It is important that clients return for the 

results of all confirmatory tests.

• If a client’s expedited or rapid test result 

is negative, that client is most likely not 

infected with HIV, unless the infection 

occurred within the past month – the test 

may not detect very recent infection.

• Test results are kept confidential. However, 

if a confirmatory test result is positive, most 

state laws require that information to be 

reported to the health department.

• There are clinics and other resources to help 

clients obtain more information as well as 

counseling, care, or treatment. The provider 

should provide specific referrals to these 

as well as assist the client in linkage to the 

referral site as soon as possible. 
Expedited HIV Testing | 119

Section 2: Testing 

and Assessment

References

• Association of Public Health Laboratories. 

Suggested reporting language for the 

HIV laboratory diagnostic testing 

algorithm. November 2013.

• Beckwith CG, Atunah-Jay A, Cohen 

J, et al. Feasibility and acceptability of 

rapid HIV testing in jail. AIDS Patient 

Care and STDS. 2007 Jan;21(1):41-7.

• Branson B. The future of HIV testing.

J Acquir Immune Defic Syndr. 2010 

Dec 15:55(Suppl 2):S102-05.

• Centers for Disease Control and 

Prevention. Estimated HIV incidence 

in the United States, 2007-2010. HIV 

Surveillance Supplemental Report 2012;17 

(No. 4). Published December 2012.

• Centers for Disease Control and 

Prevention. Detection of acute HIV 

infection in two evaluations of a new HIV 

diagnostic testing algorithm – United 

States, 2011-2013. MMWR Morb Mortal 

Wkly Rep. 2013 Jun 21;62(24):489-94.

• Centers for Disease Control and 

Prevention. Draft Recommendations: 

Diagnostic Laboratory Testing for HIV 

Infection in the United States. Presented 

at the 2012 HIV Diagnostics Conference 

Feedback Session held on December 

14, 2012. Available at www.cdc.gov/hiv/

pdf/policies_Draft_HIV_Testing_Alg_

Rec_508.2.pdf. Accessed December 1, 2013.

• Colfax GN, Buchbinder SP, Cornelisse 

PG, et al. Sexual risk behaviors and 

implications for secondary HIV transmission 

during and after HIV seroconversion.

AIDS. 2002 Jul 26;16(11):1529-35.

• Hutchinson AB, Corbie-Smith G, Thomas 

SR, et al. Understanding the patient’s 

perspective on rapid and routine HIV 

testing in an inner-city urgent care center. 

AIDS Educ Prev. 2004 Apr;16(2):101-14.

• Marks G, Crepaz N, Senterfitt JW, et 

al. Meta-analysis of high-risk sexual 

behavior in persons aware and unaware 

they are infected with HIV in the United 

States: implications for HIV prevention 

programs. J Acquir Immune Defic 

Syndr. 2005 Aug 1;39(4):446-53.

• Masciotra S, McDougal JS, Feldman J, 

et al. Evaluation of an alternative HIV 

diagnostic algorithm using specimens 

from seroconversion panels and persons 

with established HIV infections. J Clin 

Virol. 2011 Dec;52 Suppl 1:S17-22.

• Nasrullah M, Wesolowski LG, Meyer 

WA 3rd, et al. Performance of a fourthgeneration HIV screening assay and 

an alternative HIV diagnostic testing 

algorithm. AIDS. 2013 Mar 13;27(5):731-7.

• U.S. Food and Drug Administration. 

Complete List of Donor Screening 

Assays for Infectious Agents and HIV 

Diagnostic Assays. Available at www.

fda.gov/biologicsbloodvaccines/

bloodbloodproducts/approvedproducts/

licensedproductsblas/blooddonorscreening/

infectiousdisease/ucm080466.htm). 

Accessed December 1, 2013.

• U.S. Preventative Services Task Force. 

Screening for HIV. April 2013. Available 

at www.uspreventiveservicestaskforce.

org/uspstf/uspshivi.htm. Accessed 

December 20, 2013.

Resistance Testing | 121

Section 2: Testing 

and Assessment

Genotype Tests

Genotype testing works by amplifying and 

sequencing HIV taken from a patient to look 

for mutations in the HIV reverse transcriptase, 

protease, integrase, or envelope genes that are 

known to correlate with clinical resistance 

to ARV drugs. Genotype tests generally can 

detect mutations in plasma samples with 

HIV RNA levels of >1,000 copies/mL, but 

sometimes are successful with viral loads of 

500-1,000 copies/mL. Species representing 

20% or more of the amplified product usually 

can be detected by current techniques, but 

minor species may not be detected. Resistance 

mutations that developed in the past during 

treatment with certain ARV medications may 

be archived as minor species and become 

invisible to genotype testing (as early as 4-6 

weeks) after the drug is discontinued. These 

resistance mutations may reemerge and cause 

drug failure, however, if the previous drug is 

used again. By contrast, mutations acquired at 

the time of infection (from a transmitted virus 

that was already resistant) appear to persist 

for years, although the duration is not known 

precisely and may vary by mutation.

A genotype test takes 1-2 weeks to complete. 

The results are reported as a list of the mutations 

detected; most reports also include an 

interpretation that indicates the drug resistance 

likely to be conferred by those mutations 

(see “Limits of Resistance Testing,” below).

Note that the standard genotype tests detect 

only mutations that may affect reverse 

transcriptase inhibitors and PIs; a specific 

genotype for the integrase inhibitor (or fusion 

inhibitor) class must be ordered if there is 

concern for resistance to this class. Resistance 

to CCR5 antagonists is uncommon; a change 

in coreceptor tropism is a more likely cause of 

virologic failure for patients taking maraviroc. 

For such patients, a coreceptor tropism assay 

should be obtained. Afterwards, if resistance 

to CCR5 antagonists is still suspected, a 

resistance test can be obtained.

Resistance Testing

Background

Genotype and phenotype testing for resistance currently 

is commercially available for all nucleoside reverse 

transcriptase inhibitors (NRTIs), nonnucleoside reverse 

transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), 

and integrase inhibitors that have been approved by the 

U.S. Food and Drug Administration (FDA). In addition, 

standardized genotype testing is commercially available for 

enfuvirtide (a fusion inhibitor). 

Neither genotype nor phenotype predicts which 

antiretroviral (ARV) drugs will be active in a particular patient, only ARVs that are not likely to 

be active. Nevertheless, studies comparing the use of resistance testing with expert opinion alone 

have shown that resistance testing can improve virologic control of HIV. Resistance testing is used 

to guide subsequent treatment for patients whose antiretroviral therapy (ART) is failing and for 

those whose viral load is not completely suppressed after starting therapy. It also is used to select 

an initial regimen that is likely to be effective for patients who have never been treated, and it is 

recommended for all patients with HIV infection (both acute and chronic) upon entry into care, 

whether or not ART is to be initiated. In addition, resistance testing is recommended for pregnant 

women who are not on ART and for those who are on ART but have a detectable HIV viral load.

HRSA HAB Performance 

Measures

Percentage Percentage of patients, 

regardless of age, with a diagnosis of 

HIV who had an HIV drug resistance 

test performed before initiation of HIV 

antiretroviral therapy if therapy started 

during the measurement year

(All-Age measure)
122 | Guide for HIV/AIDS Clinical Care

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Genotype results must be interpreted carefully. 

Because mutations can become invisible to the 

genotype testing process when the selective 

pressure of a drug is removed, a thorough ARV 

history, a review of any past resistance tests, 

and expert clinical assessment are necessary 

to put the results of a genotype test in proper 

perspective and to identify options for further 

treatment (see “Limits of Resistance Testing,” 

below). A compilation of the most common 

HIV mutations selected by the three classes 

of antiretroviral agents is available at www.

hiv.lanl.gov/content/index. Other resources 

useful in understanding resistance testing 

and interpreting test results include the 

information complied by the International 

Antiviral Society-USA and the Stanford 

University HIV Drug Resistance Database 

(hivdb.stanford.edu).

A “virtual phenotype” is a genotype that is 

compared with a databank of patient samples 

that have been analyzed by paired genotype 

and phenotype testing. The patient’s genotype 

is matched to a banked genotype, and the 

patient’s phenotype is then predicted on 

the basis of the phenotypes paired to the 

banked genotype. A virtual phenotype can 

be completed in the same amount of time as a 

genotype. Results are reported as a genotype 

(listing the mutations detected) as well as a 

predicted fold change in the 50% inhibitory 

concentration (IC50) of each drug to the 

patient’s virus (see “Phenotype Tests,” below). 

The predicted susceptibility of the patient’s 

virus to each drug is then reported, based on 

biologic and clinical cutoffs.

Phenotype Tests

Phenotype testing works by splicing the HIV 

reverse transcriptase and HIV protease genes 

from a patient’s virus into a standardized 

laboratory strain, which is then grown in the 

presence of escalating concentrations of ARV 

drugs. The test measures the IC50 of each 

drug against the virus in vitro. Results are 

reported as fold change in IC50, as compared 

with a drug-susceptible control strain or with 

a previous test of the same patient’s blood. 

The predicted susceptibility of the patient’s 

virus to each drug is then reported, based 

on what is known about the correlation 

between fold change in IC50 of that drug 

and clinical resistance. As with genotype 

testing, the phenotype may not be able to 

detect resistance if the HIV RNA level is low 

(<1,000 copies/mL) and may not detect minor 

species. Therefore, a thorough history of ARV 

use and resistance tests, as well as expert 

interpretation, are essential for determining 

the significance of the results (see “Limits 

of Resistance Testing,” below). A phenotype 

takes 2-3 weeks to complete.
Resistance Testing | 123

Section 2: Testing 

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Choosing Between 

Genotype and Phenotype

Genotype testing is faster and cheaper than 

phenotype testing, and it can detect emerging 

resistance, that is, virus with a mixture of 

strains of which some may be sensitive and 

some may be resistant to a given drug, as long 

as they are present in sufficient quantity. It is 

therefore generally recommended (including 

by the U.S. Department of Health and Human 

Services [HHS]) for ART-naive patients and for 

patients whose first or second ART regimens 

are failing. Additionally, in some instances 

it is very important to know the exact viral 

mutation pattern in order to predict the virus’s 

response to subsequent therapy, particularly 

in patients with virologic failure on a regimen 

containing an NNRTI or integrase inhibitor. 

HHS recommends phenotype testing when 

patients are suspected of having complicated 

or multidrug resistance patterns (for example, 

in the setting of extensive prior ART), or when 

patients are found to have such patterns on 

genotype testing (especially resistance to PIs).

Using Genotype and 

Phenotype Tests at 

the Same Time

Genotype and phenotype tests have a few 

complementary properties that may, in 

some circumstances, make it desirable to 

use both tests at the same time. This strategy 

is especially advantageous when trying to 

devise a regimen for patients who have been 

exposed to many ARV agents and have few 

remaining treatment options, and for whom 

the development of additional resistance could 

be particularly dangerous. For example, early 

mutations may appear on a genotype before 

increases in inhibitory concentrations are 

detectable on a phenotype. Phenotype testing 

can detect loss or gain of drug efficacy caused 

by complex interactions of mutations that, 

by themselves, would not be predictive. In 

some cases, results of the genotype and the 

phenotype may be discordant; in these cases, 

consultation with an expert is recommended. 

Recommendations for 

Resistance Testing

An overview of when genotype 

and phenotype testing is and is not 

recommended is presented in Table 1. 
124 | Guide for HIV/AIDS Clinical Care

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Table 1. Resistance Testing Recommendations

Clinical Setting/Recommendation Rationale

Recommended

Acute HIV infection

• Genotype

• Determine whether drug-resistant virus was 

transmitted, to help design an initial regimen or to 

change a regimen accordingly.

• If ART is deferred, consider repeating genotype at the 

time of ART initiation.

Chronic HIV infection before starting ART 

• Genotype

• Determine whether drug-resistant virus was transmitted 

to help design an initial regimen.

• Perform upon entry to care (as close to the time of 

infection as possible), because transmitted drugresistant virus is more likely to be detected earlier in the 

course of HIV infection.

• If ART is deferred, consider repeating genotype at the 

time of ART initiation.

• Consider integrase genotypic resistance assay if 

integrase inhibitor resistance is a concern.

• Coreceptor tropism assay • Perform coreceptor tropism assay if use of a CCR5 

antagonist is being considered.

Virologic failure during ART

• Genotype if failure of 1st or 2nd regimen

• Both phenotype and genotype if multiple 

prior regimens, suspicion of mutations to 

multiple ARVs (especially PIs), or evidence 

of such mutations on genotype

• Coreceptor tropism assay

• Determine the role of resistance in drug failure and 

optimize the selection of active drugs for the new 

regimen, if indicated.

• Perform while patient is taking ARVs, or ≤4 weeks after 

discontinuing ARVs.

• If virologic failure on integrase inhibitor or fusion 

inhibitor, obtain specific genotypic testing for resistance 

to these to determine whether to continue them.

• Perform coreceptor tropism assay if use of a CCR5 

antagonist is being considered.

Suboptimal suppression or viral load

• Genotype or phenotype, depending on 

clinical situation (as above)

• Determine role of resistance: identify active drugs for 

new regimen.

Pregnant women

• Genotype or phenotype, depending on 

treatment history (as above)

• Perform before initiation of ART or prophylaxis.

• Perform for all on ART with detectable HIV RNA levels.

• Optimize the selection of active drugs for ARV regimen.

Not Usually Recommended

After discontinuation (>4 weeks) of ARVs • Assist in selecting optimal regimen to achieve maximal 

viral suppression.

• Drug-resistance mutations may decrease in number and 

become undetectable on assays.

Plasma viral load <500 HIV RNA copies/mL • Resistance assays are likely to be unsuccessful in 

patients with HIV RNA <500 copies/mL, because of 

the low number of RNA copies. In those with levels 

>500 but <1,000 copies/mL, testing may fail but can be 

considered. 

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected 

adults and adolescents. Department of Health and Human Services. Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.
Resistance Testing | 125

Section 2: Testing 

and Assessment

Antiretroviral-Naive Patients

With treatment-naive patients, resistance 

testing may reveal resistance mutations 

that were acquired at the time of infection, 

through infection with a strain of HIV that 

had already developed ARV resistance. 

Current guidelines recommend genotype 

testing for recently infected patients and for 

ARV-naive, chronically infected patients 

before initiation of therapy. It is important 

to test as early as possible in the course of 

HIV infection, to increase the likelihood of 

detecting transmitted mutations. The rationale 

for resistance testing in ARV-naive patients 

is twofold: 1) The prevalence of primary 

resistance is substantial, particularly in 

locations with a high prevalence of persons 

taking ART; and 2) Unknowingly starting a 

patient on ARV medications to which his or 

her virus is already resistant may risk failure 

of the initial regimen, rapid acquisition 

of additional resistance mutations, and 

curtailment of future treatment options. 

Limits of Resistance Testing

As discussed above, drug-resistant HIV evolves 

in response to selective pressure applied by the 

ARV drugs in the patient’s system. Specific 

resistance mutations develop in response 

to the pressure exerted by specific drugs 

(M184V, for example, evolves in response to 

lamivudine or emtricitabine). The presence 

of viral resistance suggests that a particular 

drug (and drugs with similar resistance 

patterns, or cross-resistance) is unlikely to be 

successful in suppressing viral replication.

In contrast, the absence of resistance to a 

drug on a genotype or phenotype test does 

not necessarily indicate that the drug will be 

effective, particularly if that drug (or drugs 

sharing cross-resistance) has been used 

previously. If a particular drug is discontinued, 

the viral strains harboring the mutations that 

confer resistance to that drug may decrease 

below the threshold of detection by the 

resistance assay, so the resistance test may not 

reveal certain resistance mutations. In such 

situations, minority populations of resistant 

viruses may exist in reservoirs and may 

emerge rapidly under selective pressure if that 

drug is restarted, or if drugs with similar or 

overlapping resistance patterns are used. The 

implications of archived mutations are twofold: 

1) Resistance tests are most reliable when the 

patient is still taking the failing regimen; and 

2) Resistance testing should be interpreted in 

the context of both the drugs that the patient 

was taking at the time of the test and the drugs 

that the patient had been exposed to previously 

(i.e., the patient’s ARV history). In addition, it 

is important to review any previous resistance 

tests, which may show resistance mutations 

that were not revealed on subsequent testing.

Resistance Testing in Patients 

with Virologic Failure

As discussed in the chapter Antiretroviral 

Therapy, factors other than resistance 

may cause failure of ART; these include 

nonadherence, drug-drug interactions, and 

malabsorption. Therefore, before assuming 

drug failure, it is important to assess the 

causes of ARV regimen failure. If resistance is 

suspected, resistance testing should be done 

while the patient is taking the failing regimen, 

for the reasons noted above. 
Patient Education

Advise patients of the following:

• Resistance testing can improve the 

likelihood of virologic control of HIV.

• Most treatment guidelines recommend 

resistance testing in certain circumstances.

• Both genotype and phenotype testing can 

detect resistance only if it exists in at least 

20% of the viral species present in a patient 

(known as the dominant species). Minor 

species may harbor resistance that remains 

undetected by either test.

• In general, a patient’s viral load must be at 

least 1,000 copies/mL for either test to be 

reliable, although samples with >500 copies/

mL sometimes can be analyzed.

• Resistance tests are most reliable when 

performed while a patient is still taking 

a failing regimen, or within 4 weeks after 

stopping.

• Neither test predicts which drugs will be 

active in a particular patient, only drugs that 

are not likely to be active. 

References

• Bartlett JG, Gallant JE, Pham PA, et al. 

2012 Medical Management of HIV Infection. 

Baltimore: Johns Hopkins University 

Division of Infectious Diseases; 2012.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Shafer RW. Genotypic Testing for HIV-1 

Drug Resistance. In: Coffey S, Volberding 

PA, eds. HIV InSite Knowledge Base

[textbook online]; San Francisco: UCSF 

Center for HIV Information; April 

2004. Available at hivinsite.ucsf.edu/

InSite?page=kb-03-02-07. Accessed 

December 1, 2013.
Karnofsky Performance Scale | 127

Section 2: Testing 

and Assessment

Karnofsky Performance Scale

Background

The Karnofsky Performance Scale is an assessment tool intended to assist clinicians and caretakers 

in gauging a patient’s functional status and ability to carry out activities of daily living.

It is important to assess a patient’s performance on a regular basis, especially as the effects of HIV 

progress. Documentation of Karnofsky scores over time may be very useful in following a patient’s 

course of illness, and can help a disabled patient in his/her application for disability benefits. It also 

is used for some research applications. 

The Karnofsky Performance Scale

Description Percent (%)

Normal; no complaints; no evidence of disease 100

Able to carry on normal activity; minor signs or symptoms of disease 90

Normal activity with effort; some signs or symptoms of disease 80

Cares for self; unable to carry on normal activity or do work 70

Requires occasional assistance, but is able to care for most personal needs 60

Requires considerable assistance and frequent medical care 50

Disabled; requires special care and assistance 40

Severely disabled; hospitalization indicated although death not imminent 30

Very sick; hospitalization necessary; requires active support treatment 20

Moribund; fatal processes progressing rapidly 10

Dead 0

Occupational Postexposure Prophylaxis | 129

Section 3: Health Maintenance 

and Disease Prevention

Occupational Postexposure Prophylaxis

Background

Health care personnel (HCP) and other individuals working in medical, public safety, sanitation, 

and laboratory settings are at risk of occupational exposure to HIV. Although avoiding exposure 

to HIV is the only reliable way of preventing HIV infection, postexposure prophylaxis (PEP), can 

reduce the risk of HIV infection in exposed HCP. PEP is defined as antiretroviral (ARV) therapy 

that is initiated soon after exposure to HIV with the intention of preventing HIV infection.

This chapter examines the general issues involved with PEP in occupational settings. The 

information is based on 2013 U.S. Public Health Service (USPHS) guidelines for occupational 

PEP (see “References,” below). For information on PEP for nonoccupational HIV exposures 

(such as sexual exposure), see chapter Nonoccupational Postexposure Prophylaxis. Note that 

other bloodborne pathogens, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV), 

also may be transmitted through occupational exposure; it is important to consider these 

potential infections when assessing occupational exposures. For information on the management 

of occupational exposures to HBV and HCV, refer to the 2001 USPHS PEP guidelines (see 

“References,” below). In addition, the National Clinicians’ Post-Exposure Prophylaxis Hotline 

(PEPline) is available for telephone consultation at 888-HIV-4911 (888-448-4911).

The risk of HIV infection after exposure depends on several factors that are related to the exposure 

itself and to the source patient (see below). To make sound PEP recommendations, the clinician 

must assess the risk of HIV infection from the particular exposure. After this, the clinician and 

the exposed worker must discuss the possible benefit of PEP (given the risk of HIV transmission 

from the injury) in relation to the willingness of the exposed worker to adhere to a 28-day course 

of ARV medicines, the potential toxicity of the regimen, and drug interactions. HCP who are 

pregnant at the time of their exposure must weigh the risk of fetal exposure to HIV against the 

potential teratogenic and other risks of the ARV drugs (it should be noted that pregnancy is not a 

contraindication to PEP, and that a number of ARVs are recommended for use during pregnancy, 

based on safety and efficacy data) (see chapter Reducing Perinatal HIV Transmission). 

The efficacy of PEP is related to the specific PEP regimen, the timing of PEP, and the exposed 

worker’s level of adherence to the PEP regimen. PEP is most likely to be effective if it is started 

within hours of an exposure, and outcomes may be compromised as the time from exposure 

increases. Nevertheless, it may be reasonable to offer PEP up to 72 hours after exposure. Adherence 

to PEP is strongly affected by factors such as the tolerability of the ARVs, the number of pills in 

the regimen, and the frequency of dosing. As current guidelines emphasize, it is very important to 

select a PEP regimen that is expected to be tolerated and that is convenient to take; any side effects 

or adherence difficulties should be managed promptly. The guidelines recommend the use of 3 (or 

more) PEP drugs for all exposures. Although the optimal duration of PEP is not known; studies 

support ARV treatment for 28 days.

In the work setting, HIV infection may occur through percutaneous injuries (e.g., needlesticks) or 

mucocutaneous exposures (e.g., mucous membrane or nonintact skin exposure) to blood or other 

potentially infectious body fluids. The risk of HIV seroconversion after occupational exposure 

with an HIV-contaminated hollow-bore needle is best described as 0.3%, on average. Another 

way of describing this to an exposed HCP is that, without PEP, HIV transmission occurs about 
130 | Guide for HIV/AIDS Clinical Care

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once in 300 instances of needlestick from a known HIV-infected source patient. In a retrospective 

case-control study of HCP with percutaneous exposure to HIV, the following exposure and source 

patient factors were associated with an increased risk of HIV transmission:

• Large-gauge (<18-gauge) hollow-bore needle

• Deep injury

• Visible blood on the device

• Procedure with needle in a blood vessel

• Terminal AIDS in the source patient

• High HIV viral load of the source patient

The factor described as “terminal AIDS in the source patient” is considered a surrogate for a source 

patient with a high HIV viral load (this study was done prior to the routine use of HIV viral load 

assays); high HIV viral load is known to be a substantial risk factor for HIV transmission. On 

the other hand, although an undetectable HIV viral load is thought to indicate a low risk of HIV 

transmission, transmission still is possible, and cases of perinatal and sexual transmission from 

sources with undetectable serum HIV RNA have been reported.

Compared with percutaneous injury, exposure of infectious body fluids to mucous membranes 

(e.g., eye or mouth) or to skin with an obvious impairment of integrity (e.g., abrasion or wound) 

typically involves a lower risk of HIV transmission (the transmission risk for mucous membrane 

exposure to HIV is approximately 1 in 1,000, and less than 1 in 1,000 for cutaneous exposure). 

However, mucocutaneous exposures that involve large volumes of blood or other infectious fluid 

from an HIV-infected patient with a high HIV RNA level or prolonged duration of contact are 

considered increased-risk exposures.

S: Subjective

An HCP reports possible exposure to 

HIV through a needlestick injury or 

mucocutaneous exposure.

Ideally, the HCP should immediately 

decontaminate the injured or exposed skin 

with soap and water, or flush the exposed 

mucous membranes with copious amounts 

of water or saline. The HCP should report 

the exposure immediately to appropriate 

authorities in the health care institution (e.g., 

the institution’s needlestick hotline).

Take a thorough history of the specific 

exposure, including the type of exposure, 

the type and amount of body fluid involved, 

the point of entry or exposure, the time it 

occurred, the HIV status of the source patient 

(if known), and HIV risk factors of the source 

patient (if HIV status is not known).

A: Assessment

Assess potential exposure to HIV (and to HBV 

and HCV). Consider the HIV status of the 

source and the characteristics of the exposure 

in deciding whether PEP should be offered. 

The guidelines recommend the use of PEP 

following percutaneous or mucous membrane 

exposures to potentially infectious body fluids. 

They note that PEP should be offered even in 

the case of an exposure to a source patient with 

an undetectable HIV viral load. Consult with 

experts if there is uncertainty about whether 

a particular exposure poses sufficient risk to 

warrant PEP.
Occupational Postexposure Prophylaxis | 131

Section 3: Health Maintenance 

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P: Plan

Laboratory Testing 

For the exposed HCP

• Perform a baseline HIV antibody test.

• Test for other infections transmitted 

through occupational exposure, particularly 

hepatitis B (HBV surface antigen, surface 

antibody, core antibody), and hepatitis C 

(HCV antibody).

• Obtain complete blood count (CBC), 

creatinine and estimated glomerular 

filtration rate (GFR), and hepatic 

transaminases at baseline, before treatment 

with ARV medications.

• For women who may be pregnant, perform a 

pregnancy test.

For the source person

• The institution should perform appropriate 

testing of the source person for bloodborne 

pathogens (e.g., HIV, HBV, and HCV) if the 

person’s status is unknown. 

• The use of rapid or expedited HIV tests 

makes it possible to render quick decisions 

about the need for HIV PEP, and the 4thgeneration Ag/Ab tests identify most cases 

of HIV during the window period of acute 

HIV infection (see chapter Expedited HIV 

Testing).

• Although a positive expedited test result 

requires confirmation before the individual 

is diagnosed as HIV infected, for the 

purposes of PEP, it should be considered a 

true positive until proven otherwise, and 

the exposed worker should be counseled 

accordingly. If, upon further testing, the 

source patient is determined to be HIV 

uninfected, PEP should be discontinued. A 

negative expedited test result is considered 

reliable unless the source has signs or 

symptoms of acute HIV (see chapters 

Expedited HIV Testing and Early HIV 

Infection). 

• PEP should not be delayed (beyond 1-2 

hours) while source patient HIV testing is 

under way.

Treatment

A regimen consisting of at least 3 ARV drugs 

is recommended for all occupational HIV 

exposures (the U.S. guidelines no longer 

recommend evaluation of the severity of 

exposure to determine the number of drugs 

in a PEP regimen). Recommendations for 

PEP regimens are based on expert opinion 

and largely follow the principles of HIV 

treatment regimens, but the PEP guidelines 

place particular emphasis on optimizing the 

tolerability and convenience of the regimen to 

facilitate adherence for 28 days.

Considerations in choosing the medications 

for a PEP regimen include:

• Possible ARV adverse effects

• Dosing schedule

• Drug-drug interactions with other 

medications the HCP may be taking 

• The likelihood that the source patient’s virus 

is resistant to 1 or more ARV medications

Provide counseling about the potential risks 

and benefits of PEP drugs, including possible 

adverse effects, drug-drug interactions, and the 

importance of close adherence. Recommended 

regimens are shown in Table 1; select one that is 

likely to be effective, tolerable, and convenient. 

Note that although these regimens are potent 

in treating HIV infection, their efficacy as 

prophylaxis has not been demonstrated. 

Consultation with experts is recommended (see 

“Expert Consultation,” below).

These recommendations are drawn from the 

2013 guidelines for occupational PEP; consult 

the most recently updated version of the 

guidelines for current information.
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Table 1. Antiretroviral Regimens for Occupational 

Postexposure Prophylaxis of HIV Infection

Preferred Regimen

• Raltegravir 400 mg BID + tenofovir 300 mg/emtricitabine 200 mg QD (Truvada)

Alternative Regimens

(combine 1 drug or drug pair from left column with 1 NRTI pair from right column)

• Raltegravir 400 mg BID

• Darunavir 800 mg QD + ritonavir 100 mg QD

• Etravirine 200 mg BID

• Rilpivirine 25 mg QD

• Atazanavir 300 mg QD + ritonavir 100 mg QD 

• Lopinavir/ritonavir 400/100 mg BID 

+

• Tenofovir + emtricitabine (Truvada), 1 tablet QD

• Tenofovir 300 mg QD + lamivudine 300 mg QD

• Zidovudine + lamivudine (Combivir), 1 tablet BID

• Zidovudine 300 mg BID + emtricitabine 200 mg QD

OR

• Elvitegravir/cobicistat/tenofovir/emtricitabine (Stribild) (complete regimen; no additional NRTIs needed)

Adapted from Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to Human 

Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis (2013). Available at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

Refer to the appendix in the updated PEP 

guidelines for more complete information 

on the advantages, and disadvantages of the 

various ARV agents available for PEP, and 

to the adult and adolescent ARV treatment 

guidelines (reference below) for more 

information about ARV adverse effects and 

drug-drug interactions.

Certain ARVs generally are not recommended 

for PEP because of elevated risk of 

toxicities; these include nevirapine (which 

is contraindicated as PEP), abacavir (testing 

for HLA- B*5701 must be done), didanosine, 

enfuvirtide, and tipranavir. Efavirenz may 

have a higher rate of significant adverse 

effects than other listed agents. Additionally, 

efavirenz should not be used with women who 

are in the first trimester of pregnancy or who 

may become pregnant while on PEP, because 

of possible teratogenicity. Some “alternative” 

ARVs may be considered for use based on 

consultation with experts.

If the source person is known or suspected to 

have infection with HIV that is resistant to 

ARV medications, seek expert consultation 

in selecting an appropriate PEP regimen. 

However, PEP should not be delayed while 

consultation is being solicited, and it is possible 

to adjust regimens based on expert advice. 

Begin ARV prophylaxis as soon as possible 

after the exposure occurs, preferably within 

a few hours and no later than 72 hours 

postexposure. Treatment should be continued 

for 28 days unless the source person is 

determined to be HIV uninfected.

Provide counseling about the efficacy of PEP, 

including timely initiation of PEP medications, 

the importance of adherence to the regimen 

for 28 days, and management of common 

adverse effects. Counsel exposed workers 

to avoid possible transmission of HIV, e.g., 

by using use latex barriers with their sex 

partners, avoiding breast feeding if possible, 

avoiding pregnancy, and avoiding blood/tissue 

donations, until transmission of HIV infection 

has been ruled out.

Follow-Up

Exposed workers should be reevaluated 

within 72 hours after exposure to review any 

available new information about the exposure 

and the source person as well as test results. 

For HCP taking PEP, early reevaluation 
Occupational Postexposure Prophylaxis | 133

Section 3: Health Maintenance 

and Disease Prevention

offers the opportunity for further education 

and counseling, including assessment and 

support of PEP adherence and evaluation and 

management of any side effects. In addition to 

health education counseling, many exposed 

workers need emotional support during their 

follow-up visits.

For persons on PEP, monitoring for 

adherence and adverse effects should be 

conducted again at 2 weeks. Blood testing 

(e.g., CBC, creatinine and electrolytes, liver 

function tests, others as indicated) should 

be done to monitor for PEP toxicity, as 

indicated by the particular ARV regimen. 

PEP is discontinued after 4 weeks, and 

monitoring for ARV toxicity generally should 

not be repeated unless there is a need to 

recheck an abnormal result. 

Follow-up HIV antibody testing should be 

done at 6 weeks, 3 months, and 6 months after 

the exposure. If a 4th-generation HIV Ag/Ab 

assay is used, the final HIV test can be done 

at 4 months rather than 6 months. Follow-up 

for 12 months is recommended for HCP who 

acquired hepatitis C via exposure to a source 

who was coinfected with HIV and HCV. 

Symptoms of acute HIV infection such as 

fever, rash, and lymphadenopathy (see chapter 

Early HIV Infection) may occur in HCP who 

are infected with HIV through occupational 

exposure. Exposed HCP should be counseled 

about the symptoms of acute HIV infection and 

instructed to return for reevaluation as soon 

as possible if symptoms develop. If symptoms 

consistent with acute HIV appear within 4-6 

weeks after an occupational exposure, the 

HCP should be evaluated immediately; an 

HIV RNA test should be performed if acute 

HIV infection is suspected. If an HCP is 

found to be infected with HIV, that individual 

should be referred immediately to an HIV 

specialist for further evaluation and care.

Expert Consultation

Consultation with experts in PEP and in ARVs 

is recommended for assistance with managing 

all occupational exposures. This is particularly 

important if the source person is known or 

suspected to have ARV-resistant virus or if 

there are unusual or perplexing elements 

about the case (e.g., if the exposed HCP is 

pregnant or breast feeding, has significant 

medical illness, or takes medications that may 

interact with PEP ARVs). Consultation on the 

treatment of occupational exposures to HIV 

and other bloodborne pathogens is available 

to the clinician managing the exposed person 

on the National Clinicians’ Post-Exposure 

Prophylaxis Hotline (PEPline) at 888-HIV4911 (888-448-4911). This service is available 

7 days a week, at no charge (additional 

information is available on the PEPline website 

at www.nccc.ucsf.edu). 

Prophylaxis Against HBV and HCV

Prophylaxis against HBV is recommended 

for patients with potential exposure to HBV 

who do not have immunity against HBV. 

Give hepatitis B immune globulin (HBIG) 

as a 0.06 mL/kg IM injection and initiate the 

vaccination series. For patients who received 

the vaccination series but did not develop 

protective antibodies (HBV sAb+), give HBIG 

at the time of the postexposure workup and 

initiate revaccination; consider repeat of HBIG 

in 1 month. For patients with immunity to 

HBV, no treatment is indicated.

For HCV, no prophylactic treatments are 

recommended. After potential exposure, 

perform a baseline HCV antibody test. If 

the source is known to have HCV infection, 

consider alanine aminotransferase (ALT) 

and HCV viral load testing at 4-6 weeks. 

HCV antibody testing should be repeated at 

4-6 months. If HCV seroconversion occurs 

(indicated by ALT elevation, detectable 

HCV viral load, or confirmed positive HCV 
134 | Guide for HIV/AIDS Clinical Care

Section 3: Health Maintenance 

and Disease Prevention

antibody test result), refer the patient to a 

hepatitis C expert because early treatment of 

HCV may be indicated.

Addendum: Workplace Obligations

The health care institution has certain 

obligations to an exposed employee.* The 

institution should do the following:

• Evaluate the circumstances of the exposure, 

the type of fluid, and possible entry points.

• Evaluate the source patient.

• Perform baseline HIV antibody testing of 

the exposed HCP.

• Counsel the exposed HCP about the possible 

risks and benefits of PEP.

• Offer or recommend PEP as soon as possible 

after the exposure, preferably within the first 

several hours.

• Counsel the HCP about avoiding secondary 

transmission to others (safer sex and other 

risk-reduction practices, as indicated).

• Support and maintain the confidentiality of 

the HCP.

• For an HCP who is taking PEP, monitor 

for medication toxicity and adherence, and 

check for drug-drug interactions with other 

medications the HCP may be taking.

• Repeat HIV testing at 6 weeks, 3 months, 

and 6 months (if a 4th-generation HIV Ag/

Ab assay is used, the final HIV test can be 

performed at 4 months).

• Report the exposure as required by 

federal and state regulations (including 

U.S. Occupational Safety and Health 

Administration requirements).

The PEP guidelines recommend that health 

care institutions have a formal mechanism 

for consultation about occupational HIV 

exposures, appropriate initial lab testing for 

source patients and exposed HCP, counseling 

for exposed HCP, availability of initial PEP 

regimens (e.g., starter packs), and a mechanism 

for outpatient follow-up. The protocols should 

be readily available to emergency department 

providers and others who manage exposure 

incidents.

* Legal issues vary from state to state. In many states, 

institutions and clinics have no obligation toward 

nonemployees or students who are exposed to 

HIV in their settings. In such situations, clinical 

supervisors or school or university officials often 

are the first contact for notification. However, 

everyone working in a health care setting should 

be familiar with the procedures and financial 

responsibilities for HIV exposure management 

to avoid delays in HIV PEP treatment.

Patient Education

• Persons who have possible exposures to 

HIV in the work setting should contact the 

PEP service of their employer or a qualified 

medical provider as soon as possible after the 

exposure, or they should go to an emergency 

department. Although PEP may be effective if 

it is started within 72 hours of exposure, the 

sooner medications are initiated, the better 

the chance for preventing HIV transmission.

• PEP medications should be taken as directed 

for the full 28-day course. Adherence to 

PEP medications is essential for successful 

treatment.

• PEP recipients should be advised to 

contact their providers if they experience 

uncomfortable side effects. Providers may 

prescribe medications to alleviate the side 

effects, or they may prescribe different PEP 

medications.

• Until HIV infection has been ruled out, 

exposed workers should be advised to use 

latex or polyurethane barriers to prevent 

transmission of HIV to their sex partners, to 

avoid pregnancy, and to avoid breast feeding 

if possible.

• Exposed HCP should be counseled about 

the symptoms of primary HIV infection and 

instructed to contact their care providers 

immediately if symptoms develop.
Occupational Postexposure Prophylaxis | 135

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and Disease Prevention

References

• Bassett IV, Freedberg KA, Walensky RP. Two 

drugs or three? Balancing efficacy, toxicity, 

and resistance in postexposure prophylaxis 

for occupational exposure to HIV. Clin Infect 

Dis. 2004 Aug 1;39(3):395-401.

• Do AN, Ciesielski CA, Metler RP, et 

al. Occupationally acquired human 

immunodeficiency virus (HIV) infection: 

national case surveillance data during 20 

years of the HIV epidemic in the United 

States. Infect Control Hosp Epidemiol. 2003 

Feb;24(2):86-96.

• Gerberding JL. Clinical practice. 

Occupational exposure to HIV in health 

care settings. N Engl J Med. 2003 Feb 

27;348(9):826-33.

• Kuhar DT, Henderson DK, Struble 

KA, et al.; U.S. Public Health Service 

Working Group. Updated U.S. Public 

Health Service Guidelines for the 

Management of Occupational Exposures 

to Human Immunodeficiency Virus 

and Recommendations for Postexposure 

Prophylaxis. Infect Control Hosp Epidemiol. 

2013 Sep;34(9):875-92.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• U.S. Department of Health and Human 

Services. Updated U.S. Public Health 

Service Guidelines for the Management of 

Occupational Exposures to HBV, HCV, and 

HIV and Recommendations for Postexposure 

Prophylaxis. MMWR Recomm Rep. 2001 

Jun 29;50(RR11);1-42.

• Wang SA, Panlilio AL, Doi PA, et 

al. Experience of healthcare workers 

taking postexposure prophylaxis after 

occupational HIV exposures: findings of the 

HIV Postexposure Prophylaxis Registry. 

Infect Control Hosp Epidemiol. 2000 

Dec;21(12):780-5.

• Zenner D, Tomkins S, Charlett A, et al. HIV 

prone occupational exposures: epidemiology 

and factors associated with initiation of 

post-exposure prophylaxis. J Epidemiol 

Community Health. 2009 May;63(5):373-8.

Nonoccupational Postexposure Prophylaxis | 137

Section 3: Health Maintenance 

and Disease Prevention

Nonoccupational Postexposure 

Prophylaxis

Background

Although avoiding exposure to HIV is the only reliable way of preventing HIV infection, 

postexposure prophylaxis (PEP) can decrease the risk of infection after exposure to HIV. 

Antiretroviral (ARV) therapy is an important prophylactic intervention for appropriate persons 

with nonoccupational exposures (e.g., sexual contact; sharing of injection drug needles or other 

equipment) as well as those with occupational exposures (e.g., needlesticks). The U.S. Department 

of Health and Human Services (HHS) has developed recommendations for nonoccupational PEP 

(nPEP) based on data from animal models, perinatal clinical trials, and observational studies. 

Efficacy of nPEP remains hypothetical, and randomized clinical trials are not possible, but nPEP 

appears to be safe.

Overall, nPEP is more likely to be effective when the exposure is a single episode and nPEP is 

initiated in a timely manner. It is not appropriate for cases of multiple sexual exposures or injection 

drug use (IDU) exposures over time or for exposures that occurred >72 hours before starting nPEP 

treatment (see Figure 1).

The model for nPEP is derived in part from protocols for occupational PEP (e.g., in terms of 

risk assessment, pretreatment testing, timing of treatment, treatment regimens, and duration 

of treatment). (For information on occupational PEP, see chapter Occupational Postexposure 

Prophylaxis.) One significant difference between the protocols is that nPEP protocols should 

include interventions to reduce the risk of future HIV acquisition. Although exposed individuals 

usually seek care because they are interested specifically in antiretroviral prophylaxis, the 

nPEP model takes advantage of a critical opportunity to provide risk-reduction counseling and 

education.

See chapter Occupational Postexposure Prophylaxis for further discussion of evaluating possible 

benefits and risks of PEP.

S: Subjective

The patient reports potential exposure to HIV 

through a sexual encounter or the sharing of 

needles or other equipment for IDU.

Take a thorough history of the specific sexual 

or drug-use activities, the time the exposure 

occurred, the HIV status of the source person 

(if known), and HIV risk factors of the source 

person (if HIV status is not known). In cases of 

sexual assault, evidence collection and specific 

paperwork may be required as well.

O: Objective

Examine for trauma and for signs or 

symptoms of sexually transmitted diseases 

(STDs), which may increase the risk of HIV 

transmission. In injection drug users, examine 

for abscesses and signs or symptoms of 

infection. For women who may be pregnant, 

perform a pregnancy test. 
138 | Guide for HIV/AIDS Clinical Care

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A: Assessment

Assess for potential exposures to HIV and 

other bloodborne pathogens and for the 

presence of other STDs. The risk of HIV 

infection depends on the HIV status of 

the source and on the characteristics of 

the source (e.g., HIV viral load) and of the 

exposure (see Figure 1). Note that, although 

an undetectable HIV viral load is thought 

to indicate a low risk of HIV transmission, 

transmission still is possible, and cases 

of sexual transmission from sources with 

undetectable serum HIV RNA have been 

reported. 

The estimated risk of HIV exposure will 

determine whether nPEP should be offered. 

An algorithm for risk evaluation and 

treatment decisions is presented in Figure 1.

P: Plan

Laboratory Testing

• Perform a baseline HIV antibody test.

• Evaluate and test for other infections 

transmitted through sexual or IDU 

exposures, including chlamydia, 

gonorrhea, syphilis, herpes simplex virus, 

hepatitis B (HBV surface antigen, surface 

antibody, and core antibody), and hepatitis 

C (HCV antibody).

• Obtain complete blood count (CBC), liver 

function tests (LFTs), and creatinine and 

estimated glomerular filtration rate (GFR) 

at baseline before treatment with ARV 

medications. 

Treatment 

Follow the algorithm in Figure 1 to determine 

whether the patient should be offered nPEP 

medications. If the patient is a candidate 

for treatment, provide counseling about the 

potential risks and benefits of nPEP.

Select an nPEP regimen that is likely to be 

effective but tolerable; consider the potential 

adverse effects and drug interactions of ARV 

agents (Table 1). Adherence to nPEP is strongly 

affected by factors such as the tolerability of 

the ARVs, the number of pills in the regimen, 

and the frequency of dosing. It is very 

important to select a regimen that is expected 

to be tolerated and that is convenient to take; 

any side effects or adherence difficulties should 

be managed promptly. 

In general, the recommendations for nPEP 

involve 3-drug combination therapy. In some 

circumstances, more than 3 ARVs may be 

appropriate (e.g., if the source virus is resistant 

to ARVs), and in some cases, 2-drug PEP may 

be considered (e.g., if the HIV status of the 

source person is unknown, the exposure is 

thought to be of relatively low risk, or there 

is a need to minimize possible toxicity); 

consultation with experts is recommended.

Substantial 

exposure risk

≤72 hours since 

exposure

≥72 hours since 

exposure

Source patient 

known to be

HIV positive

Source patient of 

unknown 

HIV status

Substantial Risk for HIV Exposure

Exposure of

vagina, rectum, eye, mouth, or other 

mucous membrane, nonintact skin, 

percutaneous contact

With

blood, semen, vaginal secretions, rectal 

secretions, breast milk, or any body 

uid that is visibly contaminated with 

blood

When

the source is known to be HIV-infected

Negligible Risk for HIV Exposure

Exposure of

vagina, rectum, eye, mouth, or other 

mucous membrane, nonintact skin, 

percutaneous contact

With

urine, nasal secretions, saliva, sweat, or 

tears if not visibly contaminated with 

blood

Regardless

of the known or suspected HIV status of 

the source

Case-by-case 

determination

nPEP

recommended

nPEP not

recommended

Negligible 

exposure risk

Figure 1. Exposure Risk Algorithm

U.S. Department of Health and Human Services. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States. MMWR Recomm Rep. 2005 

Jan 21;54(RR02);1-20.
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Section 3: Health Maintenance 

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Note that the HHS nPEP guidelines were last 

updated in 2005 and do not reflect current 

practice. The recommendations presented 

here have been adapted to reflect current 

nPEP strategies, current guidelines for 

occupational PEP, and the availability of 

newer ARVs (see Table 1). Note that a number 

of ARVs that were included in “preferred” or 

“alternative” regimens in the 2005 guidelines 

are no longer recommended in current 

practice, based on factors such as higher 

likelihood of causing adverse effects, greater 

pill burden, or inconvenient dosing. A number 

of alternatives to the recommendations 

listed below are available; consult with an 

expert. Note that, although these regimens 

are effective in treating HIV infection, 

their efficacy as prophylaxis has not been 

demonstrated.

If the source person is known or suspected to 

have infection with HIV that is resistant to 

ARV medications, seek expert consultation in 

selecting an appropriate nPEP regimen.

Certain ARVs are not currently recommended 

for PEP, including nevirapine (which is 

contraindicated for PEP), abacavir (testing 

for HLA-B*5701 must be done), didanosine, 

enfuvirtide, and tipranavir. Although the 2005 

nPEP guidelines designate it as a preferred 

agent, efavirenz may have a higher rate of 

significant adverse effects than other agents 

listed in Table 1. Additionally, efavirenz 

should not be used during the first trimester 

of pregnancy or for women who may become 

pregnant while taking PEP, because of 

possible teratogenicity. Refer to the updated 

occupational PEP guidelines and to the adult 

and adolescent ARV treatment guidelines for 

more complete information on the advantages 

and disadvantages, adverse effects, and drugdrug interactions of the various ARV agents 

available for PEP (references below). Consider 

consultation with experts (see “Expert 

Consultation,” below).

Table 1. Antiretroviral Regimens for Nonoccupational 

Postexposure Prophylaxis of HIV Infection* 

Preferred Regimens

• Raltegravir 400 mg BID + tenofovir 300 mg/emtricitabine 200 mg QD (Truvada)

Alternative Regimens

(combine 1 drug or drug pair from left column with 1 NRTI pair from right column)

• Raltegravir 400 mg BID

• Darunavir 800 mg QD + ritonavir 100 mg QD

• Etravirine 200 mg BID

• Rilpivirine 25 mg QD

• Atazanavir 300 mg QD + ritonavir 100 mg QD 

• Lopinavir/ritonavir 400/100 mg BID 

+

• Tenofovir + emtricitabine (Truvada), 1 tablet QD

• Tenofovir 300 mg QD + lamivudine 300 mg QD

• Zidovudine + lamivudine (Combivir), 1 tablet BID

• Zidovudine 300 mg BID + emtricitabine 200 mg QD

OR

• Elvitegravir/cobicistat/tenofovir/emtricitabine (Stribild) (complete regimen; no additional NRTIs needed)

* Forthcoming HHS guidelines on nPEP may differ from these recommendations; check current recommendations.

Abbreviations: NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside analogue reverse transcriptase inhibitor; PI = 

protease inhibitor 

Adapted from Kuhar DT, Henderson DK, Struble KA, et al.; U.S. Public Health Service Working Group. Updated U.S. Public Health Service 

Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure 

Prophylaxis. Infect Control Hosp Epidemiol. 2013 Sep;34(9):875-92; and U.S. Department of Health and Human Services. Antiretroviral 

Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States–January 21, 2005.

Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.
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Once the decision is made to institute nPEP, do 

the following:

• Begin ARV prophylaxis as soon as possible 

after the exposure, but always within 72 

hours. Treatment should be continued for 28 

days, unless the source person is determined 

to be HIV negative.

• Provide counseling about the efficacy of 

nPEP, timely initiation of nPEP medications, 

adherence to the regimen for 28 days, and 

the importance of preventing additional 

HIV exposures during this time.

• Counsel exposed patients to use latex 

barriers with their sex partners until 

transmission of HIV infection has been 

ruled out.

• Counsel patients, as appropriate, about ways 

to reduce risks of future exposure to HIV.

• In cases of sexual assault, refer the patient to 

a rape counselor.

Follow-Up

Patients should be evaluated within 1 week 

for review of all test results and further 

risk-reduction counseling. For patients 

taking nPEP, this follow-up should include 

adherence assessment and evaluation of 

any adverse effects. Side effects should be 

managed aggressively in order to maximize 

the likelihood of adherence to nPEP. A 2-week 

blood screening (CBC, LFTs, and creatinine) 

should be performed for patients on the 28-day 

nPEP regimen to monitor for nPEP toxicity. 

Follow-up testing for HIV antibody in patients 

with a negative baseline HIV antibody test 

should be done at 6 weeks, 3 months, and 6 

months after the exposure. If a 4th-generation 

HIV Ag/Ab assay is used, the final HIV test 

can be done at 4 months rather than 6 months. 

Patients need health education and riskreduction counseling and emotional support 

during their follow-up visits. Nonoccupational 

PEP programs should focus efforts on 

risk-reduction counseling rather than the 

continued use of medicines for prevention. To 

this end, many programs have case managers, 

social workers, and health educators as the key 

providers of follow-up and counseling after an 

exposure, with referral to clinicians as needed.

If patients develop acute HIV infection or are 

discovered to be HIV seropositive at follow-up 

testing, immediately refer to an HIV specialist 

for evaluation and care (see chapter Early HIV 

Infection).

Expert Consultation

For consultation on the treatment of exposures 

to HIV (and HBV and HCV), the clinician 

managing the exposed person can call the 

National HIV/AIDS Clinicians’ Post-Exposure 

Prophylaxis Hotline (PEPline) at 888-HIV4911 (888-448-4911). This service is available 

7 days a week at no charge. Additional 

information on the Internet is available at 

www.nccc.ucsf.edu. PEPline support may be 

especially useful in challenging situations, 

such as when drug-resistant HIV strains are 

suspected to be involved in the exposure or 

when the exposed person is pregnant.

Prophylaxis Against HBV and HCV

Prophylaxis against HBV is recommended 

for patients with potential exposure to HBV 

who do not have not have immunity against 

HBV. Give HBV immune globulin (HBIG) 

as a 0.06 mL/kg IM injection and initiate the 

vaccination series. For patients who previously 

received the vaccine series but did not develop 

protective antibody (HBV sAb+), give HBIG 

at the time of the postexposure workup and 

initiate revaccination; consider repeat of HBIG 

in 1 month. For patients with immunity to 

HBV (HBV sAb+), no treatment is indicated.

For HCV, no prophylactic treatments are 

recommended. After potential exposure, 

perform a baseline HCV antibody test. If 

the source is known to have HCV infection, 

consider alanine aminotransferase (ALT) 
Nonoccupational Postexposure Prophylaxis | 141

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and HCV viral load testing at 4-6 weeks. 

HCV antibody testing should be repeated at 

4-6 months. If HCV seroconversion occurs 

(indicated by ALT elevation, detectable 

HCV viral load, or confirmed positive HCV 

antibody test result), refer the patient to a 

hepatitis C specialist because early treatment 

of acute HCV may be indicated.

Patient Education

• Persons who have possible exposures to 

HIV should contact a medical provider 

or go to an emergency room as soon as 

possible after the potential exposure has 

occurred. PEP may be effective if it is started 

within 72 hours of exposure, but the sooner 

medications are initiated, the better the 

chance for preventing HIV transmission.

• PEP medications should be taken as directed 

for a full 28-day course. Adherence to 

PEP medications is essential for successful 

treatment.

• If patients are experiencing uncomfortable 

adverse effects, they should contact 

their care provider right away. Providers 

may prescribe medications to alleviate 

the adverse effects or select other PEP 

medications.

• Until HIV infection has been ruled out, 

exposed persons should be advised to use 

latex barriers to prevent transmission of HIV 

to their sex partners.

• Exposed persons should be counseled about 

the symptoms of primary HIV infection 

and instructed to contact their care provider 

immediately if symptoms develop.

• The most effective way to prevent HIV 

infection is to prevent exposure to HIV 

by practicing safer sex and safer IDU 

techniques. Use of condoms and other latex or 

polyurethane barriers and avoidance of needle 

sharing are successful preventive measures. 

If patients have questions about access to 

condoms or clean needles, they should contact 

their care provider for assistance.

References

• Bryant J, Baxter L, Hird S. Non-occupational 

postexposure prophylaxis for HIV: a 

systematic review. Health Technol Assess. 

2009 Feb;13(14):iii, ix-x, 1-60.

• Kuhar DT, Henderson DK, Struble 

KA, et al.; U.S. Public Health Service 

Working Group. Updated U.S. Public 

Health Service Guidelines for the 

Management of Occupational Exposures 

to Human Immunodeficiency Virus 

and Recommendations for Postexposure 

Prophylaxis. Infect Control Hosp Epidemiol. 

2013 Sep;34(9):875-92.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• U.S. Department of Health and Human 

Services. Antiretroviral postexposure 

prophylaxis after sexual, injection-drug use, 

or other nonoccupational exposure to HIV 

in the United States. MMWR Recomm Rep. 

2005 Jan 21;54(RR02);1-20. Available at 

www.cdc.gov/mmwr/preview/mmwrhtml/

rr5402a1.htm. Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. Updated U.S. Public Health 

Service Guidelines for the Management of 

Occupational Exposures to HBV, HCV, and 

HIV and Recommendations for Postexposure 

Prophylaxis. MMWR Recomm Rep. 2001 

Jun 29;50(RR11). Available at www.cdc.gov/

mmwr/preview/mmwrhtml/rr5011a1.htm. 

Accessed December 1, 2013.

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Section 3: Health Maintenance 

and Disease Prevention

Preventing HIV Transmission/

Prevention with Positives

Background

In recent years, the rate of new HIV infections 

in the United States has remained stable in 

the range of 50,000 per year. Antiretroviral 

therapy (ART) not only improves the health of 

individuals on treatment but also substantially 

reduces the risk of transmitting HIV infection. It has become a critical component of efforts to 

prevent new infections (hence the saying, “treatment is prevention”), but it is not fully effective. 

Additionally, it remains true that only a minority of persons living with HIV infection in the 

United States is taking ART and a smaller proportion has maximal suppression of HIV viral 

load. Thus, behavioral and other risk-reduction interventions remain important aspects of HIV 

prevention. This chapter will focus primarily on interacting with patients around transmission risk 

behaviors, with the goal of reducing HIV transmission. This aspect of care is often referred to as 

“prevention with positives” (PWP).

For many years HIV, prevention efforts have been targeted primarily at HIV-uninfected 

individuals, but HIV-infected persons also must be a crucial focus for HIV prevention. Helping 

HIV-infected persons reduce their risks of transmitting HIV to others is an important aspect of 

medical care for HIV-infected patients. Most people with HIV infection want to prevent others 

from being infected with HIV, but they may practice sexual or injection-drug behaviors that put 

others at risk of infection. 

Health care providers for HIV-infected patients can play a crucial role in prevention efforts, 

including but not limited to provision and monitoring of ART. Many HIV-infected individuals 

report that they want to discuss prevention with their health care providers; however, (according 

to multiple studies), one third to three fourths of HIV medical providers do not ask their patients 

about sexual behavior or drug use. Each patient visit presents an opportunity to provide effective 

prevention interventions, even in busy clinical settings.

It is clear that information alone, especially on subjects such as sexual activity and drug use, 

cannot be expected to change patients’ behavior. However, health care providers can help 

patients understand the transmission risk of certain types of behavior and help patients establish 

personal prevention strategies (sometimes based on a harm-reduction approach) for themselves 

and their partners. Some patients may have difficulty adhering to their safer sex goals. In these 

cases, referrals to mental health clinicians or other professional resources such as prevention case 

management may be helpful.

Patient-education needs are variable and must be customized. Providers must assess the individual 

patient’s current level of knowledge as part of developing a prevention plan. All the information that 

a patient needs cannot be covered during a single visit. A patient’s prevention strategy should be 

reinforced and refined at each visit with the clinician. Clinicians also should ask patients questions 

to determine life changes (e.g., a new relationship, a breakup, or loss of a job) that may affect the 

patient’s sexual or substance-use practices. If the patient can read well, printed material can be given 

to reinforce education in key areas, but it cannot replace a direct conversation with the clinician.

HRSA HAB Performance Measures

Percentage of patients with a diagnosis of 

HIV who received HIV risk counseling in the 

measurement year 

(Adult and Adolescent measure)
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Note: The U.S. Department of Health and 

Human Services is expected to publish 

guidelines on HIV prevention in the near 

future; those may contain recommendations 

that differ from the ones presented here.

National Prevention 

Intervention Efforts

The U.S. Centers for Disease Control and 

Prevention (CDC) has developed a prevention 

approach called High-Impact Prevention 

that focuses on populations at greatest risk of 

acquiring or transmitting HIV, using proven, 

scalable, and cost-effective interventions. 

Proven interventions include: 

• HIV testing and linkage to care

• ART

• Prevention programs for people living with 

HIV and their partners

• Prevention programs for people at high risk 

of HIV infection

• Access to condoms and sterile syringes

• Screening and treatment for sexually 

transmitted diseases (STDs)

• Substance abuse treatment

The CDC has identified a number of evidencebased behavioral prevention interventions 

aimed at persons with HIV infection that 

meet criteria for efficacy and scientific rigor. 

These are conducted on the individual, 

group, or community level, and a number of 

them may be implemented in the treatment 

setting. A Compendium of these interventions 

can be accessed online at the CDC website 

(see www.cdc.gov/hiv/prevention/research/

compendium/rr/index.html). Training and 

educational materials for effective intervention 

models can be found on the CDC-supported 

Diffusion of Effective Behavioral Interventions 

(DEBI) website (www.effectiveinterventions.

org/en/Home.aspx).

Among the many examples of Prevention 

Intervention Programs with Demonstrated 

Efficacy in Treatment Settings on the CDC 

website are the following:

• Options/Opciones Program: The program 

features brief, 5-10 minute patient-centered 

discussions between patients and providers 

at each clinic visit using motivational 

interviewing techniques. Providers evaluate 

sexual and drug-use behaviors, assess the 

patient’s readiness to change, and elicit 

methods from the patient on moving 

toward and maintaining safer behaviors. 

The provider and the patient develop 

an individually tailored plan, which the 

provider writes out on a prescription pad 

and gives to the patient.

• Partnership for Health: This intervention 

involves brief, 3-5 minute, one-on-one 

counseling sessions between the provider 

and the patient on self-protection, 

partner-protection, and disclosure. The 

approach features loss-framed messages 

that emphasize the risks or negative 

consequences of risky behavior. The provider 

then helps the patient develop a plan for risk 

reduction.

• Positive Choice – Interactive Video Doctor:

This program involves an approximately 

24-minute session during which HIVinfected patients complete the Positive 

Choice risk assessment on a laptop computer 

while waiting for scheduled visits with their 

providers. Based on the risk-assessment 

results, a video clip appears with the 

actor-portrayed Video Doctor who delivers 

interactive risk-reduction messages that are 

tailored to the patient’s gender, risk profile, 

and readiness to change. The messages are 

delivered with motivational interviewing 

principles, using a patient-centered, 

empathetic and nonjudgmental approach. 

After the video session, the computer prints 

out an individualized educational sheet for 

the patient and an assessment sheet for the 

patient and the provider to use for follow-up.
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Section 3: Health Maintenance 

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The U.S. Preventive Services Task Force 

(USPSTF) has recommended high-intensity 

behavioral counseling to prevent STDs 

(including HIV) in persons at risk of these 

infections; these approaches also are being 

used in persons with HIV infection to reduce 

their risk of transmitting HIV. Effective highintensity behavioral counseling typically 

comprises multiple sessions with either groups 

or individuals. Examples of these are included 

amongst the models presented on the CDC 

and DEBI websites.

Strategies for Brief, Effective 

Interventions by Providers

A number of strategies have been shown to 

be more effective than providing information 

alone. Effective and brief provider-initiated 

interventions often include the following 

elements:

• Establish rapport and provide services in 

an understanding, nonjudgmental manner. 

Patient educators, nurses, peer counselors, 

social workers, and mental health providers 

may be effective in discussing prevention 

strategies with patients.

• Conduct a quick, detailed behavioral risk 

assessment:

• See the key areas of risk assessment and 

intervention listed in Table 1, below.

• Assess where the patient’s risk behavior 

lies along the risk continuum (described 

in chapter Smoking Cessation).

• Correct misinformation and answer 

questions.

• Assess the patient’s readiness for behavior 

change (see “Stages of Change model,” 

below).

• Screen for and treat STDs: a positive STD 

test result can be a biologic marker of 

behavioral risk, and STDs may facilitate 

HIV transmission (see chapter Initial and 

Interim Laboratory and Other Tests).

• Supply medications, condoms, and 

lubricant as needed.

• Assess the patient’s readiness for change 

and approach any high-risk behavior in 

a step-wise manner, recognizing when 

the patient is ready for next steps. Such 

interventions may be carried out for 5-10 

minutes per visit over a series of visits. The 

“Stages of Change” model and appropriate 

strategies include the following: 

• Precontemplation: The patient is not 

ready to change; reassess at subsequent 

visits.

• Contemplation: The patient is 

considering a change in the future; 

discuss and help the patient to identify 

concrete next steps, such as a date for 

initiating change.

• Preparation: The patient is ready to 

change soon; discuss a concrete action 

plan and connect the patient with 

appropriate resources as needed.

• Action: The patient is actively engaged 

in changing behavior; continue to 

discuss and address challenges; offer 

encouragement.

• Maintenance: The patient has made 

behavioral changes; continue to 

discuss and address challenges, offer 

encouragement and congratulations.

• (Relapse): The patient has relapsed to 

previous risky behaviors; recognize the 

triggers and difficulties the patient had 

with maintenance and offer support and 

encouragement to try again when the 

patient is ready.

• Customize messages, as each individual 

patient’s needs are variable.

• Understand that patients often have 

competing priorities and pressures involving 

mental health needs, relationships, finances, 

housing, employment, and other issues that 

may result in risky sexual and drug-use 

behaviors.
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Prevention with Positives: Key Areas of Assessment and Intervention

These topics should be explored over time. Some sample questions and areas for intervention are 

presented in Table 1. More detailed discussions of topics follow this table. 

Table 1. Components of a Detailed Risk Assessment, with Key Areas for Intervention

Topic Sample Questions, Assessment, and Plan

General Risk 

Assessment

Subjective/objective questions to ask:

1. What do you know about HIV transmission?

2. What, if anything, are you doing that could result in transmitting HIV to another person?

Assessment and plan:

• Use this as an opportunity to help educate the patient on HIV transmission and to 

correct misinformation.

• Place the patient’s behaviors on a risk spectrum and try to prioritize the behaviors that 

are riskiest or the behaviors that the patient is most willing to address.

Sexual 

Practices

Subjective/objective questions to ask:

1. Tell me about any sexual activity since your last clinic visit.

2. What do you know about the HIV status of each sex partner?

3. Tell me about condom use during any sexual activity.

4. What has made it more difficult for you to use condoms during this sexual encounter or 

with this partner?

5. Do your sex practices differ with HIV-infected versus HIV-uninfected partners (“sexual 

positioning”)?

See below for more on partner notification.

Other information:

• Number of sex partners in the past 6 months

• Gender of each partner

• Type of relationship with each partner (main, casual, anonymous)

• Type of sexual activity engaged with each partner

• Safer and less-safe sexual practices with each partner

• Substance use, including alcohol, associated with sex

• Circumstances of risky sex behaviors (e.g., bars/clubs, anonymous partners, intoxication)

Assessment and plan:

• Assess the patient’s level of risk of sexual transmission.

• Assess the patient’s willingness and ability to use condoms during each sexual 

encounter, particularly with partners who are HIV uninfected or of unknown HIV 

serostatus.

• Assess the patient’s ability to use condoms (male and/or female) and correct any 

misinformation. See information on how to use condoms below.

• Supply the patient with condoms and lubricant.

• If the patient is unwilling to use condoms, counsel that risk of transmission can be 

reduced by screening for and treating STDs, using abundant amounts of lubrication, 

avoiding concurrent drug use, avoiding the use of spermicides and douching, and by 

choosing less risky sexual activities. Additionally, serosorting, in which the HIV-infected 

person has sex only with other HIV-infected individuals, can prevent transmission 

to uninfected persons (note: this is not an effective strategy for persons who are HIV 

uninfected or are unsure of their serostatus). 
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Partner 

Notification

Subjective/objective questions to ask:

1. What are your thoughts and experiences talking with your partner(s) about your HIV 

infection? This may be one of the hardest things you have to do.

2. (If the patient has not disclosed to main partner[s]): How might you approach this?

3. Are you afraid for your safety if you tell your partner(s)?

Assessment and plan: ways to offer help for disclosure

• Local health departments may have partner services programs that help locate and 

notify partners in a confidential manner.

• Providers and support staff can help disclose to partners with the patient present.

• Providers and support staff can help disclose to partners without the patient present. 

Antiretroviral 

Therapy (ART)

• ART has been shown to reduce the rate of HIV transmission in serodiscordant 

heterosexual couples by 96%. In other studies, lower levels of HIV in the blood (in 

particular, complete suppression of the HIV RNA through ART) have been associated 

with lower levels of HIV virus in genital secretions and with reductions in the rate of 

sexual transmission of HIV.

• Current HHS guidelines recommend ART for all HIV-infected persons, both for their own 

health and to reduce risk of HIV transmission.

• Close adherence to ART and continuous HIV suppression are likely to be key factors in 

making this an effective prevention tool; assess and reinforce adherence at every visit.

• For a number of reasons, ART alone is not completely effective in preventing 

transmission; it should be viewed as one important tool in a broader approach to 

prevention. Be watchful for attitude shifts away from safer sexual and needle-sharing 

behaviors among patients who believe that ART protects them from transmitting HIV.

STD 

Screening and 

Treatment

• The presence of an STD suggests behaviors that can increase HIV transmission, and it is 

detrimental to the patient’s health.

• Additionally, some STDs may increase the risk of HIV transmission.

• Screen all patients at baseline and regularly afterward, depending on their risk factors 

according to CDC and USPSTF guidelines. For example, screen men who have sex with 

men (MSM) every 3-6 months if multiple sex partners.

• Routinely ask patients if they have symptoms of an STD and educate about the 

importance of seeking care if symptoms are present.

• Depending on risk, it is recommended to screen for the following STDs (see chapters 

Initial History and Initial and Interim Laboratory and Other Tests for screening questions and 

lab tests):

• Syphilis: Serologic test (e.g., RPR, VDRL)

• Gonorrhea: For pharyngeal infections, use nucleic acid amplification test (NAAT) 

or culture of oral swab*; for rectal infections, use NAAT or culture of rectal swab*; for 

urethral or cervical or vaginal infections, use first-catch urine or urethral (male) or cervical 

(female) specimen for NAAT, or culture of urethral (male) or cervical (female) specimen 

• Chlamydia: For rectal infections, use NAAT or culture of rectal swab*; for urethral or 

cervical infections, use first-catch urine or urethral (men) or cervical or vaginal (women) 

specimen for NAAT; testing for pharyngeal chlamydial infection is not recommended 

although the test result often accompanies the GC pharyngeal NAAT result 

• Trichomonas: Wet mount (insensitive), culture, or NAAT on vaginal secretion

• Herpes simplex virus (HSV): Type-specific HSV-2 antibody testing

Although hepatitis B and hepatitis C are not known to increase the risk of HIV infection, 

they may be transmitted sexually, and persons with risk factors (particularly MSM with risky 

sexual practices) should be screened regularly (see chapter Initial and Interim Laboratory and 

Other Tests). 

* NAAT is not yet approved for this indication by the U.S. Food and Drug Administration (FDA), though 

there is evidence that NAAT can accurately diagnose pharyngeal and rectal gonorrhea and chlamydia 

infections. Many local public health departments and other laboratories have received Clinical Laboratory 

Improvement Amendments (CLIA) waivers to perform these tests.
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Drug and 

Alcohol Risk 

Assessment

Subjective/objective questions to ask:

1. Tell me about any drug or alcohol use since your last clinic visit.

2. How do you think your drug or alcohol use affects your sexual behaviors?

3. What are your thoughts about quitting or cutting down on drug and alcohol use, and 

about separating it from sex?

See below for follow-up on needle-sharing practices.

Assessment and plan:

• Assess the patient’s level and circumstances of risk to target your intervention.

• Emphasize that nasal straws or sniffers (e.g., for cocaine) should not be shared.

• Assess the patient’s readiness to quit or cut down on drug and alcohol use, and to 

separate these activities from sex.

• Deliver messages tailored to the patient’s readiness; for example, educate on the risks of 

harming oneself or others, facilitate a plan for harm reduction, or refer to rehabilitation/

detoxification programs and centers. 

Needle-Use 

Practices

Subjective/objective question to ask:

1. Tell me about any needle sharing since your last clinic visit.

Assessment and plan:

• After assessing the patient’s risks and readiness, and if the patient is not ready for 

treatment (e.g., referral to detoxification programs or to buprenorphine and methadone 

programs for heroin users), the following messages for harm reduction can be offered:

• Use only sterile needles and syringes, e.g., from pharmacies or syringe service 

(needle exchange) programs. (Provide information about local syringe service 

programs. Some are listed on the North American Syringe Exchange Network 

website at www.nasen.org.)

• Never reuse or share needles, syringes, or drug preparation equipment because 

it leads not only to transmission of HIV, hepatitis B, and hepatitis C, but also to 

bacterial infections and abscesses.

• Use new or disinfected cookers and new cotton filters to prepare drugs.

• Clean the skin with a new alcohol swab before injecting.

• If equipment must be reused, it should be cleaned properly with bleach or water.

• Safely dispose of syringes in a sharps container (which can be a clean detergent or 

other container), then take them to a needle exchange program or pharmacy for 

disposal. 

Mental Health 

Assessment

Mental illnesses such as bipolar disorder, depression, and post-traumatic stress disorder 

can increase the chances of risky sexual and drug-use behaviors. Ask about mental health 

illnesses directly and pay attention to any symptoms that may indicate a psychiatric illness 

(e.g., manic episodes, depressive episodes, hallucinations).

Subjective/objective questions to ask:

1. Tell me about any previous diagnoses or hospitalizations for mental health illnesses.

2. Have you taken any medications for mental health illnesses?

3. Perform a depression screen: see chapter Major Depression and Other Depressive Disorders. 

Assessment and plan:

See section Neuropsychiatric Disorders for more information.
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Pregnancy 

Screening 

Subjective/objective questions to ask:

For women of childbearing potential:

1. Are you currently pregnant or wanting to become pregnant at some point in the future?

2. Have you missed any periods recently? Are you having any symptoms of pregnancy?

3. What are your thoughts and plans about birth control?

For men with female sex partners:

1. What are your thoughts on having a baby with your partner? What are your thoughts 

about fathering?

2. What are your thoughts on using birth control with your partner? 

Assessment and plan:

See chapter Health Care of HIV-Infected Women Through the Life Cycle.

Sexual Transmission and 

Prevention of HIV

Begin the education process by learning what 

the patient and his or her immediate family 

members (if the family is aware of the patient’s 

HIV status) believe about HIV transmission. 

Also be sure the patient understands how 

the virus is not transmitted (e.g., via sharing 

plates and eating utensils or using the same 

bathrooms) to allay any unnecessary fear.

Advise the patient not to share toothbrushes, 

razors, douche equipment, or sex toys to 

avoid transmitting HIV via blood or sexual 

secretions. This also will help prevent the 

transmission of other bloodborne or sexually 

transmitted diseases, including hepatitis C, 

from coinfected patients. The patient should not 

donate blood, plasma, tissue, organs, or semen 

because these can transmit HIV to the recipient.

There is no reason why a person with 

HIV cannot have an active, fulfilling, and 

intimate sex life. However, the patient must 

be counseled properly about the risk of 

transmission. This discussion between the 

provider and patient should be client centered. 

This means that the provider should let the 

patient guide the discussion, starting from 

the patient’s current point of knowledge and 

practice, always addressing any presenting 

concerns the patient may have prior to 

proceeding with a discussion about sexual 

transmission and risk. The provider should 

ask open-ended questions, in a nonjudgmental 

manner, to elicit information about the 

patient’s relationships, sexual behaviors, and 

current means of reducing transmission risk.

It is important to recognize that not every 

patient seeks the complete elimination of risk 

(e.g., via abstinence) but rather a reduction in 

risk, chosen after the options are discussed 

with the provider. The clinician may help the 

patient select and practice behaviors that are 

likely to be less risky. There are many methods 

for reducing risk, including the following: 

• Disclosing HIV status

• Maintaining maximal suppression of HIV 

through ART

• Reducing the number of sex partners

• Using condoms, particularly for anal or 

vaginal intercourse (insertive or receptive)

• Avoiding drug use in conjunction with sex

• Using adequate lubrication to avoid trauma 

to genital or rectal mucosa 

If the patient requires more extensive 

counseling to support behavioral changes, the 

provider should refer the patient to support 

groups or prevention case management to meet 

those needs. Certainly, if the patient is dealing 

with a dual or triple diagnosis (including 

substance abuse or mental illness), a referral to 

address those needs is indicated. 
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Partner Notification and 

Partner Services

A good way to begin a discussion about HIV 

prevention and transmission is with an inquiry 

about any previous experiences disclosing to 

partners. The provider then can ask whether 

the patient currently has a need to disclose to 

one or more partners and whether he or she 

is ready and motivated to share information 

about HIV status. The provider should prompt 

patients to consider several questions about 

disclosure, including how they might approach 

the discussion, how their partners might 

react, what information they might offer their 

partners, whether partners are likely to keep 

their status confidential, and whether they 

have any concerns about personal safety (e.g., 

owing to fear of a violent reaction). If patients 

fear violence or retaliation or are not ready 

to share their status but want their partners 

to know, the provider may offer assistance 

with partner services, for example through 

the local health department, through which 

partners can be notified and linked to services 

in a confidential manner. As an alternative, 

patients may want the provider to talk with 

their partners, and that option can be offered 

as well. See the CDC website (www.cdc.gov/

nchhstp/partners/Partner-Services.html) for 

information on partner services.

Antiretroviral Therapy

ART that results in maximal HIV suppression 

is an important means of HIV prevention. 

In serodiscordant heterosexual couples, one 

randomized controlled trial showed that ART 

reduced the risk of sexual transmission of HIV 

by 96%. Similar study data for MSM, injection 

drug users, and other HIV risk groups do 

not exist, but multiple other lines of evidence 

suggest that effective ART sharply reduces 

risk of HIV transmission. Thus, ART should 

be offered to all HIV-infected persons, both to 

benefit their own health and to reduce risk of 

HIV transmission to others, as recommended 

in HHS guidelines. Support patients’ 

adherence to ARVs in order to optimize the 

effectiveness of ART as both treatment and 

prevention.

Note that ART does not eliminate HIV 

transmission risk. In some individuals, there 

can be substantial discrepancies between 

HIV RNA levels in the serum and the sexual 

fluids. There have been case reports of HIV 

transmission from HIV-infected individuals 

who had maximal virologic suppression on 

ART. Thus, other behavioral and biologic riskreduction approaches (e.g., screening for and 

offering interventions or treatment for risky 

sexual behaviors, substance use, depression, 

STDs, and other factors listed in Table 1) are 

important aspects of prevention in patients 

taking ART, as in patients not taking ART. 

Helping Patients Reduce the Risk 

of Sexual Transmission

Standard Condom Use

Make sure that the patient understands how 

HIV is transmitted and which types of sexual 

acts are more and less risky than others. 

For vaginal or anal sex, correct use of latex 

or polyurethane condoms reduces the risk 

of HIV transmission considerably. Patients 

should be encouraged to use condoms as much 

as possible. For HIV-infected individuals, 

condom use is effective in reducing the risk of 

contracting another illness (such as hepatitis C 

or another STD) and the (apparently low) risk 

of becoming reinfected with another strain 

of HIV. It should be noted that condoms are 

less effective in reducing the transmission 

of organisms such as human papillomavirus 

(HPV) and HSV, which may result from viral 

shedding from skin. In the event of allergy to 

latex or other difficulty with latex condoms, 

polyurethane male or female condoms may 

be substituted. “Natural skin” or “lambskin” 

condoms are not recommended for HIV 

prevention.
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Of course, condoms must be used correctly to be 

highly effective in preventing HIV transmission. 

Be sure that the patient knows exactly how 

to use a condom. Table 2, in the Appendix, 

provides instructions for condom use.

Advise patients to avoid using nonoxynol-9 

(N-9) spermicides. Data suggest that N-9 may 

increase risk of HIV transmission during 

vaginal intercourse and can damage the rectal 

lining. N-9 never should be used for anal 

intercourse.

For patients who complain about lack of 

sensitivity with condom use, the following 

techniques may help:

• Apply a drop of lubricant inside the condom 

(not more, because it increases the risk that 

the condom will come off).

• Use polyurethane condoms instead of latex 

because they conduct heat and may feel 

more natural.

• Use insertive (female) condoms, which are 

not as restrictive to the penis.

• Use specially designed condoms that do not 

restrict the top of the penis (e.g., Inspiral, 

Xtra Pleasure).

For patients who are unable or unwilling to use 

condoms, the following suggestions may help 

reduce HIV transmission risk:

• Use plenty of lubricant to reduce friction and 

microtrauma, which create portals of entry 

for the virus.

• Avoid spermicides that damage the vaginal 

or anorectal linings.

• Avoid douching products.

• Avoid recreational drugs, especially 

methamphetamine, that impair the ability to 

maintain “safer” sexual behaviors.

• Avoid the use of drugs such as nitrates 

(poppers) that enhance blood flow to the 

genitals. 

Insertive (Female) Condom Use

The insertive “female” condom may be used 

for vaginal or anal intercourse. It is a thin 

polyurethane pouch with a flexible ring at 

the opening, and another unattached flexible 

ring that sits inside the pouch to keep it in 

position in the vagina (for use in the anus, the 

inner ring must be removed and discarded). 

The female condom may be an option for 

women whose male partners will not use 

male condoms or for couples who do not 

like standard condoms. Female condoms 

are more expensive than male condoms, 

but may be procured at a lower cost at some 

health departments or Planned Parenthood 

clinics. They generally are less well known 

to patients and may be unacceptable to some 

women whose culture or religion prohibits or 

discourages touching one’s own genitals. Note 

that the female condom cannot be used at the 

same time as a male condom.

Be sure the patient knows how to use the 

insertive condom before she or he needs 

it; after teaching, encourage practice when 

alone at home and unhurried. Women who 

have used the diaphragm, cervical cap, or 

contraceptive sponge may find it easy to use 

the female condom. Illustrated directions are 

included in each box of insertive condoms. 

Instructions on the use of insertive condoms 

are provided in Table 3, in the Appendix. 

Oral Sex

Although there is evidence that some people 

have become infected through receptive 

oral sex, the risk of HIV transmission via 

oral sex, in general, is much lower than the 

risk of transmission by vaginal or anal sex. 

Thus, most public health and prevention 

specialists focus their attention on riskier 

sexual and drug-use behaviors. However, 

because HIV transmission can occur with 

oral sex, clinicians should address this issue 

with patients and help them make informed 

decisions about risk reduction. Sores or lesions 
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in or around the mouth or on the genitals 

may increase the risk of HIV transmission, 

as may a concurrent STD. Patients (and their 

partners) should avoid oral-genital contact if 

they have these conditions. Similarly, patients 

and partners can further reduce risk by not 

brushing or flossing teeth before oral sex. 

Individuals who wish to further reduce the risk 

of HIV transmission during oral sex may use 

barriers such as condoms, dental dams, and 

flexible plastic nonporous kitchen wrap.

Individuals who smoke crack cocaine often 

develop open burns, cracked lips, or damaged 

mucous membranes inside the mouth and thus 

may be at elevated risk of HIV transmission via 

oral sex. HIV-infected crack users should be 

counseled about the risk of transmitting HIV 

to uninfected partners through those portals 

of entry during oral sex and should receive 

risk-reduction counseling. In addition, they (or 

their partners) may benefit from techniques 

such as insulating the end of the crack pipe 

to reduce burns while smoking (e.g., with a 

rubber band or spark plug cap) and avoiding 

the brittle or sharp-edged copper scrubbing 

pads used as screens in the crack pipe. 

Influence of Substance Use on 

Sexual Behavior

Alcohol and drug use can contribute 

significantly to the risk of sexual transmission 

of HIV, because of behavioral disinhibition. 

While intoxicated, substance users may, for 

example, forgo condom use, practice riskier 

sexual behaviors, have multiple partners, or 

use erectile dysfunction agents to sustain 

sexual activity. Addressing substance use 

issues is an important aspect of PWP. Patients 

should be assessed for HIV transmission 

risks associated with alcohol and injection 

or noninjection drug use, including crystal 

methamphetamine, in the context of their 

sexual behaviors (for injection drug use, see 

below). As always, it is important to approach 

the patient in a nonjudgmental manner. If 

alcohol or other drugs are posing barriers 

to practicing safer behaviors, the provider 

should counsel the patient to reduce or avoid 

substance use before engaging in sex, or refer 

the patient to prevention case management 

for more specialized risk reduction. Often, the 

provider can help the patient identify methods 

for reducing HIV transmission risk, including 

means that do not require abstaining from 

alcohol and drug use. 

Injection Drug Use and 

Prevention of HIV

Clinicians should discuss substance use, 

including steroid use, and reinforce the 

patient’s understanding of the adverse effects 

that these drugs can have on the body and the 

immune system. Assess whether referral for 

treatment is appropriate, and be knowledgeable 

about referral resources and mechanisms. If 

the patient is using injection drugs (including 

steroids and other hormones), emphasize the 

fact that HIV is readily transmitted by sharing 

needles and other injection equipment and that 

reusing or sharing needles and syringes can 

cause additional infections (e.g., endocarditis, 

hepatitis C). Assess the patient’s readiness to 

change his or her drug injection practices, 

and refer to drug treatment programs as 

appropriate. Refer to an addiction counselor 

for motivational interviewing or other 

interventions, if available. After completion 

of substance abuse treatment, relapse 

prevention programs and ongoing support 

will be needed. If the patient continues to use 

needles, discuss safer needle-use practices 

(Table 1) and consider referral to a syringe 

service (needle exchange) program, if one is 

available, so that syringes and needles are not 

reused. A partial listing of needle exchange 

sites may be found on the North American 

Syringe Exchange Network website at www.

nasen.org, although many states either do not 

have facilities or are prohibited from listing 

them. Local harm-reduction activists may be 
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aware of specific programs for obtaining clean 

needles and syringes. Patient-education flyers 

on safer injection practices, safer stimulant 

use, overdose prevention, and other topics are 

available on the Midwest AIDS Education and 

Training Center website (www.uic.edu/depts/

matec/resource.html). 

Noninjection Drug Use and 

Prevention of HIV Transmission

Exposure to HIV through contaminated 

blood may occur with the use of noninjection 

drugs; for example, by sharing cocaine straws 

or sniffers through which cocaine is inhaled. 

These straws easily can penetrate fragile nasal 

mucosa and become contaminated with blood 

from one user before being used by another 

individual, who may then experience mucous 

membrane exposure or even a cut or break in 

the mucous membrane from the bloody object. 

Straws or sniffers should not be shared. 

Tattoo, Piercing, and 

Acupuncture Equipment

Patients should be aware of the risk of 

contamination of tattoo equipment, inks, and 

piercing equipment, and they should avoid 

situations wherein they might either transmit 

HIV or pick up other bloodborne pathogens. 

Acupuncturists generally use sterile needles, 

but clients should verify that before using their 

services. 

Perinatal HIV Transmission

HIV-infected women can have healthy 

pregnancies, with good health outcomes 

for both mother and baby. For this to occur, 

women must know their HIV status as early 

as possible, preferably before becoming 

pregnant, and must receive effective ART. 

Although intervention to reduce the risk of 

perinatal infection is most effective if begun 

early in pregnancy, or preferably before 

pregnancy, it may be beneficial at any point 

in the pregnancy, even as late as during labor. 

For further information, see chapter Reducing 

Perinatal HIV Transmission.

Preexposure Prophylaxis (PrEP)

Preexposure prophylaxis (PrEP) refers to 

the use of oral or topical ARVs before HIV 

exposure with the goal of preventing HIV 

infection. Studies have evaluated PrEP 

strategies using either oral tenofovir + 

emtricitabine (Truvada), oral tenofovir, or 

vaginal tenofovir to prevent sexual acquisition 

of HIV in MSM and high-risk heterosexually 

active women and men. Most have shown 

efficacy (ranging from about 40% to 75%) in 

reducing infection risk, but two others have 

not demonstrated protective benefit. A study 

of PrEP using tenofovir in injection-drug users 

also showed a reduction in HIV infections 

in the tenofovir group (a 49% reduction in 

incidence). In all studies, the effectiveness 

of PrEP has been strongly related to the 

study participants’ adherence to the PrEP 

medication. It should be noted that, in these 

PrEP studies, the ARV prophylaxis was given 

in conjunction with other risk-reduction 

interventions, including counseling, condom 

provision, and STD testing and treatment. 

The CDC has issued interim guidelines on the 

use of oral tenofovir-emtricitabine as PrEP 

in MSM, heterosexually active adults, and 

injection-drug users (see “References,” below); 

these guidelines offer recommendations for 

PrEP screening and use, as well as ongoing 

monitoring for adherence, safety, and HIV 

infection. They emphasize that PrEP should 

be delivered in the context of a comprehensive 

package of health and prevention services. 

In 2012, the FDA approved the fixed-dose 

combination tenofovir/emtricitabine (Truvada) 

to reduce the risk of sexually acquired HIV-1 

in adults at high risk; it has not yet approved 

an indication for PrEP in injection-drug users.

U.S. Public Health Service (PHS) guidelines for 

PrEP use are currently in development.
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Postexposure Prophylaxis for 

Nonoccupational HIV Exposure

Postexposure prophylaxis (PEP) may be 

considered for certain sexual exposures, 

sexual assaults, and other nonoccupational 

exposures to HIV. As with occupational 

PEP, a risk assessment must be completed 

and PEP medications, if indicated, must be 

started as soon after exposure as possible. 

The risks and toxicities of ARV drugs must 

be weighed against potential benefits, 

and the client’s informed consent must be 

obtained. For further information, see chapter 

Nonoccupational Postexposure Prophylaxis. 

Appendix

Table 2. Instructions for Use 

of Standard Condoms 

• Use a new latex or polyurethane condom with 

each act of sex (oral, anal, or vaginal). Make 

sure that the condom is undamaged, and that 

its expiration date has not passed.

• Carefully handle the condom to avoid damage 

(e.g., from fingernails, teeth).

• Being sure that the condom roll faces out, 

unroll the condom onto the erect penis before 

any genital contact with partner.

• Ensure that the tip of the condom is pinched 

when applying it to the top of the penis, 

to eliminate air in the tip that could cause 

breakage during ejaculation.

• Use only water-based lubricants with latex 

condoms. Oil-based lubricants (such as 

mineral oil, cooking oil, massage oil, body 

lotion, and petroleum jelly) can weaken 

latex or cause it to break, although they are 

fine with the use of polyurethane condoms. 

Adequate lubrication during intercourse helps 

reduce the risk of condom breakage.

Table 3. Instructions for Use of 

Insertive (Female) Condoms

Vaginal Intercourse

• Open the pouch by tearing at notched edge 

of packet, and take out the female condom. Be 

sure that the lubricant is evenly distributed on 

the inside by rubbing the outsides together.

• Find a comfortable position, such as standing 

with one foot on a chair, sitting with knees 

apart, or squatting. Be sure the inner ring is 

inside, at the closed end of the pouch.

• Hold the pouch with the open end hanging 

down. While holding the outside of the pouch, 

squeeze the inner ring with your thumb and 

middle finger. Still squeezing, spread the labia 

with your other hand and insert the closed 

end of the pouch into the vagina.

• Now, put your fingers into the pouch itself, 

which should be inside the vagina, and push 

the inner ring and the pouch the rest of the 

way up into the vagina with your index finger. 

Check to see that the front side of the inner 

ring is just past the pubic bone. The back part 

of the inner ring should be up behind the 

cervix. The outer ring and about an inch of the 

pouch will be hanging outside the vagina.

• Until you and your partner become 

comfortable using the female condom, 

use your hand to guide the penis into the 

vagina, keeping it inside the pouch. If, during 

intercourse, the outer ring is pushed inside the 

vagina, stop, remove the female condom, and 

start over with a new one. Extra lubricant on 

the penis or the inside of the female condom 

may help keep this from happening.

• After intercourse, take out the condom by 

squeezing and twisting the outer ring to keep 

the semen inside the pouch. Throw away in a 

trash can; do not flush. Do not reuse.

• More information is available on the 

Planned Parenthood website (www.

plannedparenthood.org). 

Anal Intercourse

• Remove the inner ring and discard it. Put the 

female condom on the penis of the insertive 

partner and insert the condom with the penis, 

being careful not to push the outer ring into 

the rectum. The outer ring remains outside the 

anus, for ease of removal after ejaculation.
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References

• Centers for Disease Control and Prevention. 

Compendium of Evidence-Based HIV 

Behavioral Interventions. Available at 

www.cdc.gov/hiv/prevention/research/

compendium/rr/index.html. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

High-Impact HIV Prevention: CDC’s 

Approach to Reducing HIV Infections in 

the United States. Atlanta: U.S. Centers for 

Disease Control and Prevention; August 

2011. Available at www.cdc.gov/hiv/strategy/

hihp. Accessed December 1, 2013.

• Centers for Disease Control and Prevention. 

Interim guidance for clinicians considering 

the use of preexposure prophylaxis for the 

prevention of HIV infection in heterosexually 

active adults. MMWR Morb Mortal Wkly 

Rep. 2012 Aug 10;61(31):586-9.

• Centers for Disease Control and Prevention. 

Interim Guidance: Preexposure Prophylaxis 

for the Prevention of HIV Infection in Men 

Who Have Sex with Men. MMWR Recomm 

Rep. 2011 Jan 28;60(RR-3):65-69. Available 

at www.cdc.gov/mmwr/PDF/wk/mm6003.

pdf. Accessed December 1, 2013.

• Centers for Disease Control and Prevention. 

Recommendations for partner services 

programs for HIV infection, syphilis, 

gonorrhea, and chlamydial infection. 

MMWR Recomm Rep. 2008 Nov 7;57(RR9):1-83; quiz CE1-4.

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 

17; 59 (No. RR-12):1-110. Available at 

www.cdc.gov/STD/treatment/2010. 

Accessed December 1, 2013.

• Centers for Disease Control and Prevention 

(CDC); Health Resources and Services 

Administration; National Institutes of 

Health; HIV Medicine Association of the 

Infectious Diseases Society of America. 

Incorporating HIV prevention into the 

medical care of persons living with HIV. 

MMWR Recomm Rep. 2003 Jul 18;52(RR12):1-24.

• Cohen MS, Chen YQ, McCauley M, et al.; 

HPTN 052 Study Team. Prevention of HIV-1 

infection with early antiretroviral therapy. N 

Engl J Med. 2011 Aug 11;365(6):493-505.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Richardson JL, Milam J, McCutchan A, et al. 

Effect of brief safer-sex counseling by medical 

providers to HIV-1 seropositive patients: a 

multi-clinic assessment. AIDS. 2004 May 

21;18(8):1179-86.

• U.S. Department of Health and Human 

Services, Health Resources and Services 

Administration. A Guide to Primary Care 

for People with HIV/AIDS, 2004 Edition. 

Washington: U.S. Department of Health and 

Human Services; 2004.

• U.S. Department of Veterans Affairs. 

Prevention for Positives. In: Primary Care of 

Veterans with HIV. April 2009. Available at 

www.hiv.va.gov/provider/manual-primarycare/prevention-for-positives.asp. Accessed 

December 1, 2013.

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Immunizations for HIV-Infected 

Adults and Adolescents

Background

Immunocompromised individuals are at higher risk 

of acquiring many types of infections compared with 

immunocompetent people. Although HIV-infected 

persons could benefit greatly from immunization 

against preventable infections, little specific research 

on the effectiveness of immunizations in this 

population has been completed. In general, vaccines 

have better efficacy in HIV-infected patients when 

immune function is relatively well preserved, notably 

when the CD4 count is >200 cells/μL. Persons with 

advanced immunodeficiency may have an impaired 

humoral response, and may not respond to vaccines, 

or they may require supplemental doses to develop 

serologic evidence of protection. If possible, vaccines 

should be administered before the CD4 count 

decreases to <200 cells/μL; if given when the CD4 

count is <200 cells/μL, consideration should be given 

to repeating the vaccination when the CD4 count 

increases to >200-300 cells/μL (unless there is evidence of immunity).

Live vaccines generally should not be administered to individuals with HIV infection, particularly 

those with advanced immunodeficiency, unless the anticipated benefits of vaccination clearly 

outweigh the risks.

Administration of vaccines can be associated with a transient rise in plasma HIV RNA.

Recommendations about vaccination for patients with HIV infection are presented in Table 1.

HRSA HAB Performance 

Measures 

Percentage of patients, aged 6 months 

and older seen for a visit between 

October 1 and March 31, who received 

an influenza immunization OR 

who reported previous receipt of an 

influenza immunization

(All-Age measure)

Percentage of patients with a diagnosis 

of HIV who completed the vaccination 

series for hepatitis B

(Adult and Adolescent measure)

Percentage of patients with a 

diagnosis of HIV who ever received 

pneumococcal vaccine

(Adult and Adolescent measure)
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Table 1. Vaccine Recommendations

Vaccine Type Recommendation

Pneumococcal • Recommended for all.

• If CD4 count is <200 cells/μL, may be less effective; consider revaccination when CD4 

count increases in response to ART.

• Two types of pneumococcal vaccine; both should be given, as follows.

Pneumococcal 

(polysaccharide) 

(PPV23)

• 1 dose as soon as possible after HIV diagnosis (or PCV13 may be given first, see 

below); revaccinate 5 years after initial vaccination. 

• For those who received 1-2 doses of PPV23 before age 65, repeat at age ≥65 if ≥5 

years since their previous dose. 

• PPV23 should not be given <8 weeks after PPV13 (see below).

Pneumococcal 

13-valent 

conjugate 

(PPV13)

• 1 dose recommended for all HIV-infected adults; timing varies according to whether 

PPV23 has been given:

• No previous pneumococcal vaccination:

• 1 dose PCV13 followed by PPV23 ≥8 weeks after PCV13.

(If CD4 <200 cells/μL, PPV23 can be offered ≥8 weeks after PCV13 or can await 

increase of CD4 to >200 cells/μL.)

• Previous PPV23 vaccination:

• 1 dose of PCV13, given ≥1 year after last receipt of PPV23.

Hepatitis A Virus 

(HAV)

• Recommended, for persons with chronic liver disease, injection drug users, men who 

have sex with men, international travelers, and hemophiliacs. Consider for all, unless 

there is serologic evidence of previous disease.

• Serologic response (HAV IgG Ab) should be checked 1 month after completion of 

series, and nonresponders should be revaccinated.

• 2 doses (Havrix: 0, 6-12 months; Vaqta: 0, 6-18 months). 

Hepatitis B Virus 

(HBV)

• Recommended for all, unless there is evidence of immunity (HBV surface Ab+) or 

active HBV infection (HBV surface Ag+, or HBV core Ab+ and evidence of HBV activity).

• Many experts recommend giving a high dose of HBV vaccine (40 mcg), as is standard 

for hemodialysis patients; this may improve immunologic response in HIV-infected 

patients.

• Most HIV-infected patients with isolated HBV core Ab+ (without HBV viremia) are not 

immune and should receive a complete series of HBV vaccine.

• Anti-HBV surface Ab titers should be checked 1 month after completion of vaccine 

series. Patients whose titer level is ≤10 IU/mL should be revaccinated.

• Standard dosing schedule is 3 doses (0, 1, and 6 months). If 40 mcg is given, the 

recommended schedule is 3 doses of Recombivax HB at 0, 1, and 6 months or 4 doses 

of Engerix-B at 0, 1, 2, and 6 months.

Influenza 

(inactivated 

vaccine)

• Recommended (yearly).

• Vaccination is most effective among persons with CD4 counts of >100 cells/μL and HIV 

RNA of <30,000 copies/mL.

• In patients with advanced disease and low CD4 cell counts, inactivated vaccine may 

not produce protective antibodies. A second dose of vaccine does not improve 

response in these patients.

• Live, attenuated cold-adapted vaccine (LAIV, FluMist) is not recommended for use in 

patients with HIV infection as the efficacy of the vaccine in this population has not 

been evaluated.

• Close contacts of severely immunocompromised persons (including household 

members and health care personnel) should not receive live, attenuated influenza 

vaccine.
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Vaccine Type Recommendation

Tetanus, 

Diphtheria 

(Td); Tetanus, 

Diphtheria, 

Pertussis (Tdap)

• Recommended (booster is recommended every 10 years in adults; or, if potential 

exposure [wound], after 5 years).

• To protect against pertussis, substitute single dose of Tdap for Td booster in all 

patients aged 19-65 who have not received Tdap previously.

Measles, 

Mumps, Rubella 

(MMR)

• Live vaccine is contraindicated for use in patients with severe immunosuppression 

(CD4 count of <200 cells/μL).

• Recommended for all nonimmune persons with CD4 counts of ≥200 cells/μL.

Varicella-Zoster 

(VZV)

• Two doses (0, 3 months).

• Live vaccine; contraindicated for use in patients with severe immunosuppression 

(CD4 count of <200 cells/μL).

• Consider for HIV-infected, VZV-seronegative persons with CD4 counts of ≥200 cells/μL.

• If vaccination results in infection with attenuated virus, treat with acyclovir.

• Transmission of vaccine virus from vaccine recipients to susceptible individuals is 

possible; vaccine recipients should avoid close contact with high-risk susceptible 

individuals for 6 weeks after vaccination.

Varicella vaccine 

(primary 

immunization)

Zoster vaccine • One dose.

• Live vaccine; contraindicated in persons with AIDS or other clinical manifestations of 

HIV infection.

• Consider for select patients aged >50 with CD4 counts of >200 cells/μL and with 

evidence of varicella immunity (if no evidence of varicella immunity, give primary 

varicella vaccination). Limited data show safety and immunogenicity in this group.

• Transmission of vaccine virus to susceptible contacts is possible.

Human 

Papillomavirus 

(HPV)

• Two vaccines: 

• Gardasil includes HPV strains 16 and 18 (oncogenic) and 6 and 11 (wart causing); 

approved for use in women and men.

• Cervarix: includes HPV strains 16 and 18; approved for use in women.

• Gardasil or Cervarix recommended for females aged 9-26.

• Gardasil vaccine recommended for males aged 9-26.

• Not contraindicated for use in HIV-infected individuals; limited data on efficacy; may 

be less effective if CD4 count is <200 cells/μL.

Meningococcal • Two doses (0, ≥8 weeks).

• Recommended if risk factor is present (e.g., college freshmen living in dormitory, 

military recruits, asplenia, complement component deficiency, travel to or residence 

in area with outbreaks,* occupational exposure).

Abbreviations: Ab = antibody; Ag = antigen; ART = antiretroviral therapy

* In 2012, the New York City Department of Health and Mental Hygiene reported ongoing outbreak of meningococcal meningitis 

in men who have sex with men (MSM) and recommended vaccination for those with recent or future exposure risk. Many health 

departments in other areas have recommended vaccination of MSM, including HIV-infected MSM, who recently had or expect to 

have close contact with a man who is known to be, or could potentially be, from New York City.
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Immunizations for HIVInfected Patients Traveling 

to Developing Countries

Routine vaccinations should be reviewed and 

updated before travel. All patients traveling 

to other countries should be evaluated 

for both routine and destination-specific 

immunizations and prophylaxes. Inactivated 

(killed) and recombinant vaccines (e.g., 

diphtheria-tetanus, rabies, hepatitis A, 

hepatitis B, Japanese encephalitis) should be 

used for HIV-infected persons just as they 

would be used for HIV-uninfected persons 

anticipating travel. For further information, 

see the U.S. Centers for Disease Control and 

Prevention (CDC) webpage (wwwnc.cdc.

gov/travel). Recommendations specific to 

HIV-infected travelers are located in “The 

Immunocompromised Traveler” under the 

section called “Advising Travelers with Special 

Needs.” Select the “Traveler’s Health” option 

for regional travel documents and information 

on outbreaks.

Decision making about immunization for 

the HIV-infected traveler should take into 

consideration the traveler’s current CD4 cell 

count, history of AIDS-defining illness, and 

clinical manifestations of symptomatic HIV. 

In the CDC recommendations, asymptomatic 

HIV-infected persons with CD4 counts of 

200-500 cells/μL are considered to have limited 

immune deficits, whereas patients with CD4 

counts of >500 cells/μL are considered to have 

no immunologic compromise. For patients 

taking antiretroviral therapy, current CD4 

counts rather than nadir counts should be used 

in deciding about immunizations. The CDC 

recommends that newly diagnosed, treatmentnaive patients with CD4 counts of <200 

cells/μL delay travel until after immunologic 

reconstitution with antiretrovirals to minimize 

risk of infection and immune reconstitution 

illness during travel.

The following should be noted about specific 

vaccinations:

• Inactivated (killed), enhanced-potency 

polio and typhoid vaccines should be given 

instead of the live, attenuated forms. In 

adults aged >18, vaccinate 8 weeks before 

travel to allow time for the initial 2 doses of 

polio vaccine.

• Measles or measles, mumps, and rubella 

(MMR; omit if patient has evidence 

of immunity) should not be given to 

severely immunocompromised patients. 

Instead, immune globulin should be 

given to measles-susceptible, severely 

immunocompromised persons traveling to 

measles-endemic countries.

• Yellow fever vaccine is a live-virus vaccine 

with uncertain safety and efficacy for HIVinfected persons, and it should be avoided if 

possible. Travelers with asymptomatic HIV 

infection and relatively high CD4 counts 

who cannot avoid potential exposure to 

yellow fever should be offered the choice 

of vaccination. If travel to a zone with 

yellow fever is necessary and vaccination 

is not administered, patients should be 

advised about the risk of yellow fever, 

instructed about avoiding the bites of vector 

mosquitoes, and provided with a vaccination 

waiver letter (though travelers should be 

warned that not all countries accept waiver 

letters).

• The influenza season in the Southern 

Hemisphere is April through September, 

but in the tropics, influenza is a year-round 

infection. Immunocompromised patients 

should be protected on the basis of influenza 

risk at the destination. HIV-infected patients 

should not be given live intranasal influenza 

vaccine.
Immunizations for HIV-Infected Adults and Adolescents | 161

Section 3: Health Maintenance 

and Disease Prevention

References

• Aberg JA, Gallant JE, Ghanem KG, et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• ACIP Adult Immunization Work Group, 

Bridges CB, Woods L, et al.; Centers for 

Disease Control and Prevention. Advisory 

Committee on Immunization Practices 

(ACIP) recommended immunization schedule 

for adults aged 19 years and older – United 

States, 2013. MMWR Surveill Summ. 2013 

Feb 1;62 Suppl 1:9-19.

• Benson C, Hua L, Andersen J, et al. Zostavax 

is generally safe and immunogenic in HIV+ 

adults virologically suppressed on ART: 

results of a phase 2, randomized, doubleblind, placebo-controlled trial. In: Program 

and abstracts of the 12th Conference on 

Retroviruses and Opportunistic Infections; 

March 5-8, 2012; Seattle. Abstract 96.

• Centers for Disease Control and Prevention. 

The Immunocompromised Traveler. In: CDC 

Health Information for International Travel. 

Atlanta: U.S. Department of Health and 

Human Services, Public Health Service; 

2012. Available at wwwnc.cdc.gov/travel. 

Accessed December 1, 2013.

• Kroon FP, van Dissel JT, de Jong JC, et 

al. Antibody response after influenza 

vaccination in HIV-infected individuals: a 

consecutive 3-year study. Vaccine. 2000 Jul 

1;18(26):3040-9.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

Preventing Exposure to Opportunistic and Other Infections | 163

Section 3: Health Maintenance 

and Disease Prevention

Preventing Exposure to Opportunistic 

and Other Infections

Background

Persons with HIV infection are more susceptible than others to certain infections. HIV-infected 

persons may come into contact with opportunistic pathogens in the course of various aspects 

of their daily activities. Pets, children, personal and sexual contacts, and food and water, as well 

as involvement in occupational tasks, recreation, hobbies, and other activities all potentially 

can expose an HIV-infected person to opportunistic pathogens, some of which are ubiquitous 

and cannot be avoided. Among the ubiquitous pathogens are Candida, Mycobacterium avium, 

Pneumocystis jiroveci, and human herpesvirus 6 and 7. Exposure to other opportunistic pathogens 

may be minimized if patients are aware of the risks.

The following tables group opportunistic pathogens by type of exposure. Mechanisms of 

transmission and recommendations for avoidance are outlined. Note that a number of infections 

can be transmitted by several of these modes.

For information about vaccinations, see chapter Immunizations for HIV-Infected Adults and 

Adolescents; for opportunistic infection (OI) prophylaxis, see chapter Opportunistic Infection 

Prophylaxis.

Topics:

• Water related

• Food associated

• Environmental

• Respiratory and bodily contact

• Associated with sexual contact 

• Injection drug use associated

• Other bloodborne related

• Pet and animal related

• Contact with children

• Travel related
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Water Related

Pathogens • Hepatitis A virus (HAV)

• Cryptosporidium

• Shigella

• Campylobacter

• Amoeba

• Giardia

• Isospora

• Microsporidia

Transmission • Infection occurs through drinking contaminated water or eating produce or other 

food that has been washed in contaminated water.

• Water ingested accidentally during recreation also can make people sick.

Recommended 

avoidance 

measures 

• To decrease exposure from water in developing countries, take the following 

precautions:

• Do not drink tap water or use it to brush teeth.

• Avoid ice that is not made from bottled water.

• Avoid raw fruits or vegetables, as they may have been washed in tap water.

• Bring tap water to a rolling boil for at least 1 minute before consuming. If this is 

not possible, treatment with iodine or chlorine, especially in conjunction with 

filtering, reduces risk of infection.

• Additional recommendations, include the following:

• Avoid drinking untreated water.

• When choosing a home water filter, especially for filtering untreated water, be 

aware that not all filters remove the pathogens listed above.

• Do not drink water from lakes or rivers.

• Avoid swimming in water that may be contaminated with stool.

• Avoid swallowing water during recreational activities (lakes, rivers, saltwater 

beaches, pools, hot tubs, and ornamental fountains may be contaminated with 

Cryptosporidium).

• In the event of a cryptosporidiosis outbreak in the municipal water supply, boil tap 

water for at least 1 minute to eliminate risk of infection.

• Cryptosporidium may be present in municipal water outside outbreak settings, 

though the magnitude of this risk is unknown. Some HIV-infected patients may 

choose to take precautions to decrease risk.

• Be aware that bottled water may be contaminated with Cryptosporidium.

• See the discussion of travel-related topics, below.
Preventing Exposure to Opportunistic and Other Infections | 165

Section 3: Health Maintenance 

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Food Associated

Pathogens • Toxoplasma

• Salmonella, Shigella, Campylobacter 

(enteric infections)

• Listeria

• Cryptosporidium

• Other enteric pathogens

Transmission • Exposure may occur through eating or handling contaminated food.

Recommended 

avoidance 

measures

• Always wash hands before preparing and consuming food.

• Wash hands, cutting boards, counters, and utensils thoroughly after contact with 

uncooked foods.

• Do not allow raw meat or eggs to come into contact with other foods.

• Wash produce thoroughly.

• Cook meat and poultry to an internal temperature of 165-170°F. It is safest to confirm 

temperature with a thermometer. Meat that is no longer pink inside likely has reached 

a temperature of 165°F.

• Avoid raw or unpasteurized milk, including goat milk, and foods that contain 

unpasteurized milk or milk products.

• Avoid foods that might contain raw egg (e.g., Hollandaise sauce, Caesar salad 

dressing, some mayonnaises, uncooked cake and cookie batter, eggnog, homemade 

ice cream). Pasteurized eggs can be used safely in recipes that call for raw egg.

• Avoid eating raw or lightly steamed shellfish.

• Avoid eating raw seed sprouts, as these may be contaminated with enteric pathogens.

• Avoid foods from street vendors, especially in developing countries.

• Be aware that unpasteurized juices may be contaminated with Cryptosporidium.

• Rates of infection with Listeria are low, but HIV-infected people who are severely 

immunocompromised are at increased risk.

• HIV-infected persons who wish to decrease their risk of listeriosis should take the 

following precautions: 

• Avoid soft cheeses including feta, brie, camembert, blue-veined, and Mexicanstyle cheeses such as queso fresco unless they are clearly labeled as pasteurized. 

Hard cheeses, processed cheeses, cream cheese, cottage cheese, and yogurt 

generally are safe.

• Before eating leftover foods or ready-to-eat foods, such as hot dogs, cook them 

until they are steaming hot.

• Avoid foods from deli counters, such as prepared meats, salads, and cheeses, or 

heat these foods until steaming hot before eating them.

• Avoid refrigerated pâté, or heat until steaming hot. Canned or shelf-stable pâté 

generally is safe.

• Avoid refrigerated smoked seafood, unless it is part of a cooked dish. Canned or 

shelf-stable smoked seafood generally is safe.

• Also see information on travel-related infections, below.

Environmental

Pathogens • Toxoplasma gondii

• Cryptosporidium

• Coccidioides

• Histoplasma capsulatum

• Cryptococcus neoformans

• Aspergillus

Transmission • Cryptosporidium and Toxoplasma may be present in soil and sands, and infection can 

occur through handling soil during gardening or playing in or cleaning sandboxes.

• Infection with Coccidioides and Histoplasma occurs with inhalation of fungal spores 

that become airborne owing to disturbance of contaminated soil.
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Environmental

Recommended 

avoidance 

measures

• Wash hands thoroughly after contact with soil or sand.

• Endemic fungi cannot be completely avoided in certain geographic areas; however, 

avoiding high-risk activities can decrease risk of infection.

• In endemic coccidioidomycosis areas, avoid exposure to soil disturbance such as that 

which occurs during dust storms and at excavation and construction sites.

• Risk of Aspergillus infection also may be decreased by avoidance of dusty 

environments.

• Patients with CD4 counts of <150 cells/μL should avoid activities that put them at 

increased risk of exposure to Histoplasma in endemic areas, such as: 

• Cleaning, remodeling, or demolishing old buildings

• Disturbing soil beneath bird roosting sites

• Cave exploration

• Other contact with bird or bat droppings

• Limiting exposure to bird droppings may decrease risk of infection with C. neoformans.

Respiratory and Bodily Contact

Pathogens • Mycobacterium tuberculosis

• Enteric pathogens

• Influenza

• Varicella-zoster virus (VZV)

Transmission • Tuberculosis (TB) is transmitted when a person with pulmonary or laryngeal TB 

coughs, sneezes, shouts, or sings, generating infected droplets that are inhaled by a 

susceptible person.

• HIV-infected persons working or residing in certain environments, such as hospitals, 

nursing homes, homeless shelters, and correctional institutions, may become 

exposed to TB.

• Influenza virus is spread by exposure to infected respiratory droplets or contaminated 

surfaces.

• VZV is transmitted through contact with aerosolized respiratory droplets or by 

contact with skin lesions.

• Many respiratory and enteric pathogens may be spread by contact with 

contaminated fomites.

Recommended 

avoidance 

measures

• HIV-infected persons should be aware of the increased risk of TB infection associated 

with certain environments. The following measures decrease risk of infection: 

• In settings with a high risk of TB transmission, patients with known or suspected 

TB should be physically separated from others.

• All HIV-infected persons should be tested for latent TB infection.

• All HIV-infected patients with latent TB infection (LTBI) should receive a complete 

course of LTBI treatment.

• HIV-infected persons with a history of significant TB exposure should be treated 

presumptively for LTBI regardless of the results of LTBI testing, once active 

infection has been ruled out.

• Bacillus Calmette-Guérin (BCG) vaccination is not recommended in the United 

States, and it is contraindicated for HIV-infected persons.

• People susceptible to VZV should avoid persons with active chickenpox or herpes 

zoster (shingles).

• VZV-susceptible, HIV-negative household contacts should be vaccinated against VZV, 

so that they will not transmit VZV to their HIV-infected contact.

• Frequent handwashing can reduce risk of diarrhea in HIV-infected persons.
Preventing Exposure to Opportunistic and Other Infections | 167

Section 3: Health Maintenance 

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Associated with Sexual Contact

Pathogens • HIV

• Hepatitis B virus (HBV)

• Hepatitis C virus (HCV)

• Hepatitis A virus (HAV)

• Human papillomavirus (HPV)

• Cytomegalovirus (CMV)

• Herpes simplex virus (HSV)

• Syphilis

• Chlamydia

• Gonorrhea

• Trichomonas

• Lymphogranuloma venereum (LGV) 

serovars of Chlamydia trachomatis

• Cryptosporidium

• Shigella

• Campylobacter

• Amoeba

• Giardia

• Isospora

• Microsporidia

Transmission • Depending on the pathogen, infection may be transmitted by exchange of body 

fluids, by skin-skin contact, or by oral-fecal contact.

• Sexually transmitted diseases (STDs) can occur at genitals, rectum, or mouth, 

depending on sexual practices.

• A number of enteric pathogens can be transmitted during sex (by oral-fecal contact).

Recommended 

avoidance 

measures 

• Male latex condoms, when used consistently and correctly: 

• Are highly effective in preventing sexual transmission of HIV and many other STDs, 

including syphilis, chlamydia, gonorrhea, and trichomoniasis.

• Decrease risk of acquiring HSV-2, HPV, CMV, HBV, and HCV.

• Do not prevent enteric pathogen exposure (which is via fecal-oral contact).

• HIV-infected persons should be screened for STDs at least annually. Those with 

multiple partners or high-risk partners or sexual practices should be screened more 

frequently.

• To avoid infection with HSV, HIV-infected persons should avoid sexual contact when a 

partner has an overt herpetic lesion (genital or oral-labial), though HSV transmission 

also can occur during asymptomatic shedding. Consistent use of male condoms also 

has been shown to reduce HSV transmission risk in heterosexual couples.

• The use of suppressive antiviral therapy by persons with genital herpes reduces HSV-2 

transmission to susceptible partners, though the effectiveness of this approach in HIVinfected patients has not been evaluated. 

• Patients who are CMV seronegative should be advised that CMV can be sexually 

transmitted.

• To decrease risk of exposure to enteric pathogens during sex, patients can: 

• Use barriers such as dental dams during oral-anal contact.

• Change condoms after anal sex.

• Wear latex gloves during digital-anal contact.

• Wash hands after sex.
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Injection Drug Use Associated

Pathogens • HIV

• HCV

• HBV

• CMV

• Staphylococcus aureus, including MRSA

• Pseudomonas aeruginosa

• Streptococcus

• Clostridium

• Enteric bacteria and oral anaerobes

• Leishmania

• Fungi

Transmission • Injection drug users are at risk of a host of infections, including viral hepatitis, skin and 

soft-tissue infections, infective endocarditis, and pulmonary infections.

• Injection drug use also may put users at risk of acquiring TB and STDs.

• Infection may occur from contaminated drug-injection equipment (needles, syringes, 

water, and other preparation equipment).

• Infection also may occur from the user’s own skin or mouth bacteria, which can enter 

the bloodstream.

• The drug itself, or an adulterating substance, may be contaminated.

Recommended 

avoidance 

measures

• Injection drug users should be advised not to share needles or drug preparation 

equipment, and should be educated about needle exchange programs.

• If receptive, injection drug users should be referred to substance abuse treatment 

programs.

• Injection drug users should be educated about methods of reducing risk, including the 

following: 

• If equipment is being reused, clean with bleach and water.

• Avoid dangerous injection sites such as groin and neck.

• Do not crush capsules or tablets in the mouth prior to injecting, as this may 

introduce harmful oral bacteria into the bloodstream.

• Do not lick injection needles or syringes.

• Use boiled water for preparing drugs for injection; if not available, use tap water.

• Boil the drug before injecting.

• Use a new or disinfected “cooker,” and a new filter to prepare drugs for injection.

• Always clean injection sites with alcohol before injecting.

• Be aware that black tar heroin may be contaminated with Clostridium spores, 

which are not killed by heating the drug prior to use.

Other Bloodborne Related

Pathogens • HIV

• HCV

• HBV 

• CMV

Transmission • Tattooing and body piercing.

• Reuse of medical equipment and transfusion of infected blood (primarily outside the 

United States).

• Occupational exposures (e.g., needlesticks) of health care workers.

Recommended 

avoidance 

measures

• Persons considering tattooing or piercing should be educated about the potential risk 

of bloodborne pathogen transmission if proper infection control procedures are not 

followed.

• When receiving a transfusion, HIV-infected patients who are seronegative for CMV 

should be administered only CMV antibody-negative or leukocyte-reduced cellular 

blood products in nonemergency situations.

• Universal precautions always should be followed by health care workers.
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Section 3: Health Maintenance 

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Pet and Animal Related

Pathogens • Toxoplasma

• Cryptosporidium

• Salmonella

• Campylobacter

• Shiga toxin-producing Escherichia coli

• Bartonella

• Leptospira

• Brucella

• Capnocytophaga

• Cryptococcus

• Mycobacterium avium and marinum

• H. capsulatum

Transmission • For the most part, people with HIV infection can and should keep their pets.

• HIV-infected persons should be made aware of the potential risks posed by animals 

and of the avoidance measures for decreasing risks of infection.

• Exposure may occur though a lick, a bite, or a scratch, or through contact with a pet’s 

stool. Some infections may be spread though contact with an animal’s coat or skin.

• Fleas may spread some infections to pet owners.

• Patients also may be exposed while performing occupational tasks that bring 

them into contact with animals (e.g., in pet stores, veterinary clinics, farms, and 

slaughterhouses).

Recommended 

avoidance 

measures

• Always wash hands after handling animals, and after cleaning cages or aquariums.

• When acquiring a new pet, avoid animals <6 months of age (cats younger than 1 year) 

and those with diarrhea.

• Stray animals may carry many infections and should be avoided.

• Avoid contact with animal stool.

• Avoid animals with diarrhea.

• Pets with diarrhea should be examined by a veterinarian and 

should have stool checked for Cryptosporidium, Salmonella,

Campylobacter, and Shiga toxin-producing E. coli.

• Wash any bites or scratches with soap and water, and seek medical attention.

• Animals should not be allowed to lick people in the 

mouth, or on any open cuts or wounds.

• Cats may increase risk of Toxoplasma and Bartonella infection.

• To minimize risk of Toxoplasma exposure: 

• Litter boxes should be cleaned daily, preferably by someone who is not HIV 

infected or pregnant.

• If an HIV-infected person is cleaning a litter box, gloves should be used, and hands 

should be washed afterward.

• Keep cats indoors and do not allow them to hunt.

• Do not feed cats raw or undercooked meat.

• In areas where histoplasmosis is endemic, avoid contact with 

bird droppings, including soil under bird roosting sites.

• Always use gloves when cleaning aquariums to avoid 

contact with Mycobacterium marinum.

• Avoid contact with reptiles (such as lizards, snakes, and turtles), as well as chicks and 

ducklings, as these may carry Salmonella.

• Avoid exotic pets such as monkeys, ferrets, and other wild animals.
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Contact with Children

Pathogens • CMV

• Cryptosporidium

• Giardia

• HAV

• Influenza

• VZV

• Enteric pathogens

Transmission • HIV-infected persons who work as childcare providers, or who have children in 

daycare, may be exposed to opportunistic pathogens.

• The poor personal hygiene habits of children facilitate spread of infection.

• Risks specific to the individual, given his/her immune status and medical history, 

should be discussed with a health care provider.

• CMV infection may occur through contact with many body fluids, including stool, 

urine, and saliva.

• Diapering may bring a person into contact with Cryptosporidium and other enteric 

pathogens.

• In addition to opportunistic pathogens, childcare providers are exposed to other 

illnesses, carried by children, to which they may be more susceptible.

Recommended 

avoidance 

measures

• Wash hands thoroughly after contact with stool or urine.

• Wash hands after diapering and disinfect changing station often.

• Wash hands after contact with saliva or objects covered with saliva, such as cups or 

pacifiers.

• Ensure that the immunization status of HIV-infected persons is up to date, as 

appropriate for their immune status.

• HIV-infected persons who are susceptible to VZV should avoid exposure to people 

with chickenpox or shingles.

• VZV-susceptible household contacts of HIV-infected persons should be vaccinated 

against VZV if they are HIV negative, so that they will not transmit VZV to their HIVinfected contact.

Travel Related

Pathogens • Enteric pathogens

• Plasmodium species (malaria) 

• Yellow fever virus

• Dengue virus

• Other geographically specific infections

Transmission • Travelers to developing countries are at risk of foodborne and waterborne infections.

• Malaria is transmitted by the bite of an infected female Anopheles mosquito.

• HIV-infected patients are at higher risk of severe malaria.

• Yellow fever and dengue fever are spread by mosquito bites.
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Section 3: Health Maintenance 

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Travel Related

Recommended 

avoidance 

measures

• Plan the travel itinerary, vaccinations, and prophylaxis in consultation with a health 

care provider experienced in travel medicine.

• Discuss area-specific risks and avoidance measures with the health care provider.

• The U.S. Centers for Disease Control and Prevention (CDC) Traveler’s Health website 

has detailed information on most issues pertaining to infections in travelers (wwwnc.

cdc.gov/travel).

• Review and update routine vaccination history prior to travel.

• Generally, live vaccines for HIV-infected persons should be avoided, with some 

exceptions: 

• Measles vaccination is recommended for all nonimmune persons with CD4 counts 

of ≥200 cells/μL. Measles immune globulin should be considered for those with 

CD4 counts of <200 cells/μL who are traveling in measles-endemic areas.

• Varicella vaccination can be considered for VZV-seronegative persons with CD4 

counts of ≥200 cells/μL.

• Yellow fever vaccination may be considered, see below.

• Inactivated (killed) enhanced-potency polio and typhoid vaccines should be given 

instead of the live, attenuated forms.

• Killed and recombinant vaccines including influenza, diphtheria-tetanus, rabies, HAV, 

HBV, Japanese encephalitis, and meningococcal vaccines should be administered as 

they would be for HIV-uninfected persons preparing for travel.

• The oral cholera vaccine (not available in the United States) is not recommended for 

most travelers by the CDC.

Traveler’s diarrhea:

• See sections on foodborne and waterborne infections (above) for risk-reduction 

strategies.

• Antimicrobial prophylaxis is not routinely recommended for HIV-infected persons 

traveling in developing countries.

• Prophylaxis may be appropriate in select situations (for example, high risk of infection 

and short length of travel).

• For those to whom prophylaxis is given, fluoroquinolones (such as ciprofloxacin 500 

mg PO QD) may be considered for nonpregnant patients.

• HIV-infected patients traveling in developing countries should bring antibiotics to be 

used empirically in the event of developing diarrhea.

• Appropriate regimens include: 

• Ciprofloxacin 500 mg PO BID for 3-7 days

• Azithromycin 500 mg PO QD as an alternative, and for pregnant women

• Antiperistaltic agents such as loperamide or diphenoxylate can be useful in the 

treatment of traveler’s diarrhea.

• Do not use antiperistaltic agents if high fever or blood in the stool is present. Stop use 

if symptoms persist >48 hours.

• Seek medical care if diarrhea is severe, bloody, accompanied by fever and chills, leads 

to dehydration, or does not respond to empiric therapy.
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Travel Related

Recommended 

avoidance 

measures

Malaria:

• HIV-infected patients should be advised to avoid travel in malarious areas.

• If travel to a malarious area cannot be avoided, effective chemoprophylaxis should be 

given. Consult the CDC Traveler’s Health website (wwwnc.cdc.gov/travel) for specific 

information.

• Be aware that some malaria prophylaxis medications may have drug-drug 

interactions with antiretrovirals.

• Personal protection measures should be followed, including avoidance of peak biting 

times and use of insect repellants, protective clothing, and permethrin-soaked bed 

netting.

Yellow fever:

• HIV-infected patients should be discouraged from visiting areas where yellow fever 

infection is a risk.

• Vaccination may be considered in some HIV-infected persons with high CD4 counts 

who cannot avoid potential exposure, after discussion of risks and benefits.

• Vaccine response may be poor, and serologic testing can be considered.

• If vaccination is not administered, patients should be advised about the risk of yellow 

fever, instructed about avoiding the bites of vector mosquitoes, and provided with a 

vaccination waiver letter.

• Personal protection measures should be followed, including avoidance of peak biting 

times and use of insect repellants, protective clothing, and permethrin-soaked bed 

netting.

Other geographically specific opportunistic infections include visceral leishmaniasis, 

Penicillium marneffei infection, coccidiomycosis, histoplasmosis, and TB.

References

• Aberg JA, Gallant JE, Ghanem KG, et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• Centers for Disease Control and Prevention. 

Preventing Infections from Pets. CDC 

Brochures for Persons Living with HIV/

AIDS. Available at www.cdc.gov/hiv/

resources/brochures/pets.htm. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

CDC Health Information for International 

Travel 2012. Atlanta: U.S. Department 

of Health and Human Services, Public 

Health Service; 2012. Chapter 8. The 

Immunocompromised Traveler. Available at 

wwwnc.cdc.gov/travel. Accessed December 

1, 2013.

• Gordon RJ, Lowy FD. Bacterial infections 

in drug users. N Engl J Med. 2005 Nov 

3;353(18):1945-54.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
Opportunistic Infection Prophylaxis | 173

Section 3: Health Maintenance 

and Disease Prevention

Opportunistic Infection Prophylaxis

Background

Prophylaxis against an opportunistic 

infection (OI) is treatment given to 

HIV-infected individuals to prevent 

either a first episode of an OI (primary 

prophylaxis) or the recurrence of an OI 

(secondary prophylaxis). Prophylaxis 

is recommended to prevent three important OIs: Pneumocystis jiroveci pneumonia (PCP), 

Mycobacterium avium complex (MAC), and toxoplasmosis. Prophylaxis also is recommended to 

prevent tuberculosis (TB) in patients with latent Mycobacterium tuberculosis infection (see chapter 

Latent Tuberculosis Infection). In endemic regions, prophylaxis against Histoplasma capsulatum

and Coccidioides species is advised. And in some situations, prophylaxis against other OIs may be 

reasonable; see the OI prevention recommendations of the U.S. Centers for Disease Control and 

Prevention, the National Institutes of Health, and the HIV Medicine Association (reference below) 

for additional information. 

HRSA HAB Performance Measures 

Percentage of patients, aged 6 weeks or older 

with a diagnosis of HIV/AIDS, who were prescribed 

Pneumocystis jiroveci pneumonia prophylaxis

(Core measure)

Pneumocystis jiroveci 

Pneumonia

Background

PCP remains the most common lifethreatening infection among U.S. residents 

with advanced HIV disease. 

Primary Prophylaxis: Indications

• Prophylaxis should be administered to all 

HIV-infected patients with a CD4 count of 

<200 cells/μL, a history of an AIDS-defining 

illness, or a history of oral thrush. PCP 

prophylaxis also is indicated for patients 

with CD4 counts of >200 cells/μL in the 

presence of a CD4 percentage <14%.

• For patients whose CD4 counts are declining 

toward 200 cells/μL, the CD4 count should 

be monitored closely. PCP prophylaxis 

should be considered for patients with a 

CD4 count of 200-250 cells/μL if laboratory 

monitoring will not be possible within 3 

months. 

Prophylaxis Options: 

Recommended Regimens

• Trimethoprim-sulfamethoxazole (TMPSMX) (also known as cotrimoxazole, 

Bactrim, and Septra) 1 double-strength (DS) 

tablet PO QD (Note: This regimen also is 

effective in preventing toxoplasmosis.)

• TMP-SMX 1 single-strength tablet PO QD 

(this lower-dose regimen may be better 

tolerated) (Note: This also is likely to be 

effective in preventing toxoplasmosis.) 

• Warning: Many patients have adverse 

reactions to sulfa medications. Severe 

reactions may include persistent 

neutropenia, rash (including severe 

erythroderma), and Stevens-Johnson 

syndrome (bullae and desquamation 

of the skin). For patients with milder 

reactions, chemoprophylaxis with TMPSMX should be continued if clinically 

possible. Some patients with a history of 

serious adverse reaction may undergo 

desensitization, but this must be done 

cautiously and it requires diligence from 

the patient and careful management 

by the provider (see chapter Sulfa 

Desensitization). 
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Prophylaxis Options: Alternative 

Regimens

Other options for prophylaxis include the 

following: 

• TMP-SMX DS, 1 tablet TIW (e.g., Monday, 

Wednesday, and Friday) (Note: This regimen 

also is likely to be effective in preventing 

toxoplasmosis.)

• Dapsone 100 mg PO QD or 50 mg PO 

BID (Note: These regimens do not prevent 

toxoplasmosis.)

• Dapsone 50 mg PO QD + pyrimethamine 

50 mg PO once weekly + leucovorin 25 

mg PO once weekly (Note: This regimen 

also is effective in reducing the risk of 

toxoplasmosis.)

• Warning: Glucose-6-phosphate dehydrogenase (G6PD) deficiency can increase the 

risk of hemolytic anemia or methemoglobinemia in patients receiving dapsone. 

Screen for G6PD deficiency before starting dapsone. (G6PD deficiency is found in 

approximately 10% of African-American 

males, and in 1-2% of males of Mediterranean, Indian, and Asian descent.) 

• Dapsone 200 mg PO once weekly + 

pyrimethamine 75 mg PO once weekly + 

leucovorin 25 mg PO once weekly

• Aerosolized pentamidine 300 mg once 

per month, via Respirgard II nebulizer 

(Note: This regimen does not prevent 

toxoplasmosis.) 

• Warning: Aerosolized pentamidine 

may increase the risk of extrapulmonary 

pneumocystosis, pneumothorax, and 

bronchospasm. It increases the risk of 

TB transmission to others if the patient 

has active pulmonary tubercular disease, 

unless ventilation (negative-pressurized 

facility with outside venting) is adequate. 

Do not use for patients in whom TB is 

suspected. The availability of treatment 

facilities offering aerosolized pentamidine 

may be limited. 

• Atovaquone 1,500 mg QD (Note: This 

also is effective in reducing the risk of 

toxoplasmosis.) Atovaquone is more 

expensive than dapsone. It should be taken 

with high-fat meals for optimal absorption.

• Atovaquone 1,500 mg + pyrimethamine 

25 mg + folinic acid 10 mg, all taken PO 

QD (Note: This regimen also is effective in 

reducing the risk of toxoplasmosis.) 

Secondary Prophylaxis 

Indications

Prophylaxis should be given to all patients 

with a history of PCP.

Discontinuing Prophylaxis

Primary or secondary prophylaxis can be 

discontinued if the CD4 count has increased to 

≥200 cells/μL for at least 3 months in response 

to effective antiretroviral therapy (ART), with 

the following cautions: 

• If the patient had PCP in the past and the 

episode of PCP occurred at a CD4 count of 

>200 cells/μL, it may be prudent to continue 

PCP prophylaxis for life, regardless of how 

high the CD4 count rises as a consequence 

of ART.

• PCP prophylaxis should be reinitiated if the 

CD4 count decreases to <200 cells/μL or 

the patient meets other criteria as indicated 

above. 

Prophylaxis During Pregnancy

TMP-SMX is the recommended agent for use 

during pregnancy; dapsone may be used as an 

alternative. Some experts recommend highdose folate supplementation (e.g., 4 mg daily) 

for pregnant women receiving TMP-SMX, 

because TMP-SMX may worsen folate deficiency; 

however, this may increase risk of TMP-SMX 

failure; if high-dose folate supplementation is 

given, it should be limited to the first trimester. 

Prophylaxis that includes pyrimethamine 

generally should be deferred until after 

pregnancy. During the first trimester, aerosolized 
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pentamidine (which is not systemically absorbed) 

can be used if the potential teratogenicity of oral 

agents is a concern. 

Mycobacterium avium

Complex 

Background

MAC is common among patients with 

advanced HIV disease and it generally occurs 

in people with CD4 counts of <50 cells/μL. 

Primary Prophylaxis: Indications

Prophylaxis should be administered to all 

HIV-infected patients with CD4 counts of <50 

cells/μL. Before starting prophylaxis, rule out 

active MAC infection by clinical assessment 

and, if warranted, by acid-fast bacilli (AFB) 

blood cultures (see chapter Mycobacterium 

avium Complex Disease). Also rule out active 

TB prior to starting any rifabutin-containing 

regimen for MAC prophylaxis. Review the 

current drug regimen for medications that may 

interact with MAC prophylaxis. 

Prophylaxis Options: 

Recommended Regimens

• Azithromycin 1,200 mg PO weekly

• Clarithromycin 500 mg PO BID (Note: 

Clarithromycin is not recommended for use 

during pregnancy, and it can have significant 

interactions with efavirenz, atazanavir, 

and other drugs; see chapter Drug-Drug 

Interactions with HIV-Related Medications.)

• Azithromycin 600 mg PO BIW

Prophylaxis Options: Alternative 

Regimens

Rifabutin 300 mg QD (Note: Rifabutin has 

significant interactions with many drugs; 

certain nonnucleoside reverse transcriptase 

inhibitors and protease inhibitors should be 

avoided or dosage adjustment of rifabutin 

may be required. See chapter Drug-Drug 

Interactions with HIV-Related Medications.) 

Secondary Prophylaxis

Patients should receive lifelong chronic maintenance therapy, unless immune reconstitution 

occurs in response to ART. See chapter Mycobacterium avium Complex Disease. 

Discontinuing Prophylaxis

Primary prophylaxis for MAC can be 

discontinued in persons who have responded 

to effective ART with sustained increases 

in CD4 counts to >100 cells/μL for at least 3 

months. Careful observation and monitoring 

are required, and prophylaxis should be 

restarted if the patient’s CD4 count decreases 

to <50 cells/μL.

Secondary prophylaxis can be discontinued 

in patients who received at least 12 months of 

treatment for MAC, are asymptomatic, and 

have sustained (for at least 6 months) CD4 

counts of >100 cells/μL on ART. Secondary 

prophylaxis should be reintroduced if the CD4 

count decreases to <100 cells/μL.

Prophylaxis During Pregnancy

Azithromycin is the prophylactic drug of 

choice during pregnancy, although evidence 

for its safety in the first trimester is limited. 

Clarithromycin is teratogenic in animals. 

Toxoplasmosis

Background

Toxoplasmic encephalitis (TE) usually is 

caused by reactivation of latent Toxoplasma 

gondii infection in patients with advanced 

immunosuppression (especially those with 

CD4 counts of <100 cells/μL). The CDC/NIH 

recommendations state that all HIV-infected 

patients should be tested for Toxoplasma

immunoglobulin G (IgG) antibody soon after 

the diagnosis of HIV infection. Toxoplasma

IgG-negative patients should be counseled 
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to avoid sources of infection (see chapter 

Preventing Exposure to Opportunistic and 

Other Infections), and should be retested for 

Toxoplasma IgG if CD4 counts fall to <100 

cells/μL to determine whether they have 

seroconverted and are therefore at risk of 

TE. (See chapter Toxoplasmosis for more 

information on active disease and secondary 

prophylaxis.) 

Primary Prophylaxis: Indications

Prophylaxis should be administered to all 

HIV-infected patients with CD4 counts 

of <100 cells/μL who are seropositive for 

Toxoplasma. IgG-negative patients should 

avoid exposure to Toxoplasma; see “Patient 

Education,” below, and chapter Preventing 

Exposure to Opportunistic and Other Infections. 

Prophylaxis Options: 

Recommended Regimens

• TMP-SMX DS, 1 tablet QD (Note: This 

option also is effective in preventing PCP.)

Prophylaxis Options: Alternative 

Regimens

(Note: The following options also are effective 

in preventing PCP.)

• TMP-SMX DS, 1 tablet PO TIW

• TMP-SMX single strength, 1 tablet PO QD

• Dapsone 50 mg PO QD + pyrimethamine 

50 mg PO weekly + folinic acid 25 mg PO 

weekly

• Dapsone 200 mg PO weekly + 

pyrimethamine 75 mg PO weekly + folinic 

acid 25 mg PO weekly 

• Warning: G6PD deficiency can 

increase the risk of hemolytic anemia or 

methemoglobinemia in patients receiving 

dapsone. Screen for G6PD deficiency 

before starting dapsone. (G6PD deficiency 

is found in approximately 10% of AfricanAmerican males, and in 1-2% of males 

of Mediterranean, Indian, and Asian 

descent.) 

• Atovaquone 1,500 mg PO QD, with 

or without pyrimethamine 25 mg PO 

QD + folinic acid 10 mg PO QD (This 

alternative is quite expensive.)

• Neither aerosolized pentamidine nor 

dapsone alone provides protection

against TE. 

Secondary Prophylaxis

Patients should receive lifelong chronic 

maintenance therapy, unless immune 

reconstitution occurs in response to ART (see 

chapter Toxoplasmosis). 

Discontinuing Prophylaxis

Primary prophylaxis for TE can be discontinued in patients who have responded to effective 

ART with sustained CD4 counts of >200 cells/

μL for at least 3 months. CD4 counts should be 

monitored carefully, and prophylaxis should 

be restarted in patients whose CD4 counts decrease to <100-200 cells/μL.

Secondary prophylaxis may be discontinued 

if TE signs and symptoms have resolved with 

treatment and if patients have sustained (for at 

least 6 months) CD4 counts of >200 cells/μL on 

ART. Secondary prophylaxis should be reintroduced if CD4 counts drop to <200 cells/μL.

Prophylaxis During Pregnancy

TMP-SMX may be used as primary 

prophylaxis during pregnancy. Risks of TMPSMX in the first trimester must be balanced 

against the risks of reactivated toxoplasmosis. 

Some experts recommend high-dose folate 

supplementation (e.g., 4 mg QD) for pregnant 

women receiving TMP-SMX, because TMPSMX may worsen folate deficiency; however, 

this may increase risk of TMP-SMX failure; 

if high-dose folate supplementation is given, 
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it should be limited to the first trimester. 

Pyrimethamine has been associated with birth 

defects in animal studies, but limited data in 

human studies have not shown an increased 

risk; guidelines support its use after the first 

trimester. Secondary prophylaxis generally 

should be provided using the same guidelines 

as for nonpregnant women.

Histoplasmosis

Background

Infection with Histoplasma capsulatum is 

common in several geographic areas, including 

the Ohio and Mississippi River Valleys as 

well as parts of Central and South America, 

Asia, and Africa. Symptomatic disease can 

occur via primary infection or reactivation 

of previously silent infection in the setting 

of waning cellular immunity. CD4 counts of 

≤150 cells/μL, along with positive Histoplasma

serology and environmental exposure, are 

associated with increased risk of symptomatic 

disease. Histoplasmosis can cause a range of 

clinical manifestations including respiratory, 

gastrointestinal, central nervous system (CNS), 

and cutaneous disease.

Primary Prophylaxis: Indications

Prophylaxis can be considered for HIVinfected patients with CD4 counts of ≤150 

cells/μL who are at high risk because of 

occupational exposure and for those who 

live in an area where histoplasmosis is highly 

endemic. HIV-infected patients with CD4 

counts of ≤150 cells/μL should be educated to 

avoid exposure.

Prophylaxis Options: 

Recommended Regimens

• Itraconazole 200 mg PO QD (Note: 

Itraconazole has significant interactions 

with many drugs, including nonnucleoside 

reverse transcriptase inhibitors, protease 

inhibitors, and maraviroc. Dosage 

adjustments may be required, and some 

combinations may be contraindicated; 

consult with a pharmacist or other 

specialist.)

Secondary Prophylaxis

Patients with a history of severe disseminated 

disease or CNS infection and those who have 

relapsed despite receiving appropriate therapy 

should receive long-term suppressive therapy. 

Discontinuing Prophylaxis

Primary prophylaxis can be discontinued 

once CD4 counts are ≥150 cells/μL for at least 

6 months. CD4 counts should be monitored 

carefully, and prophylaxis should be restarted 

for patients whose CD4 counts decrease to 

<150 cells/μL.

Secondary prophylaxis may be discontinued 

if patients have received at least 1 year of 

itraconazole, have negative blood cultures, 

have had CD4 counts of ≥150 cells/μL for 

at least 6 months on ART, and have serum 

Histoplasma antigen <2 units. Suppressive 

therapy should be restarted for patients whose 

CD4 counts decrease to <150 cells/μL.

Prophylaxis During Pregnancy

Azoles should be avoided during pregnancy, 

especially during the first trimester, because of 

teratogenicity concerns.
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Coccidiomycosis

Background

The Coccidioides species fungus is endemic 

to many arid regions. In the United States, it 

is found primarily in the Sonoran Desert in 

Arizona and the San Joaquin “Central” Valley 

in California, but also in areas of New Mexico, 

western Texas, Nevada, and Utah. It also is 

endemic to many arid regions in Central 

and South America. Immune response to 

Coccidioides species declines as CD4 counts 

decrease, and risk of developing symptomatic 

disease in endemic areas is increased when the 

CD4 count is <250 cells/μL. In HIV-infected 

patients, six syndromes have been described: 

focal pneumonia, diffuse pneumonia, 

cutaneous involvement, meningitis, liver or 

lymph node involvement, and positive serology 

without localized infection. 

Primary Prophylaxis: Indications

• Primary prophylaxis is not beneficial and is 

not recommended. Patients in endemic areas 

cannot avoid Coccidioides but should be 

educated to avoid extensive exposure (e.g., 

through disturbed soil and dust storms). 

Annual monitoring for seroconversion 

of HIV-infected patients in endemic 

areas is reasonable; in patients with CD4 

counts of <250 cells/μL who develop a new 

positive IgM or IgG, antifungal therapy is 

recommended to preempt active disease 

(fluconazole 400 mg PO QD).

Secondary Prophylaxis

Patients who have completed initial treatment 

for coccidiomycosis should receive lifelong 

suppressive therapy. 

Discontinuing Prophylaxis

Patients with a history of meningeal disease 

should be treated with suppressive therapy for 

life, as they are at high risk of relapse. Patients 

with a history of diffuse pulmonary disease or 

nonmeningeal disseminated infection also are 

at high risk of relapse; consult with experts. 

Patients with focal coccidioidal pneumonia 

who have had good clinical response to 

antifungals can discontinue secondary 

prophylaxis once they have received 12 months 

of therapy, and have CD4 counts of >250 cells/

μL on ART. These patients should undergo 

close radiologic and serologic monitoring for 

recurrence.

Prophylaxis During Pregnancy

Women who acquire coccidiomycosis in the 

second or third trimester of pregnancy are 

at increased risk of dissemination. Azoles 

should be avoided during the first trimester of 

pregnancy because of teratogenicity concerns.
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Patient Education

• Discuss adverse effects of the selected 

medication(s) and how the patient should 

respond in the event of rashes, diarrhea, and 

other complications.

• Explain the purpose of each medication, and 

be sure that patients understand the dosage 

and frequency of administration.

• Reinforce the need to continue taking the 

medication indefinitely (potentially for life) 

to reduce the risk of the OI.

• OIs can occur despite prophylaxis. Instruct 

patients to contact their health care provider 

if they become ill.

• Counsel patients who are Toxoplasma IgG 

negative to avoid exposure to Toxoplasma. 

Specifically, they should avoid eating raw or 

undercooked meat, especially pork, lamb, 

game, and venison. Patients should wash 

hands after handling raw meat and after 

gardening or contact with soil. Encourage 

patients not to adopt or handle stray 

cats, and, if they own cats, to wash hands 

thoroughly after cleaning litter boxes. (See 

chapter Preventing Exposure to Opportunistic 

and Other Infections.)

• For women of childbearing potential who 

are taking clarithromycin, emphasize 

the need for effective contraception to 

avoid potential teratogenic effects of 

clarithromycin.

• Educate patients in Histoplasma- and 

Coccidioides-endemic areas regarding 

measures to decrease exposure. (See chapter 

Preventing Exposure to Opportunistic and 

Other Infections.) 

References

• Centers for Disease Control and 

Prevention. Coccidiomycosis. In: CDC 

Health Information for International 

Travel 2012. Atlanta: U.S. Department of 

Health and Human Services, Public Health 

Service, 2012. Available at wwwnc.cdc.

gov/travel. Accessed December 1, 2013.

• Centers for Disease Control and 

Prevention. Histoplasmosis. In: CDC 

Health Information for International 

Travel 2012. Atlanta: U.S. Department of 

Health and Human Services, Public Health 

Service, 2012. Available at wwwnc.cdc.

gov/travel. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

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Latent Tuberculosis Infection

Background

Latent (or inactive) tuberculosis (TB) infection occurs 

when an individual has dormant Mycobacterium 

tuberculosis organisms and no active disease. It can be 

diagnosed by a tuberculin skin test (TST) or by a blood 

test called an interferon-gamma release assay (IGRA); 

both are described below. HIV-infected persons with 

latent TB infection (LTBI) have a much higher risk 

of developing active TB (estimated at 3-16% per year) 

than the general population (estimated at <10% in a 

lifetime). Whereas treatment of HIV infection with 

antiretroviral therapy (ART) reduces the risk of active TB, this risk remains higher than that for 

HIV-uninfected persons. The risk of an HIV-infected individual with LTBI developing active 

TB can be reduced 60% with treatment of LTBI. Hence, identifying and treating HIV-infected 

persons with LTBI is a high priority. Treatment of LTBI not only reduces the risk of disease to the 

individual but also reduces the risk of further TB transmission within the community. Standard 

treatment with isoniazid (INH) is effective and safe.

Issues of concern regarding treatment of LTBI among HIV-infected persons include the following:

• Excluding active pulmonary or extrapulmonary TB disease before treatment with INH alone

• Assessing the risk of latent infection with drug-resistant TB

• Avoiding or managing drug interactions if rifamycin-containing regimens are used (rifampin, 

rifabutin, rifapentine)

HRSA HAB Performance 

Measures 

Percentage of patients aged 3 months 

and older with a diagnosis of HIV/AIDS, 

for whom there was documentation 

that a tuberculosis screening test was 

performed and results interpreted (for 

tuberculin skin tests) at lease once since 

the diagnosis of HIV infection

(All-Age measure)

S: Subjective

Ask about symptoms of active TB, including 

fever, cough, and weight loss; see chapter 

Mycobacterium tuberculosis. Patients with 

symptoms that could represent active TB 

must be evaluated for active TB and ruled 

out by appropriate diagnostic methods before 

initiating treatment (see “Assessment,” below). 

HIV-infected persons are eligible for LTBI 

treatment if they have positive LTBI screening 

results, no symptoms of active TB, and have not 

been treated previously for active or latent TB 

(re-treatment of LTBI should be considered if a 

patient is a close contact to an active TB case).

Persons who have had bacillus CalmetteGuérin (BCG) vaccine can be evaluated by an 

IGRA (preferably) or by a TST with correct interpretation. Immigrants from many countries 

will have had childhood BCG vaccination.

Health care providers should ask about a 

history of potential exposure to TB. Close 

contact with an active TB case is an indication 

for LTBI treatment, after active TB has been 

excluded, regardless of the screening results on 

TST or IGRA.

O: Objective

Diagnostic Evaluation 

Current U.S. Centers for Disease Control and 

Prevention (CDC) and U.S. Department of 

Health and Human Services (HHS) guidelines 

strongly recommend LTBI testing for all 

newly diagnosed HIV-infected persons. 

Repeat testing is recommended for patients 

whose CD4 lymphocyte count increases 
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from low numbers to counts of >200 cells/μL, 

and annual testing is suggested for patients 

whose initial test result is negative and who 

are considered at high risk of repeated or 

ongoing exposure to TB (risk factors include 

incarceration, residence in a congregate 

setting, active drug use, and residence in or 

travel to a TB-endemic setting). 

CDC and HHS guidelines recommend use of 

either the TST or one of the three currently 

available IGRAs (QuantiFERON-TB Gold, 

QuantiFERON-TB Gold In-Tube [QFT-GIT], 

or TSPOT-TB). The TST evaluates delayed 

hypersensitivity to antigens from a number 

of Mycobacterium species (including nontuberculosis species). The IGRAs are in vitro 

tests of lymphocyte recognition and response 

to antigens more specific to M. tuberculosis, 

but they still may cross-react with M. kansasii, 

M. marinum, or M. szulgai. Because the IGRAs 

use antigens more specific to M. tuberculosis, 

they generally are thought to have greater 

specificity and a lower false-positive rate. A 

positive TST or IGRA result suggests previous 

contact with M. tuberculosis, and it implies 

latent or active TB infection. Neither TST nor 

IGRA screening can distinguish between LTBI 

and active TB infection.

Use of an IGRA is preferred for persons with 

previous BCG exposure and for patient groups 

at risk of not returning for TST readings. 

The TST is preferred for children under 5 

years of age. The cost of an IGRA is higher 

than the cost of a TST, and individual clinics 

should compare the total costs of both testing 

approaches, including the costs involved in 

TST protocols of recalling patients who miss 

visits, repeating TSTs, and treating persons 

with previous BCG exposure who may have 

false-positive TST results. Both IGRAs and 

TST testing have increased rates of anergic test 

results in HIV-infected patients with advanced 

immunosuppression (particularly those with 

CD4 counts of <100 cells/μL).

Tuberculin skin test

The TST is administered as an intradermal 

injection of 0.1 mL (5 tuberculin units) of 

purified protein derivative (PPD), which raises 

a wheal in the skin. This is sometimes referred 

to as the Mantoux test. Multiple-puncture tests 

such as tine tests and the use of other strengths 

of PPD are considered unreliable. Anergy 

testing with Candida and mumps antigens 

is not routinely recommended because a 

randomized controlled study of HIV-infected 

patients in the United States did not show an 

advantage to treating anergic, tuberculinnegative persons.

PPD tests are not designed for reading by the 

patient; a trained health care worker must 

measure the area of induration (not erythema) 

48-72 hours after the test is administered. 

Induration of 5 mm or more is considered a 

positive result for HIV-infected persons, other 

immunosuppressed persons, anyone with 

recent TB exposure, and anyone with fibrosis 

on chest X-ray that is consistent with previous 

TB. For HIV-uninfected health care workers, 

10 mm of induration is a positive result; in 

various other populations, either 10 mm or 15 

mm of induration may be considered positive. 

Care providers at many large HIV clinics find 

it challenging to ensure that their patients 

return for the PPD reading. One randomized 

study found that offering incentives (e.g., a 

fast-food coupon) plus counseling was more 

effective than counseling alone in obtaining 

return visits for PPD readings.

Interferon-gamma release assay

IGRA tests performed on peripheral blood 

samples are available in the United States 

from two manufacturers. Although the tests 

are expensive, results are obtained without 

the patient having to make a return visit 

to the clinic, and false-positive readings 

following BCG vaccination do not occur. 

In addition, IGRAs do not appear to be 

boosted by prior TST testing and two-step 

testing is not required. Three test results 
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are possible with IGRA testing: positive, 

negative, and indeterminate. Unlike the TST, 

interpretation of IGRA test results does not 

vary by the risk category of the person tested. 

An indeterminate test indicates either a high 

background IFN-gamma level or failure 

of the mitogen to respond, and should be 

interpreted as “no test result” (not as “partially 

positive”). Repeating the IGRA once may 

yield interpretable test results. However, if the 

subsequent IGRA result is indeterminate, no 

further testing is recommended until there is a 

change in the patient’s immune status, such as 

reconstitution with ART. 

Limited data suggest that the QFT-GIT is the 

most specific test (lowest rate of false-positive 

results) and the T-SPOT is the most sensitive 

test (with the lowest rate of false-negative 

results). However, few studies have compared 

the IGRA assays, and there is no reliable “gold 

standard” for sensitivity or specificity for 

latent TB infection. Although these tests do 

not detect previous BCG exposure, they will 

yield positive results in all three TB-causing 

species of the M. tuberculosis complex – M. 

tuberculosis, M. bovis, and M. africanum – 

and may yield positive results in persons with 

exposure to certain mycobacteria other than 

M. tuberculosis (M. kansasii, M. marinum, and 

M. szulgai).

There are accumulating data to support the use 

of IGRA testing in HIV infection. Data suggest 

that IGRAs are more specific than the TST 

and correlate more closely with risk factors for 

TB infection. As with TST, false-negative and 

indeterminate test results are more likely with 

advanced immunosuppression. One case series 

suggests that a significant number of QTF tests 

may be falsely positive on initial testing but 

negative on retesting, particularly in patients 

who were not born in TB-endemic settings. 

Accordingly, for patients with a positive IGRA 

result but no risk factors for TB other than HIV 

infection, it may be reasonable to repeat the 

IGRA and confirm positivity before treatment.

A: Assessment

After screening for symptoms (see 

“Subjective”), a chest X-ray should be obtained 

for all HIV-infected persons with positive TST 

or IGRA test results. Asymptomatic patients 

with negative chest X-ray results should be 

offered treatment for LTBI. (As above, it 

may be reasonable to repeat the IGRA for 

HIV-infected patients in non-TB-endemic 

settings who have no other risk factors for 

TB prior to LTBI treatment.) Persons with 

symptoms consistent with pulmonary or 

extrapulmonary TB, and those with abnormal 

chest radiography, require further assessment 

before LTBI treatment. This assessment 

may include sending two to three separate 

sputum specimens for acid-fast bacilli (AFB) 

stain, nucleic acid amplification testing if 

available, and culture, or obtaining other 

specimens depending on the suspected site 

of extrapulmonary TB. If suspicion of TB is 

low, patients with negative sputum smears (or 

other biopsy or tissue samples) can begin LTBI 

treatment. If suspicion of active disease is high, 

treatment for active disease should be started 

while the culture results are pending (see 

chapter Mycobacterium tuberculosis). HIVinfected persons with significant exposure 

(close contact) to someone with infectious TB 

should receive a full course of TB prophylaxis 

regardless of TST or IGRA results. Health 

departments can assist clinicians in assessing 

the degree of exposure for an HIV-infected 

patient and in determining whether there is a 

need for a full course of treatment.

An HIV-infected person with fibrosis on a 

chest X-ray that is consistent with previous 

TB and with no history of TB treatment (or 

a history of inadequate treatment) should be 

evaluated for active TB regardless of TST or 

IGRA results. If found not to have active TB, 

the patient should be treated for LTBI. If the 

patient is strongly suspected to have active TB, 

standard treatment for active TB should be 

given while culture analysis is under way. If 
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cultures are negative, patients may be switched 

to LTBI treatment. Highly suspect but culturenegative patients may be given a 4-month total 

course of treatment for active TB. (See chapter 

Mycobacterium tuberculosis.)

P: Plan

As with any treatment of TB, adherence to the 

regimen is required for success. Treatment 

regimens for LTBI in the United States 

and other low-prevalence TB countries are 

presented in Table 1. Treatment should be 

offered to all HIV-infected persons with 

evidence of LTBI or close contact with an 

active TB case, regardless of age.

In some highly TB-endemic settings outside 

the United States, LTBI treatment given to 

TST-negative patients or patients of unknown 

TB status has led to reduction of active TB, 

although TST- or IGRA-positive patients 

appear to benefit most from LTBI treatment. 

INH is preferred for treatment of LTBI because 

of extensive data supporting its efficacy and 

because it has no significant interactions 

with ARV medications. Treatment with INH 

for 9 months is recommended. Rifampinbased LTBI treatment is an alternative and is 

given for 4 months. However, rifampin has 

substantial drug interactions with a number 

of ARVs (see “Potential ARV Interactions,” 

below). Rifabutin is an alternative for patients 

on PI-based regimens, although there are 

limited data for use in LTBI. Rifapentine, in 

combination with INH, has been approved as 

part of a 12-week treatment course for LTBI; 

however, it is not recommended for ARTtreated patients outside clinical trials because 

of possible interactions with ARV medications. 

Rifampin + pyrazinamide is not recommended 

for LTBI treatment owing to unacceptable rates 

of hepatoxicity.

For treatment of LTBI in persons exposed to 

drug-resistant TB, there are limited data on 

efficacy of various regimens in preventing 

progression to disease; consult with experts.

ART is indicated for all persons with LTBI.

Table 1. Treatment Regimens for Latent Tuberculosis

Drug

Dosage

(taken orally) Frequency

Duration

(minimum number of doses 

for completion)

Preferred therapies

INH* Adults: 300 mg

Children: 5 mg/kg

Daily 9 months or 270 doses within 

12 months

INH* Adults: 900 mg

Children: 10-20 mg/kg

Twice weekly (DOT)** 9 months or 76 supervised 

doses within 12 months

Alternative therapies

Rifampin# Adults: 600 mg

Children: 10-20 mg/kg

Daily 4 months or 120 doses in 6 

months; if used in children, 6 

months is recommended

Rifabutin# Dose according to 

ARV medications

Daily 4 months or 120 doses in 6 

months

Exposure to Multidrug-Resistant TB

Treatment options 

depend on sensitivity 

of the organism. 

Seek expert advice from public health authorities and those experienced in treatment of multidrug-resistant TB. Treatment may be postponed until sensitivity test 

results are available or may be based on resistance pattern of index case, if known.

* 25 mg of pyridoxine (vitamin B6) should be given with each INH dose to reduce the risk of INH-induced peripheral neuropathy.

** DOT = directly observed treatment

# Rifampin and rifabutin have significant interactions with a number of ARV and other medications. See text and “Potential ARV 

Interactions,” below, about contraindicated combinations and dosage adjustments.
Latent Tuberculosis Infection | 185

Section 3: Health Maintenance 

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Length of LTBI Treatment

LTBI treatment is recommended for 9 months 

with INH (4 months with rifampin/rifabutin) 

in low-prevalence TB settings such as the 

United States. Accumulating data suggest that 

36 months or indefinite LTBI treatment may be 

of benefit in some highly TB-endemic settings 

where TB reinfection may be common.

Monitoring on therapy

INH may cause liver toxicity and it should 

be used cautiously in patients with active 

alcohol consumption, liver disease, or 

chronic hepatitis B or C infection. INH is 

contraindicated for use in patients with acute 

hepatitis or decompensated liver disease. 

Baseline liver function tests are recommended 

for all HIV-infected persons prior to starting 

LTBI treatment. Monthly assessment to 

screen for signs and symptoms of hepatoxicity 

(e.g., abdominal pain, jaundice, nausea, 

vomiting, and fatigue) and neuropathy is 

recommended. Patients with abnormal 

hepatic enzymes at baseline or liver disease 

such as viral hepatitis should receive regular 

checks of transaminases. If patients develop 

abnormalities in liver transaminases while 

taking INH (ALT or AST >3 times the upper 

limit of normal [ULN] with symptoms, or 

>5 times above the ULN in the absence of 

symptoms), the INH should be withheld. 

Obtain expert consultation before treating 

patients with abnormal liver function or 

advanced liver disease. All patients should 

receive pyridoxine (vitamin B6) 25 mg QD 

during INH treatment to reduce the risk of 

peripheral neuropathy. 

Rifampin and rifabutin may cause liver and 

bone marrow toxicity. Before use, obtain 

baseline liver and renal function tests and a 

complete blood count. Given the potential 

for interaction with ARV and other drugs, a 

careful review of current medications should 

be done to assess for possible drug interactions. 

Follow-up is the same as for INH use.

Potential ARV Interactions

Rifampin and rifabutin have important 

interactions with certain antiretroviral 

drugs, and dosage adjustments or treatment 

modifications may be required. Rifampin 

reduces the blood levels of nonnucleoside 

reverse transcriptase inhibitors (NNRTIs), 

protease inhibitors (PIs), integrase 

inhibitors, and the CCR5 antagonist 

maraviroc; it also may decrease elvitegravir/

cobicistat levels. Rifampin can be used by 

persons taking efavirenz or the integrase 

inhibitors raltegravir or dolutegravir, 

though dosage adjustments may be 

required. Coadministration of rifampin 

and maraviroc is not recommended, but 

may be possible with appropriate dosage 

adjustment of maraviroc; consult with an 

expert. Rifampin should not be used with 

nevirapine, etravirine, or rilpivirine, or 

with PIs or elvitegravir/cobicistat. (In some 

cases, the adverse pharmacokinetic effect 

of rifampin on PIs may be overcome with 

large doses of ritonavir, but consultation 

with a specialist should be obtained before 

this approach is undertaken; rifampin 

should not be used in combination with 

ritonavir-boosted saquinavir because 

of high rates of hepatic toxicity.)

No data are available on the use of rifabutin 

for treatment of LTBI. Nevertheless, 

rifabutin may be considered in place of 

rifampin for patients taking antiretroviral 

combinations that include certain NNRTIs 

(other than efavirenz) or PIs (other than 

ritonavir alone), and the integrase inhibitor 

raltegravir. In these cases, the dosages of 

both rifabutin and the antiretroviral agent 

usually require adjustment. 

See Table 3 in chapter Mycobacterium 

tuberculosis for details on dosage adjustments. 
186 | Guide for HIV/AIDS Clinical Care

Section 3: Health Maintenance 

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Other Drug Interactions

Rifampin decreases the blood concentrations 

of estrogens, anticonvulsants, hypoglycemic 

agents, and many other drugs. Review all 

medications a patient is taking before initiating 

rifampin and make adjustments as necessary. 

(See Table 12, “Clinically Significant DrugDrug Interactions Involving the Rifamycins,” 

at www.cdc.gov/mmwr/preview/mmwrhtml/

rr5211a1.htm#tab12.)

Pregnancy

HIV-infected pregnant women with positive 

LTBI test results and no evidence of active 

TB should be evaluated for prophylaxis. The 

potential risks of INH should be evaluated in 

light of the potential risks of active TB. Consult 

with an expert. All pregnant women should 

receive ART for prevention of perinatal HIV 

transmission; ART also serves to reduce risk of 

LTBI progression.

Patient Education

• Patients should know that TB bacteria in 

their bodies cannot be passed to others 

while the TB is latent. However, because they 

have HIV infection, the TB bacteria is more 

likely to make them sick at some point in the 

future.

• Treatment for LTBI will help kill the TB 

bacteria and reduce patients’ chances of 

becoming sick with active TB.

• Patients must take all of their medicine, 

every day, to prevent the TB from spreading 

and making them sick.

• Advise patients to contact their health care 

provider immediately if they have adverse 

effects to the medication, such as rash 

or itching. Occasionally, INH can cause 

tingling or numbness in the hands or feet. 

The pyridoxine (vitamin B6) they are taking 

should help prevent that, but they should let 

their provider know if it occurs.

• Advise patients to avoid the consumption 

of alcohol while taking INH. The medicines 

for TB are processed by the liver and, when 

combined with alcohol, they easily can 

overload the liver. Acetaminophen (Tylenol) 

also is processed by the liver, so patients 

should keep their intake to a minimum. 

(Patients with hepatitis C, liver disease, 

or chronic alcohol consumption should 

be cautioned to strictly limit their use of 

acetaminophen.)

• Tell patients that blood tests may be done 

regularly to make sure the liver is working 

well, so it is important to keep follow-up 

appointments. They should take all their 

medications, vitamins, and supplements 

with them to the clinic so that their health 

care provider can review them and make 

sure there are no drug interactions.

• If patients experience nausea, vomiting, poor 

appetite, or abdominal pain; if they notice 

their urine darkening or becoming “cola” 

colored; or if they notice their eyes or skin 

yellowing, they should contact the clinic 

immediately. These problems may indicate 

that the liver is being overwhelmed, and it 

is important to find out before permanent 

damage is done.

• Rifampin and rifabutin will cause sweat, 

tears, urine, and plastic contact lenses to 

turn orange; this is not harmful.

• Rifampin and rifabutin can make birth 

control pills ineffective. Patients should use 

a backup method of contraception until 

treatment is complete. Condoms can help 

prevent HIV transmission and reduce the 

likelihood of pregnancy.
Latent Tuberculosis Infection | 187

Section 3: Health Maintenance 

and Disease Prevention

References

• Akolo C, Adetifa I, Sheppard S, et al. 

Treatment of latent tuberculosis infection 

in persons with HIV infection. Cochrane 

Database Syst Rev. 2004;(1):CD000171.

• American Thoracic Society. Targeted 

tuberculin testing and treatment of latent 

tuberculosis infection. MMWR Recomm 

Rep. 2000 Jun 9;49(RR-6):1-51. Available at 

www.cdc.gov/mmwr/PDF/rr/rr4906.pdf. 

Accessed December 1, 2013.

• Blumberg HM, Leonard MK, Jasmer RM. 

Update on the treatment of tuberculosis and 

latent tuberculosis infection. JAMA. 2005 Jun 

8;293(22):2776-84.

• Centers for Disease Control and Prevention. 

Managing Drug Interactions in the Treatment 

of HIV-Related Tuberculosis. 2007. Available 

at www.cdc.gov/tb/publications/guidelines/

TB_HIV_Drugs/PDF/tbhiv.pdf. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

Recommendations for use of an isoniazidrifapentine regimen with direct observation 

to treat latent Mycobacterium tuberculosis 

infection. MMWR Morb Mortal Wkly Rep. 

2011 Dec 9;60(48):1650-3.

• Centers for Disease Control and Prevention, 

American Thoracic Society. Update: adverse 

event data and revised American Thoracic 

Society/CDC recommendations against 

the use of rifampin and pyrazinamide for 

treatment of latent tuberculosis infection – 

United States, 2003. MMWR Morb Mortal 

Wkly Rep. 2003 Aug 8;52(31):735-9.

• Golub JE, Pronyk P, Mohapi L, et al. 

Isoniazid preventive therapy, HAART, and 

tuberculosis risk in HIV-infected adults in 

South Africa: a prospective cohort. AIDS. 

2009 Jul 17;23(11):1444-6.

• Golub JE, Saraeini V, Cavalcante SG, et al. 

The impact of antiretroviral therapy and 

isoniazid preventive therapy on tuberculosis 

incidence in HIV-infected patients in 

Rio de Janeiro, Brazil. AIDS. 2007 Jul 

11;21(11):1441-8.

• Mazurek GH, Jereb J, Vernon A, et al.; 

IGRA Expert Committee; Centers for 

Disease Control and Prevention. Updated 

guidelines for using Interferon Gamma 

Release Assays to detect Mycobacterium 

tuberculosis infection – United States, 2010.

MMWR Recomm Rep. 2010 Jun 25;59(RR5):1-25. Available at www.cdc.gov/mmwr/

preview/mmwrhtml/rr5905a1.htm. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Samandari T, Agizew TB, Nyirenda S, 

et al. 6-month versus 36-month isoniazid 

preventive treatment for tuberculosis in 

adults with HIV infection in Botswana: a 

randomised, double-blind, placebo-controlled 

trial. Lancet. 2011 May 7;377(9777):1588-98

Smoking Cessation | 189

Section 3: Health Maintenance 

and Disease Prevention

Smoking Cessation 

Jeffery Kwong, MS, MPH, ANP

Background

According to the U.S. Centers for Disease Control and 

Prevention, smoking prevalence among the general 

adult population in the United States is approximately 

20%. Among HIV-infected persons, the prevalence 

of cigarette smoking appears to be two to three times 

greater than in the general population, with estimates 

ranging from 50% to 70%.

The health effects of cigarette smoking are 

extensive and have been well documented. There 

are approximately 400,000 smoking-related deaths 

annually in the United States. HIV-infected smokers 

appear to be at higher risk of a variety of tobacco-related conditions than HIV-uninfected smokers. 

These include lung cancer, head and neck cancers, cervical and anal cancers, oral candidiasis, and 

oral hairy leukoplakia. HIV-infected smokers who smoke are more likely to develop the conditions 

listed above, as well as bacterial pneumonia, Pneumocystis jiroveci pneumonia, other pulmonary 

conditions, and cardiovascular disease. Additionally, HIV-infected smokers have been shown to 

have a decreased immunologic and virologic response to antiretroviral therapy.

Thus, for HIV-infected persons, even more so than for HIV-uninfected persons, clinicians should 

consider smoking cessation a health care priority. Although many care providers may feel that they 

can do little to affect the smoking behaviors of patients, evidence suggests that brief interventions 

by physicians are quite effective. Studies indicate that smoking cessation interventions as brief as 

3 minutes in duration, when delivered by a provider, have a positive impact on abstinence rates of 

current smokers. Furthermore, studies have found that more than half of current HIV-infected 

smokers have expressed interest in, or have thought about, smoking cessation.

Cigarettes are highly addictive; the U.S. Surgeon General has equated the addictive potential of 

cigarettes to that of heroin and cocaine. This is in part because nicotine stimulates the release 

of several neurotransmitters in the brain, including dopamine. Over time, chronic exposure 

to nicotine causes physiologic changes in the brain that contribute to the addictive potential of 

cigarettes.

Cigarette smoking involves dependence on more than a single chemical compound, however. It is 

a multidimensional behavior that has both physiologic and psychological components. Therefore, 

smoking cessation efforts often require a combined approach to be successful.

Behavioral Model for 

Smoking Cessation

Several behavioral models present a 

psychological framework for understanding 

individuals who are attempting to change 

behaviors. The transtheoretical model of health 

behavior change is one of the more frequently 

cited frameworks for understanding the stages 

of behavior change of smokers. According to 

this model, there are five phases of behavior 

change: precontemplation, contemplation, 

preparation, action, and maintenance. 

Using this framework, clinicians can devise 

HRSA HAB Performance 

Measures 

Percentage of patients aged 18 

years and older who were screened 

for tobacco use one or more times 

within 24 months AND who received 

cessation counseling intervention if 

identified as a tobacco user

(Adult and Adolescent measure)
190 | Guide for HIV/AIDS Clinical Care

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interventions that are most appropriate for the 

patient’s current stage on the continuum.

• Precontemplation: The individual 

does not expect to make any change in 

behavior within the next 6 months. At this 

stage, the individual is resistant to hearing 

or learning about health behavior change.

• Contemplation: The individual plans to 

make a behavior change within the next 

6 months. This stage is characterized by 

ambivalence about smoking.

• Preparation: The individual anticipates 

making a behavior change within the next 

month. Individuals in this phase have 

made plans for taking action and intend 

to make a change.

• Action: The individual has made a 

significant change; in the case of smoking 

cessation, this means that the individual 

has quit completely.

• Maintenance: The individual attempts to 

prevent relapse. 

Patients may move back and forth among these 

stages at various points during the process of 

smoking cessation.

Cessation interventions in the clinic

As suggested above, brief smoking cessation 

interventions delivered by clinicians can 

significantly increase abstinence rates of 

current smokers. The U.S. Surgeon General 

has developed guidelines for clinicians to use 

during clinic visits to help patients who are 

interested in smoking cessation. These include 

use of the Five A’s model, which provides a 

brief and structured framework for addressing 

smoking cessation in clinical settings (see 

Table 1).

Table 1. The Five A’s Model for Treating Tobacco Use and Dependence

Component Action Example

ASK every 

patient about 

tobacco use

Identify and document 

tobacco use at every visit. 

Incorporate questions about tobacco use when obtaining 

vital signs or when reviewing a patient’s history.

• “Do you currently use tobacco?”

• “Do you currently smoke cigarettes?”

ADVISE to 

quit

Using a clear, strong, and 

personalized message, urge 

every tobacco user to quit.

• “It is important for you to quit smoking now.”

• “Quitting is the most important thing you can do to 

protect your health.”

• “I can help you quit.”

Also link smoking with something specific to the patient, 

such as secondhand exposure to children or partners, his/

her own lung, cardiovascular, or cancer risk, or the expense 

of cigarettes.

ASSESS

readiness to 

make a quit 

attempt

Determine whether the 

tobacco user is willing and 

ready to make a quit attempt 

within 30 days.

• “Are you willing to give quitting cigarettes a try?”

ASSIST in the 

quit attempt

For the patient willing to quit, 

assist in developing a quit 

plan.

Provide practical counseling, 

support, and supplementary 

materials.

• Have patient set a quit date and enlist the support of 

his/her family and friends.

• Offer pharmacotherapy, as appropriate, including 

nicotine replacement.

• Provide counseling that includes problem solving and 

skills building.
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Section 3: Health Maintenance 

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Component Action Example

ARRANGE for 

follow-up

Arrange for follow-up 

contacts beginning within 

the first week after the quit 

date.

• Contact patient via telephone or in person soon after 

the quit date. This can be done by the primary clinician 

or other trained staff members.

• During the follow-up encounter, assess and identify 

any problems, review medication use and side effects, 

provide reminders about additional resources.

• Congratulate patients on their successes.

• Help those with relapses assess problems with and 

barriers to quitting, and offer additional or different 

assistance.

• For patients who report a relapse, help them identify 

the circumstances that led the relapse and assist them 

with recommitting to smoking abstinence.

Adapted from Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline. Rockville, 

MD: U.S. Department of Health and Human Services, Public Health Service; May 2008. Available at www.ncbi.nlm.nih.gov/books/

NBK63952. Accessed December 1, 2013.

For patients who are not ready to quit, 

techniques such motivational interviewing 

(MI) can be used in conjunction with the 

stages-of-change model to explore the smokers’ 

beliefs, feelings, and barriers to successful 

cessation efforts. Components of MI include: a) 

expressing empathy; b) developing discrepancy; 

c) rolling with resistance; and d) supporting 

self-efficacy. Effective use of MI involves 

specialized training. Partnering with clinic staff 

or outside agencies that are familiar with MI 

techniques can help improve behavior change 

outcomes, such as smoking cessation. (For 

further information, see “References,” below.)

Pharmacologic interventions

In addition to counseling, the use of 

pharmacologic interventions such as nicotine 

replacement therapy and other adjuvant 

therapies should be considered. These therapies 

were developed for the general population, but 

current clinical guidelines suggest that they 

should be efficacious for HIV-infected smokers.

Clinicians should be aware of potential 

medication adverse effects (see Table 2). 

S: Subjective

• Ask all patients about their smoking status 

at every visit. This can be easily incorporated 

as part the initial intake when vital signs are 

obtained.

• Document smoking history, including the 

number of cigarettes smoked per day.

• If the patient is not ready to quit, use MI 

techniques to identify beliefs and barriers 

and to create ambivalence about smoking.

• For the smoker interested in quitting: 

• Help identify triggers to smoking, and 

develop a quit plan.

• Assess for potential complications of or 

considerations related to pharmacologic 

smoking cessation treatments such 

as history of seizure disorders, sleep 

disturbances, mood disorders, and 

pregnancy.

• For patients who recently quit, congratulate 

them on their accomplishments and 

reinforce the benefits of continued cessation.

• For patients who recently relapsed, help 

them identify what led to the relapse and 

how to avoid relapses in the future. Assist 

them in getting back on track with a 

cessation program.
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O: Objective

During the physical examination, assess for 

evidence of smoking-related illnesses and the 

comorbid conditions that may be affected 

by smoking. At a minimum, measure blood 

pressure and oxygen saturation and examine 

for oral lesions, abnormal breath sounds, and 

decreased peripheral perfusion.

A/P: Assessment and Plan

Determine the smoker’s readiness to change 

(see behavioral model for smoking cessation, 

above). For those smokers in the preparation 

or action stage, assist with implementing a 

quit plan. For those who are in the relapse 

stage, reinforce self-efficacy and encourage 

them to recommit to cessation. For those in 

the maintenance stage, congratulate them and 

reinforce the benefits of smoking cessation.

For patients willing to quit, offer resources 

and information that will help them to be 

successful in their quit attempt. Evidence 

suggests that the combination of counseling 

and medication is more effective than either 

intervention alone. Therefore, every effort 

should be made to combine counseling 

sessions with pharmacotherapy for patients 

who are motivated and ready to quit smoking.

Components of effective counseling include 

problem solving, skills training, and social 

support. Problem solving and skills training 

should focus on how to deal with triggers 

or urges that may lead to relapse. Examples 

include recognition of situations or events that 

may prompt a person to smoke (e.g., drinking 

alcohol, being around other cigarette smokers, 

situational stress) and means of reducing or 

coping with these situations. Social support 

interventions include providing reassurance 

that the patient has the ability to succeed with 

smoking cessation, communicating caring and 

concern, and encouraging the patient to talk 

about the quit process.

Offer medications, if there are no 

contraindications to pharmacologic 

interventions (see Table 2). All currently 

available over-the-counter and prescription 

medications have been shown to be 

effective. However, studies have shown that 

combination therapy may be more efficacious 

than monotherapy. The current tobacco 

cessation guidelines recommend the following 

combinations, all of which include nicotine 

preparations: long-term nicotine patch (>14 

weeks) with ad lib use of nicotine gum or 

spray, nicotine patch with nicotine inhaler, 

and nicotine patch with sustained-release (SR) 

bupropion.

Both bupropion SR and varenicline may 

cause sleep disturbance, and varenicline 

may cause exacerbation of neuropsychiatric 

symptoms. For HIV-infected patients who 

take efavirenz as part of their antiretroviral 

therapy, concomitant use of either bupropion 

SR or varenicline may increase the possibility 

of these side effects. Additional research in this 

area is needed. 
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Section 3: Health Maintenance 

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Table 2. Pharmacologic Options for Smoking Cessation

Drug

Recommended Dosing

Common Side 

Effects Comments

Nicotine Formulations*

Nicotine Patch

(available OTC)

Dosage varies by 

brand:

Nicoderm or 

Habitrol:

• 21 mg/24 hours

• 14 mg/24 hours

• 7 mg/24 hours

Nicotrol:

• 15 mg/24 hours

• 10 mg/24 hours

• 5 mg/24 hours

Dosing recommendations 

vary based on the number 

of cigarettes smoked. 

Individualize treatment.

Sample treatment 

recommendation for smokers 

who smoke ≥10 cigarettes 

per day: 

• High-dose patch for 4-6 

weeks, then

• Medium-dose patch for 2 

weeks, then

• Low-dose patch for 2 

weeks

For smokers who smoke <10 

cigarettes per day: 

• Medium-dose patch for 

6-8 weeks, then

• Low-dose patch for 2 

weeks

Local skin 

reaction, 

insomnia or vivid 

dreams

• Apply upon awakening.

• Place patch on a relatively 

hairless location, rotating sites 

to avoid irritation.

• If experiencing sleep 

disturbance, remove patch 

prior to bedtime or use the 16-

hour patch.

Nicotine Lozenge

(available OTC)

• 2 mg and 4 mg 

• For patients who smoke 

their first cigarette >30 

minutes after waking, 

start with 2 mg dose. 

For patients who smoke 

their first cigarette within 

the first 30 minutes after 

waking, start with 4 mg.

• Most patients should use 

1 lozenge Q1-2H during 

the first 6 weeks.

• Allow lozenges to 

dissolve, do not chew or 

swallow. Most individuals 

use 9 lozenges per day; 

maximum is 20 per day.

• Lozenges should be 

used for up to 12 weeks, 

decreasing dosing from 

1 lozenge Q1-2H for the 

first 6 weeks, to 1 lozenge 

Q2-4H during weeks 7-9, 

and 1 lozenge Q4-8H 

during weeks 9-12.

Nausea, hiccups, 

heartburn, 

headache, cough

• Do not eat or drink anything 

except water for 15 minutes 

before using a lozenge.
194 | Guide for HIV/AIDS Clinical Care

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Drug Recommended

Dosing

Common Side 

Effects

Comments

Nicotine Formulations*

Nicotine Inhaler

(prescription only)

• 4 mg per 

inhalation

• 10 mg cartridge

Recommended dosage: 6-16 

cartridges per day.

Duration of therapy: up to 6 

months, taper dosage in last 

3 months.

Local irritation in 

the mouth and 

throat, cough, 

rhinitis; may cause 

bronchospasm 

(<1%)

• Use caution in persons with 

severe reactive airway disease.

Nicotine 

Nasal Spray 

(prescription only)

• 0.5 mg per 

spray

• Patient should use 1-2 

sprays each nostril per 

hour (total 1-2 mg per 

hour), increasing as 

needed for symptom 

relief.

• Minimum recommended 

treatment is 16 sprays 

(8 mg) per day, with a 

maximum limit of 80 

sprays per day (10 sprays 

per hour).

• Recommended duration 

of therapy: 3-6 months.

• Do not sniff, swallow, or 

inhale through the nose 

while administering 

doses. Tilt head slightly 

back when dosing.

Nasal irritation, 

transient changes 

in sense of 

smell and taste; 

may cause 

bronchospasm 

(<1%)

• Use caution in persons with 

severe reactive airway disease.

• Nicotine nasal spray has 

highest dependence potential 

of the nicotine replacement 

therapies.

Non-Nicotine Medications, First Line 

Bupropion SR

• 150 mg 

Begin 1-2 weeks before quit 

date. 

• Start at 150 mg daily for 3 

days, then increase to 150 

mg BID for 7-12 weeks.

• May consider longer-term 

therapy.

Insomnia, dry 

mouth

• May lower seizure threshold in 

certain patients.

• Levels increased in patients on 

P450 3A4 inhibitors.

• Use with caution in patients 

with history of seizures or 

eating disorders, and those 

who have used a monoamine 

oxidase (MAO) inhibitor in the 

past 14 days.
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Section 3: Health Maintenance 

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Drug Recommended

Dosing

Common Side 

Effects

Comments

Varenicline

• 0.5 mg and 

1 mg

Begin 1 week before quit 

date. 

• Start with 0.5 mg daily 

for 3 days, increase to 0.5 

mg BID for 4 days, then 

1 mg BID for duration of 

therapy.

• Typical duration: 12 

weeks.

• Varenicline is approved 

for maintenance therapy 

for up to 6 months. 

Nausea; 

flatulence; 

headache; sleep 

disturbance; 

abnormal, 

vivid, or 

strange dreams; 

depression; 

agitation; suicidal 

ideation; and 

suicide

FDA Black 

Box warning 

regarding 

neuropsychiatric 

adverse effects

• Use with caution in patients 

with history of psychiatric 

illness. Monitor closely for 

mood and behavior changes.

• Dosage reduction 

recommended for patients 

who have creatinine clearance 

(CrCl) of <30 mL/min or are on 

dialysis.

• To reduce nausea, should be 

taken with food. To reduce 

insomnia, second pill can be 

taken at dinner rather than at 

bedtime.

• Dosage may be reduced for 

patients with adverse effects.

Non-Nicotine Medications, Second Line 

Clonidine

• 0.1 mg tablet

• 0.1 mg 

transdermal 

patch

• 0.1 mg tablet PO BID

OR

• 0.1 mg transdermal patch 

per day. Can increase by 

0.1 mg/day per week if 

needed.

• Duration of treatment: 

3-10 weeks.

• Do not discontinue 

therapy abruptly.

Dry mouth, 

drowsiness, 

dizziness, 

sedation, and 

constipation

Rebound 

hypertension 

if discontinued 

abruptly 

• Monitor blood pressure 

when using this medication. 

If discontinuing, taper 

medication to avoid rebound 

hypertension.

• If using patch, place on 

relatively hairless location 

between the neck and waist.

• Avoid in elderly patients

Nortriptyline • Begin 10-28 days before 

quit date.

• Start at 25 mg QD and 

increase to target dosage 

of 75-100 mg QD if 

tolerated.

• Treatment duration: 

approximately 12 weeks; 

some may consider 

extending treatment up 

to 6 months. 

Sedation, dry 

mouth, blurred 

vision, urinary 

retention, 

lightheadedness, 

tremor, cardiac 

conduction 

abnormalities 

• Use with caution in patients 

with cardiac conduction 

abnormalities disease.

• Do not coadminister with MAO 

inhibitors.

• Overdose may produce lifethreatening cardiovascular 

toxicity, as well as seizures and 

coma.

• Avoid in elderly patients 

* Use with caution for patients with cardiovascular disease (particularly those within 2 weeks of myocardial infarction), those with 

serious arrhythmias, and those with unstable angina pectoris (however, note that, for many patients, continued smoking may be 

more dangerous than nicotine replacement).

The adverse effects of cigarette smoking during pregnancy are well established, and smoking generally is more harmful than the use 

of nicotine replacements. Smoking cessation aids may help motivated patients quit during pregnancy.
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All patients who are actively quitting should 

have close follow-up, and they should be 

offered support. Research has shown that 

ongoing support during the quit phase results 

in higher abstinence rates.

Follow-up can include telephone calls or inperson evaluation.

For patients who recently quit or 

relapsed, continue to provide support and 

encouragement. Assist individuals who 

relapsed with the opportunity to continue with 

cessation plans.

Refer patients to smoking cessation groups, 

classes, and other resources.

Patient Education

• For patients who have decided on 

pharmacologic interventions and for whom 

there are no contraindications, provide 

education regarding medication side effects, 

anticipated withdrawal symptoms, and 

strategies for managing withdrawal.

• Review and reinforce strategies in the event 

of relapse.

• For those who are not ready to quit, inform 

them of the consequences of continued 

smoking and remind them about the 

available resources.

Suggested Resources:

• National Telephone Counseling and Quit 

Line (800-QUIT-NOW) (800-784-8669)

• American Cancer Society (www.cancer.org)

• American Lung Association (maintains 

profiles of state tobacco control activities) 

(www.lungusa.org)

• National Cancer Institute (www.cancer.gov)

• Office on Smoking and Health at the Centers 

for Disease Control and Prevention (www.

cdc.gov/tobacco)

References

• Cook PF, Bradley-Springer L, Corwin 

M. Motivational Interviewing and HIV: 

Reducing Risk, Inspiring Change. Mountain 

Plains AIDS Education Training Center; 

January 2012. Available at www.mpaetc.org/

Products/Motivational-Interviewing-andHIV. Accessed December 1, 2013.

• Crothers K, Goulet JL, Rodriguez-Barradas 

MC, et al. Impact of cigarette smoking on 

mortality in HIV-positive and HIV-negative 

veterans. AIDS Educ Prev. 2009 Jun;21(3 

Suppl):40-53.

• Fiore MC, Jaen CR, Baker TB, et al. Treating 

Tobacco Use and Dependence: 2008 Update. 

Clinical Practice Guideline. Rockville, MD: 

U.S. Department of Health and Human 

Services, Public Health Service; 2008.

• Prochaska JO. Decision making in 

the transtheoretical model of behavior 

change. Med Decis Making. 2008 NovDec;28(6):845-9.

• Prochaska JO, Velicer WF. The 

transtheoretical model of health behavior 

change. Am J Health Promot. 1997 SepOct;12(1):38-48.

• Reynolds NR. Cigarette smoking and HIV: 

more evidence for action. AIDS Educ Prev. 

2009 Jun;21(3 Suppl):106-21. 

• Vidrine DJ. Cigarette smoking and HIV/

AIDS: health implications, smoker 

characteristics and cessation strategies. AIDS 

Educ Prev. 2009 Jun;21(3 Suppl):3-13.

• Walters ST, Wright JA, Shegog R. A review 

of computer and internet-based interventions 

for smoking behavior. Addict Behav. 2006 

Feb;31(2):264-77.
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Nutrition

Background

Maintaining good nutritional status is important to support overall health and immune system 

function for people with HIV/AIDS. Many HIV-related conditions affect and are affected by 

the body’s nutritional status. These include conditions related to HIV itself (e.g., opportunistic 

infections and other illnesses), comorbid conditions, and adverse effects of therapies.

Inadequate nutrition in people with HIV infection may result from many factors, including 

conditions such as nausea, vomiting, and anorexia (see chapter Nausea and Vomiting) that may 

prevent adequate intake of nutrients and medications; diarrheal infections (see chapter Diarrhea) 

that prevent absorption of nutrients and medications; poor oral health conditions that interfere 

with chewing or tasting food (see chapter Oral Health); systemic illnesses (including HIV itself) 

that create a catabolic state; and psychological conditions (such as depression) that impair patients’ 

ability to nourish themselves. In addition, financial constraints may limit patients’ access to 

nutritious food.

Evaluation and enhancement of patients’ nutritional status may help correct or compensate for 

deficiencies (e.g., in the case of weight loss or nutrient deficits), may be a key treatment modality for 

certain conditions (e.g., dyslipidemia, hyperglycemia), and may help to maintain good health and 

immune function. This chapter focuses on the evaluation of patients with nutritional deficiencies, 

particularly weight loss, and on simple strategies for maintaining good nutrition in individuals 

with barriers to maintaining adequate weight.

It should be noted that obesity and overweight conditions are increasingly common in HIVinfected individuals; many of the principles described here also may be applied to the evaluation 

of overweight patients. Recommendations for weight reduction for HIV-infected patients are the 

same as for the general population and will not be discussed in detail; for overweight patients with 

lipohypertrophy, diabetes, dyslipidemia, or coronary artery disease, see the respective chapters on 

these conditions.

Ideally, HIV-infected individuals will receive the services of HIV-experienced nutrition specialists, 

who may contribute to the patient care team in the following ways:

• Conducting routine screening to identify and treat nutritional problems

• Preparing a tailored nutritional plan to optimize patients’ nutritional status, immune status, and 

overall well-being

• Screening and developing interventions for growth problems in children

• Developing strategies to prevent loss of weight and lean body mass

• Adapting dietary recommendations to help reduce the risk of comorbid conditions such as 

diabetes and heart disease, or treating these complications

• Educating patients about how to modify their dietary habits to maximize the effectiveness of 

medical and pharmacologic treatments

• Tailoring nutritional recommendations to fit patients’ lifestyles and financial resources

• Counseling patients to promote nutrition self-care using available resources
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• Providing nutritional support to patients may help to do the following: 

• Address common problems associated with HIV disease and its treatment (e.g., weight 

loss, wasting, fatigue, loss of appetite, adverse changes in taste, dental problems, 

gastrointestinal complaints)

• Treat chronic comorbid conditions (e.g., cardiovascular disease, hypertension, diabetes, 

cirrhosis)

• Improve quality of life

• Enhance immune responses, slow disease progression, and prolong life

S: Subjective

History

Identify nutrition risk factors at the start of 

care through interview, questionnaire, or 

both. Update the history at least annually. 

The history should elicit signs and symptoms 

related to nutrition issues, indications 

regarding dietary habits, and symptoms that 

suggest nutritional deficiencies. 

Nutrition-Related Questions 

Factor Areas to Explore

Signs, Symptoms, and 

Comorbid Conditions

• Poor or sporadic appetite

• Early satiety

• Weight gain or loss

• Trouble chewing or swallowing

• Dental problems including poor 

dental hygiene

• Gastrointestinal complaints, 

including nausea, diarrhea, 

constipation, heartburn, gas

• Changes in body contours with fat 

gain in abdomen, back of neck, and 

breasts (lipodystrophy) or fat loss in 

extremities and face (lipoatrophy)

• Depression, stress

• Fatigue

• Chronic pain

• Other diseases affecting diet and 

nutrition

• Medications, including over-thecounter and herbal products

Medication-Related 

Factors

• Medication side effects

• Difficulty coordinating meals with 

medicines 

• Use of nutritional supplements

Social and Behavioral 

Factors

• Frequent eating out

• Smoking

• Alcohol or substance abuse

• Erratic meal patterns

• Unbalanced diet (e.g., high intake 

of low-nutrient foods; deficiency in 

key nutrients)

• Resources to ensure secure, 

continued food access

• Availability of food storage and 

preparation facilities

• Housing (stable, homeless, 

marginally housed, or in transition)

• Nutrition literacy
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To develop a specific dietary history, ask about the following: 

Dietary History

Usual Dietary Intake Factors That May Affect or Limit Intake

• Frequency of intake of foods providing key 

nutrients (e.g., dairy products, fortified or whole 

grains, fruits and vegetables, eggs, beans, fluids, 

meat) as well as those that perhaps should be 

limited (fast-food items, highly processed or 

salted products)

• Usual meal patterns (number of times per day, 

snacks) and whether meals are prepared and 

eaten at home or eaten at restaurants or fast-food 

establishments

• Specific information about nutritional 

supplements (e.g., vitamins, minerals, herbs, 

protein), including contents, amounts, 

formulation (pills, powders, drinks), cost, and 

overlap among products 

• Amount of money available for food, or 

participation in food assistance programs (e.g., 

food stamps, food pantries)

• Appetite, general well-being (e.g., fatigue, pain, 

depression)

• Food allergies, intolerances

• Problems with dentition, swallowing, heartburn, 

diarrhea, constipation

• Coordination of foods and supplements with 

medications (HIV or other)

Elicit symptoms that may be related to nutritional deficiencies. 

Symptoms with Possible Relationship to Nutritional Deficiencies

• General symptoms (e.g., fatigue, decreased 

cognitive function, headache)

• Behavioral changes (e.g., irritability, apathy, 

decreased responsiveness, anxiety, attention 

deficit)

• Body habitus changes (e.g., loss or gain of fat)

• Gastrointestinal symptoms (e.g., diarrhea, 

constipation, bloating)

• Changes in skin, nails, hair (e.g., dryness, 

breaking, thinning)

• Muscle loss

• Neurologic symptoms (e.g., weakness, sensory 

changes, gait abnormalities)

O: Objective

Physical Examination

Perform a careful physical examination, 

if possible with anthropometric and body 

composition testing as described below 

(Table 1). Compare current findings with past 

assessments and review at least every 6 months.

The physical examination should include the 

following: 

• Vital signs, with orthostatic vital signs if 

dehydration is suspected

• Weight (compare with previous values) and 

body mass index (BMI)

• General appearance and gross nutritional 

status (e.g., obesity, cachexia, wasting)

• Body habitus: loss of subcutaneous fat 

in face, buttocks, arms and legs and/or 

increased fat in abdomen, breasts, neck, and 

upper back (“buffalo hump”)

• Muscle mass

• Mouth: breakdown in oral mucosa, cheilosis, 

angular stomatitis, glossitis, papillar atrophy

• Abdomen: hepatomegaly (may be caused by 

fatty infiltration)

• Skin: dryness, peeling, breakdown, pallor, 

hypopigmentation or hyperpigmentation

• Nails: pale nail beds, fissures or ridges

• Neurologic system, including strength, 

sensation, coordination, gait, deep tendon 

reflexes

Anthropometric and body composition tests 

are usually performed by registered dietitians. 

They can provide important information about 

patients’ nutritional status. 
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Table 1. Anthropometric Measurements for Adults and Children 

Height Weight Assessment for Changes over Time

Adults Measure at 

baseline (selfreport is not 

accurate).

• Measure at least quarterly and 

consider intervention when 

small changes are observed. Do 

not wait until major amounts 

of weight have been lost or 

gained.

• Record sequentially at the 

front of the patient’s chart and 

monitor for trends.

Use healthy, premorbid weight to 

assess change, not the first clinic weight 

or the ideal weight. (Use the patient’s 

weight at a time when the patient 

is healthy, feels well, and can easily 

maintain that weight.)*

Children Measure at least 

quarterly using 

length board 

(0-2 years) or 

wall-mounted 

stadiometer (≥2 

years).

• Measure at least quarterly and 

consider intervention when 

small changes are observed. Do 

not wait until the patient has 

dropped significantly on the 

growth chart.

• Calculate age and plot the 

measurements on growth 

charts specific for age, sex, and 

country.#

Assessment of optimal growth is 

based on the observed pattern over 

time. General goals include a weight 

relatively “matched” for length or 

height (about the same percentile) and 

relative stability of percentile tracking 

over time.* #

* BMI (body mass index) is useful as an evaluative index. See chapter Initial Physical Examination, and the U.S. Centers for Disease 

Control and Prevention (CDC) online calculator at www.cdc.gov/healthyweight/assessing/bmi. Accessed December 1, 2013.

# Growth charts for children in the United States are available online from the CDC at www.cdc.gov/growthcharts. A variety of growth 

charts are available for children from specific ethnic groups (e.g., Chinese, Vietnamese, Thai), children with selected conditions 

affecting growth (e.g., Down syndrome), or those who are born prematurely. Percentiles for both height and weight should be 

recorded sequentially.

Body Composition Testing

Body composition commonly is tested by bioelectrical impedance analysis (BIA) (Table 2) or 

skinfold thickness and circumference (Table 3).

Table 2. Bioelectrical Impedance Analysis

BIA testing is the standard of care for adults but has not been well validated for children: 

• BIA is useful for assessing disease progression or health maintenance, documenting response to 

treatment, and justifying the cost of nutritional supplements and AIDS-wasting medications.

• The test is simple, noninvasive, and quick (<5 minutes). However, staff training and specialized software 

are required to interpret the results.

• Perform BIA at baseline, if possible. Update every 6-12 months or more frequently if the patient is ill, has a 

decline in immune status, or has a weight change of 5-10%.

• The BIA test reports the following: 

• Body cell mass (BCM): the target component, reflecting cells in muscles, organs, and the circulation; 

losses may indicate AIDS wasting. BCM is recorded in pounds. Monitor for trends.

• Fat: an index of energy stores; recorded in pounds and percentage.

• Phase angle: a measure of cellular integrity, an independent indicator of morbidity and mortality in 

HIV-infected patients.
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Table 3. Skinfold Thickness and Circumference Measures

Skinfold thickness and circumference measures can be used for adults and children in resource-limited 

settings, and for situations in which bioelectrical impedance analysis is not available. Circumference 

measures also can be used to monitor changes over time associated with lipodystrophy in adults.

• Skinfold thickness is measured with calipers.

• Circumference measures are taken at specific anatomical landmarks with nonstretchable tape.

• Techniques and protocols for taking anthropometric measurements can be found at the CDC website 

(www.cdc.gov/nchs/data/nhanes/nhanes_03_04/BM.pdf).

Laboratory Testing

Perform basic laboratory (blood) tests, 

including the following:

• Hemoglobin and/or hematocrit

• Total protein, albumin

• Fasting blood glucose

• Fasting lipids (triglycerides, total cholesterol, 

low-density lipoprotein cholesterol [LDL], 

high-density lipoprotein cholesterol [HDL])

• CD4 cell count and HIV viral load, if no 

recent values are available

• Specific vitamin and nutrient tests as 

indicated by symptoms (e.g., iron studies 

in case of anemia, vitamin B12 in case of 

peripheral neuropathy)

• Others tests, such as testosterone and 

thyroid hormone levels as appropriate, to 

rule out other causes of symptoms 

A: Assessment

Assess subjective information and objective 

findings to evaluate nutritional status.

Identify Nutrition Concerns

Several factors may influence nutrition, 

including the following: 

• Barriers to good nutrition (e.g., lack of 

knowledge or motivation for self-care, poor 

appetite, lack of money for food, lack of 

facilities for food storage and preparation)

• Lifestyle factors (e.g., smoking, substance 

abuse, frequent eating out, erratic eating 

patterns, hectic schedule, high stress)

• Physical problems affecting food and 

nutrient intake (e.g., poor appetite, nausea, 

fatigue, pain, weakness, mouth or throat 

pain, acid reflux, missing or decayed teeth, 

poorly fitting dentures, poor eyesight, 

constipation)

• Nutrient losses (e.g., owing to diarrhea, 

vomiting)

• Potential confounding factors (e.g., use 

of multiple overlapping or questionable 

supplements, eating disorders) 

Evaluate Dietary Intake

Assess the following diet-related issues:

• Expected excesses or deficiencies from 

dietary history or interview

• Rating of food security, including access to 

cooking and refrigeration

• Food intolerances, aversions, or allergies 

likely to affect adequacy of intake

• Special needs related to other conditions 

(e.g., documented cardiovascular disease, 

diabetes, hypertension) 

Evaluate Weight, Body Composition, 

and Weight Distribution

Assess physical findings of malnutrition and 

confirm with nutrition history, laboratory 

tests, and anthropometric evidence. Normal 

and abnormal findings of anthropometric tests 

and recommendations for monitoring changes 

over time are presented in Table 4. 
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Table 4. Evaluating the Findings of Anthropometric Tests 

Monitoring Trends and Recommendations

Adults

• Chart trends over time relative to previous measurements 

and the following population norms: 

• BMI (healthy range: 19-25) 

• BIA:

• BCM (percentage of weight): women 30-35%; men 40-45% 

• Fat (percentage of weight): women 20-30%; men 15-25% 

• Phase angle: women >5; men >6 

• Skinfold thicknesses and circumferences: Chart changes in absolute 

measures and percentiles 

• Changes in body contours: Evaluate lipodystrophy (excess accumulation 

of fat in abdomen, breasts, dorsocervical area) and lipoatrophy (loss of 

subcutaneous fat in face, extremities, buttocks)

Children

• Plot measurements 

on growth charts and 

track percentiles over 

time (the consistency 

of percentiles 

rather than the 

absolute percentile is 

important) 

• Skinfold thicknesses 

and circumferences:

Chart changes in 

absolute measures 

and percentiles

Abbreviations: BCM = body cell mass; BIA = bioelectrical impedance analysis; BMI = body mass indexx 

Evaluate Laboratory Findings

• Evidence of malnutrition (e.g., low iron or protein stores)

• Evidence of disease or risk of disease for which dietary treatment is 

indicated (e.g., high fasting glucose, hypertension, hyperlipidemia) 

Develop a Problem List

The following suggests a useful format for a nutrition-related problem list. 

Nutrition-Related Problem List

Problem 

Number Description of Problem (circle/describe)

Nutrition barriers: insufficient knowledge, poor appetite, food insecurity, no food preparation 

or storage facilities, homelessness 

Lifestyle: substance abuse, smoking, erratic eating, frequent fast-food intake, high stress

Weight or body composition: undesirable weight gain or loss (adult), changes in growth 

trajectory (children), loss of lean body mass (wasting), gain of excess fat (obesity), lipoatrophy or 

lipodystrophy

Physical problems: fatigue, pain, early satiety, poor dentition, clinical signs of malnutrition 

Laboratory findings: low hematocrit or hemoglobin, low protein or albumin, low or high fasting 

glucose, high total cholesterol, high LDL, high triglycerides, low HDL, low testosterone 

Gastrointestinal: diarrhea, vomiting, reflux, constipation 

Poor diet: poor food choices, bingeing, skipping meals, high sugar intake, high alcohol 

consumption, high intake of refined foods, low fruit and vegetable intake, insufficient protein, 

insufficient calcium, food allergies or intolerances that limit intake

Comorbid conditions: diabetes, hypertension, cardiovascular disease, cancer, gastroesophageal 

reflux disease (GERD)

Medications: drug-drug or drug-nutrient interactions or difficulty coordinating medicines with 

meals

Supplements: insufficient or excessive intakes, cost of supplements unaffordable, supplements 

with potential or unknown risks
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P: Plan

Develop a nutritional plan and provide 

practical nutrition education for common 

problems (see “Resources,” below).

Evaluate and treat concurrent medical 

problems (e.g., diarrhea, nausea, infections, 

malignancies, depression, pain). For severe 

or persistent nutritional problems, or for 

specific needs, refer to a nutrition specialist for 

evaluation and treatment. 

Common nutrition-related problems are 

presented in Table 5, along with simple 

management suggestions that may help resolve 

them and help patients maintain adequate 

nutrition. 

Table 5. Practical Interventions for Common Nutrition-Related Problems

Problem Suggestions

Weight Loss (decrease 

in both body cell mass 

and fat)

• Early identification and ongoing monitoring are key.

• Identify and treat underlying risk factors.

• Try to add calories without adding “bulk”: 

• Fat (9 calories/gram): butter, margarine, avocado, cream, mayonnaise, 

salad dressing

• Carbohydrate (4 calories/gram): jam, jelly, sugar, icing, gum drops

• Protein (4 calories/gram): protein powders, cheese, nut butters, trail mix, 

powdered breakfast drinks, nonfat dry milk

• Eat more frequently.

• Maximize good days.

• Use canned supplements (e.g., Ensure, Boost).

• For wasting or substantial weight loss, consider referral for therapies such as 

appetite stimulants or human growth hormone.

Diarrhea • Increase soluble fiber; decrease insoluble fiber.

• Replenish beneficial bacteria (e.g., with lactobacilli or other probiotic preparations).

• Avoid intestinal irritants and stimulants.

• Decrease dietary fat.

• Decrease or eliminate lactose.

• Increase fluids and provide electrolytes (sodium, potassium).

• Treat with pancreatic enzymes.

Early Fullness • Take small, frequent meals.

• Concentrate on solid foods, with liquids between meals.

• Eat lower-fat, lower-fiber foods.

• Wear loose-fitting clothing.

• Sit up while eating.

• Eat, walk, and eat again.

Nausea • Take small, frequent meals.

• Try dry snack foods.

• Avoid fried foods, very sweet foods, spicy 

foods, and foods with strong odors.

• Try cool, clear beverages, popsicles.

• Try ginger-containing foods and drinks.

• Keep liquids to a minimum at meals.
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Problem Suggestions

Changes in Taste • Eat a variety of foods, not only favorite foods.

• Try protein sources other than red meat.

• Marinate foods, use sauces.

• Use more and stronger seasonings.

• Try tart foods.

• Use sugar or salt to tone down the flavor of foods.

• Try a mouth rinse of 1 teaspoon of baking soda in 1 cup of warm water 

before eating.

Loss of Appetite • Rely on favorite foods.

• Ask family members and friends to prepare meals.

• Eat small, frequent meals.

• Keep snacks handy for nibbling.

• Eat before bedtime.

• Eat in a pleasant place, with other people.

• Make the most of good days.

• Try light exercise to stimulate appetite.

• Add extra calories without adding bulk.

• Consider appetite stimulants (e.g., megestrol, dronabinol).

Difficulty Chewing or 

Swallowing or Sore 

Mouth and Throat

• Choose soft, nutritious foods.

• Blend or puree foods (e.g., soup or stew, smoothies).

• Add cream sauces, butter, or gravy for lubrication.

• Sip liquids with foods.

• Use a straw or drink foods from a cup.

• Choose bland, low-acid foods.

• If hot foods cause pain, serve foods cold or at room temperature.

• Avoid alcohol and tobacco.

• Soothing lozenges or sprays may help.

Food Insecurity • Refer to social services for assistance with accessing resources such as food 

stamps, community meals, or a food pantry program.

• Refer to a dietitian for assistance with low-cost food ideas.

• Use materials provided by CheapCooking.com 

(www.cheapcooking.com/index.htm).

Unbalanced Diet and 

Other Conditions 

Requiring Dietary 

Modification

• Refer to a dietitian for counseling and education.
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Section 3: Health Maintenance 

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Nutrition Specialists

Whenever possible, nutritional services should 

be provided by a registered dietitian (RD) who 

is a qualified HIV care provider. In the United 

States, holding this status requires a nutrition 

degree from an accredited college, graduation 

from an approved internship or master’s 

degree program, and maintenance with 75 

continuing-education units every 5 years, 

including specific and ongoing HIV training. 

An RD with HIV/AIDS expertise in the United 

States can be located by going to www.eatright.

org, clicking on “Find a Registered Dietitian,” 

entering the patient’s zip code or city, and 

selecting “HIV/AIDS” under areas of specialty. 

Membership in the Infectious Diseases 

Nutrition Dietetic Practice Group (idndpg.org) 

also may indicate HIV experience. 

Resources

The following online resources provide 

information, guidelines, and tools for 

providers and patients in managing issues 

related to nutrition and HIV: 

• 2000 CDC Growth Charts: United States

Center for Disease Control and Prevention, 

National Health and Nutrition Examination 

Survey. Available at www.cdc.gov/

growthcharts.

• Center for Disease Control and Prevention 

National Center for Health Statistics

Available at www.cdc.gov/nchs/

products/series.htm.

• CheapCooking.com

Website with recipes using low-cost 

ingredients and tips for frugal meal planning. 

Available at www.cheapcooking.com.

• Infectious Diseases Nutrition Dietetic 

Practice Group

Affiliate of the American Dietetic 

Association. Website includes screening 

tool (Nutrition Screen and Referral Criteria 

for Adults with HIV/AIDS). Formerly HIV/

AIDS Dietetic Nutrition Practice Group. 

Available at idndpg.org.

• ChooseMyPlate.gov

A U.S. Department of Agriculture website 

with dietary guidelines, tips, resources, and 

consumer-oriented information. Available at 

www.choosemyplate.gov. 

• Health Care and HIV: Nutritional 

Guide for Providers and Clients 

Manual from HRSA. Available at 

aidsetc.org/aidsetc?page=etresdisplay&resource=etres-193

• Nutrition.gov

Available at www.nutrition.gov

References

• Association of Nutrition Services Agencies. 

ANSA Nutrition Guidelines and Fact Sheets. 

Washington, DC: ANSA; 2006.

• Bartlett JG. Introduction. Integrating 

nutrition therapy into medical management 

of human immunodeficiency virus. Clin 

Infect Dis. 2003 Apr 1;36(Suppl 2):S51.

Antiretroviral Therapy | 207

Section 4: HIV Treatment

Antiretroviral Therapy

Susa Coffey, MD 

Background

Potent combination antiretroviral therapy (ART), 

typically consisting of three or more antiretroviral (ARV) 

drugs, has greatly improved the health and survival rates 

of HIV-infected patients in areas of the world with access 

to ARVs. More than 20 individual ARVs in six classes are 

available in the United States, in addition to several fixeddose combination preparations. These can be combined 

to construct a number of effective regimens for initial and 

subsequent therapy. Although ART has its limitations 

(see below), it saves lives and improves immune system 

function, reduces the risk of many HIV-related and 

“non-AIDS” complications, and reduces the risk of HIV 

transmission. Increasingly, several lines of evidence point 

to the benefit of ART even for patients with high CD4 counts.

Mortality and morbidity benefits of ART are particularly obvious in patients with relatively 

advanced immune suppression or with symptoms related to HIV infection. For asymptomatic 

patients with higher CD4 counts (particularly >500 cells/μL), the question of when to initiate ART 

remains an area of research and debate. It is clear there is a spectrum of risk for adverse outcomes 

that increases as the CD4 count declines. In persons with CD4 counts of <200 cells/μL, effective 

ART dramatically decreases morbidity and mortality. For persons with CD4 counts of 200-350 

cells/μL, data from randomized controlled studies as well as cohort studies also demonstrate a 

reduction in both AIDS and non-AIDS events among those who start ART. For patients with 

higher pretreatment CD4 levels, randomized and cohort studies also have found decreased rates of 

complications and death in those who initiated ART with CD4 counts of >350 cells/μL rather than 

<350 cells/μL, and some (though not all) observational evidence suggests a mortality benefit of ART 

among persons with CD4 counts of >500 cells/μL. For patients with CD4 counts of >500 cells/μL, 

the limited data that are currently available (from cohort studies) are inconsistent on the question 

of whether initiation of ART results in better outcomes. A randomized clinical trial of earlier (>500 

cells/μL) versus deferred (<350 cells/μL) treatment is under way, and the results of that study along 

with those from the cohort studies may help define an optimal threshold at which to initiate ART.

Meanwhile, in recent years, a growing body of evidence has demonstrated ongoing and adverse 

effects of untreated HIV on many organ systems and aspects of functioning, even in persons with 

high or relatively high CD4 counts (>350-500 cells/μL). These include the following: 

HRSA HAB Performance 

Measures

Percentage of clients, regardless of 

age, with a diagnosis of HIV who were 

prescribed antiretroviral therapy

for the treatment of HIV infection 

during the measurement year

(Core measure)

Percentage of patients, regardless of 

age, with a diagnosis of HIV with an HIV 

viral load of <200 copies/mL at last HIV 

viral load test during the measurement 

year

(Core measure)

• Cardiovascular disease

• Kidney disease, 

specifically HIV-associated 

nephropathy (HIVAN)

• Liver disease, particularly 

among patients with 

chronic hepatitis B virus 

(HBV) or hepatitis C virus 

(HCV)

• Neurocognitive deficits, 

including dementia

• Cancers, both AIDSmalignancies and nonAIDS malignancies
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Many of these effects appear to be mediated through persistent immune system activation and 

ongoing inflammation in various organ systems. ART with virologic suppression appears to reduce 

immune activation and protect against many of these morbidities, but it may not restore immune 

system function to normal and may not fully reverse disease processes. The beneficial effects of 

ART may be attenuated for patients who start ART with lower CD4 cell counts. Additionally, the 

risk of certain ARV-related adverse events may be greater for those who start ART at lower CD4 

levels.

Although ART can confer substantial health benefits, it has significant limitations. ART does 

not cure HIV infection and it requires that multiple medications be taken for life (i.e., potentially 

many decades). It may cause a variety of adverse effects (some severe), is expensive, requires 

close adherence to be effective and to prevent the emergence of resistance, and it sometimes fails 

(because of the patient’s imperfect adherence or other factors). The failure of an ARV regimen 

when accompanied by drug resistance may mean that subsequent regimens are less likely to 

succeed, despite the availability of second-line ARV combinations.

In past years, many of the available ARVs presented challenges in the realms of adverse effects, pill 

quantity, dosing frequency, and durability. Given these limitations of ART, much attention was 

devoted to estimating the point at which the potential benefits of ART outweighed the potential 

risks of ART. Today, the newer ARV regimens, specifically those currently recommended by the 

U.S. Department of Health and Human Services (HHS) for initial therapy, are for most patients, 

simple, tolerable, and effective. As a result of both the availability of ARV regimens that are less 

toxic and easier to administer, and the increasing appreciation of the adverse impacts of untreated 

HIV, the balance between the potential benefit and the potential risk of ART has shifted strongly 

toward treatment for all willing individuals regardless of CD4 count, unless there are compelling 

reasons not to treat (see “When to Initiate Therapy: HHS ARV Guidelines,” below; also see the 

HHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents for a 

full discussion of these issues).

Recent data also demonstrate that ART very substantially reduces the risk of transmission of HIV 

between serodiscordant heterosexual partners. The prevention effect of ART in men who have sex 

with men (MSM) and other risk groups has not yet been established in randomized controlled 

trials, but other lines of evidence suggest that ART strongly protects against HIV transmission in 

all risk groups. Thus, an additional benefit of earlier treatment with ART is a reduction in the risk 

of HIV transmission.

Of course, in deciding when to start ART for the individual patient, practitioners must weigh 

the expected benefits of ART for that person (e.g., improvements in health, reduction in 

HIV transmission) against the possible risks of ART (e.g., toxicity, drug resistance, adverse 

drug interactions). Patients must be willing to start and to continue on treatment, with an 

understanding that high levels of adherence are needed for treatment success.

Although implementing and monitoring ART is complex, a number of guidelines from expert 

panels are available to help clinicians select effective regimens for particular patients. HHS keeps a 

repository of frequently updated recommendations on the use of ARV medications for adults and 

adolescents, pregnant women, and children. All clinicians who treat HIV-infected patients should 

be familiar with the most current versions of these treatment guidelines. They are available on 

the Internet at the AIDSinfo website (www.aidsinfo.nih.gov/guidelines). The HHS Guidelines are 

referenced frequently in this chapter.
Antiretroviral Therapy | 209

Section 4: HIV Treatment

HHS Guidelines: When 

to Start Therapy

The following recommendations have been 

adapted from the HHS Guidelines.

HHS guidelines recommend ART for all 

HIV-infected individuals, both for their own 

health and to prevent transmission:

“ART is recommended for all HIV-infected 

individuals to reduce the risk of disease 

progression. The strength and evidence for this 

recommendation vary by pretreatment CD4 

cell count:”

• CD4 count 

<350 cells/μL:

Strongly 

recommended 

• CD4 count

350-500 cells/μL

Strongly 

recommended

• CD4 count 

>500 cells/μL

Moderately 

recommended 

“ART also is recommended for HIV-infected 

individuals for the prevention of transmission 

of HIV. The strength and evidence for this 

recommendation vary by transmission risks:”

• Perinatal 

transmission: 

Strongly

recommended 

• Heterosexual 

transmission:

Strongly

recommended

• Other transmission 

risk groups:

Strongly 

recommended 

Note that these recommendations assume 

that resources are available for universal ART 

provision. In settings with limited resources, 

persons with lower CD4 counts or coexisting 

conditions (as below) may be prioritized.

ART also is strongly recommended for persons 

with certain conditions, regardless of CD4 

count. These conditions include the following: 

• Pregnancy (see chapters Reducing Perinatal 

HIV Transmission and Care of HIV-Infected 

Pregnant Women)

• History of AIDS-defining illness (including 

HIV-associated dementia)

• HIVAN (see chapter Renal Disease)

• HBV coinfection (see chapter Hepatitis B 

Infection)

• Acute HIV infection (see chapter Early HIV 

Infection)

In some situations, ART may be needed 

relatively urgently. These include the following: 

• Pregnancy

• Acute/recent HIV infection

• AIDS-defining conditions

• Acute opportunistic infections

• HIVAN

• HBV coinfection

• HCV coinfection

• Lower CD4 counts (e.g., <200 cells/μL)

• Rapidly declining CD4 counts (e.g., >100 

cells/μL/year)

• Higher viral loads (e.g., >100,000 copies/mL)

S: Subjective

Obtain the patient’s history and review of 

systems, including the following (see chapter 

Initial History): 

• CD4 cell count history, including nadir

• HIV RNA (viral load) history, including 

pretreatment values if the patient is 

currently taking ARVs

• History of HIV-related conditions

• Previous and current ARV regimens, 

including start and stop dates, regimen 

efficacy, toxicity, resistance

• Current medications, including herbal 

preparations, supplements, and over-thecounter medications

• Medication allergies, intolerances, or 

prominent adverse effects
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• Comorbid conditions (e.g., HBV, HCV, 

depression)

• Current and previous substance use, 

including alcohol and recreational drugs

• Self-assessment of adherence to previous 

regimens

• Desire to start or continue an ARV regimen

• Commitment to adherence (see chapter 

Adherence)

• Occupation and daily schedule

• Willingness and indicators of ability to 

adhere to various types of regimens (e.g., 

QD, BID, with or without food) given 

current life situation

• For women of childbearing potential: 

last menstrual period, current 

method of birth control (if any), 

current pregnancy status, thoughts on 

whether or when to have children

O: Objective

Perform the following objective tests: 

• Complete physical examination (see chapter 

Initial Physical Examination).

• Current CD4 count and HIV viral load: 

preferably two or more separate results 

approximately 1 month apart.

• Drug resistance test, as appropriate; to look 

for transmitted ARV resistance mutations, 

a genotype should be performed for all 

patients before initiating ART; this should 

be done as early in the course of infection 

as possible, because mutations may revert 

to wild-type. Review the results of previous 

resistance testing or obtain a baseline 

resistance test, if this was not done earlier; if 

a test was done in the past, consider retesting 

before ART is begun (see chapter Resistance 

Testing). Patients on ART whose viral loads 

are not suppressed also should undergo 

resistance testing.

• Complete blood count (CBC) and 

platelet count, liver function tests 

(LFTs), renal function tests, fasting 

lipid panel, fasting glucose, rapid 

plasma reagin (RPR), tuberculin skin 

test, hepatitis serologies, Toxoplasma

IgG, urinalysis, (see chapter Initial and 

Interim Laboratory and Other Tests).

A: Assessment

Make the following basic decisions: 

• This is or is not an appropriate time to start 

ART (e.g., do potential benefits of starting 

at this time outweigh the risks at this time?). 

See the HHS Guidelines noted above, which 

thoroughly address the issue, and note that 

many experts are increasingly concerned 

about the potential harm of untreated HIV 

infection, even in individuals with high 

CD4 cell counts. See chapters Risk of HIV 

Progression/Indications for ART and CD4 

Monitoring and Viral Load Testing.

• The patient is or is not willing to start ARVs 

at this time (the choice to accept or decline 

therapy ultimately lies with the patient). 

If not, work with the patient on readiness 

issues, with more urgency if the CD4 

count is low or the patient has symptoms, 

comorbidities, or coexisting conditions that 

suggest treatment is needed.

• The patient is or is not likely to adhere to 

an ARV regimen (an adherence counselor, 

with or without a mental health clinician, 

may be able to assist with this assessment 

and should be called upon if available). No 

patient should be automatically excluded 

from consideration for ART; the likelihood of 

adherence must be discussed and determined 

individually (see chapter Adherence).

P: Plan

After educating the patient about the purpose 

and logistics of the proposed regimen and 

assessing the patient’s potential for adherence, 

ART can be initiated, changed, or postponed 

accordingly.
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Section 4: HIV Treatment

The primary goals of therapy are to reduce 

HIV-related morbidity and mortality and 

to prevent HIV transmission; this includes 

improving the quality of life, maximally and 

durably suppressing HIV virus, and improving 

immune function and reducing HIVassociated inflammation. 

Considerations Before Initiating ART

No “average patient” exists. Some patients 

will do better during treatment and some 

will do worse than clinical studies would 

predict. Health care providers must work with 

each patient to develop a treatment strategy 

that is both clinically sound and appropriate 

for that individual’s needs, priorities, and 

circumstances of daily life. Despite the fact 

that the regimens currently recommended 

by the HHS Guidelines are more compact 

and have fewer adverse effects than earlier 

regimens, not all patients will be able to 

take or tolerate all drugs, and the patient’s 

understanding, readiness to commit to the 

regimen, and history of adherence to previous 

regimens must be considered when choosing 

ARV combinations. Major considerations are 

as follows: 

• Degree of immunodeficiency and risk of 

disease progression as reflected by the CD4 

count and HIV RNA level. ART is more 

urgent for patients with lower or rapidly 

declining CD4 counts and also is less likely 

to be successful in those with low CD4 

counts or very high HIV RNA levels (see 

“HHS Guidelines, When to Start Therapy.” 

above, and chapters Risk of HIV Progression/

Indications for ART and CD4 Monitoring 

and Viral Load Testing)

• Comorbidities

• Potential benefits and risks of ARV drugs

• Resistance, if any, to ARV medications 

(obtain resistance testing prior to ARV 

initiation for ARV-naive patients)

Of course, the patient’s willingness to begin 

ART is critical, as mentioned above. Patients 

have the right to decline or postpone ART. This 

decision should not affect any other aspect 

of care, and ART should be offered again at 

each visit to patients for whom treatment is 

indicated. If mental health issues, addiction, 

or the patient’s social situation are barriers to 

adherence, initiate appropriate referrals and 

reassess adherence barriers at regular intervals.

Preparing the Patient for ART

Before starting ART, it is important to have 

a detailed discussion with patients about 

their readiness to commit to a medication 

regimen, the expected benefits and possible 

adverse effects, and required monitoring and 

follow-up visits. Patients must understand 

that the first treatment regimen offers 

the best opportunity for effective viral 

suppression and immune reconstitution, 

which are primary goals of ART.

Supporting Adherence

Numerous strategies have been tested for their 

effectiveness in supporting patients’ adherence 

to the ART regimen. Successful approaches 

include extensive patient education, telephone 

contact with office staff members who can 

answer questions about adverse effects or 

other difficulties, family meetings, and peer 

support. Trust and accessibility appear to be 

important predictors of adherence, and some 

practitioners see the patient for two or three 

appointments before starting ART.

Compact regimens consisting of fewer pills 

and once-daily dosing often encourage 

adherence. Advise patients about potential 

adverse effects and at the same time let them 

know that many adverse effects may be treated 

or that substitutions often can be made for 

problematic ARVs. The choice to accept or 

decline ART ultimately lies with the patient 

(see chapter Adherence).

Anticipating Difficulties

Choosing an initial regimen that fits the 

patient’s lifestyle and that is likely to be 

tolerable and easy to take will improve the 

likelihood of long-term success with that 

regimen. If patients develop toxicities to one 
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or more components of an initial regimen, 

substitutions typically can be made without 

limiting the success of the regimen. Close 

monitoring and “check-in” appointments 

allow these adjustments to be made under 

clinical supervision. Close monitoring also 

can help to identify medication toxicities that 

may limit treatment and to detect early signs 

of inadequate medication adherence; early 

intervention to treat adverse effects and to 

support adherence may increase the likelihood 

of treatment success.

Considerations in Regimen Selection

Regimens should be selected with 

consideration of both patient factors and 

medication factors. The patient’s schedule, 

adherence history, and self-defined goals 

of ART should be considered in selecting 

a regimen to which the patient will adhere 

closely. The patient’s comorbid conditions and 

potentially interacting medications should be 

evaluated for possible contraindications or 

synergism with ARVs. The ARV history and all 

resistance profiles should be reviewed carefully 

so that a regimen that will be likely to achieve 

durable viral suppression can be chosen. Other 

factors should be evaluated with regard to 

specific ARV medications. For example, the 

HLA-B*5701 status and viral tropism should 

be determined if abacavir or maraviroc, 

respectively, are being considered: the HIV 

RNA level and creatinine clearance (CrCl) 

should be reviewed if rilpivirine or elvitegravir/

cobicistat is being considered, and creatinine 

and Cr/Cl should be evaluated if tenofovir is 

being considered. The patient’s HBV status 

will influence selection of NRTIs (tenofovir + 

emtricitabine or lamivudine should be included 

in the ART regimen, for co-treatment of HIV 

and HBV, unless contraindicated). In women 

who are pregnant or likely to become pregnant, 

FDA pregnancy categories and teratogenicity 

potential for specific ARVs should be taken into 

account. Drug interactions among ARVs or 

between ARVs and other medications should 

be evaluated, as dosage adjustments may be 

required or certain combinations may be 

contraindicated (see relevant tables in the HHS 

Guidelines).

The advantages and disadvantages of 

various drug classes and individual drugs 

recommended for use in initial therapy are 

reviewed in Table 6 of the HHS Guidelines.

Use of Multiple Classes of Drugs

For initial therapy in patients with wild-type HIV 

virus, the HHS Guidelines recommend the use 

of two nucleoside reverse transcriptase inhibitors 

(NRTIs) in combination with a nonnucleoside 

reverse transcriptase inhibitor (NNRTI), a 

ritonavir-boosted protease inhibitor (PI), or an 

integrase inhibitor (INSTI). Alternative types of 

combinations generally do not reduce virus levels 

as effectively as these recommended types. The 

question of whether to use an NNRTI, a PI, or 

an INSTI in initial therapy is a matter of debate. 

Some clinicians advocate using an NNRTI or 

INSTI initially to preserve use of the PI class for 

later and to avoid PI-related toxicities. Others are 

more concerned about the potential toxicities of 

NNRTIs or the low genetic barrier to resistance 

presented by NNRTIs and some INSTIs, and 

instead recommend starting with a PI-containing 

regimen. Each of the initial regimens proposed 

by the HHS Guidelines is highly effective if taken 

as directed, and each has specific advantages and 

disadvantages (see Table 6 of the HHS Guidelines). 

In the end, the regimen should be selected with 

the individual patient in mind because the only 

effective combination for that patient is the one 

that he or she is willing and able to take on a 

consistent basis. See the information on drug 

resistance and toxicities below as well as the full 

text of the HHS Guidelines for more complete 

discussions.

Salvage therapy for patients with ARV-resistant 

HIV often comprises agents from three or more 

ARV classes; consult with an expert.

Boosted Protease Inhibitors

Ritonavir is used at low doses in combination 

with most other PIs to enhance or “boost” the 

serum level and prolong the half-life of the PI. 

This strategy generally decreases the dosing 
Antiretroviral Therapy | 213

Section 4: HIV Treatment

frequency and the number of pills required, 

and it improves the activity of some PIs. Several 

currently used PIs require boosting with 

ritonavir, and some require ritonavir boosting 

when used with certain other medications, 

in order to overcome drug-drug interactions 

(e.g., atazanavir must be boosted with ritonavir 

if tenofovir also is a component of the ARV 

regimen); see “Drug Interactions,” below, and 

appropriate tables in the HHS Guidelines.

Preferred Starting Regimens

More than 20 ARVs in six drug classes have 

been approved for use in the United States by 

the U.S. Food and Drug Administration (FDA) 

(see relevant tables in the HHS Guidelines). 

In recent years, an increasing number of 

fixed-dose combinations (FDCs) have become 

available to simplify dosing and reduce pill 

burden.

These include four NRTI combinations:

• Abacavir + lamivudine (Epzicom)

• Abacavir + lamivudine + zidovudine 

(Trizivir)

• Tenofovir + emtricitabine (Truvada)

• Zidovudine + lamivudine (Combivir)

One PI coformulation:

• Lopinavir + ritonavir (Kaletra)

And three one-pill-per-day formulations of 

two NRTIs + one NNRTI or one INSTI:

• Efavirenz + tenofovir + emtricitabine 

(Atripla)

• Rilpivirine + tenofovir + emtricitabine 

(Complera)

• Elvitegravir + cobicistat + tenofovir + 

emtricitabine (Stribild)

Other FDCs are in development and may 

become available in coming years.

The HHS Guidelines suggest “preferred” and 

“alternative” components for initial therapy 

(Table 1). Clinicians should note that these 

recommendations change over time as new 

data regarding efficacy or toxicity become 

available and should refer to the most upto-date HHS guidelines. Among regimens 

with adequate potency (taking into account 

possible ARV resistance), regimen selection 

should be guided by factors such as anticipated 

tolerability, pill burden, drug interactions, and 

the patient’s comorbid conditions.

Table 1. Recommended Regimens for 

Initial Antiretroviral Treatment

Preferred Regimens

NNRTI 

based

Efavirenz1/tenofovir/emtricitabine2

PI based Atazanavir/r + tenofovir/emtricitabine 

(TDF/FTC)2

Darunavir/r (QD) + TDF/FTC2

INSTI 

based 

Raltegravir + TDF/FTC2

Elvitegravir/cobicistat/TDF/FTC2,3

Dolutegravir (QD) + abacavir/

lamivudine (ABC/3TC)2,4

Dolutegravir (QD) + TDF/FTC2

Alternative Regimens

NRTI 

based

Efavirenz1 + ABC/3TC2,4

Rilpivirine5/TDF/FTC2

Rilpivirine5 + ABC/3TC2,4

PI based Atazanavir/r + ABC/3TC2,4

Darunavir/r + ABC/3TC2,4

Fosamprenavir/r (QD or BID) + 

ABC/3TC2,4 or TDF/FTC2

Lopinavir/r (QD or BID) + ABC/3TC2,4 or 

TDF/FTC2

INSTI 

based

Raltegravir + ABC/3TC4

1 Efavirenz is teratogenic in nonhuman primates. Strongly 

consider alternative agent for women who plan to 

become pregnant or are not using effective and consistent 

contraception. 2 3TC can be used in place of FTC and vice versa. 3 Should be considered only for patients with estimated CrCl 

≥70 mL/min. 4 Abacavir should not be used by patients who test positive 

for HLA-B*5701; use with caution if HIV RNA level is >100,000 

copies/mL or if there is a high risk of cardiovascular disease. 5 Rilpivirine is not recommended if the pretreatment HIV RNA is 

>100,000 copies/mL; caution if the CD4 count is <200 cells/μL.

Abbreviations: /r = low-dose ritonavir; INSTI = integrase inhibitor; 

NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = 

nucleoside/nucleotide analogue; PI = protease inhibitor

Adapted from Panel on Antiretroviral Guidelines for Adults and 

Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department of Health and Human 

Services. Available at www.aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013. 
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Note: Many other ART combinations are 

possible, and in some cases a different option 

may be most appropriate for the individual 

patient. The HHS Guidelines also list regimens 

that are “Acceptable,” those that “May be 

acceptable,” but are “less satisfactory” or 

lack definitive data, and several that “May be 

acceptable but should be used with caution”; 

see Table 5b in the HHS Guidelines. 

Once-Daily Regimens

The use of convenient and simplified 

dosing is an obvious strategy for improving 

adherence, particularly with the availability 

of coformulations that reduce pill burden (see 

“Preferred Starting Regimens,” above). The 

HHS Guidelines emphasize the importance of 

simple regimens and currently include six oncedaily combinations among “preferred” regimens 

for initial therapy, and list a number of other 

possibilities among “alternative” regimens.

Avoiding Drug Resistance

ARV medications never should be given 

as single agents, in two-drug regimens, in 

suboptimal regimens, or in lower dosages 

than recommended, because of the potential 

for development of resistance. Highlevel resistance to NNRTIs, as well as to 

emtricitabine and lamivudine, may develop 

quickly (i.e., within days to weeks) in these 

situations, and the same may be true for the 

INSTIs raltegravir and elvitegravir. It may take 

longer for high-level resistance to develop to 

other NRTIs and to ritonavir-boosted PIs, and 

perhaps also the INSTI dolutegravir. Patients 

must be instructed to take the full dosage of all 

medications on schedule and to avoid skipping 

doses or taking “days off” from their regimens. 

Careful medication dosing is important 

because resistance to one drug within a 

particular class may transfer to other drugs 

in the same class (cross-resistance). Crossresistance can limit the options for future 

therapy significantly or necessitate the use of 

very complicated regimens in the future. Once 

resistant viral strains have developed, they may 

be transmitted to other people.

Acquired or “primary” resistance, in which 

a patient is infected with ARV-resistant 

virus, is common in parts of the United 

States. Because both multi- and single-class 

resistance has been found among ARV-naive 

persons in many U.S. cities, it is recommended 

that individuals with newly diagnosed HIV 

infection and all others entering care should 

receive a baseline resistance test. This test 

should be obtained as early as possible, in 

order to maximize the likelihood of detecting 

transmitted mutations, and before initiation of 

ART (see chapter Resistance Testing).

Drug Interactions

Many of the ARVs interact with one another as 

well as with other common medications. When 

starting or changing an ARV regimen, review 

all the patient’s current medications carefully 

for possible drug interactions. See chapter 

Drug-Drug Interactions with HIV-Related 

Medications for a summary of this issue and for 

references and resources to review medication 

lists and combinations. For further information 

on drug interactions involving ARVs, see 

relevant tables in the HHS Guidelines.

Drugs and Drug Combinations That 

Should Not Be Used

Most clinicians in the United States avoid 

using the NRTIs zidovudine (except for 

pregnant women), stavudine, or didanosine 

if other options are available, because of the 

high rates of metabolic and other adverse 

effects associated with these agents. Stavudine, 

in particular, is likely to cause peripheral 

neuropathy and lipoatrophy. Drugs with 

additive or overlapping toxicities, such as 

stavudine and didanosine, should not be 

combined. Zidovudine and stavudine, which 

compete intracellularly and therefore cause 

antagonism, should not be used together.

Drugs with similar mechanisms of action and 

resistance mutations (e.g., lamivudine and 

emtricitabine, or efavirenz and nevirapine) 

offer no significant advantage when combined 

and may increase toxicities. Certain drug 
Antiretroviral Therapy | 215

Section 4: HIV Treatment

combinations have suboptimal efficacy and 

are not recommended (e.g., tenofovir + 

didanosine as an NRTI backbone; three-NRTI 

regimens). Some ARVs require specific dosing 

intervals in particular patients. For example, 

once-daily dosing of lopinavir/ritonavir is 

not recommended for patients receiving 

concomitant efavirenz or nevirapine, and some 

once-daily PIs or combinations should not be 

used for treatment-experienced patients. For 

further information, see relevant tables in the 

HHS Guidelines.

Follow-Up of Patients Starting ART

Patients who start a new ARV regimen ideally 

should be seen at least twice within the first 

month to allow for an assessment of their 

adherence to therapy and the tolerability and 

adverse effects of the regimen.

When patients have been on a new regimen 

for 2-8 weeks, clinicians should check the 

following: 

• HIV viral load, to monitor initial virologic 

response to therapy, then every 4-8 weeks 

until the viral load is below the level of 

detection

• CBC with platelets, for patients starting a 

zidovudine-containing regimen, to monitor 

for anemia

• LFTs, to monitor for hepatotoxicity (patients 

starting a nevirapine-containing regimen 

should be monitored closely for the first 18 

weeks of treatment)

• Serum electrolytes, blood urea nitrogen, and 

creatinine (particularly for patients taking 

tenofovir)

• Fasting glucose and lipids (after 1-3 months) 

CD4 cell count should be checked after about 

3 months.

For further information, and for 

recommendations about monitoring stable 

patients, see chapter Initial and Interim 

Laboratory and Other Tests.

Regimen Failure

An ART regimen may fail for several reasons, 

including the following:

Incomplete virologic response

• Viral load is >200 copies/mL on consecutive 

tests after 24 weeks on therapy. (For some 

patients with multidrug resistance, it may 

not be possible to decrease plasma HIV viral 

load to undetectable levels, and stabilization 

of viral load below the previous baseline may 

be an appropriate goal of therapy.)

Virologic rebound

• Virus is repeatedly detected in plasma (>200 

copies/mL) after suppression to undetectable 

levels. Confirmatory testing is required to 

rule out “blips” of virus (isolated elevations 

in viral load of less than several hundred 

copies/mL) that are not clinically significant 

and to ensure that the increase is not caused 

by infection, vaccination, or problems with 

test methodology. Note that some patients 

may have persistently detectable low-level 

viremia (<200 copies/mL); the clinical 

significance of this is not clear.

Immunologic failure

• Despite virologic suppression on ART, 

the CD4 cell count shows an inadequate 

response or a persistent decline.

Clinical progression

• Recurrent, persistent, or new HIV-related 

illness occurs after ≥3 months on ART. 

Note that new or recurrent symptoms 

of opportunistic illness occurring in 

the first weeks to months after starting 

ART, especially in patients with severe 

immunosuppression, may not reflect a 

failure of ART. Rather, these symptoms 

could be attributable to persistence of 

opportunistic infections that may require 

longer treatment, or they could be caused 

by an immune reconstitution inflammatory 

syndrome (see chapter Immune 

Reconstitution Inflammatory Syndrome).
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Responding to Apparent 

Treatment Failure

• Carefully assess patient adherence, 

because inadequate adherence to ART is 

a common reason for regimen failure. In 

some cases, adherence support, treatment 

of adverse drug effects, substitution for 

poorly tolerated ARVs, or other measures to 

enhance adherence may result in virologic 

suppression (see chapter Adherence). In 

other cases, ARV resistance may have 

developed. Poor adherence may affect the 

decision to change therapy, and adherence 

issues should be addressed before a 

new regimen is initiated. If resistance is 

suspected, obtain an appropriate resistance 

test (or CCR5 tropism assay, if the patient is 

taking a CCR5 antagonist) while the patient 

is on the failing regimen; see below.

• The availability of effective alternative 

ARVs is a critical consideration in deciding 

whether or when to change therapies. The 

development of new ARVs and new ARV 

classes in recent years has made virologic 

suppression possible for most patients, even 

those with extensive resistance. For the few 

patients in whom treatment possibilities are 

limited or nonexistent, it may be necessary 

to weigh the value of partial virologic 

suppression with the current regimen 

against the likelihood of further resistance 

developing. Strongly consider consultation 

with an experienced HIV provider and 

the use of HIV resistance testing when 

considering changes in therapy. When no 

treatment options remain among currently 

approved drugs, refer the patient to an 

appropriate clinical trial, if possible.

Note that the optimal management of 

immunologic failure is uncertain and is an 

active area of research. Consult with an HIV 

expert and consider referral to a research study.

Resistance and Coreceptor 

Tropism Testing

If resistance is suspected, obtain an 

appropriate resistance test (see chapter 

Resistance Testing). Resistance testing is 

recommended, before changing regimens, in 

cases of virologic rebound during ARV therapy 

or suboptimal suppression of viral load on 

ARV therapy. Resistance testing often is crucial 

in identifying ARVs that are not likely to be 

effective against the patient’s virus. It should 

be done while the patient is taking the failing 

regimen (or within 4 weeks of discontinuation) 

to maximize the likelihood that resistant 

viral populations will be present in detectable 

numbers. In virologic failure of a first regimen, 

it is fairly common to see resistance to only one 

or two drugs in a multidrug combination. The 

test results should be interpreted in the context 

of the patient’s ARV history and the results of 

previous resistance tests.

Standard genotypes test give information 

about resistance that may affect NRTI, NNRTI, 

and PI agents. If INSTI (or fusion inhibitor) 

resistance is suspected, a specific genotype test 

must be ordered. For patients with virologic 

failure while taking a CCR5 antagonist, a 

coreceptor tropism assay should be obtained 

(though the result does not rule out the 

possibility of resistance to CCR5 antagonists).

Cross-resistance exists among ARVs, such 

that resistance to one drug in a class of agents 

often extends to other drugs in that class. For 

example, cross-resistance between efavirenz 

and nevirapine is almost complete, and 

resistance mutations to NRTIs, INSTIs, and 

PIs often decrease viral susceptibility to other 

drugs in those classes. As a result, selecting a 

new ARV regimen can be complicated because 

it requires knowledge of expected resistance 

patterns. The likelihood of sustained viral 

suppression is lower when resistant virus is 

present, unless three ARVs that are fully active 

against the patient’s virus can be included in 

the subsequent regimen.
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Section 4: HIV Treatment

If treatment with a CCR5 antagonist is 

being considered, a tropism test must be 

obtained to verify that the patient has only 

CCR5-tropic virus (the currently available 

agent in this class is not effective in patients 

with any degree of CXCR4 virus). The 

standard test requires an HIV viral load 

of >1,000 copies/mL at the time of testing; 

a newer proviral DNA assay can identify 

coreceptor tropism in blood samples with 

HIV RNA levels below the limit of detection 

(this has not been clinically validated).

Suggestions for Changing 

an ARV Regimen for 

Suspected Drug Failure

The following recommendations are adapted 

from the HHS Guidelines.

Distinguish between the need to change 

a regimen because of drug intolerance or 

inability to adhere to the regimen and the 

failure to achieve the goal of sustained viral 

suppression. In the event of intolerability, 

single agents usually can be changed without 

resistance testing.

In general, do not change a single drug or add 

a single active drug to a failing regimen; it is 

important to use at least two or, preferably, 

three fully active ARVs (e.g., ARVs selected on 

the basis of resistance testing or because they 

are from a drug class to which the patient’s 

virus has not been exposed). If resistance 

testing (performed while the patient is taking 

the failing regimen) shows resistance to only 

one agent in a regimen, it may be possible to 

replace only that drug; however, consultation 

with an expert is recommended.

In general, the goal of ART is to suppress 

HIV RNA to undetectable levels, in order 

to improve or maintain immune function. 

This usually is possible even for patients with 

resistance to multiple drugs as new ARV 

agents and new classes of ARVs have become 

available. Nevertheless, some patients have 

limited options for new regimens that will 

achieve durable virologic suppression. In 

some of these cases, it may be reasonable to 

continue the same regimen if partial virologic 

suppression and clinical and immunologic 

stability are maintained. The risk of continuing 

patients on a partially suppressive regimen, 

however, is the emergence of additional 

resistance mutations.

Data on the value of restarting a drug that the 

patient has previously received are limited. 

Resistant virus can be archived and will 

reemerge for patients who are rechallenged 

with regimens on which they had previously 

developed resistance. As a result, resistance 

tests from previous regimens should be used 

with current resistance tests to determine what 

drugs might be active in a new regimen.

Making the decision to change therapy and 

choosing a new ARV regimen require that the 

clinician have considerable expertise in the 

care of people with HIV infection. Those less 

experienced in the care of persons with HIV 

are strongly encouraged to obtain assistance by 

consulting with or referring to an expert.

Follow-Up of Patients 

Not Started on ART

Patients who are not on ART

These patients should continue their regular 

visits for monitoring, prophylaxis, and 

other medical treatment (see section Testing 

and Assessment for chapters on physical 

examinations and laboratory tests). ART 

should be discussed again and offered at 

regular intervals to anyone who initially 

refuses treatment. Routine clinic visits present 

ongoing chances to discuss the benefits of 

ART and the risks of delayed treatment, and 

to educate patients about new medications and 

research findings. Decreases in patients’ CD4 

count or declines in their condition should 

be taken as opportunities to reassess their 

decisions about ARVs. If lack of readiness or 
218 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

probable adherence difficulties are at issue, an 

adherence counselor (if available) or a mental 

health provider should be engaged to bolster 

the patients’ support and coping mechanisms 

(see chapter CD4 Monitoring and Viral Load 

Testing and the HHS Guidelines). 

Special Situations for ART

ART during acute or recent HIV 

infection

There are no definitive data that demonstrate 

long-term benefit if ART is started during early 

HIV infection, though emerging clinical data 

as well as theoretical considerations suggest 

early treatment may reduce the severity of 

immune system disruption and lessen both 

the short-term and the long-term impact of 

HIV infection. In addition early treatment may 

decrease the risk of HIV transmission during 

the highly infectious period of acute HIV. 

The HHS Guidelines recommend treatment 

of acute HIV (if identified during pregnancy, 

ART should be started as quickly as possible to 

reduce the risk of perinatal HIV transmission). 

Before starting an ARV regimen, patients 

must be counseled carefully about potential 

limitations, such as toxicity, pill burden, 

cost, and the possible development of drug 

resistance. Patients should be monitored 

with HIV viral load, CD4 counts, and other 

parameters, as with patients with established 

infection who are receiving ART. See chapter 

Early HIV Infection.

Pregnant women

Combination ARV regimens are recommended 

for all women during pregnancy, regardless 

of CD4 count or HIV RNA level. The goal of 

ART for pregnant women is to reduce the risk 

of transmission to the infant and to treat HIV 

infection in the mother, through maximal 

virologic suppression. Obviously, the decision 

of whether to start ART during pregnancy 

is the choice of the woman, and her choice 

must be respected. There are a number of 

specific considerations about ART for pregnant 

women, including the timing of ART initiation 

(for those not already on treatment), specific 

ARVs that are recommended or that should be 

avoided (because of toxicity or teratogenicity 

concerns), pharmacokinetic variations and 

dosing requirements in pregnancy, and 

indications for resistance testing. See chapters 

Reducing Perinatal HIV Transmission and 

Care of HIV-Infected Pregnant Women; 

also refer to the HHS Recommendations 

for Use of Antiretroviral Drugs in Pregnant 

HIV-1-Infected Women for Maternal Health 

and Interventions to Reduce Perinatal HIV 

Transmission in the United States. 

Older persons

Older persons with HIV infection may 

experience earlier development of a number of 

conditions that are associated with aging, such 

as cardiovascular disease and neurocognitive 

impairment. Additionally, older persons may 

have dampened immunologic responses to 

ART. For these reasons as well as others, ART 

initiation in older persons probably should 

not be delayed. Current HHS Guidelines

recommend ART for all patients older than 50 

years of age.

Acute opportunistic infections

The presence of opportunistic infections is a 

strong signal of the need for ART and effective 

immune reconstitution. For some of these 

infections, ART is the primary therapy, and 

for others it is adjunctive. Although ART 

sometimes causes immune reconstitution 

inflammatory syndromes if initiated in the 

setting of acute opportunistic infection, 

clinical data for many such infections 

(including Pneumocystis jiroveci pneumonia 

and tuberculosis in persons with very low 

CD4 counts) suggest improved outcomes, 

including better survival, if ART is started 

early. Exceptions to this recommendation 

include cryptococcal meningitis, for which 

most experts recommend a short period of 

antifungal treatment before ART is started. 
Antiretroviral Therapy | 219

Section 4: HIV Treatment

For further information, see chapter Immune

Reconstitution Inflammatory Syndrome and the 

Guidelines for the Prevention and Treatment of 

Opportunistic Infections in HIV-Infected Adults 

and Adolescents: Recommendations from CDC, 

the National Institutes of Health, and the HIV 

Medicine Association of the Infectious Diseases 

Society of America (see “References,” below).

Hepatitis B coinfection

If treatment for either HIV or HBV is to be 

started, both infections generally should 

be treated simultaneously, by including in 

the ART regimen two NRTIs with activity 

against both viruses (tenofovir + emtricitabine 

or tenofovir + lamivudine), if possible. The 

use of a single NRTI with activity against 

both viruses (resulting in monotherapy for 

HBV) is not recommended. If tenofovir 

is contraindicated, another anti-HBV 

drug should be used in combination with 

lamivudine or emtricitabine. Flares of HBV 

may occur if tenofovir, emtricitabine, or 

lamivudine is discontinued; monitor closely 

or consider substitution of another anti-HBV 

drug. See chapter Hepatitis B Infection and the 

HHS Guidelines for additional information.

HIV-associated nephropathy

ART is a primary treatment for HIVAN and 

should be started urgently for patients with 

suspected HIVAN. See chapter Renal Disease. 

Expert Consultation

The National HIV/AIDS Clinicians’ 

Consultation Center is a valuable resource 

for any clinician seeking expert advice about 

ART, HIV clinical manifestations, laboratory 

evaluations, and other issues. Its National HIV 

Telephone Consultation Service (Warmline) 

is staffed by HIV-experienced physicians and 

pharmacists. The Warmline operates Monday 

through Friday, 9 a.m. to 8 p.m. eastern time 

and is available free of charge in the United 

States at 800-933-3413. 

Patient Education

• Making the decision to start ART is rarely 

an emergency situation. Before starting 

patients on ART, health care providers must 

work with them to determine what goals of 

therapy are likely to be achieved, and which 

personal issues are pertinent for selecting 

the best regimen to fit their lifestyles,

• Providers should review the proposed 

drug regimen with their patients. Be sure 

patients understand the instructions about 

dosage, scheduling, food requirements or 

restrictions, drug storage, adverse effects, 

toxicities, and type of reactions that must be 

reported immediately, as well as remedies 

for common adverse effects.

• Providers should explain to patients that 

successful ART requires a commitment 

to taking the medications every day, as 

prescribed. If ARVs are taken incorrectly, 

HIV can quickly become resistant to the 

medications. This will mean even fewer 

choices and less-effective treatment in the 

future. It also may mean that patients could 

transmit resistant virus to a partner or, if 

they are pregnant, to an infant.

• Patients should know that HIV medications 

may reduce the risk of HIV transmission 

substantially but do not offer perfect 

protection against infecting others. 

Recommend prevention measures such as 

using latex barriers during sex (safer sex) 

and not sharing needles or other drug-using 

equipment, even with other HIV-infected 

persons (see chapter Preventing HIV 

Transmission/Prevention with Positives for 

more information).

• HCV, HBV, and other sexually transmitted 

diseases such as syphilis and gonorrhea can 

be transmitted between two HIV-infected 

partners.

• Patients should be advised to check with 

their provider before discontinuing ARVs. 
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Section 4: HIV Treatment

If ARVs must be discontinued, it is usually 

best to stop all ARVs at once. The exception 

to this recommendation may be NNRTIcontaining regimens. In this case, blood 

levels of the NNRTIs may be detectable 

for several weeks after discontinuation; 

if NRTIs are stopped, that may result 

in NNRTI monotherapy and the risk of 

NNRTI resistance. The optimal strategy 

for discontinuing NRTIs is not clear; some 

experts recommend continuing the NRTIs 

for a period of time after discontinuation of 

the NNRTI or switching from an NNRTI to 

a PI for some time before stopping all agents. 

• Patients should be encouraged to advise 

their provider of all other medications 

that they take, including over-the-counter 

medications, herbal remedies, and 

nutritional supplements.

• Discuss contingencies in the event the 

client is unable to take ARVs for a day or 

more (e.g., illness, severe adverse effects, 

hospitalization, or other unexpected 

circumstances).

References

• McNicholl I. Database of Antiretroviral 

Drug Interactions. HIV InSite. Coffey S, 

Volberding PA, eds. San Francisco: UCSF 

Center for HIV Information. Available at 

hivinsite.ucsf.edu/insite?page=ar-00-02. 

Accessed December 1, 2013.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. Recommendations for Use of 

Antiretroviral Drugs in Pregnant HIV-1-

Infected Women for Maternal Health and 

Interventions to Reduce Perinatal HIV 

Transmission in the United States. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.
Reducing Perinatal HIV Transmission | 221

Section 4: HIV Treatment

Reducing Perinatal HIV Transmission

Carolyn K. Burr, EdD, RN

Background 

This chapter describes strategies for reducing the risk of perinatal HIV, based on the U.S. 

Department of Health and Human Services (HHS) Recommendations for Use of Antiretroviral Drugs 

in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV 

Transmission in the United States. It is not intended to be a comprehensive discussion of these topics, 

and all HIV-infected pregnant women should be treated by an HIV-experienced obstetrician and 

an HIV specialist. For centers that do not have HIV specialists available, experts at the National 

Perinatal HIV Consultation and Referral Service are available for consultation through the Perinatal 

HIV Hotline (888-448-8765). For more information on other aspects of caring for HIV-infected 

pregnant women, see chapter Care of HIV-Infected Pregnant Women.

Unless otherwise referenced, the information in this chapter is based on the most recent HHS 

perinatal guidelines available at the time this chapter was published. Consult the AIDSinfo website 

(aidsinfo.nih.gov/guidelines) for the most current recommendations.

Overview of Prevention of 

Perinatal HIV Transmission

In the absence of antiretroviral (ARV) 

prophylaxis or other interventions, the rate 

of perinatal HIV transmission in the United 

States ranges from 16% to 25%. Antiretroviral 

therapy (ART) is highly effective in reducing 

the risk of perinatal transmission of HIV, 

to as low as <1%. It probably prevents HIV 

transmission in several ways, including by 

reducing the mother’s viral load in blood and 

genital secretions and by providing pre- and 

postexposure prophylaxis for the infant. All 

pregnant women with HIV infection should 

be educated about the risks of perinatal HIV 

transmission and offered ART and other 

medical management to maintain or improve 

their own health and to reduce the risk of HIV 

transmission to their infants.

In 1994, the Pediatric AIDS Clinical Trial 

Group study 076 (PACTG 076) found that ARV 

treatment during pregnancy could significantly 

reduce the risk of HIV transmission to infants. 

The intervention, consisting of zidovudine 

(ZDV) given PO to the women during the 

last weeks of pregnancy and IV during labor 

and delivery, as well as to the newborns for 

6 weeks, reduced the rate of infant infection 

from 25.5% to 8.3%. The ZDV regimen quickly 

became the standard of care in the United 

States and other high-income countries. 

Subsequent studies showed that combination 

ARV regimens with suppression of maternal 

HIV viral load to undetectable levels further 

reduced the risk of perinatal infection.

Studies in resource-limited countries as well 

as in resource-abundant areas have examined 

various ARV strategies for reducing the risk 

of perinatal HIV transmission. The Petra 

study, a placebo-controlled trial in a breastfeeding population in Uganda, South Africa, 

and Tanzania, found a transmission rate of 

8.9% among women who received PO ZDV 

plus lamivudine (3TC) intrapartum and for 

1 week postpartum and whose infants also 

received 1 week of ZDV/3TC, compared with 

a rate of 15.3% in the placebo group. The HIV 

NET 012 trial in a breast-feeding population in 

Uganda compared the efficacy of a single dose 

of nevirapine (NVP) given to the mother at the 

onset of labor plus a single dose given to the 

newborn 48 hours postpartum with that of PO 
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ZDV given to the mother during labor and to 

the newborn. The transmission rate was 11.8% 

in the NVP arm, compared with 20.0% in the 

ZDV arm. The results of this study and the low 

cost of NVP prompted a number of resourcelimited countries to institute NVP prophylaxis 

as the standard of care for preventing motherto-child transmission of HIV. Numerous other 

trials have demonstrated the efficacy of various 

ARV strategies, combining different ARVs 

with different treatment durations and given 

to mothers, newborns, or both, in both breastfeeding and non-breast-feeding populations. 

Research has shown that ARV interventions 

even late in the peripartum or newborn 

periods may decrease the infant’s risk of HIV 

infection. A retrospective study of subjects 

in New York found that the rate of perinatal 

HIV transmission was 9.3-10% if ZDV was 

given either to both the mothers intrapartum 

and their newborns or to the newborns only, 

compared with 26.6% if no ARV medication 

was given. This study underscores the 

importance of offering ARV interventions to 

pregnant women with HIV infection whenever 

they are identified during pregnancy or during 

labor and delivery, or as an intervention with 

the newborn.

In the United States, the PACTG 076 regimen 

remains an important component in the 

prevention of perinatal HIV transmission, 

and usually is incorporated into combination 

ART for pregnant women. For international 

settings, other guidelines have been developed 

by global agencies such as the World Health 

Organization (see “References,” below) and by 

individual governments.

Mother-to-child transmission also can occur 

through breast-feeding. Recent studies have 

shown that ART given to the nursing mother 

and/or her infant decreases but does not 

eliminate the risk of HIV transmission to the 

infant. In the United States, because substitute 

feeding is safe, affordable, feasible, sustainable, 

and available, mothers in the United States 

should not breast-feed.

HIV Testing During Pregnancy

The success of interventions to reduce the 

risk of perinatal HIV transmission has been 

achieved through the routine HIV testing 

and counseling of all pregnant women. 

Interventions to prevent transmission can 

be effective only if women know their HIV 

status and have access to treatment. HHS 

has recommended universal HIV counseling 

and testing for pregnant women since 1995. 

Many national professional and governmental 

organizations, including the American 

Academy of Pediatrics, the American College 

of Obstetricians and Gynecologists, and 

the U.S. Preventive Services Task Force, 

endorse those recommendations. Current 

recommendations from the U.S. Centers for 

Disease Control and Prevention (CDC) feature 

the following three approaches to HIV testing 

during pregnancy: 

• Routine testing as part of first-trimester 

prenatal screening tests for all pregnant 

women, using an “opt-out” policy whereby 

a pregnant woman is tested unless she 

specifically declines testing

• Routine “opt-out” testing with a rapid HIV 

test for women who present in labor with 

unknown or undocumented HIV status, in 

order to offer ARV prophylaxis during labor 

for those who test positive for HIV

• Expedited HIV testing for newborns of 

mothers of unknown HIV status so that they 

can receive postexposure ARV prophylaxis, 

if indicated

The CDC also recommends repeat HIV 

testing in the third trimester for women who 

receive health care in jurisdictions with an 

elevated incidence of HIV or AIDS among 

women, as well as for women at high risk of 

acquiring HIV (e.g., a history of injection 

drug use, exchange of sex for money or drugs, 

multiple sex partners, or a partner known 

to be HIV infected). Jurisdictions in which 

repeat third-trimester testing is recommended 

include Alabama, Connecticut, Delaware, 
Reducing Perinatal HIV Transmission | 223

Section 4: HIV Treatment

District of Columbia, Florida, Georgia, 

Illinois, Louisiana, Maryland, Massachusetts, 

Mississippi, Nevada, New Jersey, New York, 

North Carolina, Pennsylvania, Puerto Rico, 

Rhode Island, South Carolina, Tennessee, 

Texas, and Virginia. A number of states 

mandate a third-trimester HIV test for all 

pregnant women.

Any pregnant woman with signs or symptoms 

of acute HIV infection should be evaluated (see 

chapter Early HIV Infection) and receive an HIV 

plasma RNA test as well as an antibody test.

State laws regarding HIV testing during 

pregnancy vary widely, and many are currently 

under review. A number of states have 

adopted the opt-out approach, whereas some 

still require written informed consent before 

an HIV test is done. Others require patient 

education and a chart note from the providers. 

Clinicians should be familiar with relevant 

state laws regarding HIV testing during 

pregnancy, opt-out or consent provisions, and 

regulations about rapid HIV testing during the 

intrapartum or newborn period. (Information 

on state laws regarding HIV testing during 

pregnancy can be found at the National HIV/

AIDS Clinicians’ Consultation Center’s 

Compendium of State HIV Testing Laws at 

www.nccc.ucsf.edu.) Whatever the consent 

process, a woman should know that an HIV 

test is being done and should receive at least 

the information outlined below.

HIV Education and Counseling of 

Pregnant Women

Educating pregnant women about the 

importance of HIV testing is a critical element 

in preventing perinatal HIV transmission. 

However, extensive pretest counseling is not 

essential. A woman must be told that HIV 

testing is a standard component of prenatal 

care, that her clinician recommends the 

tests, and that all pregnant women should 

be tested for HIV because knowing about 

HIV infection is important for their health 

and the health of their babies. Research has 

shown that a provider’s strong endorsement of 

HIV testing is a major predictor of whether a 

woman receives an HIV test. Testing should 

be voluntary and free of coercion, and a 

woman should know that she can decline 

testing without the risk of being denied care. A 

woman’s age, cultural background, educational 

level, and primary language may influence 

her knowledge about HIV transmission and 

her willingness to be tested; the clinician 

should consider these factors carefully when 

providing education and information.

The following minimum information should 

be provided through an educational session 

with a health care provider or through written 

or electronic media (e.g., brochures, videos): 

• HIV is the virus that causes AIDS.

• Without treatment, approximately 25% of 

babies born to HIV-infected women will be 

infected, either during pregnancy, during 

labor and delivery, or by breast-feeding.

• A woman could be at risk of HIV infection 

and not know it.

• ART is highly effective in protecting the 

infant from being infected with HIV and 

can improve the mother’s health.

• HIV testing is recommended for all 

pregnant women.

• Women who decline testing will not be 

denied care.

Women should be told that test results are 

confidential to the extent allowed by law and 

that medical and other services are available 

for women with HIV infection. Reporting 

requirements for the specific state should be 

explained.

HIV testing should be performed as early 

in pregnancy as possible to allow for 

interventions to prevent transmission and 

for effective management of a woman’s HIV 

infection, if the woman is found to be HIV 

seropositive. The CDC recommends repeat 

HIV testing in the third trimester for women 

who have risk factors for HIV or who live in 
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areas with a high incidence of HIV in women; 

some states mandate third-trimester testing for 

all pregnant women. 

If the client declines testing at any point, the 

clinician should inquire about her reasons and 

follow up at subsequent visits. If the provider is 

persistent, the woman may choose to have an 

HIV test at a later visit.

In the United States, the vast majority of 

pregnant women who are tested for HIV will 

be HIV seronegative. When giving test results 

to an HIV-negative woman, the clinician 

should take the opportunity to discuss riskreduction strategies to help ensure that she 

remains uninfected by HIV. Women at risk 

of HIV infection should be referred for more 

extensive counseling because some research 

indicates that pregnancy may place them at 

greater risk of acquiring HIV infection, and 

acute HIV infection may confer greater risk of 

transmission to the fetus.

Counseling a pregnant woman with a positive 

HIV test result requires knowledge and 

sensitivity. The clinician should explain that, 

even though the woman may feel well, she is 

infected with the virus. The woman should 

be told about the importance of medical 

management of HIV for her own health and 

for the prevention of perinatal transmission, 

and she should be guided to the medical 

and social services available in her local 

community. She also should be referred to an 

HIV obstetric specialist who can work closely 

with her primary obstetric and HIV providers 

to manage her care during the pregnancy. 

The patient may be surprised or shocked 

upon receiving the HIV diagnosis, or she may 

have known her status but been reluctant to 

disclose it. The clinician should emphasize the 

importance of emotional and social support, 

assess the patient’s social support resources, 

and offer her referrals as needed.

Expedited HIV Testing During 

Labor

As discussed earlier, beginning ART during 

pregnancy offers the greatest chance for 

preventing perinatal transmission of HIV, 

but interventions during the intrapartum 

and neonatal periods also offer opportunities 

to decrease the risk of HIV transmission. 

Expedited HIV testing for women who present 

in labor with unknown or undocumented HIV 

status can identify women who are infected 

with HIV so that interventions can be offered. 

Available rapid HIV antibody tests are both 

sensitive and specific and provide results in 

as little as 20 minutes. Fourth-generation 

antigen-antibody HIV tests also are becoming 

increasingly available through hospital 

laboratories using random access machines 

that deliver results in 30 minutes to 2 1/2 hours. 

Women who should receive HIV testing 

during labor include the following: 

• Those who have had little or no prenatal care

• Those who were not offered testing earlier in 

pregnancy

• Those who declined previously

• Those whose HIV test results are not 

available at the time of labor

Education and counseling for the woman 

in labor who needs an HIV test should 

incorporate the information for prenatal 

education discussed earlier, with consideration 

given to the special circumstances of labor. 

Special educational formats such as flip charts 

have been developed to help with patient 

education. Confidentiality should be assured 

for the information and consent process and 

for treatment. If an opt-out approach is used 

in the labor setting, a woman of unknown 

serostatus should be told that no HIV test is 

found on her chart, that HIV testing is part 

of routine care, and that she can decline if 

she wishes, but that experts recommend HIV 

testing because available interventions can 
Reducing Perinatal HIV Transmission | 225

Section 4: HIV Treatment

decrease her baby’s risk of becoming infected 

with HIV if she is found to be seropositive.

Women who present in labor with unknown 

HIV serostatus should undergo expedited HIV 

antibody testing. If the results are positive, a 

confirmatory HIV test should be sent as soon 

as possible but maternal prophylaxis should 

be started immediately (intravenous ZDV). 

This should be followed by combination ARV 

prophylaxis (ZDV + NVP) for the infant 

beginning as soon as possible after birth. ARV 

drugs should be initiated pending results of the 

confirmatory test. If the confirmatory HIV test 

result is positive, infant ARV drugs should be 

continued for 6 weeks. If the confirmatory test 

result is negative, the infant ARV drugs should 

be stopped.

Factors Influencing Perinatal HIV 

Transmission

Perinatal transmission is most likely to occur 

in the intrapartum period. Several factors 

influence the risk of transmission from mother 

to infant. One of these is the mother’s HIV 

RNA level (viral load). Clinical trials and 

observational studies have shown a strong 

positive correlation between maternal HIV 

viral load during pregnancy or during delivery 

and the risk of perinatal HIV transmission, 

even among women receiving treatment with 

ARVs. However, HIV transmission may occur 

at any level of maternal HIV RNA, including 

(rarely) when the viral load is undetectable. 

HIV RNA levels in the blood and the genital 

tract generally correlate but discordance may 

occur. Low-level cervical-vaginal HIV shedding 

has been found even in women on ART with 

undetectable plasma HIV RNA, particularly in 

the presence of genital infections.

ARV prophylaxis is a critical factor in reducing 

HIV transmission. For women on effective 

combination ART with undetectable HIV 

RNA, the rate of perinatal HIV transmission 

is approximately 1%. Thus, ARV prophylaxis 

with full suppression of HIV RNA is 

recommended for all pregnant women with 

HIV infection, regardless of HIV viral load. 

Note that ART may exert protective effects not 

only by lowering maternal HIV RNA but also 

(for ARVs with good transplacental passage) by 

providing pre- and postexposure prophylaxis 

for the infant.

Other maternal factors associated with 

increased risk of perinatal transmission include 

low CD4 cell count, sexually transmitted 

diseases, active genital herpes during labor, 

illicit drug use, cigarette smoking, and 

unprotected sex with multiple partners.

Obstetric factors also affect the risk of HIV 

transmission. Infection risk increases linearly 

with the increased duration of ruptured 

membranes, although the effect of ruptured 

membranes in women with low viral loads is 

not known. Invasive procedures performed 

at any time during pregnancy, such as 

amniocentesis, placement of scalp electrodes, 

artificial rupture of membranes, episiotomy, 

or operative (forceps) delivery may increase 

risk by exposing the fetus to maternal blood; 

these procedures should be avoided (though 

the risk of transmission in women on fully 

suppressive ART is not clear). In addition, the 

mode of delivery, whether vaginal or cesarean, 

can influence the risk of HIV transmission. 

Scheduled cesarean delivery decreases the rate 

of perinatal infection for women with an HIV 

RNA level of >1,000 copies/mL, but its efficacy 

is not clear for women whose labor has begun 

or for those whose membranes have ruptured; 

see “Intrapartum Management and Mode of 

Delivery,” below, for further information.

Infant risk factors for HIV infection include 

premature birth, low birth weight, skin and 

mucous membrane lesions such as thrush, and 

breast-feeding. Breast-feeding increases the risk 

of HIV transmission by 5-20%. In the United 

States, where safe, affordable replacement 

feeding and clean water routinely are available, 

women with HIV should not breast-feed. 
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However, some women with HIV will be under 

tremendous cultural and familial pressure 

to breast-feed and will need the clinician’s 

ongoing support to use substitute formula.

Because many factors that affect the risk of 

perinatal HIV transmission may be modified, 

clinicians should educate pregnant women 

carefully about the importance of ARV 

prophylaxis and other strategies to reduce the 

risk of maternal-fetal transmission of HIV.

Antiretroviral Therapy During 

Pregnancy

The goals of ART for the pregnant woman are 

the same as those for any person living with 

HIV: 

• To suppress the level of HIV as low as 

possible for as long as possible

• To preserve and restore immune function

• To prolong life and improve quality of life

• To reduce risk of HIV transmission to sex 

partners

An additional, and crucial, goal of ART for 

pregnant women is to reduce the risk of 

perinatal HIV transmission through maximal 

HIV suppression. 

The HHS recommendations discuss in detail 

the multiple issues that must be considered 

when balancing the woman’s need for 

therapy for her own health and the need to 

decrease the risk of transmission to the infant. 

Combination ART is recommended for all 

HIV-infected pregnant women regardless of 

CD4 count or HIV viral load. Decisions about 

ART are complex and should be made by the 

woman and her health care provider after 

discussing the risks and benefits. Clinicians 

are urged to consult an HIV specialist and the 

most current HHS recommendations when 

making therapeutic decisions. The Perinatal 

HIV Hotline (888-448-8765) provides free 

clinical consultation on all aspects of perinatal 

HIV care. The following discussion addresses 

some of the issues in determining ART 

strategies and is taken from the HHS Perinatal 

ARV Guidelines.

The HHS Perinatal HIV Guidelines Working 

Group recommends fully suppressive 

combination ART for all pregnant women, 

unless there are compelling reasons based 

on pregnancy-specific maternal and fetal 

safety issues to modify this approach. Key 

recommendations from the HHS Perinatal 

ARV Guidelines include the following: 

• Assess the woman’s HIV disease status and 

make recommendations about initiating 

or altering an ARV regimen, as part of the 

initial evaluation.

• Recommend ARV prophylaxis to all 

pregnant women regardless of HIV viral 

load or CD4 count.

• Discuss known benefits and potential risks 

of ART.

• If HIV RNA level is >500-1,000 copies/mL, 

perform drug-resistance testing prior to 

starting or changing ART. 

• If HIV is diagnosed late in pregnancy, ART 

should be initiated promptly without waiting 

for results of resistance testing.

• Emphasize the importance of adherence to 

the regimen.

• Ensure that the woman has access to and 

coordination of services among perinatal, 

primary care, and HIV providers as well as 

mental health and drug abuse services and 

income support as needed.

• Considerations about continuing ART after 

pregnancy are the same as for nonpregnant 

individuals. 

A fundamental principle of the Guidelines is 

that therapies of known benefit should not be 

withheld during pregnancy unless they may 

cause adverse effects to the woman, fetus, or 

infant, and these adverse effects outweigh the 

potential benefits. Thus, women should be 

advised of the potential risks and benefits of 

ART (to the woman, fetus, and infant) and of 

the limited long-term data on outcomes for 
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Section 4: HIV Treatment

infants with in utero exposure to ARVs, but 

treatment decisions should be guided by the 

woman’s clinical, virologic, and immunologic 

status and by the goal of preventing perinatal 

transmission. An additional benefit of ART 

is the reduction in risk of transmission to 

sex partners. Women should be educated 

and counseled on the importance of close 

adherence to the ART regimen (see chapter 

Adherence). 

Drug-resistance testing should be conducted 

for all pregnant women before the initiation 

of therapy, and for women who are already on 

ART without fully suppressed HIV RNA.

All women receiving ARVs during pregnancy 

for prophylaxis or for treatment should 

receive a combination containing at least 

three agents, with the aim of viral suppression 

to undetectable levels (i.e., <20-75 copies/

mL, depending on the assay). Monotherapy 

(e.g., with ZDV) and dual therapy are not as 

effective and generally are not recommended. 

Current Guidelines recommend that the 

regimen include two nucleoside reverse 

transcriptase inhibitors (NRTIs) and either a 

nonnucleoside reverse transcriptase inhibitor 

(NNRTI) or a protease inhibitor (PI). Regimen 

selection should be individualized on the 

basis of factors such as anticipated safety and 

efficacy, ARV history, results of resistance 

testing, and comorbidities (e.g., hepatitis 

B virus [HBV]) (see chapter Antiretroviral 

Therapy for considerations in selecting ARVs). 

It should be recognized that only limited 

information is available for many ARVs 

and ARV combinations regarding potential 

toxicities for the fetus or infant (see Table 5 of 

the Guidelines), and for dosage requirements 

with pregnant women.

The HHS Perinatal ARV Guidelines offer 

recommendations on the use of specific 

ARV agents during pregnancy. The table 

below shows “Preferred” and “Alternative” 

ARVs; others are classified as “Use in 

special circumstances” or “Insufficient data 

to recommend use.” For more complete 

information, see Table 5 of the Guidelines).

Recommendations for ARV 

Use During Pregnancy

ARV 

Class

Preferred 

Agents

Alternative

Agents

NRTI • Lamivudine 

• Zidovudine

• Abacavir #

• Emtricitabine

• Tenofovir

NNRTI • Nevirapine*

PI • Atazanavir/

ritonavir

• Lopinavir/

ritonavir 

(Kaletra)

• Darunavir/

ritonavir

• Saquinavir/

ritonavir

* For women with CD4 counts of >250 cells/μL, NVP should be 

initiated only if benefit clearly outweighs risk, owing to the 

increased risk of potentially life-threatening hepatotoxicity 

in women with high CD4 counts. Women who are already 

taking NVP at the start of pregnancy and are tolerating it well 

may continue NVP, regardless of CD4 count. # Risk of hypersensitivity reaction; should be given only 

to patients who test negative for HLA-B*5701. Test for 

HLA-B*5701 before starting abacavir.

Adapted from U.S. Department of Health and Human Services. 

Recommendations for Use of Antiretroviral Drugs in Pregnant 

HIV-1-Infected Women for Maternal Health and Interventions to 

Reduce Perinatal HIV Transmission in the United States. Available at 

aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.

The guidelines’ preferred NRTI component 

is ZDV/3TC, because of data showing safety 

and efficacy in pregnancy. Alternative NRTIs 

listed above may be used for women with 

intolerance to ZDV (e.g., severe anemia) or 

documented resistance to ZDV (see “Safety 

and Toxicity of Antiretroviral Medications 

During Pregnancy,” below). Tenofovir + 3TC 

or FTC is the preferred NRTI pair for women 

with hepatitis B coinfection (see “Special 

Circumstances,” below).

Of the NNRTIs, NVP may be started for 

women with CD4 counts of ≤250 cells/μL 

or continued for women who are already on 

NVP-containing regimens. NVP generally 

should not be started for treatment-naive 

women with CD4 counts of >250 cells/μL 

because of an increased risk of symptomatic 

and potentially fatal hepatic and rash toxicity. 

Efavirenz is not recommended for use during 

the first 5-6 weeks of pregnancy because of 

concern for potential teratogenicity, but it 

can be continued in pregnant women already 
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Section 4: HIV Treatment

taking an effective efavirenz-based regimen 

who present for antenatal care in the first 

trimester, and it can be considered for other 

women (after the first 6 weeks of pregnancy) 

if other agents are not appropriate (see “Safety 

and Toxicity of Antiretroviral Medications 

During Pregnancy,” below). There are 

insufficient pharmacokinetic and safety data to 

recommend the use of etravirine or rilpivirine 

during pregnancy.

Atazanavir + ritonavir and lopinavir/ritonavir 

are recommended PIs based on efficacy 

studies in adults and experience in pregnant 

women. For both of these (and for darunavir), 

serum levels may be low in the second and 

third trimesters; see the Guidelines for 

recommendations about dosage adjustments. 

The alternative PIs are ritonavir-boosted 

darunavir and ritonavir-boosted saquinavir, 

although pharmacokinetic data during 

pregnancy are limited. Nelfinavir has been 

used widely for pregnant women but current 

guidelines recommend its use only in “special 

circumstances” because, in nonpregnant 

adults, it has shown inferior efficacy compared 

with first-line agents. Indinavir also may be 

considered when preferred and alternative 

agents are not available. Fosamprenavir and 

tipranavir are not recommended because of 

lack of data in pregnancy, but they may be 

considered if other agents are not tolerated or 

are not appropriate.

The integrase inhibitor raltegravir may be 

considered if preferred or alternative agents 

are not appropriate. Pharmacokinetic and 

safety data in pregnancy are not sufficient 

to recommend the use of maraviroc or 

enfuvirtide, and they do not consider the 

newer agents rilpivirine, etravirine/cobicistat, 

or dolutegravir; these may be considered for 

use by women for whom drugs in other classes 

have failed but they should be prescribed in 

consultation with HIV and obstetric specialists.

ART Recommendations 

by Clinical Scenario

Recommendations for ARV Use by 

Pregnant Women

The HHS Perinatal ARV Guidelines offer 

recommendations on ART for pregnant 

women based on four clinical scenarios; these 

are categorized by the woman’s ART status 

when she presents for care (see Table 6 of 

the Guidelines). Note that current adult and 

adolescent guidelines recommend ART for 

all, regardless of CD4 cell count (see chapter 

Antiretroviral Therapy).

HIV-infected pregnant women currently 

receiving ART

Women already receiving ART should, 

in general, continue to receive it during 

pregnancy if it is suppressing viral replication. 

If the woman has detectable virus (e.g., >500-

1,000 copies/mL) on therapy, HIV drugresistance testing should be performed, and the 

regimen should be optimized to maximize the 

likelihood of achieving virologic suppression. 

Women presenting in the first trimester should 

be counseled about the risks and benefits of 

ART during this period. Discontinuation of 

therapy could lead to increased viral load and 

potential for transmission to the fetus. 

Pregnant women receiving NVP-containing 

regimens should continue them, regardless of 

CD4 count, if they are virologically suppressed 

and tolerating the regimen. For women who 

become pregnant while taking efavirenz, 

current Guidelines state that, because the risk 

of neural tube defects is limited to the first 5 to 

6 weeks of pregnancy and pregnancy is rarely 

recognized before 4 to 6 weeks of pregnancy, 

efavirenz can be continued (assuming the 

regimen is maximally suppressive).

HIV-infected pregnant women who are 

ARV naive 

All pregnant women should start potent 

combination ART. The drug regimen should 

be based on the recommendations of the 

Perinatal ARV Guidelines (see above and Table 

5 of the Guidelines). As in other scenarios, 
Reducing Perinatal HIV Transmission | 229

Section 4: HIV Treatment

drug-resistance testing should guide ARV 

selection. 

Starting ART early in pregnancy may be 

more effective in reducing perinatal HIV 

transmission but the potential benefits of early 

ART must be weighed against potential fetal 

effects of first-trimester exposure. Starting 

ART after the first trimester can be considered 

in women with high CD4 T-lymphocyte (CD4-

cell) counts and low HIV RNA levels.

Inclusion of NRTIs with good placental 

passage (zidovudine, lamivudine, 

emtricitabine, tenofovir, or abacavir) is 

recommended.

ART should be continued intrapartum. ZDV 

should be administered to HIV-infected 

women by continuous IV infusion if they 

have HIV RNA levels of >400 copies/mL (or 

unknown HIV RNA levels) near delivery, 

regardless of ART regimen or mode of delivery. 

After delivery, consider the indications for 

continuing ART and the woman’s willingness 

and ability to do so (note that ART currently is 

recommended for all adults and adolescents); 

see “Postpartum Follow-Up of HIV-Infected 

Women,” below, and chapter Antiretroviral 

Therapy.

HIV-infected pregnant women who 

previously have received ART or 

prophylaxis but are not currently 

receiving any ARV medications

In some instances, a pregnant woman has 

been on ART for her own treatment or for 

prophylaxis during a previous pregnancy and 

subsequently discontinued the medications. 

ARV drug-resistance testing should be 

conducted prior to initiating ART. The 

regimen should be chosen on the basis of 

previous ART experience and the reasons 

for stopping and results of past and current 

resistance testing, with avoidance of drugs and 

combinations with adverse maternal effects. 

The selection of an ART regimen for women 

with advanced HIV disease or a history of 

extensive prior therapy can be challenging, 

and consultation with an HIV specialist is 

recommended. Principles of ARV selection are 

as described above.

For women who present late in pregnancy, 

ART should be started promptly, without 

waiting for results of resistance testing. The use 

of raltegravir during late pregnancy for women 

who have high viral loads has been suggested 

because of its ability to suppress viral load 

rapidly (an approximately 2-log10 copies/mL 

decrease by week 2 of therapy). However, the 

efficacy and safety of this approach have not 

been evaluated and only anecdotal reports are 

available. Until more data become available on 

the safety of raltegravir use during pregnancy, 

this approach cannot be recommended for 

treatment-naive women.

Intrapartum ZDV infusion should be given as 

described above if the HIV viral load is >400 

copies/mL near the time of delivery.

HIV-infected women who have received 

no ARV before labor and their Infants 

HIV-infected pregnant women who have 

not received ARV prior to labor should be 

given ZDV as a continuous infusion during 

labor. The mother’s need for continuing 

ARV treatment postpartum should be 

evaluated. Infants born to women who had 

no ART during pregnancy should begin ARV 

prophylaxis as close to birth as possible. In 

addition to receiving ZDV for 6 weeks, the 

infant should also be given three doses of NVP 

in the first week of life (at birth, 48 hours later, 

and 96 hours after the second dose).

Pharmacokinetic Considerations 

During Pregnancy

Physiologic changes that occur during 

pregnancy (e.g., prolonged gastrointestinal 

transit time; increase in body fat and water; 

and changes in cardiac, circulatory, hepatic, 

and renal function) may affect the kinetics of 

drug absorption, distribution, and elimination. 

Few pharmacokinetic studies have been 

conducted on levels of ARVs during pregnancy, 

but available data suggest that altered dosing 

for some PIs (e.g., atazanavir/ritonavir, 
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Section 4: HIV Treatment

darunavir/ritonavir, lopinavir/ritonavir) may 

be required (see Table 5 of the Guidelines).

Special Circumstances

Hepatitis B Coinfection

Screening for HBV infection with hepatitis 

B surface antigen (HBsAg), hepatitis B core 

antibody (anti-HBc), and hepatitis B surface 

antibody (anti-HBs) is recommended for 

all pregnant women who have not been 

screened during the current pregnancy. The 

HBV vaccine series should be administered 

to pregnant women who screen negative for 

hepatitis B.

For pregnant women coinfected with HIV and 

HBV, providers should treat both infections at 

once, by including a two-NRTI combination 

that is active against both infections. The 

NRTI combination tenofovir + 3TC or FTC is 

preferred for pregnant women with HIV/HBV, 

in combination with an NNRTI or PI. Liver 

transaminases should be monitored for signs 

of hepatotoxicity or HBV flare. Treatment 

may be complicated, and consultation with 

an expert is recommended. Also see the 

relevant discussion in the HHS Perinatal ARV 

Guidelines, and chapter Hepatitis B Infection in 

this manual.

HBV-infected pregnant women who are not 

immune to hepatitis A should be vaccinated. 

Infants born to coinfected women should 

receive HBV immune globulin and start the 

HBV vaccine series within 12 hours after birth 

(with subsequent vaccine doses per usual 

protocol).

Hepatitis C Coinfection

Treatment for hepatitis C virus (HCV) 

is not recommended during pregnancy. 

Recommendations for ART during pregnancy 

are the same for women who are HIV/

HCV coinfected as for those without HCV 

coinfection. Liver transaminases should be 

monitored for signs of hepatotoxicity.

Coinfected pregnant women should be tested 

for immunity to hepatitis A and HBV; if not 

immune, they should be vaccinated. Infants 

born to coinfected women should be evaluated 

for HCV infection.

See the relevant discussion in the HHS Perinatal 

ARV Guidelines, and chapter Hepatitis C 

Infection in this manual.

Safety and Toxicity of Antiretroviral 

Medications During Pregnancy

Limited data are available on the safety of 

ARVs during pregnancy, particularly when 

ARVs are used in combination. The existing 

safety and toxicity information is derived from 

animal and human studies, clinical trials, 

registry data, and anecdotal experience.

Several drugs are of special concern when used 

during pregnancy (see HHS Perinatal ARV 

Guidelines; Table 5), including the following: 

• Efavirenz: Efavirenz is classified by the 

U.S. Food and Drug Administration 

(FDA) as a Pregnancy Class D drug 

because malformations have occurred in 

monkeys receiving efavirenz during the 

first trimester. Several cases of neural tube 

defects in humans after first-trimester 

exposure to efavirenz have been reported. 

As mentioned above, the Guidelines state 

that alternative ARVs should be strongly 

considered in women who are planning to 

become pregnant or are not using effective 

contraception with male partners. For 

pregnant women who present for antenatal 

care in the first trimester, discontinuation of 

efavirenz is not necessary, because the risk of 

neural tube defects is limited to the first 5-6 

weeks of pregnancy and pregnancy is rarely 

recognized before 4-6 weeks.

• Nevirapine: Women, including pregnant 

women, who begin NVP therapy when their 

CD4 count is >250 cells/μL have nearly a 

10 times higher incidence of hepatotoxicity 

than women initiated on NVP at lower CD4 

counts. Symptoms of hepatotoxicity include 

fatigue, malaise, anorexia, nausea, jaundice, 

liver tenderness, and hepatomegaly. NVP 

should be initiated as part of an ARV 
Reducing Perinatal HIV Transmission | 231

Section 4: HIV Treatment

regimen for pregnant women with CD4 

counts of >250 cells/μL only if the benefits 

clearly outweigh the risks (see Table 5 of the 

Guidelines). Women with higher CD4 cell 

counts who are already taking and tolerating 

NVP may continue it.

• Didanosine + stavudine: The combination 

of didanosine and stavudine may cause 

fatal lactic acidosis and hepatic steatosis 

and should be avoided unless no alternative 

is available. Patients may present with 

symptoms 1-6 weeks in duration that 

include nausea, vomiting, abdominal pain, 

dyspnea, and weakness; clinicians should be 

alert for early signs and symptoms of lactic 

acidosis and evaluate them promptly.

In addition, PIs have been associated with 

an increased risk of new-onset diabetes, 

worsening diabetes, and diabetic ketoacidosis. 

Of course, pregnancy itself is a risk factor for 

hyperglycemia. Clinicians should monitor the 

glucose levels of pregnant women taking PIs 

and should educate them about the symptoms 

of hyperglycemia. The HHS Perinatal ARV 

Guidelines recommend that pregnant women 

on ART should be screened with a standard 50 g 

glucose loading test at 24-28 weeks (see chapter 

Care of HIV-Infected Pregnant Women).

Information on ARV toxicity during 

pregnancy should be consulted carefully 

before treatment choices are made. The HHS 

Guidelines provide information on each 

ARV drug, including preclinical and clinical 

data, pharmacokinetic and toxicity data, 

and recommendations regarding use during 

pregnancy. These guidelines are updated 

routinely as information is received (see 

Table 5 and Appendix A of the Guidelines). 

Numerous other medications also are 

contraindicated for use during pregnancy, 

and potential toxicity should be considered 

carefully before any medication is given to a 

pregnant woman.

Adverse Events Related to ARV 

Drugs During Pregnancy

A number of studies have identified an 

increased risk (up to double) of preterm 

delivery in women who take combination 

therapy during pregnancy (whether started 

before or during pregnancy), while other 

studies have not. Given the conflicting data, 

the Guidelines advise clinicians to be aware of 

a possible small increased risk of preterm birth 

among women who receive ART. However, the 

benefit of ART for the mother’s health and for 

prevention of perinatal transmission is clear, 

and combination ART should not be withheld. 

Until more is known, pregnant women who 

are taking combination regimens should 

be monitored closely for complications and 

toxicities and should be educated about the 

signs of premature labor.

Antiretroviral Pregnancy Registry

The Antiretroviral Pregnancy Registry 

collects observational data on HIV-infected 

pregnant women taking ARV medications 

to determine whether patterns of fetal or 

neonatal abnormalities occur. This is a project 

initiated by the pharmaceutical industry 

and overseen by an advisory committee 

comprising representatives from the CDC, 

National Institutes of Health, FDA, pediatric 

and obstetric providers, and others. Providers 

who care for pregnant women taking ARVs are 

encouraged to enroll patients in the registry at 

the time of initial evaluation. Information is 

confidential and patients’ names are not used. 

More information can be obtained by visiting 

the registry website (www.apregistry.com/) or 

by calling 800-258-4263, 8:30 a.m. to 5:30 p.m. 

eastern time.

Intrapartum Management and 

Mode of Delivery

In 2012, a significant change was made in 

the Guidelines recommendation regarding 

intrapartum management of the woman with 

HIV infection. For women on ART with HIV 
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Section 4: HIV Treatment

RNA levels of <400 copies/mL near delivery, 

IV ZDV during labor can be considered but 

is not required (though they should continue 

their usual ARV medications). IV ZDV is 

recommended for HIV-infected women with 

HIV RNA levels of ≥400 copies/mL (or with 

unknown viral loads) near delivery, regardless 

of antepartum regimen or mode of delivery. 

IV ZDV should be given to the woman during 

labor as a 1-hour loading dose of 2 mg/kg 

followed by a continuous infusion of 1 mg/kg 

per hour until delivery. Women on ART should 

continue their regimen on schedule as much 

as possible during labor, except that women 

receiving ZDV or a ZDV-containing fixeddose combination whose viral load is ≥400 

copies/mL should be given IV ZDV, with other 

components continued orally. For women on a 

stavudine-containing regimen, the stavudine 

component should be discontinued while IV 

ZDV is being administered.

For women on ART who have detectable viral 

load at the time of delivery, the addition of 

the single-dose NVP protocol (single dose to 

the woman during labor, single dose to the 

neonate) is not recommended in the United 

States, because clinical trials have not shown 

benefit and there is a risk of NVP resistance. 

For the neonate, an expanded infant 

prophylaxis regimen may be indicated (see 

“Follow-Up of HIV-Exposed Infants,” below).

Studies conducted before the availability of 

viral load testing found that cesarean delivery 

performed before the onset of labor or rupture 

of membranes significantly reduced the risk of 

perinatal transmission. However, in the United 

States and other settings where HIV-infected 

pregnant women typically receive potent 

combination ART, rates of HIV transmission 

rates are very low (<1%, unadjusted for mode 

of delivery) and it is difficult to determine 

whether delivery by cesarean section further 

decreases the risk of peripartum transmission.

For a woman with a viral load of <1,000 

copies/mL, cesarean delivery is not routinely 

recommended; decisions on mode of delivery 

should be individualized and based on 

discussions between the woman and her 

obstetric clinician. The woman and her health 

care providers should decide about mode of 

delivery before the onset of labor, based on her 

current viral load, her health status, and the 

outcome of discussions about other concerns, 

which should include counseling about the 

risks and benefits of cesarean delivery. If 

cesarean delivery is planned for standard 

obstetrical indications it should be scheduled 

for 39 weeks’ gestation.

For a woman with HIV RNA levels of 

>1,000 copies/mL at or near the time 

of delivery, the HHS Perinatal ARV 

Guidelines and the American College 

of Obstetricians and Gynecologists 

recommend delivery by scheduled 

cesarean section at 38 weeks’ gestation.

IV ZDV should be started 3 hours before a 

scheduled cesarean delivery. Prophylactic 

antibiotics are recommended at the time of 

cesarean delivery for HIV-infected women to 

decrease the risk of maternal infection.

It is not clear whether cesarean delivery 

provides any benefits in preventing perinatal 

HIV transmission once labor has begun or 

membranes are ruptured. Management of a 

woman for whom a scheduled cesarean was 

planned but who presents in labor or with 

ruptured membranes should be individualized 

on the basis of her HIV viral load, current 

ART regimen, length of time since membrane 

rupture, duration of labor, and other clinical 

factors.

The HHS Perinatal ARV Guidelines outline 

several scenarios in which the clinician must 

decide whether cesarean delivery is needed; 

see Table 8 of the Guidelines for further 

information. The data on the benefits of 

cesarean delivery are complex and must be 

considered alongside the increased risk to the 

mother after surgery. The clinician should 

consult an obstetric/HIV specialist to discuss 

specific situations. 
Reducing Perinatal HIV Transmission | 233

Section 4: HIV Treatment

A woman who presents in labor without 

a documented HIV status should receive 

an expedited HIV antibody test and, if the 

result is positive, should be presumed to be 

infected until the confirmatory HIV test 

result is received. She should receive IV ZDV 

immediately to prevent perinatal transmission, 

and her infant should start infant prophylaxis 

pending the mother’s confirmatory results (see 

“Follow-Up of HIV-Exposed Infants,” below). 

She will need confirmation and staging of her 

HIV infection (e.g., CD4 cell count, HIV RNA 

viral load) as well as referral to care for her own 

health and ongoing psychological support.

Questions remain about the management 

of labor when a vaginal delivery is planned. 

Because the duration of ruptured membranes 

is a risk factor for perinatal transmission, 

pregnant women with HIV infection should 

be counseled to go to a hospital for care at the 

first signs of labor or rupture of membranes. If 

the membranes rupture spontaneously before 

labor occurs or early in labor, the clinician 

should consider interventions to decrease the 

interval to delivery, such as administration 

of oxytocin. Procedures that potentially 

increase the neonate’s exposure to maternal 

blood, such as the use of scalp electrodes or 

artificial rupture of membranes, should be 

avoided. Operative interventions with forceps 

or vacuum extractor and episiotomy should be 

performed only in select circumstances.

For management of postpartum hemorrhage 

owing to uterine atony, note that Methergine 

has significant interactions with PIs and 

with NNRTIs, and may interact with 

the pharmacokinetic booster cobicistat. 

Methergine should not be administered to 

women taking PIs, if possible. If alternative 

treatments are not available and Methergine 

must be used, it should be given at the lowest 

possible dosage and for the shortest possible 

duration. If Methergine is given to women 

taking NNRTIs, its dosage may need to be 

increased or additional uterotonic medications 

may be needed.

Postpartum Follow-Up of 

HIV-Infected Women

Women with HIV infection who have recently 

delivered need access to a comprehensive array 

of services for themselves and their infants. 

The clinician should refer the postpartum 

woman not only to her primary obstetric 

and HIV providers for family planning and 

HIV management but also to a pediatric HIV 

specialist for care of her infant. She should 

be referred as needed for mental health, 

substance abuse, and social support services. 

The clinician should be alert for indications 

of postpartum depression and should offer 

treatment promptly, if indicated. Adherence 

to ARV regimens may be particularly difficult 

for a woman in the immediate postpartum 

period because of postpartum physical and 

psychological changes and the demands of 

caring for a newborn; accordingly, the woman 

may require new or continued support services.

Women who are diagnosed through 

preliminary rapid HIV testing in labor will need 

thorough evaluation and management including 

confirmatory HIV testing and immediate 

linkage for medical and social services. They 

should not breast-feed unless the results of the 

confirmatory tests are received as negative.

Women should be evaluated regarding 

their ongoing need and desire for ART 

postpartum. Long-term ART generally should 

be recommended for all women, regardless of 

nadir CD4 count, in accordance with current 

HHS adult and adolescent guidelines. If ART 

was given only or primarily to reduce the risk 

of perinatal transmission, a discussion about 

continuing ART should include factors such as 

the woman’s health status, her CD4 counts, the 

HIV status of her partner(s), and adherence 

issues. If the woman elects to discontinue 

ART postpartum, her need for treatment 

and willingness to restart ART should be 

reevaluated on an ongoing basis. 

If ART is being discontinued, all drugs should 

be stopped at the same time if they have 
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Section 4: HIV Treatment

similar half-lives. NNRTIs have longer halflives than other agents, so an NNRTI should 

be discontinued for a period of time (the 

duration of this time has not been defined) 

before other ARVs, in order to avoid a period 

of NNRTI monotherapy and the development 

of NNRTI resistance mutations. Alternatively, 

a PI may be substituted for the NNRTI several 

weeks before stopping all the ARV agents. 

Note that, for women with HBV coinfection, 

discontinuation of NRTIs with anti-HBV 

activity (e.g., 3TC, emtricitabine, tenofovir) 

may result in a flare of HBV; consult with an 

expert before discontinuing ART.

Contraceptive counseling is an important 

aspect of postpartum care. Women should 

be offered dual-method contraception if 

pregnancy is not desired in the short-term 

future or if the ART regimen contains 

potentially teratogenic drugs such as efavirenz. 

Note that there are significant interactions 

between some hormonal contraceptives and 

PIs, NNRTIs, and elvitegravir/cobicistat. (See 

chapters Care of HIV-Infected Pregnant Women

and Health Care of HIV-Infected Women 

Through the Life Cycle.)

Breast-feeding is not recommended in the 

United States or other parts of the world where 

replacement feeding is affordable, feasible, 

acceptable, sustainable, and safe. Women may 

experience culture-based and family pressure 

to breast-feed and may need support to use 

replacement feeding.

Follow-Up of HIV-Exposed Infants

The HIV-exposed neonate born to a mother 

with HIV infection should receive ZDV syrup 

at a dose based on the infant’s gestational age. 

Infants at ≥35 weeks’ gestation infant should 

be given ZDV syrup at a 4 mg/kg/dose PO 

BID, beginning as soon as possible after birth, 

preferably within 6-12 hours, and continuing 

for 6 weeks. Dosing for premature infants is 

detailed in the Guidelines. In the United States, 

the use of ARV drugs other than ZDV and NVP 

cannot be recommended for premature infants 

because of lack of dosing and safety data.

Newborns should be discharged home with 

a supply of PO ZDV syrup. The use of ZDV 

for the neonate is recommended regardless of 

whether the mother has a history of resistance 

to ZDV. Two-drug therapy – specifically, 

ZDV by standard protocol for 6 weeks plus 

3 doses of NVP given at birth, 48 hours 

later, and 96 hours after the second dose – is 

recommended for infants of mothers who did 

not receive ART before delivery or received 

ZDV only intrapartum. Few data are available 

to guide use of other combination therapies for 

neonates; consult with a pediatric HIV expert. 

Every HIV-exposed infant should be referred 

to a pediatric HIV specialist for diagnostic 

testing and monitoring of health status.

For an infant born to a mother whose HIV 

status is unknown, expedited HIV testing 

of the mother or the infant should be done 

as soon as possible. If the result for either 

is positive, ZDV prophylaxis for the infant 

should be started immediately. A confirmatory 

HIV test (e.g., Western blot) should be done 

at the same time and prophylaxis should 

be discontinued if the result is negative. If 

positive, the infant should be tested with 

an HIV DNA polymerase chain reaction 

(PCR) assay or an HIV RNA assay. If the 

newborn’s HIV viral load test result is positive, 

prophylaxis should be discontinued and 

the infant should be referred urgently to a 

pediatric HIV specialist for management of 

HIV infection using combination ART.

Traditional HIV antibody testing cannot be 

used with infants because maternal antibodies 

may persist for up to 18 months. Diagnosis 

of HIV infection in infants requires virologic 

testing (HIV DNA or HIV RNA). Virologic 

testing should be performed by age 14-21 days, 

then at 1-2 months, and at 4-6 months. HIV 

can be diagnosed in an infant on the basis 

of two positive results from virologic tests 

done on separate blood samples at any time. 
Reducing Perinatal HIV Transmission | 235

Section 4: HIV Treatment

HIV can be excluded presumptively in an 

infant with two or more negative results from 

virologic tests, with one done at ≥14 days of 

age and one done at ≥1 month of age, or one 

negative virologic test result at ≥2 months of 

age, or one negative HIV antibody test result 

at ≥6 months of age. HIV can be excluded 

definitively with two or more negative 

virologic test results, with one test done at 

age ≥1 month and one done at ≥4 months. 

However, these tests may not be accurate in 

infants who are receiving combination ART. 

Some experts recommend retesting, using 

an antibody test, at age 12-18 months as a 

confirmatory test.

Infants should have a baseline complete 

blood count and differential and should be 

monitored for anemia while they are taking 

ZDV. Monitoring for anemia should be based 

on the infant’s gestational age, ZDV dose, 

clinical condition, and maternal ARV history. 

Infants on ZDV/3TC prophylaxis should have 

a hemoglobin and neutrophil count at 4 weeks 

after initiation of ARVs.

Pneumocystis jiroveci pneumonia (PCP) 

prophylaxis for HIV-exposed infants is 

recommended starting at 6 weeks when 

the ZDV prophylaxis regimen is completed 

and continued until they are determined 

presumptively or definitively to be HIV 

seronegative. Initiation of PCP prophylaxis 

should be stopped or avoided altogether when 

HIV has been presumptively excluded.

Parents and family caregivers must be 

taught how to monitor the infant for signs 

of illness until an HIV diagnosis is made or 

ruled out. They also need to know that the 

infant’s exposure to ARV agents in utero is 

an important part of the infant’s medical 

history and should be shared with future 

health care providers. Although no enduring 

consequences of ARV exposure have been 

confirmed, the child may be at risk of longterm problems.

Patient Education

• The clinician should provide the pregnant 

woman with the most current information 

on the risk of perinatal HIV transmission 

and the importance of ARV prophylaxis.

• The clinician and the patient should have a 

detailed discussion about ART, both for the 

patient’s own health and for decreasing the 

risk of perinatal transmission.

• The clinician should review with the patient 

the critical importance of her adherence to 

ART regimens before prescribing a regimen.

• The clinician should review possible adverse 

effects of the ARVs and give the patient 

specific instructions about managing them 

if they are mild or seeking medical advice 

if they are more serious, such as ongoing 

fatigue, persistent nausea and vomiting, or 

signs of hyperglycemia.

• The clinician should explain the signs and 

symptoms of early labor to the patient 

and emphasize the importance of seeking 

medical care if she has signs and symptoms 

of early labor or premature rupture of 

membranes.

• Early in the third trimester, the clinician 

and the patient should discuss the risks and 

potential benefits of cesarean section based 

on her viral load and clinical status.

• Intrapartum management, including the 

possible need to use intrapartum ZDV, 

should be discussed with the patient so that 

she knows to tell the delivery team about her 

HIV status when she presents in labor.

• The clinician should discuss infant feeding 

plans with the mother and reinforce that she 

should not breast-feed. The clinician may 

need to provide ongoing support for formula 

feeding.

• The clinician should advise HIV-infected 

mothers against premastication of the 

infant’s food and promote safer feeding 

options.
236 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

• The clinician should discuss follow-up plans 

and make referrals for the patient and her 

infant. If possible, the woman should meet 

the pediatric HIV team before delivery or 

in the postpartum period. The importance 

of ARV prophylaxis and follow-up for the 

newborn should be emphasized.

References

• American College of Obstetricians and 

Gynecologists, Committee on Obstetric 

Practice. Prenatal and perinatal human 

immunodeficiency virus testing: expanded 

recommendations. ACOG Committee 

Opinion No. 418. Washington, DC: 

American College of Obstetricians and 

Gynecologists; 2008.

• American College of Obstetricians 

and Gynecologists. Routine human 

immunodeficiency virus screening. ACOG 

Committee Opinion No. 411. Washington, 

DC: American College of Obstetricians and 

Gynecologists; 2008.

• American College of Obstetricians and 

Gynecologists. Scheduled cesarean delivery 

and the prevention of vertical transmission of 

HIV infection. ACOG Committee Opinion 

No. 234. Washington, DC: American College 

of Obstetricians and Gynecologists; 2000.

• Antiretroviral Pregnancy Registry Steering 

Committee. Antiretroviral Pregnancy 

Registry International Interim Report for 

1 January 1989 through 31 January 2013.

Wilmington, NC: Registry Coordinating 

Center; 2009. Available at www.apregistry.

com/forms/interim_report.pdf. Accessed 

December 1, 2013.

• Branson BM, Handsfield HH, Lampe MA, 

et al.; Centers for Disease Control and 

Prevention. Revised recommendations 

for HIV testing of adults, adolescents, and 

pregnant women in health-care settings.

MMWR Recomm Rep. 2006 Sep 22;55(RR14):1-17.

• Bulterys M, Jamieson D, O’Sullivan MJ, 

et al. Rapid HIV-1 testing during labor: 

a multicenter study. JAMA. 2004 Jul 

14;292(2):219-23.

• Centers for Disease Control and Prevention. 

U.S. Public Health Service recommendations 

for human immunodeficiency virus 

counseling and voluntary testing for pregnant 

women. MMWR Recomm Rep. 1995 Jul 

7;44(RR-7):1-15.

• Centers for Disease Control and Prevention. 

Rapid HIV-1 Antibody Testing during 

Labor and Delivery for Women of Unknown 

HIV Status: A Practical Guide and Model 

Protocol. January 30, 2004. Available at 

www.cdc.gov/hiv/topics/testing/resources/

guidelines/rt-labor&delivery.htm. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

Recommendations of the U.S. Public Health 

Service Task Force on the use of zidovudine 

to reduce perinatal transmission of human 

immunodeficiency virus. MMWR Recomm 

Rep. 1994 Aug 5; 43(RR-11):1-20.

• International Perinatal HIV Group. 

Duration of ruptured membranes and 

vertical transmission of HIV-1: a metaanalysis from 15 prospective cohort studies.

AIDS. 2001 Feb 16;15(3):357-68.

• Ioannidis JP, Abrams EJ, Ammann A, 

et al. Perinatal transmission of human 

immunodeficiency virus type 1 by pregnant 

women with RNA virus loads <1000 copies/ml.

J Infect Dis. 2001 Feb 15; 183(4):539-45.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.
Reducing Perinatal HIV Transmission | 237

Section 4: HIV Treatment Section 4: HIV Treatment

• Panel on Antiretroviral Therapy and Medical 

Management of HIV-Infected Children. 

Guidelines for the Use of Antiretroviral 

Agents in Pediatric HIV Infection. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Petra Study Team. Efficacy of three 

short-course regimens of zidovudine and 

lamivudine in preventing early and late 

transmission of HIV-1 from mother to child 

in Tanzania, South Africa, and Uganda 

(Petra study): a randomised, double-blind, 

placebo-controlled trial. Lancet. 2002 Apr 

6;359(9313):1178-86.

• Sperling RS, Shapiro DE, Coombs RW, et 

al.; Pediatric AIDS Clinical Trials Group 

Protocol 076 Study Group. Maternal viral 

load, zidovudine treatment, and the risk of 

transmission of human immunodeficiency 

virus type 1 from mother to infant. N Engl J 

Med. 1996 Nov 28;335(22):1621-9.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.

• U.S. Department of Health and Human 

Services. Recommendations for Use of 

Antiretroviral Drugs in Pregnant HIV-1-

Infected Women for Maternal Health and 

Interventions to Reduce Perinatal HIV 

Transmission in the United States. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• World Health Organization. Rapid advice: 

use of antiretroviral drugs for treating 

pregnant women and preventing HIV 

infection in infants. Geneva: World Health 

Organization; November 30, 2009. Available 

at www.who.int/hiv/pub/mtct/advice/en. 

Accessed December 1, 2013.

Section 4: HIV Treatment

Care of HIV-Infected Pregnant Women | 239

Care of HIV-Infected Pregnant Women

Background 

This chapter describes the elements involved in caring for the pregnant woman with HIV infection, 

whether the woman was known to be HIV infected before conception or was found to be HIV 

infected during pregnancy. It is not intended to be a comprehensive discussion of this topic, and 

an HIV-experienced obstetrician and an HIV specialist should be involved in the management of 

all HIV-infected pregnant women. For centers that do not have HIV specialists available, experts 

at the National Perinatal HIV Consultation and Referral Service are available for consultation 

through the Perinatal HIV Hotline (888-448-8765).

The goals of HIV management during pregnancy are to maintain and support the woman’s 

health, provide optimal antiretroviral treatment (ART) to preserve or restore her immune system 

and suppress viral replication, and to offer interventions that decrease the risk of perinatal 

HIV transmission. According to the U.S. Department of Health and Human Services perinatal 

guidelines, Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for 

Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, all 

HIV-infected pregnant women should be given ART during pregnancy to prevent mother-to-child 

transmission of HIV, and ART also is recommended for all women for their own health, regardless 

of pregnancy status (see chapter Reducing Perinatal HIV Transmission).

The first task in caring for an HIV-infected woman who is pregnant or considering pregnancy is 

to provide counseling that will allow her to make informed reproductive choices. Taking a careful 

reproductive history and providing preconception counseling should be part of any woman’s 

routine primary care. To make informed choices about pregnancy, the patient needs education and 

information about the risk of perinatal transmission of HIV, potential complications of pregnancy, 

continuation or modification (or possibly, initiation) of ART, and the support she will need to 

optimize maternal and fetal outcomes. See chapter Health Care of HIV-Infected Women Through 

the Life Cycle for a more detailed discussion of preconception evaluation.

 An appropriate ART regimen should be started before pregnancy to attain a stable, maximally 

suppressed maternal viral load prior to conception. This will support the woman’s own health 

and greatly reduce the risk of HIV transmission either to a fetus or to a sex partner. Antiretroviral 

(ARV) resistance testing should be performed before ART is initiated. For women who intend 

to conceive, particular ARVs should be avoided, including those with increased risk of causing 

teratogenicity (e.g., efavirenz) or metabolic complications such as lactic acidosis (e.g., didanosine 

and stavudine). See chapter Reducing Perinatal HIV Transmission. It should be noted that most 

fetal organogenesis occurs in the early weeks of pregnancy, before most women know that they 

are pregnant. Thus, any medication with potential teratogenicity or fetal toxicity, whether an ARV 

or another drug, should not be administered to women who intend to become pregnant or may 

become pregnant. Certain medications (e.g., ribavirin) also should be avoided by male partners of 

women who may become pregnant.

Folate supplementation to reduce the risk of neural tube defects in the developing fetus should be 

started at least 1 month before conception, if possible, because the neural tube forms in the early 

weeks of pregnancy (see below).

Section 4: HIV Treatment
240 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Evaluation and Counseling of 

Pregnant Women

All HIV-infected pregnant women should 

receive thorough education and counseling 

about perinatal transmission risks, strategies 

to reduce those risks, and potential effects of 

HIV infection or HIV treatment on the course 

or outcomes of pregnancy. 

• The goals of therapy for pregnant women 

receiving ART, as for all persons being 

treated for HIV infection, are to suppress 

the HIV viral load maximally (preferably to 

undetectable levels) for as long as possible, 

to improve quality of life, to restore or 

preserve immune function, and to prevent 

transmission to sexual (or injection drug 

equipment-sharing) partners. For pregnant 

women, an additional, and critical, goal is to 

reduce the risk of perinatal transmission as 

much as possible.

• Therapy-associated adverse effects, including 

hyperglycemia, anemia, and hepatic toxicity, 

may have a negative effect on maternal 

and fetal health outcomes. Pregnant 

women should be advised about possible 

ARV-related adverse effects and should be 

monitored regularly for these events.

• HIV-infected women should receive 

evaluation and appropriate prophylaxis for 

opportunistic infections (OIs), as well as the 

vaccinations indicated for persons with HIV 

infection (see below).

• Some medications, both ARVs and other 

drugs, may cause fetal anomalies or toxicity 

when taken during pregnancy. These 

should be avoided in pregnant women, 

unless the anticipated benefit outweighs 

the risk. Consult with an HIV or obstetric 

specialist, a pharmacist, or the drug labeling 

information before prescribing medications 

for pregnant women.

• Options for mode of delivery should be 

discussed early. The benefits and risks of 

vaginal vs. cesarean delivery are outlined 

in the perinatal guidelines. If the HIV viral 

load is >1,000 copies/mL at 36 weeks of 

pregnancy, a scheduled cesarean delivery 

at 38 weeks’ gestation is recommended to 

further reduce the risk of transmission.

Other evaluation and support measures for 

pregnant women should include the following: 

• Screening for other potential maternal 

health problems, such as diabetes and 

hypertension

• Maternal nutritional evaluation and 

support, including initiation of a prenatal 

multivitamin containing folate (0.4 mg PO 

QD) to reduce the risk of fetal neural tube 

defects; for women receiving trimethoprimsulfamethoxazole, some experts recommend 

higher folate doses in the first trimester; 

consult with an HIV-experienced obstetric 

specialist.

• Screening for psychiatric and neurologic 

disease

• Counseling about the risks of tobacco 

smoking; smoking cessation support as 

indicated (see chapter Smoking Cessation)

• Counseling about the risks of alcohol or 

drug use and support for discontinuation of 

these activities as needed

• Intimate partner violence screening

• Review of medications, including overthe-counter and nutritional agents, and 

discontinuation of medications with the 

potential for fetal harm

• Immunizations (e.g., influenza, Tdap, 

hepatitis B) as indicated

• Institution of the standard measures for 

evaluation and management (e.g., assessment 

of reproductive and familial genetic history, 

screening for infectious diseases or sexually 

transmitted diseases [STDs])

• Planning for maternal-fetal medicine 

consultation, if desired or indicated

• Selection of effective and appropriate 

postpartum contraceptive methods, if 

desired
Care of HIV-Infected Pregnant Women | 241

Section 4: HIV Treatment

Comprehensive Care of Pregnant 

Women with HIV Infection

Comprehensive care is important for pregnant 

women with HIV infection to achieve a healthy 

pregnancy and delivery. A multidisciplinary 

approach is the most effective way to address 

the medical, psychological, social, and 

practical challenges. For example, while 

her medical care is being managed by her 

obstetrician and an HIV specialist, the 

pregnant woman may need help from a social 

worker to find appropriate social services for 

food, housing, child care, and parenting issues. 

The pregnant woman may need counseling 

and psychological support for herself and her 

partner, as well as referrals for substance abuse 

and detoxification programs. Peer counselors 

may be of particular assistance. Some patients 

may need legal or domestic violence services 

during and after pregnancy. Cooperation and 

communication between the obstetrician or 

nurse/midwife and the primary HIV provider 

are imperative throughout the pregnancy 

and early postpartum period. Referral to a 

maternal-fetal medicine specialist may be 

needed in complicated obstetric cases.

Prenatal Care

All pregnancy-related complications seen in 

HIV-uninfected women, such as hypertensive 

disorders, ectopic pregnancy, psychiatric 

illness, multiple gestation, preterm delivery, 

and STDs, also can occur in HIV-infected 

women. These problems must be recognized 

quickly and treated appropriately to avoid 

life-threatening complications. Ideally, HIVinfected pregnant women are managed by 

both an experienced obstetrician-gynecologist 

and an HIV specialist. Communication 

between these specialists about medications, 

expectations, and complications is vital for 

the health and well-being of both mother and 

baby. If complications occur or abnormalities 

are detected, they should be evaluated and 

treated as indicated by the condition, and 

referral should be made to a maternal-fetal 

medicine specialist, if possible. Antenatal 

fetal surveillance and testing to identify fetal 

abnormalities should be carried out using 

guidelines established by the American 

College of Obstetricians and Gynecologists.

The suggested testing and monitoring practices 

for pregnant women with HIV infection, from 

the first trimester to labor and delivery, are 

presented in Tables 1 and 2.
242 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Table 1. Recommended Evaluation and Routine Monitoring 

of the Pregnant Woman with HIV Infection

Evaluation Frequency

History

HIV History Date of diagnosis Initial

Signs and symptoms Initial and at every visit

Nadir CD4 and current CD4 cell count; HIV 

viral load

Initial

ARV history, including regimen efficacy, 

toxicity, and ARV resistance

Initial

Opportunistic infections and malignancies Initial and at every visit

History of STDs Initial

Adherence Initial and at every visit

Obstetric History Number of pregnancies; complications 

and outcomes (GPAL [gravida, para, 

abortion, living children]); mode of 

deliveries

Initial

History of genetic disorders Initial

Use of ARV prophylaxis during previous 

pregnancies

Initial

HIV status of children Initial

Current Pregnancy Last menstrual period (LMP) Initial

Pregnancy: intended or not Initial

Contraceptive methods used, if any Initial

Gestational age (can be calculated in a 

woman with regular menses by counting 

weeks from LMP)

Initial and at every visit

Estimated date of delivery Initial

Signs or symptoms of maternal 

complications: elevated blood 

pressure, headache, significant edema, 

gastrointestinal or genitourinary 

symptoms, vaginal discharge or bleeding, 

decreased fetal movement (fetal 

movement is usually first detected at 18-

24 weeks of pregnancy)

Initial and at every visit

Screen for depression Initial

Screen for intimate-partner violence Initial and at every visit
Care of HIV-Infected Pregnant Women | 243

Section 4: HIV Treatment

Evaluation Frequency

Physical Examination

General Vital signs and weight Initial and at every visit

Funduscopy, breast examination Initial and as indicated

Gynecologic/

Obstetric (usually 

performed by the 

obstetric provider)

Pelvic examination, STD screening, 

examination for perineal or vaginal lesions 

(discoloration, condyloma, ulcerative 

lesions, vaginal discharge), cervical lesions, 

discharge or bleeding

Initial and as indicated

Fundal height, correlating with gestational 

age (concordant between 18 and 30 

weeks)

Every visit starting the second 

trimester

Fetal heart beat and rate: may be audible 

with Doppler devices as early as 12 weeks

Initial and at every visit

Fetal movements and position in third 

trimester

Every visit starting at 24 weeks

Laboratory and Other Studies

HIV HIV antibody test (if not already 

documented)

Initial

HIV viral load and CD4 count (total and 

percentage); results obtained at 35-36 

weeks guide decisions on the mode of 

delivery

Viral load at initial visit, 2-4 weeks 

after starting or changing ART, every 4 

weeks until undetectable, then at least 

every 3 months

CD4 count at initial visit and at least 

every 3 months

Genotype if ARV naive or detectable HIV 

RNA while on ART

Initial and as indicated

Cytomegalovirus (CMV) immunoglobulin 

G (IgG)

Initial

Toxoplasma IgG Initial

G6PD level in appropriate ethnic or racial 

groups if PCP prophylaxis with dapsone is 

anticipated

Initial

General Complete blood count (CBC) Initial and every 3 months or more 

frequently, based on ARV regimen or 

symptoms; check weeks 24-28

Chemistries, liver enzymes (LFTs) Initial and every 3 months or more 

frequently, based on ARV regimen or 

symptoms

If on NRTIs, monitor electrolytes and 

hepatic enzymes monthly in third 

trimester

Fasting lipids and glucose Initial and as indicated

Blood group Indicated

Rh antibody screen Indicated
244 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Evaluation Frequency

Pregnancy Specific Ultrasound First trimester: confirm gestational 

age and potential timing for cesarean 

delivery if necessary

Second trimester: assess fetal anatomy 

for women on combination ART 

during first trimester

Screening for chromosomal abnormalities Screen for neural tube and abdominal 

wall defect, trisomy 21, and trisomy 

18; first-trimester testing may include 

laboratory and ultrasound exam, 

whereas patients in their second 

trimester are evaluated by multiple 

marker screening 

Abnormal result requires further 

investigation – consider amniocentesis 

only if abnormality is detected on 

multiple marker screening or level-2 

sonogram and the woman is on 

suppressive ART (to decrease risk 

of HIV transmission); voluntary and 

requires counseling

Diabetes screening Consider at 20 weeks; check glucose 1 

hour after 50 g glucose load; perform 

3-hour glucose tolerance test if screen 

is abnormal

If 3-hour test result is abnormal, 

perform regular glucose monitoring, 

especially in women taking protease 

inhibitors (PIs)

Rubella antibody Initial

Varicella IgG for those without history of 

chickenpox or shingles

Initial

Screening for syphilis: rapid plasma 

reagin (RPR) or Venereal Disease Research 

Laboratory (VDRL)

Initial and during weeks 32-36

Consider bacterial vaginosis (BV) 

screening (BV increases risk of preterm 

labor)

Week 24-28

Screening for streptococcus B (if result is 

positive, intrapartum chemoprophylaxis is 

indicated)

Week 32-36

Screening with herpes simplex virus-2 

serology in high-risk patients is 

recommended by some experts

Initial

Urinalysis and clean-catch urine culture Initial and as indicated

Papanicolaou test Initial and as indicated (colposcopy 

is done on pregnant women, but 

biopsy is avoided; management 

resumes postpartum, after the 6-week 

postpartum visit)
Care of HIV-Infected Pregnant Women | 245

Section 4: HIV Treatment

Evaluation Frequency

Hepatitis Serologies Hepatitis A virus (HAV) antibody (IgG) Initial

Hepatitis B virus (HBV): HBsAg, HBcAb , 

HBsAb

Initial

Hepatitis C virus (HCV) antibody Initial

TB Screening Tuberculin skin test (purified protein 

derivative [PPD]), more reliable if CD4 

count is >200 cells/μL (induration >5 

mm is positive); or interferon-gamma 

release assay (IGRA); note there is limited 

experience with IGRAs in pregnant 

women

Initial

Disease Specific Consider hemoglobin electrophoresis, 

if anemic or at increased risk of 

hemoglobinopathies

Initial

Serum screening for Tay-Sachs disease – 

both partners – if at increased risk

Initial

Urine toxicology screen Initial and as indicated

Table 2. Recommended Evaluation and Routine Monitoring of the 

Pregnant Woman with HIV Infection: Labor and Delivery

Test Comment

Record Review • Documentation of HIV serostatus, blood type and Rh, hepatitis serologies, RPR

• Review of ART, if any, during pregnancy

• Review of HIV viral load results during pregnancy

Physical 

Evaluation

• Vital signs and fetal heart rate

• Frequency and intensity of contractions

• Fetal lie, presentation, attitude, and position

• Vaginal examination: rule out HSV lesions; detect ruptured membranes; determine 

cervical effacement, dilatation, and position

• Avoid procedures that increase risk of perinatal HIV transmission (e.g., fetal scalp 

electrodes, scalp sampling, or assisted rupture of membranes)

Admission 

Laboratory 

Tests

• Complete blood count

• Liver function tests

• RPR or VDRL, if not done recently

• Repeat hepatitis B and C testing, if at risk of acquisition of hepatitis B or C, to prevent 

perinatal transmission of these infections

• Others, as required by specific state laws
246 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Immunizations and Opportunistic 

Infection Prophylaxis

Immunizations During Pregnancy

Generally, immunizations should be given 

before pregnancy, if possible. However, 

immunizations should be considered during 

pregnancy when the risk of exposure to an 

infection is high, the risk of infection to 

the mother or fetus is high, and the vaccine 

is unlikely to cause harm. The inactivated 

influenza virus and Tdap vaccines both meet 

this criteria and are generally recommended 

during pregnancy, as are certain others (see 

Table 3). Some vaccinations (particularly livevirus vaccines such as measles/mumps/rubella 

and varicella vaccines) are contraindicated, 

and others should be given only if the 

anticipated benefit of the vaccination 

outweighs the risk. Special considerations for 

immunizations in HIV-infected individuals 

are discussed in chapter Immunizations for 

HIV-Infected Adults and Adolescents.

Because vaccinations may cause a transient 

increase in the HIV viral load and theoretically 

may increase the risk of perinatal HIV 

transmission, vaccination should be given after 

pregnant women are on ART.

Table 3. Immunizations and Postexposure Prophylaxis 

in Pregnant Women with HIV Infection

Immunization Comment

Hepatitis A virus (HAV) Recommended for susceptible patients at risk of becoming infected, 

those with chronic HBV or HCV, those traveling to endemic areas, 

injection drug users, and those in the setting of a community outbreak.

Hepatitis B virus (HBV) Generally recommended for susceptible patients at risk of HBV infection 

during pregnancy.

Human Papilloma Virus (HPV) Not recommended during pregnancy.

Influenza Inactivated influenza vaccine is recommended for all pregnant women, 

before or during flu season. Live attenuated vaccines should not be used.

Measles/Mumps/Rubella (MMR) Contraindicated.

Pneumococcus Generally recommended. Limited data on safety during pregnancy for 

both the PPSV23 and PCV13 vaccines: no reports of adverse effects with 

PPSV23; limited experience with PCV13.

Tetanus-diphtheria-pertussis 

(Tdap)

Recommended during each pregnancy. Can be given at any time in 

pregnancy, but optimally between 27 and 36 weeks’ gestation (to 

maximize maternal antibody response and passive antibody transfer to 

the infant).

In addition, family members and caregivers should receive Tdap 

vaccination.

Varicella

• Primary vaccination

• Zoster vaccination

Contraindicated
Care of HIV-Infected Pregnant Women | 247

Section 4: HIV Treatment

Opportunistic Infection 

Prophylaxis

Some OIs can have an adverse effect on 

pregnancy. In turn, pregnancy can affect the 

natural history, presentation, treatment, and 

significance of some OIs. Women should 

be monitored carefully for OIs during 

pregnancy, with special attention given 

to nonspecific symptoms such as fatigue, 

back pain, and weight loss, which may be 

attributable to HIV-related illness rather 

than to pregnancy. Respiratory symptoms in 

particular merit rapid, aggressive investigation. 

Clinicians should follow the most current 

recommendations of the U.S. Centers for 

Disease Control and Prevention (CDC), 

National Institutes of Health, and Infectious 

Diseases Society of America, Guidelines for 

the Prevention and Treatment of Opportunistic 

Infections in HIV-Infected Adults and 

Adolescents, which give special consideration 

to pregnant women for each OI discussed. 

The indications and recommendations for 

OI prophylaxis generally should follow the 

guidelines for adults (see chapter Opportunistic 

Infection Prophylaxis). However, because 

of the risks of teratogenicity or harm to the 

developing fetus, some drugs routinely used 

for prophylaxis of OIs in nonpregnant adults 

are contraindicated during the first trimester 

of pregnancy, whereas others should not be 

used at any time during pregnancy.

Special Considerations for OI 

Prophylaxis During Pregnancy

Trimethoprim-sulfamethoxazole use

In pregnant women, folate deficiency 

increases the risk of neural tube defects in 

the developing fetus. Trimethoprim inhibits 

the synthesis of metabolically active folic 

acid and thus increases the risk of folate 

deficiency and congenital anomalies. 

Pregnant women, or women who may become 

pregnant, who are taking trimethoprimsulfamethoxazole (TMP-SMX, Septra, 

Bactrim, cotrimoxazole) should be given folate 

supplementation to reduce the risk of neural 

tube defects. However, folate also counteracts 

the activity of TMP, and may compromise 

the therapeutic efficacy of TMP-SMX. 

The recommended dosage of folic acid 

usually is 0.4 mg/day, but the optimal dosage 

in women on TMP-SMX is not clear. Some 

experts recommend higher dosages during the 

first trimester, when the fetus is at greatest risk 

for teratogenic effect. 

TMP-SMX is the recommended drug for 

women who require prophylaxis against PCP 

during pregnancy; alternatives to TPM-SMX 

during first trimester include aerosolized 

pentamidine and atovaquone.

Immunization Comment

Immune globulins 

(for postexposure prophylaxis

in susceptible individuals)

Measles Recommended after measles exposure.

Hepatitis A Recommended after exposure (close contact or sex partner), or in case of 

travel to endemic areas.

Varicella-zoster virus immune 

globulin (VariZIG)

Recommended for susceptible individuals after close contact with 

someone with varicella or herpes zoster (give as soon as possible, and 

within 10 days of exposure).

Hepatitis B immune globulin 

(HBIG)

Recommended for susceptible individuals after needlestick or sexual 

exposure to a person with hepatitis B infection.
248 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Genital herpes

Women with HIV infection are more likely 

than HIV-uninfected women to experience 

outbreaks of genital herpes. If HSV is 

transmitted to the infant, neonatal infection 

can be severe, even if it is detected and treated 

early. In addition, there is increased genital 

shedding of HIV in those with active genital 

HSV lesions though it is not known whether 

this remains true in women treated with 

effective ART. Some experts recommend 

obtaining HSV-2 serologies in a woman 

whose clinical history is unclear. Treatment 

for symptomatic HSV infections should be 

offered during pregnancy, and suppressive 

therapy should be given to women with 

frequent recurrences. Suppressive therapy with 

acyclovir or valacyclovir also should be offered 

to any woman with an HSV recurrence during 

pregnancy, starting at 36 weeks’ gestation. If a 

woman has an active outbreak of genital HSV 

or experiences prodromal symptoms at the 

time of labor or membrane rupture, delivery 

by cesarean section is indicated. Prophylaxis 

for pregnant women who are seropositive for 

HSV-2 but who do not have a history of genital 

lesions is not recommended.

Tuberculosis

Prophylaxis is recommended for any woman 

with a positive PPD skin test result (≥5 mm 

induration), a positive IGRA result, or a 

history of exposure to someone with active 

tuberculosis, after active disease has been 

ruled out. Patients receiving isoniazid also 

should receive pyridoxine to reduce the risk of 

neurotoxicity.

Toxoplasmosis

All HIV-infected persons should be tested 

for IgG antibodies to Toxoplasma soon after 

HIV diagnosis, and this should be a part of 

antenatal testing for pregnant women with 

HIV infection. Women with a negative IgG 

titer should be counseled to avoid exposure 

to Toxoplasma (e.g., by avoiding raw or 

undercooked meats, unwashed or uncooked 

vegetables, and cat feces). Women with 

previous exposure to Toxoplasma (positive 

IgG titer) should be given prophylaxis during 

pregnancy, if the CD4 count is <100 cells/μL. 

For women who require prophylaxis, TMPSMX is the preferred agent (see considerations 

for TMP-SMX, above). 

HIV-infected pregnant women who have 

evidence of primary or reactivated Toxoplasma

infection should be managed by a specialist.

Antiretroviral Therapy

The current HHS guidelines recommend 

treating HIV infection in all pregnant women, 

using the same principles and modalities 

as used for nonpregnant individuals. HIVinfected pregnant women should receive 

potent combination ART regimens comprising 

at least three ARVs. The choice of ARV 

regimen should be based on what is likely to be 

optimal for the woman’s health, the potential 

effect on the fetus and infant, resistance test 

results, the woman’s previous experience, if 

any, with ART, and her stage of pregnancy. 

ARV resistance testing should be performed 

before initiating or changing therapy, but 

should not delay the initiation of ART in late 

stages of pregnancy. Combination ART in 

pregnancy should include ZDV or another 

NRTI with good placental passage. ARV 

agents with potential teratogenic effects should 

be avoided in the early weeks of pregnancy 

(however, efavirenz may be continued during 

pregnancy, provided the regimen is tolerated 

and is providing effective virologic control). 

Women who have very high CD4 cell counts 

and are taking ART only for the prevention of 

perinatal transmission may delay initiation of 

therapy until after the first trimester, though 

effectiveness in preventing transmission may 

be decreased. For women already taking ART 

at the time they become pregnant, the regimen 

should be reevaluated for its appropriateness 

during pregnancy to avoid potentially toxic 

medications and to ensure maximal virologic 
Care of HIV-Infected Pregnant Women | 249

Section 4: HIV Treatment

suppression. Generally, any ART regimen that 

is effective and tolerated by the woman may 

be continued during pregnancy. If necessary, 

the ART regimen may be changed but therapy 

should continue without interruption. 

Discontinuation of ART could lead to an 

increase in viral load, which could result in a 

decline in immune status and an acceleration 

of disease progression, thereby increasing the 

risk of HIV transmission to the fetus.

For further information about ART during 

pregnancy, see chapter Reducing Perinatal 

HIV Transmission and the HHS Perinatal 

ARV Guidelines. The guidelines include 

recommendations regarding ARV regimens, 

modes of delivery (vaginal vs. cesarean 

section), and potential adverse events, as well 

as a detailed discussion of individual ARV 

agents. Additionally, the treatment of pregnant 

women with HIV/HBV coinfection and HIV/

HCV coinfection is discussed.

Antiretroviral Pregnancy Registry

To improve tracking of pregnancyrelated adverse events and fetal effects, an 

Antiretroviral Pregnancy Registry has been 

established as a collaborative project among 

the pharmaceutical industry, pediatric 

and obstetric providers, the CDC, and the 

National Institutes of Health. The registry 

collects observational data on HIV-infected 

pregnant women taking ARV medications to 

determine whether patterns of fetal or neonatal 

abnormalities occur. Pregnant women taking 

ARVs can be placed in this confidential followup study by calling 800-258-4263, 8:30 a.m. 

to 5:30 p.m. eastern time; the fax number is 

800-800-1052. Information is confidential and 

patients’ names are not used. Providers are 

encouraged to add to the available information 

on fetal risk by using this registry at first 

contact with a pregnant woman receiving ART. 

More information can be obtained at www.

APRegistry.com.

Pregnancy-Specific Complications 

and Management

Nutrition risk and inadequate

weight gain

Maternal nutrition and weight must be 

monitored throughout the pregnancy. A food 

diary may be a useful tool in assessing intake, 

and nutritional counseling is recommended.

Nausea and vomiting

Women with signs of dehydration should 

be assessed and treated appropriately in 

collaboration with the obstetrician or nurse/

midwife. Any medication used for nausea 

and vomiting must be assessed for drug-drug 

interactions with all HIV-related medications 

the patient is taking.

Hyperglycemia

Pregnancy is a risk factor for hyperglycemia, 

and women treated with PIs may have an 

even higher risk of glucose intolerance 

than other pregnant women and must be 

monitored carefully. New-onset hyperglycemia 

and diabetes mellitus, and exacerbation of 

existing diabetes, all have been reported in 

patients taking PIs. Clinicians should educate 

women taking PIs about the symptoms of 

hyperglycemia and closely monitor glucose 

levels. Women with HIV-infection should 

receive standard glucose screening at 24-28 

weeks’ gestation. Women who were taking a 

PI-based regimen prior to pregnancy may be 

screened earlier according to recommendations 

for women at high risk of glucose intolerance. 

The newborn should be checked for neonatal 

hypoglycemia at 1 and 4 hours after birth.

Lactic acidosis

Lactic acidosis is a rare but life-threatening 

complication that has been reported in 

pregnant women taking nucleoside reverse 

transcriptase inhibitors, particularly 

didanosine and stavudine. The combination 

of didanosine and stavudine should be 

avoided during pregnancy. Clinical suspicion 
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Section 4: HIV Treatment

of lactic acidosis should be prompted 

by vague symptoms such as malaise, 

nausea, or abdominal discomfort or pain. 

Hyperbilirubinemia

Women taking atazanavir or indinavir 

frequently develop elevated indirect bilirubin, 

but it is not known whether treatment 

during pregnancy exacerbates physiologic 

hyperbilirubinemia in newborns. Women who 

are taking indinavir may have an increased 

risk of nephrolithiasis, but evidence of harm 

to their newborns has not been demonstrated. 

Indinavir should be used during pregnancy 

only when preferred and alternative agents are 

not acceptable, and it must be boosted with 

low-dose ritonavir.

Pain management

Pain management during labor and delivery 

may be complicated by drug interactions with 

ARV agents and by the higher medication 

tolerance in women who have addictions. 

Additional pain medication may be needed for 

women with histories of drug use.

Invasive perinatal procedures

The risk of HIV transmission to the 

fetus during invasive procedures (e.g., 

amniocentesis, chorionic villus sampling, 

and percutaneous or umbilical cord blood 

sampling) must be weighed carefully against 

the possible benefits of these procedures. 

Current HHS guidelines suggest that women 

undergoing such procedures should be on 

effective ART, preferably with undetectable 

HIV RNA. The use of fetal scalp electrodes 

and artificial rupture of membranes should 

be avoided if possible, and forceps or vacuum 

extractors and episiotomy should be used only 

if there are clear obstetric indications.

Postpartum considerations

Because HIV can be transmitted to the infant 

through breast-feeding, breast-feeding is 

contraindicated in the United States and 

other resource-adequate countries where safe 

replacement feeding is available. Breast-feeding 

information should be removed from patient 

educational material pertaining to labor and 

delivery. Lactation suppression techniques 

can be used as needed to reduce lactation 

discomfort. Clinicians should recognize that 

women in some cultural groups are expected 

to breast-feed and they may need additional 

support to use formula rather than breast-feed.

ART should be continued, unless the woman 

refuses ARVs. Maternal and infant medication 

adherence must be discussed with the new 

mother. Adherence barriers for the mother 

during the postpartum period may be different 

from those during pregnancy (e.g., because of 

changes in daily routine, sleep/wake cycles, 

and meals).

New mothers should be observed carefully for 

signs of bleeding or infection.

If the mother’s glucose tolerance test result was 

abnormal during pregnancy, she should be 

reevaluated 6-12 weeks postpartum and should 

be screened yearly for diabetes.

At the infant’s 2-week follow-up visit, the 

HIV pediatric clinician should address the 

mother’s concerns, screen for postpartum 

depression, assess adherence to her own and 

the infant’s ARV medications, and ensure 

follow-up for the 6-week postpartum visit with 

the obstetric provider and soon thereafter with 

the primary HIV care provider. These visits 

provide an opportunity to address the woman’s 

contraceptive needs and options, if this was 

not done previously (see chapter Health Care of 

HIV-Infected Women Through the Life Cycle). 

Contraception

Many contraceptive choices are available 

for HIV-infected women; considerations 

are discussed in chapter Health Care of 

HIV-Infected Women Through the Life Cycle. 

Consistent condom use should be emphasized, 

and for women who wish to avoid pregnancy 

a “dual-protection” strategy, condom use plus 

another method of birth control, should be 
Care of HIV-Infected Pregnant Women | 251

Section 4: HIV Treatment

emphasized. This strategy effectively prevents 

pregnancy, prevents transmission of HIV to 

sex partners, and prevents the acquisition of 

sexually transmitted diseases. It is important to 

provide women with all contraceptive options 

including long-acting reversible contraceptive 

methods such as the intrauterine device and 

implants.

Patient Education

• Reinforce regularly and clearly the notion 

that, when the mother cares for herself, she 

is caring for her infant. Talk with the patient 

about stress, the importance of adequate 

mild-to-moderate exercise, and sufficient rest.

• Emphasize that regular prenatal care 

is extremely important to prevent 

complications of pregnancy.

• Use of a prenatal vitamin supplement is 

important, but cannot replace healthy food 

intake. Develop a plan with the patient for 

attaining the desired weight gain during 

pregnancy, while maintaining a healthy 

nutritional intake.

• Cigarette, alcohol, and drug use contribute 

to poor maternal nutrition and can harm the 

developing fetus. Illicit drug use increases 

the risk of transmitting HIV to the infant. 

Injection drug use can transmit HBV, 

HCV, and CMV to the mother and to the 

baby. Encourage cessation of cigarette, 

alcohol, and drug use, and offer referrals for 

treatment, as needed.

• Be sure the woman understands all planned 

procedures and treatments and understands 

their potential risks and benefits both to 

herself and to the fetus.

• Discuss the risks and benefits (to the woman 

and fetus) of each medication to be taken 

during pregnancy, including those for which 

there are limited data on teratogenicity.

• Discuss ART as a benefit to the woman’s 

health and as part of the strategy to reduce 

the risk of perinatal HIV transmission to the 

fetus or newborn. Also discuss the effect of 

ART on reducing risk of HIV transmission 

to sex partners.

• For women at risk, diligent use of “safer 

sex” during pregnancy is important for 

preventing infection with STDs and CMV, 

which can cause more complications 

when HIV is present. STDs can harm fetal 

development and may increase the risk of 

HIV transmission to the baby. New genital 

herpes infections during pregnancy can 

cause severe complications and even death 

in neonates.

• For women with negative Toxoplasma titers, 

explain the need to avoid undercooked meat, 

soil, and cat feces.

• Teach the pregnant woman how to obtain 

medical attention quickly at the first signs 

of OI or other complication. Discuss what 

to watch for and how to get help when 

emergencies arise in the evenings or on 

weekends or holidays.

• Help the patient clarify her child care 

options and support systems for raising a 

family. 

References

• ACIP Adult Immunization Work Group, 

Bridges CB, Woods L, et al.; Centers for 

Disease Control and Prevention. Advisory 

Committee on Immunization Practices 

(ACIP) recommended immunization schedule 

for adults aged 19 years and older – United 

States, 2013. MMWR Surveill Summ. 2013 

Feb 1;62 Suppl 1:9-19.

• American College of Obstetricians and 

Gynecologists. Gestational Diabetes Mellitus.

ACOG Practice Bulletin No. 137; 2013.

• American College of Obstetricians and 

Gynecologists. Update on Immunization and 

Pregnancy: Tetanus, Diphtheria, and Pertussis.

ACOG Committee Opinion No. 566; 2013.
252 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

• American College of Obstetricians 

and Gynecologists. Screening for Fetal 

Chromosomal Abnormalities. ACOG 

Practice Bulletin No.77; 2007.

• Antiretroviral Pregnancy Registry Steering 

Committee. Antiretroviral Pregnancy 

Registry International Interim Report for 1 

January 1989 – 31 January 2013. Available at 

www.apregistry.com/forms/interim_report.

pdf. Accessed December 1, 2013.

• Centers for Disease Control and Prevention. 

Guidelines for Vaccinating Pregnant 

Women. April 2013. Available at www.cdc.

gov/vaccines/pubs/preg-guide.htm#hepb. 

Accessed December 1, 2013.

• Centers for Disease Control and 

Prevention. Prevention and Control 

of Seasonal Influenza with Vaccines: 

Recommendations of the Advisory 

Committee on Immunization Practices – 

United States, 2013-2014. MMWR Recomm 

Rep. 2013 Sep 20;62(RR-07):1-43.

• Centers for Disease Control and Prevention. 

Sexually transmitted diseases treatment 

guidelines 2010. MMWR Recomm Rep. 2010 

Dec 17;59(RR-12):1-110.

• Centers for Disease Control and Prevention. 

Updated Recommendations for Use of 

Tetanus Toxoid, Reduced Diphtheria Toxoid, 

and Acellular Pertussis Vaccine (Tdap) in 

Pregnant Women – Advisory Committee 

on Immunization Practices (ACIP), 2012.

MMWR Morb Mortal Wkly Rep. 2013 Feb 

22;62(7):131-5.

• Centers for Disease Control and Prevention. 

Use of 13-Valent Pneumococcal Conjugate 

Vaccine and 23-Valent Pneumococcal 

Polysaccharide Vaccine for Adults with 

Immunocompromising Conditions: 

Recommendations of the Advisory 

Committee on Immunization Practices 

(ACIP). MMWR Morb Mortal Wkly Rep. 

2012 Oct 12;61(40):816-9.

• Ethics Committee of the American Society 

for Reproductive Medicine. Human immunodeficiency virus and infertility treatment. Fertil 

Steril. 2004 Sep;82 Suppl 1:S228-31.

• Kutty P, Rota J, Bellini W, et al. Manual 

for the Surveillance of Vaccine-Preventable 

Diseases (6th Edition, 2013). Available at 

www.cdc.gov/vaccines/pubs/surv-manual/

index.html. Accessed December 1, 2013.

• Minkoff H. Human immunodeficiency virus 

infection in pregnancy. Obstet Gynecol. 2003 

Apr;101(4):797-810.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.

• U.S. Department of Health and Human 

Services. Recommendations for Use of 

Antiretroviral Drugs in Pregnant HIV-1-Infected 

Women for Maternal Health and Interventions 

to Reduce Perinatal HIV Transmission in the 

United States. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.
Health Care of HIV-Infected Women Through the Life Cycle | 253

Section 4: HIV Treatment

Health Care of HIV-Infected 

Women Through the Life Cycle

Background 

Women with HIV infection have the same reproductive and life cycle health needs and concerns 

as women without HIV infection. However, for women with HIV infection, certain gynecologic 

problems may be more common or more frequent. In addition, issues regarding antiretroviral 

therapy (ART), contraception, and preconception counseling require special attention. This 

chapter addresses some of the unique health care needs of HIV-infected women across the lifespan, 

from menarche through postmenopause, and describes the essential elements of care. For further 

information, see chapters Reducing Perinatal HIV Transmission, Care of HIV-Infected Pregnant 

Women, and Antiretroviral Medications and Hormonal Contraceptive Agents.

Epidemiology and Factors 

Affecting HIV Transmission

Heterosexual transmission of HIV is more 

efficient from man to woman than from 

woman to man. Transmission can occur 

through intact vaginal tissue; no damage to 

the vaginal lining is required. Women have 

specific risks of HIV acquisition at different 

phases of the lifespan: 

• Young adolescents have immature genital 

tracts and increased cervical ectopy 

(increased vulnerability to HIV and other 

sexually transmitted diseases [STDs])

• Women of reproductive age may desire 

pregnancy and childbearing (potentially 

increasing risky sexual behaviors)

• Married or partnered women may be 

monogamous with male partners who have 

risk factors for HIV infection (women may 

lack awareness of partner’s risk behaviors)

• Postmenopausal or posthysterectomy 

women may have vaginal atrophy 

(decreasing the anatomic barrier to HIV), 

or may have no fear of pregnancy or have 

a perception that they are at low risk of 

infection (increasing risky sexual behaviors)

• Additionally, woman-to-woman transmission may occur if risk factors are present

Psychosocial/Emotional Factors 

Unique to Women

Women may inherit social roles and 

responsibilities as caretakers for extended 

family members and often for friends, and 

may not give sufficient priority to their own 

medical care. Furthermore, heterosexual women 

frequently are faced with unequal power and 

socioeconomic relationships with their male 

partners. These women may be more likely to 

exchange sex for money, less likely to successfully 

negotiate protected sex, and less likely to leave a 

relationship they perceive as risky. They may be 

fearful about disclosing their HIV status.

Sexual abuse appears to increase the risk of 

HIV transmission to HIV-uninfected women. 

For HIV-infected women, intimate partner 

violence and sexual coercion appear to occur 

at about the same rates as for HIV-uninfected 

women (>60% in one review). However, 

HIV-infected women appear to be subjected 

to more frequent and more severe abuse. 

HIV-infected women should be screened for 

intimate partner violence and referred to 

intervention services, if indicated. The U.S. 

Centers for Disease Control and Prevention 

(CDC) and the U.S. Preventive Services Task 

Force recommend several screening tools (see 

“References,” below). The Abuse Assessment 

Screen (AAS) is one tool recommended by the 
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Section 4: HIV Treatment

CDC. It originally was intended 

for screening pregnant women but 

has since been used more widely.

Abuse Assessment Screen

• Have you ever been emotionally 

or physically abused by your 

partner or someone important 

to you?

• Within the last year, have you 

been hit, slapped, kicked, or 

otherwise physically hurt by 

someone? If yes, by whom? How 

many times?

• Since you have been pregnant, 

have you been hit, slapped, 

kicked, or otherwise physically 

hurt by someone? If yes, by 

whom? How many times and 

where?

• In the last year, has anyone forced 

you to have sexual activities? If so, 

whom? How many times?

• Are you afraid of your partner or 

anyone you listed above?

ART Issues Particular to 

Women

In general, women on ART have 

virologic and immunologic 

responses comparable to those of 

men; however, several studies have 

shown that women discontinue 

ART more frequently than men. 

Women have higher rates of 

adverse effects from a number of 

antiretroviral (ARV) medications, 

in part because serum levels of 

at least some ARVs are higher in 

women. Pregnancy may require 

changes in ART, either because 

of pharmacokinetic changes or 

because of toxicity. See Table 1.

Table 1: Special Considerations for Use of 

Antiretrovirals with Women

ARV Issues 

for Women Considerations

ARV adverse 

effects

Some ARV adverse effects may be more 

severe in women: 

• Abacavir hypersensitivity

• Anemia (zidovudine)

• Bone loss, especially after menopause

• Hepatotoxicity (nevirapine)

• Lactic acidosis (particularly with 

stavudine + didanosine)

• Lipoaccumulation: central fat accumulation 

in breasts, abdomen; lipoatrophy: face

• Neuropathy (stavudine, didanosine)

• Severe rash (nonnucleoside reverse 

transcriptase inhibitors [NNRTIs], darunavir, 

tipranavir)

Pregnancy Teratogenicity:

• Efavirenz (EFV) is associated with neural 

tube defects in primates with in utero exposure. Consider alternatives, if feasible, 

in women who 1) are planning to become 

pregnant or 2) are sexually active with male 

partners and not using effective contraception. In women who become pregnant while 

taking EFV, EFV may be continued because 

the risk of neural tube defects is restricted to 

the first 5-6 weeks of pregnancy and pregnancy is rarely recognized before 4-6 weeks 

of pregnancy. Efavirenz is classified by the 

U.S. Food and Drug Administration (FDA) as 

a Pregnancy Category D drug.

Pharmacokinetic (PK) changes: 

• Serum levels of some ARVs may be 

decreased during pregnancy (e.g., 

unboosted protease inhibitors [PIs], and 

boosted PIs including atazanavir/ritonavir, 

darunavir/ritonavir, and lopinavir/ritonavir). 

• Some ARVs should be avoided and certain 

ARVs may require dosage adjustment in the 

third trimester. 

• PK studies in pregnancy are not available 

for some ARVs.

See chapter Reducing Perinatal HIV 

Transmission

Contraception There are significant interactions between 

some hormonal contraceptive agents and 

certain ARVs; see “Contraception,” below.
Health Care of HIV-Infected Women Through the Life Cycle | 255

Section 4: HIV Treatment

Baseline Reproductive History

Taking a careful reproductive history should 

be a part of routine primary care for any 

woman. Important information to gather 

includes the following:

• Age of menarche

• Menstrual history: last menstrual period 

(LMP), amenorrhea, menstrual irregularity, 

uterine fibroids, endometriosis

• Obstetrical history: G-P-A-L 

• G (gravida, or number of pregnancies), P 

(parity, or number of births), A (abortion; 

number of miscarriages or terminations), L 

(number of living children)

• Pregnancy complications and outcomes: 

full-term, premature births, mode of 

deliveries

• Use of ART during pregnancy

• HIV status of children

• Sexual activity: vaginal, oral, anal; condom 

use; number of partners; sex of partners; 

HIV status of partners

• Plans and desires for childbearing 

• Contraception, past and current

• Date of last Papanicolaou (Pap) test and 

results; history of abnormal Pap test results

• Gynecologic procedures: colposcopy/biopsy, 

loop electrosurgical excision procedure 

(LEEP), cervical surgery, tubal ligation, 

partial or total hysterectomy; and indication 

for these

• History of STDs, bacterial vaginosis, 

vulvovaginal candidiasis, herpes, warts; 

especially recurrence

• Current symptoms: vaginal discharge, 

vulvar/vaginal/anal pain, dysuria, 

dyspareunia (pain with intercourse), lesions, 

intermenstrual bleeding, postcoital bleeding

Elements of Gynecological Care

Women with HIV infection should receive 

routine screening for gynecologic cancers 

and infections. The incidence, prevalence, 

and persistence of human papillomavirus 

(HPV) infection and cervical, vaginal, vulvar, 

and anal dysplasia are more common in 

women with HIV infection, especially among 

women with low CD4 counts. It is not clear 

that initiation of suppressive ART improves 

clinical outcomes of women with dysplasia 

(see chapter Cervical Dysplasia). Other 

common gynecological problems include 

recurrent yeast vaginitis, pelvic inflammatory 

disease; vaginal, vulvar, and anal warts; and 

perineal/perianal herpes.

Women also should be evaluated for risk of 

breast cancer, for contraceptive needs, and for 

preconception counseling
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Section 4: HIV Treatment

Table 2: Routine Gynecologic Screening and Counseling for Women

Medical 

Service Comments

Cervical and 

anal cancer 

screening 

Women with HIV infection should have more frequent screening than uninfected women: 

• Screen all HIV-infected women for cervical cancer (cervical Pap test) at initial visit, at 6 

months, then annually unless abnormal.

• For HIV-infected women (any age) with ASCUS or higher-grade abnormality, colposcopy 

generally is recommended; alternatively, the Pap can be repeated in 6-12 months.

• Consider anal cancer screening (anal Pap test) for all HIV-infected women if high 

resolution anoscopy is available to evaluate abnormal findings.

• See chapters Cervical Dysplasia and Anal Dysplasia

• Perform pelvic examination.

• Include vulvar and anal examination

• Assess for potentially dysplastic lesions

• CDC recommendations for HPV vaccination of children and young women should be followed.

STD 

screening

Gonorrhea, chlamydia, syphilis at least annually, and more frequently depending on risk 

factors or symptom exam findings

Breast cancer 

screening

Mammography 

• Mammogram every 1-2 years recommended for women 50-69 years of age

• Consider annual mammogram for women 40-50 years of age

• Consider starting earlier if risk factors are present

• For women ≥70 years of age, decisions about whether to continue screening should take 

into account the woman’s life expectancy and clinical status

Clinical breast examination

• Annually

• Breast self-examination (BSE) monthly (assess technique)

Contraceptive 

counseling

• Assess life dynamics and need for contraception at every visit.

• Stop only after hysterectomy or sterilization.

• See “Contraception,” below.

Preconception 

counseling

Annually or more often for all women of reproductive age 

• Ask about pregnancy desires at every visit

• See “Preconception Counseling,” below

Contraception

Many contraceptive choices are available for 

HIV-infected women; some considerations 

are presented in the table below. For more 

information about interactions between ARVs 

and hormonal agents, see chapter Antiretroviral 

Medications and Hormonal Contraceptive 

Agents. Depending on the woman’s (and 

her partner’s) risk factors, consistent 

condom use should be emphasized, with or 

without other methods of contraception, 

to prevent the transmission of HIV and the 

acquisition or transmission of other STDs. 

Dual contraception (e.g., use of condoms 

plus additional contraception) is the optimal 

contraceptive strategy for serodiscordant 

heterosexual couples since it reduces the risk of 

transmission of HIV and other STDs as well as 

providing effective contraception. 
Health Care of HIV-Infected Women Through the Life Cycle | 257

Section 4: HIV Treatment

Table 3: Advantages and Disadvantages of Various Contraceptives

Contraceptive Type Advantages Disadvantages

Barrier Methods

Male and female 

condom

• Only contraceptive 

method that also protects 

against transmission of 

HIV and STDs

• Requires partner cooperation and correct 

technique

• High failure rate when used incorrectly or 

inconsistently

Diaphragm and 

cervical cap

• Requires correct technique

• High failure rate when used incorrectly or 

inconsistently

• Use of diaphragms with spermicide can disrupt 

the cervical mucosa, which may increase risk of 

HIV transmission to uninfected sex partners

Hormonal Methods* • Do not prevent STD or HIV transmission

Oral • Very effective 

contraception if used as 

prescribed

• Lighter menstrual flow

• May have significant drug-drug interactions with 

PIs, some NNRTIs, and elvitegravir/cobicistat that 

may affect the efficacy and toxicity of estradiol or 

the progestin, and of certain PIs*

• Alternative or additional methods recommended 

for women taking certain PIs or NNRTIs, or 

elvitegravir/cobicistat.

Injectable depot 

medroxyprogesterone acetate (DMPA, 

Depo-Provera)

• Effective contraception for 

3 months

• May cause amenorrhea

• Concern about osteoporosis with long-term use

• Irregular bleeding, especially initially

• Weight gain

• Limited and conflicting data show possible 

increased risk of HIV transmission (from HIVinfected woman to male partner) or acquisition 

(by uninfected woman from HIV-infected man) 

for women on DMPA (note: no study participants 

were on ART)

Transdermal (patch) • Effective contraception if 

used as prescribed 

• Lighter menstrual flow

• No data on pharmacokinetic interactions with 

ARVs, but of possible significance; use same 

precautions as with oral hormonal agents (see 

above)

Vaginal ring • Effective contraception if 

used as prescribed

• Lighter menstrual flow

• No data on pharmacokinetic interactions with 

ARVs, but of possible significance; use same 

precautions as with oral hormonal agents (see 

above)

Intrauterine devices 

(IUDs) (copper IUD 

and levonorgestrelcontaining IUD)

• Effective for long-term use

• No evidence of increased 

HIV viral shedding

• Progestin-releasing 

IUD may cause lighter 

menstrual flow

• Possible blood loss with Copper T IUD

• Insertion of IUD not recommended for women 

with advanced immunosuppression 

Etonogestrel

implant

• Effective

• Amenorrhea

• No data on pharmacokinetic interactions with 

ARVs, but of possible significance; Use same 

precautions as with oral hormonal agents (see 

above)
258 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Contraceptive Type Advantages Disadvantages

Emergency 

contraception: 

• Levonorgestrel

• Ulipristal acetate

• Effective

• Efavirenz lowers levonorgestrel levels; use 

alternative method

• No data on pharmacokinetic interactions with 

ARVs, but of possible significance; use same precautions as with oral hormonal agents (see above)

• Copper T IUD • Appropriate for women 

who present 4-5 days after 

intercourse

• Heavy blood loss

Surgical Methods

Bilateral tubal 

ligation (female)

• Effective; permanent • Does not prevent transmission 

of HIV or other STDs

• No future fertility (usually not reversible)

Vasectomy (male) • Effective; permanent • Does not prevent transmission 

of HIV or other STDs

• No future fertility (usually not reversible)

Spermicides

Spermicides • Not currently recommended

• Nonoxynol-9 causes mucosal damage to vagina

• Do not prevent transmission of HIV or other STDs

* See chapter Antiretroviral Medications and Hormonal Contraceptive Agents and Panel on Antiretroviral Guidelines for Adults and 

Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human 

Services. Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013. 

Preconception Counseling

As discussed above, every visit with an HIVinfected woman in her reproductive years 

presents an opportunity to discuss pregnancy 

desires and options, including gathering 

information about her partner. It is important 

to assess the couple’s sexual history, sexual 

decision making, and control of reproductive 

options. The goals of preconception counseling 

are to improve the health of the woman 

prior to conception and identify, and when 

possible intervene around, risk factors for 

adverse maternal and fetal outcomes. When a 

woman desires pregnancy, it is important to 

discuss the topics listed below, with the goals 

of educating her and decreasing risk of HIV 

transmission to an HIV-uninfected partner or 

to the fetus. Ideally, the partner will take part 

in the discussion. 

• Options for conception that decrease risk 

of HIV transmission to an HIV-uninfected 

partner (see below)

• Recommendations for ART before and during 

pregnancy, at delivery, and postpartum

• Optimization of maternal health status and 

suppression of HIV viral load before pregnancy

• Effect of HIV and ARVs on pregnancy and 

outcomes

• Effect of non-HIV-related factors (e.g., age, 

drug use) and other medical conditions 

(e.g., hypertension, diabetes, depression) on 

pregnancy course

• Counseling on safer sexual practices

• Counseling on other aspects of health promotion (e.g., smoking and alcohol cessation, 

drug treatment)

• Perinatal HIV transmission risk and prevention: ARVs for mother and infant, mode of 

delivery, avoidance of breast-feeding

• Treatment and care of an HIV-exposed or 

HIV-infected infant

• Long-term planning including advance 

directives and guardianship of a child if one 

or both parents were to become ill or die

Any history of infertility or low fertility in 

either the patient or her partner should be 
Health Care of HIV-Infected Women Through the Life Cycle | 259

Section 4: HIV Treatment

evaluated and options for having children 

should be discussed, including current 

information on gamete donation, other assisted 

reproductive techniques, and adoption.

If the heterosexual couple is serodiscordant, 

techniques to minimize the risk of transmission 

to the uninfected partner should be discussed. 

These same techniques should be explained to 

couples when both partners are HIV infected, 

if there is a risk of transmitting different HIV 

“strains.” Some of the recommended techniques 

include the following: 

• If the male partner is HIV uninfected: the 

woman does self-insemination of ejaculate 

using a syringe (no HIV exposure risk to the 

male partner)

• Maximal suppression of the HIV viral load 

of the infected partner with ART

• Screening for and treatment of STDs

• Assisted reproductive technology

• Sperm washing with polymerase chain 

reaction (PCR) testing and intrauterine 

insemination (IUI), in vitro fertilization 

(IVF), or intracytoplasmic sperm 

injection (ICSI), if the male partner is 

HIV infected and the female partner is 

HIV uninfected

The couple should be fully educated about 

other options, including the following:

• Preexposure prophylaxis (PrEP) for the 

uninfected partner

• Estimating the time of ovulation and 

limiting unprotected intercourse to this 

period, with or without use of PrEP. This 

approach should be considered only if 

HIV viremia is maximally suppressed 

and intercourse is limited to times when 

conception is most likely.

• Postexposure prophylaxis for an uninfected 

partner

The CDC has issued interim guidelines on use 

of PrEP by heterosexually active individuals as 

well as a fact sheet on PrEP (see “References,”). 

Both address the use of PrEP during attempts 

to conceive. Few clinical data are available 

at this time to guide practice; when treating 

serodiscordant couples who wish to conceive 

using PrEP, providers should review current 

guidelines and consult with experts in the field.

If an HIV-infected woman who is considering 

pregnancy initiates ART, an appropriate 

regimen should be started before pregnancy, 

avoiding agents with increased risk of 

teratogenicity (e.g., efavirenz), hepatotoxicity 

(e.g., nevirapine, in women with CD4 counts 

of >250 cells/μL), or metabolic complications 

such as lactic acidosis (e.g., didanosine and 

stavudine). See chapter Reducing Perinatal 

HIV Transmission and the U.S. Department 

of Health and Human Services Perinatal HIV 

Guidelines (see “References,” below). It should 

be noted that most fetal organogenesis occurs 

in the early weeks of pregnancy, before most 

women know that they are pregnant. Thus, 

any medication with potential teratogenicity 

or fetal toxicity, whether an ARV or another 

drug, should be avoided for use by women 

who are intending to become pregnant or who 

may become pregnant. Certain medications 

(e.g., ribavirin) should be avoided by male 

partners of women who may become 

pregnant.

Folate supplementation to reduce the risk of 

neural tube defects in the developing fetus 

should be started at least 1 month before 

conception, if possible, because the neural tube 

forms in the early weeks of pregnancy (see 

chapter Care of HIV-Infected Pregnant Women).
260 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Menopause

There is evidence that HIV-infected women 

may be more likely to undergo premature 

physiologic menopause. Earlier onset of 

menopause also is associated with non-HIV 

factors such as ethnicity and a history of 

intravenous drug use. Menopausal women 

are more at risk of premature bone loss, 

osteopenia, and osteoporosis; this risk may be 

increased by HIV infection and certain ARVs. 

If indicated, bone density screening (DEXA) 

should be considered.

Hormone replacement therapy (HRT), 

especially of long duration, has been associated 

with an increased risk of breast cancer and 

cardiovascular and thromboembolic events, 

and its routine use is not recommended. HRT 

may be considered for women who experience 

severe vasomotor symptoms and vaginal 

dryness, but should be used only for a limited 

period of time and at the lowest effective 

dosage.

References

• Aaron EZ, Criniti SM. Preconception health 

care for HIV-infected women. Top HIV Med. 

2007 Aug-Sep;15(4):137-41.

• ACOG Committee on Practice Bulletins – 

Gynecology. ACOG Practice Bulletin No. 117: 

Gynecologic care for women with Human 

Immunodeficiency Virus. (2010). ACOG 

Practice Bulletin No. 117. Obstet Gynecol, 

2010 Dec;116(6):1492-509. (December 2010; 

Reaffirmed 2012).

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency 

virus: 2013 update by the HIV Medicine 

Association of the Infectious Diseases 

Society of America. Clin Infect Dis. 2014 

Jan;58(1):e1-e34.

• Centers for Disease Control and Prevention. 

Interim guidance for clinicians considering 

the use of preexposure prophylaxis for the 

prevention of HIV infection in heterosexually 

active adults. MMWR Morb Mortal Wkly 

Rep. 2012 Aug 10;61(31):586-9.

• Centers for Disease Control and Prevention, 

CDC Fact Sheet. PrEP: A New Tool for HIV 

Prevention. August 2012. Available at www.

cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdf. 

Accessed January 15, 2014.

• Centers for Disease Control and Prevention, 

Division of Reproductive Health, National 

Center for Chronic Disease Prevention and 

Health Promotion. U.S. Selected Practice 

Recommendations for Contraceptive 

Use, 2013: Adapted from the World 

Health Organization selected practice 

recommendations for contraceptive use, 2nd 

edition. MMWR Recomm Rep. 2013 Jun 

21;62(RR-05):1-60.

• Cejtin HE. Gynecologic issues in the HIVinfected woman. Infect Dis Clin North Am. 

2008 Dec;22(4):709-39, vii.
Health Care of HIV-Infected Women Through the Life Cycle | 261

Section 4: HIV Treatment

• Collazos J, Asensi V, Cartón JA. Sex 

differences in the clinical, immunological 

and virological parameters of HIV-infected 

patients treated with HAART. AIDS. 2007 

Apr 23;21(7):835-43.

• dePommerol, M, Hessamfar, M, LawsonAyayi, S, et al.; Groupe d’Epidémiologie 

Clinique du SIDA en Aquitaine (GECSA). 

Menopause and HIV infection: age at onset 

and associated factors, ANRS CO3 Aquitaine 

cohort. Int J STD AIDS. 2011 Feb;22(2):67-72. 

• Hoyt, MJ, Storm DS, Aaron E, et al. 

Preconception and contraceptive care for 

women living with HIV. Infect Dis Obstet 

Gynecol. 2012;2012:604183.

• Kojic EM, Wang CC, Cu-Uvin S. HIV and 

menopause: a review. J Womens Health 

(Larchmt). 2007 Dec;16(10):1402-11.

• McNicholl I. Database of Antiretroviral 

Drug Interactions. HIV InSite. Coffey S, 

Volberding PA, eds. San Francisco: UCSF 

Center for HIV Information. Available at 

hivinsite.ucsf.edu/insite?page=ar-00-02. 

Accessed December 1, 2013.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. Recommendations for Use of 

Antiretroviral Drugs in Pregnant HIV-1-

Infected Women for Maternal Health and 

Interventions to Reduce Perinatal HIV 

Transmission in the United States. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

Palliative Care and HIV | 263

Section 4: HIV Treatment

Palliative Care and HIV

Background 

Palliative care is not curative care, but is supportive, symptom-oriented care. It may be needed at 

any point in the course of disease progression to relieve patients’ suffering and promote quality 

of life. Palliative care is important for patients with any medical condition, even if they are not 

actively in hospice. It may be used in conjunction with disease-specific care or as the sole approach 

to care. Palliative care includes the following: 

• Management of symptoms (e.g., fatigue, pain)

• Treatment of adverse effects (e.g., nausea, vomiting)

• Psychosocial support (e.g., depression, advance care planning)

• End-of-life care

The U.S. Health Resources and Services Administration (HRSA) HIV/AIDS Bureau Working 

Group on Palliative Care in HIV has provided the following working definition of palliative care:

Palliative care is patient- and family-centered care. It optimizes quality of life by active 

anticipation, prevention, and treatment of suffering. It emphasizes use of an interdisciplinary 

team approach throughout the continuum of illness, placing critical importance on the building 

of respectful and trusting relationships. Palliative care addresses physical, intellectual, emotional, 

social, and spiritual needs. It facilitates patient autonomy, access to information, and choice.

(Excerpted from: HRSA Working Group on HIV and Palliative Care. 

Palliative and Supportive Care. HRSA Care ACTION, July 2000)

Palliative care for patients with HIV infection comprises a continuum of treatment consisting of 

therapy directed at AIDS-related illnesses (e.g., infection or malignancy) and treatments focused 

on providing comfort and symptom control throughout the lifespan. This care may involve 

multidimensional and multidisciplinary services, including HIV medicine, nursing, pharmacy, 

social work, complementary or alternative medicine, and physical therapy.

Palliative Care in the Era of Antiretroviral Therapy

With advances in HIV-specific therapy and care, HIV infection is no longer a rapidly fatal illness. 

Instead, patients who are able to tolerate antiretroviral therapy (ART) usually experience a 

manageable, chronic illness.

The death rate from AIDS, however, continues to be significant: approximately 15,000 deaths per 

year in the United States. In many parts of the world, patients still are not able to obtain specific 

treatments for HIV or for opportunistic illnesses, and supportive or palliative care may be the 

primary mode of care available to patients with advanced AIDS. Regardless of access to diseasespecific treatment, people living with HIV continue to experience symptoms from HIV disease 

and its comorbid conditions, and those taking ART may experience adverse effects. Integrating 

palliative care and disease-specific care is important for treating patients with HIV in order to 

promote quality of life and relieve suffering.
264 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

S: Subjective

he patient with advanced HIV disease 

complains of one or more of the following: 

• Agitation

• Anorexia

• Chronic pain

• Constipation

• Cough

• Decubitus ulcers 

or pressure sores

• Delirium

• Dementia

• Depression

• Diarrhea

• Dry mouth

• Dry skin

• Dyspnea

• Fatigue

• Fever

• Hiccups

• Increased 

secretions 

(“death rattle”)

• Nausea

• Pruritus

• Sleep disturbance

• Sweats

• Vomiting

• Weakness

• Weight loss

O: Objective

Conduct a complete symptom-directed 

physical examination.

To evaluate pain, please refer to chapter Pain 

Syndrome and Peripheral Neuropathy. 

A/P: Assessment and Plan

Treatment

Common symptoms of persons with latestage HIV infection and their possible 

causes are listed in Table 1. Also included 

are disease-specific treatments and palliative 

interventions. Depending on the situation, 

either or both of these types of treatments may 

be appropriate. Consider the patient’s disease 

stage and symptom burden, the risks and 

benefits of therapies, and the patient’s wishes.

When assessing each of the patient’s 

symptoms, include the psychiatric review of 

symptoms (depression, anxiety, psychosis), 

and consider the following aspects of each 

symptom: 

• Onset, progression, frequency, severity

• Degree of distress and impact on function

• Aggravating and alleviating factors

• Previous treatments and their efficacy

• What the patient believes is causing the 

symptom

• Coping strategies and supports

• The patient’s personal goals of care with this 

particular symptom

Practitioners should note that some of the 

palliative treatments may have substantial 

long-term adverse effects and should be used 

to alleviate symptoms only in late-stage or 

dying patients.
Palliative Care and HIV | 265

Section 4: HIV Treatment

Table 1. Common Symptoms in Patients with AIDS and Possible 

Disease-Specific and Palliative Interventions

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

CONSTITUTIONAL

Fatigue, 

weakness

• AIDS

• Opportunistic 

infection

• Anemia

• Hypoandrogenism

• ART

• Treat specific 

infections

• Erythropoietin, 

transfusion

• Testosterone/

androgens in men 

with concomitant 

hypogonadism; for 

women, androgens 

are investigational 

and not approved 

by the U.S. 

Food and Drug 

Administration for 

this use

• Psychostimulants: give in 

the morning; also useful as 

treatment for depression and 

sedation owing to opioids; avoid 

in patients with anxiety and 

agitation (e.g., methylphenidate, 

dextroamphetamine, modafinil; 

pemoline is not first-line because of 

hepatotoxicity risk)

• Corticosteroids (prednisone, 

dexamethasone)

Weight loss/

anorexia

• HIV 

• Malignancy

• ART

• Specific treatment 

of malignancy

• Nutritional support

• Testosterone/androgens in men with 

hypogonadism (see above)

• Oxandrolone for 2-4 week courses; 

an anabolic steroid that may be a 

useful adjunct, can help increase 

lean body mass but also has virilizing 

effects

• Megestrol acetate can improve 

appetite and fatigue but has not 

been shown to improve nutritional 

status; possible adverse effects 

include deep vein thrombosis, 

glucose intolerance, and 

hypoandrogenism in men

• Dronabinol is a cannabinol derivative 

that helps increase appetite but over 

the long term (≥12 months) does not 

significantly increase weight

• Recombinant human growth 

hormone can improve lean body 

mass, but is associated with 

significant side effects (headache, 

edema, myalgias) and is expensive; 

consider for patients with severe 

wasting if no other therapies are 

effective

• Corticosteroids can help increase 

appetite in the short term but not 

increase weight, and the duration of 

effect is short-lived
266 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

Fevers, 

sweats

• Disseminated 

Mycobacterium 

avium complex 

and other 

infections 

(opportunistic or 

other)

• Lymphoma 

and other 

malignancies

• Immune 

reconstitution 

inflammatory 

syndrome

• Medication 

reaction

• Specific treatment 

of opportunistic 

infection or 

malignancy

• ART

• Discontinue 

causative 

medication (if drug 

reaction)

• Acetaminophen

• NSAIDs (ibuprofen, naproxen, 

indomethacin)

• Anticholinergics can be useful 

for sweats (hyoscyamine, 

glycopyrrolate)

• H2 antagonists can be useful for 

sweats (ranitidine, famotidine; 

dose at least 12 hours apart from 

atazanavir or rilpivirine; note that 

cimetidine should be avoided in 

patients taking fosamprenavir 

or delavirdine because of drug 

interactions)

PAIN

Nociceptive, 

somatic, 

visceral

• Opportunistic 

infections

• HIV-related 

malignancies, 

nonspecific

• Specific treatment 

of disease entities

• See chapter Pain Syndrome and 

Peripheral Neuropathy for detailed 

treatment options

• Refer to the World Health 

Organization (WHO) analgesic 

ladder: NSAIDs and opioids

• Corticosteroids can be useful for 

treating inflammatory-mediated 

pain, often as an adjunct to opioids 

(may worsen some conditions)

• Benzodiazepines or muscle relaxants 

for muscle spasms (clonazepam, 

diazepam, baclofen)

• Nonpharmacologic therapies (e.g., 

massage, physical therapy)

Neuropathic • HIV-related 

peripheral 

neuropathy 

• Cytomegalovirus 

• Varicella-zoster 

virus 

• Medications 

(e.g., stavudine, 

isoniazid, 

vincristine)

• ART 

• Discontinue 

offending 

medication 

• Change 

antiretroviral or 

other regimen

• See chapter Pain Syndrome and 

Peripheral Neuropathy for detailed 

treatment options

• Refer to the WHO analgesic ladder: 

NSAIDs and opioids

• Neuropathic pain medications: 

• Tricyclics (nortriptyline, 

imipramine)

• Anticonvulsants (gabapentin, 

pregabalin, lamotrigine)

• Muscle relaxants (e.g., baclofen)

• Benzodiazepines can be 

useful adjuncts (clonazepam, 

diazepam)

• Corticosteroids can be useful for 

treating inflammatory-mediated 

pain, often as an adjunct to opioids 

(may worsen some conditions)

• Acupuncture
Palliative Care and HIV | 267

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

GASTROINTESTINAL

Nausea, 

vomiting

• Antiretroviral 

medications

• Esophageal 

candidiasis

• Cytomegalovirus 

esophagitis

• Specific treatment 

of disease entities

• Change 

antiretroviral 

regimen

• Dopamine antagonists 

(prochlorperazine, haloperidol)

• Prokinetic agents (metoclopramide)

• Serotonin antagonists (granisetron, 

ondansetron, dolasetron)

• Antihistamines (diphenhydramine, 

promethazine, meclizine)

• Anticholinergics (hyoscyamine, 

scopolamine)

• Somatostatin analogues in patients 

with bowel obstruction, to reduce 

gut motility; can be used with 

anticholinergics (octreotide)

• Benzodiazepines (lorazepam)

• Marijuana, dronabinol can help 

increase appetite

Diarrhea • Mycobacterium 

avium complex 

• Cryptosporidiosis

• Cytomegalovirus 

colitis

• Microsporidiosis

• Other intestinal 

infections

• Malabsorption

• Medications 

(e.g., protease 

inhibitors)

• Specific treatment 

of disease entities

• Discontinue 

offending 

medication

• Bismuth, methylcellulose

• Psyllium

• Kaolin

• Diphenoxylate + atropine

• Loperamide

• Calcium carbonate

• Ferrous sulfate

• Tincture of opium for severe chronic 

diarrhea unresponsive to other 

therapies

• Crofelemer for ARV-related diarrhea

• Octreotide for profuse, refractory 

watery diarrhea; expensive and 

needs subcutaneous administration

Constipation • Dehydration

• Malignancy

• Anticholinergic 

medications

• Opioids

• Reduced activity

• Hydration

• Radiation and 

chemotherapy

• Medication 

adjustment

• Activity/diet modification

• Prophylaxis for patients taking 

opioids with docusate + senna

• Peristalsis-stimulating agents:

• Anthracenes (senna)

• Polyphenolics (bisacodyl)

• Softening agents:

• Surfactant laxatives (docusate)

• Bulk-forming agents (bran, 

methylcellulose)

• Osmotic laxatives (lactulose, 

sorbitol)

• Saline laxatives (magnesium 

hydroxide)
268 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

RESPIRATORY

Dyspnea • Pneumocystis 

jiroveci 

pneumonia

• Bacterial 

pneumonia

• Anemia

• Pleural effusion, 

mass, or 

obstruction

• Decreased 

respiratory muscle 

function

• Specific treatment 

of disease entities

• Erythropoietin, 

transfusion

• Drainage, radiation, 

or surgery

• Use of fan, open windows

• Relaxation techniques, massage, 

guided imagery

• Oxygen supplement titrated to 

comfort, if the patient is hypoxic

• Bronchodilators (albuterol, 

ipratropium, inhaled steroids) if 

there is bronchospasm

• Opioids, particularly morphine, to 

decrease sense of air hunger and 

respiratory rate

• Benzodiazepines (e.g., lorazepam) 

to reduce the anxiety that often 

accompanies dyspnea

Cough • Pneumocystis 

jiroveci

pneumonia

• Bacterial 

pneumonia

• Tuberculosis

• Acid reflux

• Postnasal drip

• Specific treatment 

of disease entities

• Cough suppressants 

(dextromethorphan, codeine, 

hydrocodone, morphine, aerosolized 

lidocaine)

• Bronchodilators (albuterol, 

ipratropium, inhaled steroids) if 

there is bronchospasm

• H2 blockers or proton-pump 

inhibitors (ranitidine, omeprazole) 

if there is acid reflux (caution: 

interactions with atazanavir, 

rilpivirine)

• Decongestants (pseudoephedrine, 

phenylephrine, steroid nasal sprays) 

for postnasal drip

Increased 

secretions 

(“death 

rattle”)

• Fluid shifts

• Ineffective cough

• Sepsis

• Pneumonia

• Antibiotics as 

indicated

• Atropine, hyoscyamine, transdermal 

scopolamine, glycopyrrolate

• Fluid restriction, discontinue 

intravenous fluids

Hiccups • Aerophagia 

(swallowing air)

• Candida and 

other causes 

of esophagitis, 

including GERD

• Vagus and phrenic 

nerve irritation

• CNS mass lesions

• Uremia

• Alcohol 

intoxication

• Anesthesia

• Treatment of 

underlying etiology 

(e.g., antifungals 

for Candida

esophagitis, acid 

reducers for GERD)

• Metoclopramide can promote 

gastric emptying

• Chlorpromazine (antipsychotic) 

can reduce the CNS response, start 

at low dosage to reduce the risk of 

dystonia and drowsiness

• Baclofen can reduce the CNS 

response
Palliative Care and HIV | 269

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

DERMATOLOGIC

Dry skin • Dehydration

• End-stage renal 

disease

• End-stage liver 

disease

• Malnutrition 

medications (e.g., 

indinavir)

• Hydration

• Dialysis

• Nutritional support

• Discontinue 

offending 

medication

• Avoid soaps, most of which 

dry the skin further

• Emollients with or without salicylates

• Emollients with urea 

(e.g., Ultra Mide 25)

• Emollients with lactate 

(e.g., Lac-Hydrin)

• Lubricating ointments or creams 

(e.g., petrolatum, Eucerin)

Pruritus • Fungal infection

• End-stage renal 

disease

• End-stage liver 

disease

• Dehydration; dry 

skin

• Eosinophilic 

folliculitis

• Opioid side effect

• Antifungal agents 

(e.g., itraconazole 

for eosinophilic 

folliculitis)

• Dialysis

• Hydration

• Topical 

corticosteroids

• Avoid soaps and hot baths/showers

• Warm compresses

• Treatments for dry skin, as above

• Topical agents (menthol, phenol 

[e.g., Sarna lotion], calamine, 

doxepin, capsaicin)

• Antihistamines (hydroxyzine, 

doxepin, diphenhydramine)

• Corticosteroids (topical or systemic)

• Opioid antagonists (naloxone, 

naltrexone) can be useful for treating 

uremic and biliary-associated 

pruritus

• Antidepressants

• Anxiolytics

• Thalidomide in intractable pruritus, 

but beware of side effects, including 

neuropathy

Decubitus 

ulcers, 

Pressure 

sores

• Poor nutrition

• Decreased 

mobility, 

prolonged bed 

rest

• Increase mobility

• Enhance nutrition

• Prevention (nutrition, 

mobility, skin integrity

• Wound protection (semipermeable 

film, hydrocolloid dressing)

• Debridement (normal saline, 

enzymatic agents, alginates)
270 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

NEUROPSYCHIATRIC

Delirium/

agitation

• Electrolyte 

imbalances, 

glucose 

abnormalities

• Dehydration

• Hypoxia

• Toxoplasmosis

• Cryptococcal 

meningitis

• CNS masses and 

metastases

• Sepsis

• Medication 

adverse 

effects (e.g., 

benzodiazepines, 

opioids, efavirenz, 

corticosteroids)

• Intoxication or 

withdrawal

• Correct imbalances

• Hydration

• Oxygen 

supplementation

• Specific treatment 

of disease entities

• Discontinue 

offending 

medications

• Neuroleptics (haloperidol, 

risperidone, chlorpromazine) to 

induce sedation in severe agitation

• Benzodiazepines (e.g., lorazepam, 

diazepam, midazolam) in the 

“terminal restlessness” of the last 

few days of life to relieve myoclonus, 

seizures, restlessness (Note: in some 

patients, these may have adverse 

effects)

Dementia • HIV-associated 

dementia

• Other dementia 

(e.g., Alzheimer 

dementia, 

Parkinson 

dementia, multiinfarct dementia)

• ART • Psychostimulants (methylphenidate)

• Memantine (NMDA antagonist) 

has been used in patients with 

Alzheimer dementia but has unclear 

benefit for patients with HIVassociated dementia

• Low-dose neuroleptics (haloperidol, 

chlorpromazine) can be useful in 

psychotic delirium
Palliative Care and HIV | 271

Section 4: HIV Treatment

Symptom Possible Causes

Disease-Specific or 

Curative Treatment Palliative Treatment

Depression • Chronic illness

• Reactive 

depression, major 

depression

• Antidepressants • Antidepressants are useful when 

the patient has a life expectancy 

of several months or more: SSRIs, 

SNRIs, mirtazapine (useful in lowest 

dosages for insomnia), bupropion, 

(though beware of lowering the 

seizure threshold); note that tricyclic 

antidepressants are not considered 

first- or second-line therapy 

owing to side effects, though 

they may be useful for treating 

refractory melancholic or delusional 

depression (see chapter Major 

Depression and Other Depressive 

Disorders for further information, 

including dosages)

• Psychostimulants are useful for 

patients who have urgent, severe 

depression or are weeks from 

death (methylphenidate, pemoline, 

dextroamphetamine, modafinil)

Abbreviations: ART = antiretroviral therapy; CNS = central nervous system; GERD = gastroesophageal reflux disease; NMDA = 

N-methyl- D-aspartate; NSAID = nonsteroidal antiinflammatory drug; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor

Adapted from Selwyn PA, Rivard M. Palliative care for AIDS: Challenges and opportunities in the era of highly active antiretroviral therapy. 

Innovations in End-of-Life Care. 2002;4(3). Available at www2.edc.org/lastacts/archives/archivesmay02/ovessay.asp. Accessed December 

1, 2013.

Advance Care Planning

Advance care planning involves planning for 

future medical care. Two main documents are 

produced: 

• Advance directive (living will)

• Health care proxy (a person to speak for the 

patient or make decisions if the patient is too 

sick to do so)

The clinician should initiate these 

conversations and make referrals to helpful 

resources. 

Patient Education

• Discuss advance care planning with patients, 

and the option of hospice care, if appropriate.

• Provide patients and their family members 

with detailed information so that they 

understand the illness and associated 

treatments.

• Instruct patients to discuss their pain or 

other bothersome symptoms with their 

health care provider.

• Encourage patients to talk with their health 

care provider if they are feeling anxious, 

depressed, or fearful.

• Discuss with patients what their death 

might be like. Some patients may feel 

relieved to be able to talk openly about their 

last days. Assure them that their pain will 

be controlled and that their health care 

provider will be there to help them.
272 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

References

• American Academy of HIV Medicine. 

Palliative Care. In: The HIV Medicine 

Self-Directed Study Guide (2003 ed.). Los 

Angeles: American Academy of HIV 

Medicine; 2003.

• American Academy of HIV Medicine. 

Palliative Care and End-of-Life Support. In: 

AAHIVM Fundamentals of HIV Medicine

(2007 ed.). Washington: American Academy 

of HIV Medicine; 2007.

• National Hospice Organization. Guidelines 

for Determining Prognosis for Selected NonCancer Diagnoses. Alexandria, VA: National 

Hospice Organization; 1996.

• O’Neill JF, McKinney M. Care for the 

Caregiver. In: O’Neill JF, Selwyn PA, 

Schietinger H, eds. The Clinical Guide 

to Supportive and Palliative Care for 

HIV/AIDS. Rockville, MD: Health 

Resources and Services Administration; 

2003. Available at hab.hrsa.gov/

deliverhivaidscare/files/palliativecare2003.

pdf. Accessed December 1, 2013.

• Selwyn PA, Rivard M. Palliative care for 

AIDS: challenges and opportunities in the 

era of highly active anti-retroviral therapy. 

J Palliat Med. 2003 Jun;6(3):475-87.

• University of Washington Center for 

Palliative Care Education. Module 1: 

Overview of HIV/AIDS Palliative Care. 

Available at depts.washington.edu/

pallcare/training/overview.shtml. Accessed 

December 1, 2013.

• U.S. Health Resources and Services 

Administration. A Guide to Primary Care 

of People with HIV/AIDS, 2004 Edition. 

Rockville, MD: Health Resources and 

Services Administration; 2004;123-131. 

Available at hab.hrsa.gov/deliverhivaidscare/

files/primary2004ed.pdf. Accessed 

December 1, 2013.

• Weinreb NJ, Kinzbrunner BM, Clark M. 

Pain Management. In: Kinzbrunner BM, 

Weinreb NJ, Policzer JS, eds. 20 Common 

Problems: End-of-life Care. New York: 

McGraw Hill Medical Publishing Division; 

2002;91-145.

• World Health Organization. Cancer Pain 

Relief and Palliative Care, Report of a WHO 

Expert Committee. Geneva: World Health 

Organization; 1990.
Adherence | 273

Section 4: HIV Treatment

Adherence

Background

For HIV-infected patients with wild-type virus who are taking antiretroviral therapy (ART), 

adherence to ART is the major factor in ensuring the virologic success of an initial regimen and is 

a significant determinant of survival. Adherence is second only to the CD4 cell count as a predictor 

of progression to AIDS and death. Adherence rates approaching 100% are needed for optimal 

viral suppression, yet the average ART adherence in the United States is approximately 70%. 

Individualized assessment of and support for adherence are essential for patients to be successful 

with ART.

Patients with suboptimal adherence are at risk not only of HIV progression, but also of the 

development of drug resistance (see chapter Resistance Testing) and consequent narrowing of 

options for future treatment. In one cohort study, it was estimated that drug-resistant mutations 

will occur in 25% of patients who report very high but not perfect (92-100%) adherence to ART. It 

is important to note, though, that the relationship between suboptimal adherence and resistance to 

antiretroviral (ARV) medications is very complex and is not thoroughly understood.

Characteristics of the ARV regimen and individual patient pharmacokinetic variables also 

influence the likelihood of both virologic suppression and the development of resistance mutations. 

For example, in patients with wild-type virus on initial ART regimens, it appears that more drug 

resistance occurs in regimens that are based on an unboosted protease inhibitor or a nonnucleoside 

reverse transcriptase inhibitor, where the genetic barrier to resistance is relatively low, than 

in regimens that include a ritonavir-boosted protease inhibitor. In patients with suboptimal 

adherence, these factors can influence outcomes of therapy more strongly.

S: Subjective

Studies indicate that health care providers’ 

assessments of their patients’ adherence often 

are inaccurate, so a calm and open approach to 

this topic is very important.

Adherence assessment is most successful 

when conducted in a positive, nonjudgmental 

atmosphere. Patients need to know that their 

provider understands the difficulties associated 

with taking an ARV regimen. Within a trusting 

relationship, a provider may learn what is 

actually happening with the patient’s adherence 

rather than what the patient thinks the 

provider wants to hear. See Table 1 for examples 

of questions to assess adherence in patients who 

are on ART. For patients who are considering 

initiation of ART, it is important to lay the 

groundwork for optimal adherence in advance, 

and to anticipate barriers to adherence; see 

Table 2 for exploratory questions.

Common reasons for nonadherence include 

the following: experiencing adverse drug 

effects, finding the regimen too complex, 

having too many pills, having difficulty with 

the dosing schedule (not fitting into the daily 

routine), forgetting to take the medications, 

being too busy with other things, oversleeping 

and missing a dose, being away from home, not 

understanding the importance of adherence, 

and being embarrassed to take medications 

in front of family, friends, or coworkers. 

Other contributors to incomplete adherence 

include psychosocial issues (e.g., lack of social 

support, homelessness), psychiatric illness, 

and active substance abuse. It is important to 

look for these and other potential barriers to 

adherence. (See chapter Initial History.)
274 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

O: Objective

Evaluate the following:

• CD4 cell count

• HIV viral load (indicating the effectiveness 

of ART in suppressing viremia; an indirect 

indicator of adherence)

• Current drug list (including over-thecounter medications, vitamins, and herbal 

remedies); check for potential adverse drugdrug interactions with ARV medications

• Pharmacy refill records or missed doses 

remaining in pill organizers (e.g., medi-sets 

pill boxes, bubble packs)

A: Assessment

Assess adherence at each visit using questions 

such as those in Tables 1 and 2, and assessment 

scales such as those found in Tables 4, 5, and 

6 (Appendix). Ask these questions in a simple, 

nonjudgmental, structured format and listen 

carefully to the patient to invite honesty about 

issues that may affect adherence. Asking about 

adherence over the last 3 to 7 days gives an 

accurate reflection of longer-term adherence.

Ideally, a multidisciplinary team that 

includes primary providers as well as nurses, 

pharmacists, medication managers, and 

social workers works together to evaluate and 

support patient adherence. 

Table 1. Important Questions to Ask 

Patients Taking ART

• Do you manage your own medications? If 

not, who manages them for you?

• What HIV medications do you take and 

what is their dosage? When do you take 

these?

• What is your average daily schedule like? 

How well does taking your HIV medications 

at this time fit into your daily schedule?

• How do you remember to take your 

medications?

• How many doses of your HIV medication 

have you missed in the past 72 hours, past 

week, past 2 weeks, and past month?

• On a scale of 1 to 10, where would you say 

you are? A score of 1 indicates that you do 

not take your medicines as directed at all; 

for example, not every day or not at the 

same time every day; 10 indicates that you 

take your medications perfectly every day, 

at the same time every day. (Visual analog 

scales are also used to assess adherence; 

see Appendix.)

• If not a 10, what causes you not to be a 10?

• When are you most likely to miss doses?

• Do you have any adverse effects from your 

HIV medications? If so, what are they?

• Are you comfortable taking medications in 

front of others?

• What is most difficult about taking your 

medications?

• How do you like working with your 

pharmacy?

Table 2. Important Questions to Ask 

Patients Considering Initiation of ART

• What is your attitude toward ART?

• Do you believe that ART is effective?

• What are your biggest concerns about 

starting ART?

• What do you hope these medications will 

do for you?

• Are you ready to take the medication every 

day, around the same time each day?

• What is your level of commitment and 

motivation to take the medication every 

day for the rest of your life?

• Who knows about your HIV status?

• What other medications are you taking: 

prescription, over-the-counter, herbals?

• Are you a morning or afternoon person?

• What is your daily routine, including waking 

and bed times?

• How many meals and snacks do you eat per 

day, and at what times?

• Do you use alcohol, marijuana, cocaine, or 

injectable drugs? If so, how much do you 

use and how long have you used them?

• What are your ARV regimen preferences? 

What are some of the most important 

things you want to avoid in an ARV regimen 

(e.g., specific side effects, number of pills, 

frequency of dosing)?

The patient’s self-report has been shown to be 

the most effective measure of adherence. Although, according to some studies, self-report of 

good adherence has limited value as a predictor 
Adherence | 275

Section 4: HIV Treatment

of good adherence; self-report of suboptimal 

adherence should be taken seriously and considered a strong indicator of nonadherence.

Before initiating (or changing) ART, it is important to assess the patient’s readiness for 

ART. Patient factors that have been associated 

with poor adherence in the United States and 

western Europe include:

• Active alcohol or drug use

• Competing priorities (e.g., housing, 

childcare, food, work)

• Depression

• Lack of belief in treatment efficacy

• Lack of social support

• Lack of support from a partner

• Low literacy

• More advanced HIV infection

• Unstable housing

• Young age

Most of these factors are modifiable. Before 

starting ART, appropriate interventions should 

be made, and sources of adherence support 

should be identified to help patients overcome 

potential barriers to adherence.

It is important to note that sociodemographic 

variables such as sex, HIV risk factors, and education level generally are not associated with 

adherence. In addition, a history of substance 

or alcohol abuse is not a barrier to adherence.

Assess the patient’s support system, and 

ask who knows about his or her HIV status. 

Supportive family members or friends can 

help remind patients to take their medications 

and assist with management of adverse 

effects. For patients who have accepted their 

HIV infection as an important priority in 

their lives, taking medications can become 

routine despite other potential adherence 

barriers such as alcohol or drug use.

Assess patients’ willingness to accept and tolerate common adverse effects of ART. Patients 

may identify some adverse effects that they 

wish to avoid completely and others that they 

are willing to accept and manage; this may help 

in tailoring the selection of ARV medications 

to the individual patient. Describe strategies for 

the management of adverse effects before starting a regimen (see chapters Patient Education

and Adverse Reactions to HIV Medications), 

and emphasize that adverse effects often can be 

treated quite effectively, and that they should 

notify their providers if they experience them.

For patients taking ART, it is important to 

assess adherence at every clinic visit. Tools 

such as those in the Appendix to this chapter 

may be useful in predicting adherence. 

Adverse effects are a common cause of 

suboptimal adherence to ART. Continue to 

ask whether the patient has adverse effects 

from the ARV medications and assess his or 

her ability to accept and tolerate these. Work 

closely with the patient to treat adverse effects, 

and consider changes in ART if adverse effects 

are not tolerated. Continue to offer support 

to improve or maintain optimal adherence.

Before prescribing ARVs, some clinicians have 

their patients conduct adherence trials using 

placebo tablets or jelly beans to measure the 

patients’ readiness to start therapy and their 

ability to adhere to a regimen. Such a trial allows patients to experience what a regimen 

will entail in real life, how therapy will affect 

their daily lifestyles, and what changes will 

be needed to accommodate the regimen. The 

shortcoming of placebo trials is that patients 

are not challenged with adverse effects as they 

might be with an actual regimen.

P: Plan

Start the ARV regimen when the patient is 

ready (recognizing that in some cases the need 

for ART is urgent). Starting it too early may 

result in poor acceptance of ART by the patient, 

inadequate adherence, failure of the regimen, 

and increased risk of ARV resistance. Comorbid 

conditions that may interfere with adherence, 

such as mental health issues or depression, may 

need to be treated initially. It is important to 

consider the patient’s preferences and to involve 

her or him in selecting the drug regimen. The 
276 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

regimen must fit into the patient’s daily routine, 

and the patient must believe in the potential 

success of ART. It is extremely important to 

simplify the ARV regimen to the extent possible 

with once-daily regimens and the lowest number of pills (and lowest total expense to the patient), while maintaining efficacy and minimizing adverse effects; this will help to maximize 

adherence and avoid pill fatigue. Starting ART 

is rarely an emergency situation, so taking time 

to identify the patient’s wishes for care, making 

a thorough readiness assessment, selecting the 

ARV regimen, and planning for adherence support are important measures for maximizing 

the likelihood of treatment success. (See Table 3 

for additional suggestions.)

Table 3. Strategies for Improving 

Adherence to ART

• Use a multidisciplinary team approach

• Establish a trusting relationship with the 

patient

• Establish readiness to start ART

• Assess and simplify regimens if possible 

• Involve the patient in ARV regimen selection

• Identify potential barriers to adherence prior to 

starting ART

• Provide mental health and substance abuse 

resources for the patient if needed

• Provide resources to obtain prescription drug 

coverage 

• Assess adherence at every clinic visit

• Use educational aids including pictures, 

pillboxes, and calendars

• Identify the type of nonadherence and the 

reasons for nonadherence

• Anticipate and treat adverse effects

• If resources allow, select from among available 

effective interventions

Adapted from Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of antiretroviral agents 

in HIV-1-infected adults and adolescents. Department of Health 

and Human Services. Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2103.

Patients who can identify their medications 

(in their own words) and describe the proper 

dosing and administration have higher 

adherence rates. Providing patient education 

before writing a prescription helps ensure 

adherence to ARV regimens. Education 

can be provided in oral, written, or graphic 

form to assist the patient’s understanding 

of the medications and their dosing. Basic 

information, including number of pills, 

dosages, frequency of administration, dietary 

restrictions, possible adverse effects, tips for 

managing adverse effects, and duration of 

therapy, will help patients to understand their 

ARV regimens. Patients should understand 

that the success of ART depends upon taking 

the medications every day and that very high 

adherence levels (in some cases perhaps >95%) 

are important in preventing virologic failure.

Close follow-up by telephone, clinic visits, 

or other contact with the patient during 

the first few days of therapy is useful in 

identifying adverse effects, assessing the 

patient’s understanding of the regimen, and 

addressing any concerns before they become 

significant adherence barriers. Individualized 

interventions should be designed to optimize 

outcomes for each patient. Pharmacists, 

peer counselors, support groups, adherence 

counselors, behavioral intervention counselors, 

and community-based case managers are 

useful in supporting adherence for the HIVinfected patient. Multidisciplinary teams that 

include nurses, case managers, nutritionists, 

and clinical pharmacists, in which each care 

provider focuses on adherence at each contact 

with the patient, are extremely effective, and 

peer support groups, in which patients share 

with one another their strategies for improving 

adherence, may be beneficial.

Many physical devices can be used to 

support adherence. The following are simple, 

inexpensive, and easy to incorporate into the 

routine of the HIV patient:

• Medication organizers include pillboxes 

and medi-sets. These are available in several 

shapes and sizes to fit the needs of the 

individual patient. They can be filled weekly 

so that the patient can easily determine 

whether a dose of medication was missed.

• Reminder devices include alarm watches, 

beepers, and cell phone alarms. They are ef-
Adherence | 277

Section 4: HIV Treatment

fective in reminding the patient when to take 

medications. Medication diaries may be used 

for the patient to record doses that were taken.

• Visual medication schedules are calendars 

featuring photos or images of the patient’s 

medications to remind the patient which 

drugs to take and at what dosages.

• Interventions for successful adherence are 

an ongoing effort, not one-time events. 

Studies have suggested that adherence rates 

decline when patient-focused interventions 

are discontinued. Therefore, positive 

reinforcement at each clinic visit or contact 

is extremely important. Reinforce what the 

patient has done well and assist the patient 

in identifying and problem-solving areas 

for improvement. Whenever possible, share 

positive information about the patient’s 

health, such as improvements in quality 

of life, CD4 cell count, and viral load, to 

encourage a high level of adherence. 

Special Populations and Issues

Mental Illness

Patients with mental health issues may have 

difficulty with adherence. In this population, it 

is particularly important to incorporate ARV 

medications into structured daily routines. 

Medication cassettes, reminder signs, and 

calendars have been very effective for these 

patients. Nursing care providers and family 

members may be instrumental in filling medication boxes or ordering prescription refills.

Pediatrics

Adherence can be a challenge for young children 

who rely on parents and caregivers to provide 

their medications, but adolescents are more likely 

than younger children to have poor adherence. 

To improve adherence in this population, it is 

important to support the family. The Department 

of Health and Human Services Guidelines for 

the Use of Antiretroviral Agents in Pediatric HIV 

Infection (available at aidsinfo.nih.gov/guidelines) 

address some of the adherence issues and considerations for this patient population.

Low Literacy

Health literacy is an important predictor of 

treatment adherence, particularly in low-income 

populations and some immigrant populations. 

Adherence interventions are necessary in this 

population to accommodate individuals who 

have difficulty reading and understanding 

medical instructions. Providers often fail to 

recognize this disability. In addition, adherence 

support is needed for patients who have difficulty 

navigating the health care system.

Resource-Limited Settings

Research has shown that the level of adherence 

in resource-limited countries is at least as good 

as in resource-rich settings and that rates of 

virologic suppression are equivalent or better. 

Lack of access to a consistent supply of ARV 

medications, including financial barriers that 

may cause interruptions in treatment, appears 

to be the primary obstacle to adherence in 

resource-limited settings.

Patient Education

• Educate patients about the importance of 

adherence and the need to take their ARV 

medications exactly as prescribed and to 

take every dose, every day.

• Advise patients that, if they miss an ARV 

dose on a rare occasion, that usually will 

not result in failure of the regimen. On the 

other hand, if they frequently miss or skip 

doses of their ARV medications, the regimen 

may become ineffective, and the HIV may 

develop resistance to ARVs.

• Tell patients to notify the clinic if they miss 

doses of the ARV medications.

• Work with patients to devise ways to 

improve their adherence, and reinforce good 

adherence behavior.

• Advise patients in advance that some people 

have adverse effects from the medications, 

and tell them to notify the clinic if they 

develop adverse effects. Discuss ways to 

reduce these effects. 
278 | Guide for HIV/AIDS Clinical Care

Section 4: HIV Treatment

Appendix

Table 4. Visual Analog Scale Used in a Research Study to 

Assess Adherence to HIV Medication Regimens 

Script for Interviewing Patients About Adherence

Interviewer Now I’m going to ask some questions about your HIV medications.

Most people with HIV have many pills or other medications to take at different times during the 

day. Many people find it hard to always remember to take their pills or medicines. For example:

• Some people get busy and forget to carry their pills with them.

• Some people find it hard to take their pills according to all the instructions, such as “with 

food” or “on an empty stomach,” “every 8 hours,” or “with plenty of fluids.”

• Some people decide to skip taking pills to avoid adverse effects or to just not take pills that day.

We need to understand what people with HIV are really doing with their pills or medicines. Please 

tell us what you are actually doing. Don’t worry about telling us you don’t take all your pills or 

medicines. We need to know what is really happening, not what you think we “want to hear.”

Which antiretroviral medications have you been prescribed to take within the last 30 days?

INTERVIEWER: LIST CODES FOR ALL ANTIRETROVIRALS THAT SUBJECT WAS 

PRESCRIBED TO TAKE IN LAST 30 DAYS. IDENTIFY UP TO 4 DRUGS.

DRUG A: DRUG C:

DRUG B: DRUG D:

Interviewer Now, I am going to ask you some questions about these drugs. Please put an “X” on the line 

below at the point showing your best guess about how much (DRUGS A-D) you have taken in 

the last 3-4 weeks. We would be surprised if this were 100% for most people.

HAND INSTRUMENT AND PEN TO RESPONDENT

Interviewer • 0% means you have taken no (DRUG A)

• 50% means you have taken half your (DRUG A)

• 100% means you have taken every single dose of (DRUG A)

Adherence Self-Assessment Instrument

Instructions 

for Patient:

Put an “X” on the line below at the point showing your best guess about how much of each 

drug you have taken in the last 3 to 4 weeks.

• 0% means you have taken none of the drug

• 50% means you have taken half of the drug

• 100% means you have taken every single dose of the drug

DRUG A: 0 1 2 3 4 5 6 7 8 9 10

DRUG B: 0 1 2 3 4 5 6 7 8 9 10

DRUG C: 0 1 2 3 4 5 6 7 8 9 10

DRUG D: 0 1 2 3 4 5 6 7 8 9 10

Adapted from Machtinger EL, Bangsberg DR. Adherence to HIV Antiretroviral Therapy. In: Coffey S, Volberding PA, eds. HIV InSite 

Knowledge Base [textbook online]; San Francicsco: UCSF Center for HIV Information; May 2005. Available at hivinsite.ucsf.edu/

InSite?page=kb-03-02-09. Accessed December 1, 2013.
Adherence | 279

Section 4: HIV Treatment

Table 5. Morisky Scale to Assess Adherence to HIV 

Medications: Dichotomous Response Options

Subjects were asked: “Thinking about the medications PRESCRIBED to 

you by your doctor(s), please answer the following questions.” NO YES

Do you ever forget to take your medications?

Are you careless at times about taking your medications?

When you feel better, do you sometimes stop taking your medications?

Sometimes, if you feel worse when you take your medications, do you stop taking them?

Adapted from Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence.

Med Care 1986;24:67-74. 

Table 6. Morisky Scale to Assess Adherence to HIV 

Medications: 5-Point Response Options 

Subjects were asked:

“Thinking of the medications PRESCRIBED to you by your doctor(s), please answer the following questions.”

Response options: never = 0; rarely = 1; sometimes = 2; often = 3; always = 4 0 1 2 3 4

Do you ever forget to take your medications?

Are you careless at times about taking your medications?

When you feel better, do you sometimes stop taking your medications?

Sometimes, if you feel worse when you take your medications, do you stop taking 

them?

Adapted from Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence.

Med Care 1986;24: 67-74. 

References

• Bangsberg DR, Moss AR, Deeks SG. 

Paradoxes of adherence and drug resistance 

to HIV antiretroviral therapy. J Antimicro 

Chemother 2004: 53: 696-99.

• Gaithe J Jr. Adherence and potency with 

antiretroviral therapy: a combination for 

success. J Acquir Immune Defic Syndr. 2003 

Oct 1;34 Suppl 2:S118-22.

• Golin CE, Smith SR, Reif S. Adherence 

counseling practices of generalist and 

specialist physicians caring for people living 

with HIV/AIDS in North Carolina. J Gen 

Intern Med. 2004 Jan;19(1):16-27.

• Machtinger EL, Bangsberg DR. Adherence 

to HIV Antiretroviral Therapy. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [textbook online]; San Francisco: 

UCSF Center for HIV Information; May 

2005. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-03-02-09. 

Accessed December 1, 2013.

• Malcolm SE, Ng JJ, Rosen RK, et al. An 

examination of HIV/AIDS patients who have 

excellent adherence to HAART. AIDS Care. 

2003 Apr;15(2):251-61.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.

gov/guidelines. Accessed December 1, 2013.

• Protopopescu C, Raffi F, Roux P, et al.; ANRS 

CO8 APROCO-COPILOTE Study Group. 

Factors associated with non-adherence to 

long-term highly active antiretroviral therapy: 

a 10 year follow-up analysis with correction 

for the bias induced by missing data. J 

Antimicrob Chemother. 2009 Sep;64(3):599-

606.

• Stone VE, Smith KY. Improving adherence 

to HAART. J Natl Med Assoc. 2004 Feb;96(2 

Suppl):27S-29S.

Diarrhea | 281

Section 5: Common 

Complaints

Diarrhea

Background 

Diarrhea is a common complaint among HIV-infected individuals, and has a variety of causes. 

Episodes may be acute and brief, intermittent or recurrent, or, in some cases, chronic and severe. 

If diarrhea persists, it may cause dehydration, poor nutrition, and weight loss. Diarrhea may 

diminish patients’ quality of life significantly, and may interfere with adherence to and efficacy of 

antiretroviral (ARV) medications.

Diarrhea is defined in various ways, but commonly as more than 4 loose or watery stools per day 

for more than 3 days. Duration is classified as follows: 

• Acute: <2 weeks

• Persistent: 2-4 weeks

• Chronic: >4 weeks

The causes of diarrhea, both infectious and noninfectious, found in HIV-infected individuals with 

normal or mildly depressed CD4 cell counts are likely to be similar to those in HIV-uninfected 

persons. Among the noninfectious causes of diarrhea, adverse effects of ARVs and other 

medications are particularly common. Persons with advanced immunodeficiency are more likely 

to have infections, including opportunistic infections, as the cause of diarrhea.

Infectious diarrhea typically involves either the small or the large intestine, and the patient’s 

history often suggests the site of the problem. Infections of the small intestine (enteritis) commonly 

produce generalized or periumbilical abdominal cramps, large-volume diarrhea without blood, 

and frequently dehydration. Large-intestine infections (colitis) often produce lower abdominal 

pain, an unproductive urge to defecate, and frequent small-volume stools with blood and pus.

S: Subjective

The patient complains of diarrhea. Take a 

thorough history, including the following:

• Onset of diarrhea: sudden or gradual

• Frequency (times per day, last episode)

• Stool consistency (soft vs. liquid)

• Stool color (gray, white, or greasy stools: 

possible cholelithiasis or pancreatitis; dark 

stools: possible gastrointestinal bleeding)

• Bloody stools (may indicate 

invasive organisms, inflammation, 

ischemia, or neoplasm)

• Rectal bleeding

• Straining at stool

• Pain with defecation, rectal discharge 

(consider sexually transmitted 

diseases, herpes simplex virus)

• Nausea or vomiting (within 6 

hours of ingesting food, consider 

foodborne illness, gastroenteritis)

• Weight loss: quantify amount 

and time frame

• Abdominal pain or cramping; 

location if present

• Fever (consider invasive pathogens: 

Shigella, Campylobacter, Salmonella,

Clostridium difficile)

• Other associated symptoms 

(e.g., bloating, flatus)
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• Allergies (to foods or medications)

• Aggravating factors (e.g., dairy 

products, fatty or spicy foods)

• Alleviating factors (e.g., fasting)

• Treatments tried (e.g., over-thecounter antidiarrheals)

• Contact with others with similar symptoms

• Previous episodes of diarrhea

• History of cytomegalovirus (CMV), 

Mycobacterium avium complex 

(MAC), or other infections involving 

the gastrointestinal tract

• Family history of inflammatory 

bowel disease, celiac disease

• Oral-anal sexual contact (males and females)

• Receptive anal intercourse

• Exposure to unsafely prepared food 

(e.g., raw, undercooked, spoiled), 

unpasteurized milk or juices

• Exposure to possibly contaminated 

water (swimming in or drinking 

from well, lake, or stream) (consider 

parasites, including Giardia)

• Exposure to non-toilet-trained 

infants and children (e.g., at a daycare 

facility), pets, farm animals, reptiles 

(consider Giardia, Salmonella)

• Recent travel (enterotoxigenic Escherichia 

coli, Shigella, Rotavirus, Salmonella,

Campylobacter, Giardia, Entamoeba 

histolytica)

• Antibiotic use or exposure in recent 

weeks or months or recent hospitalization 

(consider C. difficile)

• ARV medications, especially ritonavirboosted protease inhibitors; check 

relationship of diarrhea onset to initiation 

of ARVs

• Other current and recent medications 

(prescribed or over-the-counter), including 

supplements and herbal preparations

• Dietary factors, especially “sugarfree” foods (containing nonabsorbable 

carbohydrates), fat substitutes, milk 

products, and shellfish, or heavy intake 

of fruits, fruit juices, or caffeine

• Alcohol and recreational 

drug use; withdrawal

O: Objective

Record vital signs, including temperature, 

orthostatic heart rate, blood pressure 

measurements, and weight. Compare these 

with recent or baseline values. Perform a 

thorough physical examination, including 

evaluation of the following: 

• Hydration status (skin turgor, 

mucous membrane moistness)

• Nutritional status (body habitus, 

muscle mass, skin and hair integrity)

• Oropharynx (lesions, candidiasis, 

ulcerations, Kaposi sarcoma)

• Optic fundi (signs of CMV infection)

• Abdomen (distention, bowel 

sounds, tenderness, organomegaly, 

masses, adenopathy)

• Rectum (masses, tenderness, bloody stool)

Review recent CD4 cell counts. Low CD4 

counts increase the risk of chronic or systemic 

illnesses and opportunistic infections.
Diarrhea | 283

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A: Assessment

The differential diagnosis of diarrhea is 

broad and includes the following infectious 

and noninfectious causes. The CD4 cell 

count is important in stratifying risk of 

infection with opportunistic pathogens; some 

organisms cause disease only with severe 

immunosuppression.

Infectious Causes

Table 1. Infectious Causes 

Severity Differential Diagnosis

Active 

diarrhea, 

any CD4 

count

• Viruses (especially Norwalk virus)

• Viral hepatitis

• Herpes enteritis

• C. difficile (suspect in patients 

who have recently undergone 

treatment with antibiotics, or 

hospitalization)

• Salmonella

• Shigella

• Campylobacter

• E. coli O157:H7

Chronic 

diarrhea, 

any CD4 

count

• C. difficile (suspect in patients 

who have been treated with 

antibiotics

• Giardia lamblia

• E. histolytica

Chronic 

diarrhea, 

CD4 count 

<300 

cells/μL

• Microsporidia

• Cryptosporidium parvum

• MAC (CD4 count <50 cells/μL)

• Isospora belli

• CMV (CD4 count <50 cells/μL)

Adapted from: Infectious Causes of Diarrhea in Patients with 

HIV, Table 8-8. In: Bartlett JG, Cheever LW, Johnson MP, et al., 

eds. A Guide to Primary Care of People with HIV/AIDS. Rockville, 

MD: U.S. Department of Health and Human Services, Health 

Resources and Services Administration; 2004. Available at hab.

hrsa.gov/deliverhivaidscare/files/primary2004ed.pdf. Accessed 

December 1, 2013.

Noninfectious Causes

• Medication adverse effects, common with 

many medications including some ARVs: 

• Protease inhibitors (especially ritonavir 

and nelfinavir)

• Didanosine buffered tablets (no longer 

available in the United States)

• Cobicistat (present in Stribild)

• Irritable bowel syndrome

• Inflammatory bowel disease (ulcerative 

colitis, Crohn disease)

• Lymphoma

• Lactose intolerance

• Celiac disease

• Small intestinal bacterial overgrowth

• Pancreatic insufficiency

• Diverticulitis

• Fecal incontinence

• Laxative abuse

P: Plan

Diagnostic Evaluation

For suspected infections, perform laboratory 

studies including complete blood count with 

differential, serum electrolyte panel, and liver 

function tests. Check stool for white blood cells 

and blood. Perform stool studies as indicated 

by the patient’s presentation (bacterial 

culture, ova and parasites, microsporidia, 

cryptosporidia, Giardia antigen, C. difficile

toxin assay). Order additional studies as 

suggested by the history (e.g., blood cultures, 

MAC cultures, hepatitis serologies, retinal 

examination for CMV). If noninfectious 

causes are suspected, perform evaluation 

for these etiologies as indicated (e.g., fecal 

fat concentration [for steatorrhea], stool 

osmolar gap [for osmotic diarrhea], antitissue transglutaminase [TTG] antibody [for 

celiac disease], or D-xylose [for pancreatic 

insufficiency]).
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If the patient is febrile, perform a complete 

fever workup as appropriate (see chapter 

Fever).

Check the CD4 cell count and HIV viral load, 

if not checked recently.

If stool study results are negative (ova and 

parasite negative in three successive samples) 

and the patient has severe symptoms, 

particularly in the case of advanced 

immunodeficiency, refer to a gastroenterologist 

for colonoscopy or flexible sigmoidoscopy 

with biopsy. Endoscopy with biopsy is the best 

procedure for identifying certain conditions, 

including CMV colitis and inflammatory 

bowel disease. If all study results are negative 

but the diarrhea persists, consider repeat 

endoscopy in 6-8 weeks regardless of the 

level of immunodeficiency. Pathogens may be 

difficult to identify.

Treatment

Once a diagnosis is made, initiate appropriate 

treatment. For seriously ill patients, 

presumptive treatment may be started while 

diagnostic tests are pending. If the cause of the 

diarrhea cannot be identified, consult with an 

HIV expert or a gastroenterologist. 

• For moderate to severe acute diarrhea, 

including dysentery (bloody diarrhea), 

empiric treatment can be given pending 

stool study results or in settings with limited 

resources for workup. If bacterial pathogens 

are suspected, use oral fluoroquinolones 

(e.g., ciprofloxacin 500 mg BID or 

levofloxacin 500 mg QD) for 5 days. Monitor 

effectiveness and adjust therapy according 

to the results of diagnostic studies and 

clinical response. Specific treatment with 

antimicrobials is guided by the pathogens 

identified in stool studies or on biopsy.

• For suspected small intestinal bacterial 

overgrowth consider treatment with an 

appropriate antimicrobial (e.g., rifaximin 

1,200-1,600 mg per day for 7-10 days).

• For mild persistent diarrhea with no 

identified pathogen, treat with an 

antidiarrheal agent (see below). For patients 

whose diarrhea is suspected to be caused 

by ARV agents or other medications, 

symptomatic treatment also may be tried. 

Diarrhea owing to protease inhibitors 

often decreases after a few weeks without 

treatment. For persistent, daily ARVassociated diarrhea, antidiarrheal agents 

may be given on a scheduled basis (rather 

than as needed). If the diarrhea cannot be 

controlled, a change in ARV regimen should 

be considered.

Symptomatic treatments

• Antimotility agents such as loperamide 

(Imodium) in over-the-counter or 

prescription strengths and atropine/

diphenoxylate (Lomotil) are useful for many 

patients. The suggested dosage is 2 tablets 

after each loose bowel movement, not to 

exceed 8 tablets per day. These agents should 

not be used if patients have bloody diarrhea 

or if the presence of C. difficile is suspected.

• Pharmaco-nutritional approaches include 

the use of calcium supplementation (500 

mg BID or TID). Patients with diarrhea 

related to protease inhibitors may find that 

taking calcium with each dose of protease 

inhibitors can decrease or prevent diarrhea. 

Note that magnesium supplements may 

worsen diarrhea.
Diarrhea | 285

Section 5: Common 

Complaints

• Pancrelipase can be useful in managing 

chronic diarrhea caused by malabsorption. 

It comes in different formulations with 

differing amounts of pancreatic enzymes; 

usual dosage is 2-3 capsules TID with meals, 

titrated downward according to response.

• Cholestyramine or psyllium (e.g., 

Metamucil) may reduce diarrhea by slowing 

peristalsis and adding bulk to stools. Avoid 

administering cholestyramine with other 

medications because it may impair their 

absorption.

• Crofelemer, an antisecretory antidiarrheal 

agent, is approved by the U.S. Food and 

Drug Administration for treatment of 

noninfectious diarrhea in HIV-infected 

adults on antiretroviral therapy (ART). The 

dosage is 135 mg BID. Infectious causes 

should be ruled out before treatment with 

crofelemer.

• A combination of these treatments may be 

needed to control chronic diarrhea, and 

they can be continued for patients after an 

infectious process has been ruled out.

Nutrition and hydration

Encourage frequent intake of soft, easily 

digested foods such as bananas, rice, wheat, 

potatoes, noodles, boiled vegetables, crackers, 

and soups. Encourage hydration with fruit 

drinks, tea, “flat” carbonated beverages, 

and water. Patients should avoid high-sugar 

drinks, caffeinated beverages, alcohol, highfiber foods, greasy or spicy foods, and dairy 

products. Many patients may benefit from a 

trial of a lactose-free, low-fiber, or low-fat diet. 

Patients should use nutritional supplements 

as needed or as recommended by a dietitian. 

In case of chronic or severe diarrhea, or 

significant weight loss, refer to a dietitian for 

further recommendations.

Patients with severe diarrhea must maintain 

adequate hydration, by mouth if possible. 

In severe cases, IV administration of fluids 

may be necessary. Oral rehydration solutions 

include the World Health Organization 

formula, Pedialyte, Rehydralyte, Rice-Lyte, 

and Resol. Homemade alternatives include the 

following:

• Combine 1/2 teaspoon of salt, 1 teaspoon 

of baking soda, 8 teaspoons of sugar, and 8 

ounces of orange juice; add water to make 1 

liter and drink.

• Drink 1 glass containing 8 ounces of apple, 

orange, or other juice; 1/2 teaspoon of corn 

syrup or honey; and a pinch of salt; then 

drink 1 glass containing 8 ounces of water 

and 1/4 teaspoon of baking soda.

• Mix 1/2 cup of dry, precooked baby rice 

cereal with 2 cups of water (boil first in areas 

with poor water quality); add 1/4 teaspoon of 

salt and drink.

Patient Education

• Diarrhea can have many causes. Instruct 

patients to notify their health care provider 

if they develop new or worsening symptoms.

• Instruct patients to take their medications 

exactly as directed and to call their health 

care provider if they experience worsening 

diarrhea or other symptoms such as fever, 

nausea, vomiting, or pain.

• Patients must stay nourished and well 

hydrated even if they are having diarrhea. 

Instruct patients to eat small, frequent meals 

and to avoid dairy products, greasy food, 

and high-fat meals.

• Instruct patients to maintain good 

handwashing practices during diarrheal 

illnesses to prevent infection in close 

contacts or household members.

• Some diarrheal illnesses are reportable; 

advise patients that they may be contacted 

by the local health department.
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Section 5: Common 

Complaints

References

• American Medical Association, American 

Nurses Association – American Nurses 

Foundation, Centers for Disease Control and 

Prevention, Center for Food Safety and Applied 

Nutrition, Food and Drug Administration, 

Food Safety and Inspection Service, US 

Department of Agriculture. Diagnosis 

and Management of Foodborne Illnesses. 

MMWR 2004; 53(RR04);1-33. Available at 

www.cdc.gov/mmwr/preview/mmwrhtml/

rr5304a1.htm. Accessed December 1, 2013.

• Beatty GW. Diarrhea in patients infected 

with HIV presenting to the emergency 

department. Emerg Med Clin North Am. 2010 

May;28(2):299-310.

• Nysoe TE, Paauw DS. Symptom Management. 

In: Bartlett JG, Cheever LW, Johnson MP, et 

al., eds. A Guide to Primary Care of People with 

HIV/AIDS. Rockville, MD: U.S. Department 

of Health and Human Services, Health 

Resources and Services Administration; 

2004;55-65. Available at hab.hrsa.gov/

deliverhivaidscare/files/primary2004ed.

pdf. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment of 

opportunistic infections in HIV-infected adults 

and adolescents: recommendations from the 

Centers for Disease Control and Prevention, 

the National Institutes of Health, and the HIV 

Medicine Association of the Infectious Diseases 

Society of America. Available at aidsinfo.nih.

gov/guidelines. Accessed December 1, 2013.

• Wilcox CM. Diseases of the Esophagus and 

Stomach and Bowel. In: Dolin R, Masur H, 

Saag M, eds. AIDS Therapy, 3rd Edition. New 

York: Churchill Livingstone Elsevier; 2008.
Ear, Nose, Sinus, Mouth | 287

Section 5: Common 

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Ear, Nose, Sinus, Mouth

Background 

HIV-infected individuals frequently experience infections and neoplasms that affect the ears, nose, 

sinuses, and mouth. The degree of immunosuppression, as reflected by a patient’s CD4 cell count, 

can affect the severity, likelihood of recurrence, and response to therapy for various infections and 

neoplasms.

Patients may present with ear, nose, sinus, or mouth complaints early in the course of HIV 

infection, perhaps even before they are aware of their infection. Some conditions arise more 

commonly in patients with advanced HIV infection. Certain conditions (e.g., oral candidiasis) 

should prompt consideration of HIV testing in patients without known infection.

Ears

HIV-infected patients may experience 

recurrent acute otitis media and serous otitis 

media. Nasopharyngeal lymphoid hyperplasia, 

sinusitis, or allergies may contribute to 

dysfunction of the eustachian tubes. Unilateral 

and bilateral sensorineural hearing loss has 

been reported and may be caused by HIV 

infection involving the central nervous system 

(CNS) or the auditory nerve. Hearing loss 

also may be caused by syphilis, other CNS 

infections, chronic otitis media, neoplasms, 

and certain medications (including nucleoside 

analogues in rare cases). The pathophysiology, 

causative organisms, and incidence of 

external-ear infections appear to be the same 

in HIV-infected patients as in HIV-uninfected 

individuals.

S: Subjective

The patient may complain of ear pain, 

decreased hearing or hearing loss, a feeling 

of fullness in the ear, vertigo, or a popping or 

snapping sensation in the ear.

Obtain information regarding the following 

during the history: 

• Medications (prescription and over-thecounter) and herbal supplements, current 

and past

• Current or recent sinus infection

• Associated symptoms

• Drainage or blood from the ear

• Head or ear trauma

O: Objective

CD4 count is an important measure of 

immunosuppression and a recent CD4 

count is important in determining whether 

the patient is at risk of opportunistic 

infections as causes of ear complaints.

Perform visual and otoscopic inspection, 

including evaluation for skin abnormalities, 

lesions, cerumen impaction or foreign 

body, lymphadenopathy, and adenotonsillar 

hypertrophy.
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If hearing loss is reported or suspected, 

evaluate hearing and refer the patient for an 

audiogram. Perform a neurologic examination 

and test for syphilis (e.g., rapid plasma reagin 

[RPR] or Venereal Disease Research Laboratory 

[VDRL] test) and other possible causes.

A/P: Assessment and Plan

Otitis Externa/Interna

Proceed as with an immunocompetent 

patient. A chronic or atypical presentation in 

an HIV-infected patient warrants a thorough 

evaluation, including cultures, biopsy, 

radiographic scans, and referral to an ear, 

nose, and throat (ENT) specialist.

Hearing Loss

A patient with hearing loss should be referred 

for evaluation or treated, depending on the 

cause. Avoid ototoxic medications (e.g., 

furosemide, aminoglycosides).

Nose and Sinuses

Nasal and paranasal sinus conditions occur 

frequently in HIV-infected patients. Sinusitis, 

nasal obstruction, allergic rhinitis, and nasal 

lesions are common. Epistaxis can occur in 

patients with platelet disorders (e.g., idiopathic 

thrombocytopenic purpura [ITP]).

S: Subjective

The patient may complain of “stuffy nose,” 

rhinorrhea, epistaxis, frontal or maxillary 

headaches (worse at night or early morning), 

pain in the nostrils, persistent postnasal 

drip, mucopurulent nasal discharge, general 

malaise, aching or pressure behind the eyes, or 

toothache-like pain.

Obtain information regarding the following 

during the history: 

• Medications (prescription and over-thecounter) and herbal supplements, current 

and past

• Current or recent sinus infection

• Previous sinus surgery

• Recent or current upper respiratory 

infection (URI)

• Nasal bleeding or discharge

• Facial trauma

• Allergic rhinitis

• Positional pain; worse when patient bends 

forward?

• Tobacco use

• Fever

• Headache

• Mucopurulent nasal drainage

O: Objective

CD4 count is an important measure of 

immunosuppression and a recent CD4 count 

is a key element in determining whether the 

patient is at risk of opportunistic infections as 

causes of nasal and sinus complaints.

Examine the nose and sinuses. Check the nasal 

mucosa with a light and a speculum, looking 

for areas of bleeding, purulent drainage, 

ulcerated lesions, or discolored areas. Palpate 

or percuss the sinuses for areas of tenderness, 

look for areas of swelling over the sinuses, 

and visualize the posterior pharynx for 

mucopurulent drainage. Transillumination 

may be helpful. Examine the teeth and gums 

for caries and inflammation of the gingivae. 

Check maxillary teeth with the use of a 

tongue blade (5-10% of maxillary sinusitis is 

attributable to dental root infection). Refer to a 

dentist for tooth sensitivity or caries.
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Section 5: Common 

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A: Assessment

• Possible causes of epistaxis include 

coagulopathy, ITP, lesions of herpes simplex 

virus (HSV), and Kaposi sarcoma (KS) or other 

tumors. Suspect ITP if the platelet count is low 

and bleeding is difficult to control.

• Acute infection of one or more of the 

paranasal sinuses is common. Streptococcus 

pneumoniae, Haemophilus influenzae, 

and Moraxella catarrhalis are seen in 

both HIV-uninfected and HIV-infected 

patients, whereas Staphylococcus aureus and 

Pseudomonas aeruginosa are found more 

often in HIV-infected patients. Fungi may 

be the causative agents, especially in patients 

with severe immunosuppression.

• Chronic sinusitis occurs frequently in patients 

with HIV infection and may be polymicrobial 

or anaerobic. In patients with low CD4 cell 

counts, fungal sinusitis may occur.

• Nasal obstruction may be caused by 

adenoidal hypertrophy, chronic sinusitis, 

allergic rhinitis, or neoplasm.

• Tumors may be caused by KS, squamous 

papilloma, or lymphoma; biopsy is necessary 

for determining the cause.

• Painful, ulcerated vesicles in the nasal 

mucosa may be caused by HSV or other 

infections.

P: Plan

Acute Sinusitis

Combination therapy with antibiotics, 

decongestants, mucolytics, saline nasal spray, 

and topical nasal steroids may be effective. 

See chapter Sinusitis for details. Note: 

For patients taking antiretroviral (ARV) 

regimens that include ritonavir or cobicistat, 

fluticasone (Flonase) nasal spray should 

not be used, and budesonide (Rhinocort 

Aqua) should be avoided if possible; see 

“Potential ARV Interactions,” below.

Chronic Sinusitis

Treat with a systemic decongestant (e.g., 

guaifenesin) or a saline nasal spray BID. 

Patients with exacerbations of sinusitis should 

be treated as for acute sinusitis. For more 

detailed information, see chapter Sinusitis. 

With patients taking ritonavir-boosted PIs, 

avoid fluticasone and budesonide nasal sprays; 

see “Potential ARV Interactions,” below.

Allergic Rhinitis

Patients should avoid exposure to known or 

suspected allergens. Nasal steroids may be very 

effective, but avoid fluticasone and budesonide 

nasal sprays with patients taking ritonavir or 

cobicistat (see “Potential ARV Interactions,” 

below). Second-generation nonsedating 

antihistamines such as cetirizine, fexofenadine, 

and loratadine are not as effective as nasal 

steroids, but may give additional symptom 

relief. Note that ritonavir may increase the 

serum levels and half-life of cetirizine. Daily 

nasal lavage with normal saline often is 

beneficial.

Nasal Obstruction

Perform magnetic resonance imaging (MRI) or 

computed tomography (CT) scan with biopsy 

for mass lesions or asymmetric nasal lymphoid 

tissue. Refer to an ENT specialist.

Epistaxis

Epistaxis caused by coagulopathy or tumor is 

managed the same as for immunocompetent 

patients with these conditions. Cauterization 

of an identified bleeding point or packing 

may be necessary. ITP should be managed 

in collaboration with a hematologist; 

antiretroviral therapy (ART) typically is used 

for chronic management, and corticosteroids 

or other therapies may be used for acute 

management.
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Potential ARV Interactions

Caution: Protease inhibitors (PIs), particularly 

ritonavir-boosted PIs, and cobicistat [e.g., in 

coformulated elvitegravir/cobicistat/tenofovir/

emtricitabine (Stribild)] may increase serum 

glucocorticoid levels if used concurrently 

with nasal steroids. Fluticasone (Flonase) 

nasal spray should not be used with ritonavirboosted PIs or cobicistat unless expected 

benefits outweigh possible risks, and should 

be avoided, if possible, in patients taking 

unboosted PIs. Budesonide (Rhinocort Aqua) 

nasal spray should be avoided with ritonavirboosted PIs and cobicistat. Interactions of PIs 

and cobicistat with other nasal steroids have 

not been well studied.

Ritonavir and cobicistat may increase serum 

levels of cetirizine and may prolong its half-life; 

start with low dosage and monitor for adverse 

effects.

Mouth and Throat

The oral cavity is one of the most common 

areas of symptoms in patients with HIV 

infection. Conditions that arise in the oral 

cavity may result from infectious, benign 

inflammatory, neoplastic, or degenerative 

processes.

S: Subjective

The patient may complain of white patches and 

red areas on the dorsal surface of the tongue 

and the palate, decreased taste sensation, white 

lesions along the lateral margins of the tongue, 

ulcers, nonhealing lesions at the corners of the 

mouth, sore gums, loose teeth, dysphagia, or 

odynophagia.

Obtain information regarding the following 

during the history:

• Medications (prescription and overthe-counter) and herbal supplements 

(note that some medications 

may cause aphthous ulcers)

• Usual oral hygiene (toothbrushing, 

tongue brushing or scraping, 

flossing, use of mouthwash)

• Date of last dental examination

• Use of tobacco (cigarettes, chewing tobacco)

• Involuntary weight loss

O: Objective

Because the CD4 count reflects degree of 

immunosuppression, a recent CD4 count is 

helpful in determining whether the patient is 

at risk of opportunistic infections as causes of 

oral complaints.

Thorough examination of the mouth and 

throat with a tongue depressor and a good 

light is mandatory. Observe for white patches 

or plaques on the mucous membranes that 

can be partially removed by scraping with a 

tongue blade (candidiasis). Examine the dorsal 

surface of the tongue and hard and soft palates 

for red, flat, subtle lesions (erythematous 

candidiasis). Look for ribbed, whitish lesions 

on the lateral aspects of the tongue that 

cannot be scraped off (oral hairy leukoplakia). 

Check for ulcerations, inflamed gums, and 

loose teeth (see section Oral Health). Look for 

discoloration or nodular lesions on the hard 

palate (Kaposi sarcoma). Check the pharynx 

for adenotonsillar hypertrophy. Rule out HIVunrelated causes of pharyngitis, including 

streptococci or respiratory viruses.
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Section 5: Common 

Complaints

A/P: Assessment and Plan

Perform biopsy, culture, and potassium 

hydroxide (KOH) preparation of lesions as 

indicated.

Oral Candidiasis (Thrush)

Oral candidiasis is most likely to occur when 

the CD4 count is <200 cells/μL, but it can 

occur at any CD4 level and in HIV-uninfected 

individuals. It may appear as creamy white 

plaques on the tongue or buccal mucosa or as 

erythematous lesions on the dorsal surface of 

the tongue or the palate. The most common 

treatment strategy is empiric therapy with 

topical or systemic antifungal agents. For more 

details, see chapter Candidiasis, Oral and 

Esophageal.

Angular Cheilitis

Angular cheilitis is also caused by Candida

species, and it is characterized by fissuring at 

the corners of the mouth. For information on 

treatment, see chapter Candidiasis, Oral and 

Esophageal.

Oral Hairy Leukoplakia

Oral hairy leukoplakia (OHL) is caused by 

Epstein-Barr virus and appears as raised, 

ribbed, “hairy” white lesions along the lateral 

margins of the tongue. Lesions are primarily 

asymptomatic, and treatment generally is not 

needed. Lesions often resolve with effective 

ART. For more details, see chapter Oral Hairy 

Leukoplakia.

Kaposi Sarcoma

KS appears as red, blue, or purplish lesions that 

are flat or nodular, and solitary or multiple. 

Lesions appear most commonly on the hard 

palate but also occur on the gingival surfaces 

and elsewhere in the mouth. A definitive 

diagnosis requires biopsy and histologic 

examination. KS often resolves with ART and 

successful immune reconstitution. If lesions 

do not respond to ART or if they are severe or 

numerous, refer to an oncology specialist for 

chemotherapy. For more details, see chapter 

Kaposi Sarcoma.

Gingivitis

See chapter Necrotizing Ulcerative Periodontitis 

and Gingivitis for details.

Herpes Simplex Virus

HSV lesions occur on the palate, gingivae, 

or other mucosal surfaces. They appear as 

single or clustered vesicles and may extend 

onto adjacent skin of the lips and face to 

form a large herpetic lesion. Lesions tend to 

be more common, persist longer, recur more 

often, and be larger and more numerous 

in HIV-infected patients, especially those 

with significant immunosuppression, than 

in healthy individuals. Empiric treatment 

with valacyclovir, famciclovir, or acyclovir 

is appropriate. For more details, see chapter 

Herpes Simplex, Mucocutaneous.

Aphthous Ulcers

Aphthous ulcers are eroded, well-defined 

lesions surrounded by erythema, ranging in 

size from <6 mm to several centimeters in 

diameter. The ulcers can appear anywhere 

in the oral cavity or pharynx and may 

be recurrent; they are extremely painful. 

Treatment may involve topical steroids or 

other methods. For more details, see chapter 

Oral Ulceration.
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Oral Warts (Human Papillomavirus)

Oral warts may appear as solitary or multiple 

nodules. The lesions may be smooth, raised 

masses resembling focal epithelial hyperplasia, 

or small papuliferous or cauliflower-like 

projections. See chapter Oral Warts.

Neisseria gonorrhoeae Pharyngitis

Neisseria gonorrhoeae may be transmitted 

by orogenital exposure; the patient may 

have mild symptoms (e.g., sore throat) or 

be asymptomatic. Physical examination 

may reveal an erythematous pharynx or 

exudates. Anterior cervical lymphadenopathy 

also may be present. Most cases of N. 

gonorrhoeae pharyngeal infection will 

resolve spontaneously without treatment 

and usually do not cause adverse sequelae. 

However, treatment should be initiated to 

reduce the spread of the infection (see chapter 

Gonorrhea and Chlamydia). Regular screening 

is recommended for patients at risk of N. 

gonorrhoeae infection.

Medication-Related Causes

of Mouth or Throat Lesions

• Candidiasis: antibiotics

• Xerostomia: antihistamines, 

anticholinergics, tricyclics, antipsychotic

• Gingival hyperplasia: phenytoin, calcium 

channel blockers

Other Conditions

Most of the above complications also 

can occur in the esophagus. See chapters 

Esophageal Problems; Candidiasis, Oral and 

Esophageal; and Cytomegalovirus Disease.

If patient is having mouth pain, anorexia, 

or problems with taste, treat the condition 

appropriately and refer to an HIV-experienced 

dentist for evaluation and further treatment as 

needed. Refer to a dietitian for assistance with 

dietary needs (e.g., nutritional supplements).

References

• Greenspan JS, Greenspan D. Oral 

Complications of HIV Infection. In: 

Sande MA, Volberding PA, eds. Medical 

Management of AIDS, 6th ed. Philadelphia: 

WB Saunders; 1999:157-169.

• Gurney TA, Murr AH. Otolaryngologic 

manifestations of human immunodeficiency 

virus infection. Otolaryngol Clin North Am. 

2003 Aug;36(4):607-24.

• Lee K, Tami T. Otolaryngologic 

Manifestations of HIV. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [online textbook]. San Francisco: 

UCSF Center for HIV Information; August 

1998. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-13. 

Accessed December 1, 2013.

• Miller KE. Diagnosis and Treatment of 

Neisseria gonorrhoeae Infections. American 

Family Physician; 2006. Available at www.

aafp.org/afp/2006/0515/p1779.html.

• Sande MA, Eliopoulos GM, Moellering 

RC, et al. The Sanford Guide to HIV/AIDS 

Therapy. Hyde Park, VT: Antimicrobial 

Therapy, Inc.; 2008.
Esophageal Problems | 293

Section 5: Common 

Complaints

Esophageal Problems | 293

Esophageal Problems

Background 

Esophageal problems in HIV-infected patients include difficulty swallowing (dysphagia) or midline 

retrosternal pain when swallowing (odynophagia). Pain may be diffuse throughout the esophagus 

or localized in specific areas.

Several conditions may cause esophageal problems. Of the infectious causes of dysphagia 

in HIV-infected patients, Candida is the most common (50-70%). Drug-induced dysphagia, 

gastroesophageal reflux disease (GERD), vomiting, and hiatal hernia also can cause esophagitis. 

Less commonly, esophageal cancer or another cause of stricture may produce symptoms. 

Neuromuscular or neurological causes may be seen in patients with advanced AIDS.

If untreated, esophageal problems may result in esophageal ulcers, scarring of the esophagus, 

dehydration, and weight loss.

S: Subjective

The patient may complain of difficulty 

swallowing, a feeling of something being 

“stuck in the throat,” retrosternal pain when 

eating, “hiccups,” indigestion (“heartburn”), 

retrosternal burning, acid reflux, nausea, 

vomiting, or abdominal pain. Ascertain the 

following during the history:

• Medications (prescription and over-thecounter) and herbal supplements, current 

and past

• Concurrent gastrointestinal (GI) symptoms, 

such as abdominal pain or diarrhea

• Recent dietary history

• Location and characteristics of pain (diffuse 

or focal)

• Oral thrush

• Aphthous ulcers

• Cytomegalovirus (CMV)

• Candida esophagitis

• Gastroesophageal reflux disease (GERD)

• Hiatal hernia

• Presence of dysphagia to solids, liquids,

or both

• Hematemesis or melena

O: Objective

Include the following in the physical 

examination:

• Measure vital signs (temperature may be 

elevated with certain infections, such as 

CMV, but not with herpes simplex virus 

[HSV], candidiasis, or idiopathic ulcers).

• Record weight (and compare with previous 

weights).

• Assess for oral candidiasis, lesions, and 

masses.

• Examine optic fundi to evaluate for CMV 

retinitis (in patients with CD4 counts of 

<50-100 cells/μL).

• Palpate for thyroid enlargement.

• Palpate the neck and supraclavicular and 

infraclavicular areas for lymphadenopathy.

• Assess the abdomen for masses, tenderness, 

and organomegaly.

• Perform a rectal examination to obtain stool 

for occult blood.

• Perform a neurologic examination.

• Check the CD4 cell count and HIV 

viral load to determine the level of 

immunosuppression and assess the risk 

of opportunistic infections as causes of 

esophageal complaints.
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Complaints

A: Assessment

Common causes of esophageal problems are as 

follows: 

• Candidiasis (common with a CD4 count of 

<200 cells/μL or recent exposure to steroids 

or antibiotics)

• Most medications, including antiretroviral 

agents, can cause nausea and GI-related 

symptoms; the following medications 

are commonly associated with difficulty 

swallowing or heartburn: aspirin, 

nonsteroidal antiinflammatory drugs, 

potassium chloride, iron, tetracycline, 

theophylline, anticholinergic agents, 

calcium channel blockers, meperidine, and 

progesterone tablets

• Foods can irritate the esophagus, including 

citrus fruits, mints, coffee, chocolate, and 

spicy foods

• GERD

Less-common causes of esophageal problems 

include:

• CMV, HSV, idiopathic or aphthous ulcers

• Kaposi sarcoma, lymphoma, tuberculosis, 

Mycobacterium avium complex (MAC), 

histoplasmosis

• Cardiac chest pain

P: Plan

Diagnostic Evaluation

Diagnosis often can be made on clinical 

grounds; in this case, empiric treatment may 

be initiated (see below). If the diagnosis is 

unclear, consider endoscopy or radiographic 

imaging (e.g., computed tomography or 

barium swallow).

If the patient has dysphagia, odynophagia, 

unexplained weight loss, GI bleeding, anemia, 

or atypical symptoms, refer promptly for GI 

evaluation and endoscopy, or other evaluation 

as suggested by symptoms.

Treatment

Determine whether the patient is able to 

swallow pills before giving oral medications. 

If pills are not tolerated, the patient may need 

liquids or troches.

For patients with severe oral or esophageal 

pain, viscous lidocaine 1% 5-10 mL 2-4 

times daily (with swallowing precautions) 

or Magic Mouthwash (viscous lidocaine 1%, 

tetracycline, diphenhydramine, and nystatin 

compounded 1:1:1:1) may be tried.

Other treatments may depend on the 

underlying cause: 

• Esophageal candidiasis: Fluconazole is the 

drug of choice. If symptoms resolve within 

7-10 days, no further testing is required. See 

chapter Candidiasis, Oral and Esophageal

for more treatment options and for dosing 

information.

• Medication related: Remove the offending 

drug(s), and institute a trial of H2 blockers 

or proton pump inhibitors (PPIs) as 

appropriate (caution: see “Potential ARV 

Interactions,” below).

• Food related: Modify the diet and institute 

a trial of H2 blockers or PPIs as appropriate 

(caution: see “Potential ARV Interactions,” 

below).

• “Heartburn” or GERD: Patients whose 

primary symptoms are more typical of 

“heartburn” or reflux, especially those with 

a history of GERD, should receive a trial of 

H2 blockers or a PPI as appropriate (these 

may decrease absorption of atazanavir and 

rilpivirine; see “Potential ARV Interactions,” 

below). Reevaluate after 2-4 weeks; if 

symptoms are controlled, treat for 4-8 

weeks, then reduce the dosage to the lowest 

effective amount.

Patients may require maintenance therapy 

for an indefinite period because of the high 

likelihood of recurrence. If symptoms do not 

respond to full-dose acid-blocking therapy, 

refer for GI evaluation. 
Esophageal Problems | 295

Section 5: Common 

Complaints

• GERD: For nonpharmacologic treatment, 

in cases of obesity, counsel patients to lose 

weight, stop smoking, elevate the head of the 

bed, eat smaller meals, avoid eating food 2-3 

hours before bedtime, and reduce fat in the 

diet to ≤30% of calorie consumption.

• CMV: Treat with anti-CMV medications 

(e.g., oral valganciclovir). See chapter 

Cytomegalovirus Disease for details.

• HSV: Treat with antiviral medications, 

including acyclovir, famciclovir, and 

valacyclovir. See chapter Herpes Simplex, 

Mucocutaneous.

• Aphthous ulcers: These may respond to oral 

corticosteroids (consult with a specialist 

before this is undertaken). Alternatively, a 

combination of H2 blockers and sucralfate 

may be effective. In some circumstances, 

thalidomide 200 mg Q24H may be used. 

(Note: Thalidomide is teratogenic, and 

women of childbearing potential are not 

candidates for this therapy unless the 

potential benefits clearly outweigh the risks 

and appropriate prevention of pregnancy 

is undertaken.) Up to 40-50% of patients 

with aphthous ulcers experience relapse and 

require repeat treatment.

• Neoplastic disease: Treating this condition 

requires referral to an oncologist.

Esophageal conditions that do not resolve with 

treatment require referral to a GI specialist 

for diagnostic endoscopy, with biopsy and 

brushing for histopathology and cultures as 

appropriate.

Diet

It is important that patients maintain 

adequate caloric intake, preferably with foods 

and liquids that can be swallowed easily. 

Nutritional supplements along with soft, bland, 

high-protein foods are recommended. Refer to 

a nutritionist as needed.

References

• DeVault KR, Castel DO; American 

College of Gastroenterology. Updated 

guidelines for the diagnosis and treatment 

of gastroesophageal reflux disease. Am J 

Gastroenterol. 2005 Jan;100(1):190-200.

• Dieterich DT, Poles MA, Cappell MS, 

et al. Gastrointestinal Manifestations of 

HIV Disease, Including the Peritoneum 

and Mesentery. In: Merigan TC, Bartlett 

JG, Bolognesi D, eds. Textbook of AIDS 

Medicine, 2nd ed. Baltimore: Williams & 

Wilkins, 1999;542-6.

• Wilcox CM, Monkemuller KE. 

Gastrointestinal Disease. In: Dolin R, Masur 

H, Saag MS, eds. AIDS Therapy. New York: 

Churchill Livingstone, 1999;752-56.

Potential ARV Interactions

Caution: H2 blockers and PPIs interfere with 

the absorption of atazanavir and rilpivirine. 

For atazanavir, specific dosing strategies 

are required, and some combinations are 

contraindicated. For rilpivirine, PPIs are 

contraindicated and H2 blockers require 

specific dose timing. Polyvalent cations (e.g., 

magnesium, calcium, iron) contained in 

antacids, supplements, and other medications 

may lower serum levels of integrase inhibitors 

and require separate administration. See 

package inserts for dosage recommendations.

Eye Problems | 297

Section 5: Common 

Complaints

Eye Problems

Background 

The immunosuppression caused by HIV infection increases the incidence of eye infections. 

However, the risk of serious eye problems associated with advanced immunosuppression, such 

as blindness caused by cytomegalovirus (CMV) retinitis, is much lower in patients treated 

with effective antiretroviral therapy (ART). Common problems not unique to HIV-infected 

patients include dry eye, blepharitis, keratitis, and presbyopia. Infections that may affect the 

eye include herpes simplex virus (HSV), herpes zoster virus (HZV), and syphilis. More severely 

immunocompromised patients (CD4 count <100 cells/μL) may experience CMV retinitis, 

Toxoplasma retinochoroiditis, cryptococcal chorioretinitis, and other conditions. Retinal 

detachment can result. Kaposi sarcoma (KS) also can affect the eye.

Immune reconstitution inflammatory syndrome (IRIS) may affect the eye in patients with 

advanced HIV disease soon after the initiation of effective ART. IRIS may lead to exacerbation 

of a previously treated opportunistic infection or a new presentation (often with unusual 

manifestations) of a previously subclinical infection. In the case of CMV, IRIS may present as 

retinitis, or less commonly as uveitis or vitreitis. IRIS retinitis typically occurs in patients whose 

CD4 counts have increased from <50 cells/μL to 50-100 cells/μL while receiving ART.

Drug-induced ocular toxicity can be caused by many medications, including rifabutin, ethambutol, 

and cidofovir, and less often by high-dose didanosine (ddI, Videx), IV ganciclovir, IV acyclovir, and 

atovaquone.

S: Subjective

The patient complains of dry eyes, 

blurred vision, floaters, sharp pains, 

flashing lights, central vision loss (“black 

holes”), vision field defects (“can only 

see half the page”), or peripheral vision 

loss (“looks like I’m in a tunnel”).

Ascertain the following during the history:

• Pain: clarify type and characteristics

• Unilateral or bilateral problem

• Visual defects (central or peripheral vision 

loss or distortion), scotomata (an area of lost 

or depressed vision surrounded by an area 

of less-depressed or normal vision); occurs 

with reading, distance, or both?

• Time course of symptoms

• Fever

• Headache

• Previous eye or vision problems

• Medications (prescription and over-thecounter) and herbal supplements, current 

and past

• Use of corrective lenses

• Date of last eye examination

• Recent or current varicella-zoster virus 

(VZV) or HSV infection

O: Objective

Evaluate recent CD4 cell count and HIV viral 

load to determine whether the patient is at risk 

of opportunistic infections as causes of eye 

complaints. Also, do the following:

• Consider the patient’s age.

• Check vital signs, including blood pressure 

and temperature.

• Administer a visual acuity examination using 

the Snellen chart. Test the patient’s ability 

to read small print, such as classified ads.
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Section 5: Common 

Complaints

• Consider using an Amsler grid to locate 

areas of retinal pathology.

• Examine the eyelids for lesions, 

inflammation, and swelling.

• Examine the external eye for edema, ptosis, 

conjunctival injection, and corneal clarity.

• Test cranial nerves II, III, IV, and VI.

• Perform funduscopic examination with 

pupillary dilatation, if available. Note retinal 

appearance, lesions, and condition of the 

disc, vessels, and macula.

• Examine the temples and scalp for 

tenderness.

A/P: Assessment and Plan

Refer to an HIV-experienced ophthalmologist 

for dilated retinal or slit-lamp examination 

and definitive diagnosis. If symptoms raise 

suspicion of serious or vision-threatening 

conditions such as herpes ophthalmicus, CMV 

retinitis, or retinal necrosis, ophthalmologic 

evaluation should occur within 24-72 hours. 

Note that patients with HSV or VZV lesions 

in the V1 distribution (including the forehead, 

eyelids, or nose) should receive urgent 

ophthalmologic evaluation.

The differential diagnosis includes the 

following conditions:

Dry Eye (Keratoconjunctivitis Sicca)

The patient may complain of intermittent eye 

pain, intermittent blurred vision that clears 

with blinking, and mild eye irritation. The 

condition worsens with extended reading or 

computer use. Keratoconjunctivitis sicca is 

related to HIV-mediated inflammation with 

damage to the lacrimal glands. It occurs in 

10-20% of HIV-infected patients, most often in 

those with advanced HIV disease. In patients 

with a CD4 count of >400 cells/μL and no 

other signs or symptoms, confirm that results 

of a recent eye examination were normal or 

refer for same, prescribe artificial tears, and 

monitor.

Blepharitis

Blepharitis is inflammation of the eyelids, a 

common condition with dry eyes. The patient 

may complain of discharge and erythema of 

the eyes or eyelids. Of the bacterial causes, 

Staphylococcus aureus is the most common. 

Treatment includes cleaning of the eyelashes 

with warm water and mild shampoo, and 

applying antibiotic ointment if indicated.

Infectious Keratitis

The patient may complain of photophobia, 

eye pain, decreased vision, and irritation. 

Infectious keratitis may be caused by VZV, 

HSV, CMV, bacteria, fungi, or Microsporidia. 

VZV and HSV are the most common 

infectious causes of keratitis in HIV-infected 

patients. Bacterial and fungal keratitis occur 

with equal frequency in HIV-infected and 

HIV-uninfected persons. Fungal infections 

are caused most often by Candida species, 

especially in intravenous drug users. Keratitis 

may be more severe and may recur more 

frequently in HIV-infected patients than 

in HIV-uninfected persons. Evaluation 

should include slit-lamp examination by an 

ophthalmologist.

Refraction Problems

The patient may complain of blurring vision 

with near or distance vision. Other findings 

include an abnormal Snellen test or inability 

to read fine print. The condition may be 

attributable to presbyopia or other causes. 

Refer for ophthalmologic examination.

Iridocyclitis/Anterior Uveitis

The patient may complain of redness or 

watering of the eyes, constriction of the 

pupil, and blurred vision. Anterior-chamber 

inflammation is fairly common among 

patients with HIV infection and is often 

associated with CMV or HSV retinitis. Ocular 

bacterial infections, syphilis, toxoplasmosis, 

and tuberculosis can cause severe symptoms. 

Fungal retinitis rarely causes iridocyclitis. 

Other causes include other systemic conditions 
Eye Problems | 299

Section 5: Common 

Complaints

(e.g., reactive arthritis, sarcoidosis) and drug 

toxicity (e.g., rifabutin, cidofovir, ethambutol). 

Evaluation should include slit-lamp 

examination by an ophthalmologist.

Treatment should be directed at the causative 

pathogen or illness. If drug toxicity is 

suspected, the offending drug should be 

discontinued or reduced in dosage, if possible. 

Topical steroids may be indicated as an 

adjunctive measure. CMV IRIS may present as 

posterior uveitis; for suspected IRIS, consult an 

HIV-experienced ophthalmologist.

HIV Retinopathy

The patient typically has no symptoms, but 

may complain of blurred vision, visual field 

defects, floaters, or flashing lights. Cotton wool 

spots on the retina appear as small fluffy white 

lesions with indistinct borders and without 

exudates or hemorrhages. Usually, these 

findings are benign and do not progress. Refer 

for ophthalmologic examination to rule out 

other causes.

CMV Retinitis

Patients with retinitis caused by CMV 

infection may be asymptomatic or may 

experience blurred vision, floaters, 

scotomata, or central or peripheral vision 

loss or distortion. Retinal examination shows 

creamy to yellowish lesions, white granular 

areas with perivascular exudates, and 

hemorrhages (“cottage cheese and ketchup”). 

The abnormalities initially appear in the 

periphery, but progress if untreated to involve 

the macula and optic disc. CMV is a common 

complication of advanced HIV infection 

in patients with CD4 counts of <50 cells/

μL. Vision loss usually is permanent. Urgent 

ophthalmology consultation and initiation of 

anti-CMV therapy are required. See chapter 

Cytomegalovirus Disease.

Acute Retinal Necrosis

The patient may complain of eye pain, 

decreased visual acuity, and floaters. Rapidly 

progressing peripheral necrosis frequently 

causes blindness. Retinal necrosis usually is 

caused by VZV, although HSV and CMV also 

have been implicated. Treatment should be 

initiated urgently.

Toxoplasma Retinochoroiditis

Toxoplasma retinochoroiditis may occur 

in patients with CD4 counts of <100 cells/

μL and cause blurred vision, visual field 

defects, floaters, or flashing lights. In HIVinfected patients, ocular manifestations 

often appear after the infection of the central 

nervous system with Toxoplasma (see 

chapter Toxoplasmosis). Retinal examination 

may reveal yellow-white infiltrates without 

hemorrhage and active vitreous inflammation. 

Evaluation requires consultation with an HIVexperienced ophthalmologist. If toxoplasmosis 

is confirmed or strongly suspected, treatment 

should be initiated as quickly as possible.

Neuro-Ophthalmologic 

Manifestations

Symptoms or signs of papilledema, optic 

neuritis, cranial nerve palsies, and visual 

field defects may indicate encephalopathy, 

increased intracranial pressure, neurosyphilis, 

toxoplasmosis, progressive multifocal 

leukoencephalopathy, meningitis, or 

central nervous system lymphomas. A 

thorough neurologic examination is 

required to determine whether additional 

diagnostic testing, such as imaging studies 

or cerebrospinal fluid testing, is needed in 

addition to ophthalmologic evaluation.

Retinal Detachment

The patient may complain of flashes of light, 

sudden loss of vision, or both. This condition 

requires immediate referral to an emergency 

department.
300 | Guide for HIV/AIDS Clinical Care

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Complaints

Patient Education

• Patients should report any changes in vision 

to their health care provider as soon as 

possible.

• Patients with CD4 counts of <50 cells/μL 

should be examined by an ophthalmologist 

at baseline and every 6 months thereafter.

References

• Ahmed I, Ai E, Chang E, et al. Ophthalmic 

Manifestations of HIV. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [textbook online]; San Francisco: 

UCSF Center for HIV Information; August 

2005. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-12. 

Accessed December 1, 2013.

• Copeland R. Ocular Manifestations of HIV.

eMedicine.com [online medical reference]; 

January 20, 2005. Available at emedicine.

medscape.com/article/1216172-overview. 

Accessed December 1, 2013.

• Cunningham Jr ET. Ocular Complications of 

HIV Infection. In: Sande MA, Volberding PA, 

eds. Medical Management of AIDS, 6th ed.

Philadelphia: WB Saunders, 1999;171-184.

• Gnann JW Jr. Varicella-Zoster Virus 

Infections. In: Dolin R, Masur H, Saag MS, 

eds. AIDS Therapy. New York: Churchill 

Livingstone; 1999.

• Jacobson M. Clinical Implications of Immune 

Reconstitution in AIDS. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [textbook online]; San Francisco: 

UCSF Center for HIV Information; January 

2005. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-03-04-03. 

Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
Fatigue | 301

Section 5: Common 

Complaints

Fatigue

Julie Barroso, PhD, ANP-BC, APRN, FAAN

Background 

Fatigue is one of the most common and debilitating complaints of HIV-infected people, with 

an estimated prevalence of 33-88%. Fatigue is defined by the NIH Patient Reported Outcomes 

Measurement Information System (PROMIS) initiative as “mild subjective feelings of tiredness to 

an overwhelming, debilitating, and sustained sense of exhaustion that is likely to decrease one’s 

ability to carry out daily activities, including the ability to work effectively and to function at one’s 

usual level in family or social roles. Fatigue is divided conceptually into the experience of fatigue 

(such as its frequency, duration, and intensity), and the impact of fatigue upon physical, mental 

and social activities.” The consequences of severe fatigue may include curtailment of work and 

other activities, need for frequent breaks, limitations in involvement with family and friends, and 

difficulty completing even the simplest household chores.

In HIV-infected individuals, fatigue may be caused by comorbid conditions or by HIV itself. 

HIV-related fatigue is a broad term referring to fatigue that begins or significantly worsens 

after the patient is infected with HIV and that has no other identifiable causes. HIV-infected 

people with fatigue should be evaluated carefully for reversible causes, such as depression, 

anemia, hypothyroidism, hypogonadism, poor sleep quality, and medication adverse effects; if 

these are found, they should be treated aggressively. In some patients, fatigue may be related to 

advanced immunosuppression (e.g., low CD4 cell counts) or to high levels of circulating HIV 

virus. Unfortunately, for many patients, a specific cause of fatigue is not identified, and fatigue 

in many HIV-infected individuals may result from a complex interplay between physiologic 

and psychosocial variables. Recent research has examined genes that are predictive of low vs. 

high fatigue; abnormal neuronal circuitry involving striatal-cortical pathways that may play a 

role in HIV-related fatigue; prior use of didanosine or stavudine; and the presence of clinical 

lipodystrophy syndrome. From a psychosocial standpoint, stress, with its attendant anxiety and 

depression, seems to be the most consistent predictor of HIV-related fatigue.

S: Subjective

The patient complains of tiredness, easy 

fatigability, a lack of energy, a need for frequent 

rest or naps, or waking in the morning feeling 

unrefreshed. The patient may report difficulty 

working, difficulty concentrating, inability 

to exercise without experiencing profound 

fatigue, or impairment in social relations 

because of fatigue.

Consider the following during the history: 

• No objective clinical indicators exist for 

fatigue; thus, making a diagnosis of fatigue 

rests on subjective data. 

• Fatigue assessment tools may help in 

diagnosing fatigue and estimating its 

severity. One such tool, the HIV-Related 

Fatigue Scale, was developed specifically 

for use with HIV-infected individuals; this 

assesses the intensity of fatigue (on the day 

of the assessment and during the previous 

week), the circumstances surrounding 

fatigue (including patterns), and the 

consequences of fatigue. 

• Take a thorough history of the fatigue 

symptoms, including onset, duration, 

exacerbating and alleviating factors, 

and associated symptoms. Evaluate 
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Section 5: Common 

Complaints

for symptoms of other conditions that 

cause fatigue (e.g., hypothyroidism, 

hypogonadism, anemia, heart failure, poor 

nutrition). 

• Depression can cause significant fatigue 

and is common among HIV-infected 

patients with fatigue. Screen the patient for 

depression. A single question – “Are you 

depressed?” – has been shown to be as valid 

and reliable as most depression instruments. 

See chapter Major Depression and Other 

Depressive Disorders for further information. 

• Inquire about social history, specifically 

any life stressors including those related to 

housing status, work stress, and personal 

relationships. 

• Evaluate the patient’s sleep patterns. 

HIV infection can interfere with sleep 

architecture early in the illness. 

• Inquire about substance use or abuse. 

• Obtain a list of all current medications, 

including herbal and over-the-counter 

preparations. 

• Conduct a nutritional assessment.

O: Objective

Check vital signs, including orthostatic 

blood pressure and heart rate measurements, 

if indicated. Perform a physical 

examination including evaluation of 

nutritional status, affect, conjunctivae 

and skin (for pallor), thyroid, lungs and 

heart, and deep tendon reflexes.

A: Assessment

The differential diagnosis includes the 

following:

• Anemia 

• Depression 

• Hypogonadism 

• Hypothyroidism 

• Insomnia or poor-quality sleep 

• Malnutrition 

• Medication adverse effects (e.g., zidovudine, 

interferon) 

• Opportunistic infections, malignancy, 

chronic hepatitis B or C, mononucleosis, 

other illnesses 

• Pregnancy

• Substance use or abuse

P: Plan

Diagnostic Evaluation

To rule out reversible causes of fatigue, 

perform laboratory tests, including: 

• Hemoglobin and hematocrit 

• Thyroid function tests 

• Testosterone (in both men and women) 

• Pregnancy test, if applicable

• CD4 and HIV viral load (if not done 

recently), electrolytes, creatinine, and liver 

function tests

Fatigue assessment tools, as mentioned above, 

may be used to assess the intensity of fatigue, 

the circumstances surrounding fatigue, and 

the consequences of fatigue.

Treatment

If testing reveals a specific cause of fatigue, 

treat appropriately. For example:

• Treat anemia, hypothyroidism, or 

hypogonadism, as indicated. 

• Treat depression with antidepressant 
Fatigue | 303

Section 5: Common 

Complaints

medication, psychotherapy, or both; see 

chapter Major Depression and Other 

Depressive Disorders. 

• Treat insomnia and review good sleephygiene practices with the patient; see 

chapter Insomnia. 

• Refer for treatment of substance use or abuse, 

if possible. 

• Provide counseling regarding any current life 

stressors that may be contributing to fatigue. 

Involve social work and case management 

services regarding housing issues or other social 

needs that may be contributing to fatigue. 

• Treat malnutrition, ideally in conjunction 

with a nutritionist. 

• Treat opportunistic infections and other 

illnesses. (See section Comorbidities, 

Coinfections, and Complications.) 

• Control other symptoms that could be 

causing fatigue (e.g., diarrhea). 

• If fatigue seems to be related to antiretroviral 

medication(s), weigh the benefits of the 

medication(s) against the possible adverse 

effects, and discuss these with the patient.

After appropriate evaluation, if the fatigue is 

thought to be related to HIV infection or if no 

specific cause is identified, consider the following: 

• If HIV infection is inadequately controlled, 

particularly if the CD4 count is low or the 

HIV viral load is high, initiate or optimize 

antiretroviral therapy (ART), if otherwise 

appropriate. 

• Patients taking effective ART may still 

experience HIV-related fatigue. Prepare 

patients for the possibility that fatigue may 

persist despite ART initiation. 

• Encourage patients to track their patterns of 

fatigue with a fatigue diary. Once patients 

recognize their individual patterns, they can 

better cope with fatigue by planning their 

daily activities accordingly (e.g., performing 

the most strenuous tasks during times of 

peak energy or staggering activities to avoid 

excessive fatigue). 

• Ask patients what seems to aggravate their 

fatigue. This information, too, will help 

patients determine their patterns of fatigue 

and identify self-care actions they might take 

to avoid triggers that will worsen the fatigue. 

• Recommend moderate exercise 

and frequent rest. 

• Refer the patient to community-based 

agencies for assistance with housekeeping. 

• Evaluate the need for occupational therapy 

(e.g., energy conservation techniques) or 

physical therapy (e.g., reconditioning and 

strengthening exercises). 

• Medications such as stimulants (e.g., 

modafinil) may be helpful for some patients 

with severe or debilitating fatigue.

Patient Education

• Fatigue is often unrelated to the CD4 cell 

count or HIV viral load. Teach patients not to 

dismiss feelings of fatigue if they have higher 

CD4 counts and lower viral loads. Encourage 

them to discuss their symptoms with a health 

care provider. 

• For patients with depression, advise them that 

appropriate treatment may reduce fatigue. 

• Help patients identify how current life 

circumstances and stressors may contribute 

to fatigue and encourage them to seek the 

appropriate social services to help manage 

appropriately. 

• Talk to patients about their sleep habits 

and recommend changes, as appropriate, to 

improve their sleep hygiene. 

• Prepare patients to accept the fact that 

their fatigue (in some cases) may be a 

chronic condition, in which case it can 

be best managed by maintaining open 

communication with their providers and 

remaining engaged in care.
304 | Guide for HIV/AIDS Clinical Care

Section 5: Common 

Complaints

References

• Aaronson LS, Teel CS, Cassmeyer V, et al. 

Defining and measuring fatigue. Image J 

Nurs Sch. 1999;31(1):45-50. 

• Barroso J, Hammill BG, Leserman J, et al. 

Physiological and psychosocial factors that 

predict HIV-related fatigue. AIDS Behav. 

2010 Dec;14(6):1415-27.

• Barroso J, Harmon JL, Madison JL, et al. 

Intensity, chronicity, circumstances, and 

consequences of HIV-related fatigue: A 

longitudinal study. Clin Nurs Res. 2013 Jun 27.

• Barroso J, Voss JG. Fatigue in HIV and AIDS: 

An analysis of the evidence. J Assoc Nurses 

AIDS Care. 2013 Jan/Feb;24(1S): S5-S14.

• Dacosta DiBonaventura M, Gupta S, Cho 

M, et al. The association of HIV/AIDS 

treatment side effects with health status, work 

productivity, and resource use. AIDS Care. 

2012;24(6):744-55.

• Galmado CE, Spira AP, Hock RS, et 

al. Sleep, function, and HIV: A multimethod assessment. AIDS Behav. 2013 

Oct;17(8):2808-15.

• Jong E, Oudhuff LA, Epskamp C, et 

al. Predictors and treatment strategies 

of HIV-related fatigue in the combined 

antiretroviral therapy era. AIDS. 

2010 Jun 19;24(10):1387-405.

• Lee KA, Gay C, Portillo CJ, et al. 

Types of sleep problems in adults 

living with HIV/AIDS. J Clin Sleep 

Med. 2012 Feb 15;8(1):67-75.

• Payne BA, Hateley CL, Ong EL, et al. 

HIV-associated fatigue in the era of 

highly active antiretroviral therapy: 

Novel biological mechanisms? HIV 

Med. 2013 Apr;14(4):247-51.

• Rabkin JG, McElhiney MC, Rabkin R. 

Modafinil and armodafinil treatment for 

fatigue in HIV-positive patients with and 

without chronic hepatitis C. Int J STD AIDS. 

2011 Feb;22(2):95-101.

• Safren SA, Hendriksen ES, Smeaton L, et 

al. Quality of life among individuals with 

HIV starting antiretroviral therapy in diverse 

resource-limited areas of the world. AIDS 

Behav. 2012 Feb;16(2):266-77. 

• Schifitto G, Deng L, Yeh TM, et al. Clinical, 

laboratory, and neuroimaging characteristics 

of fatigue in HIV-infected individuals. J 

Neurovirol. 2011 Feb;17(1):17-25.
Fever | 305

Section 5: Common 

Complaints

Fever

Background 

Although fever may accompany HIV infection at various stages of disease, fever in a patient with a 

low CD4 count (<200 cells/μL) should prompt the clinician to rule out opportunistic infections. 

S: Subjective

The patient complains of persistent fever, or 

new-onset fever of >101°F (38.3°C).

Assess the following during the history: 

• Duration of fever

• Associated symptoms, including chills, 

sweats, weight loss

• Visual disturbances (see 

chapter Eye Problems)

• Nasal or sinus symptoms

• Asymmetric, tender, or new 

lymphadenopathy

• Cough or shortness of breath (see chapter 

Pulmonary Symptoms)

• Diarrhea, tenesmus (see chapter Diarrhea)

• Rash, lesions, soft-tissue inflammation

• Pain (for headache, see chapter Headache)

• Neurologic symptoms (see chapter 

Neurologic Symptoms)

• Vaginal or urethral discharge

• Other localizing symptoms

• Unprotected sexual contacts

• Recent injection drug use

• Intravenous line or venous access device

• Travel within the past 6-12 months

• Medications (as a cause of fever)

• Use of antipyretic agents including aspirin, 

nonsteroidal antiinflammatory drugs 

(NSAIDs), and acetaminophen; when was 

most recent dose taken?

O: Objective

Document fever. Check other vital signs, 

including orthostatic measurements. Check 

weight and compare with previous values.

Search for evidence of an infectious focus. 

Perform a complete physical examination, 

including evaluation of the eyes (including 

fundus), sinuses, oropharynx, ears, lymph 

nodes, lungs and heart, abdomen, joints, 

genitals, uterus, rectum, skin, and neurologic 

system.

Review recent CD4 measurements, if 

available, to determine the patient’s risk of 

opportunistic illnesses as a cause of fever.

A: Assessment

The differential diagnosis varies depending 

on the CD4 count. Possibilities include the 

following:

Conditions More Likely 

with Low CD4 Count

• Aspergillosis

• Cryptococcosis

• Cytomegalovirus (CMV) infection

• Disseminated Mycobacterium avium 

complex (MAC)

• Disseminated histoplasmosis

• HIV infection itself

• Lymphoma, other neoplasms

• Pneumocystis jiroveci pneumonia (PCP)

• Toxoplasmosis

• Tuberculosis (atypical or extrapulmonary)
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Conditions That May Occur with Any 

CD4 Count

• Abscess, cellulitis

• Acute hepatitis

• Autoimmune process

• Bacteremia or sepsis

• Bacterial pneumonia or bronchitis

• Disseminated herpes simplex virus; 

chickenpox

• Drug-induced fever (common culprits 

include abacavir, nevirapine, sulfonamides, 

dapsone, penicillin, clindamycin, 

carbamazepine, phenytoin, barbiturates, and 

bleomycin)

• Endocarditis

• Immune reconstitution syndromes, related 

to opportunistic infections, are often 

associated with fever (see chapter Immune 

Reconstitution Inflammatory Syndrome)

• Influenza

• Otitis

• Malaria

• Pelvic inflammatory disease (PID)

• Sexually transmitted diseases

• Sinusitis

• Tuberculosis (pulmonary)

• Urinary tract infection (UTI)

P: Plan

Diagnostic Evaluation

Perform laboratory work and other diagnostic 

studies as suggested by the history, physical 

examination, and differential diagnosis. These 

may include the following: 

• CD4 count (if not done recently) to help with 

risk stratification for opportunistic illnesses

• Complete blood count (CBC) with 

differential

• Blood cultures (bacterial, mycobacterial, 

fungal)

• Urinalysis, urine culture if UTI symptoms 

are present

• Liver transaminases, renal panel

• Chest X-ray

• Sinus films if indicated by symptoms and 

physical examination findings

• If respiratory symptoms and signs are 

present: sputum evaluation (Gram stain 

and acid-fast bacilli smear, evaluation for 

PCP), with culture of sputum for bacterial 

pathogens, acid-fast bacilli, viruses, and 

fungi as indicated; consider sputum 

induction or bronchoscopy if indicated

• Serum cryptococcal antigen, particularly if 

CD4 count is <100 cells/μL and symptoms 

are consistent with cryptococcosis

• If neurological symptoms and signs are 

present: computed tomography (CT) or 

magnetic resonance imaging (MRI) of head, 

lumbar puncture

• For new lymphadenopathy: aspirate with 

culture (including acid-fast bacilli and 

fungal) and cytology

• For cytopenias: bone marrow aspirate 

and biopsy may be needed; see applicable 

treatment guidelines
Fever | 307

Section 5: Common 

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• For fever of unknown origin (FUO), defined 

as persistent fever >101°F for >3 weeks 

without findings on initial workup, more 

intensive workup may be needed, such as 

lumbar puncture, other scans or biopsies; 

consult with a specialist in infectious 

diseases or an HIV expert to determine 

whether hospitalization or other laboratory 

tests are needed

• For patients who recently started abacavir 

or nevirapine, or other medications, rule 

out hypersensitivity reactions (see chapter 

Adverse Reactions to HIV Medications)

Treatment

Once a diagnosis is made, appropriate 

treatment should be initiated. In seriously ill 

patients, presumptive treatment may be started 

while diagnostic tests are pending. In some 

cases, the source of fever cannot be identified. 

Consult with an HIV expert.

Symptomatic treatment may include NSAIDs 

(e.g., ibuprofen, naproxen), acetaminophen, 

and analgesics. Monitor for adverse 

gastrointestinal effects with NSAIDs. Cold 

compresses also can be used to relieve fever 

symptoms. Refer to a dietitian to avoid weight 

loss during the hypermetabolic state. See 

section Comorbidities, Coinfections, and 

Complications in this manual if an HIV-related 

cause is identified.

Patient Education

• Patients should report any new fever to their 

health care provider. They should measure 

their temperature using a thermometer at 

home in order to report actual temperatures.

• Patients should know that fever usually 

is a sign that their bodies are battling an 

infection. Their health care providers may 

need to do special tests to find out what 

could be causing the fever.

• Many over-the-counter remedies are 

available to treat fevers. Patients should 

check with their care provider before taking 

these. Acetaminophen-containing products 

(e.g., Tylenol) generally are well tolerated. 

Persons with liver disease should use 

acetaminophen only as prescribed. NSAIDs 

(e.g., ibuprofen, naproxen) may be used, 

but they can cause adverse gastrointestinal 

effects, especially if taken without food. 

Patients should let their care provider know 

if they need to take these medicines for more 

than 2 or 3 days.

References

• Bartlett JG, Gallant JE, Pham PA. 2012 

Medical Management of HIV Infection. 

Baltimore: Johns Hopkins University School 

of Medicine; 2012.

• Cross KJ, Hines, JM, Gluckman SJ. Fever of 

Unknown Origin. In: Buckley RM, Gluckman 

SJ, eds. HIV Infection in Primary Care 2002.

Philadelphia: WB Saunders; 2002.

Headache | 309

Section 5: Common 

Complaints

Headache

Background 

Headache in HIV-infected persons may result from many causes, particularly if the CD4 cell count 

is low. Possible causes include infections (opportunistic and other) and central nervous system 

malignancies, HIV-related systemic illnesses, and medication toxicity. In addition, headache may 

be caused by any of the processes that cause headache in HIV-uninfected individuals. New or 

severe headache should be evaluated carefully.

S: Subjective

The patient complains of a new type of 

headache.

Determine the following during the history:

• History of headaches or migraines

• Characteristics of the headache (e.g., 

location, quality of pain, timing, duration)

• Recent head trauma

• Fever

• History of sinusitis

• Allergies

• Visual changes

• Dizziness, vertigo, nausea

• Mental status changes

• Seizures

• Focal or other neurologic symptoms (see 

chapter Neurologic Symptoms)

• New rashes or ulcerations

• Other symptoms

• Caffeine intake; recent changes in intake

• New medications (e.g., zidovudine, 

dolutegravir)

• Relief of headache by any medication

• Unprotected sex, new sex partner

O: Objective

Perform a physical examination as follows:

• Check vital signs. Look for fever, orthostasis, 

and hypertension.

• Examine the head and neck for trauma, 

sinus tenderness, scalp or temple tenderness, 

and neck mobility; check lymph nodes.

• Check the eyes, including funduscopic 

examination, for lesions or papilledema.

• Look for oral lesions, dental abscess, thrush, 

and pharyngeal drainage.

• Examine the lungs for abnormal sounds.

• Check the skin, including palms and soles, 

for rashes or lesions.

• Perform a complete neurologic examination, 

including mental status examination.

• Review recent CD4 measurements, if 

available, to determine the patient’s risk 

of opportunistic illnesses as a cause of 

headache.
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A: Assessment

A partial differential diagnosis includes the 

following: 

• Anemia

• Caffeine withdrawal

• Central nervous system lymphoma

• Cryptococcal meningitis

• Cytomegalovirus (CMV) 

meningoencephalitis or retinitis

• Dehydration

• Depression, anxiety disorder

• Fever

• Hypertension

• Medication adverse effect

• Migraine or cluster headache

• Neurosyphilis

• Other encephalitis

• Progressive multifocal 

leukoencephalopathy (PML)

• Sinusitis

• Stress or tension headache

• Systemic infection

• Temporal arteritis

• Toxoplasmic encephalitis

• Tuberculous meningitis; other meningitis

Other causes of headache unrelated to HIV 

should be considered.

P: Plan

Diagnostic Evaluation

Evaluation should include the following:

• CD4 cell count (if not done recently), to help 

with risk stratification for opportunistic 

illnesses

• Complete blood count with differential (if 

fever or suspected anemia); see chapter Fever

• Blood chemistries, including liver function 

tests, electrolytes, creatinine, glucose

• Serum cryptococcal antigen (if fever is 

present and CD4 count is <100 cells/μL); see 

chapter Cryptococcal Disease

• Toxoplasma immunoglobulin G (consider if 

previously negative and CD4 count is <100 

cells/μL; may indicate risk of toxoplasmosis); 

see chapter Toxoplasmosis

• Syphilis testing: rapid plasma reagin (RPR) 

or Venereal Disease Research Laboratory 

(VDRL) test; see chapter Syphilis

When indicated, also consider:

• Computed tomography (CT) scan with 

contrast or magnetic resonance imaging of 

the head; see chapter Neurologic Symptoms

• Lumbar puncture with cerebrospinal fluid 

(CSF) studies to include opening pressure, 

cell count, chemistries, bacterial cultures; 

fungal and acid-fast bacilli evaluations 

and cultures; India ink stain; cryptococcal 

antigen, VDRL, as indicated

• Sinus imaging

• Erythrocyte sedimentation rate, if temporal 

arteritis is suspected
Headache | 311

Section 5: Common 

Complaints

Treatment

• Once a diagnosis is made, appropriate 

treatment should be initiated. In seriously 

ill patients, presumptive treatment may 

be initiated while diagnostic test results 

are pending. In some cases, the source of 

headache cannot be identified. Consult with 

an HIV expert or a neurologist.

• Refer to disease-specific treatment 

guidelines or primary care management 

guidelines as appropriate.

• Treat symptomatically with nonsteroidal 

antiinflammatory drugs (NSAIDs), 

acetaminophen, or narcotics, if indicated, to 

control pain.

Patient Education

• Headache can be a sign of an opportunistic 

infection, especially in patients with low 

CD4 cell counts. Patients should notify their 

health care provider if they develop a new 

headache.

• Providers should inform patients that they 

may have to do additional tests to determine 

the cause of the headache.

• Many over-the-counter remedies are 

available for headache. Patients should 

check with their health care provider before 

taking these. Acetaminophen-containing 

products (e.g., Tylenol) generally are well 

tolerated. Persons with liver disease should 

use acetaminophen only as prescribed. 

NSAIDs (e.g., ibuprofen, naproxen) may be 

used, but these agents can cause adverse 

gastrointestinal effects, especially if taken 

without food. Patients should inform their 

care provider if they need to take these 

medicines for more than 2 or 3 days.

References

• McGuire D. Neurologic Manifestations 

of HIV. In: Coffey S, Volberding 

PA, eds. HIV InSite Knowledge Base

[textbook online]; San Francisco: UCSF 

Center for HIV Information; June 

2003. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-02. 

Accessed December 1, 2013.

Lymphadenopathy | 313

Section 5: Common 

Complaints

Lymphadenopathy

Background 

Lymphadenopathy is very common among HIV-infected individuals and may occur at any stage of 

HIV infection. It may be the first indication of a serious local or systemic condition, and it should 

be evaluated carefully. Rapid enlargement of a previously stable lymph node or a group of nodes 

requires evaluation to identify the cause and to determine whether treatment is needed. Similarly, 

nodes that are abnormal in consistency, tender to palpation, fluctuant, asymmetrical, adherent to 

surrounding tissues, or accompanied by other symptoms should be evaluated promptly.

Lymphadenopathy may be generalized or localized and usually is characterized by lymph nodes 

that are >1 cm in diameter. A multitude of conditions can cause lymphadenopathy, including HIV 

itself, opportunistic or other infections, and malignancies. The likely causes of lymphadenopathy, 

and thus the diagnostic workup, will depend in part on the patient’s degree of immunosuppression. 

The risk of opportunistic and certain malignant conditions increases at lower CD4 cell counts (see 

chapter Risk of HIV Progression/Indications for ART).

Many individuals with primary HIV infection (see chapter Early HIV Infection) have generalized 

lymphadenopathy that may resolve or may persist for months to years. If lymphadenopathy of >2 

cm in size occurs in two or more noncontiguous sites and persists for more than 3 months, and if 

appropriate evaluation reveals no other cause, the patient is diagnosed with persistent generalized 

lymphadenopathy (PGL). PGL usually is caused by follicular hyperplasia from chronic HIV 

infection. Antiretroviral therapy (ART) should be initiated or optimized, but as long as enlarged 

nodes are stable in number, location, and size, persons with PGL require no specific management 

other than monitoring of nodes at each physical examination. Changes in the character of the 

lymph nodes should prompt further evaluation. Rapid involution of PGL may occur with advanced 

HIV disease and is a poor prognostic sign.

S: Subjective

The patient complains of new, worsening, or 

persistent glandular swellings in the neck, 

axilla, groin, or elsewhere.

Ascertain the following during the history:

• Symptoms that accompany the 

lymphadenopathy, particularly constitutional 

symptoms such as fever, sweats, fatigue, and 

unintentional weight loss

• Localized symptoms or conditions 

that involve areas of the body with 

lymphatic drainage into the area of 

abnormal lymph nodes (e.g., in the 

case of axillary lymphadenopathy, ask 

about breast masses and skin conditions 

or trauma involving the arm)

• A full review of systems

• HIV-related or other malignancies, 

opportunistic illnesses

• Recent travel, country or region of origin, 

disease exposures (e.g., tuberculosis [TB], 

sexually transmitted diseases [STDs]), and 

risk behaviors (e.g., injection drug use)

• Recent initiation of ART (may indicate 

immune reconstitution inflammatory 

syndrome [IRIS])

• Trauma or injury (including cat scratches)

• Exposure to household pets

• Current medications
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O: Objective

• Review recent CD4 cell counts and HIV 

viral load measurements.

• Check vital signs.

• Perform a complete examination of 

lymph nodes, including the cervical, 

submandibular, supraclavicular, axillary, 

epitrochlear, and inguinal sites. Document 

the location, size, consistency, mobility, 

and presence or absence of tenderness of 

all abnormal nodes. In cases of localized 

lymphadenopathy, examine the area drained 

by the node.

• Check for hepatosplenomegaly.

• Perform a focused examination (e.g., lung, 

breast, skin, genitals) to identify signs of 

local or systemic illness.

A: Assessment

The differential diagnosis of lymphadenopathy 

in HIV-infected patients depends in part 

on the degree of immunosuppression. For 

further information, see chapter Risk of HIV 

Progression/Indications for ART.

Infectious Causes

Generalized lymphadenopathy

• HIV infection, including PGL

• Mononucleosis; Epstein-Barr virus

• Mycobacterium avium complex

• TB

• Cytomegalovirus

• Secondary syphilis

• Toxoplasmosis

• Histoplasmosis, other fungal diseases

• Bartonella infection

• Hepatitis B

• Lyme disease

• Widespread skin infections

• IRIS involving various infections

• Follicular hyperplasia

• Castleman disease

Localized lymphadenopathy

• Any of the above

• Oropharyngeal and dental infections

• Cellulitis or abscesses

• TB (scrofula)

• Chancroid

• Chlamydia (lymphogranuloma 

venereum [LGV])

• Other STDs

Neoplastic Causes

• Lymphoma

• Acute and chronic lymphocytic leukemias

• Other malignancy; metastatic cancer

• Kaposi sarcoma

Other Causes

• Reactive process (benign)

• Sarcoidosis

• Hypersensitivity reaction to medications

• Serum sickness

• Rheumatoid arthritis
Lymphadenopathy | 315

Section 5: Common 

Complaints

P: Plan

Diagnostic Evaluation

After the history and physical examination, 

the cause of lymphadenopathy may be clear 

and further diagnostic testing may not be 

necessary. If the cause of the lymphadenopathy 

is still uncertain, perform diagnostic testing 

as indicated by the patient’s presentation. This 

may include the following tests:

• CD4 count (with or without HIV viral 

load), to determine the risk of opportunistic 

illnesses

• Complete blood count with differential; liver 

function tests; urinalysis

• Chest X-ray

• TB screening (tuberculin skin test [TST] or 

interferon-gamma release assay [IGRA])

• Syphilis screening (rapid plasma reagin 

[RPR] or Venereal Disease Research 

Laboratory [VDRL] test)

• Blood cultures, if patient is febrile (bacterial, 

mycobacterial, and fungal, as indicated)

• Testing for specific infections if suspected 

(e.g., Bartonella, LGV)

If a node is large, fixed, nontender, or otherwise 

worrisome, or if the diagnosis is unclear 

after initial evaluation, fine-needle aspiration 

(FNA) biopsy may provide a diagnosis. If FNA 

is nondiagnostic (false-negative results are 

relatively common), obtain an excisional biopsy 

for definitive evaluation. Biopsy specimens 

should be sent for bacterial, mycobacterial, 

and fungal cultures; acid-fast staining for 

mycobacteria; and cytologic examination.

If a node is large, inflamed, tender, or 

fluctuant, and a bacterial infection is 

suspected, consider initiating empiric 

antibiotic treatment and monitoring the 

patient over the course of 1-2 weeks. If the 

node does not respond to antibiotic treatment 

or the patient becomes more symptomatic, 

arrange for FNA or open biopsy to establish 

the diagnosis.

Treatment

Treatment will depend on the cause 

of lymphadenopathy. Refer to section 

Comorbidities, Coinfections, and Complications

or to OI management guidelines as 

appropriate. In the case of HIV-related 

lymphadenopathy, ART may be effective.

Patient Education

• Lymphadenopathy may come and go 

throughout the course of HIV infection, but 

it may be a sign of a serious condition.

• Advise patients to notify their care provider 

if lymph nodes increase in size or change in 

character.

References

• Boswell SL. Approach to the Patient with 

HIV Infection. In: Goroll AH, Mulley AG, 

eds. Principles of Primary Care, 5th ed. 

Philadelphia: JB Lippincott, 2005;78-91.

• Kocurek K, Hollander H. Primary and 

Preventive Care of the HIV-Infected Adult. 

In: Sande MA, Volberding PA, eds. Medical 

Management of AIDS, 6th ed. Philadelphia: 

WB Saunders, 1999;125-126.

• Simon HB. Evaluation of Lymphadenopathy. 

In: Goroll AH, Mulley AG, eds. Principles 

of Primary Care, 5th ed. Philadelphia: JB 

Lippincott, 2005;73-77.

Nausea and Vomiting | 317

Section 5: Common 

Complaints

Nausea and Vomiting

Background 

Nausea with or without vomiting, and occasionally vomiting without nausea, can occur at any 

stage of HIV infection. Nausea is a common adverse effect of many antiretroviral (ARV) and other 

medications, and it often occurs within weeks of starting new medications. In some cases, nausea 

causes significant discomfort and may interfere with medication adherence. Nausea and vomiting 

also may be symptoms of a serious complication of ARV therapy, or signs of an opportunistic 

infection or neoplasm in patients with late-stage AIDS. Clinicians must identify the cause of 

nausea and vomiting and initiate appropriate treatment.

S: Subjective

The patient experiences nausea with or without 

vomiting, or vomiting without nausea.

Ascertain the following during the history:

• Duration of symptoms

• Characteristics, timing, and 

precipitating factors

• Vomiting, including hematemesis

• Diarrhea

• Abdominal pain

• Fever

• Jaundice

• Lightheadedness, dizziness, vertigo, or 

orthostatic symptoms

• Polyuria

• Polydipsia

• Headache

• Changes in vision

• Neck stiffness

• Pruritus

• Medications, new and ongoing

• Nutritional supplements and nonprescription medications

• Possibility of pregnancy (for women) (e.g., 

missed menses)

• Alcohol intake, substance use or abuse

• History of: 

• Hepatitis

• Kidney disease

• Pancreatitis

• Cytomegalovirus

• Central nervous system (CNS) infections, 

including toxoplasmosis, cryptococcosis, 

chronic meningitis

• CNS lymphoma

O: Objective

Check vital signs, including orthostatic blood 

pressure and heart rate measurements.

Conduct a thorough physical examination, 

including evaluation of the following: 

• Skin turgor

• Eyes and fundi (retinal abnormalities 

such as papilledema)

• Oropharynx (dryness of oral mucosa, 

thrush, ulcerations)

• Neck (stiffness or other signs of meningeal 

irritation)

• Abdomen (tenderness, distention, masses, 

organomegaly)

• Pelvis (tenderness, masses)
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• Neurologic system (mental status, focal 

neurologic abnormalities)

Review recent CD4 measurements, if available, 

to determine the patient’s risk of opportunistic 

illnesses.

A: Assessment

A partial differential diagnosis includes the 

following conditions:

• Medication effect or reaction

• Foodborne illness

• Viral or other infectious gastroenteritis

• Pancreatitis

• Hepatitis, infectious or drug related (see 

chapters Hepatitis B Infection and Hepatitis 

C Infection)

• Appendicitis

• Esophagitis (see chapter Esophageal 

Problems)

• Lactic acidosis attributable to 

nucleoside analogues

• Pregnancy

• Adrenal insufficiency

• CNS lymphoma

• Meningitis

• Uremia

• Diabetic ketoacidosis

• Influenza

• Pelvic inflammatory disease (see chapter 

Pelvic Inflammatory Disease)

• Myocardial infarction

P: Plan

Diagnostic Evaluation

Perform laboratory work and other diagnostic 

studies as suggested by the history, physical 

examination, and differential diagnosis. Tests 

may include the following:

• Complete blood count with differential

• Electrolytes, creatinine, blood urea nitrogen

• Glucose

• Amylase and lipase if symptoms of 

pancreatitis are present

• Liver function tests and hepatitis serologies 

for possible acute or chronic hepatitis

• Blood cultures and other fever workup as 

needed (see chapter Fever)

• Computed tomography scan of the brain 

if neurologic symptoms are present (see 

chapter Neurologic Symptoms)

• Cortisol and cosyntropin stimulation 

test if indicated (e.g., fatigue, weakness, 

unexplained abdominal pain, weight loss, 

orthostasis; usually in late-stage AIDS)

• If odynophagia or dysphagia is present, see 

chapter Esophageal Problems

• Lactic acid levels if lactic acidosis is 

suspected

• Pregnancy test if indicated

• Electrocardiogram if patient has chest pain 

or suspicious symptoms

Consult with an HIV expert to determine 

whether hospitalization or other laboratory 

tests are needed.
Nausea and Vomiting | 319

Section 5: Common 

Complaints

Treatment

Once the diagnosis is made, appropriate 

treatment should be initiated. In seriously ill 

patients, presumptive treatment may be started 

while diagnostic test results are pending. See 

appropriate chapters in section Comorbidities, 

Coinfections, and Complications and relevant 

guidelines.

In the case of significant adverse effects 

from ARVs or other medications, substitute 

a less-emetogenic ARV for the problematic 

medication, if possible (without compromising 

the efficacy of the treatment regimen). In the 

case of serious or life-threatening medication 

toxicities (e.g., lactic acidosis or abacavir 

hypersensitivity reaction), discontinue the 

problematic medication (see chapter Adverse 

Reactions to HIV Medications).

After the workup and exclusion of lifethreatening illness, symptomatic treatment 

can be considered. If nausea and vomiting are 

attributable to medications that are vital to 

the patient, and these complications are not 

life-threatening, antiemetic therapy may be the 

best treatment. Chronic therapy is not always 

necessary. Some patients obtain adequate relief 

by breaking the “nausea cycle” with effective 

antiemetics for 1-2 days and then establishing 

meals or snacks with medications. Patients 

with dehydration may require administration 

of fluids (PO or IV) to relieve nausea. For 

patients with chronic nausea resulting 

in weight loss, refer to a nutritionist for 

assessment and nutritional support.

Symptomatic treatment

Consider the following strategies for 

symptomatic treatment: 

• For nausea that occurs in relation to an 

event or action (e.g., after taking ARVs) 

antiemetics may be given preemptively (e.g., 

30 minutes beforehand).

• Ginger capsules have proven effective 

in clinical trials for the management of 

pregnancy-related and chemotherapy-related 

nausea. Foods and beverages containing 

ginger (e.g., tea, cookies, ginger ale, candies) 

may help provide relief.

• Promethazine (Phenergan) may be given as 

a 12.5-25 mg PO tablet Q4-6H as needed. 

For patients unable to tolerate the PO 

formulation, promethazine suppositories 

(12.5 or 25 mg) may be used.

• Prochlorperazine (Compazine) may be 

given as a 5 mg or 10 mg PO tablet, or a 25 

mg rectal suppository, Q6-8H as needed. 

Extended-release spansule, 10 mg Q12H or 

15 mg QAM, also can be considered.

• Lorazepam (Ativan) may be given as a 0.5 

mg PO tablet 30 minutes before taking 

medications for symptoms of anticipatory 

nausea. Patients with anticipatory nausea 

develop significant nausea or vomiting 

when even thinking about medications or 

reaching for the medications.

• Dronabinol (Marinol) may relieve nausea, 

especially when nausea is accompanied by a 

loss of appetite. This remedy is best tolerated 

by patients who have tolerated inhaled 

marijuana. The starting dosage is 2.5 to 5 mg 

BID or TID.

• 5-Hydroxytryptamine (5-HT3) receptor 

antagonists such as dolasetron 50 mg and 

100 mg, granisetron 1 mg, and ondansetron 

4 mg and 8 mg are highly effective are 

highly effective in relieving severe nausea 

and vomiting resulting from chemotherapy 

and other causes. However, access to these 

medications is limited by their cost. Their 

use should be considered a short-term 

strategy or reserved for cases of nausea/

vomiting refractory to other antiemetics.

• Metoclopramide (Reglan) may be used to 

enhance gastrointestinal motility in patients 

who experience nausea and vomiting caused 

by gastroparesis. The typical PO dose is 

5-10 mg Q4-6H, or it can be taken TID with 

meals if the nausea or vomiting is associated 

with eating.
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• H2 antagonists or proton pump inhibitors 

may be helpful in treating nausea/vomiting 

related to gastritis or acid reflux (caution: 

these agents interfere with absorption of 

atazanavir and rilpivirine; consult dosing 

recommendations); see chapter Esophageal 

Problems and relevant tables in the U.S. 

Department of Health and Human Services 

Guidelines for the Use of Antiretroviral 

Agents in HIV-1-Infected Adults and 

Adolescents (see Appendix).

Patient Education

• Nausea and vomiting can have many 

different causes. Patients should let their 

health care provider know if they are having 

these symptoms so that the most likely cause 

can be determined.

• Patients should stay nourished and well 

hydrated even if they are experiencing 

nausea and vomiting. Eating small, frequent 

meals may be best tolerated, while avoiding 

dairy products, spicy or greasy foods, and 

high-fat meals. Taking medications with 

food may reduce symptoms of nausea (note 

that some medications must be taken on an 

empty stomach).

• Patients should not stop taking any of their 

medications without first discussing it with 

their health care provider. Many medications 

must be continued despite nausea. Nausea 

and vomiting owing to ARVs may resolve or 

become tolerable over time.

• Many patients wonder whether they should 

take their medicines again if they vomit 

after taking a dose. Generally, the medicines 

are still in the body unless the pills actually 

come back up. Patients should call their 

health care provider if they have any 

questions.

• Ginger may help to relieve nausea. Ginger 

can be taken in a variety of ways, including 

ginger ale, tea, cookies, candies, and ginger 

capsules. Patients can choose the form of 

ginger that works best for them.

References

• Chubineh S, McGowan J. Nausea and 

vomiting in HIV: a symptom review. Int J 

STD AIDS. 2008 Nov;19(11):723-8.

• Hill A, Balkin A. Risk factors for 

gastrointestinal adverse events in HIV treated 

and untreated patients. AIDS Rev. 2009 JanMar;11(1):30-8.

• Sulkowski MS, Chaisson RE. 

Gastrointestinal and Hepatobiliary 

Manifestations of HIV Infection. In: Mandell 

GL, Bennett JR, Dolin R, eds. Principles 

and Practice of Infectious Diseases, 6th 

ed. Philadelphia: Churchill Livingstone, 

2005;1575-80.
Neurologic Symptoms | 321

Section 5: Common 

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Neurologic Symptoms

Background 

The nervous system may be a site of complications throughout the course of HIV infection, and 

neurologic complaints are common among HIV-infected individuals. Neurologic symptoms may 

be caused by many factors, including infections (opportunistic and other), central nervous system 

(CNS) malignancies, medication toxicities, comorbid conditions (e.g., diabetes, cerebrovascular 

disease, chronic hepatitis, mental illness), and nervous system injuries related to HIV itself.

The risk of some conditions, such as CNS infection, malignancy, and dementia, increases with 

advancing immunosuppression, and the CD4 cell count will help to stratify the patient’s risk 

of opportunistic illnesses (see Table 1 in chapter Risk of HIV Progression/Indications for ART). 

This chapter presents a general approach to neurologic symptoms in HIV-infected patients, 

with reference to other chapters in this manual for more detailed reading. For information on 

peripheral neuropathy, see chapter Pain Syndrome and Peripheral Neuropathy; for information on 

neurocognitive disease, see HIV-Associated Neurocognitive Disorders.

S: Subjective

The patient, or a friend or family member 

on his or her behalf, reports new neurologic 

symptoms such as pain, headache, seizures, 

altered mental status, or weakness.

Ascertain the following during the history:

• Onset and duration: rapid (hours to days), 

subacute, chronic

• Characteristics of the symptoms (e.g., 

location, quality, timing)

• Progression or stability of symptoms

• Constitutional symptoms: fever, night 

sweats, unintentional weight loss

• Associated symptoms, including other 

neurologic, muscular, psychiatric, or 

behavioral symptoms

• Recent trauma to the head or other area

• Visual changes, photophobia

• Dizziness, vertigo

• Mental status changes (including changes in 

behavior, personality, or cognition; shortterm memory loss; mental slowing; reading 

comprehension difficulties; changes in 

personal appearance and grooming habits)

• Seizures (description, duration, number)

• Pain

• Sensory symptoms

• Weakness (distinguish weakness from 

fatigue or pain; determine whether bilateral 

or focal, proximal or distal)

• Bowel or bladder changes

• Rash or ulcerations

• Medications: current, past, and recently 

initiated medications, including 

antiretroviral (ARV) medications

• Alcohol or drug use; date of last use

• Exposures (sexual, environmental), travel 

history

• Psychiatric history and past psychiatric care

• Most recent CD4 cell count and HIV viral 

load, previous AIDS-defining illnesses

• Functional impact of the symptoms: social 

functioning, ability to work and perform 

activities of daily living

Differentiate delirium and dementia. 

Delirium presents as acute onset of clouded 

sensorium, disturbed and fluctuating 

Section 5: Common 

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level of consciousness, disorientation, 

cognitive deficits, and reduced attention, 

sometimes with hallucinations. Delirium 

often is caused by medication toxicities, 

infections, hypoxia, hypoglycemia, 

electrolyte imbalances, or mass lesions, 

and it frequently is correctable. Dementia 

emerges more gradually and is characterized 

by cognitive impairment and behavioral, 

motor, and affective changes. See chapter 

HIV-Associated Neurocognitive Disorders.

O: Objective

• Check vital signs (temperature, blood 

pressure, heart rate, respiratory rate, 

and oxygen saturation) and orthostatic 

measurements.

• Perform a careful physical examination as 

guided by the history, with special attention 

to the following: 

• General appearance: mood, affect, 

mannerisms

• Head and neck: signs of trauma, sinus 

tenderness, lymph node status, neck 

mobility

• Eyes, including fundi: lesions, papilledema

• Lungs, heart: abnormal sounds

• Extremities: muscle tone and bulk

• Skin, mucous membranes: rash, lesions

• Conduct a thorough neurologic 

examination, including cranial nerves, 

motor function, sensory function, 

coordination, gait, and deep tendon reflexes.

• Conduct a mental status examination.

• Review recent CD4 measurements, if 

available, to determine the patient’s risk of 

opportunistic illnesses.

A: Assessment

The differential diagnosis of neurologic 

abnormalities in patients with HIV infection 

may be broad, particularly if the CD4 count 

is low. Both HIV-related and HIV-unrelated 

causes should be considered; remember that 

more than one cause of symptoms may be 

present.

Possible Causes of 

Neurologic Abnormalities

Causes related to the cerebrum 

or cranial nerves

• Toxoplasmic encephalitis

• Primary CNS lymphoma

• Cryptococcal meningitis

• Cytomegalovirus (CMV) encephalitis

• Other meningitis (bacterial, tuberculous, 

fungal, viral)

• Progressive multifocal 

leukoencephalopathy (PML)

• Neurosyphilis

• CNS coccidioidomycosis, histoplasmosis

• HIV-related dementia

• Cerebrovascular accident; stroke

• Metabolic abnormalities, including hypo- or 

hyperglycemia, electrolyte abnormalities

• Alcohol or drug intoxication or withdrawal 

(medications or illicit drugs); chronic 

alcohol abuse

• Medication adverse effects (e.g., efavirenz, 

corticosteroids, anticholinergics,

many others)

• Depression, mania, anxiety, psychosis
Neurologic Symptoms | 323

Section 5: Common 

Complaints

Causes related to the spinal cord, nerve 

roots, peripheral nerves, and muscle

• Inflammatory demyelinating 

polyneuropathy (e.g., Guillain-Barré 

syndrome)

• Polyradiculitis (e.g., CMV, 

herpes simplex virus)

• Vitamin deficiency

• Myositis

• Myopathy (e.g., owing to zidovudine)

• Myelopathy (e.g., HIV vacuolar myelopathy)

• Epidural abscess or mass

• Mononeuritis multiplex

• Lactic acidosis

• Electrolyte abnormality (e.g., hypokalemia)

• Peripheral neuropathy

• Distal sensory polyneuropathy

• Antiretroviral toxic neuropathy (especially 

stavudine, didanosine)

• Other neuropathy (e.g., owing to diabetes, 

alcohol, medications [isoniazid, dapsone, 

many others])

Note that organic causes of neurologic 

symptoms must be ruled out before concluding 

that symptoms are psychiatric in nature.

P: Plan

Diagnostic Evaluation

Unstable or seriously ill patients should be 

hospitalized for evaluation and treatment. 

Criteria for hospitalization include acutely 

altered mental status, fever with focal 

neurologic findings, and new or unstable 

seizures.

Perform laboratory work and other diagnostic 

studies as suggested by the history, physical 

examination, and differential diagnosis. This 

may include the following:

• Establish the CD4 count (if not done 

recently) to help with risk stratification for 

opportunistic illnesses.

• Determine which laboratory tests are 

appropriate, depending on the patient’s 

presentation. The initial evaluation often 

includes a complete blood count with 

differential and monitoring of electrolyte 

and glucose levels. 

• In patients with CNS symptoms or signs 

and low CD4 counts (<100 cells/μL), check 

serum levels of Toxoplasma antibody 

(IgG) if not previously checked. Check 

serum cryptococcal antigen (CrAg) titer.

• In patients with symptoms of neuropathy 

or dementia, check serum levels of 

vitamin B12 and thyroid-stimulating 

hormone (TSH).

• In patients with cranial nerve 

abnormalities, meningoencephalitis, 

symptoms of dementia, or any symptoms 

of neurosyphilis, check syphilis serology 

by rapid plasma reagin (RPR), Venereal 

Disease Research Laboratory (VDRL) test, 

or treponemal enzyme immunoassay (see 

chapter Syphilis).

• When CNS symptoms or signs are present, 

brain imaging by computed tomography 

(CT) scan with contrast is usually adequate 

as the initial test. Magnetic resonance 

imaging (MRI) is the modality of choice if 

the neurologic examination is nonfocal or if 

physical examination suggests a lesion in the 

posterior fossa.

• For patients with fever and CNS findings, 

perform lumbar puncture (LP) with 

cerebrospinal fluid (CSF) sampling. CT or 

MRI should be performed before the LP, if 

possible, to rule out a mass lesion that could 

cause herniation.

• Record the opening pressure, and send CSF 

for cell count and differential with protein 

and glucose measurements. Depending on 

the clinical suspicion, the fluid also should 

be sent for bacterial culture, India ink stain 

for fungal organisms (75-85% sensitive), 

acid-fast bacilli smear and culture, VDRL 

test, and CrAg titer (95% sensitive).
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• If CMV is suspected, perform polymerase 

chain reaction (PCR) for CMV DNA in

the CSF.

• For suspected drug or alcohol use, perform 

urine or serum toxicology screen. (Note that 

alcohol usually has been metabolized by the 

time withdrawal symptoms set in, typically 

7-48 hours after the last alcohol intake.)

• For new-onset seizures, perform an 

electroencephalogram (EEG).

• Consult with neurology specialists if the 

workup or the diagnosis is in question.

Treatment

• Specific treatment will depend on the cause 

of neurologic symptoms. Consult relevant 

chapters in this manual. For complex 

cases, consult with an HIV-experienced 

neurologist.

Patient Education

• Inform patients that keeping the CD4 count 

>200 cells/μL (and preferably higher) with 

ART is the best way to prevent most HIVassociated neurologic diseases.

• Advise patients to take prophylaxis, as 

appropriate, to prevent opportunistic 

infections.

• When an antibiotic treatment is prescribed, 

advise patients to complete the entire 

regimen to prevent relapse of symptoms. 

Long-term treatment (secondary 

prophylaxis) will be needed to prevent 

recurrence of certain infections.

• Advise patients who have seizures that 

driving and other potentially dangerous 

activities will be prohibited until the 

condition is stable.

• Counsel patients to avoid substances that 

impair the nervous system, such as alcohol 

and recreational drugs.

• If a patient is forgetful, educate other 

members of the household about the 

medication regimen and help devise a 

plan for adherence to medications and 

appointments.

References

• Cantor CR, McCluskey L. CNS 

Complications. In: Buckley RM, Gluckman 

SJ, eds. HIV Infection in Primary Care. New 

York: WB Saunders; 2002.

• McArthur JC, Brew BJ, Nath A. Neurological 

complications of HIV infection. Lancet 

Neurol. 2005 Sep;4(9):543-55.

• McGuire D. Neurologic Manifestations of 

HIV. In: Coffey S, Volberding PA, eds. HIV 

InSite Knowledge Base [textbook online]. 

San Francisco: UCSF Center for HIV 

Information; 2003. Available at hivinsite.ucsf.

edu/InSite?page=kb-00&doc=kb-04-01-02. 

Accessed December 1, 2013.

• Portegies P, Solod L, Cinque P, et al. 

Guidelines for the diagnosis and management 

of neurological complications of HIV 

infection. Eur J Neurol. 2004 May;11(5):297-

304.
Pulmonary Symptoms | 325

Section 5: Common 

Complaints

Pulmonary Symptoms

Background 

Shortness of breath and cough are manifestations of common acute or chronic respiratory diseases, 

but also may be symptoms of HIV-related opportunistic infections. Further, these symptoms 

may indicate nonpulmonary conditions such as anemia, cardiovascular disease, and sinusitis, or 

adverse effects of medications such as angiotensin-converting enzyme inhibitors (ACEIs).

The onset and duration of symptoms, and the presence or absence of other factors such as sputum 

production, fever, and weight loss, will guide the evaluation. In addition, the patient’s CD4 

cell count will establish a context for the evaluation, because it will help to stratify the risk of 

opportunistic infections.

S: Subjective

The patient complains of dyspnea or cough.

Determine the following factors relating to the 

patient’s history:

Recent History

• Onset and duration of symptoms: rapid 

(hours to days), subacute, chronic

• Progression or stability of symptoms

• Dyspnea at rest or with exertion

• Cough: productive (character of sputum), 

hemoptysis

• Associated symptoms (e.g., chest pain, 

pleuritic pain)

• Constitutional symptoms: fever, night 

sweats, unintentional weight loss

• Sinus congestion, facial tenderness, 

postnasal discharge, sore throat

• Orthopnea, paroxysmal nocturnal dyspnea 

(PND), peripheral edema

• Wheezing

Past History

• CD4 nadir, current CD4 count

• If the CD4 count is <200 cells/μL, ask 

whether the patient is taking Pneumocystis 

jiroveci pneumonia (PCP) prophylaxis 

(primary or secondary); if taking PCP 

prophylaxis and adhering to the regimen, 

the diagnosis of PCP is less likely

• Tuberculosis (TB): date and result of 

tuberculin skin test (TST) or interferongamma release assay (IGRA), risk factors for 

Mycobacterium tuberculosis infection

• PCP, bacterial or other pneumonia, 

bronchitis

• Smoking (and secondhand smoke exposure), 

pack-years, related symptoms

• Cardiovascular diseases, including congestive heart failure, coronary heart disease, 

arrhythmia, pulmonary hypertension

• Asthma, emphysema

• Pollen, dander, or dust allergies

• Drug allergies, specifically to penicillins and 

sulfa drugs

• Medications (e.g., ACEIs)

• Travel history (exposure to regions 

endemic for particular infections, such as 

coccidioidomycosis or histoplasmosis)

• Use of inhaled stimulants, injection drugs
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• Prolonged exposure (via 

inhalation) to chemicals 

or other harmful 

pulmonary irritants (e.g., 

asbestos)

O: Objective

Check vital signs, oxygen 

saturation (resting and after 

exercise), and weight.

Conduct a thorough 

physical examination that 

includes evaluation of the 

following:

• Ears, nose, oropharynx

• Neck

• Lungs

• Heart

• Extremities

Note: If patients are 

coughing, strongly consider 

having them wear a 

surgical mask in the clinic 

or office until TB or other 

transmissible infection is 

ruled out. Covering both the 

nose and the mouth should 

prevent the discharge of 

infectious particles into the 

environment.

A: Assessment

The differential diagnosis 

of pulmonary symptoms 

is broad (see Table 1). Both 

HIV-related and HIVunrelated causes should be 

considered; the patient’s 

risk of HIV-related causes is 

strongly influenced by the 

CD4 count. More than one 

cause of symptoms may be 

present.

Table 1. Partial Differential Diagnosis 

of Pulmonary Symptoms 

CD4 Cell 

Count Possible Cause

Any Count • Upper respiratory tract illness

• Upper respiratory tract infection (URI)

• Sinusitis

• Pharyngitis

• Acute or chronic bronchitis

• Bacterial pneumonia

• TB

• Influenza

• Chronic obstructive pulmonary disease

• Reactive airway disease, asthma

• Pulmonary embolus

• Congestive heart failure

• Pulmonary hypertension

• Pneumothorax

• Bronchogenic carcinoma

• Non-Hodgkin lymphoma

• Anemia

• Gastroesophageal reflux (may cause cough)

• Lactic acidosis

• Medication adverse effect

≤500 cells/μL • Bacterial pneumonia (recurrent)

• Pulmonary Mycobacterium pneumonia 

(nontuberculous)

≤200 cells/μL • PCP

• Cryptococcus neoformans pneumonia or 

pneumonitis

• Bacterial pneumonia (associated 

with bacteremia or sepsis)

• Disseminated or extrapulmonary TB

≤100 cells/μL • Pulmonary Kaposi sarcoma

• Bacterial pneumonia (risk of gram-negative bacilli 

and Staphylococcus aureus is increased)

• Toxoplasma pneumonitis

≤50 cells/μL • Disseminated histoplasmosis

• Disseminated coccidioidomycosis

• Cytomegalovirus pneumonitis

• Disseminated Mycobacterium avium complex

• Disseminated Mycobacterium (nontuberculous)

• Aspergillus pneumonia

• Candida pneumonia

Adapted from: Huang L. Pulmonary Manifestations of HIV (Table 4). In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF 

Center for HIV Information; January 2009. Available at hivinsite.ucsf.edu/InSite?page=kb00&doc=kb-04-01-05. Accessed December 1, 2013.
Pulmonary Symptoms | 327

Section 5: Common 

Complaints

P: Plan

Diagnostic Evaluation

Perform laboratory work and other diagnostic 

studies as suggested by the history, physical 

examination, and differential diagnosis. This 

may include the following: 

• Chest X-ray, especially if the patient has 

abnormal findings on chest examination, 

fever, or weight loss, or if the CD4 count is 

<200 cells/μL. Consider further imaging 

such as chest computed tomography (CT) 

scan or high-resolution chest CT (HRCT) 

if chest X-ray result is unremarkable in 

a setting of suspected PCP or persistent 

symptoms, or if there is question of 

pulmonary nodules or suspected empyema.

• Arterial blood gas (ABG) on room air, 

particularly if PCP is suspected, of if the 

oxygen saturation is low.

• Complete blood count and white blood cell 

(WBC) count with differential, metabolic 

panel, and lactate dehydrogenase (LDH).

• If fever is present (especially temperature 

>38.5°C), obtain routine blood cultures (two 

specimens) for bacteria. If the CD4 count is 

<50 cells/μL, obtain blood culture for acidfast bacilli (AFB); if <100 cells/μL, check the 

serum level cryptococcal antigen (CrAg) 

and consider checking urine Histoplasma

antigen.

• Induced sputum (outside, or in a negativepressure room or area that is safely vented to 

the outside, to prevent TB aerosolization) for 

AFB smear and cultures (three specimens), 

Gram stain and bacterial cultures, PCP 

stains, fungal stains and cultures, and 

cytology, as indicated.

• CD4 count and HIV viral load, if recent 

values are not known.

• Bronchoscopy with bronchoalveolar lavage 

(BAL) or biopsy if sputum studies are 

negative, if the diagnosis is unclear after 

initial evaluation or if the patient is not 

responsive to empiric therapy.

• Pulmonary function tests if no infectious 

or HIV-related pulmonary diagnosis is 

suspected and symptoms persist.

• Lactate level if lactic acidosis is suspected 

(e.g., nausea, tachypnea, abdominal 

pain, fatigue, in the setting of long-term 

nucleoside analogue therapy).

• Toxicology screen if symptoms are suspected 

to be related to recent drug use (e.g., crack 

cocaine pneumonitis).

Treatment

Once the diagnosis is made, appropriate 

treatment should be initiated. In seriously 

ill patients, presumptive treatment may 

be started while diagnostic test results are 

pending. See the appropriate chapter in 

section Comorbidities, Coinfections, and 

Complications or relevant guidelines. In some 

cases, the source of dyspnea or cough cannot 

be identified. In these cases, consult with an 

HIV expert or a pulmonologist.
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Patient Education

• Shortness of breath and cough can be signs 

of an opportunistic illness, especially in 

patients with low CD4 counts. Patients 

should notify their health care provider if 

they develop new or worsening symptoms.

• Patients taking antibiotics should be 

instructed to take their medications exactly 

as directed and to call their health care 

provider if they experience worsening fevers, 

shortness of breath, inability to take the 

prescribed medications, or other problems.

• Counsel smokers about the importance of 

smoking cessation; refer to tobacco cessation 

programs and prescribe cessation supports, 

as indicated; see chapter Smoking Cessation.

• Counsel drug users (particularly those who 

smoke or inject drugs) regarding the impact 

of illicit drugs on their overall health and 

especially their lungs; refer to appropriate 

cessation programs or rehabilitation 

programs.

References

• Huang L. Pulmonary Manifestations of 

HIV (Table 4). In: Coffey S, Volberding 

PA, eds. HIV InSite Knowledge Base 

[textbook online]; San Francisco: UCSF 

Center for HIV Information; January 

2009. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-05. 

Accessed December 1, 2013.

• Mandell LA, Bartlett JG, Dowell SF, et 

al. Update of practice guidelines for the 

management of community-acquired 

pneumonia in immunocompetent adults.

Clin Infect Dis. 2003 Dec 1;37(11):1405-33.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
Vaginitis/Vaginosis | 329

Section 5: Common 

Complaints

Vaginitis/Vaginosis

Background 

Vaginitis is defined as inflammation of the vagina, usually characterized by a vaginal discharge 

containing many white blood cells (WBCs); it may be accompanied by vulvar itching and 

irritation. Vaginosis presents with increased vaginal discharge without inflammation. Vaginitis 

usually is caused by an infection, but may be caused by other factors, such as chemicals or irritants. 

Vaginal infections are common among HIV-infected women. The presence of vaginal infections 

or inflammation, in the case of bacterial vaginosis in particular, may facilitate acquisition of 

HIV and other sexually transmitted diseases (STDs), and trichomoniasis may facilitate HIV 

transmission to HIV-uninfected partners. This chapter focuses on two of the most common types 

of vaginal infections: trichomoniasis and bacterial vaginosis (BV). For information on the topic of 

vulvovaginal candidiasis, see chapter Candidiasis, Vulvovaginal.

S: Subjective

The patient complains of vaginal discharge 

with or without odor, itching, burning, pelvic 

pain, vulvar pain, or pain during intercourse.

Take a focused history, including the 

following: 

• Duration of symptoms

• Sexual history, especially recent new 

partners, unprotected sex

• Relationship of symptoms to sexual contacts

• Contraceptive use, especially: 

• Vaginal contraceptive film

• Other products containing 

nonoxynol-9 (N-9)

• Condoms; type of condoms

• Use of feminine hygiene products (e.g., 

sprays, deodorants)

• Douching

• Use of perfumed toiletries (e.g., bath salts, 

scented toilet tissue, or sanitary napkins)

• Use of any vaginal creams

• Postcoital bleeding

• Vulvar pain

• Pain or burning during urination

• Pain with intercourse

• Recent antibiotic use

• History of STDs, pelvic inflammatory 

disease (PID)

• Medications, including supplements

O: Objective

Perform a focused physical examination of the 

external genitalia, including perineum and 

anal area, for the following:

• Inflammation

• Edema

• Excoriation

• Lesions

Perform speculum examination for:

• Discharge (note color, quality; note that the 

character of the discharge is not diagnostic)

• Erythema, edema, erosions, lesions

• Cervical friability

• Foreign body

Perform a bimanual examination for masses or 

tenderness, if indicated.
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A: Assessment

A partial differential diagnosis includes the 

following:

• BV

• Candidiasis

• Trichomoniasis

• PID

• Latex or condom allergy

• Urinary tract infection (UTI)

• Condyloma

• Herpes simplex virus (HSV)

• Contact dermatitis (e.g., from irritants, 

perfumes)

• Chlamydia

• Gonorrhea

• Normal vaginal discharge

P: Plan

Diagnostic Evaluation

• Obtain a cervical sample for STD testing, if 

indicated.

• Obtain samples (swabs) from the vaginal 

wall for wet mounts and pH testing.

• Wet mounts: Perform microscopic 

examination of saline and potassium 

hydroxide (KOH) preparations for the 

following: 

• WBCs, clue cells, motile trichomonads 

(saline slide)

• Yeast forms (KOH)

• Perform a whiff test of KOH preparation; 

if positive, check pH (if >4.5, likely BV or 

trichomoniasis).

Treatment depends on the specific diagnosis, 

and in general is the same as for HIVuninfected women.

Trichomoniasis

Trichomoniasis is caused by the protozoan 

Trichomonas vaginalis. Many infected women 

have a diffuse, malodorous, yellow-green 

discharge. Most men who are infected with 

T. vaginalis have no symptoms; others have 

symptoms of nongonococcal urethritis. The 

diagnosis usually is made by visualization 

of motile trichomonads on microscopic 

examination of wet mounts. Antigen or 

nucleic acid assays have greater specificity and 

sensitivity than wet mount preparations, and 

may be used if microscopy is negative. Culture 

of vaginal secretions is the most sensitive and 

specific diagnostic test for T. vaginalis, and also 

may help to rule out other infections.

Treatment: Recommended regimen

• Metronidazole 2 g PO in a single dose

• Tinidazole 2 g PO in a single dose

Treatment: Alternative regimen

• Metronidazole 500 mg PO BID for 7 days

Treatment during pregnancy

• Metronidazole, as in nonpregnant women 

(see above); the 7-day regimen may be better 

tolerated.

• Counsel patients about the potential 

risks and benefits of therapy. In pregnant 

women with asymptomatic trichomoniasis, 

deferring therapy until after 37 weeks’ 

gestation may be considered; consult with a 

specialist.

Treatment notes:

• Single-dose metronidazole is associated with 

more side effects than the other treatment 

regimens.

• Sex partners should be treated. Patients 

should refrain from unprotected intercourse 

until both partners have resolution of 

symptoms and have completed treatment; 

this should be at least 7 days after singledose therapy.
Vaginitis/Vaginosis | 331

Section 5: Common 

Complaints

• Patients must avoid alcohol while taking 

metronidazole or tinidazole, and for at least 

1 day after discontinuing metronidazole and 

3 days after discontinuing tinidazole. The 

combination of alcohol and these drugs may 

cause a disulfiram-like reaction. Patients 

taking ritonavir capsules or tipranavir also 

may experience symptoms because of the 

small amount of alcohol in the capsules.

Treatment failure

Certain strains of T. vaginalis have diminished 

susceptibility to metronidazole and must 

be treated with higher dosages. If treatment 

failure occurs on metronidazole, consider 

tinidazole as above, or if single-dose 

metronidazole was used initially, consider 

metronidazole 500 mg PO BID for 7 days. If 

this is not effective, consult with a specialist.

Bacterial Vaginosis

BV is a clinical syndrome resulting from 

loss of the normal vaginal flora, particularly 

Lactobacillus, and replacement with anaerobic 

and other bacteria such as Gardnerella 

vaginalis and Mycoplasma hominis. The 

diagnosis is made on clinical and laboratory 

criteria. Usually, three of the following four 

characteristics should be present (note: only 

the clue cells are specific to BV): 

• Homogeneous, gray-white, 

noninflammatory discharge 

on the vaginal walls

• Clue cells on the wet-mount slide

• Vaginal fluid pH level of >4.5

• Fishy odor to the vaginal discharge before or 

after the addition of KOH (whiff test)

Vaginal culture does not help establish the 

diagnosis. Rapid diagnostic test cards are 

available in some settings.

Many studies have documented an 

association between BV and infections such as 

endometritis, PID, and vaginal cuff cellulitis 

after gynecologic procedures. Therefore, 

the U.S. Centers for Disease Control and 

Prevention (CDC) recommends screening for 

and treating BV before invasive gynecologic 

procedures.

The sex partners of women with BV do not 

need to be treated.

Treatment: Recommended regimens

• Metronidazole 500 mg PO BID for 7 days

• Metronidazole gel 0.75%, 1 full applicator 

(5 g) intravaginally QHS for 5 days

• Clindamycin cream 2%, 1 full applicator 

(5 g) intravaginally QHS for 7 days

Treatment: Alternative regimens

• Tinidazole 2 g PO QD for 2 days

• Tinidazole 1 g PO QD for 5 days

• Clindamycin 300 mg PO BID for 7 days

• Clindamycin ovules 100 g intravaginally 

QHS for 3 days

Treatment during pregnancy

• Symptomatic pregnant women should be 

treated with oral metronidazole (500 mg 

BID or 250 mg TID) or oral clindamycin 300 

mg BID for 7 days.

Treatment notes:

• Patients must avoid alcohol while taking 

metronidazole or tinidazole, and for at least 

1 day after discontinuing metronidazole and 

3 days after discontinuing tinidazole. The 

combination of alcohol and these drugs may 

cause a disulfiram-like reaction. Patients 

taking ritonavir capsules or tipranavir also 

may experience symptoms because of the 

small amount of alcohol in the capsules.

Treatment failure

Consider re-treatment for 7 days with 

metronidazole or clindamycin. Consider the 

possibility of an alternative or second cause of 

the patient’s symptoms, as multiple conditions 

or pathogens may present concurrently. 

Perform testing for other conditions as 
332 | Guide for HIV/AIDS Clinical Care

Section 5: Common 

Complaints

suggested by symptoms, or if symptoms to do 

not resolve with initial treatment:

• Perform herpes culture if indicated by 

lesions; see chapter Herpes Simplex, 

Mucocutaneous.

• Test for chlamydia and gonorrhea if 

indicated; see chapter Gonorrhea and 

Chlamydia.

• Perform urinalysis (with or without culture 

and sensitivities) if urinary symptoms are 

prominent.

• If an irritant or allergen is suspected, 

including N-9, discontinue use.

• If symptoms are related to the use of latex 

condoms, switch to polyurethane male or 

female condoms.

• For tenderness on cervical motion or 

other symptoms of PID, see chapter Pelvic 

Inflammatory Disease.

• Perform workup or obtain referral as needed 

for other abnormalities found on bimanual 

examination.

For information on other STDs or related 

conditions, see the CDC treatment guidelines 

at www.cdc.gov/std/treatment.

Patient Education

• Advise patients to avoid any form of alcohol 

while taking metronidazole or tinidazole 

and for 24 hours after taking the last dose 

(72 hours after the last tinidazole dose). 

Alcohol and metronidazole together can 

cause severe nausea, vomiting, and other 

immobilizing symptoms.

• Patients taking ritonavir capsules may 

experience these symptoms because of the 

small amount of alcohol in the capsules and 

should be told to contact their health care 

provider if nausea and vomiting occur.

• Advise patients that clindamycin cream and 

ovules are oil based and will weaken latex 

condoms, diaphragms, and cervical caps. 

Patients should use alternative methods to 

prevent pregnancy and HIV transmission.

• Recurrence of BV is common. 

Patients should contact their health 

care provider and return for repeat 

treatment if symptoms recur.

• Instruct patients to avoid douching.

• To avoid being reinfected by Trichomonas, 

patients should bring their sex partners to 

the clinic for evaluation and treatment.

References

• Abularach S, Anderson J. Gynecologic 

Problems. In: Anderson JR, ed. A Guide 

to the Clinical Management of Women 

with HIV. Rockville, MD: Health 

Resources and Services Administration, 

HIV/AIDS Bureau; 2005.

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 17; 59 

(No. RR-12):1-110. Available at www.cdc.gov/

STD/treatment/2010. Accessed December 1, 

2013.

• Cohn SE, Clark RA. Sexually transmitted 

diseases, HIV, and AIDS in women. In: The 

Medical Clinics of North America, Vol. 87; 

2003:971-995.

• Hawkins JW, Roberto-Nichols DM, StanleyHaney JL. Protocols for Nurse Practitioners 

in Gynecologic Settings, 7th Edition. New 

York: Tiresias Press, Inc.; 2000.

• Schwebke JR. Gynecological consequences 

of bacterial vaginosis. In: Obstetrics and 

Gynecology Clinics of North America, Vol. 

30; 2003:685-694.
Abnormalities of Body-Fat Distribution | 333

Section 6: Comorbidities, 

Coinfections, and Complications

Abnormalities of Body-Fat Distribution

Background 

Abnormalities of body-fat distribution are a recognized complication of HIV infection and of 

antiretroviral therapy (ART), and they are a common concern of patients. They include central fat 

accumulation (lipohypertrophy) and subcutaneous fat wasting (lipoatrophy). These morphologic 

changes are often referred to as lipodystrophy, though that term fails to distinguish between 

the two phenomena. Abnormalities in fat distribution and body shape have been noted in up to 

40-50% of patients treated with older antiretroviral (ARV) medications, but the incidence may 

be much lower with the use of newer, less lipotoxic ARVs and with earlier initiation of ART. 

Lipohypertrophy and lipoatrophy are associated with other metabolic abnormalities, such as 

dyslipidemia and insulin resistance, and visceral fat accumulation (at least in HIV-uninfected 

persons) is a risk factor for cardiovascular disease.

Research on fat maldistribution has yielded varying results, in part because there are no standard 

clinical case definitions of lipodystrophy, lipoatrophy, or lipohypertrophy. The pathogenesis of fat 

abnormalities in HIV-infected individuals is not well understood, but research to date suggests that 

it is multifactorial and is associated with HIV-related immune depletion and immune recovery, 

ARV medications, disregulation of fatty acid metabolism, hormonal influences, individual genetic 

predispositions, and factors that are not related to HIV such as diet and obesity. Lipodystrophy has 

been associated with lower nadir CD4 count as well as with gender (central lipohypertrophy may 

be more common in women) and age (more common in older patients), and longer exposure to 

ART. Lipohypertrophy has not been definitively proven to be related to specific ARVs or to specific 

ARV classes, but has been variably associated with protease inhibitors (PIs) and with nucleoside 

reverse transcriptase inhibitors (NRTIs). However, morphologic changes occasionally develop in 

ARV-naive individuals. Lipoatrophy is most commonly associated with NRTIs, notably stavudine, 

as well as didanosine and zidovudine.

The most common morphologic changes seen in lipohypertrophy are a firm enlarged abdomen 

caused by central or visceral fat accumulation, breast enlargement (gynecomastia) in both men 

and women, development of a dorsocervical fat pad (“buffalo hump”), and neck enlargement. 

Lipoatrophy most commonly appears as the loss of subcutaneous fat in the face, arms, legs, and 

buttocks. Lipoatrophy differs from the generalized wasting seen in advanced AIDS, because 

lean cell mass generally is preserved. When lipohypertrophy and lipoatrophy occur together, the 

affected individuals show a mixed picture of abdominal obesity with thinning in the face, arms, 

and legs.

Severe lipoaccumulation can cause discomfort and, in some cases, impairment of breathing 

or other bodily functions. It may be associated with other metabolic abnormalities, including 

dyslipidemia, insulin resistance, and the metabolic syndrome. Both lipoaccumulation and 

lipoatrophy can be disfiguring, can damage self-image and quality of life, and can negatively 

influence ARV adherence.
334 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

The patient may report any of the following: 

abdominal fat accumulation with change in 

waist size, increased neck size, “buffalo hump,” 

enlarged breasts, and reduced range of motion. 

Alternatively (or in addition), the patient may 

report sunken cheeks, decreased arm or leg 

circumference, prominence of veins in the 

arms or legs, or buttock flattening.

Determine CD4 cell count nadir, ARV 

medication history with particular attention 

to past use of thymidine analogues and 

PIs, and duration of and response to each 

regimen. Ask about past medical and family 

history, specifically regarding hyperlipidemia, 

diabetes or insulin resistance, other metabolic 

disorders, and cardiovascular disease. Evaluate 

the effect of body-shape changes on the 

patient’s self-esteem, medication adherence, 

and interpersonal relationships.

O: Objective

Compare past and current weights. Calculate 

body mass index (BMI); see chapter Initial 

Physical Examination for information on BMI.

Measure and document waist and hip 

circumferences. A waist circumference of 

>102 cm (39 inches) in men and >88 cm (35 

inches) in women is the clinical definition of 

abdominal obesity and is associated with the 

metabolic syndrome. Waist-to-hip ratios of 

>0.95 in men and >0.85 in women have been 

associated with an increased risk of coronary 

heart disease.

Examine the head, neck, back, breasts, and 

abdomen for fat accumulation, especially 

looking for dorsocervical fat pad and facial, 

neck, or breast enlargement. Examine the face 

and extremities for subcutaneous fat loss (e.g., 

in the cheeks, temples, limbs, and buttocks).

Review laboratory history (glucose, lipid 

panel) to identify other metabolic disorders. 

(See chapters Dyslipidemia and Insulin 

Resistance, Hyperglycemia, and Diabetes on 

Antiretroviral Therapy.)

A: Assessment

No uniform standard criteria are available 

for defining or grading lipohypertrophy or 

lipoatrophy in clinical practice. Clinicians 

must base their assessment on patient selfreport, physical examination (for characteristic 

body-shape changes), associated symptoms, 

and psychological consequences.

In research settings, modalities such as 

dual-energy X-ray absorptiometry (DEXA), 

computed tomography (CT), and magnetic 

resonance imaging (MRI) have been used to 

characterize and quantify lipoaccumulation 

and lipoatrophy. Anthropometric 

measurements may be made in the clinic by 

trained personnel (e.g., nutritionists), but do 

not measure visceral fat directly. Although 

measurements such as waist circumference 

cannot be used to assess lipohypertrophy, 

they have been validated (in HIV-uninfected 

individuals) as an assessment of cardiovascular 

risk (see chapters Dyslipidemia and Coronary 

Heart Disease Risk). Bioelectrical impedance 

analysis (BIA) does not measure regional body 

composition and thus is not used to measure 

abnormal body-fat changes.

Differential diagnosis of lipohypertrophy 

includes obesity or excess weight gain, ascites, 

and Cushing syndrome.

Differential diagnosis of lipoatrophy includes 

weight loss and wasting.
Abnormalities of Body-Fat Distribution | 335

Section 6: Comorbidities, 

Coinfections, and Complications

P: Plan

Diagnostic Evaluation

Laboratory

Check for other metabolic abnormalities 

associated with the use of ARVs, such as 

dyslipidemia and impaired glucose metabolism 

(check fasting lipids and random or fasting 

glucose). See chapters Dyslipidemia and Insulin 

Resistance, Hyperglycemia, and Diabetes on 

Antiretroviral Therapy for further information 

about workup and treatment.

Treatment

Treatments for lipohypertrophy and 

lipoatrophy have not reliably reversed body 

shape changes once these changes have 

occurred. In general, treatment interventions 

have shown poor results in patients with 

marked or severe fat maldistribution and 

inconsistent or limited responses in those with 

milder conditions. The best approaches to 

managing lipodystrophy are prevention and 

early intervention.

Clinicians can help to prevent body fat 

abnormalities by avoiding, whenever possible, 

ARV agents known to confer a greater risk 

of this disorder (particularly stavudine, 

didanosine, and zidovudine, which are 

most closely associated with lipoatrophy). 

All patients who take ARVs should be 

monitored carefully for the development of fat 

maldistribution. If abnormalities are noticed, 

the suspect ARV should be discontinued and 

a more benign ARV started in its place, if 

possible.

The optimal management strategy for 

established lipoaccumulation or lipoatrophy is 

not known, although the following approaches 

can be considered (see below). Also consider 

referring the patient to clinical studies of 

lipodystrophy treatment, and for psychological 

or adherence support and counseling, if 

indicated. If the patient is distressed enough 

to consider discontinuing or interrupting 

ART, review with the patient any gains he or 

she has made on ART and discuss treatment 

options (see below). In some cases the patient 

may insist on discontinuing ARV medications; 

in this situation, carefully review the risks 

of treatment interruption as well as the 

alternatives to discontinuing treatment.

ARV Substitutions

Avoiding thymidine analogue NRTIs, 

particularly stavudine, and avoiding the NRTI 

combination stavudine + didanosine have been 

shown to reduce the risk of lipoatrophy.

In patients with lipoatrophy, modest 

slow improvement in limb fat has been 

demonstrated after switching from thymidine 

analogues (stavudine, zidovudine) to 

nonthymidine NRTIs (such as abacavir or 

tenofovir) or to NRTI-sparing regimens. In 

patients with lipohypertrophy, similar NRTI 

switch strategies have had little effect on 

visceral or trunk fat. Studies in which PIs were 

eliminated from the ART regimen generally 

have not shown significant effects on body fat 

measures.

Before switching therapies, carefully assess the 

potential risk to the patient’s long-term HIV 

management.
336 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Nonpharmacologic Measures

Diet

The effects of diet on lipohypertrophy have not 

been evaluated thoroughly. If overall weight 

reduction is needed, recommend dietary 

changes and exercise. Avoid rapid weight 

loss plans, as lean body mass often is lost 

disproportionately. Refer to a dietitian to help 

the patient decrease intake of saturated fat, 

simple sugars, and alcohol.

Exercise

Regular, vigorous cardiovascular exercise may 

help control central fat accumulation, whereas 

resistance exercises (strength training) will 

improve the ratio of muscle to fat. Some studies 

of exercise (done alone or in combination with 

diet) have shown a reduction in visceral fat 

accumulation with minimal or no changes 

in peripheral lipoatrophy. Moderate aerobic 

exercise should be encouraged for all patients.

Pharmacologic Measures

Insulin-sensitizing agents

In diabetic and non-HIV lipodystrophy, 

treatment with thiazolidinediones may 

decrease visceral fat, increase peripheral 

fat, and improve glycemic control. In HIVinfected patients with lipoatrophy, studies of 

thiazolidinediones, specifically rosiglitazone 

and pioglitazone, have shown mixed results. 

Some patients have reported improvement 

in limb fat, particularly those with insulin 

resistance; however, a larger, 48-week 

randomized trial of rosiglitazone found 

no significant increase in limb-fat mass. 

In patients with visceral fat accumulation, 

thiazolidinediones have not been found to be 

effective.

In clinical studies, metformin has been 

modestly effective in treating visceral adiposity 

in patients with insulin resistance, but may 

cause worsening of lipoatrophy. Metformin 

should be used with caution in patients with 

chronic liver or renal disease.

Growth hormone-releasing factor

Tesamorelin, a synthetic growth hormonereleasing factor analogue, is approved by the 

U.S. Food and Drug Administration (FDA) 

for treatment of excess abdominal fat in HIVinfected persons with lipodystrophy. It has 

been shown to reduce central fat accumulation 

by about 18% over the course of 12 months, 

without adverse effects on glucose or lipid 

parameters. Unfortunately, patients rapidly 

regain visceral fat when tesamorelin is 

discontinued. That, along with its expense, has 

limited the use of tesamorelin. No long-term 

safety data are available. 

Recombinant human growth hormone

Treatment with recombinant human growth 

hormone (rHGH), 3-6 mg/day for 12 weeks 

followed by maintenance therapy with lower 

doses of 1-2 mg/day, has been shown to reduce 

visceral fat in many patients with minimal 

impact on peripheral fat wasting; other studies 

suggest efficacy (and improved tolerability) 

of lower dosages of rHGH. However, the high 

cost of rHGH, the high rate of adverse effects 

(including insulin resistance), and the frequent 

recurrence of visceral fat accumulation once 

rHGH is discontinued have resulted in a 

limited role for this treatment.

Plastic and reconstructive surgery

Various techniques have been investigated, 

but generally have limited applicability 

and efficacy. Poly-L-lactic acid (Sculptra, 

New-Fill) and a calcium hydroxylapatite 

preparation (Radiesse) are approved by the 

FDA as treatments for facial lipoatrophy. 

These injectable materials have shown good 

cosmetic results and often significantly 

improve patients’ satisfaction with their 

appearance. Treatment effects of both agents 

typically wane with time and the procedures 

often must be repeated. Other facial fillers, 

as well as cheek implants and autologous fat 

transfer, have been used successfully in some 

cases. For lipoaccumulation, treatments such 

as liposuction for focal areas of fat deposition 
Abnormalities of Body-Fat Distribution | 337

Section 6: Comorbidities, 

Coinfections, and Complications

(e.g., dorsocervical) and breast reduction may 

be effective in the short term, though fat often 

reaccumulates.

These interventions may be covered by privateand public-payer sources, but still often are 

deemed to be the financial responsibility of 

the patient. In some cases, they may be only 

a temporary solution, because abnormalities 

may reappear after treatment.

Patient Education

• Instruct patients who are receiving ARV 

medications to inform their health care 

provider if they notice changes in the shape 

or appearance of their bodies.

• Review the importance and benefits of ART 

and assess adherence to the regimen.

• For patients with lipohypertrophy, 

recommend aerobic and resistance exercise 

to reduce fat and build muscle. Assess local 

resources for safe muscle-strengthening.

• If weight reduction is needed, refer to a 

dietitian for consultation. Remind the 

patient that quick weight-loss diets may 

result in excessive muscle loss.

• For patients with severe facial lipoatrophy, 

consider referral to an experienced 

dermatologist or plastic surgeon for 

restorative treatment.

References

• Carr A, Workman C, Carey D, et al. No 

effect of rosiglitazone for treatment of HIV-1 

lipoatrophy: randomised, double-blind, 

placebo-controlled trial. Lancet. 2004 Feb 

7;363(9407):429-38.

• Chow D, Day L., Souza S, et al. Metabolic 

Complications of HIV Therapy. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [online textbook]. San Francisco: 

UCSF Center for HIV Information; 

2006. Available at hivinsite.ucsf.edu/

InSite?page=kb-03-02-10.

• Egrifta [prescribing information]. EMD 

Serono: Rockland, MA. Available at www.

accessdata.fda.gov/scripts/cder/drugsatfda/

index.cfm. Accessed December 1, 2013.

• Falutz J, Allas S, Blot K, et al. Metabolic 

effects of a growth hormone-releasing factor 

in patients with HIV. N Engl J Med. 2007 

Dec 6;357(23):2359-70.

• Falutz J, Potvin D, Mamputu JC, et al. 

Effects of tesamorelin, a growth hormonereleasing factor, in HIV-infected patients with 

abdominal fat accumulation: a randomized 

placebo-controlled trial with a safety 

extension. J Acquir Immune Defic Syndr. 

2010 Mar 1;53(3):311-22.

• Gallant JE, Staszewski S, Pozniak AL, et 

al.; 903 Study Group. Efficacy and safety of 

tenofovir DF vs stavudine in combination 

therapy in antiretroviral-naive patients: a 

3-year randomized trial. JAMA. 2004 Jul 

14;292(2):191-201.

• Haubrich RH, Riddler SA, DiRienzo AG, 

et al.; AIDS Clinical Trials Group (ACTG) 

A5142 Study Team. Metabolic outcomes 

in a randomized trial of nucleoside, 

nonnucleoside and protease inhibitor-sparing 

regimens for initial HIV treatment. AIDS. 

2009 Jun 1;23(9):1109-18.
338 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

• Martin A, Smith DE, Carr A, et al.; 

Mitochondrial Toxicity Study Group. 

Reversibility of lipoatrophy in HIV-infected 

patients 2 years after switching from 

a thymidine analogue to abacavir: the 

MITOX Extension Study. AIDS. 2004 Apr 

30;18(7):1029-36.

• Moyle G. Metabolic issues associated with 

protease inhibitors. J Acquir Immune Defic 

Syndr. 2007 Jun 1;45 Suppl 1:S19-26.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.

• Pirmohamed M. Clinical management of HIVassociated lipodystrophy. Curr Opin Lipidol. 

2009 Aug;20(4):309-14.

• Rubenoff R, Schmitz H, Bairos L, et al. 

Reduction of abdominal obesity in lipodystrophy 

associated with human immunodeficiency virus 

infection by means of diet and exercise: case 

report and proof of principle. Clin Infect Dis. 

2002 Feb 1;34(3):390-3.

• Schambelan M, Benson CA, Carr A, et al.; 

International AIDS Society-USA. Management 

of metabolic complications associated with 

antiretroviral therapy for HIV-1 infection: 

recommendations of International AIDS 

Society-USA panel. J Acquir Immune Defic 

Syndr. 2002 Nov 1;31(3):257-75.

• Wohl DA. Diagnosis and management of body 

morphology changes and lipid abnormalities 

associated with HIV Infection and its therapies. 

Top HIV Med. 2004 Jul-Aug;12(3):89-93.
Dyslipidemia | 339

Section 6: Comorbidities, 

Coinfections, and Complications

Dyslipidemia

Susa Coffey, MD

Background 

HIV-infected individuals, both those on antiretroviral 

therapy (ART) and those who are untreated, appear to 

have higher rates of coronary heart disease (CHD) than 

HIV-uninfected individuals and higher rates of various risk 

factors for CHD, including dyslipidemia. As the average 

lifespan of patients on effective ART lengthens, and as people 

living with HIV become older, morbidity and mortality from 

CHD are likely to continue to increase. Thus, identification 

and reduction of modifiable risk factors for CHD are 

important aspects of primary care for HIV-infected patients. 

Dyslipidemia is a well-described independent risk factor for CHD, and it occurs in a high 

proportion of persons with HIV infection. Current research suggests that this dyslipidemia is 

caused by a combination of factors related to HIV disease, ART regimens, and individual patient 

characteristics. HIV itself causes lipid perturbations, particularly in persons with more advanced 

immunosuppression; HIV-infected individuals who are not on antiretroviral (ARV) medications 

often have elevations in triglyceride (TG) levels and decreases in high-density lipoprotein (HDL) as 

well as in low-density lipoprotein (LDL) cholesterol and total cholesterol (TC). Lipid abnormalities 

also may be caused by or compounded by ARVs (see chapter Coronary Heart Disease Risk). They may 

appear or worsen within a few weeks to months after starting ART. With some patients, this may, at 

least in part, represent a return to pre-illness lipid levels, whereas the ARVs cause the abnormality in 

other cases. 

Not all ART-treated patients experience lipid abnormalities to the same degree. Patients with a 

personal or family history of dyslipidemia, glucose intolerance, diabetes, obesity, or a combination 

of these health problems may be genetically predisposed to lipid abnormalities that become 

evident once ART is initiated. 

The use of potent combination ART, particularly the use of protease inhibitors (PIs), has increased 

the prevalence of abnormally high TG, TC, and LDL levels among HIV-infected patients. In fact, 

dyslipidemia has been associated not only with certain PIs but also with certain nonnucleoside 

reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs). 

In the PI class, ritonavir-boosted PIs (though unusually with atazanavir or darunavir) are 

particularly likely to cause marked elevations of TG and LDL levels. Although NNRTIs also may 

contribute to increases in TC, LDL, and TG levels the effects, particularly with efavirenz, are more 

variable (and efavirenz may increase HDL). Of the NRTIs, stavudine, zidovudine, and perhaps 

abacavir may increase TC and TG levels. To date, available agents from the integrase inhibitor and 

CCR5 antagonist classes do not appear to have significant adverse impacts on lipid levels. 

The largest prospective study of CHD events related to ARVs (the D:A:D study) showed a small 

but significant increase in the risk of myocardial infarction among HIV-infected patients treated 

with ARVs; moreover, the effect increased with cumulative years of ARV exposure. This effect was 

largely but not entirely associated with increases in LDL cholesterol (see chapter Coronary Heart 

Disease Risk). 

HRSA HAB Performance 

Measures

Percentage of patients, regardless 

of age, with a diagnosis of 

HIV who were prescribed HIV 

antiretroviral therapy and who 

had a fasting lipid panel during 

the measurement year

(All-Age measure)
340 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

The history should focus on factors that suggest 

CHD, risk equivalents, or risk factors for CHD. 

Both CHD risks and CHD equivalents should be 

the focus of lifestyle modification strategies and 

lipid-normalizing treatment.

• CHD includes the following: 

• A history of myocardial infarction

• Angina

• CHD procedures

• Evidence of clinically significant 

myocardial ischemia

• CHD risk equivalents are considered to be 

equal in terms of risk level to known CHD. 

These include the following: 

• Diabetes mellitus

• Peripheral vascular disease

• Symptomatic carotid artery disease

• Abdominal aortic aneurysm

• Transient ischemic attacks

• Two or more CHD risk factors with a 10-

year risk of CHD >20% (see “Calculations 

to Estimate the 10-Year Risk of Cardiac 

Events for Men and Women,” below, or 

the online risk calculator at cvdrisk.nhlbi.

nih.gov/calculator.asp.

• CHD risk factors are conditions associated 

with a greater risk of serious cardiac events. 

These are as follows: 

• Male sex

• Age (≥45 in men; ≥55 in women)

• Hypertension

• Cigarette smoking

• Low HDL (<40 mg/dL); if >60 mg/dL, 

subtract one risk factor

• Family history of premature CHD (firstdegree relative aged <55 [men] or <65 

[women])

• Assess for causes of secondary dyslipidemias, 

including insulin resistance, diabetes, 

hypothyroidism, obstructive liver diseases, 

chronic renal failure, and medications such 

as corticosteroids and progestins.

• Screen for other factors that contribute to 

hyperlipidemia, including obesity, chronic 

liver diseases, alcohol abuse, high-fat or 

high-carbohydrate diet, and prothrombotic 

or proinflammatory states.

• Screen for health behaviors that increase 

CHD risk, including smoking, highfat diet, sedentary lifestyle, and use of 

recreational drugs such as cocaine and 

methamphetamine.

Identification and management of dyslipidemia in HIV-infected patients is an important part of 

HIV primary care. For patients with CHD or CHD risk equivalents (see below), ART regimens 

should, if possible, be selected to minimize the risk of hyperlipidemia. 

Guidelines for the evaluation and management of dyslipidemia have been developed by the National 

Cholesterol Education Program (NCEP). These recommendations are based on studies of HIVuninfected persons and may not be entirely applicable to HIV-infected persons, in whom HIV 

itself may increase risk of CHD events. Despite this limitation, expert panels generally recommend 

similar treatment goals when evaluating and managing dyslipidemia in patients with HIV infection. 

(For recommendations on screening, see chapter Initial and Interim Laboratory and Other Tests.) 

Note: The American College of Cardiology and the American Heart Association released new 

guidelines on treatment of hyperlipidemia late in 2013. These take a different approach to many 

aspects of lipid management, including the evaluation of patients for lipid-lowering therapy, the 

use and monitoring of lipid lowering agents, and the use of treatment targets. These guidelines have 

generated controversy. As their appropriateness to the management of HIV-infected individuals is 

not clear at this time, this chapter will discuss the approach presented in the NCEP guidelines.
Dyslipidemia | 341

Section 6: Comorbidities, 

Coinfections, and Complications

• Review the patient’s family history for 

premature CHD (as discussed above), 

obesity (body mass index [BMI] ≥30), 

diabetes, and lipid abnormalities.

• Review the patient’s medications, with 

special attention to ARVs known to increase 

LDL or TG levels (particularly ritonavir and 

ritonavir-boosted PIs).

O: Objective

Check vital signs with special attention to 

blood pressure and weight. Calculate BMI 

(see chapter Initial Physical Examination for 

information on BMI).

Perform a focused physical examination with 

particular attention to signs of hyperlipidemia, 

such as xanthelasma and xanthoma, and to the 

cardiovascular system.

A: Assessment

Determine whether a specific intervention is 

appropriate based on the patient’s lipid values 

and identified CHD risks, as indicated in 

Tables 1 and 2.

LDL is the main indicator for treatment, 

and the main target for lipid-lowering 

therapy. Hypertriglyceridemia is associated 

with CHD risk, but thresholds of risk have 

not been defined precisely, and targets 

for intervention are not entirely clear (for 

persons with triglyceride levels of ≥500 mg/

dL, the triglycerides usually are treated 

first; see “Treatment,” below). Severe 

hypertriglyceridemia (e.g., TG >1,000 mg/dL) 

also increases the risk of pancreatitis.

For patients who do not have diabetes or 

preexisting CHD and who have two or more 

CHD risk factors, calculate the “10-year risk 

of cardiovascular events” by using the Risk 

Assessment Tool for estimating the 10-year 

risk of a major CHD event. Use the riskestimate tool at the end of this chapter or the 

online risk calculator at the National Institutes 

of Health website (cvdrisk.nhlbi.nih.gov/

calculator.asp).

Table 1. Low-Density Lipoprotein 

Cholesterol Goals and 

Thresholds for Treatment* 

Risk 

Category

LDL 

Goal*

Initiate 

Therapeutic 

Lifestyle 

Changes

Consider 

Drug 

Therapy

Lower risk:

No CHD or 

CHD risk 

equivalents 

and <0-1 

risk factor 

<160 mg/

dL (<4.1 

mmol/L)

LDL ≥160 

mg/dL (≥4.1 

mmol/L)

≥190 mg/

dL (≥4.9 

mmol/L); 

at 160-

189 mg/

dL, LDL 

drug 

therapy is 

optional

Moderate 

risk: No 

No CHD or 

CHD risk 

equivalents 

and ≥2 risk 

factors, with 

10-year 

estimated 

risk <10%

<130 mg/

dL (<3.4 

mmol/L)

LDL ≥130 

mg/dL (≥3.4 

mmol/L)

≥160 mg/

dL (≥4.1 

mmol/L)

Moderately 

high risk: 

No CHD or 

CHD risk 

equivalents 

and ≥2 risk 

factors and 

10-year 

estimated 

risk 10-20%

<130 mg/

dL (<3.4 

mmol/L) 

(optional 

goal of 

<100 mg/ 

dL)

LDL ≥130 

mg/dL (≥3.4 

mmol/L)

≥130 mg/

dL (≥3.4 

mmol/L)

High risk: 

CHD or 

CHD risk 

equivalent 

(see above)

<100 mg/

dL (<2.6 

mmol/L) 

(optional 

goal of 

<70 mg/

dL#)

LDL ≥100 

mg/dL (≥2.6 

mmol/L)

≥100 mg/

dL (≥2.6 

mmol/L)

# This goal (LDL <70 mg/dL) is preferred by many cardiologists 

for persons with CHD or risk equivalents.

Adapted from Adult Treatment Panel III, National Cholesterol 

Education Program. Detection, Evaluation, and Treatment of High 

Blood Cholesterol in Adults. September 2002; NIH publication 

02-5215. Available at www.nhlbi.nih.gov/guidelines/cholesterol/

index.htm. Accessed December 1, 2013.
342 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Table 2. Classification of 

Triglyceride Levels

Risk Category

Triglyceride 

Measurement

Initiate 

therapy

Normal 

triglycerides

<150 mg/dL

Borderline-high 

triglycerides

150-199 mg/dL

High 

triglycerides

200-499 mg/dL Start 

therapeutic 

lifestyle 

changes; 

consider 

medication 

if CHD, CHD 

equivalents, 

or high risk

Very high 

triglycerides

≥500 mg/dL Start 

therapeutic 

lifestyle 

changes; 

consider 

medication

Adapted from Adult Treatment Panel III, National Cholesterol 

Education Program. Detection, Evaluation, and Treatment of High 

Blood Cholesterol in Adults. September 2002; NIH publication 

02-5215. Available at www.nhlbi.nih.gov/guidelines/cholesterol/

index.htm. Accessed December 1, 2013.

P: Plan

Diagnostic Evaluation

The fasting serum lipid panel should be 

performed at least 8 hours, but ideally 12 hours, 

after last food and beverage intake. It measures 

TC, HDL, TG, non-HDL cholesterol with 

calculated LDL, and TC/HDL cholesterol ratio.

A fasting lipid panel should be checked at 

baseline, before patients start ART.

Repeat the fasting lipid panel within 3-6 

months after ARVs are started, and sooner for 

patients who have abnormal values at baseline.

Patients with normal lipid values should 

be rechecked annually (sooner if ARVs are 

changed). Those with dyslipidemia may need 

more intensive monitoring (e.g., every 4-6 

weeks) until the LDL goal is met, after which 

monitoring every 4-6 months is adequate.

Treatment

Treatment of dyslipidemia usually involves 

a multimodal approach, including diet 

and exercise in all cases, lipid-modifying 

medication, and consideration of changes in 

ARV medication. The primary goal of lipidlowering therapy is to reduce LDL to target 

levels. For persons with CHD and CHD risk 

equivalents, the type and intensity of LDL 

lowering therapies are adjusted according 

to LDL baseline levels. Note that other 

interventions to reduce CHD risk also should 

be undertaken (e.g., smoking cessation if 

appropriate).

For patients with serum TG level of >400 

mg/dL, the LDL cholesterol calculation 

is unreliable. In this situation, non-HDL 

cholesterol (TC minus HDL) can be used as 

a surrogate target of therapy; the non-HDL 

goal is 30 mg/dL higher than the LDL goal. 

For these individuals, dietary intervention 

is warranted, and drug therapy to decrease 

LDL (or non-HDL) can be considered if TC 

is >240 mg/dL or HDL cholesterol is <35 mg/

dL. For those with TG levels of 200-500 mg/

dL, achieving the LDL cholesterol target is 

the primary goal, and lowering non-HDL 

cholesterol levels is a secondary goal (see Table 

1 for LDL intervention levels).

The NCEP guidelines recommend that very 

high TG levels (≥500 ml/dL) be reduced before 

LDL is treated directly (see “Treatment of 

hypertriglyceridemia,” below).

The LDL levels at which either therapeutic 

lifestyle change (TLC) or drug therapy should 

be initiated are shown in Table 1, along with 

the target goals for LDL cholesterol. The 

response to therapy should be monitored and 

therapeutic interventions should be intensified 

or augmented until lipid targets are met.

Therapeutic lifestyle change

TLC, consisting of diet modification and 

exercise, is fundamental to the management of 

dyslipidemia for HIV-infected patients.
Dyslipidemia | 343

Section 6: Comorbidities, 

Coinfections, and Complications

Target goals for lipid abnormalities are 

difficult to achieve without prioritizing these 

behavioral change efforts. Although TLC 

is hard to maintain, it can yield significant 

results in reducing CHD risk and improving 

quality of life. Effective TLC is best achieved 

with a multidisciplinary team approach. HIV 

primary care providers should be instrumental 

in identifying TLC as a treatment priority and 

providing referrals to nutritionists for dietary 

counseling, to mental health professionals for 

assessment of treatable mood disorders, and 

to social workers, peer counselors, or clinical 

nurse specialists for assistance with healthbehavior changes, self-care strategies, and 

identification of resources in the community 

for smoking cessation support and exercise 

programs. Specific recommendations for 

TLC goals and behavior change strategies 

are contained in the Adult Treatment Panel 

guidelines, which are available at www.nhlbi.

nih.gov/guidelines/cholesterol/index.htm.

Pharmacologic treatment for 

hypercholesterolemia

All patients with elevated lipid levels should 

initiate TLC. If pharmacologic intervention 

is indicated, statins (hydroxymethylglutaryl 

coenzyme A [HMG-CoA] reductase inhibitors) 

are the first-line treatment for most patients. 

These agents can be effective in reducing 

TC, LDL, and non-HDL cholesterol levels 

in HIV-infected patients (see Table 3). More 

importantly, they have been shown to reduce 

the risk of cardiovascular events in persons 

with or at risk of CHD. 

Recommended starting dosages of statins for 

patients taking PIs are as follows (Note: see 

“Potential ARV Interactions,” below):

• Pravastatin: 20 mg PO QD

• Atorvastatin: 10 mg PO QD

Fibrates may be considered as an alternative 

or adjunct to statins (see “Treatment of 

hypertriglyceridemia,” below, for further 

information). When given concomitantly, 

statins and fibrates increase the risk of 

rhabdomyolysis and must be used cautiously 

and with careful monitoring). Niacin may 

be effective as adjunctive therapy, but it has 

not been shown to decrease CHD events. It 

may worsen insulin resistance and may cause 

hepatotoxicity. It also causes uncomfortable 

flushing in some patients; the sustained-release 

formulations are better tolerated. Ezetimibe 

(Zetia) appears to be effective in combination 

with statins for patients whose cholesterol is 

not controlled adequately with a statin alone, 

but it also has not been shown to decrease 

CHD events. Bile acid sequestrants generally 

should be avoided because they may interfere 

with the absorption of other drugs and may 

increase TG levels.

Table 3. Drug Treatments for Lipid Abnormalities 

Lipid 

Abnormality

First 

Choice

Second 

Choice Comments

Isolated high 

LDL, non-HDL 

cholesterol

Statin Fibrate Start with pravastatin* or atorvastatin* (available as generics). 

Use low statin dosages and titrate upward; patients taking PIs 

have increased risk of myopathy.

Isolated high TG Fibrate Statin, N-3 

(omega-3) 

fatty acids

Start with gemfibrozil or fenofibrate. Combined statin and 

fibrate may increase myopathy risk.

High LDL and 

TG (TG level 

200-500 mg/dL)

Statin Fibrate Start with pravastatin or atorvastatin* (available as generics). 

Use fluvastatin,* rosuvastatin,* pitavastatin,* gemfibrozil, or 

fenofibrate as alternatives. Combined statin and fibrate may 

increase myopathy risk.

High LDL and 

TG (TG level 

>500 mg/dL)

Fibrate N-3 (omega-3) 

fatty acids, 

niacin, statin

Start with gemfibrozil or fenofibrate. Niacin is associated with 

insulin resistance. May need to add statin if cholesterol is not 

controlled adequately.

* May have significant interactions with certain ARVs; see Table 4. 
344 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Potential ARV Interactions

Clinicians should note that there are clinically significant drug interactions between most statins and 

PIs, NNRTIs, and the pharmacokinetic enhancer cobicistat (see Table 4). PIs and cobicistat can increase 

serum levels of most statins significantly, thus increasing the risk of severe statin adverse events such 

as rhabdomyolysis. Of the statin drugs, pravastatin is the least affected by most PIs (darunavir is an 

exception) and is the recommended statin for most patients with hypercholesterolemia without 

hypertriglyceridemia. Atorvastatin, if used, should be initiated at low dosage (10 mg) and titrated 

slowly upward to achieve target lipid levels (note that atorvastatin may lower TG, TC, and LDL levels). 

Lovastatin and simvastatin are contraindicated for use by patients taking PIs or cobicistat. These can 

result in severe statin-related adverse events if prescribed. Other available statins include rosuvastatin, 

pitavastatin, and fluvastatin. These have not been as well studied but may be used with most PIs (there 

are exceptions; see table on the following page). When statins are given concurrently with interacting 

PIs, the statins should be started at low dosage and increased incrementally, if indicated; in general, 

maximum dosages should not be used.

NNRTIs decrease levels of most statins (however, etravirine increases fluvastatin levels); higher 

dosages of statins may be needed to overcome this interaction. Be aware that various formulations 

and combination products contain these statins; check the generic name of components in new or 

unfamiliar cardiac prescriptions to determine whether they contain lipid-lowering agents.

The integrase inhibitors dolutegravir and raltegravir, and other classes of ARV drugs (NRTI, fusion 

inhibitor, CCR5 antagonist), do not have recognized interactions with statins. Other types of lipidlowering medications generally are not metabolized by hepatic cytochrome P450 and are not affected 

by ARVs (an exception to this is gemfibrozil, whose levels are decreased by lopinavir/ritonavir, by an 

unknown mechanism).
Dyslipidemia | 345

Section 6: Comorbidities, 

Coinfections, and Complications

Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin* Simvastatin

Protease InhibitorsAtazanavir ! No data



(unboosted)

! (ritonavir 

boosted)

! ! Rosuvastatin 

AUC ↑ 213%; Cmax

↑ 600%



Darunavir/ ritonavir

! No data



 ! Pravastatin AUC ↑ 81% 

to 500%

! 

Fosamprenavir ! No data

 No data

May need to ↑

pravastatin dosage





Indinavir ! No data



 ! ! 

Lopinavir/ritonavir

! Atorvastatin AUC ↑

488%

No data





pravastatin AUC ↑ 33% ! Rosuvastatin 

AUC ↑108%; Cmax

↑ 466%



Nelfinavir ! No data

 No data ! No data



Ritonavir ! No data

 No data ! No data



Saquinavir ! No data

 No data

saquinavir + ritonavir: 

May need to ↑

pravastatin dosage

No data



Tipranavir

Atorvastatin AUC 

↑ 836%

No data

 No data ! Rosuvast AUC 

↑ 26%



Nonnucleoside Reverse Transcriptase InhibitorsEfavirenz^

May need to ↑

atorvastatin dosage

No data

May need 

to ↑ lovastatin 

dosage

No data

May need to ↑

pravastatin dosage

No data

May need to 

↑ simvastatin 

dosage

Etravirine

May need to ↑ 

atorvastatin dosage

No data; May ↑

fluvastatin levels

May need 

to ↑ lovastatin 

dosage

No data

 No data

May need to 

↑ simvastatin 

dosage

Rilpivirine

 No data No data No data No data No data No data

Integrase Inhibitor/Cobicistat CombinationElvitegravir/cobicistat

! No data

 No data No data

Rosuvast AUC 

↑ 38%



^ Nevirapine in combination with statins has not been well studied; its interactions would be expected to be similar to those of efavirenz. Delavirdine’s interactions would be expected 

to be similar to those of PIs.

* Other risk factors for elevated rosuvastatin levels include Asian or Pacific Islander heritage, renal insufficiency, and concurrent treatment with gemfibrozil; use with extra caution. Adapted from: Coffey S. Interactions between ARVs and Statin Medications: Recommendations for Coadministration of PIs and NNRTIs with Statins. San Francisco: HIV InSite; UpTable 4. Interactions Between Statin Agents and Antiretroviral Medications 

Code:

 Generally safe to begin treatment 

with usual starting dosage

! Caution; start with low dosage, 

monitor effects

 Coadministration is 

contraindicated
346 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

dated October 2012. Available at hivinsite.ucsf.edu/

InSite?page=md-rr-30. Accessed December 1, 2013.

Treatment of hypertriglyceridemia

Patients with TG levels of 200-500 mg/dL 

should begin non-drug interventions such 

as diet modification, reduction in alcohol 

consumption, aerobic exercise, and smoking 

cessation. When the TG level is ≥500 mg/

dL, a low-fat diet (<15% of caloric intake) is 

recommended to help prevent pancreatitis, 

and pharmacologic therapy probably will 

be required. Patients with CHD or CHD 

equivalents, those at high risk of CHD, and 

those with TG levels >200 mg/dL may need 

pharmacologic therapy.

Fibrates are the first-line drug option 

for isolated hypertriglyceridemia 

and are an alternative treatment for 

combined hypertriglyceridemia and 

hypercholesterolemia. Fenofibrate or 

gemfibrozil reduce TG levels effectively 

in patients on ARVs. Because they are 

not metabolized by the cytochrome P450 

hepatic enzyme system, they do not have 

significant drug interactions with most 

ARVs (an exception may be gemfibrozil with 

dolutegravir: dolutegravir levels may be 

increased). Fibrates are contraindicated for use 

by patients with renal failure. Recommended 

dosages of these agents are as follows:

• Fenofibrate: 40-200 mg PO QD

• Gemfibrozil: 600 mg PO BID, 30 minutes 

before meals

If a fibrate alone is inadequate in reducing TG 

levels, several options are possible. A statin 

(e.g., atorvastatin, which acts on TGs as well 

as cholesterol) could be added cautiously, 

although there is an increased risk of skeletal 

muscle toxicity with concomitant use of a 

fibrate and a statin. N-3 (omega-3) fatty acid 

supplements (e.g., fish oils), administered at 

1-2 g BID or TID, have decreased TG levels in 

patients taking ART. Extended-release niacin 

at 1,500-2,000 mg/day also decreases both 

TG and TC levels, although its clinical utility 

is restricted because of associated insulin 

resistance and flushing.

Switching antiretroviral therapy

For patients with CHD or CHD equivalents, 

ARV medications should, if possible, 

be selected to minimize the risk of 

hyperlipidemia. In patients with dyslipidemia 

caused by ARV agents, data suggest that it 

may be beneficial to discontinue ARVs known 

to increase lipids if reasonable alternatives 

exist. Substituting atazanavir or an integrase 

inhibitor in place of a lipogenic PI or replacing 

stavudine with tenofovir may improve the 

lipid profile. Before making ARV substitutions, 

however, consider carefully the possible effect 

of the substitution on HIV virologic control 

and the potential adverse effects of new ARVs. 

In some cases, antihyperlipidemic agents may 

be necessary even after ARV substitution. 
Dyslipidemia | 347

Section 6: Comorbidities, 

Coinfections, and Complications

Appendix: 

Calculations to Estimate the 10-Year Risk of Cardiac Events for Men and Women — 

Framingham Calculator 

To calculate the 10-year risk of cardiac events, add up points from the following five tables 

pertaining to age, HDL, systolic blood pressure, TC, and smoking status (Tables 5.1-5.5). Note 

that in Tables 5.3-5.5, women’s points are in parentheses. After adding points from all of the 

tables, consult Table 5.6. (Alternatively, an online calculator is available at cvdrisk.nhlbi.nih.gov/

calculator.asp.)

(The Framingham Heart Study risk calculator has not been validated for HIV-infected individuals 

and may underestimate the risk in this population.) 

Table 5.1. Estimate of 10-Year Risk

of Cardiac Events: Age

Age (Year) Points (Men) Points (Women) 

20-34 -9 -7

35-39 -4 -3

40-44 0 0

45-49 3 3

50-54 6 6

55-59 8 8

60-64 10 10

65-69 11 12

70-74 12 14

75-79 13 16

Table 5.2. Estimate of 10-Year Risk 

of Cardiac Events: High-Density 

Lipoprotein Cholesterol

HDL (mg/dL) Points (Men) Points (Women) 

≥60 -1 -1

50–59 0 0

40–49 1 1

<40 2 2

Table 5.3. Estimate of 10-Year Risk of

Cardiac Events: Systolic Blood Pressure 

Systolic 

Blood 

Pressure

Points if 

Untreated — Men 

(Women) 

Points if

Treated — Men 

(Women) 

<120 0 (0) 0 (0)

120–129 0 (1) 1 (3)

130–139 1 (2) 2 (4)

140–159 1 (3) 2 (5)

≥160 2 (4) 3 (6)

Table 5.4. Estimate of 10-Year Risk

of Cardiac Events: Total Cholesterol 

Points for Men (Women) 

Total

Cholesterol 

(mg/dL) 

Age 

20–39

Age 

40–49

Age 

50–59

Age 

60–69

Age 

70–79

<160 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

160–199 4 (4) 3 (3) 2 (2) 1 (1) 0 (1)

200–239 7 (8) 5 (6) 3 (4) 1 (2) 0 (1)

240–279 9 (11) 6 (8) 4 (5) 2 (3) 1 (2)

≥280 11 (13) 8 (10) 5 (7) 3 (4) 1 (2)

Table 5.5. Estimate of 10-Year Risk

of Cardiac Events: Smoking Status 

Smoking 

Status Points for Men (Women) 

Age 

20-39

Age 

40-49

Age 

50-59

Age 

60-69

Age 

70-79

Nonsmoker 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Smoker 8 (9) 5 (7) 3 (4) 1 (2) 1 (1)
348 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

 Table 5.6. Estimate of 10-Year Risk

of Cardiac Events: Calculating Risk 

Men Women

Point 

Total

10-Year

Risk (%) 

Point 

Total

10-Year

Risk (%) 

<0 <1 <9 <1

0 1 9 1

1 1 10 1

2 1 11 1

3 1 12 1

4 1 13 2

5 2 14 2

6 2 15 3

7 3 16 4

8 4 17 5

9 5 18 6

10 6 19 8

11 8 20 11

12 10 21 14

13 12 22 17

14 16 23 22

15 20 24 27

16 25 ≥25 ≥30

≥17 ≥30

Patient Education

• Review the importance of reducing 

cardiovascular risk factors. This is of 

increasing importance for all patients with 

HIV infection, particularly as they age.

• Educate patients about the benefits of diet 

and exercise in improving lipid levels and 

reducing cardiovascular risk.

• If lipid-lowering medications are prescribed, 

advise patients on possible adverse effects, 

and advise them to contact their health care 

provider if these develop.

• Advise patients to talk with their health 

care provider before starting any new 

medications so they can be evaluated for 

possible drug-drug interactions. 
Dyslipidemia | 349

Section 6: Comorbidities, 

Coinfections, and Complications

References

• Chow D, Day L, Souza S, et al. Metabolic 

Complications of HIV Therapy. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [online textbook]. San Francisco: 

UCSF Center for HIV Information; 

May 2006. Available at hivinsite.ucsf.

edu/InSite?page=kb-03-02-10. Accessed 

December 1, 2013.

• Dube MP, Stein JH, Aberg JA, et al. 

Guidelines for the evaluation and 

management of dyslipidemia in human 

immunodeficiency virus (HIV)-infected 

adults receiving antiretroviral therapy: 

recommendations of the HIV Medical 

Association of the Infectious Disease Society 

of America and the Adult AIDS Clinical 

Trials Group. Clin Infect Dis. 2003 Sep 

1;37(5):613-27.

• Expert Panel on Detection Evaluation 

and Treatment of High Blood Cholesterol 

in Adults. Executive summary of the 

third report of the National Cholesterol 

Education Program (NCEP) Expert Panel 

on Detection, Evaluation, and Treatment 

of High Blood Cholesterol in Adults (Adult 

Treatment Panel III). JAMA. 2001 May 

16;285(19):2486-97.

• Friis-Moller N, Weber R, Reiss P, et al.; DAD 

study group. Cardiovascular disease risk 

factors in HIV patients – association with 

antiretroviral therapy. Results from the DAD 

study. AIDS. 2003 May 23;17(8):1179-93.

• Grundy SM, Cleeman JI, Merz CN, et al. 

Implications of recent clinical trials for the 

National Cholesterol Education Program 

Adult Treatment Panel III guidelines. 

Circulation. 2004 Jul 13;110(2):227-39.

• Ho JE, Hsue PY. Cardiovascular 

manifestations of HIV. Heart. 2009 

Jul;95(14):1193-202.

• McNicholl I. Database of Antiretroviral 

Drug Interactions. In: Coffey S, Volberding 

PA, eds. HIV InSite. San Francisco: UCSF 

Center for HIV Information; 2006. Available 

at hivinsite.ucsf.edu/insite?page=ar-00-02. 

Accessed December 1, 2013.

• Riddler SA, Smit E, Cole SR, et al. Impact of 

HIV infection and HAART on serum lipids in 

men. JAMA. 2003 Jun 11;289(22):2978-82.

• Schambelan M, Benson CA, Carr A, et al. 

Management of metabolic complications 

associated with antiretroviral therapy for 

HIV-1 infection: recommendations of an 

International AIDS Society-USA panel. J 

Acquir Immune Defic Syndr. 2002 Nov 

1;31(3):257-75.

• Shor-Posner G, Basit A, Lu Y. 

Hypocholesterolemia is associated with 

immune dysfunction in early human 

immunodeficiency virus-1 infection. Am J 

Med. 1993 May;94(5):515-9.

• Stone NJ, Robinson J, Lichtenstein AH, et al. 

2013 ACC/AHA Guideline on the Treatment 

of Blood Cholesterol to Reduce Atherosclerotic 

Cardiovascular Risk in Adults: A Report of 

the American College of Cardiology/American 

Heart Association Task Force on Practice 

Guidelines. J Am Coll Cardiol. 2013 Nov 7.

Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy | 351

Section 6: Comorbidities, 

Coinfections, and Complications

Insulin Resistance, Hyperglycemia, and 

Diabetes on Antiretroviral Therapy

Background 

Diabetes is a substantial risk factor for coronary artery disease, stroke, and peripheral vascular 

disease, as well as for a number of other conditions including retinopathy and kidney disease. 

Patients taking antiretroviral (ARV) medications, especially certain protease inhibitors (PIs) 

and nucleoside reverse transcriptase inhibitors (NRTIs), appear to have an increased risk of 

hyperglycemia and diabetes mellitus. In particular, the ARVs indinavir and stavudine (now seldom 

used in the United States) have been shown to induce insulin resistance in short-term studies of 

healthy HIV-uninfected volunteers, but other ARVs also perturb glucose homeostasis.

Disorders of glucose metabolism may present as the following:

• Insulin resistance: a state in which higher concentrations of insulin are required to exert normal 

effects; blood glucose levels may be normal but fasting insulin levels may be high because of 

compensatory insulin secretion by the pancreas

• Impaired glucose tolerance: glucose 140-199 mg/dL 2 hours after a 75 g oral glucose load

• Impaired fasting glucose: glucose 100-125 mg/dL after an 8-hour fast

• Diabetes mellitus: any of the following four criteria may be used (results must be confirmed by 

retesting on a subsequent occasion):

• Fasting glucose ≥126 mg/dL

• Glycosylated hemoglobin (HbA1c) level ≥6.5% (note that HbA1c testing has not been validated 

in HIV-infected persons; see “Diagnostic Evaluation,” below)

• 2-hour glucose level ≥200 mg/dL during glucose tolerance testing

• Random glucose values ≥200 mg/dL in the presence of symptoms of hyperglycemia

The incidence of new-onset hyperglycemia among HIV-infected patients on ARV therapy (ART) 

has been reported as about 5%, on average. Even if fasting glucose levels remain normal in 

patients taking ARVs, up to 40% of those on a PI-containing regimen will show impaired glucose 

tolerance. The etiology of insulin resistance and hyperglycemia in HIV-infected patients probably 

is multifactorial, with varying contributions from traditional risk factors (e.g., obesity, family 

history), comorbid conditions (e.g., hepatitis C virus infection), and ARV-related factors (e.g., 

direct effects of PIs, cumulative exposure to NRTIs, hepatic steatosis, and fat redistribution).

Patients who have preexisting diabetes should be monitored closely when starting ART; some 

experts would consider avoiding PIs for these patients, if other options are feasible. Alternatively, 

PIs with favorable metabolic profiles (e.g., atazanavir) may be preferred for such patients. 

Patients with no history of diabetes should be advised about the warning signs of hyperglycemia 

(polydipsia, polyuria, and polyphagia) and the need to use diet and exercise to maintain an ideal 

body weight.
352 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

Clinicians should consider the potential for 

abnormal glucose metabolism in the following 

types of patients:

• Those who are about to begin ART

• Those on an ARV regimen that includes a PI

• Those with extensive exposure to NRTIs

• Those who are obese or overweight

• Those with central fat accumulation or 

lipoatrophy

Although most patients with hyperglycemia 

are asymptomatic, some (rarely) may report 

polydipsia, polyuria, polyphagia, or blurred 

vision.

When recording the patient’s history, ask 

about the following:

• Risk factors:

• Family history of diabetes

• Obesity

• Habitual physical inactivity

• Racial or ethnic heritages (higher risk: 

African-American, Hispanic, Native 

American, Asian/Pacific Islander)

• Gestational diabetes or delivery of an 

infant weighing >9 lb (4.1 kg)

• Current pregnancy

• Hepatitis C virus coinfection

• Polycystic ovary syndrome

• Medications, including PIs, NRTIs, 

niacin, corticosteroids, antipsychotics

• Comorbidities:

• Hypertension

• Low level of high-density lipoprotein 

(HDL)

• Elevated triglycerides

• Coronary artery disease

• Fat redistribution on ARVs (see chapter 

Abnormalities of Body-Fat Distribution)

• Smoking

O: Objective

Perform a physical examination that includes 

the following:

• Blood pressure, weight, body mass index 

(BMI) (see chapter Dyslipidemia)

• Heart and lung examination

• Peripheral pulses

• Examination of neck, dorsocervical area, 

breasts, and abdomen for fat accumulation; 

measurement of waist circumference

• For patients with hyperglycemia or diabetes: 

• Retinal examination (refer to 

ophthalmologist for dilated examination)

• Visual inspection of feet (for ulcers)

• Sensory examination of feet (for 

neuropathy)

A/P: Assessment and Plan

Diagnostic Evaluation

Determine whether the patient has normal 

blood glucose, impaired fasting glucose, or 

diabetes.

Most experts recommend routine checks of 

fasting blood glucose levels at baseline and 

within 3-6 months after starting or changing 

ART, if baseline results are normal. For patients 

with normal glucose levels, recheck every 6-12 

months. Monitoring should be more frequent if 

abnormalities are detected or if any additional 

risk factors exist. Patients with risk factors for 

diabetes must be counseled about prevention of 

hyperglycemia before starting ART.

The role of 2-hour postprandial glucose 

measurements or the 75 g oral glucose 

tolerance test for diabetes is uncertain but 

these screenings may be appropriate for 

patients with multiple risk factors. The use of 

HbA1c testing to screen for diabetes has yet to 

be validated for the HIV-infected population. 

Of note, HbA1c values may underestimate 

glycemia in HIV-infected patients, especially 
Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy | 353

Section 6: Comorbidities, 

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in the setting of elevated red blood cell mean 

corpuscular volume (MCV) (e.g., owing to 

zidovudine) or anemia.

For patients with diabetes, monitor the 

following:

• HbA1c, every 3 months for patients who 

have elevated HbA1c or whose therapy has 

changed, every 3-6 months for patients with 

stable and adequate glucose control

• Fasting lipid panel

• Electrolytes, creatinine, estimated 

glomerular filtration rate (eGFR) (see 

chapter Renal Disease)

• Urine albumin/creatinine ratio 

(microalbuminuria: 30-299 mg/g)

Treatment

Patients with insulin resistance

For patients with insulin resistance who

have normal blood glucose levels, current 

evidence is inadequate to recommend drug 

treatment. However, it may be possible to 

prevent the development of diabetes, and 

lifestyle modifications can be recommended, 

including exercise, avoidance of obesity, weight 

loss if indicated, and diet changes. Weight 

loss is strongly recommended if the patient 

is overweight. Refer the patient to a dietitian, 

if possible. Studies of insulin resistance in 

HIV-infected individuals are under way, and 

patients with access to clinical trials may be 

referred to these studies.

Patients with insulin resistance and 

hyperglycemia require treatment. A trial of 

lifestyle modifications may be attempted, 

including weight loss (if indicated), diet 

changes, and exercise.

For patients with diabetes and those whose 

lifestyle changes are not adequate to control 

blood glucose, specific treatment should be 

started.

Patients with diabetes

• Treatment should be instituted to 

control blood sugar and to modify other 

cardiovascular risk factors, with the aim of 

preventing heart disease and other endorgan disease. 

• Control glucose: maintain the HbA1c level 

at <7%, while avoiding hypoglycemia.

• For hyperglycemia that is associated with 

the use of PIs, switching to an alternative 

agent (e.g., a nonnucleoside reverse 

transcriptase inhibitor, an integrase 

inhibitor, or a different PI) may be 

effective if the HIV treatment history and 

resistance profile permit.

• Metformin usually is the initial drug 

of choice for overweight patients; other 

options include sulfonylureas and 

thiazolidinediones.

• Metformin can worsen lipoatrophy 

and should be avoided in the presence 

of significant lipoatrophy. Metformin 

increases risk of lactic acidosis; it should 

not be used for patients with elevated 

serum creatinine (>1.5 mg/dL in men 

or >1.4 mg/dL in women), hepatic 

impairment, or metabolic acidosis.

• Sulfonylureas may cause hypoglycemia. 

In starting therapy, shorter-acting agents 

(e.g., glipizide) may be preferable to 

longer-acting agents (e.g., glyburide). 

Some agents should not be used for 

patients with renal impairment (CrCl <50 

mL/min).

• Thiazolidinediones should be avoided 

in patients with significant liver disease. 

Rosiglitazone may increase the risk of 

myocardial infarction and death (study 

results conflict); both rosiglitazone 

and pioglitazone have been associated 

with congestive heart failure and are 

contraindicated for use by patients with 

this condition.
354 | Guide for HIV/AIDS Clinical Care

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• In some cases, insulin may be the 

safest drug therapy for patients 

with symptomatic hyperglycemia, 

although episodes of hypoglycemia 

are much more common with insulin 

than with most oral agents.

• Treat dyslipidemia: maintain low-density 

lipoprotein (LDL) at <100 mg/dL and 

maintain triglycerides at <150 mg/dL. (Note 

that diabetes is considered a coronary heart 

disease equivalent state when evaluating 

goals for lipid management; see chapter 

Dyslipidemia.)

• Treat hypertension: Maintain systolic blood 

pressure at <130 mm Hg and diastolic blood 

pressure at <80 mm Hg.

• Reduce cardiovascular risks through lifestyle 

modifications such as smoking cessation, 

exercise, weight loss, nutritional counseling, 

and moderation of alcohol intake.

• Decrease the risk of end-organ 

complications: 

• Measure urine microalbumin and 

creatinine; if the urine albumin/

creatinine ratio is >30 mg/g, treat with 

an angiotensin-converting enzyme 

inhibitor (ACEI) or angiotensin receptor 

blocker (ARB) to slow the progression of 

nephropathy.

• Schedule annual retinal examination by 

an ophthalmologist.

• Perform an annual foot examination.

• Start aspirin therapy (75-162 mg daily) if 

the patient has evidence of macrovascular 

disease or a history of vascular events. 

Consider daily aspirin for those with 

increased coronary heart disease risk (e.g., 

men >50 years and women >60 years of age 

with ≥1 coronary heart disease risk factor, 

such as a family history of coronary artery 

disease or a history of smoking) (see chapter 

Coronary Heart Disease Risk).

For further information, see the American 

Diabetes Association, Clinical Practice 

Recommendations, Diabetes Care, available at 

care.diabetesjournals.org.

Patient Education

• ART can increase the risk of diabetes in 

some individuals. Patients should report 

any difficulty with excessive hunger and 

thirst and increased urination. Health care 

providers will monitor blood glucose when 

doing laboratory work, but it is important 

for the patient to report the presence of any 

symptoms.

• Review the patient’s eating habits and 

explain the need to work with a dietitian to 

keep blood glucose (and triglycerides) within 

normal limits. Eating a proper diet can 

reduce the risk of permanent damage to the 

blood vessels of the eye, the kidney, and the 

brain, and it can reduce the risk of a heart 

attack.

• Emphasize other lifestyle modifications, 

such as weight loss (if appropriate).

• Encourage patients to get regular 

cardiovascular exercise; work with them to 

identify activities that might be realistic and 

acceptable for them.

• Provide medication-specific education, 

especially if the patient will be taking 

diabetes medications.

• Consider referral to a diabetes clinic for 

specialty needs.
Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy | 355

Section 6: Comorbidities, 

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References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency 

virus: 2013 update by the HIV Medicine 

Association of the Infectious Diseases 

Society of America. Clin Infect Dis. 2014 

Jan;58(1):e1-e34.

• American Diabetes Association. Standards 

of Medical Care in Diabetes – 2010. Diabetes 

Care. 2010; 33:S11-61.

• Dubé MP. Disorders of glucose metabolism 

in patients infected with human 

immunodeficiency virus. Clin Infect Dis. 

2000 Dec;31(6):1467-75.

• Eckhardt BJ, Holzman RS, Kwan CK, et al. 

Glycated hemoglobin A(1c) as screening for 

diabetes mellitus in HIV-infected individuals. 

AIDS Patient Care STDS. 2012 April; 26(4): 

197–201.

• Kim PS, Woods C, Georgoff P, et al. 

Hemoglobin A1c underestimates glycemia 

in HIV Infection. Diabetes Care. 2009 

Sep;32(9):1591-3.

• Samaras K. Prevalence and pathogenesis of 

diabetes mellitus in HIV-1 infection treated 

with combined antiretroviral therapy. J 

Acquir Immune Defic Syndr. 2009 Apr 

15;50(5):499-505.

• Schambelan M, Benson CA, Carr A, et al. 

Management of metabolic complications 

associated with antiretroviral therapy for 

HIV-1 infection: recommendations of an 

International AIDS Society-USA panel. J 

Acquir Immune Defic Syndr. 2002 Nov 

1;31(3):257-75.

Coronary Heart Disease Risk | 357

Section 6: Comorbidities, 

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Coronary Heart Disease Risk

Marshall Glesby, MD, PhD

Background 

Epidemiologic studies suggest that the incidence of myocardial infarction or hospitalization for 

coronary heart disease (CHD) is increased up to twofold in HIV-infected individuals compared 

with age-matched controls without HIV infection. This increased risk of ischemic events likely is 

attributable to a higher prevalence of certain CHD risk factors that are independent of HIV status, 

such as smoking, as well as to both HIV infection and antiretroviral (ARV) medications. These 

various factors may interact in ways that are complex and incompletely understood.

Among the traditional CHD risk factors, dyslipidemia is common among persons with HIV 

infection, and can be caused both by HIV itself (e.g., resulting in low high-density lipoprotein 

[HDL] cholesterol) and by ARV therapy (ART); see chapter Dyslipidemia. Insulin resistance and 

diabetes also appear to be more prevalent in HIV-infected patients. (See chapter Insulin Resistance, 

Hyperglycemia, and Diabetes on Antiretroviral Therapy.) Visceral fat accumulation, a poorly 

understood complication of HIV or ART, also may contribute to CHD risk in certain patients (see 

chapter Abnormalities of Body-Fat Distribution). 

Several studies have suggested that low CD4 cell counts are associated with myocardial infarction 

and stroke. Additionally, a number of studies suggest that inflammation and immune activation 

owing to uncontrolled HIV infection also likely contribute to atherosclerosis. For example, in the 

Strategic Management of Antiretroviral Therapy (SMART) study, CHD events were more common 

in patients on intermittent ART than in those on continuous ART, possibly because of adverse 

effects of intermittent HIV viremia on inflammation, coagulation, and lipid parameters. There is 

even preliminary evidence that so-called elite controllers – patients with undetectable HIV viremia 

and preserved CD4 counts in the absence of ART – have increased carotid intima-medial thickness 

(a marker of atherosclerotic burden) compared with HIV-uninfected subjects, after adjusting for 

other CHD risk factors. Limited data also suggest that initiation of ART leads to improvement of 

endothelial dysfunction (an early marker of atherosclerosis that is predictive of future CHD events) 

and to improvement in markers of inflammation and immune activation. Taken together, these 

observations suggest that earlier initiation of ART could reduce CHD risk.

On the other hand, even patients with virologic suppression on ART appear to have higher levels 

of various physiologic markers of cardiovascular risk than the HIV-uninfected persons, perhaps 

owing to persistent immune activation. Additionally, exposure to ARVs has been linked to risk of 

myocardial infarction in large cohort studies such as the D:A:D study. In particular, the risk has 

been associated with use of ARV regimens that are based on protease inhibitors (PIs) rather than 

nonnucleoside reverse transcriptase inhibitors (NNRTIs). The risk is attributable in part to adverse 

changes in lipid profiles, but there appears to be additional risk associated with PIs that is not 

accounted for by changes in lipids; this remains poorly understood. Among the nucleoside reverse 

transcriptase inhibitors (NRTIs), abacavir and didanosine have been associated with increased risk 

of myocardial infarction in some but not all studies. The mechanism of this potentially increased 

risk has not been determined.
358 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

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S: Subjective

Clinicians should ask all patients about CHD, 

CHD risk equivalents, and CHD risk factors. 

Assess the following during the history:

• Age (>45 for men, >55 for women)

• History of angina, myocardial infarction, or 

other heart disease

• Family history of premature CHD in firstdegree relatives (men aged <55, women aged 

<65) and diabetes mellitus

• Smoking history

• Glucose intolerance or diabetes mellitus

• Hypertension

• Dyslipidemia

• CHD risk-equivalent states: 

• Diabetes mellitus

• Peripheral vascular disease

• Cerebrovascular disease

• Abdominal aortic aneurysm

• Use of cocaine or amphetamines

• Physical inactivity

O: Objective

Perform a physical examination to include the 

following:

• Vital signs, including blood pressure, pulse, 

weight, and body mass index (BMI); see 

chapter Dyslipidemia

• Jugular venous distention

• Heart and lung examination

• Auscultation for carotid or femoral bruits

• Peripheral pulses and evaluation of 

extremities for peripheral edema

• Abdominal examination for fat 

accumulation, ideally with measurement of 

waist circumference

A: Assessment

• Determine whether the patient has 

established CHD or a CHD risk-equivalent 

state (see above).

• Stratify risk based on the number of 

CHD risk factors and the Framingham 

risk calculator if two or more major 

CHD risk factors are present. The 

risk calculator is available at cvdrisk.

nhlbi.nih.gov/calculator.asp. 

• Check fasting lipids and glucose annually; 

more frequently if abnormal.

• Patients with established or suspected CHD 

should undergo standard evaluations such 

as electrocardiography and exercise stress 

testing; refer to a cardiologist as appropriate.

P: Plan

• Work closely with patients to reduce their 

risks of CHD events.

• For patients who smoke, smoking cessation 

is the single most important intervention 

to reduce risk of CHD events (see chapter 

Smoking Cessation).

• Manage dyslipidemia according to 

established guidelines (see chapter 

Dyslipidemia).

• Manage hypertension by lifestyle 

intervention (e.g., sodium restriction, 

exercise, weight loss) and pharmacologic 

therapy as indicated.

• Optimize glycemic control in patients 

with diabetes mellitus (see chapter Insulin 

Resistance, Hyperglycemia, and Diabetes on 

Antiretroviral Therapy).

• Encourage weight loss in overweight and 

obese patients, with referral to a dietitian as 

appropriate.

• Encourage exercise, ideally 30 minutes at 

moderate intensity 5-6 times per week.

• Encourage a healthy diet that is low in 

saturated fats.
Coronary Heart Disease Risk | 359

Section 6: Comorbidities, 

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• Consider aspirin 81 mg QD for primary 

prevention of CHD in patients at 

moderate to high risk who do not have 

contraindications to aspirin use.

• For patients who use cocaine or 

amphetamines, encourage cessation.

Patient Education

• Both HIV infection and ARV medications 

may contribute to the risk of CHD, and the 

available data suggest that the risk of CHD is 

increased in HIV-infected patients relative to 

the general population.

• Review the benefits of smoking cessation.

• Review exercise possibilities to determine 

which activities might be realistic and 

acceptable for the patient.

• Review the patient’s eating habits and 

explain the need to work with a dietitian to 

optimize lipid levels and keep blood glucose 

within normal ranges.

• Emphasize the importance of other lifestyle 

modifications, such as weight loss (if 

appropriate).

• Educate patients about any pharmacologic 

therapy that is indicated.

References

• Aberg JA. Cardiovascular complications in 

HIV management: past, present, and future.

J Acquir Immune Defic Syndr. 2009 Jan 

1;50(1):54-64.

• Currier JS, Lundgren JD, Carr A, et al.; 

Working Group 2. Epidemiological evidence 

for cardiovascular disease in HIV-infected 

patients and relationship to highly active 

antiretroviral therapy. Circulation. 2008 Jul 

8;118(2):e29-35.

• Dube MP, Stein JH, Aberg JA, et al. 

Guidelines for the evaluation and 

management of dyslipidemia in human 

immunodeficiency virus (HIV)-infected 

adults receiving antiretroviral therapy: 

recommendations of the HIV Medical 

Association of the Infectious Disease Society 

of America and the Adult AIDS Clinical 

Trials Group. Clin Infect Dis. 2003 Sep 

1;37(5):613-27.

• El Sadr WM, Lundgren JD, Neaton JD, et al.; 

Strategies for Management of Antiretroviral 

Therapy (SMART) Study Group. CD4+ 

count-guided interruption of antiretroviral 

treatment. N Engl J Med. 2006 Nov 

30;355(22):2283-96.

• Friis-Møller N, Reiss P, Sabin CA, et al.; 

D:A:D Study Group. Class of antiretroviral 

drugs and the risk of myocardial infarction. N 

Engl J Med. 2007 Apr 26;356(17):1723-35.

• Glesby M. HIV and Cardiovascular Risk 

(Oxford American Pocket Notes). New York: 

Oxford University Press; November 2010.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Stein JH, Hadigan CM, Brown TT, 

et al.; Working Group 6. Prevention 

strategies for cardiovascular disease 

in HIV-infected patients. Circulation. 

2008 Jul 8;118(2):e54-60.

• Triant VA, Lee H, Hadigan C, et al. 

Increased acute myocardial infarction rates 

and cardiovascular risk factors among 

patients with human immunodeficiency 

virus disease. J Clin Endocrinol Metab. 2007 

Jul;92(7):2506-12.

Renal Disease | 361

Section 6: Comorbidities, 

Coinfections, and Complications

Renal Disease 

Alfredo Tiu, DO

Background

The prevalence of renal complications among patients with HIV infection has increased as more 

patients with HIV are living longer as a result of effective antiretroviral therapy (ART) and 

opportunistic infection prophylaxis. More widespread access to and earlier initiation of ART 

has decreased the incidence of HIV-associated nephropathy (HIVAN), but other causes of renal 

disease persist, and in some cases are increasing in prevalence. These may be infections and 

other conditions related to HIV infection, other comorbidities (e.g., hypertension, diabetes), or 

medication adverse effects, including those caused by some antiretroviral (ARV) medications (see 

“Kidney disease associated with HIV infection” and Table 2, below).

Risk factors for renal disease in HIV-infected patients include the following:

• CD4 count <200 cells/μL

• HIV viremia, particularly RNA levels >4,000 copies/mL

• African-American race

• Family history of kidney disease

• Use of nephrotoxins (including medications; see Table 2, below)

• Comorbidities 

• Diabetes mellitus

• Hypertension

• Hepatitis C

Renal disease in HIV-infected individuals can occur as a primary disease, as a secondary disease in 

the setting of other systemic illness, or as an adverse effect of medications. In the United States, the 

most common causes of end-stage renal disease in the general population are diabetes mellitus and 

hypertension. HIV-infected patients are at a fourfold higher risk of developing diabetes mellitus and 

a threefold higher risk of developing hypertension compared with seronegative individuals. Chronic 

hepatitis C, seen in 30-40% of HIV-infected individuals in the United States, is associated with 

several types of chronic kidney disease, including progressive secondary glomerulonephropathy, 

membranoproliferative glomerulonephropathy, and mixed cryoglobulinemia.

Note that ART should be given to HIV-infected individuals with renal disease, according to usual 

criteria for ART initiation; however, some ARVs must be avoided and some should be given at 

modified dosages according to the degree of renal dysfunction (see Table 3). Additionally, for 

patients with HIVAN, ART is the primary treatment.
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Screening

Screening for kidney disease in HIV-infected persons is an important aspect of primary care, 

as patients typically have no symptoms until very late. High-risk patients (see list of risk factors, 

above) should be identified and monitored. Early identification of patients with renal dysfunction 

allows early intervention targeted at reversing the process of renal injury or slowing its progression. 

Current guidelines of the U.S. Department of Health and Human Services (HHS) and the 

Infectious Diseases Society of America recommend screening at entry to care, with subsequent 

screening as indicated by the patient’s risk factors.

Screening consists of three tests: 

• Serum creatinine (Cr) and calculated estimate of renal function (eGFR); the eGFR 

usually is provided by the laboratory but may be calculated as follows:

• eGFR by the Modification of Diet in Renal Disease (MDRD) equation:

GFR (mL/min/1.73 m2) = 186 x [serum Cr (mg/dL)]-1.154 x [age (years)]-0.203 x [0.742 if 

female] x [1.212 if African-American]

Normal GFR: ≥90 mL/min/1.73 m2

Chronic kidney disease (CKD): GFR <60 mL/min/1.73 m2

An online eGFR calculator is available at www.nkdep.

nih.gov/lab-evaluation/gfr-calculators.shtml.

• The creatinine clearance (CrCl) can be used as a surrogate for eGFR but is considered 

to be less accurate. Note that CrCl is used in determining medication dosages.

CrCl (Cockroft-Gault equation):

(140 – age) × (weight in kilograms); multiply by 0.85 for females 

 72 × serum Cr (mg/dL) 

• Urinalysis, for proteinuria, hematuria

• Quantitative test for proteinuria (if eGFR <60 mL/min/1.73m2 or ≥1+ protein on dipstick):

• Random urinary protein to urinary Cr ratio (U Pr/U Cr)

• This estimates 24-hour protein excretion and correlates well with grams per day of 

proteinuria; for example, a random U Pr/U Cr of 1.0 correlates with 1 g/day of proteinuria 

(normal is ≤0.2)

Suggested follow-up for patients with normal screening test results is shown in Figure 1; suggested 

follow-up of abnormal screening test results is shown in “Diagnostic Evaluation.”
Renal Disease | 363

Section 6: Comorbidities, 

Coinfections, and Complications

Figure 1. Follow-Up for Patients with Normal Screening Test Results

Normal screening tests

With risk factors (see above) 

for kidney disease:

• Rescreen at least annually

• For patients on potential renal 

toxins (including tenofovir), 

consider more frequent 

monitoring (e.g., every 3-6 months)

Without risk factors for kidney disease:

• Reevaluate based on signs and 

symptoms

• Follow-up clinically

S: Subjective

As noted above, patients usually have no 

symptoms until late in the course of kidney 

disease and are diagnosed on the basis of 

laboratory abnormalities. 

In symptomatic patients, presenting signs or 

symptoms are nonspecific. Patients with renal 

failure may present with fatigue, weakness, 

anorexia, nausea, pruritus, vomiting, edema, 

diminished urine output, discolored urine, 

altered mental status, and seizures. Those with 

renal disease associated with systemic illnesses 

may present with fever, arthralgias, respiratory 

symptoms, flank pain, abdominal pain, and 

diarrhea.

For patients with renal disease suspected on 

the basis of laboratory abnormalities (e.g., 

elevated serum Cr [azotemia], electrolyte 

disturbances, acid-base disorders, proteinuria, 

hematuria, and anemia), and for symptomatic 

patients with known kidney disease, ask about 

the risk factors and symptoms described 

above, and about the following:

• Systemic illness

• Night sweats, fever, weight loss

• Shortness of breath, cough, hemoptysis, 

nasal congestion, rhinorrhea

• Diarrhea, hematochezia, melena

• Dysuria, frequency, urgency, polyuria, 

decreased urine output, discoloration of 

urine

• Skin rash or skin lesions

• Edema, arthralgias, painful swollen joints, 

myalgias

• Family history of kidney disease, hypertension, diabetes mellitus

• Recent radiographic imaging with IV 

contrasts (including those containing 

gadolinium or iodinated agents)

Review the patient’s medication list (see

Table 1).

• Include over-the-counter medications, 

nonsteroidal antiinflammatory drugs, 

phosphate-containing enemas
364 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

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O: Objective

Check blood pressure, temperature, and weight. 

Compare these with values from previous 

readings. Perform a physical examination, 

including evaluations of the following:

• Volume status (blood pressure, 

pulse, skin turgor, mucous 

membrane moistness, edema)

• Optic fundi (signs of retinopathy)

• Cardiovascular system (peripheral 

pulses, bruits), to assess for 

peripheral vascular disease

• Abdomen (auscultate for unilateral 

bruit [renal artery stenosis], distention, 

mass, organomegaly, tenderness)

• Musculoskeletal system (bruises, muscle 

pain, muscle weakness, swollen joints)

• Skin (rash to help evaluate for 

drug reaction, vasculitis)

• Rectum (enlarged prostate, if 

obstruction is suspected)

Review previous laboratory values (e.g., serum 

Cr, blood urea nitrogen [BUN], electrolytes, 

urinalysis) to determine whether the kidney 

disease is acute or chronic.

• Acute kidney injury (AKI) is assumed if 

there are no previous serum Cr values.

The presence of an abnormal GFR (≤60 mL/

min for at least 3 months) suggests chronic 

kidney disease (CKD).

Review the CD4 cell count and HIV viral load.

A: Assessment

Once the duration of the elevated serum Cr is 

assessed, a differential diagnosis can be made.

The causes of renal failure are classified 

traditionally based on the area of the renal 

anatomy where the injury occurred: prerenal, 

renal, and postrenal (obstructive uropathy). 

Acute tubular necrosis (ATN) is the most 

common cause of acute kidney injury.

Table 1. Causes of Renal Failure

Prerenal Renal Postrenal

Laboratory Data

• Urine sodium (Na) 

<30 mEq/L

• Fractional excretion 

of Na (FeNa) <1% 

(see below)

• Fractional excretion 

of urea <35%

• Serum BUN: serum 

Cr ratio ≥20

• Urine Na >30 mEq/L

• FeNa >1% (see below)

• Fractional excretion of urea >50

• Serum BUN: serum Cr ratio ≥10

Hematuria

Imaging showing 

obstruction
Renal Disease | 365

Section 6: Comorbidities, 

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Prerenal Renal Postrenal

Partial Differential Diagnosis

Decreased renal 

perfusion

• Volume depletion

• Effective volume 

depletion

• Heart failure

• Cirrhosis

• Shock

Vascular disease

• Renal artery 

stenosis

Medication induced

• Prostaglandin 

inhibition (NSAID)

• ACE inhibitors 

and angiotensin 

receptor blockers

Acute Tubular Necrosis

Ischemia leading to ATN

• Prolonged hypotension attributable to any cause 

• Sepsis syndrome

• Volume depletion (gastrointestinal bleeding)

• Atheroembolism and thromboembolism

• Systemic vasculitis

• Thrombotic microangiopathy (TTP, HUS)

Endogenous toxins

• Myoglobin (rhabdomyolysis)

• Uric acid and calcium-phosphate 

complexes (tumor lysis syndrome)

Exogenous-induced ATN

• Aminoglycosides

• Amphotericin B

• Foscarnet

• Ganciclovir

• Intravenous pentamidine

• Tenofovir

• Chemotherapeutic agents (methotrexate, cisplatinum)

Glomerulonephropathy

• Many specific types; some associated with HIV 

(including HIVAN) or associated infections and other 

conditions

Other intrarenal lesions

• Acute interstitial nephritis (AIN)

• Drug induced

• Infections associated with AIN 

• Bacterial (Streptococcus, Mycobacteria, Legionella, 

Pneumococcus)

• Viral (Epstein-Barr, herpes simplex type 1, 

cytomegalovirus, BK virus)

• Fungal (histoplasmosis, candidiasis)

• Other infections (toxoplasmosis, syphilis, 

schistosomiasis, malaria, leptospirosis)

• Infectious

• Granulomatous (mycobacterial disease, 

coccidioidomycosis, histoplasmosis)

• Tumors

• Multiple myeloma

• Lymphoma

• Nephrolithiasis

• Intratubular obstruction

• Drug-induced crystalluria

Antiviral (acyclovir, indinavir, atazanavir)

Antibiotic (trimethoprim/sulfamethoxazole)

Prostate hypertrophy

Tumors

Stones or crystal 

deposition

Abbreviations: ACE = angiotensin-converting enzyme; HUS = hemolytic uremic syndrome; NSAID = nonsteroidal antiinflammatory 

drug; TTP = thrombotic thrombocytopenic purpura
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Section 6: Comorbidities, 

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Kidney Disease Associated 

with HIV Infection

A discussion of glomerulonephropathy 

is beyond the scope of this chapter, but 

HIV and associated comorbidities (e.g., 

infections such as hepatitis C, hepatitis B, and 

cytomegalovirus, along with malignancies, 

heroin use, nephrotoxic medications, diabetes 

mellitus, and hypertension) are among the 

many causes of glomerulonephropathy. The 

condition most closely associated with HIV is 

HIVAN. This is a collapsing focal segmental 

glomerulosclerosis (FSGS) that usually occurs 

in persons of African heritage, and particularly 

those with a low CD4 count or high HIV RNA 

level. The clinical presentation includes the 

following:

• Nephrotic syndrome or nonnephrotic 

proteinuria

• Normal blood pressure

• Elevated Cr, often with rapid progression to 

end-stage renal disease (<6 months)

• Renal ultrasound usually reveals normal size 

or slightly enlarged echogenic kidneys

• Renal biopsy shows a collapsing FSGS

In addition, several conditions may be caused 

by ARV medications. Tenofovir may cause, 

though rarely, AKI with type 2 renal tubular 

acidosis (RTA) and Fanconi syndrome. 

Alternatively, it more commonly causes a 

gradual increase in serum Cr over a period of 

months or years; this appears to occur more 

frequently in persons concomitantly taking 

ritonavir-boosted PIs and perhaps also in those 

taking cobicistat. Patients who take tenofovir 

should have renal function monitored every 

3-6 months. Indinavir can cause crystalluria, 

nephrolithiasis, and acute interstitial nephritis, 

and atazanavir can cause nephrolithiasis.

Some other medications commonly used in 

the treatment of patients with HIV infection 

and associated conditions may cause acute or 

chronic kidney injury. See Table 1, above, and 

Table 2, below.

It should be noted that several ARVs 

(including the NNRTI rilpivirine and the 

integrase inhibitor dolutegravir) as well as the 

pharmacokinetic inhibitor cobicistat (in the 

coformulation elvitegravir/cobicistat/tenofovir/

emtricitabine, Stribild) may inhibit renal 

tubular secretion of creatinine and thus cause 

modest increases in serum Cr (in the range of 

0.1-0.2 mg/dL) and modest decreases in eGFR. 

This does not result from kidney injury, and 

actual GFR remains stable. These creatinine 

increases occur in the initial weeks of 

treatment with one of these agents and remain 

stable afterward (if increases in Cr exceed what 

is expected for these drugs, it is important to 

conduct an evaluation for other causes).
Renal Disease | 367

Section 6: Comorbidities, 

Coinfections, and Complications

Table 2. Selective Drugs Causing Acute or Chronic Kidney Injury in HIVInfected Patients

Drugs Acute Tubular Necrosis Acute Interstitial 

Nephritis

Other Associated 

Abnormalities

Antiretroviral Medications

Abacavir +/-

Atazanavir + Nephrolithiasis

Indinavir + Crystalluria

Tenofovir + Fanconi syndrome 

(hypokalemia, non-gap 

metabolic acidosis, 

hypophosphatemia, 

glycosuria)

May cause a slow 

increase in Cr

Other Medications

TMP-SMX (Bactrim, 

Septra)

+++ Hyperkalemia, 

crystalluria

Beta-lactams ++

Sulfonamides ++

Fluoroquinolones +

Aminoglycosides 

(e.g., streptomycin, 

gentamycin, amikacin)

+++

Rifampin + +

Isoniazid + Overdose leads to high 

anion gap metabolic 

acidosis

Dapsone +/- Papillary necrosis

Amphotericin B +++ Hypokalemia, 

hypernatremia 

(nephrogenic diabetes 

insipidus)

Pentamidine +++ Crystalluria

Foscarnet +++

Ganciclovir +

Acyclovir + Crystalluria

NSAIDs + Proteinuria, secondary 

minimal change disease, 

papillary necrosis
368 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

P: Plan

Diagnostic Evaluation

Figure 2. Workup of Abnormal

Screening Test Results

Proteinuria > 1+

• Check random urine 

protein-to-creatinine ratio

• See "Proteinuria," below

CrCl or eGFR <60 mL/min per 1.73m2

• Kidney ultrasound

• Consider nephrology consultation

Abnormal screening tests:

elevated serum Cr, low eGFR, or abnormal 

urinalysis (proteinuria and/or hematuria)

Determine whether the renal disease is acute 

or chronic, as above (see “O: Objective”).

Perform a targeted laboratory evaluation, 

depending on results of initial tests, history, 

and physical examination.

• Urinalysis with microscopy and 

examination of urine sediment (e.g., 

hematuria, pyuria, casts) can help in 

identifying etiologies such as nephritic 

syndrome, ATN, or infection.

• Quantify the proteinuria by obtaining a 

random urine protein-to-urine creatinine 

ratio (U Pr/U Cr), if not done already; 

this correlates well with grams per day of 

proteinuria, as discussed above.

• Fractional excretion of sodium (FeNa) may 

be helpful in distinguishing causes of acute 

kidney injury. 

• FeNa = Urine sodium ÷ Serum sodium

 Urine Cr ÷ Serum Cr

• FeNa <1 is highly suggestive 

of prerenal state

• FeNa >1 is suggestive of 

intrinsic renal injury 

• Urine culture, if urinary tract infection is 

suspected

Further workup will depend on the findings 

and the suspected cause.

Proteinuria

Proteinuria can be present in patients with 

primary renal disease, and also in those with 

hypertension, diabetes mellitus, vascular 

disease, collagen vascular disease, malignancy, 

or certain infections. Proteinuria is not always 

pathologic and may be caused by 

transient conditions such 

as pregnancy, strenuous 

exercise, fever, seizure, or 

congestive heart failure; in 

some cases, it may be benign. 

However, proteinuria should 

be evaluated if it persists. If 

present with hematuria, proteinuria is highly 

suspicious for a glomerular disease.

The major classifications of persons with 

proteinuria are as follows:

Nephrotic syndrome: 

• >3.5 g/day proteinuria

• “Bland” sediment, with no or few red or 

white blood cells

• Edema

• Hyperlipidemia

• Hypoalbuminemia

• Check serum complements (C3 and C4):

• Low complements: glomerulonephritis 

associated with subacute bacterial 

endocarditis, infection (postinfectious), 

lupus, membranoproliferative 

glomerulonephritis, and mixed 

cryoglobulinemia

Glomerulonephritis: 

• Proteinuria

• “Active” sediment, with white and red blood 

cells; may see red blood cell casts

• Further categorized into those with normal 

renal function and those with abnormal 

renal function
Renal Disease | 369

Section 6: Comorbidities, 

Coinfections, and Complications

Hematuria 

For asymptomatic isolated microscopic 

hematuria, obtain a follow-up urinalysis. If 

hematuria is persistent, obtain a renal and 

bladder ultrasound. If the result is normal, 

the eGFR is normal, and there are no other 

urine abnormalities, conduct routine followup with urinalysis and serum Cr testing. Refer 

patients aged ≥40 with persistent hematuria 

to a urologist for formal evaluation. Consider 

checking urine cytology, though that test is 

not sensitive enough to rule out genitourinary 

malignancy. 

Red blood cell casts

Red blood cell casts strongly suggest 

glomerulonephritis, which can progress rapidly.

ATN

ATN is the most common cause of AKI. A 

history of certain medication exposures, 

recent IV contrast, and concurrent illness may 

provide important clues to ATN. Laboratory 

findings that are consistent with ATN include 

increasing serum Cr and a characteristic urine 

sediment that shows “muddy brown” casts, 

which are casts that contain densely packed 

tubular cells.

AIN 

During AIN, the classic triad of AKI, fever, and 

rash is not always present. Laboratory findings 

suggestive of AIN in the setting of AKI include 

sterile pyuria and eosinophiluria. 

Sterile pyuria 

Sterile pyuria also may occur in malignancy 

(e.g., renal, bladder), and in genitourinary 

tuberculosis. If tuberculosis is suspected, 

further testing usually requires three firstvoid urine specimens sent for acid-fast bacilli 

culture. 

Crystalluria and nephrolithiasis

Usual causes of nephrolithiasis should be 

considered in patients with hematuria, 

particularly if symptoms consistent with 

nephrolithiasis are present. Other causes in 

persons with HIV infection include some 

medications, including the ARVs indinavir and 

(rarely) atazanavir; see Table 2 above.

Obtain radiographic imaging (see below) 

as part of the initial evaluation, and send 

the passed renal stone, if available, for 

analysis in order to provide more specific 

recommendations for management. If there 

is suspicion that the condition is caused by a 

medication, order specific chemical analysis 

(e.g., for atazanavir).

In patients with multiple renal stones, active 

renal stone formation, and recurrent kidney 

stones, a metabolic evaluation should be done. 

This includes a serum intact parathyroid 

hormone measurement and 24-hour urine 

collection for Cr, sodium, calcium, oxalate, 

uric acid, and citrate. 

Imaging 

Radiographic imaging of the kidneys is 

important in the evaluation of renal disease. 

The size and echogenicity of the kidneys may 

help differentiate acute and chronic kidney 

disease. Small and echogenic kidneys are 

consistent with CKD, though HIV, diabetes, 

and some other chronic conditions are 

associated with normal size or large kidneys. 

Imaging also helps identify obstruction 

(though the absence of hydronephrosis does 

not completely rule that out), malignancy, and 

other conditions.

Both spiral computed tomography (CT) 

scan and renal ultrasound are acceptable 

radiographic imaging studies for 

nephrolithiasis. The advantage of spiral CT 

scan is its ability to localize stones and assess 

their size without the use of contrast. Gallium 

renal scan may be helpful in AIN.

Renal biopsy 

Biopsy is not always indicated for patients 

with renal disease, but it can be very helpful in 

establishing some diagnoses and determining 

treatment options.
370 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Treatment

Patients with proteinuria will benefit from 

angiotensin-converting enzyme inhibitors 

(ACEIs) or angiotensin receptor blockers 

(ARBs). Follow the serum potassium and Cr 

during treatment with an ACEI or ARB (check 

1 week after initiation, then periodically). 

Follow the JNC VII (Joint National Committee 

on Prevention, Detection, Evaluation and 

Treatment of Blood Pressure) guidelines for 

blood pressure control. For patients with 

hypertension and proteinuria, the target blood 

pressure is <125/80 mm Hg.

The cornerstone of HIVAN management 

is fully suppressive ART, and this should 

be quickly initiated or optimized in all 

patients, if possible. An ACEI or ARB also 

should be used to treat proteinuria. A trial of 

corticosteroids can be considered for patients 

with deteriorating kidney function while on 

effective ART plus an ACEI or ARB; consult 

with a specialist.

For ATN and AIN, discontinue the offending 

medications and provide supportive care, 

which may include gentle volume repletion, 

replacement of bicarbonate deficit, and 

management of electrolyte abnormalities (e.g., 

hyperkalemia); consult with a renal specialist.

Other modalities of treatment such as steroids 

or immunomodulators may be needed, 

depending on the specific glomerular disease 

diagnosed by renal biopsy.

Uncomplicated nephrolithiasis can be managed 

with hydration and pain control. Oral fluid 

intake should be titrated to produce ≥2 liters 

of urine output per day. Recommendations 

for dietary modifications should be based 

on the 24-hour urine metabolic evaluation. 

A low-calcium diet usually is not helpful for 

patients with normal serum calcium and 

may be detrimental to patients with oxalate 

renal stones. If the crystalluria is caused 

by medications, discontinue the offending 

medications, if possible (in the case of ARVs, 

make substitutions to maintain optimal 

virologic suppression).

Patients with complicated nephrolithiasis 

or pyelonephritis require urgent urologic 

evaluation.

Follow-Up

• Acute kidney injury 

• Monitor serum electrolytes, BUN and Cr

• After these normalize, perform routine 

follow-up

• Acute interstitial nephritis 

• Avoid offending medications

• Chronic kidney disease 

• Follow blood pressure closely 

• If hypertensive, consider an ACEI or 

ARB as first-line medication, as above

• Target blood pressure is <130/80 mm Hg

• If evidence of nephropathy, target 

blood pressure is <125/75 mm Hg

• For patients with diabetes, optimize blood 

glucose control

• Address other risk factors for cardiovascular disease (see chapter Coronary 

Heart Disease Risk)

• Dyslipidemia

• Cigarette smoking

• Obesity

• Physical inactivity

• Monitor serum electrolytes, BUN, Cr, and 

hemoglobin

• Risk of secondary hyperparathyroidism:

• Serum calcium <9.5 mg/dL

• Parathyroid hormone level >35 pg/mL

• Management:

• Low-phosphate diet

• Phosphate binders with meals

• Vitamin D supplement
Renal Disease | 371

Section 6: Comorbidities, 

Coinfections, and Complications

• Anemia

• Consider recombinant human 

erythropoietin and iron supplement 

(consult with a nephrologist)

• Target hemoglobin 11-12 g/dL

• Avoid nephrotoxins, if possible

• Adjust medication dosages based on renal 

function (eGFR); see below

Patients with severe or chronic renal disease 

should be referred to Nephrology for further 

evaluation and assistance with the following:

• Management

• Education

• Evaluation for renal replacement therapy

• Peritoneal dialysis 

• Hemodialysis

• Kidney transplant evaluation

Medication Dosage Adjustment 

Dosages of many medications, including 

most nucleoside analogues (NRTIs), must be 

adjusted for patients with CKD, and for those 

on hemodialysis; see Table 3, below.

Table 3. Dosing of Antiretroviral Drugs in Adults with 

Chronic Kidney Disease and Hemodialysis

Drug Standard Dosage Dosing in Chronic Kidney Disease and Hemodialysis 

Abacavir 300 mg PO BID Dosage adjustment for CKD does not appear necessary

Didanosine 

(enteric-coated 

capsules)

250 mg to 400 mg 

PO QD, depending 

on weight

CrCl (mL/min) Weight ≥60 kg Weight <60 kg

≥60 400 mg QD 250 mg QD

30-59 200 mg QD 125 mg QD

10-29 125 mg QD 125 mg QD

<10 125 mg QD Formulation not suitable

HD 125 mg QD Formulation not suitable

Emtricitabine 200 mg PO QD CrCl (mL/min)

≥50 200 mg QD

30-49 200 mg Q48H

15-29 200 mg Q72H

<15 200 mg Q96H

HD 200 mg Q96H, take after dialysis

Lamivudine

150 mg PO BID or 

300 mg PO QD

150 mg PO BID or 

300 mg PO QD 

CrCl (mL/min)

≥50 150 mg BID or 300 mg QD

30-49 150 mg QD

15-29 150 mg first dose, then 100 mg QD

5-14 150 mg first dose, then 50 mg QD

<5 50 mg first dose, then 25 mg QD

HD 50 mg first dose, then 25 mg QD, take after dialysis

Stavudine 20 mg to 40 mg PO 

BID, depending on 

weight

CrCl (mL/min) Weight ≥60 kg Weight <60 kg

>50 40 mg BID 30 mg BID

26-50 20 mg BID 15 mg BID

10-25 20 mg QD 15 mg QD

HD 20 mg QD, take 

after dialysis

15 mg QD, take after dialysis
372 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Drug Standard Dosage Dosing in Chronic Kidney Disease and Hemodialysis 

Tenofovir 300 mg PO QD Experience in patients with CrCl <60 mL/min is limited. 

CrCl (mL/min)

≥50 300 mg QD

30-49 300 mg Q48H

10-29 300 mg BIW (i.e., Q 3-4 days)

<10 Not recommended

HD 300 mg once weekly, after dialysis

Zidovudine 300 mg PO BID CrCl (mL/min)

<15 100 mg TID (or 300 mg QD)

HD 100 mg TID (or 300 mg QD); take after dialysis 

Fixed-Dose Combinations

Drug Standard Dosage Dosing in Chronic Kidney Disease and Hemodialysis

Atripla (efavirenz/

tenofovir/

emtricitabine)

1 tab PO QHS Substitute component drugs, adjusting 

dosage of each drug for CrCl

Combivir 

(zidovudine/

lamivudine)

1 tab PO BID Substitute component drugs, adjusting 

dosage of each drug for CrCl

Complera 

(rilpivirine/

tenofovir/

emtricitabine)

1 tab PO QD Substitute component drugs, adjusting 

dosage of each drug for CrCl

Epzicom or 

Kivexa (abacavir/

lamivudine)

1 tab PO QD Substitute component drugs, adjusting 

dosage of each drug for CrCl

Trizivir 

(zidovudine/

abacavir/

lamivudine)

1 tab PO BID Substitute component drugs, adjusting 

dosage of each drug for CrCl

Stribild 

(elvitegravir/

cobicistat/

tenofovir/

emtricitabine)

1 tab PO QD Do not initiate if CrCl <70 mg/mL; discontinue if CrCl <50 mg/mL

Truvada 

(emtricitabine/

tenofovir)

1 tab PO QD CrCl (mL/min)

≥50 1 tablet QD

30-49 1 tablet Q48H

<30 Substitute component drugs, adjusting dosage 

of each drug for CrCl

Abbreviations: CrCl = creatinine clearance; HD = hemodialysis

Adapted from McNicholl I, Rodriguez R. Dosing of Antiretroviral Drugs in Adults with Chronic Kidney Disease and Hemodialysis. In: HIV 

InSite, Coffey S, Volberding P, eds. San Francisco: UCSF Center for HIV Information. Available at hivinsite.ucsf.edu/InSite?page=md-rr-18. 

Accessed December 1, 2013.
Renal Disease | 373

Section 6: Comorbidities, 

Coinfections, and Complications

Protease inhibitors (PIs) and nonnucleoside 

reverse transcriptase inhibitors (NNRTIs) do 

not appear to require dosage adjustment in 

persons with CKD. Some PIs and NNRTIs, 

however, do require changes in dosing strategy 

for patients on hemodialysis. (It should be 

noted that most PIs have not been studied 

in the setting of hemodialysis.) The CCR5 

antagonist maraviroc should not be used 

for certain patients with CKD. Available 

recommendations for hemodialysis patients 

include the following: 

Atazanavir

• Unboosted atazanavir should not be used.

• Treatment-naive patients: atazanavir must 

be boosted by ritonavir.

• Treatment-experienced patients: 

atazanavir (boosted or unboosted) is not 

recommended.

Lopinavir/ritonavir

• QD dosing should not be used.

• In patients with PI resistance, lopinavir/

ritonavir levels may be subtherapeutic.

Maraviroc 

• CrCl <30 mL/min or on HD: not 

recommended with potent CYP3A 

inhibitors or inducers. Without potent 

CYP3A inhibitors or inducers: 300 mg BID 

(150 mg BID if postural hypotension occurs).

Nevirapine 

• An additional dose (200 mg) should be given 

after each dialysis session.

Patient Education

• Early diagnosis of kidney disease is 

important. Acute kidney injury usually 

is reversible but may take time and may 

require temporary hemodialysis support.

• Advise patients to report all the medications 

they take, including over-the-counter 

medications and herbs or supplements.

• Risk factors for kidney disease are 

uncontrolled HIV infection (viral load above 

4,000 copies/mL and CD4 count <200 cells/

μL), coexisting conditions (diabetes mellitus, 

hypertension, hepatitis C), and ethnicity 

(African-Americans, Hispanic Americans, 

Asians, Pacific Islanders, and American 

Indians). Advise patients that it is important 

to reduce any modifiable risks, including 

optimizing HIV control and diabetes 

mellitus or hypertension management.

• Advise patients that control of blood 

pressure is important in slowing the 

progression of renal disease. Hypertension 

control can be maximized by both lifestyle 

modifications (e.g., weight lost, exercise, 

avoiding excessive alcohol intake) and 

antihypertensive medications. ACEIs or 

ARBs are the drugs of choice for patients 

with hypertension and kidney disease. 

Target blood pressure is <125/75 mm Hg for 

patients with proteinuric kidney disease.

• Educate patients that management of 

chronic kidney disease helps avoid or control 

complications such as high blood pressure, 

weak bones (osteodystrophy), anemia, and 

nerve damage (neuropathy).

• When the kidney disease progresses to 

end-stage renal disease, several options 

can be explored. These are dialysis, kidney 

transplant, or palliative care. There are 

two modes of dialysis, hemodialysis and 

peritoneal dialysis. A nephrologist and the 

patient can decide which option is best. 

HIV control (suppressed viral load, optimal 

CD4) is required if kidney transplant is to be 

considered.
374 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary care 

guidelines for the management of persons 

infected with human immunodeficiency 

virus: 2013 update by the HIV Medicine 

Association of the Infectious Diseases 

Society of America. Clin Infect Dis. 2014 

Jan;58(1):e1-e34.

• Atta MG, Gallant JE, Rahman H, et al. 

Antiretroviral therapy in the treatment of 

HIV-associated nephropathy. Nephrol Dial 

Transplant. 2006 Oct;21(10):2809-13.

• Berliner AR, Fine DM, Lucas GM, et al. 

Observations on a cohort of HIV-infected 

patients undergoing native renal biopsy. Am J 

Nephrol. 2008;28(3):478-86.

• Brown TT, Li X, Cole SR, et al. Cumulative 

exposure to nucleoside analogue reverse 

transcriptase inhibitors is associated with 

insulin resistance markers in the Multicenter 

AIDS Cohort Study. AIDS. 2005 Sep 

2;19(13):1375-83.

• Campbell LJ, Ibrahim F, Fisher M, et al. 

Spectrum of chronic kidney disease in 

HIV-infected patients. HIV Med. 2009 

Jul;10(6):329-36.

• Gupta SK, Eustace JA, Winston JA, et al. 

Guidelines for the management of chronic 

kidney disease in HIV-infected patients: 

recommendations of the HIV Medicine 

Association of the Infectious Diseases Society 

of America. Clin Infect Dis. 2005 Jun 

1;40(11):1559-85.

• McNicholl I, Rodriguez R. Dosing of 

Antiretroviral Drugs in Adults with Chronic 

Kidney Disease and Hemodialysis. In: 

HIV InSite, Coffey S, Volberding P, eds. 

San Francisco: UCSF Center for HIV 

Information. Available at hivinsite.ucsf.edu/

InSite?page=md-rr-18. Accessed December 

1, 2013.

• Mocroft A, Kirk O, Reiss P, et al.; EuroSIDA 

Study Group. Estimated glomerular 

filtration rate, chronic kidney disease and 

antiretroviral drug use in HIV-positive 

patients. AIDS. 2010 Jul 17;24(11):1667-78.

• National Kidney Foundation. K/DOQI 

clinical practice guidelines for chronic kidney 

disease evaluation: evaluation, classification, 

and stratification. Am J Kidney Dis. 2002 

Feb;39(2 Suppl 1):S1-266.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Post FA, Campbell LJ, Hamzah L, et 

al. Predictors of renal outcome in HIVassociated nephropathy. Clin Infect Dis. 2008 

Apr 15;46(8):1282-9.

• Szczech LA, Gupta SK, Habash R, et al. 

The clinical epidemiology and course of 

the spectrum of renal diseases associated 

with HIV infection. Kidney Int. 2004 

Sep;66(3):1145-52.

• Verdecchia P, Staessen J, Angeli F, et 

al. Usual versus tight control of systolic 

blood pressure in non-diabetic patients 

with hypertension (Cardio-Sis): an openlabel randomized trial. Lancet. 2009 Aug 

15;374(9689):525-33.

• U.S. Department of Veterans Affairs. Renal 

Disease. In: Ross D, Coffey S, eds. Primary 

Care of Veterans with HIV. Washington: U.S. 

Department of Veterans Affairs, Veterans 

Health Administration; April 2009;211-

25. Available at www.hiv.va.gov/provider/

manual-primary-care/renal-disease.asp. 

Accessed December 1, 2013.

• Zietse R, Zoutendijk R, Hoorn EJ. Fluid, 

electrolyte and acid-base disorders associated 

with antibiotic therapy. Nat Rev Nephrol. 

2009 Apr;5(4):193-202. 
Immune Reconstitution Inflammatory Syndrome | 375

Section 6: Comorbidities, 

Coinfections, and Complications

Immune Reconstitution 

Inflammatory Syndrome

Background 

For most patients, initiating antiretroviral therapy (ART) improves immune responses to a wide 

range of opportunistic pathogens. The process of ART-induced immune reconstitution typically 

is uneventful. However, a small percentage of patients develop inflammatory disease in response 

to specific opportunistic pathogens within a few weeks or months after initiating therapy. This 

exuberant inflammatory response has been called the immune reconstitution inflammatory 

syndrome (IRIS), also known as immune reconstitution syndrome (IRS) or immune reconstitution 

disease (IRD).

The term IRIS is used to describe two distinct entities:

• An exacerbation of a partially or successfully treated opportunistic infection (OI), referred to as 

paradoxical IRIS

• An inflammatory response to a previously undiagnosed (subclinical) OI, often more pronounced 

than the typical presentation of this OI, referred to as unmasking IRIS

IRIS may occur in response to many pathogens. IRIS commonly occurs in association with 

Mycobacterium tuberculosis, Mycobacterium avium complex (MAC), cytomegalovirus (CMV), 

and Cryptococcus, and it may occur with Pneumocystis, Toxoplasma, hepatitis B and C, human 

herpes virus 8 (HHV-8, which causes Kaposi sarcoma), and JC virus (which causes progressive 

multifocal leukoencephalopathy, PML).

Risk factors for development of paradoxical IRIS include low CD4 cell count (particularly <50 

cells/μL) at time of ART initiation and high baseline HIV RNA. Starting ART in close proximity 

to initiation of treatment for a recognized OI also increases the risk of IRIS, though data also show 

that earlier ART initiation tends to reduce mortality and AIDS progression, particularly in persons 

with advanced immunosuppression (see “Timing of ART initiation,” below).

Paradoxical IRIS also can occur in the absence of ART, as has been reported during tuberculosis 

(TB) treatment. The specific mechanisms involved in the pathogenesis of IRIS are not well 

understood and may vary from one infection to another. However, experts believe that IRIS is 

caused by an enhanced and dysregulated immune response to disease-specific antigens, which 

leads to an overproduction of inflammatory mediators.

IRIS may be difficult to identify in clinical practice because the clinical presentation is nonspecific 

and, currently, there are no laboratory markers to identify the syndrome. To make the diagnosis of 

IRIS, the following must be excluded:

• Presence of a new OI or concomitant illness

• Failure of treatment for HIV infection (e.g., 

owing to poor adherence or drug resistance)

• Failure of treatment for a known OI (e.g., 

owing to drug resistance, inadequate 

treatment, or poor adherence)

The severity of IRIS varies widely, from mild to life-threatening. Treatment varies according to the 

specific pathogen and clinical situation, but typically includes continuing ART if possible, treating 

the OI as indicated, and adding antiinflammatory therapy (including corticosteroids) as needed.
376 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Clinical Presentation

IRIS is largely a clinical diagnosis, and other 

conditions must be excluded, as indicated 

above. To consider IRIS in the differential 

diagnosis, clinicians must recognize the 

clinical findings (typical or atypical) of a 

specific OI and the temporal association with 

treatment (usually after ART initiation, but 

IRIS may occur with treatment of the OI 

alone). For example, for a patient with TB who 

has recently initiated ART after responding 

to treatment of TB, the “red flags” for a 

diagnosis of IRIS (rather than progression 

of the TB) would include new or worsening 

fever, new effusions, and new or worsening 

lymphadenopathy, in the absence of poor 

adherence to TB treatment or drug-resistant 

TB.

The clinical manifestations of IRIS associated 

with some common OIs are described below. 

(This is not an exhaustive list, but it includes 

most of the important IRIS manifestations 

seen in patients with HIV infection.)

Tuberculosis

The signs and symptoms of TB IRIS may 

include various clinical or radiologic features 

(e.g., new or worsening enlarged lymph nodes, 

fevers, weight loss, pulmonary symptoms, and 

radiographic features of TB such as infiltrates 

and pleural effusions). Nonpulmonary 

presentations may include expanding central 

nervous system (CNS) deficits or lesions, 

lymphadenopathy (mediastinal or peripheral), 

ascites, pericardial effusions, skin or visceral 

abscesses, bone lesions, and hypercalcemia. 

In a patient who is receiving therapy for 

active TB, the onset of TB IRIS typically 

occurs within weeks to several months after 

the patient begins ART and is more common 

among patients with low CD4 cell counts 

at the time of ART initiation (see chapter 

Mycobacterium tuberculosis).

Mycobacterium avium Complex

Lymphadenitis and fever are the characteristic 

symptoms of MAC IRIS, but pulmonary 

symptoms, abdominal pain, bone and hepatic 

involvement, and CNS manifestations may 

develop. Signs and symptoms of MAC IRIS 

may be clinically indistinguishable from active 

MAC. In contrast to disseminated MAC, MAC 

IRIS is associated with a rapid and striking 

increase in CD4 count (usually from <50 cells/

μL to ≥100 cells/μL), and MAC bacteremia 

usually is absent. MAC IRIS can be mild and 

localized or it can be severe, requiring systemic 

antiinflammatory therapy (sometimes for long 

periods), in addition to anti-MAC therapy.

Cytomegalovirus

CMV IRIS is usually localized to the eye, as 

described below. However, CMV IRIS will 

rarely present with extraocular disease such as 

colitis, pancreatitis, or pneumonitis.

CMV retinitis

CMV retinitis may occur in patients with a 

history of CMV retinitis or in patients with 

no previous evidence of retinitis. In those 

with a previous diagnosis of CMV retinitis, 

a new opacified retinal lesion develops, 

frequently at the site of an earlier lesion. 

CMV retinitis IRIS is identical to active CMV 

retinitis on ophthalmologic examination. 

Clinical information, therefore, will guide the 

diagnosis, and patients should be monitored 

closely. As with other IRIS reactions, 

symptoms often are associated temporally with 

initiation of ART.

In order to initiate appropriate treatment, and 

to avoid IRIS, an ophthalmic examination to 

assess for the presence of CMV retinal infection 

should be performed for all patients with CD4 

cell counts of <50 cells/μL), preferably prior 

to the initiation of ART. This is particularly 

important for patients who report visual 

symptoms such as floaters or abnormal vision.
Immune Reconstitution Inflammatory Syndrome | 377

Section 6: Comorbidities, 

Coinfections, and Complications

For patients who experience IRIS after being 

adequately treated for CMV retinitis, serial 

ophthalmologic examinations will reveal that 

the lesions clear without a new or different 

therapy for CMV. This clinical picture differs 

from that of retinal lesions caused by active 

CMV infection and uncontrolled CMV 

replication, in which lesions will increase in 

size or new lesions will appear, if appropriate 

CMV therapy has not been introduced (see 

chapter Cytomegalovirus Disease).

CMV vitreitis and CMV uveitis

CMV vitreitis and CMV uveitis are seen 

exclusively in patients with previous CMV 

retinitis infection who responded to ART.

CMV vitreitis

CMV vitreitis IRIS is an alarming syndrome, 

but a benign one. Patients who are receiving 

anti-CMV therapy typically present with 

acute onset of blurred vision and “floaters” 

caused by posterior segment inflammation. 

Ophthalmologic examination reveals 

numerous inflammatory cells in the vitreous 

humor. Symptoms usually resolve in 1 month 

without specific treatment and without any 

lasting visual effects.

CMV uveitis

In patients with a history of CMV retinitis, 

CMV uveitis IRIS may occur within months 

of ART initiation, but typically is a late 

complication, occurring about 3 years after 

patients begin ART. Uveitis is painless and 

primarily involves inflammation in the iris, the 

ciliary body, and the choroid layers. However, 

CMV uveitis may have serious sequelae. It 

often results in macular edema, epiretinal 

membrane formation, or cataracts, which can 

lead to permanent vision loss. Because of the 

risk of vision loss, clinicians should have a high 

index of suspicion for CMV uveitis.

Cryptococcal Meningitis

In patients with or without previously 

diagnosed cryptococcal meningitis, 

presentation of cryptococcal IRIS typically 

includes fever, headache, eye pain, and 

photophobia, and may include meningeal 

signs. In cryptococcal IRIS, analysis of 

cerebrospinal fluid (CSF) is characterized 

by high opening pressure and, unlike initial 

presentation of cryptococcal meningitis, an 

elevated white blood cell count and sterile 

fungal cultures. Onset has been reported 

between 1 week and 11 months after initiation 

of ART. Lymphadenitis, pulmonary disease, 

and cutaneous involvement also have been 

reported (see chapter Cryptococcal Disease).

Pneumocystis jiroveci Pneumonia

Pneumocystis jiroveci pneumonia (PCP) IRIS 

may occur in patients with current or recent 

PCP who are starting ART in the early weeks 

after initiation of PCP treatment. IRIS may 

present as worsening pulmonary symptoms 

(typically after corticosteroids given for the 

initial PCP treatment have been tapered or 

discontinued) and high fever in patients who 

had been improving on PCP therapy or in 

patients with recent successful treatment of 

PCP. Chest X-rays may show worsening lung 

involvement, and oxygen saturation or arterial 

blood gas measurements may show worsening 

hypoxia or alveolar-arterial oxygen gradient. 

PCP IRIS sometimes causes severe acute 

respiratory failure (see chapter Pneumocystis 

Pneumonia).
378 | Guide for HIV/AIDS Clinical Care

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S: Subjective

Symptoms of IRIS will vary according to the 

specific illness.

Include the following in the history:

• Specific symptoms and time course of 

symptoms

• History of OIs, including 

recently diagnosed OIs

• Treatment of OIs, including date of 

initiation, medication adherence, duration of 

therapy, and clinical response

• ART initiation date, specific antiretroviral 

regimen, medication adherence, and 

previous history of ART

• CD4 cell count and HIV viral load before 

ART initiation

• Current CD4 cell count and HIV viral load, 

if known

• Other medications, especially new 

medications, including over-the-counter and 

herbal preparations

O: Objective

Obtain vital signs, including temperature, 

heart rate, blood pressure, respiratory rate, and 

oxygen saturation.

Perform a thorough physical examination 

based on symptoms and suspicion of systems 

involved.

A: Assessment

In the appropriate clinical setting (especially 

in patients with advanced AIDS who recently 

initiated ART), IRIS should be considered 

in the differential diagnosis of patients who 

present with new or worsening symptoms. In 

these patients, the differential is broad, and 

causes other than IRIS should be considered 

carefully, including:

• Worsening or progression of a known 

OI despite treatment (e.g., owing to drug 

resistance or inadequate therapy)

• A new infection or illness

• Drug toxicity (e.g., hypersensitivity reaction)

• Failure of ART; progression of AIDS

Perform the appropriate diagnostic tests to 

exclude other etiologies. Consider consulting 

with an HIV specialist if the diagnosis is in 

question.

P: Plan

Diagnostic Evaluation

It is important to rule out new, incompletely 

treated, or untreated infections; malignancy; 

and other illnesses before concluding the 

patient has IRIS.

The workup of the patient with possible 

IRIS will depend on the specific clinical 

presentation. Perform laboratory tests, 

blood cultures, and other diagnostic tests as 

appropriate for the individual patient. These 

may include the following:

• Complete blood count (CBC) with 

differential, electrolytes and creatinine, liver 

function tests

• CD4 cell count and HIV viral load

• Blood cultures for bacteria, acid-fast bacteria 

(MAC), fungi

• Chest X-ray; other radiographic studies

• Sputum stain and culture
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• Biopsy or culture of skin or other lesions

• Lumbar puncture and cerebrospinal fluid 

studies, if a CNS process is suspected

• Ophthalmologic examination

• Drug resistance testing for the OI being 

treated, if indicated

Treatment

Prevention and treatment recommendations 

from randomized prospective trials are 

lacking for most IRIS syndromes. However, 

the majority of cases of IRIS reported in the 

medical literature are not life-threatening and 

appear to have resolved within a matter of 

weeks to months with the following:

• Continuing the current ART regimen 

(unless the clinical presentation is lifethreatening)

• Treating any newly identified, untreated OI

• If indicated, administering 

antiinflammatory medications to suppress 

the inflammatory process (prednisone was 

shown in one study to decrease hospital days 

and improve symptoms in TB IRIS in subSaharan Africa; anecdotal data support the 

use of nonsteroidal antiinflammatory drugs 

in mild-to-moderate IRIS)

For patients with recent OIs that resolved 

with a full course of appropriate therapy, it is 

not always necessary to resume antimicrobial 

therapy or to change maintenance therapy. 

For example, if a patient with TB IRIS has 

finished a full course of treatment for TB, 

repeat treatment is not indicated, once 

recurrent TB infection has been ruled out. If 

a patient with previously treated cryptococcal 

meningitis is receiving maintenance therapy 

and IRIS develops, the therapy does not need 

to be altered. However, if IRIS reveals a new, 

untreated OI, that infection should be treated 

appropriately. For instance, if new cryptococcal 

meningitis presents as IRIS, the cryptococcus 

should be treated as indicated. If treatment is in 

question, consult with an HIV specialist.

Timing of ART initiation

The risk of IRIS is highest for patients who 

start ART with low CD4 counts (<50-100 cells/

μL) and those for whom ART is initiated soon 

after OI treatment is begun. The optimal time 

for ART initiation in the setting of some OIs is 

not known, but increasing evidence, including 

from randomized controlled trials, suggests 

a mortality benefit to early ART initiation in 

patients with a variety of newly diagnosed 

OIs. For patients with TB and HIV infection, 

for example, data from three randomized 

studies show reductions in mortality and/

or AIDS progression with early initiation 

of ART, though the urgency of ART varied 

with CD4 count: for those with CD4 counts 

of <50 cells/μL, benefit was seen if ART was 

initiated within 2 weeks of TB treatment 

start (compared with delaying until week 

8-12 of TB treatment). For those with CD4 

counts of 50-200 cells/μL, data support ART 

initiation between 2 weeks and 2 months after 

the start of TB treatment. ART should not 

be deferred until after TB treatment for any 

patient, regardless of the CD4 cell count. In TB 

meningitis, however, the optimal ART start 

time is not clear; in one study, immediate ART 

increased the risk severe adverse effects and 

death. In cryptococcal meningitis, data about 

timing of ART initiation are conflicting; many 

experts advise delaying ART until 2-10 weeks 

after the start of cryptococcus treatment.

Decisions about the timing of ART initiation 

may depend on a number of variables, 

including the specific pathogen, the severity 

of the OI, whether the CNS is involved (IRIS 

in the CNS may be life-threatening), the 

medication burden, and the potential for 

drug toxicity or drug interactions. In most 

cases, ART initiation should be considered 

within 1-2 weeks after initiation of OI therapy, 

particularly in patients with TB and CD4 

counts of <50 cells/μL. For patients with TB 

meningitis, cryptococcal meningitis, or other 

CNS or ocular infections, many specialists 
380 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

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would recommend delaying ART until they 

have received appropriate OI treatment for at 

least 2 weeks. For decisions about initiating 

ART in patients with active OIs, consult with 

an HIV specialist.

IRIS in resource-limited settings

As access to ART improves in resourcelimited countries, IRIS increasingly is 

being recognized in patients receiving 

ART. Clinicians should include IRIS in the 

differential diagnosis when evaluating patients 

who recently have begun ART and present 

with new or worsening symptoms of an OI. 

However, limited diagnostic testing resources 

may make it difficult to establish IRIS and 

other diagnoses.

Given that coinfection with HIV and TB is 

epidemic in many countries, and because 

IRIS is not uncommon in patients with TB, 

clinicians should be particularly vigilant 

about symptoms that may signal IRIS. As in 

resource-sufficient countries, consultation with 

a clinician trained in caring for patients with 

HIV is recommended if diagnosis or treatment 

is in question.

Patient Education

• Patients starting ART who have CD4 counts 

of <100 cells/μL or known concomitant OIs 

should be counseled about the likelihood of 

IRIS.

• All patients starting ART should be advised 

to contact the clinic promptly if they 

experience new or worsening symptoms.

• Advise patients to take their medications for 

HIV and for the treatment or prevention of 

OIs exactly as prescribed.

References

• Abdool Karim SS, Naidoo K, Grobler A, et 

al. Timing of initiation of antiretroviral drugs 

during tuberculosis therapy. N Engl J Med. 

2010 Feb 25;362(8):697-706. 

• Havlir DV, Kendall MA, Ive P, et al.; AIDS 

Clinical Trials Group Study A5221. Timing 

of antiretroviral therapy for HIV-1 infection 

and tuberculosis. N Engl J Med. 2011 Oct 

20;365(16):1482-91. 

• Blanc FX, Sok T, Laureillard D, et al.; 

CAMELIA (ANRS 1295–CIPRA KH001) 

Study Team. Earlier versus later start of 

antiretroviral therapy in HIV-infected adults 

with tuberculosis. N Engl J Med. 2011 Oct 

20;365(16):1471-81.

• DeSimone JA, Pomerantz RJ, Babinchak TJ. 

Inflammatory reactions in HIV-1-infected 

persons after initiation of highly active 

antiretroviral therapy. Ann Intern Med. 2000 

Sep 19;133(6):447-54. 

• French MA. HIV/AIDS: immune 

reconstitution inflammatory syndrome: 

a reappraisal. Clin Infect Dis. 2009 Jan 

1;48(1):101-7.

• Jacobson MA. Clinical Implications of 

Immune Reconstitution in AIDS. In: 

Coffey S, Volberding PA, eds. HIV InSite 

Knowledge Base [textbook online]. 

San Francisco: UCSF Center for HIV 

Information; 2006. Available at hivinsite.

ucsf.edu/InSite?page=kb-03-04-03. Accessed 

December 1, 2013.

• Lawn SD, Wilkinson RJ, Lipman MC, et al. 

Immune reconstitution and “unmasking” of 

tuberculosis during antiretroviral therapy. 

Am J Respir Crit Care Med. 2008 Apr 

1;177(7):680-5.

• Manosuthi W, Van Tieu H, Mankatitham 

W, et al.; N2R Study Team. Clinical 

case definition and manifestations of 

paradoxical tuberculosis-associated immune 

reconstitution inflammatory syndrome. 

AIDS. 2009 Nov 27;23(18):2467-71.
Immune Reconstitution Inflammatory Syndrome | 381

Section 6: Comorbidities, 

Coinfections, and Complications

• Meintjes G, Lawn SD, Scano F, et al.; 

International Network for the Study of 

HIV-associated IRIS. Tuberculosis-associated 

immune reconstitution inflammatory 

syndrome: case definitions for use in resourcelimited settings. Lancet Infect Dis. 2008 

Aug;8(8):516-23.

• Meintjes G, Rabie H, Wilkinson RJ, 

et al. Tuberculosis-associated immune 

reconstitution inflammatory syndrome 

and unmasking of tuberculosis by 

antiretroviral therapy. Clin Chest Med. 2009 

Dec;30(4):797-810.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Ratnam I, Chiu C, Kandala NB, et al. 

Incidence and risk factors for immune 

reconstitution inflammatory syndrome in an 

ethnically diverse HIV type 1-infected cohort.

Clin Infect Dis. 2006 Feb 1;42(3):418-27.

• Shelburne SA, Montes M, Hamill RJ. Immune 

reconstitution inflammatory syndrome: 

more answers, more questions. J Antimicrob 

Chemother. 2006 Feb;57(2):167-70.

• Shelburne SA, Visnegarwala F, Darcourt J, 

et al. Incidence and risk factors for immune 

reconstitution inflammatory syndrome 

during highly active antiretroviral therapy. 

AIDS. 2005 Mar 4;19(4):399-406.

• Shelburne SA 3rd, Darcourt J, White AC, 

et al. The role of immune reconstitution 

inflammatory syndrome in AIDS-related 

Cryptococcus neoformans disease in the era 

of highly active antiretroviral therapy. Clin 

Infect Dis. 2005 Apr 1;40(7):1049-52.

• Zolopa A, Andersen J, Powderly W, et al. 

Early antiretroviral therapy reduces AIDS 

progression/death in individuals with acute 

opportunistic infections: a multicenter 

randomized strategy trial. PLoS One. 

2009;4(5):e5575.

Anal Dysplasia | 383

Section 6: Comorbidities, 

Coinfections, and Complications

Anal Dysplasia

Background 

Anal cancer is a squamous cell cancer associated with human papillomavirus (HPV), the same virus 

that is associated with cervical cancer (see chapter Cervical Dysplasia). The anal canal and cervical 

canal share a common embryologic origin: both have a squamocolumnar transition zone and are 

prone to infection with HPV, a sexually transmitted virus. HPV infection, in combination with 

cofactors, may stimulate dysplastic changes in the cervix or anus that may develop through precursor 

stages into squamous cell cancer. In the United States, the incidence of anal cancer in the general 

population is approximately 1:100,000 per year. In HIV-infected men and women, the incidence 

of anal cancer and the prevalence of its precursors are significantly higher than in the general 

population. Advanced immunosuppression, as demonstrated by lower CD4 cell counts, appears to 

increase the risk of anal intraepithelial neoplasia (AIN), a precursor to cancer, and anal cancer.

Rates of anal cancer also are higher among men who have sex with men (MSM), whether HIV 

infected or uninfected, compared with the general population. Current rates in an HIV-infected 

MSM population have been estimated to be as high as 70-144 per 100,000. Although most studies 

have examined anal dysplasia and cancer in MSM, its prevalence also is high among HIV-infected 

women and heterosexual men. Some studies of HIV-infected individuals have shown that anal 

HPV infection is present in 93% of MSM and 76% of women, and that anal dysplasia (any grade) is 

present in 56% of MSM and 26% of women. In some studies of HIV-infected women, anal dysplasia 

has been seen more frequently than cervical dysplasia, and it has not been exclusive to those with 

behavioral risk factors (e.g., history of receptive anal intercourse). HIV-infected heterosexual men 

with no history of receptive anal intercourse also have elevated risks of anal HPV infection. Thus, 

although receptive anal intercourse may increase the likelihood of anal HPV infection, it is not a 

prerequisite for anal HPV or dysplasia. 

Screening strategies for anal dysplasia and cancer and the optimal management of abnormal 

test results are areas in which questions remain unanswered. The rationale for screening for anal 

cancer and its precursors is based on the success of cervical Papanicolaou (Pap) screening in 

reducing cervical cancer incidence and mortality. Because of the similarities between cervical 

and anal dysplasia, many experts postulate that many of the paradigms of managing cervical 

cytologic abnormalities may be translated to management of anal dysplasia. However, there are no 

randomized clinical trials that document the value of screening for anal precancers.

Current guidelines from the HIV Medicine Association of the Infectious Diseases Society of America 

recommend anal pap tests for MSM, women with a history of abnormal cervical Pap tests or a 

history of anal receptive sex, and all HIV-infected persons with genital warts, though they do not 

specify screening intervals. The New York State Department of Health AIDS Institute recommends 

that an anal Pap test be done at baseline and annually thereafter for MSM, patients with a history 

of anogenital warts, and women with abnormal cervical or vulvar histology, and many HIV clinics 

elsewhere do routine screening. Further investigations are ongoing to define appropriate screening 

intervals, diagnostic approaches, indications for therapy, and modalities of treatment.

ART and subsequent immune reconstitution does not appear to alter the prevalence or distribution 

of anal cancers and anorectal disease nor does it appear to reduce the progression of AIN and other 

cancer precursors.

For information on prevention of HPV infection, see “Prevention,” below.
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S: Subjective

Patients with anal dysplasia usually are 

asymptomatic, and the condition cannot be 

identified without screening tests. Exophytic 

anal condylomata may cause itching, 

discomfort, or bleeding, but are usually 

associated with low-risk phenotypes of HPV 

and low-grade dysplasia (note, however, that 

oncogenic HPV types also may be present). 

Anal cancer may cause nonspecific symptoms 

such as pain (with defecation or after 

intercourse), itching, bleeding, or sensation of 

a rectal mass.

Risk factors for anal dysplasia and cancers 

include the following:

• HIV infection

• CD4 count of <200 cells/μL

• RAI

• HPV infection

• Genital warts (or history of genital warts)

• Immunosuppression

• High-grade cervical or vulvar dysplasia

• Cigarette smoking

• Multiple sex partners

Ask patients about these risk factors, about 

previous history of anal dysplasia or cancer, 

and about previous screening.

O: Objective

Examine the genital and perianal region, 

and perform a digital anorectal examination. 

Look and feel for masses, condylomata, 

and other abnormalities such as hypo- or 

hyperpigmented plaques or lesions, and lesions 

that bleed. Note that simple visual examination 

may not reveal abnormalities. In women, 

also examine the vulva, vagina, and cervix. 

Examine the inguinal lymph nodes.

If the digital examination is performed in 

conjunction with an anal Pap test, the Pap 

specimen should be obtained before the 

introduction of lubrication.

Anoscopic examination with the naked eye 

may not reveal any abnormality because 

dysplastic tissue tends to be flat and difficult 

to differentiate from normal anal tissue; 

application of 3% acetic acid is required (see 

below for a description of how high-resolution 

anoscopy [HRA] is performed).

A: Assessment

HIV-infected individuals with anal dysplasia 

have an increased risk of progression to anal 

cancer. If the history or physical examination 

reveals abnormalities suggestive of anal 

dysplasia or anal cancer, an appropriate 

evaluation should be undertaken. Because 

most patients with anal dysplasia have no 

symptoms, anal cancer screening using a Pap 

test can be considered if follow-up evaluation 

of an abnormal cytologic result (ASCUS or 

higher, see Bethesda 2001 grading system, 

below) by high-resolution anoscopy is available 

either on-site or by referral.

P: Plan

Screening

As mentioned above, some organizations 

and many experts recommend that anal Pap 

tests and digital anal examination be part 

of the initial evaluation of both male and 

female HIV-infected patients. The intervals 

for screening have not been established, but 

(based on recommendations for cervical 

cancer screening) if the first test result is 

normal, the anal Pap usually is repeated in 

approximately 6 months. If both results are 

normal, then anal Pap tests can be performed 

annually. Some clinicians would consider 

more frequent screening in patients with 

genital warts, cervical dysplasia, or a history of 

treatment for anal dysplasia. Any patients with 

positive results should be referred for further 

evaluation; see below.

An anal Pap test is done using a standard Pap 
Anal Dysplasia | 385

Section 6: Comorbidities, 

Coinfections, and Complications

kit. The swab or cytobrush should be inserted 

into the anal canal, past the anorectal junction, 

and withdrawn while rotating it against the anal 

walls to collect cells. The sample should then 

be handled according to the kit manufacturer’s 

instructions. (See “References,” below, for 

information about a video on how to conduct 

an anal Pap screen that is available from the 

Johns Hopkins University Local Performance 

Site of the Pennsylvania/MidAtlantic 

AIDS Education and Training Center.)

As with cervical cytology, anal cytology is 

graded using the Bethesda 2001 system, which 

categorizes disease in increasing order of 

severity as follows:

• Negative for intraepithelial 

lesion or malignancy

• Atypical squamous cells of 

undetermined significance (ASCUS)

• Atypical squamous cells – cannot 

exclude HSIL (ASC-H)

• Low-grade squamous 

intraepithelial lesion (LSIL)

• High-grade squamous 

intraepithelial lesion (HSIL)

• Squamous cell carcinoma (SCC)

Other abnormalities, such as atypical 

glandular cells (AGC), may be noted.

All individuals with abnormal anal cytology, 

defined as ASCUS or higher, should be referred 

for HRA and biopsy to grade the lesion. HRA 

typically is performed at specialty anal cancer 

practices or clinics, colorectal surgery and 

gastrointestinal specialty facilities, and some 

academic medical centers.

There currently are no recommendations 

concerning HPV testing of anal specimens.

Evaluation of Cytologic Abnormalities

HRA of the anal canal should be performed 

using a colposcope for magnification (16x) 

and the application of 3% acetic acid with 

or without Lugol iodine solution to aid in 

visualization of dysplastic lesions. Abnormal 

areas should be examined by biopsy. 

Anoscopic features of high-grade disease 

are similar to those seen in the cervix; these 

include coarse punctation, mosaicism, and the 

presence of ring glands.

Treatment

The goal of treatment is to prevent progression 

to anal cancer. Treatment of HSIL to prevent 

anal cancer is biologically plausible, following 

the model of cervical dysplasia treatment. 

However, the indications for treatment of 

anal dysplasia, the efficacy of treatment, and 

the most effective treatments have not been 

optimally defined.

The focus of treatment is on high-grade, 

premalignant AIN. Patients should be referred 

to an anal dysplasia specialist specialty clinic, 

if possible. Specific treatment may vary 

depending on the size, location, extent of 

the lesions, and histological grade. Therapies 

include topical 5-fluorouracil, cryotherapy, 

infrared coagulation, laser therapy, and 

surgical excision. Infrared coagulation, an 

in-office procedure, has been shown to be 

effective in treating HIV-infected patients 

with high-grade dysplasia. With some 

therapies, treatment-associated pain and other 

complications may occur, and recurrence of 

dysplastic lesions is common.

LSIL is not considered premalignant, but it 

frequently progresses to high-grade dysplasia. 

Some specialists do not treat LSIL but monitor 

regularly instead with HRA, whereas others 

choose to treat LSIL to prevent progression.

Prevention

Prevention of HPV infection can be challenging. 

Latex or plastic barriers may block transmission 

of HPV in areas covered by these barriers 

and their use is recommended to prevent 

transmission or acquisition of HPV (as well as 

HIV and other sexually transmitted diseases). 

However, infection may occur through bodily 

contact outside the area covered by the barriers.
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A quadrivalent HPV vaccine against certain 

oncogenic (types 16 and 18) and wartcausing (types 6 and 11) types of HPV is FDA 

approved for prevention of anal dysplasia 

and anal cancer caused by the covered types 

in males and females 9-26 years of age, and 

for prevention of genital warts, its use is 

recommended. (The quadrivalent vaccine also 

is approved for prevention of cervical cancer 

and cervical, vaginal, and vulvar dysplasia). 

A second vaccine against HPV types 16 and 

18 has been approved for females (see chapter 

Cervical Dysplasia).

The vaccine is not effective against HPV types 

other than those covered by the vaccine, and it 

may not be protective against a covered type to 

which a patient has been exposed previously. 

For optimal protection, the vaccine should 

be given before the individual is exposed to 

HPV through sexual activity. It is likely to be 

less effective in older adolescents and adults 

who may already have been infected with one 

or more of the covered HPV types. There are 

few data on the use of the vaccines in persons 

older than 26 years, and they are not approved 

for this group. Importantly, vaccination does 

not offer perfect protection from all oncogenic 

HPV viruses, so consideration should be 

given to screening individuals who have been 

vaccinated in the same way as unvaccinated 

individuals, as described above.

Patient Education

• All HIV-infected men and women should be 

encouraged to use condoms during vaginal, 

anal, and oral sex to prevent the spread 

of HPV. However, condoms do not offer 

complete protection from HPV.

• All patients should be counseled on how to 

reduce or avoid unprotected anal receptive 

intercourse.

• Both women and men who are HIV infected 

have an increased risk of developing anal 

dysplasia and cancer. MSM are at higher risk 

than other men of developing anal dysplasia.

• Emphasize the importance of keeping 

follow-up appointments to allow for early 

detection of precancerous lesions, further 

grading of abnormalities by HRA, and 

appropriate monitoring and treatment of 

abnormalities.

• Patients who have anal dysplasia should be 

informed about anal cancer symptoms, such 

as new-onset anal pain, bleeding, or the 

development of a mass. Patients should call 

their health care provider if these symptoms 

develop.

• If an anal Pap test is to be performed, advise 

patients to avoid having anal sex, douching, 

or using enemas before the test.
Anal Dysplasia | 387

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References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• Chiao EY, Giordano TP, Palefsky JM, et al. 

Screening HIV-infected individuals for anal 

cancer precursor lesions: a systematic review. 

Clin Infect Dis. 2006 Jul 15;43(2):223-33.

• Chin-Hong PV, Palefsky JM. Natural history 

and clinical management of anal human 

papillomavirus disease in men and women 

infected with human immunodeficiency virus.

Clin Infect Dis. 2002 Nov 1;35(9):1127-34.

• Diamond C, Taylor TH, Aboumrad T, et al. 

Increased incidence of squamous cell anal 

cancer among men with AIDS in the era 

of highly active antiretroviral therapy. Sex 

Transm Dis. 2005 May;32(5):314-20.

• Hessol NA, Holly EA, Efird JT, et al. Anal 

Intraepithelial neoplasia in a multisite study 

of HIV-infected and high-risk HIV-uninfected 

women. AIDS. 2009 Jan 2;23(1):59-70.

• Massad LS, Einstein MH, Huh WK, et 

al.; 2012 ASCCP Consensus Guidelines 

Conference. 2012 updated consensus 

guidelines for the management of abnormal 

cervical cancer screening tests and cancer 

precursors. J Low Genit Tract Dis. 2013 

Apr;17(5 Suppl 1):S1-S27.

• Palefsky JM, Holly EA, Efirdc JT, et al. Anal 

intraepithelial neoplasia in the highly active 

antiretroviral therapy era among HIVpositive men who have sex with men. AIDS. 

2005 Sep 2;19(13):1407-14.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Piketty C, Darragh TM, Da Costa M, 

et al. High prevalence of anal human 

papillomavirus infection and anal cancer 

precursors among HIV-infected persons in the 

absence of anal intercourse. Ann Intern Med. 

2003 Mar 18;138(6):453-9.

* * * * * * *

• A video titled Anal Pap Smear: A Simple, 

Fast and Easy Procedure is available on 

CD-ROM at-cost to health care professionals 

($12.00 for 1-4 copies) by calling the Johns 

Hopkins University Local Performance Site 

of the Pennsylvania Mid/Atlantic AIDS 

Education and Training Center to order: 

888-333-2855 (toll free) or by downloading 

the order form on the AETC NRC website. 

Available at aidsetc.org/aetc?page=etresdisplay&resource=etres-229. Accessed 

December 1, 2013.

Candidiasis, Oral and Esophageal | 389

Section 6: Comorbidities, 

Coinfections, and Complications

Candidiasis, Oral and Esophageal

Background 

Oropharyngeal candidiasis (“thrush”), a fungal disease of the oral mucosa and tongue, is the most 

common intraoral lesion among persons infected with HIV. In the absence of other known causes 

of immunosuppression, oral thrush in an adult is highly suggestive of HIV infection. Although 

thrush in the absence of esophageal disease is not an AIDS-defining condition, it usually occurs 

with CD4 counts of <200 cells/μL. Three clinical presentations of thrush are common in people 

with HIV: pseudomembranous, erythematous, and angular cheilitis. Candida also may infect 

the esophagus in the form of esophageal candidiasis, which causes dysphagia (difficulty with 

swallowing) or odynophagia (pain with swallowing). Esophageal candidiasis is an AIDS-defining 

condition, generally occurring in individuals with CD4 counts of <200 cells/μL. It is the most 

common cause of esophageal infection in persons with AIDS.

Oropharyngeal and esophageal candidiasis are caused most commonly by Candida albicans, 

although non-albicans species increasingly may cause disease and may be resistant to first-line 

therapies.

S: Subjective

Oropharyngeal Candidiasis 

The patient may complain of painless white 

patches on the tongue and oral mucosa, 

smooth red areas on the dorsal tongue, 

burning or painful areas in the mouth, a bad 

or unusual taste, sensitivity to spicy foods, or 

decreased appetite. 

Esophageal Candidiasis 

The patient complains of difficulty or pain 

with swallowing, or the sensation that food 

is “sticking” in the retrosternal chest. Weight 

loss is common, and nausea and vomiting may 

occur. Fever is not common with candidal 

esophagitis and suggests another cause. The 

patient may note symptoms of oral candidiasis 

(as above).

O: Objective

Perform a thorough oropharyngeal 

examination. Patients presenting with oral 

candidiasis may be totally asymptomatic, 

so it is important to inspect the oral cavity 

thoroughly. Patients with esophageal 

candidiasis usually have oral thrush and often 

experience weight loss.

Lesions can occur anywhere on the hard and 

soft palates, under the tongue, on the buccal 

mucosa or gums, or in the posterior pharynx. 

Pseudomembranous oral candidiasis appears 

as creamy white, curdlike plaques on the 

buccal mucosa, tongue, and other mucosal 

surfaces. Typically, the plaques can be wiped 

away, leaving a red or bleeding underlying 

surface. Lesions may be as small as 1-2 mm, or 

they may form extensive plaques that cover the 

entire hard palate.

Erythematous oral candidiasis presents as one 

or more flat, red, subtle lesions on the dorsal 

surface of the tongue or the hard or soft palate. 

The dorsum of the tongue may show loss of 

filiform papillae.

Angular cheilitis causes fissuring and redness 

at one or both corners of the mouth and may 

appear alone or in conjunction with another 

form of oral Candida infection. 
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A: Assessment

A partial differential diagnosis for the two 

conditions is as follows: 

Oropharyngeal Candidiasis 

• Oral hairy leukoplakia

• Abrasion of the mucosa or a topical burn

• Bacterial gingivitis

• Periodontitis 

Esophageal Candidiasis 

• GERD

• Cytomegalovirus (CMV)

• Herpes simplex virus (HSV)

• Aphthous ulceration 

P: Plan

Diagnostic Evaluation 

Oropharyngeal candidiasis 

Clinical examination alone usually is 

diagnostic. If the diagnosis is unclear, 

organisms may be detected on smear or 

culture if necessary. 

• On a potassium hydroxide (KOH) 

preparation of a smear collected by 

gentle scraping of the affected area with a 

wooden tongue depressor, visible hyphae 

or blastospheres on KOH mount indicate 

Candida infection.

• Culture is diagnostic and may detect nonalbicans species in cases resistant to first-line 

therapies. Sensitivities also may be needed 

in such cases to diagnose azole-resistant 

infections. 

Esophageal candidiasis 

A presumptive diagnosis usually can be made 

with a recent onset of typical symptoms, 

especially in the presence of thrush, and 

empiric antifungal therapy may be started as a 

diagnostic trial. If the patient fails to improve 

clinically after 3-7 days of therapy, endoscopy 

should be performed for a definitive diagnosis. 

Treatment 

Treatment of oropharyngeal candidiasis 

• Oral therapy is convenient and very effective 

as first-line treatment. Note that azole 

antifungal drugs are not recommended for 

use during pregnancy. Topical therapy is less 

expensive, safe for use during pregnancy, 

and effective for mild to moderate disease. 

All therapies should be given for 7-14 days.

• Preferred oral therapy: Fluconazole 100 mg 

PO QD

• Preferred topical therapy:

• Clotrimazole troches 10 mg dissolved in 

the mouth 5 times daily

• Miconazole mucoadhesive tablet 50 mg 

PO QD

• Alternative oral therapy:

• Itraconazole oral solution 200 mg PO QD

• Posaconazole oral solution 400 mg PO 

BID for 1 day, then 400 mg PO QD

(Note: These agents may present a 

greater risk of drug interactions (see 

“Potential ARV Interactions,” below) and 

hepatotoxicity than do fluconazole or 

topical treatments)

• Alternative topical therapy: Nystatin oral 

suspension 4-6 mL “swish and swallow” 

QID or 1-2 pastilles 4-5 times daily

Treatment of esophageal candidiasis 

• Duration of therapy: 14-21 days

• Preferred therapy:

• Fluconazole 100 mg PO (up to 400 mg) 

QD; IV therapy can be given if the patient 

is unable to swallow pills.

• Itraconazole oral solution 200 mg PO QD 

• Alternative therapy:

• Voriconazole 200 mg PO or IV BID

• Posaconazole 400 mg PO BID

• IV therapy with an echinocandin 
Candidiasis, Oral and Esophageal | 391

Section 6: Comorbidities, 

Coinfections, and Complications

(caspofungin, micafungin, anidulafungin), 

or amphotericin, if the patient is unable 

to tolerate PO therapy (Note: Treatment 

with echinocandins is associated with 

a higher rate of relapse; see “Potential 

ARV Interactions,” below, regarding 

potential drug-drug interactions between 

voriconazole or posaconazole and ARVs)

Treatment of refractory candidiasis

Oral or esophageal candidiasis that does not 

improve after at least 7-14 days of appropriate 

antifungal therapy can be considered refractory 

to treatment. The primary risk factors for 

development of refractory candidiasis are 

CD4 counts of <50 cells/μL and prolonged, 

chronic antifungal therapy (especially with 

azoles). In such cases, it is important to confirm 

the diagnosis of candidiasis. As noted, other 

infections such as HSV, CMV, and aphthous 

ulcerations can cause similar symptoms. Once 

refractory candidiasis is confirmed, several 

treatment options are available, including the 

following: 

• Posaconazole 400 mg PO BID

• Itraconazole oral solution ≥200 mg PO QD

• Voriconazole 200 mg PO or IV BID (see 

“Potential ARV Interactions,” below)

• Therapy with an echinocandin (caspofungin 

50 mg QD; micafungin 150 mg QD; 

anidulafungin 100 mg for 1 dose, then 50 mg 

QD), or amphotericin B deoxycholate or lipid 

preparation

(Note: Treatment with echinocandins is 

associated with a higher rate of relapse. See 

“Potential ARV Interactions,” below, for 

information on potential drug interactions.)

The choice of treatment depends upon 

anticipated drug-drug interactions, the patient’s 

preferences and tolerability, availability of 

medications, and the provider’s experience. 

Consult with an HIV or infectious disease 

expert for advice about treatment regimens. 

Maintenance therapy

Use caution when considering chronic 

maintenance therapy, because it has been 

associated with refractory and azole-resistant 

candidiasis, as noted above. Fluconazole 100 

mg PO QD or TIW can be effective for patients 

who have had multiple or severe recurrences 

of oral disease (azole sensitive). Fluconazole 

100-200 mg PO QD or posaconazole 400 mg 

PO BID (see “Potential ARV Interactions,” 

below) can be considered for patients who have 

had frequent or severe recurrent esophageal 

candidiasis. 

There are no data to guide this decision; it is 

reasonable to discontinue maintenance therapy 

in patients who achieve immunologic responses 

on fully suppressive ART (i.e., with an increase 

in CD4 count to ≥200 cells/μL). Patients 

with fluconazole-refractory oropharyngeal 

or esophageal disease who respond to IV 

echinocandins are recommended to take 

posaconazole or voriconazole suppression until 

they achieve immune reconstitution on ART, 

because of high relapse rates. 

Potential ARV Interactions

There may be significant drug-drug interactions between certain systemic antifungals 

(particularly itraconazole, voriconazole, and 

posaconazole) and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse 

transcriptase inhibitors (NNRTIs), elvitegravir/

cobicistat, or maraviroc. Some combinations 

are contraindicated and others require dosage adjustment of the ARV, the antifungal, 

or both. Check for adverse drug interactions 

before prescribing. For example, voriconazole 

use is not recommended for patients taking 

ritonavir-boosted PIs, and dosage adjustment 

of both voriconazole and NNRTIs may be required when voriconazole is used concurrently 

with NNRTIs. See relevant tables in the U.S. 

Department of Health and Human Services 

Guidelines for the Use of Antiretroviral Agents in 

HIV-1-Infected Adults and Adolescents, or consult 

with an expert.
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Section 6: Comorbidities, 

Coinfections, and Complications

Patient Education

• Patients should maintain good oral hygiene 

by brushing teeth after each meal.

• A soft toothbrush should be used to avoid 

mouth trauma.

• Advise patients to rinse the mouth of 

all food before using lozenges or liquid 

medications.

• Tell patients to avoid foods or liquids that 

are very hot in temperature or very spicy.

• Patients who have candidiasis under a 

denture or partial denture should remove 

the prosthesis before using topical agents 

such as clotrimazole or nystatin. When not 

in use, the prosthesis should be stored in a 

chlorhexidine solution.

• Pregnant women and women who may 

become pregnant should avoid azole drugs 

(e.g., fluconazole, itraconazole, voriconazole) 

during pregnancy because they can cause 

skeletal and craniofacial abnormalities in 

infants.

• Patients should be informed of proper 

storage of oral solutions (e.g., refrigeration 

requirements). 

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• Klein RS, Harris CA, Small CB, et al. 

Oral candidiasis in high-risk patients as 

the initial manifestation of the acquired 

immunodeficiency syndrome. N Engl J Med. 

1984 Aug 9;311(6):354-8.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Pappas PG, Kauffman CA, Andes D, 

et al.; Infectious Diseases Society of 

America. Clinical practice guidelines for the 

management of candidiasis: 2009 update by 

the Infectious Diseases Society of America. 

Clin Infect Dis. 2009 Mar 1;48(5):503-35.

• Skiest DJ, Vazquez JA, Anstead GM, et al. 

Posaconazole for the treatment of azolerefractory oropharyngeal and esophageal 

candidiasis in subjects with HIV infection.

Clin Infect Dis. 2007 Feb 15;44(4):607-14.
Candidiasis, Vulvovaginal | 393

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

The patient may complain of itching, 

burning, or swelling of the labia and vulva; 

a thick white or yellowish vaginal discharge; 

painful intercourse; and pain and burning on 

urination.

The most important elements in the history 

include the following:

• Type and duration of symptoms

• Previous vaginal yeast infection

• Oral contraceptive use

• Recent or ongoing broad-spectrum 

antibiotic therapy

• Recent corticosteroid therapy

• Sexual exposures (to evaluate for sexually 

transmitted diseases)

• Diabetes history

• Cushing syndrome

• Obesity

• Hypothyroidism

• Pregnancy

• Use of douches, vaginal 

deodorants, or bath additives

O: Objective

Perform a focused physical examination of the 

external genitalia, vagina, and cervix. This may 

reveal inflammation of the vulva with evidence 

of discharge on the labial folds and vaginal 

opening. Speculum examination usually 

reveals a thick, white discharge with plaques 

adhering to the vaginal walls and cervix. 

Bimanual examination should not elicit pain 

or tenderness and otherwise should be normal.

A: Assessment

Rule out other causes of vaginal 

discharge and pruritus:

• Bacterial vaginosis

• Atrophic vaginitis

• Chemical or mechanical causes

• Trichomoniasis

• Gonorrhea, chlamydia, and other sexually 

transmitted diseases

• Scabies

• Pediculosis

Candidiasis, Vulvovaginal

Background 

Vulvovaginal candidiasis is a yeast infection caused by several types of Candida, typically Candida 

albicans. This disease is common in all women, but may occur more frequently and more severely 

in immunocompromised women.

Although refractory vaginal Candida infections by themselves should not be considered indicators 

of HIV infection, they may be the first clinical manifestation of HIV infection and can occur early 

in the course of disease (at CD4 counts of >500 cells/μL). The frequency of vaginal candidiasis 

tends to increase as CD4 counts decrease; however, this may be attributable in part to increased use 

of antibiotics among women with advanced HIV infection.

Risk factors for candidiasis include diabetes mellitus and the use of oral contraceptives, 

corticosteroids, or antibiotics.
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P: Plan

Diagnostic Evaluation

A presumptive diagnosis is made on the basis 

of the clinical presentation and potassium 

hydroxide (KOH) preparation:

• Perform microscopic examination of a 

KOH preparation of vaginal secretions. This 

usually reveals pseudohyphae and Candida

spores (presumptive diagnosis).

• Definitive diagnosis rarely is needed, but 

may be made by analysis of a culture of 

vaginal secretions; this may be useful if 

azole-resistant or non-albicans species are 

suspected.

• In the presence of urinary tract symptoms 

(beyond external vulvar burning), perform 

urinalysis, culture, or both on a clean-catch 

urine specimen.

• Consider testing for gonorrhea and 

chlamydia in patients with a history of 

possible sexual exposure.

Treatment

Uncomplicated infections

Topical medications

• Prescribe topical vaginal antifungal agents 

in the form of cream or suppositories, 

including the following: butoconazole, 

clotrimazole, miconazole, nystatin, 

terconazole, and tioconazole. Treat for 3-7 

days and offer refills depending on the time 

to the next scheduled clinic visit. The creams 

also may be used on the vulva for treatment 

of pruritus.

Note that the mineral-oil base in topical 

vaginal antifungal preparations may erode 

the latex in condoms, diaphragms, and dental 

dams. Advise the patient to use alternative 

methods to prevent HIV transmission or 

conception, or to discontinue intercourse while 

using these medications. Nonlatex condoms 

(plastic and polyethylene only) or “female” 

condoms (polyurethane) can be used.

Oral medications

Preferred

• Fluconazole 150 mg PO, single dose (see 

“Treatment notes,” below)

Alternative

• Itraconazole oral solution 200 mg PO QD 

for 3-7 days (see “Treatment notes,” below)

Complicated infections

Severe or recurrent candidiasis

Severe or recurrent candidiasis is defined as 

four or more episodes within 1 year. Consider 

the following treatments:

• Fluconazole 100-200 mg PO QD for ≥7 days 

(see Treatment notes,” below)

• Topical therapy as described above, for ≥7 

days

For severe cases that recur repeatedly, 

secondary prophylaxis can be considered (e.g., 

fluconazole 150 mg PO once weekly).

Treatment notes

• Systemic azole drugs should not be used 

during pregnancy, and women taking azoles 

should use effective contraception. Topical 

azoles are recommended for the treatment of 

pregnant women.

• Resistance to azole medications may 

develop, especially with prolonged use of 

oral agents.

• Avoid ketoconazole: Case reports have 

associated ketoconazole with a risk of 

fulminant hepatitis (1 in 12,000 courses 

of treatment with oral ketoconazole). 

Experts agree that the risks may outweigh 

the benefits for women with vulvovaginal 

candidiasis. Ketoconazole interacts 

with many other drugs, including some 

antiretroviral drugs.
Candidiasis, Vulvovaginal | 395

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Potential ARV Interactions

There may be significant drug-drug 

interactions between certain systemic 

antifungals (particularly itraconazole, 

voriconazole, and posaconazole) and 

ritonavir-boosted protease inhibitors 

(PIs), nonnucleoside reverse transcriptase 

inhibitors (NNRTIs), elvitegravir/cobicistat, 

or maraviroc. Some combinations are 

contraindicated and others require dosage 

adjustment of the ARV, the antifungal, or 

both. Check for adverse drug interactions 

before prescribing. For example, 

voriconazole use is not recommended for 

patients taking ritonavir-boosted PIs, and 

dosage adjustment of both voriconazole and 

NNRTIs may be required when voriconazole 

is used concurrently with NNRTIs. See 

relevant tables in the U.S. Department of 

Health and Human Services Guidelines for the 

Use of Antiretroviral Agents in HIV-1-Infected 

Adults and Adolescents, or consult with an 

expert.

Patient Education

• Advise patients to wash external genitals 

daily with a fresh washcloth or watersoaked cotton balls and to wipe the vulva 

and perirectal area from front to back after 

toileting. Women should not use baby wipes 

on inflamed vulval tissue because they may 

increase irritation.

• Women should avoid the use of perfumed 

soaps, bubble baths, feminine hygiene 

or vaginal deodorant products, and bath 

powders.

• Advise women not to douche.

• Women should wear cotton underwear 

and avoid tight, constrictive clothing, 

particularly pantyhose.

• If patients are prescribed medication for 

vaginal candidiasis, they should take the 

medication exactly as prescribed and finish 

the medicine even during a menstrual 

period.

• Women who continue to have symptoms 

can purchase miconazole (e.g., Monistat) or 

clotrimazole (e.g., Gyne-Lotrimin) vaginal 

cream over the counter. Advise patients to 

start using these as soon as symptoms return 

and to contact the clinic if symptoms worsen 

while they are taking these medicines.

• Women taking oral fluconazole, 

ketoconazole, or other azoles must avoid 

pregnancy. Some birth defects have been 

reported.

• The mineral-oil base in topical vaginal 

antifungal preparations may erode the latex 

in condoms, diaphragms, and dental dams. 

Advise patients to use alternative methods to 

prevent HIV transmission or conception or 

to discontinue intercourse while using these 

medications. Nonlatex condoms (plastic and 

polyethylene only) or “female” condoms 

(polyurethane) can be used.

• Sex toys, douche nozzles, diaphragms, 

cervical caps, and other items can reinfect 

patients if not properly cleaned and 

thoroughly dried after use.

• Some studies have suggested that eating 

yogurt with live cultures (check labels) 

can reduce the occurrence of vaginal yeast 

infections.
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References

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 17; 

59 (No. RR-12):1-110. Available at www.

cdc.gov/STD/treatment/2010. Accessed 

December 1, 2013.

• Cohn SE, Clark RA. Sexually transmitted 

diseases, HIV, and AIDS in women. In: The 

Medical Clinics of North America, Vol. 87; 

2003:971-995.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.
Cervical Dysplasia | 397

Section 6: Comorbidities, 

Coinfections, and Complications

Cervical Dysplasia

Background

Precancerous lesions and cancer of the cervix are associated with human papillomavirus (HPV), 

a sexually transmitted virus. Carcinogenic strains of HPV, in conjunction with other factors, 

may cause dysplasia and cancer not only of the cervix, but also of the vulva, vagina, anus, and 

oropharynx. HIV-infected women have a higher 

prevalence of HPV infection than do HIVuninfected women, and a higher prevalence of 

oncogenic HPV types. They are about 10 times more 

likely to develop cervical dysplasia, or intraepithelial 

neoplasia (CIN), precursors to cervical cancer. 

Unfortunately, they also have a higher risk of 

invasive cervical cancer and tend to have more 

aggressive forms of cervical cancer and poorer 

responses to treatment. Invasive cervical cancer is an AIDS-defining illness.

The risk of high-grade cervical lesions and cervical cancer appears to be higher for women with 

advanced immunodeficiency than for women with preserved CD4 cell counts. Other risk factors 

for dysplasia and cervical cancer include African-American ethnicity, a history of smoking, 

younger age at onset of sexual intercourse, and multiple sex partners. Effective antiretroviral 

therapy (ART) with immune reconstitution has not been shown to prevent the progression of CIN.

Screening for cervical cancer and appropriate intervention in women with high-grade CIN (CIN 3) 

are effective in preventing cervical cancer. Frequent monitoring and careful follow-up in women with 

low-grade lesions are essential for preventing progression to invasive disease. For all HIV-infected 

women (if they have had sex partners), including adolescents and young women, Papanicolaou (Pap) 

testing should be performed routinely. An initial test should be done at the time of HIV diagnosis, 

repeated 6 months after the first test, then performed annually thereafter if the results are normal. 

(See chapter Initial and Interim Laboratory and Other Tests.) 

Because the risk of anal dysplasia also is increased among HIV-infected women (in some studies, 

rates of anal dysplasia were higher than rates of cervical dysplasia), many experts and some 

guidelines recommend concurrent screening for anal dysplasia. For further information, see 

chapter Anal Dysplasia.

For information on prevention of HPV infection, see “Prevention,” below.

HRSA HAB Performance 

Measures

Percentage of female patients with 

a diagnosis of HIV who have a Pap 

screening in the measurement year 

(Adult and Adolescent measure)

S: Subjective

Patients with CIN or early cervical cancer 

usually are asymptomatic, and disease will not 

be diagnosed unless screening is performed. 

Genital condylomata (warts) indicate infection 

with HPV and typically are associated with 

low-risk types of HPV; however, a mixture of 

HPV types may be present, and women with 

genital warts may have concurrent dysplasia.

The classic symptom of early invasive cervical 

neoplasia is intermittent, painless bleeding 

between menstrual periods, which may present 

initially as postcoital spotting. Late symptoms 

of invasive cervical carcinoma include flank 

and leg pain, dysuria, hematuria, rectal 

bleeding, and obstipation.
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Ask all female patients about risk factors for, 

previous history of, and preventive measures 

against cervical dysplasia and cancer, 

including the following:

• Genital warts; previous or 

current HPV infection

• Previous abnormal cervical Pap test result

• Previous abnormal anal Pap test result

• Previous cervical cancer; when and how 

treated

• Sexual activity before age 20

• History of multiple sex partners

• Cigarette smoking

• CD4 count of <200 cells/μL

• Pregnancy

• Oral contraceptive use

• History of HPV vaccination

O: Objective

Perform a focused examination of the 

abdomen and pelvis. Examine the external 

genital and perianal region. Perform speculum 

and bimanual examinations to evaluate the 

vagina and cervix. Look for lesions, masses, 

warts, and cervical inflammation or discharge, 

as well as exophytic or ulcerative cervical 

lesions with or without bleeding. Note that 

simple visual examination may not reveal 

abnormalities.

A: Assessment

HIV-infected women have an increased risk of 

cervical dysplasia with progression to cervical 

cancer. If abnormalities of cervical disease are 

suspected, an appropriate evaluation should 

be performed. Because most women with CIN 

have no symptoms, routine screening should 

be performed for all women.

P: Plan

Screening

Perform Pap screening for all HIV-infected 

women. The initial test should be conducted 

at the time of HIV diagnosis, a second (if the 

first is normal) should be performed 6 months 

later. Screening should be repeated annually 

thereafter throughout life if all results are 

normal. (For HIV-uninfected adolescents and 

young women, recent guidelines recommend 

beginning cervical screening at age 21; for 

HIV-infected young women, guidelines 

suggest screening beginning within 1 year 

of first sexual activity, given the risk of 

progression of cervical abnormalities.) If a Pap 

result is abnormal, see below. Also consider 

screening for anal dysplasia with an anal Pap 

test (see chapter Anal Dysplasia).

Cervical (and anal) cytology usually is 

graded using the Bethesda 2001 system (see 

“References,” below), which categorizes disease 

in increasing order of severity as follows:

• Negative for intraepithelial lesion or 

malignancy

• Atypical squamous cells of 

undetermined significance (ASCUS)

• Atypical squamous cells, cannot 

exclude HSIL (ASC-H)

• Low-grade squamous 

intraepithelial lesion (LSIL)

• High-grade squamous 

intraepithelial lesion (HSIL)

• Squamous cell carcinoma (SCC)
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Other abnormalities may be noted, including 

the following:

• Atypical glandular cells (AGCs), including 

the following subcategories: 

• AGC not otherwise specified (AGC NOS) 

(includes endocervical, endometrial, or 

glandular cells)

• AGC, favor neoplasia (includes 

endometrial or glandular cells)

• AIS (endocervical adenocarcinoma in situ)

• Infectious organisms such as Trichomonas

Evaluation of Cytologic 

Abnormalities

Atypical squamous cells of 

undetermined significance

If ASCUS is present without inflammation or 

suspected neoplastic process, several options 

for management exist.

• Most experts recommend that all women 

with ASCUS be referred for colposcopy and 

directed biopsy, regardless of their degree 

of immunodeficiency. If the biopsy result 

shows no dysplasia (and the examination is 

adequate), the patient should be monitored 

by annual Pap tests.

• As an alternative, patients who are 

considered reliable for follow-up may repeat 

the Pap test in 6-12 months. If repeat Pap is 

reported at greater than ASCUS, the woman 

should be referred for colposcopy.

• There are limited and conflicting data to 

support the use of HPV DNA testing as part 

of the management of HIV-infected women 

with ASCUS. Current OI guidelines (see 

“References,” below) emphasize that HPV 

testing alone is not recommended.

Atypical squamous cells, 

cannot exclude HSIL

Women with abnormalities suggestive of 

high-grade dysplasia should be referred for 

colposcopy.

Low-grade squamous intraepithelial lesion

Women with LSIL should be referred for 

colposcopy and directed biopsy.

High-grade squamous intraepithelial lesion 

or squamous cell carcinoma

Women with HSIL are at high risk of highgrade intraepithelial neoplasia or cervical 

cancer and should undergo colposcopy with 

endocervical assessment and directed biopsy 

as soon as possible. Refer to an oncology 

specialist for treatment.

Atypical glandular cells

Because of the high rate of significant lesions 

in patients with AGS, colposcopy with 

endocervical sampling is recommended for all 

subcategories, including AIS. In women over 

age 35, endometrial sampling is recommended 

in addition to colposcopy and endocervical 

sampling. Refer to an appropriate specialist for 

evaluation.

Treatment

The optimal management of precancerous 

cervical lesions has not been identified clearly 

for all classes of CIN. Consult with an HIVexperienced gynecologist, oncologist, or 

other dysplasia specialist. High-grade lesions 

in women with satisfactory colposcopy are 

typically treated with ablation (e.g., cryotherapy, electrocautery, laser vaporization) 

or excision (e.g., loop electrosurgical excision 

[LEEP], laser or cold-knife conization). For 

women with unsatisfactory colposcopy, 

excisional methods are recommended. 
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Prevention

Latex or plastic barriers may block 

transmission of HPV in areas covered by 

these barriers and have been shown to reduce 

the risk of infection with oncogenic HPV. 

Although infection may occur through 

bodily contact outside the area covered by the 

barriers, the use of condoms is recommended 

to prevent transmission or acquisition of HPV 

(as well as HIV and other STDs).

Two vaccines have been approved by the 

U.S. Food and Drug Administration for the 

prevention of certain HPV strains; these 

are recommended for HIV-infected women 

and girls 9-26 years of age. They have been 

shown to reduce rates of cervical dysplasia; 

the quadrivalent vaccine also has been shown 

to protect against vulvar, vaginal, and anal 

dysplasia (as well as anogenital warts) related 

to the covered HPV types.

• Quadrivalent (Gardasil): includes HPV 

types 16 and 18 (which cause nearly 70% of 

cervical cancer, as well as vaginal, vulvar, 

and anal cancer), and types 6 and 11 (which 

cause most anogenital warts

• Bivalent (Cervarix): includes 

HPV types 16 and 18

The quadrivalent vaccine also is recommended 

for use with males aged 9-26 for prevention 

of genital warts and anal intraepithelial 

neoplasia.

These vaccines are not effective against HPV 

types other than those covered by the vaccine, 

and they may not be protective against a 

covered type to which a patient has been 

exposed previously. For optimal protection, 

these vaccines should be given before the 

individual is exposed to HPV through sexual 

activity. They are likely to be less effective 

in older adolescents and adults who already 

may have been infected with one or more of 

the covered HPV types. There are few data 

on the use of the vaccines in persons older 

than 26, and they are not approved for this 

group. Importantly, women who have been 

vaccinated should continue to be screened for 

cervical cancer as described above; vaccination 

does not protect women perfectly from all 

oncogenic HPV viruses.

Patient Education

• Recommend the use of latex or 

polyurethane male or female condoms 

for vaginal or anal intercourse and plastic 

or latex barriers for oral sex to reduce 

the risk of transmitting HPV (the usual 

cause of cervical cancer) to partners. 

Barriers also reduce the risk of exposure 

to other sexually transmitted pathogens.

• Patients who smoke should be advised 

to quit. Cigarette smoking appears to 

heighten the risk of cervical cancer and 

makes HPV more difficult to treat. Discuss 

options for smoking cessation (see chapter 

Smoking Cessation), and refer patients to 

the American Lung Association if local 

programs are available.

• Emphasize the importance of keeping 

follow-up appointments for Pap screening 

or colposcopy to allow early detection 

of precancerous lesions and appropriate 

monitoring of abnormalities.
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• For women with dysplasia who require 

treatment, emphasize that early treatment 

is essential for managing the disease and 

preventing the development of cancer. 

Advise patients to keep all medical 

appointments.

References

• Aberg JA, Gallant JE, Ghanem KG et al.; 

HIV Medicine Association of the Infectious 

Diseases Society of America. Primary Care 

Guidelines for the Management of Persons 

Infected With HIV: 2013 Update by the 

HIV Medicine Association of the Infectious 

Diseases Society of America. Clin Infect Dis. 

2014 Jan;58(1):e1-e34.

• American Congress of Obstetricians and 

Gynecologists Committee on Practice 

Bulletins – Gynecology. ACOG Practice 

Bulletin Number 131: Screening for 

cervical cancer. Obstet Gynecol. 2012 

Nov;120(5):1222-38.

• Massad LS, Ahdieh L, Benning L, et 

al. Evolution of cervical abnormalities 

among women with HIV-1: evidence 

from surveillance cytology in the women’s 

interagency HIV study. J Acquir Immune 

Defic Syndr. 2001 Aug 15;27(5):432-42.

• Massad LS, Einstein MH, Huh WK, et 

al.; 2012 ASCCP Consensus Guidelines 

Conference. 2012 updated consensus 

guidelines for the management of abnormal 

cervical cancer screening tests and cancer 

precursors. J Low Genit Tract Dis. 2013 

Apr;17(5 Suppl 1):S1-S27.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Solomon D, Davey D, Kruman R, et al. 

The 2001 Bethesda System: terminology for 

reporting results of cervical cytology. JAMA. 

2002 Apr 24;287(16):2114-9.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.

Cryptococcal Disease | 403

Section 6: Comorbidities, 

Coinfections, and Complications

Cryptococcal Disease

Background 

Cryptococcosis usually presents as a systemic or central nervous system (CNS) fungal infection 

caused by the yeast Cryptococcus neoformans. The organism is ubiquitous, and is particularly 

plentiful in soils enriched with bird droppings. It also may be present in fruit skins or juices, 

and in unpasteurized milk. In immunocompetent patients, cryptococcal infection usually is 

asymptomatic, self-limited, and confined to the lungs. In persons with advanced HIV infection 

(e.g., those with CD4 counts of <100 cells/μL), Cryptococcus may cause life-threatening illness, 

either from a new exposure or through reactivation of a previously acquired latent infection.

In HIV-infected patients, Cryptococcus can infect almost all organs in the body, but most 

commonly causes meningitis or meningoencephalitis. Disseminated disease, pneumonia, and skin 

lesions also may be seen.

S: Subjective

Symptoms depend upon the locus of infection. 

In the case of meningitis, the patient typically 

experiences subacute onset of fever, headaches, 

and malaise, which worsen over the course 

of several weeks. These symptoms may be 

accompanied by nausea with or without 

vomiting. Classic meningeal signs, nuchal 

rigidity, and photophobia are present in only 

about 25% of cases. Cryptococcal meningitis 

may cause confusion, personality or behavior 

changes, blindness, deafness, and, if left 

untreated, coma and death. If the disease 

involves the lungs, patients may experience 

cough or shortness of breath, pleuritic chest 

pain, and fever. Skin lesions may be present.

O: Objective

Perform a thorough physical examination with 

particular attention to the following:

• Vital signs, hydration status

• Funduscopic findings

• Neck (for nuchal rigidity, which is 

uncommon)

• Lungs, especially if respiratory symptoms 

are present

• Neurologic evaluation, including cranial 

nerves, visual acuity, and mental status

• Skin

Cryptococcal Meningitis

Physical examination may reveal 

papilledema with loss of visual acuity 

and cranial nerve deficits (particularly 

in cranial nerves III and VI).

Cryptococcal Pulmonary Disease

Examination may reveal 

tachypnea or fine rales.

Cutaneous Infection

Skin lesions are variable and may appear as 

papules, nodules, or ulcers; they often resemble 

molluscum lesions.

A: Assessment

The differential diagnosis for cryptococcal 

meningitis or meningoencephalitis is broad 

and includes other infectious causes of 

meningitis (fungal, mycobacterial, bacterial, 

viral), syphilis, lymphoma, mass lesions, 

intoxication, HIV encephalopathy, and 

trauma. (See chapter Neurologic Symptoms.)
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The differential diagnosis for cryptococcal 

pneumonia is broad and includes other 

infectious causes of pneumonia (fungal, 

mycobacterial, bacterial, viral), malignancy, 

and congestive heart failure. (See chapter 

Pulmonary Symptoms.)

P: Plan

Diagnostic Evaluation

The workup should include serum cryptococcal 

antigen (CrAg), which usually is very sensitive, 

and blood cultures, including bacterial, 

acid-fast bacilli (AFB), and fungal cultures. 

Patients with symptoms of disseminated or 

pulmonary infection should be evaluated 

by chest X-ray (which may show diffuse or 

focal infiltrates, sometimes appearing as 

nodular or miliary; intrathoracic adenopathy; 

or pleural effusions), sputum culture 

(including fungal and AFB cultures), and AFB 

stain. Bronchoscopy and bronchoalveolar 

lavage may be necessary for diagnosis. For 

cutaneous lesions, consider biopsy and 

histopathologic evaluation or culture. As 

part of the general fever workup, urinalysis 

and urine cultures should be checked.

Patients with a positive serum CrAg, another 

positive test for Cryptococcus, or signs or 

symptoms of meningitis should undergo 

analysis of the cerebrospinal fluid (CSF). If 

neurologic symptoms or signs are present, 

obtain a computed tomography (CT) scan of 

the brain before performing a lumbar puncture 

(LP) to rule out a mass lesion or increased 

intracranial pressure (ICP), which could cause 

herniation upon LP. Always measure the CSF 

opening pressure; a high ICP contributes to 

morbidity and mortality and determines the 

need for serial LP to manage the increased ICP. 

Send the CSF for the following:

• CrAg (usually positive at high 

titer in meningitis)

• Fungal culture

• India ink stain (less sensitive than CSF 

CrAg; perform if CSF CrAg is not available)

• Cell count

• Glucose

• Protein

For exclusion of other etiologies, perform 

CSF Venereal Disease Research Laboratory 

(VDRL) test, bacterial culture, AFB smear and 

culture, or polymerase chain reaction (PCR), 

if tuberculosis is suspected, and other tests 

as indicated by the patient’s symptoms and 

exposures.

Treatment

Cryptococcal meningitis

Acute treatment of cryptococcal meningitis 

consists of two phases: induction and 

consolidation. Acute treatment is followed by 

chronic maintenance (suppressive) therapy.

Induction

Patients with cryptococcal meningitis should 

be hospitalized to start at least 2 weeks of 

induction therapy.

Preferred therapy:

• Liposomal amphotericin B 3-4 mg/kg IV 

QD + flucytosine 25 mg/kg PO QID

Lipid formulations of amphotericin B are less 

nephrotoxic than amphotericin B deoxycholate 

and appear to be equally effective. 

Amphotericin-based therapy, in combination 

with flucytosine, is recommended. If these are 

not available, are contraindicated, or are not 

tolerated by the patient, the other indicated 

induction therapies may be considered. 
Cryptococcal Disease | 405

Section 6: Comorbidities, 

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Alternative therapy:

• Amphotericin B lipid complex 5 mg/kg IV 

QD + flucytosine 25 mg/kg PO QID

• Amphotericin B deoxycholate 0.7-1.0 mg/kg 

IV QD + flucytosine 25 mg/kg PO QID

• Liposomal amphotericin B 3-4 mg/kg IV 

QD + fluconazole 800 mg PO or IV QD

• Amphotericin B deoxycholate 0.7-1.0 mg/kg 

IV QD + fluconazole 800 mg PO or IV QD

• Liposomal amphotericin B 3-4 mg/kg IV 

QD alone

• Fluconazole 400-800 mg PO or IV QD + 

flucytosine 25 mg/kg PO QID

• Fluconazole 1,200 mg PO or IV QD alone

The primary alternative to amphotericinbased therapy is high-dose fluconazole 

(800-1,200 mg PO QD), with or without 

flucytosine. Among the newer antifungal 

agents, echinocandins have no activity 

against Cryptococcus. Voriconazole and 

posaconazole have good in vitro activity and 

may be considered for treatment of relapsed 

disease but not as first-line agents. The 

efficacy of alternative regimens is not well 

defined. See “Potential ARV Interactions,” 

below, regarding drug-drug interactions 

between these antifungals and ARVs.

Amphotericin B causes many adverse effects, 

including fever, rigors, hypotension, nausea, 

nephrotoxicity and electrolyte disturbances, 

anemia, and leukopenia. The patient’s 

hemoglobin, white blood cell (WBC) count, 

platelets, electrolytes, magnesium, and 

creatinine must be monitored closely during 

treatment. Liposomal forms of amphotericin 

cause fewer adverse effects. These should 

be should be used particularly for patients 

who have difficulty tolerating standard 

amphotericin B and for those who are at high 

risk of renal failure. Electrolytes and creatinine 

should be monitored. Flucytosine is associated 

with bone marrow and liver toxicity, and 

complete blood counts and liver function tests 

should be monitored during induction therapy. 

If available, flucytosine levels can be evaluated 

3-5 days after the start of therapy, with a target 

2-hour post-dose level of 30-80 mg/mL; a level 

of >100 mg/mL should be avoided. Note that 

the dosage of flucytosine must be adjusted for 

patients with renal insufficiency.

Resistance testing may be considered for 

patients who have relapsed and for those for 

whom fluconazole failed to sterilize the CSF.

Consolidation

After clinical improvement with 2 weeks of 

induction therapy, and a negative CSF culture 

on repeat LP, treatment can be switched 

to fluconazole (400 mg PO QD for at least 

8 weeks). Itraconazole (200 mg PO BID) 

is an alternative for patients who cannot 

take fluconazole. It should be noted that 

itraconazole is less effective than fluconazole 

and has significant drug interactions with 

commonly used medications.

Maintenance

After completing acute treatment, the patient 

should receive chronic maintenance therapy 

with fluconazole (200 mg PO QD) to prevent 

recurrence of cryptococcosis. 

Maintenance therapy should be continued for 

life, unless the patient has completed induction 

and consolidation therapy followed by at least 1 

year of maintenance therapy, and has sustained 

CD4 cell recovery in response to effective 

antiretroviral therapy (ART) (CD4 count ≥100 

cells/μL for at least 3 months during ART). 

Maintenance therapy should be restarted if 

the CD4 count declines to <100 cells/μL.

Management of elevated ICP

Elevated ICP significantly increases the 

morbidity and mortality of cryptococcal 

meningitis and should be treated by the 

removal of CSF. The CSF opening pressure 

should be checked on the initial LP. If the 

initial opening pressure is >250 mm H2O, 
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remove up to 30 mL of CSF to lower the ICP by 

50%, if possible. LP and CSF removal should 

be repeated daily as needed for ICP reduction. 

A lumbar drain or ventriculoperitoneal shunt 

may be needed if the initial opening pressure 

is >400 mm H2O, or in refractory cases. There 

is no role for acetazolamide, mannitol, or 

steroids in the treatment of elevated ICP.

A repeat LP is not required for patients who 

did not have elevated ICP at baseline and are 

responding to treatment. If new symptoms 

develop, a repeat LP is indicated. Serum CrAg 

titers are not useful in monitoring response to 

treatment.

Cryptococcal pulmonary disease, with 

negative CSF CrAg and culture results

After CSF cryptococcal disease has been 

excluded, treat with fluconazole if symptoms 

are mild or moderate and chest imaging shows 

focal infiltrates: 400 mg PO QD for 12 months, 

then 200 mg QD for maintenance. Otherwise, 

consider amphotericin induction, as described 

above with CNS disease. Maintenance therapy 

should be continued for life, unless the patient 

has sustained CD4 cell recovery in response 

to effective ART (CD4 count of ≥100 cells/μL 

for at least 6 months during ART) and with a 

minimum of 12 months of antifungal therapy. 

Therapy should be restarted if the CD4 count 

declines to <100 cells/μL.

Cutaneous infection, with negative CSF 

CrAg and culture results

Treat with fluconazole 400 mg PO QD for 6-12 

months, then continue with 200 mg QD for 

chronic maintenance therapy, as discussed above.

Asymptomatic antigenemia

Data are limited for management of 

asymptomatic antigenemia, which can be 

associated with development of subsequent 

disease. Fungal cultures of CSF and blood 

should be obtained; if either result is positive 

for cryptococcal growth, treatment should be 

initiated for symptomatic meningoencephalitis 

or disseminated disease. If no 

meningoencephalitis is found, fluconazole 

400 mg PO QD should be given until immune 

reconstitution occurs; treatment may be 

discontinued per maintenance guidelines 

described above.

Cryptococcus IRIS

Immune reconstitution through ART 

is effective for preventing recurrence of 

cryptococcal infections. However, initiating 

ART within the first 1-2 months after 

starting treatment for cryptococcal infection 

may result in worsening or recurrence of 

symptoms because of immune reconstitution 

inflammatory syndrome (IRIS). IRIS can be 

life-threatening in cryptococcal meningeal 

disease. IRIS and relapse of cryptococcal 

disease (e.g., treatment failure) must be 

differentiated; in IRIS, the serum and CSF 

cultures are negative. (See chapter Immune 

Reconstitution Inflammatory Syndrome.)

Optimal timing of ART initiation in 

cryptococcal CNS disease is not known. 

Some experts recommend treating severe 

cryptococcosis with effective antifungal 

therapy for 2-10 weeks before starting ART, to 

decrease the risk of IRIS. On the other hand, 

if the CD4 count is very low (e.g., <50 copies/

μL), it is important to initiate ART as soon as 

possible. 

Other treatment notes

Pregnancy

Fluconazole and other azole drugs should be 

avoided during the first trimester of pregnancy, 

and voriconazole and posaconazole should 

be avoided throughout pregnancy. During 

the first and second trimesters, pregnant 

women should be treated with amphotericin 

for both induction and consolidation therapy. 

Flucytosine is teratogenic at high doses in rats 

and is classified as a pregnancy class C drug; 

it should be used during pregnancy only if the 

benefits clearly outweigh the risks.
Cryptococcal Disease | 407

Section 6: Comorbidities, 

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Preventive therapy

Studies have suggested that routine primary 

prophylaxis for cryptococcal disease in 

patients with CD4 counts of <100 cells/μL is 

effective at preventing cryptococcal infection 

but is not cost efficient. Therefore, it is not 

routinely recommended.

Patient Education

• Cryptococcosis is not curable in persons 

with low CD4 cell counts and may require 

lifelong treatment. Patients should be 

instructed to take their treatment without 

interruptions. 

• Even with therapy, disease may recur. 

Patients should report fevers or recurrence 

of other symptoms immediately.

• Antiretroviral therapy and improvement 

in immune system health are essential for 

prevention of recurrence.

• Patients should avoid pregnancy while 

taking any oral antifungal drug. Fetal 

craniofacial and skeletal abnormalities have 

been reported.

References

• Bicanic T, Harrison TS. 

Cryptococcal meningitis. Br Med 

Bull. 2005 Apr 18;72:99-118.

• Brouwer AE, Rajanuwong A, Chierakul 

W, et al. Combination antifungal therapies 

for HIV-associated cryptococcal meningitis: 

a randomised trial. Lancet. 2004 May 

29;363(9423):1764-7.

• McNicholl I. Database of Antiretroviral Drug 

Interactions. In: Coffey S, Volberding PA, 

eds. HIV InSite. San Francisco: UCSF Center 

for HIV Information. Available at hivinsite.

ucsf.edu/interactions. Accessed December 

1, 2013.

• Nussbaum JC, Jackson A, Namarika 

D, et al. Combination flucytosine and 

high-dose fluconazole compared with 

fluconazole monotherapy for the treatment 

of cryptococcal meningitis: a randomized 

trial in Malawi. Clin Infect Dis. 2010 Feb 

1;50(3):338-44.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Perfect JR, Dismukes WE, Dromer F, 

et al. Clinical practice guidelines for the 

management of cryptococcal disease: 2010 

update by the Infectious Diseases Society 

of America. Clin Infect Dis. 2010 Feb 

1;50(3):291-322.

Potential ARV Interactions

There may be significant drug-drug 

interactions between certain systemic 

antifungals, (particularly itraconazole, 

voriconazole, and posaconazole) and 

ritonavir-boosted protease inhibitors 

(PIs), nonnucleoside reverse transcriptase 

inhibitors (NNRTIs), elvitegravir/cobicistat, 

or maraviroc. Some combinations are 

contraindicated and others require dosage 

adjustment of the ARV, the antifungal, or 

both. Check for adverse drug interactions 

before prescribing. For example, voriconazole 

use is not recommended for patients 

taking ritonavir-boosted PIs, and dosage 

adjustment of both voriconazole and NNRTIs 

may be required when voriconazole is used 

concurrently with NNRTIs. See relevant 

tables in the U.S. Department of Health and 

Human Services Guidelines for the Use of 

Antiretroviral Agents in HIV-1-Infected Adults 

and Adolescents, or consult with an expert.

Cryptosporidiosis | 409

Section 6: Comorbidities, 

Coinfections, and Complications

Cryptosporidiosis

Background 

Cryptosporidiosis is caused by a species of protozoan parasite that typically infects the mucosa of 

the small intestine, causing watery diarrhea. Diarrhea may be accompanied by nausea, vomiting, 

abdominal cramping, and occasionally fever. The infection is spread by the fecal-oral route, 

usually via contaminated water, and is highly contagious. The course of infection depends on the 

immune status of the host. In immunocompetent individuals, cryptosporidiosis usually is selflimited and can cause a mild diarrheal illness. However, in HIV-infected patients with advanced 

immunosuppression, cryptosporidiosis can cause severe chronic diarrhea, electrolyte disturbances, 

malabsorption, and profound weight loss. Infection also can occur outside the intestinal tract and 

can cause cholangitis, pancreatitis, and hepatitis. In severe cases, cryptosporidiosis can be lifethreatening without aggressive fluid, electrolyte, and nutritional support. Patients at greatest risk 

of acquiring cryptosporidiosis are those with CD4 counts of <100 cells/μL. Immune reconstitution 

inflammatory syndrome (IRIS) has not been described in association with cryptosporidiosis.

S: Subjective

The patient may complain of some or all of the 

following: watery diarrhea (can be profuse), 

abdominal pain or cramping, flatulence, 

nausea, vomiting, anorexia, fever, and weight 

loss.

The history should include questions about the 

presence and characteristics of the symptoms 

listed above, as well as the following:

• Stool frequency (typically 6-26 bowel 

movements daily)

• Stool volume (up to 10 liters per day and 

can be described as “cholera-like” in some 

patients with AIDS)

• Duration of symptoms 

(subacute or acute onset)

• Associated symptoms

• Exposures: recent travel to areas with 

unsafe water supply; ingestion of possibly 

contaminated water while swimming, 

boating, or camping; oral-anal contact, fecal 

exposures during sexual contact

• Recent CD4 cell count (highest risk is in 

patients with CD4 counts of <100 cells/μL)

O: Objective

Perform a thorough physical examination with 

particular attention to the following:

• Vital signs

• Hydration status (e.g., orthostatic vital signs, 

mucous membrane moistness, skin turgor)

• Weight (compare with previous values; 

document weight loss)

• Signs of malnourishment (e.g., cachexia, 

wasting, thinning hair, pallor)

• Abdominal examination for bowel sounds 

(usually hyperactive), tenderness (can be 

diffuse), rebound

• Recent CD4 count

A: Assessment

In HIV-infected patients with advanced 

immunosuppression, the differential 

diagnosis includes other infectious causes of 

subacute or chronic diarrhea or cholangitis, 

such as microsporidia, Isospora, Giardia, 

cytomegalovirus (CMV), and Mycobacterium 

avium complex (MAC), as well as lymphoma.
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P: Plan

Diagnostic Evaluation

• Test the stool for ova and parasites, 

including Cryptosporidium. Diagnosis is 

made by microscopic identification of the 

Cryptosporidium oocysts in stool. 

• Be sure to ask the laboratory to look for 

Cryptosporidium; certain labs do not look 

for these parasites or their precursor, the 

oocyst, unless requested.

• Test for fecal leukocytes. The result 

usually is negative in cryptosporidiosis; 

if positive, consider the possibility of a 

second enteric infection, especially if the 

CD4 count is low, or a different infection.

• Among persons with profuse diarrhea, a 

single stool specimen usually is adequate for 

diagnosis. For patients with milder disease, 

repeat stool sampling may be needed.

• If stool is negative for ova and parasites, 

consider a referral for biopsy of the 

gastrointestinal mucosa or flexible 

sigmoidoscopy.

• If cholangitis is suspected, consider 

abdominal ultrasound to look for biliary 

ductal dilatation, and endoscopic retrograde 

cholangiopancreatography (ERCP).

• Check electrolytes; conduct liver function 

studies including alkaline phosphatase and 

bilirubin to check for possible biliary or 

hepatic infection.

• If fever is present, obtain blood cultures.

• Conduct other diagnostic testing as 

indicated by the history and physical 

examination (e.g., evaluation for CMV, 

MAC, and other infectious causes of 

diarrhea or cholangitis) (see chapter 

Diarrhea).

Treatment

Preferred Strategy:

• Effective antiretroviral therapy (ART) with 

immune reconstitution (and CD4 count of 

>100 cells/μL) can resolve cryptosporidiosis, 

and it is the primary treatment. All patients 

with cryptosporidiosis should be initiated 

on ART (see chapter Antiretroviral Therapy). 

Patients who are on incompletely suppressive 

ART should have their regimens optimized.

• Provide supportive care and symptomatic 

relief (this may require hospitalization in 

cases of severe dehydration), including the 

following: 

• Aggressive fluid and electrolyte 

replacement as needed

• Oral rehydration (solutions containing 

glucose, sodium bicarbonate, potassium, 

magnesium, and phosphorus); in severe 

cases, IV hydration may be required

• Antidiarrheal agents: atropine/

diphenoxylate (Lomotil), loperamide 

(Imodium), tincture of opium (Paregoric)

• Antispasmodics

• Antiemetics

• Topical treatment for the anorectal area, 

as needed (witch hazel pads [e.g., Tucks]), 

sitz baths)

Alternative Management Strategies: 

No antiparasitic therapy has been proven 

to consistently and effectively cure 

cryptosporidiosis if used without ART. 

Use of nitazoxanide and paromomycin 

can be considered. They should be given in 

conjunction with ART, but never instead of 

ART; symptomatic treatment and hydration 

also should be given, as above.

• Nitazoxanide is approved for treatment 

of diarrhea caused by Cryptosporidium 

parvum, the most common strain of 

Cryptosporidium. It may increase the 

likelihood of clinical response. 
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Section 6: Comorbidities, 

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• Usual adult dosage: 500-1,000 mg PO BID 

for 14 days

• Adverse events associated with 

nitazoxanide are limited and typically 

mild; there are no important drug-drug 

interactions

• Paromomycin 50 mg QID for 14-21 days

For patients with weight loss, nutritional 

supplementation is a critical aspect of 

treatment. In some cases, partial or total 

parenteral nutrition may be necessary while 

patients are awaiting clinical improvement in 

response to ART or other therapies. Consult or 

refer to a dietitian or nutritionist, if available. If 

not, assess food intake and counsel the patient 

about increasing caloric and nutritional intake.

Cryptosporidiosis in ResourceLimited Settings

Cryptosporidium infection in HIV-uninfected 

populations is more common in countries with 

overcrowding and poor sanitary conditions. 

The disease also is associated with rainy 

seasons and is frequent among children <2 

years of age.

The prognosis for HIV-infected patients with 

cryptosporidiosis who lack access to ART is 

poor. In one study, the mean survival time of 

coinfected patients was 25 weeks.

Prevention of Disease and Exposure

• Effective ART with maintenance or 

restoration of adequate immune function 

will prevent severe cryptosporidiosis. 

• Scrupulous handwashing can prevent the 

spread of cryptosporidiosis, and HIVinfected patients should be advised to wash 

their hands after potential contact with 

human feces (diapering small children, 

handling pets, gardening, and before and 

after sex).

• HIV-infected patients should avoid sexual 

practices that could lead to direct (e.g., oralanal) or indirect (e.g., penile-anal) contact 

with feces and should be advised to use 

barrier methods during sex (e.g., condoms 

and dental dams).

• HIV-infected persons should avoid drinking 

water from lakes or rivers. Waterborne 

infection also can result from recreational 

activities such as boating, fishing, and 

swimming.

• HIV-infected patients should avoid raw 

oysters as the cryptosporidial oocysts can 

survive in oysters for >2 months. 

• Rifabutin and clarithromycin, when taken 

for MAC prophylaxis, appear to reduce the 

risk of cryptosporidiosis. However, current 

data are insufficient to recommend their use 

as prophylaxis against cryptosporidiosis.

Patient Education

• Recommend scrupulous handwashing 

for the patient and all contacts, especially 

household members and sex partners.

• Explain that effective ART is the best 

treatment for alleviating symptoms and 

helping the immune system eradicate the 

parasite.

• Advise the patient to increase fluid intake 

(not alcohol), and avoid foods that aggravate 

diarrhea. A lactose-free diet may improve 

symptoms.

• Educate the patient about healthful food 

choices that increase caloric intake and 

nutrition.

• Provide supportive counseling; discuss how 

to manage symptoms and the isolation that 

may accompany chronic diarrhea.
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References

• Abubakar I, Aliyu SH, Arumugam C, 

et al. Treatment of cryptosporidiosis in 

immunocompromised individuals: systematic 

review and meta-analysis. Br J Clin 

Pharmacol. 2007 April;63(4);387-393.

• Leder K, Weller PF. Cryptosporidiosis

In: UpToDate v14.1.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Pantenburg B, Cabada MM, White AC. 

Treatment of cryptosporidiosis. Expert Rev 

Anti Infect Ther. 2009 May;7(4):385-91.
Cytomegalovirus Disease | 413

Section 6: Comorbidities, 

Coinfections, and Complications

Cytomegalovirus Disease

Background 

Although chronic infection with cytomegalovirus (CMV) rarely causes disease among 

immunocompetent persons, it is a major cause of morbidity and mortality in HIV-infected patients 

with CD4 counts of <50 cells/μL. CMV infection causes disease in several organ systems, including 

the central nervous system (CNS) (chorioretinitis, encephalitis, polyradiculopathy, myelopathy) 

and the gastrointestinal (GI) tract (oral ulcers, esophagitis, hepatitis, colitis, intestinal perforation), 

as well as life-threatening adrenalitis and pneumonitis. The prevalence of chronic infection with 

CMV, a member of the human herpesvirus family, is high among sexually active adults (40-60% 

in resource-rich countries and 80-90% in resource-poor countries). CMV is spread by sexual or 

other types of close personal contact, blood-to-blood contact (via transfusion or needle sharing), 

organ transplantation, and perinatal transmission. As with other herpesviruses, CMV is not 

cleared from the body, but is kept in a state of latency by an intact immune system. Symptomatic 

disease represents either primary infection or reactivation of latent infection that has escaped 

immunologic control. Effective antiretroviral therapy (ART) greatly reduces the risk of CMV 

reactivation and disease.

Immune reconstitution inflammatory syndrome

Although effective ART greatly reduces the risk of CMV reactivation and disease, patients on 

effective ART may experience CMV-related visual changes.

• Patients without a previous history of CMV disease will occasionally present with full-blown 

CMV retinitis after starting ART. This is thought to reflect delayed restoration of CMV-specific 

immunity. It is diagnosed and treated in an identical manner as for patients diagnosed with 

CMV disease who are not taking effective ART.

• Approximately 20% of patients with previously treated CMV retinitis may experience CMVrelated immune reconstitution uveitis (IRU) after starting successful ART. Symptoms include 

floaters and moderate, occasionally severe, vision loss. The most common causes of vision loss 

are posterior disease, specifically cystoid macular edema (CME) and epiretinal membrane 

(ERM) formation, although inflammation of the anterior region and cataract formation also can 

occur. It is not clear whether treatment with steroids or anti-CMV antivirals is effective. (See 

chapter Immune Reconstitution Inflammatory Syndrome.)

S: Subjective

The patient may present with symptoms 

involving various organ systems, including the 

following:

• CNS, including the eye:

• Floaters, scotomata (blind spots), “flashing 

lights,” loss of peripheral or field vision 

(chorioretinitis)

• Headache, difficulty concentrating, 

sleepiness, personality changes 

(encephalitis, dementia)

• Bilateral lower extremity weakness, 

urinary retention, incontinence, spasticity 

(polyradiculopathy)

• Low-back pain, especially radiating to the 

perianal area (polyradiculopathy, myelitis)

• Family members or caregivers may report 

confusion, apathy, lethargy, somnolence, 

withdrawal, or personality changes in the 

patient (CMV encephalitis, dementia)
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• GI tract disease:

• Mouth ulcerations

• Dysphagia or odynophagia (esophagitis)

• Abdominal pain and bloody diarrhea, 

weight loss, rectal ulcers, fever (colitis)

• Disease outside the CNS or GI tract:

• Persistent fever, fatigue, weight loss 

(adrenalitis)

• Shortness of breath, dyspnea on exertion, 

dry cough (pneumonia; rare in patients 

with advanced HIV infection)

• Pancytopenia (bone marrow infection)

The history should include questions about the 

presence and characteristics of the symptoms 

listed above, as well as the following:

• Duration of symptoms

• Associated symptoms

• Recent CD4 count; nadir CD4 count (risk is 

highest when count is <50 cells/μL)

• Whether the patient is taking ART; if so, 

date initiated, specific medications, and CD4 

and HIV RNA responses

O: Objective

Perform a thorough physical examination with 

particular attention to the following:

• Vital signs: Document fever. 

• Weight: Compare with previous values; 

document weight loss.

• Eyes: Funduscopic examination in 

patients with CMV retinitis may show 

pathognomonic “cottage cheese in ketchup” 

yellow-white lesions, representing vascular 

hemorrhages and exudates.

• Nervous system: Evaluate mental status and 

perform a complete neurologic examination, 

including cranial nerves, sensation (sensory 

deficits may occur with preserved vibratory 

sense and proprioception), motor, deep 

tendon reflexes, coordination, and gait.

A: Assessment

For HIV-infected patients with advanced 

immunosuppression, the differential diagnosis 

includes the following:

• For suspected CMV retinitis: consider 

cotton-wool spots, HIV retinopathy, and 

progressive outer or acute retinal necrosis.

• For suspected CMV encephalitis: 

consider other causes of neurologic 

deterioration such as progressive multifocal 

leukoencephalopathy, toxoplasmosis, CNS 

lymphoma, and other mass lesions.

• For suspected CMV enteritis: consider 

gastrointestinal pathogens such as 

Mycobacterium avium complex, 

Cryptosporidium, other parasites, and 

lymphoma.

• For suspected CMV pneumonitis: consider 

Pneumocystis jiroveci and other respiratory 

pathogens.

P: Plan

Diagnostic Evaluation

CMV can be detected by serology, culture, 

antigen testing, nucleic acid amplification, 

or examination of tissue samples. However, 

serologic tests are not reliable for diagnosing 

CMV disease because most adults are 

seropositive and because patients with 

advanced AIDS may serorevert while 

remaining infected. Furthermore, for 

HIV-infected patients, demonstration of 

CMV in the blood, urine, semen, cervical 

secretions, or bronchoalveolar lavage 

(BAL) fluid does not necessarily indicate 

active disease, although patients with 

end-organ disease usually are viremic.

Diagnosis of end-organ disease generally 

requires demonstration of tissue invasion. The 

recommended evaluation is as follows:
Cytomegalovirus Disease | 415

Section 6: Comorbidities, 

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CMV retinitis

Dilated retinal examination should be 

performed emergently by an ophthalmologist 

experienced in the diagnosis of CMV 

retinitis. The diagnosis usually is based on the 

identification of typical lesions. Diagnosis and 

monitoring should include serial examinations 

with photography to assess and follow 

response to treatment and to detect failure to 

respond early enough to change therapy. If the 

diagnosis is uncertain, aqueous or vitreous 

fluid samples can be sent for polymerase chain 

reaction (PCR) evaluation for CMV and other 

possible infectious agents.

Other sites

Detection of CMV at other sites requires 

visualization of typical lesions (e.g., on 

endoscopy or BAL) and tissue biopsy. Viral 

inclusions (“owl’s eye cells”) in tissue biopsy 

samples demonstrate invasive disease (as 

opposed to colonization). Because retinitis 

is the most common manifestation of CMV 

disease, patients with CNS, gastrointestinal, 

or pulmonary disease should undergo 

ophthalmologic evaluation to detect 

subclinical retinal disease.

Neurologic CMV disease

• Encephalitis: Magnetic resonance imaging 

(MRI) of the brain should be done to 

rule out mass lesions. CMV effects may 

appear as periventricular or meningeal 

enhancement. Lumbar puncture should be 

performed; cerebrospinal fluid (CSF) should 

be analyzed for CMV (by PCR, which is 

sensitive and specific), cell count (may 

show lymphocytic or mixed lymphocytic 

or polymorphonuclear pleocytosis), glucose 

(may be low), and protein (may be high). 

A brain biopsy may be performed if the 

diagnosis is uncertain after imaging and 

CSF evaluation.

• Polyradiculopathy: Spinal MRI should 

be done to rule out mass lesions. In CMV 

disease, nerve root thickening may be 

present. Lumbar puncture with CSF analysis 

should be performed, as described above.

• Myelitis: Spinal MRI should be done to rule 

out mass lesions. Cord enhancement may be 

present. Lumbar puncture with CSF analysis 

should be performed, as described above.

Gastrointestinal CMV disease 

(esophagitis or colitis)

• Perform endoscopy with visualization of 

ulcers and obtain tissue biopsy to look for 

inclusion bodies.

Pulmonary CMV disease

• Perform chest radiography showing 

interstitial pneumonia and obtain lung 

biopsy to look for inclusion bodies.

Treatment

Valganciclovir, ganciclovir, foscarnet, 

and cidofovir may be effective for treating 

CMV end-organ disease. The choice of 

therapy depends on the site and severity 

of the infection, the level of underlying 

immunosuppression, the patient’s ability 

to tolerate the medications and adhere to 

the treatment regimen, and the potential 

medication interactions.

Immune reconstitution through ART is a key 

component of CMV treatment and relapse 

prevention. CMV flares may occur if patients 

develop immune reconstitution inflammatory 

syndrome (see chapter Immune Reconstitution 

Inflammatory Syndrome). Although 

decisions about the timing of ART should be 

individualized, in most cases of CMV endorgan disease, ART probably should not be 

delayed for more than 2 weeks after starting 

treatment for CMV.
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CMV retinitis

Treatment consists of two phases: initial 

therapy and chronic maintenance therapy.

Initial therapy

For patients with sight-threatening (zone 1) 

disease, the preferred treatment strategy is 

a combination of intravitreal and systemic 

therapy. Intravitreal therapy delivers high 

doses of drug to the retina immediately. 

Ganciclovir intraocular implants are no 

longer available, but patients may be treated 

with intravitreal injections of ganciclovir or 

foscarnet. 

In the past, about half of patients treated 

with only local therapy (specifically, 

ganciclovir implants) developed disease 

in the contralateral eye, and one third 

experienced systemic disease within 3 months 

of implantation. Therefore, patients who 

receive intravitreal therapy also should be 

treated systemically with valganciclovir or an 

alternative therapy as below. 

For patients with peripheral retinitis (beyond 

zone 1), systemic therapy alone may be given. 

Oral valganciclovir (see below) is the preferred 

treatment because it is easy to administer 

and is not associated with the surgery- or 

catheter-related complications seen with 

intraocular treatments and IV therapies. This 

formulation quickly converts to ganciclovir 

in the body and has good bioavailability. 

Valganciclovir should be used only if the 

patient is thought to be capable of strict 

adherence. Other possible IV treatments 

include ganciclovir, ganciclovir followed by 

oral valganciclovir, foscarnet, and cidofovir. 

See below for dosing recommendations.

For sight-threatening disease: 

• Intravitreal injection of ganciclovir (2 mg/

injection or foscarnet (2.4 mg/injection) 

1-4 doses over the course of 7-10 days plus

systemic therapy as below

Preferred systemic therapy:

• Valganciclovir 900 mg PO BID for 14-21 

days, then QD

Alternative systemic therapy:

• Ganciclovir 5 mg/kg IV Q12H for 14-21 

days, then QD

• Ganciclovir 5 mg/kg IV Q12H for 14-21 

days, then valganciclovir 900 mg PO QD

• Foscarnet 60 mg/kg IV Q8H or 90 mg/kg 

Q12H for 14-21 days, then 90 mg/kg Q24H

• Cidofovir IV 5 mg/kg weekly for 2 weeks, 

then every other week (must be given with 

probenecid [2 g PO 3 hours before, 1 g PO 

2 hours after, and 1 g PO 8 hours after the 

cidofovir infusion] and IV saline to decrease 

the risk of renal toxicity)

For peripheral lesions:

• Systemic therapy as above

Note: Valganciclovir, ganciclovir, and 

foscarnet require dosage adjustment in 

patients with renal insufficiency. Cidofovir is 

contraindicated for use by patients with renal 

insufficiency or proteinuria.

Monitor patients closely to gauge the 

response to therapy. Repeat the dilated retinal 

examination after completion of induction 

therapy, 1 month after initiation of therapy, 

and monthly during anti-CMV therapy, with 

photography to document progression or 

resolution of disease. Consult with a specialist 

if the response to therapy is suboptimal.

Note: Retinal detachment may occur in 

up to 50-60% of patients in the first year 

after diagnosis. Regular follow-up with an 

ophthalmologist is required for all patients. 

Patients should be instructed to report any 

vision loss immediately.

Chronic maintenance therapy

After initial CMV treatment, lifelong 

maintenance therapy should be given to 

prevent recurrence, and patients need regular 

reevaluation by an ophthalmologist. Select 

the specific treatment in consultation with an 

ophthalmologist. 
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Preferred therapy: 

• Valganciclovir 900 mg PO QD

Alternative therapy:

• Ganciclovir 5 mg/kg IV 5-7 times per week

• Foscarnet 90-120 mg/kg IV QD

• Cidofovir 5 mg/kg IV every other week 

(administer with probenecid and IV 

hydration, as above)

Discontinuation of maintenance therapy can 

be considered for patients with inactive CMV 

and sustained immune reconstitution on 

ART (CD4 count of >100 cells/μL for at least 

3-6 months). However, the decision should 

be guided by factors such as the extent and 

location of the CMV lesions and the status 

of the patient’s vision. An ophthalmologist 

who is experienced in caring for HIV-infected 

patients with CMV should be involved 

in making any decision to discontinue 

therapy, and patients should receive regular 

ophthalmologic follow-up. Maintenance 

therapy should be resumed if the CD4 count 

drops to <100 cells/μL or the patient develops 

other signs of HIV progression.

Neurologic CMV disease

The optimal treatment for neurologic disease 

has not been determined. Prompt initiation 

of dual therapy with IV ganciclovir and 

foscarnet may be effective for some patients. 

Chronic maintenance therapy usually is not 

recommended for patients who recover and are 

on effective ART, unless the disease recurs.

Gastrointestinal and 

pulmonary CMV disease

CMV colitis and esophagitis are usually 

treated with IV ganciclovir or foscarnet for 

21-42 days, until symptoms have resolved. 

Treatment should be changed to valganciclovir 

(900 mg QD) when the patient is able to absorb 

oral medications. In mild cases in which 

patients are able to tolerate and absorb it, 

valganciclovir may be used from the beginning 

(refer to the dosing recommendations above). 

Some specialists recommend a follow-up 

endoscopy to verify regression of lesions before 

discontinuing therapy. 

For pulmonary CMV infections, optimal 

therapy has not been defined. IV ganciclovir 

or foscarnet is recommended. The efficacy of 

valganciclovir has not been determined. 

Many experts do not recommend maintenance 

therapy for gastrointestinal or pulmonary 

CMV infections for patients whose CMV 

symptoms resolve and who are on effective 

ART. 

Immune reconstitution inflammatory 

syndrome retinitis or uveitis

Urgent consultation with experts is 

recommended. Corticosteroids may be 

beneficial.

Monitoring CMV therapies

The medications used to treat CMV have 

several important potential adverse effects, 

and monitoring for these is required. 

Valganciclovir and ganciclovir have been 

associated with bone marrow suppression, 

neutropenia, anemia, thrombocytopenia, 

and renal dysfunction. Foscarnet has been 

associated with cytopenia, renal insufficiency, 

electrolyte abnormalities, and seizures. For 

patients taking these medications, perform 

complete blood count with differential and 

check electrolytes and creatinine twice weekly 

during initial therapy and once weekly during 

maintenance therapy. Cidofovir has been 

associated with renal insufficiency and ocular 

hypotony. For patients taking cidofovir, 

check creatinine and blood urea nitrogen and 

perform urinalysis (for proteinuria) before 

each dose. Intraocular pressure must be 

checked at least every 6 months.
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Patient Education

• Educate patients about the importance of 

ART in treating CMV. Urge patients to start 

ART if they have not done so already.

• Patients with CMV retinitis may have 

to remain on suppressive therapy for 

life to prevent blindness. Patients with 

CMV esophagitis or enteritis usually see 

improvements within 2-4 weeks after 

starting therapy.

• Treatment of CMV retinitis halts 

progression of the infection but does not 

reverse the damage already done to the 

retina. Warn patients that vision will not 

return to pre-CMV status.

• Advise patients to report any visual 

deterioration immediately. Retinal 

detachment or progression of CMV must be 

treated immediately to avoid further vision 

loss.

• For patients who experience significant 

vision loss, offer referral to education, 

training, and support services to help them 

adjust.

• With gastrointestinal disease, recurrence 

of symptoms warrants repeat endoscopy. 

Advise patients to report any recurrence of 

symptoms.

• Adverse reactions to current therapies are 

common. Educate patients about these and 

advise them to promptly report any adverse 

reactions.

• Help patients cope with the possibility of 

therapeutic failure, and, in the case of CMV 

retinitis, permanent loss of vision.

• Teach patients how to maintain indwelling 

venous access lines, if used. Have patients 

demonstrate these techniques before 

discharge.

References

• Drew WL, Lalezari JP. Cytomegalovirus 

and HIV. In: Coffey S, Volberding PA, 

eds. HIV InSite Knowledge Base [textbook 

online]. San Francisco: UCSF Center for 

HIV Information; May 2006. Available 

at hivinsite.ucsf.edu/InSite?page=kb00&doc=kb-05-03-03. Accessed December 

1, 2013.

• Goldberg DE, Smithen LM, Angelilli A, et al. 

HIV-associated retinopathy in the HAART 

era. Retina. 2005 Jul-Aug;25(5):633-49.

• Jacobsen MA. AIDS-Related 

Cytomegalovirus Gastrointestinal Disease.

In: UpToDate v14.1. 

• Jacobsen MA. AIDS-Related 

Cytomegalovirus Neurologic Disease. In: 

UpToDate v14.1. 

• Jacobsen MA. Treatment of AIDS-Related 

Cytomegalovirus Retinitis. In: UpToDate 

v14.1. 

• Kempen JH, Min YI, Freeman WR, et 

al.; Studies of Ocular Complications of 

AIDS Research Group. Risk of immune 

recovery uveitis in patients with AIDS and 

cytomegalovirus retinitis. Ophthalmology. 

2006 Apr;113(4):684-94.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
Gonorrhea and Chlamydia | 419

Section 6: Comorbidities, 

Coinfections, and Complications

Gonorrhea and Chlamydia

Background 

Gonorrhea, caused by Neisseria gonorrhoeae (GC), and chlamydia, caused by Chlamydia 

trachomatis (CT), are sexually transmitted diseases (STDs). These infections may be transmitted 

during oral, vaginal, or anal sex; they also can be transmitted from a mother to her baby during 

delivery and cause significant illness in the infant.

Both organisms can infect the urethra, oropharynx, and rectum in women and men; the epididymis 

in men; and the cervix, uterus, and fallopian tubes in women. Untreated GC or CT infection in 

women may lead to pelvic inflammatory disease (PID), which can cause chronic pelvic pain and 

scarring of the fallopian tubes that results in infertility or ectopic pregnancy (tubal pregnancy). 

N. gonorrhoeae can cause disseminated infection involving the skin, joints, and other systems. 

Infection with GC or CT may facilitate transmission of HIV to HIV-uninfected sex partners.

Certain strains of CT can cause lymphogranuloma venereum (LGV). This infection is common 

in parts of Africa, India, Southeast Asia, and the Caribbean. Although relatively uncommon in 

the United States, outbreaks among men who have sex with men (MSM) have been reported in 

recent years. LGV may cause genital ulcers, followed by inguinal adenopathy; it also can cause 

proctocolitis with anorectal discharge, tenesmus, and pain.

Patients with symptoms of gonorrhea or chlamydia should be evaluated and treated as indicated 

below. Although GC or CT urethral infections in men may cause symptoms, infection in women 

and oral or rectal infections in men often cause no symptoms. Thus, sexually active individuals 

at risk of GC and CT exposure should receive regular screening for these infections as well as for 

syphilis and other STDs; for most patients, this should be at least annually, and every 3-6 months 

for persons at higher risk (see chapter Initial and Interim Laboratory and Other Tests).

S: Subjective

Symptoms will depend on the site of 

infection (e.g., oropharynx, urethra, 

cervix, rectum). Symptoms are not present 

in many patients, thus it is important 

to screen all patients at risk of STDs.

If symptoms are present, women may notice 

the following (depending on site of infection):

• Vaginal discharge

• Pain with sexual intercourse

• Pain or burning on urination

• Abdominal or pelvic pain

• Sore throat

• Rectal discharge

• Anal discomfort or tenesmus

If symptoms are present, men may notice the 

following (depending on site of infection):

• Pain or burning on urination

• Urethral discharge

• Testicular tenderness or pain

• Sore throat

• Rectal discharge

• Anal discomfort or tenesmus

During the history, ask the patient about the 

following:

• Any of the symptoms listed 

above, and their duration

• Previous diagnosis of GC, CT, or other STD

• New sex partner(s); number 

and gender of partners
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• Unprotected sex (oral, vaginal, anal; 

receptive or insertive)

• For women: last menstrual period, and 

whether the patient could be pregnant; use 

of an intrauterine device

O: Objective

Physical Examination

During the physical examination, check for 

fever and document other vital signs.

For women, focus the physical examination on 

the mouth, abdomen, and pelvis. Inspect the 

oropharynx for discharge and lesions; check 

the abdomen for bowel sounds, distention, 

rebound, guarding, masses, and suprapubic 

or costovertebral angle tenderness; perform 

a complete genital and vaginal examination 

for abnormal discharge or bleeding; check 

for uterine, adnexal, or cervical motion 

tenderness; and search for pelvic masses or 

adnexal enlargement. Check the anus for 

discharge and lesions; perform anoscopy if 

symptoms of proctitis are present. Check for 

inguinal lymphadenopathy. Check the skin for 

rashes and lesions.

For men, focus the physical examination on 

the mouth, genitals, and anus/rectum. Check 

the oropharynx for lesions, the urethra for 

discharge, the external genitalia for tenderness, 

masses, or lesions, and the anus for discharge 

and lesions; perform anoscopy if symptoms 

of proctitis are present. Check for inguinal 

lymphadenopathy. Check the skin for rashes 

and lesions.

A: Assessment

A partial differential diagnosis includes the 

following:

• Urinary tract infection

• Dysmenorrhea

• Appendicitis

• Cystitis

• Proctitis

• PID

• Irritable bowel syndrome

• Pyelonephritis

P: Plan

Diagnostic Evaluation

Test for oral, urethral, or anorectal infection, 

according to symptoms and anatomic site(s) 

of possible exposures. Perform testing for 

both gonorrhea and chlamydia (testing for 

pharyngeal CT infection generally is not 

recommended although the CT pharyngeal 

test often accompanies the GC pharyngeal 

nucleic acid amplification test [NAAT]). The 

availability of the various testing methods 

varies according to the specific clinic site. 

Consider the following:

• NAAT: urine specimens (first stream) and 

urethral (men), vaginal, and endocervical 

swab specimens; also used with pharyngeal 

and rectal swab specimens (laboratory must 

meet Clinical Laboratory Improvement 

Amendments [CLIA] specifications and 

establish validity in nongenital specimens); 

recommended unless GC antibiotic 

resistance is suspected

• GC culture (oropharynx, endocervix, 

urethra, rectum) – consider especially if 

antibiotic resistance is suspected

• Gram stain of urethral discharge for 

evidence of GC

• Serologic tests (complement fixation test) if 

LGV is suspected

Treatment

Treatments for gonorrhea and chlamydia are 

indicated below. Fluoroquinolone-resistant 

GC is widespread in the United States and 

throughout the world. Thus, the U.S. Centers 

for Disease Control and Prevention (CDC) 

recommends that fluoroquinolones not be 

used for treatment of GC. Similarly, resistance 
Gonorrhea and Chlamydia | 421

Section 6: Comorbidities, 

Coinfections, and Complications

of GC to cephalosporins is emerging, though 

third-generation cephalosporins are effective 

against most GC strains in the United 

States and remain the only recommended 

treatment for GC. GC strains with decreased 

susceptibility to azithromycin also have been 

reported, and azithromycin should be used 

to treat GC only for select patients in whom 

treatment with a cephalosporin should be 

avoided.

Adherence is essential for treatment success. 

Single-dose treatments maximize the 

likelihood of adherence and are preferred. 

Other considerations in choosing the 

treatment include antibiotic resistance, 

cost, allergies, and pregnancy. For further 

information, see the CDC STD treatment 

guidelines (see “References,” below); 

treatments should be given in accordance with 

these guidelines.

Any sex partners within the past 60 days, or the 

most recent sex partner from >60 days before 

diagnosis, also should receive treatment. Patients 

should abstain from sexual activity for 7 days 

after a single-dose treatment or until a 7-day 

treatment course is completed. Reinfection with 

GC or CT is likely if reexposure occurs; patients 

with either GC or CT should be rescreened 3 

months after treatment.

Treatment of Gonorrhea

Treatment options include the following 

(see the full CDC STD treatment guidelines, 

referenced below); the current guidelines 

emphasize that dual therapy for GC should 

be given, with ceftriaxone plus either 

azithromycin or doxycycline. Ceftriaxone is the 

recommended cephalosporin for GC infection 

at any anatomic site. Coadministration of 

azithromycin or doxycycline is intended 

to improve the likelihood of cure and may 

decrease the risk of emergent cephalosporin 

resistance; it should be given, even if test results 

for CT are negative.

Recommended regimen (for 

GC of all anatomic sites)

• Ceftriaxone 250 mg IM injection in 

a single dose, plus azithromycin 1 g 

PO in a single dose or doxycycline 

100 mg PO BID for 7 days

Alternative regimens (for GC of pharynx, 

cervix, urethra, and rectum)*

• If ceftriaxone is not available: cefixime 

400 mg PO in a single dose (tablet or 

oral suspension), plus azithromycin or 

doxycycline, as above

• If severe cephalosporin allergy: 

azithromycin 2 g PO in a single dose

* If an alternative regimen is used, a test of 

cure (TOC) should be done in 1 week: GC 

culture (preferred) or NAAT. A positive 

NAAT result should be followed by 

confirmatory culture and antimicrobial 

susceptibility testing. Possible 

cephalosporin treatment failures should be 

reported immediately to the local or state 

health department.

If penicillin or cephalosporin allergy:

• Cephalosporins are contraindicated for 

use only in patients with a history of severe 

reaction to penicillin.

• Consultation with an infectious disease 

specialist is recommended.

• Consider azithromycin 2 g PO, with TOC, 

as above. 

• Consider cephalosporin treatment following 

desensitization.

Note: Fluoroquinolones are not recommended 

for treatment of gonococcal infection because 

of widespread resistance in the United States.

Please see full CDC STD treatment guidelines 

regarding treatment of PID, epididymitis, and 

disseminated gonococcal infection.
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Treatment of Chlamydia

(See the full CDC STD treatment guidelines, 

referenced below.)

Recommended regimens

• Azithromycin 1 g PO in a single dose

• Doxycycline 100 mg PO BID for 7 days

Alternative regimens

• Erythromycin base 500 mg 

PO QID for 7 days

• Erythromycin ethylsuccinate 

800 mg PO QID for 7 days

• Levofloxacin 500 mg PO QD 

for 7 days (see Note above) 

• Ofloxacin 300 mg PO BID for 

7 days (see Note above)

Treatment of LGV

Recommended regimens

• Doxycycline 100 mg PO BID for 21 days

Alternative regimens

• Erythromycin base 500 mg 

PO QID for 21 days

• Azithromycin 1 g PO once weekly 

for 3 weeks (limited data)

For recent sex partners (within 60 days 

before the onset of patient’s symptoms), 

test for urethral or cervical CT, treat with 

azithromycin 1 g PO in a single dose or 

doxycycline 100 mg PO BID for 7 days.

Treatment During Pregnancy

Use of fluoroquinolones and tetracyclines 

should be avoided during pregnancy.

Recommended GC regimens

• Ceftriaxone 250 mg IM + azithromycin 

1 g PO in a single dose

Recommended CT regimens

• Azithromycin 1 g PO in a single dose

• Amoxicillin 500 mg PO TID for 7 days

Alternative CT regimens

• Erythromycin base 500 mg 

PO QID for 7 days

• Erythromycin base 250 mg 

PO QID for 14 days

• Erythromycin ethylsuccinate 

800 mg PO QID for 7 days

• Erythromycin ethylsuccinate 

400 mg PO QID for 14 days

Follow-Up

• For both GC and CT, evaluate the patient’s 

sex partners; treat them empirically if they 

had sexual contact with the patient during 

the 60 days preceding the patient’s onset of 

symptoms. Some clinics provide empiric 

treatment for partners via “partner packs,” 

or a treatment regimen that the patient 

takes to the partner(s); this approach may 

be effective, particularly for CT, if the 

partner(s) is/are unlikely to come to the 

clinic for evaluation and treatment.

• Most recurrent infections come from sex 

partners who were not treated.

• The CDC recommends rescreening all 

patients 3 months after GC or CT treatment 

(for possible reinfection).

• For pregnant women with CT, retest 

(by NAAT) 3 weeks after completion of 

treatment.
Gonorrhea and Chlamydia | 423

Section 6: Comorbidities, 

Coinfections, and Complications

• If symptoms persist, evaluate for the 

possibility of reinfection, treatment 

failure, or a different cause of symptoms. 

If treatment failure is suspected, perform 

culture and antimicrobial sensitivity testing.

• Screen for GC, CT, syphilis, and other STDs 

at regular intervals according to the patient’s 

risk factors. The sites of sampling (e.g., 

pharynx, urethra, endocervix, anus/rectum) 

will be determined according to the patient’s 

sexual exposures.

• Evaluate each patient’s sexual practices with 

regard to the risk of acquiring STDs and of 

transmitting HIV; work with the patient to 

reduce sexual risks.

Patient Education

• Instruct patients to take all of their 

medications. Advise patients to take 

medications with food if they are nauseated 

and to call or return to clinic right away if 

they experience vomiting or are unable to 

take their medications.

• Sex partners from the previous 60 days 

need to be tested for sexually transmitted 

pathogens, and treated as soon as possible 

with a regimen effective against GC and 

CT, even if they have no symptoms. Advise 

patients to inform their partner(s) that they 

need to be tested and treated. Otherwise, 

patients may be reinfected.

• Advise patients to avoid sexual contact until 

the infection has been cured (in themselves 

and in their partners) at least 7 days.

• Provide education about sexual risk 

reduction. Instruct patients to use condoms 

with every sexual contact to prevent 

reinfection with GC or CT, to prevent other 

STDs, and to prevent transmission of HIV to 

sex partners.

References

• Bolan GA, Sparling PF, Wasserheit 

JN. The emerging threat of untreatable 

gonococcal infection. N Engl J Med. 2012 Feb 

9;366(6):485-7.

• Centers for Disease Control and Prevention. 

Gonorrhea – CDC Fact Sheet. Available 

at www.cdc.gov/std/gonorrhea. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

Lymphogranuloma venereum among men 

who have sex with men – Netherlands, 2003-

2004. MMWR. 2004 Oct 29;53(42):985-8.

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 

17; 59 (No. RR-12):1-110. Available at 

www.cdc.gov/STD/treatment/2010. 

Accessed December 1, 2013.

• Centers for Disease Control and Prevention. 

Cephalosporin susceptibility among Neisseria 

gonorrhoeae isolates – United States, 2000-

2010. MMWR Morb Mortal Wkly Rep. 2011 

Jul 8;60(26):873-7.

• Centers for Disease Control and 

Prevention. Update to CDC’s Sexually 

transmitted diseases treatment guidelines, 

2010: oral cephalosporins no longer a 

recommended treatment for gonococcal 

infections. MMWR Morb Mortal Wkly 

Rep. 2012 Aug 10;61(31):590-4. 

Hepatitis B Infection | 425

Section 6: Comorbidities, 

Coinfections, and Complications

Hepatitis B Infection

 Rena K. Fox, MD

Background 

Hepatitis B virus (HBV) is the most common cause of 

chronic liver disease worldwide. Chronic HBV can cause 

necroinflammation and over time can cause hepatic 

fibrosis and eventually cirrhosis, end-stage liver disease, 

and hepatocellular carcinoma (HCC). It is estimated that 

350 million people have chronic HBV infection, with 

approximately 1.25 million of them in the United States. 

HBV is a DNA virus that is spread through exposure to 

infected blood and body fluids. It typically is transmitted 

by parenteral, sexual, and vertical exposures, but may be transmitted through person-to-person 

contacts among household members, especially because HBV can survive outside the body for 

long periods of time. Because HIV and HBV share transmission routes, up to 90% of HIV-infected 

patients have evidence of HBV exposure. In the United States, chronic HBV infection has been 

identified in 6-15% of HIV-infected persons.

The epidemiology of HBV infection varies by geographic region. In Southeast Asia and subSaharan Africa, HBV is highly prevalent and almost all infections occur perinatally or during 

early childhood. In the United States and Western Europe, most infections occur through sexual 

exposure or high-risk injection drug-use behavior.

To identify patients with HBV coinfection, and to identify and vaccinate susceptible individuals, 

all HIV-infected persons should be tested for HBV (see chapters Initial and Interim Laboratory and 

Other Tests and Immunizations for HIV-Infected Adults and Adolescents). In addition, all patients 

with chronic HBV infection should be tested for HIV and all patients with evidence of prior 

resolved HBV infection should be strongly considered for HIV testing.

It is universally recommended that HBV vaccination should be given to all HIV-infected persons 

who are susceptible to HBV infection (see “Interpreting HBV test results,” below, and chapter 

Immunizations for HIV-Infected Adults and Adolescents). It is recommended that the vaccine series 

be given when CD4 counts are >200 cells/μL, if possible, as doing so is associated with higher rates 

of vaccine response, but vaccination should not be delayed for persons with lower CD4 counts. 

The natural history of HBV infection is complex and dynamic, with phases of active replication 

and of inactive replication, and fluctuating alanine aminotransferase (ALT) levels. The 

likelihood of developing chronic HBV after exposure varies with age, mode of infection, and 

immunocompromised status. Among newborns born to HBV-infected mothers, 90% develop 

chronic hepatitis B, whereas 30% of exposed infants and young children and <5% of exposed adults 

develop chronic infection. Most adults who become infected with HBV are able to clear the virus 

without treatment, and they subsequently become immune to HBV. Chronic progressive HBV can 

lead to cirrhosis and then to decompensated liver disease including ascites, portal hypertension, 

esophageal varices, coagulopathy, thrombocytopenia, and hepatic encephalopathy. HCC can 

develop in patients with or without cirrhosis; in fact, 30-50% of HCC cases attributable to HBV 

occur in the absence of cirrhosis.

HRSA HAB Performance 

Measures

Percentage of patients with a 

diagnosis of HIV who completed the 

vaccination series for hepatitis B

(Adult and Adolescent measure)
426 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Factors associated with increased rates of 

cirrhosis include the following:

• Longer duration of infection 

• HBV genotype C 

• High levels of HBV DNA 

• Alcohol consumption 

• Smoking 

• Aflatoxin exposure 

• Coinfection with HIV 

• Coinfection with hepatitis D virus 

• Coinfection with HCV

Factors associated with increased rates of HCC 

include the following:

• Male gender 

• Family history of HCC 

• Older age 

• Presence of HBV envelope antigen (HBeAg); 

history of reversion from anti-HBe to 

HBeAg 

• High levels of HBV DNA 

• Presence of cirrhosis 

• HBV genotype C 

• Core promoter mutation 

• Coinfection with HCV

Among individuals who are not taking ART, HIV infection significantly modifies the natural 

history of HBV infection. HIV infection appears to increase the risk of developing chronic 

HBV infection after acute HBV, and it is associated with a higher level of HBV DNA replication 

and lower rates of spontaneous HBeAg seroconversion. In patients with chronic HBV, HIV 

coinfection is associated with faster progression of liver disease and cirrhosis and increased rates 

of liver-related deaths. Although HIV coinfection itself is not known to increase the risk of HCC 

development, it does increase the risk of cirrhosis, which in turn increases the risk of HCC.

Treatment of HIV infection with effective ART has increased the life expectancy of HIVinfected patients in recent years, and paradoxically has given HIV/HBV-coinfected patients 

a longer lifespan during which cirrhosis may develop. Partly for this reason, the relative 

proportion of deaths attributable to liver disease among HIV-infected patients is rising. On the 

other hand, ART can positively impact the natural history of HBV infection. Effective ART 

can improve patients’ immune responses against HBV. ART also may be used to cotreat HBV 

in coinfected patients. Several of the nucleoside analogues (NRTIs) used against HIV also are 

active against HBV, and these should be included in an ART regimen to treat both HIV and 

HBV for coinfected persons (see “Antiviral Treatment of Chronic HBV Infection,” below). 

Withdrawal of NRTIs with anti-HBV activity can precipitate a reactivation of HBV. ART that 

contains anti-HBV NRTIs also may prevent acute infections in patients who are receiving 

them. Current U.S. Department of Health and Human Services (HHS) guidelines recommend 

initiation of ART (and cotreatment of HBV) for all persons with HIV/HBV coinfection.
Hepatitis B Infection | 427

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

Persons with acute HBV infection may have 

symptoms including fatigue, nausea, vomiting, 

arthralgias, fever, right upper quadrant pain, 

jaundice, dark urine, and clay-colored stools. 

Some patients may have no symptoms at all.

Persons with chronic HBV, even with 

early cirrhosis, may be asymptomatic 

or may experience only fatigue or mild 

right upper quadrant tenderness. Patients 

with decompensated cirrhosis may 

experience increased abdominal girth, 

easy bruising, telangiectasis, pruritus, 

gastrointestinal bleeding, or altered 

mentation. Patients with early or small 

HCC may have no additional symptoms 

or may develop significant abdominal 

pain, weight loss, nausea, or bone pain.

Ask patients with known HBV infection about 

symptoms that suggest complications of HBV 

such as cirrhosis, decompensation, risk factors 

for worsening liver disease, and hepatotoxins. 

Questions should address the symptoms listed 

above, and the following:

• Fatigue 

• Weight loss 

• Impaired concentration 

• Chronic HCV 

• Alcohol intake 

• Substance use 

• Antiretroviral (ARV) medications that 

may cause hepatotoxicity (e.g., didanosine, 

protease inhibitors, nevirapine, maraviroc) 

• Medications with potential for 

hepatotoxicity or accumulation in persons 

with liver disease (e.g., acetaminophen, 

benzodiazepines, opiates)

O: Objective

Measure vital signs.

Perform a physical examination to include 

evaluation of the following:

• Head, ears, eyes, nose, throat (HEENT): 

temporal wasting, icterus, gum bleeding 

• Heart and lungs: signs of congestive heart 

failure 

• Chest: gynecomastia 

• Abdomen: caput medusa, venous 

prominence, distention, signs of ascites, 

hepatomegaly, splenomegaly 

• Extremities: edema 

• Neurologic: alertness, mental status, 

asterixis 

• Skin: jaundice, palmar erythema, petechiae, 

ecchymoses, spider angiomata

P: Plan

HBV Testing

As discussed above, all HIV-infected persons 

should be screened for HBV surface antigen 

(HBsAg), HBs antibody (HBsAb), and HBV 

core antibody (total) (HBcAb-total) and 

be vaccinated if not immune (see chapter 

Immunizations for HIV-Infected Adults and 

Adolescents).

Nonimmune persons with elevated 

transaminases or signs or symptoms of acute 

or chronic liver disease should be retested for 

HBV and HCV infection.

Interpreting HBV test results

Routine baseline HBV serologic screening tests 

for HIV-infected individuals are outlined in 

Table 1.

Markers of chronic hepatitis B can manifest in 

a number of patterns (see Table 1).
428 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Table 1. Interpreting HBV Laboratory Tests

Acute 

Hepatitis B

Recovery 

from Acute 

Hepatitis B

Chronic 

HBeAg+ 

Disease

Chronic 

HBeAgDiseaseOccult 

Hepatitis B

Successful 

Vaccination

Isolated 

HBcAb

HBsAg X

(may clear)

X X

Anti-HBs X X

Anti-HBc 

IgM 

X

(may be 

the only 

marker 

during 

window 

period)

Anti-HBc X X X X X X

HBeAg X X X

Anti-HBe X

(in some 

cases)

X X

(in some 

cases)

DNA* 

(PCR if 

required) 

X X X X (in rare 

cases, may 

be +) 

* Absence of detectable HBV DNA does not rule out chronic HBV infection in patients who are on ARVs with anti-HBV activity.

Because of the complexity of HBV diagnosis 

and test interpretation, it is important to test 

for HBsAg, HBcAb, and HBsAb. If the result 

for either HBsAg or HBcAb is positive, then 

test for HBV DNA. The presence of HBsAg for 

>6 months indicates chronic HBV infection, 

but detectable HBV DNA is required for the 

diagnosis. HBV DNA should be tested before 

initiation of ART, if possible, as NRTIs with 

anti-HBV activity may suppress HBV viremia 

and interfere with diagnosis. Some persons with 

HIV infection can have chronic HBV infection 

with high HBV DNA levels and hepatic 

inflammation while testing negative for HBsAg 

and positive only for HBcAb. This sometimes is 

termed “occult hepatitis B infection.” Patients 

with chronic HBV may test either positive or 

negative for HBeAg. Patients with inactive 

chronic HBV are positive for HBsAg but have 

persistently normal ALT levels, low-level 

or no detectable HBV DNA, and negative 

HBeAg results. Ongoing viral replication and 

infectiousness is indicated by the presence of 

HBV DNA or a positive result for HBeAg.

Markers of immunity or previous exposure to 

HBV also can manifest in a number of patterns 

(see Table 1). Successful vaccination to HBV 

(in someone who has never been infected) 

will result in positive HBsAb but negative 

HBcAb results. Prior exposure to HBV may 

result in positive HBcAb and HBsAb findings, 

indicating the development of immunity. 

However, prior exposure may present as 

positive HBcAb only, with negative results for 

HBsAb, HBsAg, and HBV DNA. This pattern 

shows that the patient was previously infected 

with hepatitis B but did not develop chronic 

infection, and lost the HBsAb. This sometimes 

is termed “isolated core Ab,” and it is seen 

more commonly in patients coinfected with 

HIV or HCV. It is not known whether patients 

who display this pattern would have sufficient 

immunity to ward off another HBV infection 

if they were reexposed; current guidelines 

recommend the standard HBV vaccination 

series, followed by a check of HBsAb. 
Hepatitis B Infection | 429

Section 6: Comorbidities, 

Coinfections, and Complications

In acute HBV infection, HBV DNA will be 

detectable before HBsAg, if highly sensitive 

nucleic acid testing is used. Otherwise, HBsAg 

is the only marker detected during the first 

3-5 weeks after infection. HBcAb develops 

at approximately 6 weeks after infection 

and both immunoglobulin M (IgM) and 

immunoglobulin G (IgG) will be evident. 

The IgM will decline within 6 months but the 

IgG will persist for life. Among individuals 

who recover from acute HBV infection, 

HBeAg typically seroconverts to HBeAb at 

approximately 3 months whereas, for those 

who develop chronic HBV infection, HBeAg 

typically persists for years.

Diagnostic Evaluation of 

Acute HBV Infection

When approaching the diagnosis of a patient 

with acute hepatitis B infection, the following 

steps should be taken:

1. Obtain history and perform physical 

examination.

Determine the time and route of infection if 

possible. Take a complete history, including 

HIV disease course and treatment, and 

other medical history. Perform physical 

examination, focusing on evidence of acute 

liver dysfunction.

2.Assess HBV replication serially.

As soon as acute infection is suspected, 

check HBsAg, HBV DNA, HBeAg, HBeAb, 

ALT, HBcAb-IgM, and HBsAb. HBsAg 

usually can be detected by 4 weeks (the 

range of detectability is 1-9 weeks). HBcAbIgM is detectable at the onset of symptoms. 

When ALT is abnormal and rising, 

additional tests of liver function should be 

serially evaluated until it is clear that ALT 

is trending back down. Tests should include 

albumin, total bilirubin, prothrombin time, 

and platelet count.

3. Determine whether HBV infection resolves 

or persists as chronic HBV infection.

If the HBsAg is still present at 6 months 

after acute infection, the HBV infection 

has persisted and the patient has chronic 

hepatitis B infection.

Initial Diagnostic Evaluation of Chronic 

HBV Infection

When approaching the diagnosis of a patient 

with chronic HBV infection, the following 

steps should be taken:

• Take a complete history, including family 

history of HBV or HCC, and HIV disease 

course and treatment. Perform physical 

examination. 

• Assess HBV replication to determine HBV 

DNA level, HBeAg and HBeAb serostatus, 

and ALT level. Note that HBV DNA levels 

may be difficult to interpret in patients who 

are on ARVs that have anti-HBV activity 

(HBV level may be low or undetectable 

because of these medications). 

• Assess liver disease – check complete blood 

cell count with platelet count, albumin, total 

bilirubin, transaminases (especially ALT), 

and prothrombin time. 

• Assess for possible overlying liver diseases 

(e.g., HCV, alcoholic liver disease, fatty liver 

disease). 

• Consider liver biopsy to assess histological 

degree of inflammation and fibrosis, 

especially if the result would affect the 

decision to use treatment. 

• Screen for HCC at baseline via ultrasound. 

• Test for hepatitis A antibodies (IgG) and 

vaccinate against hepatitis A if not immune.
430 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Long-Term Monitoring of Chronic 

HBV Infection

It should be noted that current HHS guidelines 

strongly recommend treatment of both 

HIV and HBV in all coinfected persons. 

Nonetheless, some patients may wish to defer 

treatment or may not tolerate treatment. For 

those patients who are not on treatment for 

HBV, regular monitoring of HBV replication 

and liver function should be performed.

For patients with the following seromarkers, 

recommendations are as indicated:

Negative HBeAg, low ALT, and low-level 

DNA (<2,000 IU/mL) (inactive HBV):

HBV DNA, HBeAg, and ALT testing should 

be performed every 3 months for the first 

year to determine whether the virus is truly 

inactive. If it remains inactive (with negative 

HBeAg, normal ALT, and low-level DNA), 

monitoring can continue every 6-12 months; 

some specialists recommend more frequent 

monitoring.

Negative HBeAg, elevated ALT, and high 

HBV DNA (>20,000 IU/mL):

Biopsy should be considered, and treatment 

should be considered. If treatment is not 

started, monitoring should occur every 3 

months.

Negative HBeAg, moderately elevated 

ALT, and moderately elevated DNA (2,000-

20,000 IU/mL):

Follow-up should be performed every 3-6 

months if treatment is not started.

Positive HBeAg, moderately elevated ALT:

Monitoring should be performed every 3 

months and, if ALT is persistently elevated, 

a biopsy should be considered to guide 

the decision regarding initiation of HBV 

treatment.

Positive HBeAg, high HBV DNA (>20,000 IU/

mL) but low-level ALT:

Monitoring should be performed every 

3-6 months to check for changes in ALT. If 

ALT rises significantly, treatment should be 

considered.

Cirrhosis:

Treatment should be considered. For patients 

who are not treated, monitoring should be 

performed every 3-6 months.

Antiviral Treatment of Chronic HBV 

Infection

HHS ARV guidelines and Centers for Disease 

Control and Prevention opportunistic 

infection guidelines recommend treatment of 

both HIV and HBV in all coinfected persons. 

The goals and markers of HBV treatment for 

HIV/HBV-coinfected patients are the same as 

for HBV-monoinfected patients.

The goals of treatment are as follows:

• To decrease progression of liver disease 

• To prevent development of cirrhosis 

• To prevent development of HCC

Treatment endpoints for the HBV/HIVcoinfected population are not well defined 

but efficacy is determined by the following 

measures:

• HBeAg seroconversion to HBeAb (this is 

harder to achieve for coinfected patients 

than for HBV-monoinfected persons) 

• HBV DNA suppression 

• ALT normalization, which usually follows 

the changes in HBV DNA

The timing of treatment and choice of 

treatment for HBV/HIV-coinfected patients 

are important.
Hepatitis B Infection | 431

Section 6: Comorbidities, 

Coinfections, and Complications

Treatment for HIV and HBV:

• All HIV/HBV coinfected patients should be 

treated for both HIV and HBV infections, if 

possible. 

• If treatment for HIV is to be started, HBV 

should be treated concurrently with the HIV 

by using a potent ART regimen that includes 

two NRTIs that are active against both 

viruses (tenofovir + emtricitabine or tenofovir 

+ lamivudine), if possible. If tenofovir is 

contraindicated, entecavir or another antiHBV drug should be used (with emtricitabine 

or lamivudine) to construct a two-drug 

therapy for HBV, and the HIV ART regimen 

should be designed for complete HIV 

suppression (see Table 2). In this situation, 

liver biopsy to stage disease is not necessary 

because HBV treatment will be undertaken 

(incorporated into the HIV regimen). Note 

that treatment of HBV with a single NRTI 

is not recommended, because of the risk of 

HBV resistance; if tenofovir cannot be used, 

entecavir (plus combination ART) is the 

preferred alternative (see Table 2). 

• Most patients receiving ART who are 

treated for HBV will require HBV treatment 

indefinitely (lifelong). 

Treatment for HBV alone:

• If HBV treatment is indicated, HIV infection 

should be treated concurrently, if possible, 

as stated above. If treatment for HIV is 

deferred, the hepatitis B should be treated if 

the patient otherwise meets criteria for HBV 

treatment (see below). 

• Inactive chronic hepatitis B (HBV DNA 

is <2,000 IU/mL, HBeAg is negative, 

and ALT is not elevated): the HBV can 

be monitored and does not require 

treatment. 

• HBeAg positive, ALT is more than two 

times the upper limit of normal (ULN), 

and HBV DNA >20,000 IU/mL: consider 

HBV treatment. 

• HBeAg negative, ALT is more than two 

times the ULN and HBV DNA >2,000 IU/

mL: consider HBV treatment. 

• HBeAg positive, HBV DNA >20,000 IU/

mL, but ALT is less than two times the 

ULN: can use a biopsy to determine the 

need for HBV treatment. 

• HBeAg negative, DNA >2,000 IU/mL, but 

ALT is less than two times the ULN: can 

use a biopsy to determine the need for 

HBV treatment. 

• Any patient with cirrhosis (if not 

decompensated) and a detectable DNA 

level: should be considered for HBV 

treatment, regardless of HBeAg status and 

regardless of ALT level. 

• Patients with decompensated cirrhosis 

should not be treated for HBV but should 

be referred for transplant. 

• Some specialists recommend HBV 

treatment for all patients with detectable 

HBV DNA, particularly if ALT is elevated 

or inflammation or fibrosis is seen on liver 

biopsy. 

• If a decision is made to treat HBV but 

not HIV, HBV treatment should not 

include agents that are dually active, as 

that could lead to early HIV resistance. 

This limits choices to pegylated interferon 

alfa-2a (although it has not been studied 

in HIV/HBV-coinfected patients) or 

adefovir dipivoxil. Tenofovir, lamivudine, 

emtricitabine, entecavir, and telbivudine 

should not be used as monotherapy for HIV/

HBV-coinfected patients, because HIV (and 

HBV) resistance may develop (see Table 2).
432 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Table 2. Antiviral Therapies for Chronic HBV Infection

Lamivudine Emtricitabine Tenofovir Adefovir Entecavir Telbivudine

Pegylated 

Interferon

Dual activity against 

HBV and HIV

Yes Yes Yes No (at the low 

HBV treatment 

dosage), but 

theoretical 

concern 

remains

Yes Possibly No

Recommended for use in 

HIV/HBV coinfection

With 

tenofovir, as 

part of fully 

suppressive 

ART

With 

tenofovir, as 

part of fully 

suppressive 

ART

With 

lamivudine or 

emtricitabine, 

as part of fully 

suppressive 

ART

If HIV is 

not being 

treated, or in 

combination 

with a 

lamivudine- or 

emtricitabinecontaining 

ART regimen, 

if tenofovir is 

not used

With fully 

suppressive 

ART

With fully 

suppressive 

ART

If HIV is 

not being 

treated

Loss of

HBV DNA

40-44% 76% 21% 67% 60% 25%

HBeAg 

seroconversion

16-21% 21% 12% 21% 22% 27–32%

Class

Nucleoside 

analogue

Nucleoside 

analogue

Nucleotide 

analogue

Nucleotide 

analogue

Nucleoside 

analogue

Nucleotide 

analogue

Interferon

Additional points about treatment for HIV/

HBV-coinfected patients:

• When lamivudine is used as a single agent, 

HBV resistance develops in many patients 

by 1-2 years. Although combination therapy 

has not been well studied, specialists 

recommend using dual-NRTI combinations 

that have activity against HBV (lamivudine 

+ tenofovir, or emtricitabine + tenofovir 

[Truvada]) as part of the ARV regimen, to 

treat HBV and to prevent HBV resistance. 

• Some patients treated with ART may 

experience worsening of HBV symptoms 

and laboratory markers in the weeks 

after ART initiation, because of immune 

reconstitution inflammatory reactions. 

Hepatic decompensation owing to immune 

reconstitution must be distinguished from 

other causes, such as medication toxicity, or 

other infection. Liver function tests should be 

monitored closely for patients starting ART. 

• Some ARV medications are hepatotoxic and 

should be avoided or used cautiously. These 

include nevirapine, tipranavir, and highdose ritonavir. Numerous other medications 

(e.g., fluconazole, isoniazid) are hepatotoxic 
Hepatitis B Infection | 433

Section 6: Comorbidities, 

Coinfections, and Complications

and can pose problems for patients with 

impaired liver function. 

• Discontinuation of HBV medications in 

patients with HIV/HBV coinfection may 

cause a flare of liver disease. Be very cautious 

when discontinuing HBV-active medications 

from an anti-HIV ART regimen. If the 

HBV DNA is suppressed, options include 

continuing the HBV-active ARVs, even if 

there is HIV resistance (modify the other 

parts of the ART regimen for maximal HIV 

suppression) or substituting other HBVactive medications to avoid rebound liver 

inflammation and decompensation. For 

example, if it is decided to discontinue a 

lamivudine/tenofovir-containing regimen 

in an HIV/HBV-coinfected patient on ART, 

consider starting interferon or possibly 

adefovir to maintain activity against 

HBV. If HBV therapy is discontinued 

and a flare occurs, consider reinstating 

HBV therapy as soon as possible.

• Limited data exist on treatment of HBV 

in the setting of HIV and HCV. Consider 

consultation with an expert if optimal 

timing for treatment of the three infections 

is not clear. 

Screening for HCC in patients with chronic 

HBV infection:

Persons with chronic HBV are at increased 

risk of developing HCC. Note that HCC 

may occur even in the absence of cirrhosis. 

HCC screening should be performed every 

6-12 months using ultrasound (computed 

tomography [CT] is an alternative); alphafetoprotein should be monitored if ultrasound 

reliability is low.

HBV-infected patients who should be screened 

for HCC include the following:

• Anyone with cirrhosis 

• Anyone over age 40 with elevated ALT or 

HBV DNA level of >2,000 copies/mL 

• Asian men aged >40 

• Asian women aged >50 

• Persons of African descent aged >20 

• Anyone with a family history of HCC

Interventions to slow progression and 

prevent complications

Persons with HCV infection should be 

counseled to avoid exposure to hepatotoxins, 

including alcohol and hepatotoxic medications 

(e.g., acetaminophen in large doses, 

fluconazole, isoniazid). Heavy alcohol use is a 

risk factor for increasing rate of fibrosis. It is 

not clear what degree of alcohol consumption 

is safe, so many experts recommend complete 

abstinence from alcohol.

• No specific dietary measures are 

recommended. 

• Patients who are not already immune to 

hepatitis A should be vaccinated against 

hepatitis A. 

• Patients should be counseled on ways to 

avoid infection with hepatitis C.

Preventing transmission

All patients with HBV infection should receive 

individualized counseling on ways to reduce 

the risk of HBV transmission (including by 

sexual or needle-sharing behavior, perinatal 

routes, or household exposure), as appropriate.

Household members and sexual contacts 

should be vaccinated against HBV.

Women who are pregnant or considering 

pregnancy should consult with a specialist 

in both HBV and HIV to discuss ways of 

decreasing the infection risk for the fetus; 

this may include treatment for HBV and 

HIV. Infants born to coinfected women 

should receive HBV immune globulin 

and start the HBV vaccine series within 

12 hours after birth (with subsequent 

vaccine doses per usual protocol).
434 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

Patient Education

• Advise patients that most people with HBV 

will remain asymptomatic for several years. 

However, ongoing injury to the liver occurs 

during this time and can culminate in liver 

failure. Patients can slow the progression 

of damage by avoiding alcohol and any 

medications (including over-the-counter 

drugs and recreational drugs) that may 

damage the liver. Patients should contact 

their pharmacist or health care provider 

if they have questions about a specific 

medication or supplement. 

• Advise patients that treatment for both HIV 

and HBV is recommended for anyone with 

HIV/HBV coinfection. ART can be used to 

treat both infections. 

• As with HIV, patients must avoid passing 

HBV to others. Instruct patients not to share 

toothbrushes, dental appliances, razors, sex 

toys, tattoo equipment, injection equipment, 

or personal care items that may have 

blood on them. Emphasize to patients the 

importance of safer sex to protect themselves 

and their partners. 

• Tell patients to discuss HBV with their sex 

partners, and suggest that partners be tested 

for HBV. 

• Nonimmune sex partners and individuals 

in close contact with persons with chronic 

hepatitis B (e.g., family and household 

members) should be vaccinated. 

• Pregnant women have a high risk of 

transmitting HIV or HBV to the fetus 

because each virus makes it easier to 

transmit the other. Women who are 

pregnant or considering pregnancy should 

talk with a specialist in HIV and HBV to 

discuss ways of decreasing the infection risk 

for the fetus. 

• Advise patients who are on treatment for 

HBV that abrupt discontinuation of HBV 

treatment can cause a flare of HBV; they 

should not stop treatment without medical 

supervision. 

• Certain ARV drugs are more likely than 

others to cause hepatotoxicity. Advise 

patients that their liver function should be 

monitored carefully if they start an ARV 

regimen, in order to determine whether the 

body is able to process the medicines.

References

• Benhamou Y. Hepatitis B in the HIVcoinfected patient. J Acquir Immune 

Defic Syndr. 2007 Jul 1;45 Suppl 2:S57-65; 

discussion S66-7. 

• Lok A, McMahon B. Chronic hepatitis 

B: update 2009. Hepatology. 2009 

Sep;50(3):661-2.

• Panel on Antiretroviral Guidelines for Adults 

and Adolescents. Guidelines for the use of 

antiretroviral agents in HIV-1-infected adults 

and adolescents. Department of Health and 

Human Services. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013. 

• Weinbaum CM, Williams I, Mast EE, et al.; 

Centers for Disease Control and Prevention. 

Recommendations for identification and 

public health management of persons with 

chronic hepatitis B virus infection. MMWR 

Recomm Rep. 2008 Sep 19;57(RR-8):1-20.
Hepatitis C Infection | 435

Section 6: Comorbidities, 

Coinfections, and Complications

Hepatitis C Infection

Rena K. Fox, MD 

Background

In the United States, an estimated 2.7-3.9 million people are living with chronic hepatitis C virus 

(HCV) infection. Without treatment, 15% to 40% of persons living with the virus will develop 

cirrhosis or cancer, and HCV is the leading cause of liver transplantation in the United States. 

Hepatitis C-related mortality has been steadily increasing in recent years, and as the baby boomer 

generation ages, the rates of cirrhosis and hepatocellular carcinoma (HCC) are expected to rise.

As antiretroviral therapy (ART) has reduced AIDS-related mortality among HIV-infected patients, 

liver disease owing to HCV infection has become a leading cause of death and the sequelae of 

chronic HCV have increased. HCV is common among persons with HIV infection in the United 

States. It is estimated that 20-30% of the HIV-infected population in the United States is coinfected 

with HCV, but the prevalence varies with risk factor for transmission. Among HIV-infected 

injection drug users and hemophiliacs, 70-95% may be coinfected with HCV; among HIV-infected 

men who have sex with men (MSM), 1-12% are coinfected with HCV. The U.S. Centers for Disease 

Control and Prevention and the U.S. Public Health Service recommend that all HIV-infected 

persons receive screening for HCV.

HCV is a single-stranded RNA virus that is transmitted mainly through blood exposure and, less 

commonly, through perinatal or sexual exposure. HCV is more likely than HIV to be transmitted 

via a bloodborne route; there is an approximately 10-fold greater risk of HCV transmission after 

needlestick exposure compared with the risk of HIV transmission, and the concentrations of 

HCV in a given volume of blood are greater than those of HIV. Perinatal transmission of HIV is 

more likely among women who are coinfected with HIV and HCV than among women with HIV 

infection alone; similarly, perinatal transmission of HCV is more likely in coinfected women than 

in those with HCV monoinfection. Breast-feeding is not known to transmit HCV, although HIVinfected women are advised against breast-feeding because of the risk of transmitting HIV.

Although sexual transmission of HCV is not efficient, 10% of acutely HCV-infected persons report 

no risk factor other than sexual contact with an HCV-infected partner. Many centers have reported 

an increase in acute HCV in MSM, and rates of sexual transmission of HCV appear to be higher in 

MSM than in the general population, especially among persons who are coinfected with HIV. In 

HIV-infected MSM, outbreaks of acute HCV have been reported, with sexual activity as the risk factor 

for transmission. Risk factors associated with sexual transmission of HCV include the presence of 

coexisting sexually transmitted diseases, unprotected anal receptive sex, and use of recreational drugs.

The natural history of HCV infection is variable. Approximately 20% of monoinfected patients 

ultimately develop cirrhosis, whereas approximately 80% of patients develop some degree 

of fibrosis (without progression to cirrhosis); patients without cirrhosis typically remain 

asymptomatic. HCV can affect organ systems outside the liver, such as dermatological and renal 

systems, but its effects most commonly are limited to the liver. Coinfection with HIV adversely 

impacts the natural history of HCV infection. HIV/HCV-coinfected patients have lower rates of 

spontaneous HCV clearance, higher HCV viral loads, lower rates of successful HCV treatment 

with interferon and ribavirin, faster progression to cirrhosis, and greater risk of developing liver 

decompensation, end-stage liver disease, and hepatocellular carcinoma (HCC). On the other hand, 

HCV coinfection does not appear to increase HIV- and AIDS-related complications or the success 

of HIV antiretroviral (ARV) treatment.
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Acute HCV Infection

Persons with acute HCV infection typically are 

asymptomatic or have only mild symptoms. 

Patients who do present with new onset of 

jaundice, weakness, anorexia, abdominal pain, 

or malaise without a known cause should be 

tested for acute HCV infection. Symptoms 

usually subside after several weeks. Patients 

who present after a potential exposure, such as 

a needlestick injury, should be tested for acute 

infection whether or not they are symptomatic. 

Overall, approximately 15-30% of patients 

acutely infected with HCV will clear the virus 

spontaneously, and 70-85% of patients will 

develop chronic infection. However, there are 

few prospective studies on the natural history 

of acute HCV infection with preexisting HIV 

infection. Because it is difficult to establish the 

precise timing of HCV infection, prospective 

natural history studies are difficult to perform.

Chronic HCV Infection

For the majority of HCV patients, other than 

laboratory abnormalities, there are no clinical 

manifestations of infection until the late stages 

of cirrhosis. Cirrhosis develops in approximately 

20% of HCV-monoinfected patients, usually 

20 years or more from the time of infection. 

A higher proportion of HIV/HCV-coinfected 

patients are thought to develop cirrhosis, and 

at a faster rate. Once patients have developed 

cirrhosis, approximately 50% will decompensate 

within the first 5 years. Typically, the first 

sign of decompensation is the development 

of ascites. Of patients with cirrhosis, 

approximately 1-4% per year will develop HCC, 

or approximately 20% of cirrhotic patients in 

total. The median survival time from the onset 

of HCC is approximately 5 months, and the 

1-year survival rate is 29%.

S: Subjective

Patients with HCV infection, whether acute 

or chronic, often have no symptoms, and the 

infection is discovered via screening tests or 

on workup of an abnormal liver test result. 

Patients with acute HCV infection typically are 

asymptomatic but may present with symptoms 

such as jaundice, abdominal pain, and malaise. 

If symptoms from acute infection develop, they 

usually do so within 4 weeks after infection 

has occurred. Most patients with chronic 

HCV cannot recall a time when they were 

acutely symptomatic, and HCV is detected 

because of an incidental finding of abnormal 

transaminases or through a screening test.

Ask patients with known chronic HCV 

infection about symptoms that suggest 

complications of HCV, such as cirrhosis, 

decompensated cirrhosis, or hepatocellular 

carcinoma. Additionally, ask patients about any 

risk factors for other liver injury, such as alcohol 

and hepatotoxic drugs, and about drugs whose 

metabolism may be affected by liver disease.

• Fatigue 

• Weight loss 

• Impaired 

concentration 

• Chronic hepatitis B 

• Alcohol intake 

• Substance use

• ARVs that may 

cause hepatotoxicity 

(e.g., didanosine, 

protease inhibitors, 

nevirapine, 

maraviroc)

• Medications with potential for 

hepatotoxicity, or accumulation in persons 

with liver disease (e.g., acetaminophen, 

benzodiazepines, opiates)

O: Objective

Measure vital signs. Calculate body mass index 

(see chapter Initial Physical Examination).

Perform physical examination to include 

evaluation of the following: 

• Head, eyes, ears, nose, and throat (HEENT): 

temporal wasting, icterus 

• Heart and lungs: signs of congestive heart failure 
Hepatitis C Infection | 437

Section 6: Comorbidities, 

Coinfections, and Complications

• Chest: gynecomastia 

• Abdomen: caput medusa, venous 

prominence, distention, signs of ascites, 

hepatomegaly, splenomegaly 

• Extremities: edema 

• Neurologic: alertness, mental status, 

asterixis 

• Skin: jaundice, palmar erythema, petechiae, 

ecchymoses, spider angiomata

P: Plan

Diagnostic Evaluation

Acute HCV infection

After initial exposure, HCV RNA can be 

detected in blood within 1-3 weeks and is 

present at the onset of symptoms. Antibodies to 

HCV can be detected in only 50-70% of patients 

at the onset of symptoms, but in >90% after 3 

months. Within an average of 4-12 weeks, liver 

cell injury is manifested by elevation of serum 

alanine aminotransferase (ALT). It is important 

to understand the timeline of these diagnostic 

tests in order to appropriately diagnose acute 

infection and follow for potential resolution 

versus persistent infection.

In patients with suspected acute HCV infection, 

check HCV antibody (IgG), HCV RNA, and 

ALT immediately and then weekly until the 

ALT has begun to decline and HCV antibody 

has seroconverted to positive status; consider 

checking interleukin-28B (IL28B ) (see below). 

The seroconversion of HCV antibody establishes 

the diagnosis of acute infection. At that point, 

check the HCV RNA every 2-4 weeks for the 

following 3 months. If HCV RNA is still present 

at 3 months, strongly consider prompt initiation 

of treatment for acute HCV. If treatment is not 

initiated and RNA is still present at 6 months 

after infection, the likelihood of spontaneous 

clearance is extremely low, and the patient is 

diagnosed with chronic infection. 

Chronic HCV Infection

The following tests are part of the evaluation of 

HCV infection.

HCV antibodies

All HIV-infected patients should be tested for 

HCV infection with the HCV antibody test. 

Patients with risk factors for HCV infection 

who test negative should be retested at regular 

intervals. A positive HCV antibody test result 

does not establish the diagnosis of active 

HCV infection but is evidence of exposure; 

HCV RNA must be checked (see below). In 

HIV-infected patients, the HCV antibody test 

result can be falsely negative, although this is 

rare. Therefore, if HCV infection is suspected 

in spite of a negative HCV antibody finding 

(e.g., because of a history of high-risk behavior, 

unexplained elevated ALT, or evidence of 

cirrhosis), the HCV RNA should be tested even 

if the HCV antibody result is negative. 

HCV RNA

All patients who test positive for HCV antibody 

should have HCV RNA testing performed. 

As noted above, if patients have negative 

results on HCV antibody tests but persistently 

abnormal transaminases or suspected acute or 

chronic infection, HCV RNA testing should be 

performed.

The definition of chronic HCV infection is 

the presence of HCV RNA 6 months after the 

estimated time of infection. If a patient is HCV 

antibody positive but HCV RNA negative, 

the patient has cleared the HCV and does not 

have chronic HCV infection. False-positive 

HCV antibody results are possible but rare; 

they are more likely to occur in the setting of 

autoimmune disease. 

There are quantitative RNA tests and qualitative 

RNA tests. Although both types of RNA tests 

are highly sensitive and specific, the qualitative 

tests can detect lower levels of viremia than 

the quantitative tests. The choice of RNA test 

can be important. The quantitative RNA tests 

will be reported as a value, with a measured 
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Section 6: Comorbidities, 

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number of international units per milliliter 

(IU/mL). Quantitative tests are useful for 

determining the prognosis of HCV treatment 

and then monitoring while on HCV treatment. 

Qualitative RNA tests will be reported as a 

present or absent value, but without a numerical 

value. They are useful for serial testing during 

suspected acute infection and for determining 

whether spontaneous viral clearance has 

occurred, a sustained virological response has 

occurred during treatment, or a relapse has 

occurred after treatment.

Genotyping

There are six main HCV genotypes, numbered 

1-6. Genotype 1 infections account for 

approximately 75% of HCV infections in the 

United States. In the absence of treatment, HCV 

genotypes are not associated with prognosis 

or progression of liver disease. However, the 

HCV genotype is one of the strongest predictors 

of response to HCV treatment and is a major 

factor in determining the appropriate treatment 

regimen for a patient. HCV genotyping 

should be performed once for all patients with 

detectable HCV RNA; it does not need to be 

repeated. 

Subtyping

HCV genotypes are further divided by 

subtypes. Subtypes are termed 1a, 1b, 2a, 

2b, among others. Subtypes are newly 

being recognized as predictors of treatment 

response, particularly with genotypes 1a and 

1b. Additionally, a polymorphism, Q80K, in 

genotype 1a patients may become clinically 

significant in determining treatment regimens 

using some of the new HCV drugs.

IL28B testing

IL28B is a host genetic polymorphism on 

chromosome 19. Three different IL28B 

polymorphisms exist: C/C, C/T, and T/T. 

Patients with C/C type have higher rates 

of spontaneous clearance after acute HCV 

infection, and much higher response rates to 

interferon-based HCV treatment, whereas 

patients with the C/T or T/T genotype have 

lower rates of spontaneous clearance and 

much lower response rates to treatment 

with interferon. With non-interferon-based 

regimens, the role of IL28B has not yet 

been determined. In regimens containing 

either sofosbuvir (with or without pegylated 

interferon) or simeprevir (with interferon), 

better response rates were seen in patients with 

IL28B CC than in those with non-CC types, but 

the differences were much less dramatic than in 

older regimens. 

Alanine aminotransferase

Monitoring of ALT can be useful to assess acute 

infection, chronic liver inflammation, and 

response to HCV treatment. However, ALT does 

not always correlate with the degree of fibrosis; 

in addition, ALT can be persistently normal 

in 25% of HCV patients, including patients 

with cirrhosis or advanced liver disease. Small 

fluctuations in ALT usually are not clinically 

significant in HCV, though trends can be 

significant during or following HCV treatment.

Additional tests

Check complete blood cell count 

with platelet count, albumin, total 

bilirubin, and prothrombin time.

Test all patients for hepatitis B (HBsAg, antiHBsAb, and anti-HBcAb). For patients with 

a positive HBsAg or a positive anti-HBcAb 

result (absent anti-HBsAb), test for active 

HBV infection (HBV DNA and HBeAg) (see 

chapter Hepatitis B Infection). Patients with 

a negative HBsAg and negative anti-HBsAb 

result should be vaccinated against HBV.

Test for hepatitis A virus (HAV) antibodies (IgG or total). All patients 

with a negative HAV antibody result 

should be vaccinated against HAV.
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Imaging

Ultrasonography can be performed to screen 

for indications of cirrhosis or focal hepatic 

masses. Repeated ultrasound every 6 months 

to screen for HCC is recommended for patients 

with known cirrhosis or advanced fibrosis (stage 

3). For noncirrhotic patients, regular repeated 

ultrasound is not recommended. Computed 

tomography (CT), magnetic resonance imaging 

(MRI), and single-photon emission computed 

tomography (SPECT) are more expensive and 

generally are reserved for further evaluation of 

liver masses detected by ultrasound.

Fibrosis staging 

For any patient with HCV, it is useful to 

determine the degree of fibrosis (scarring) 

in the liver. Fibrosis stage is one of the most 

important pieces of information in determining 

a patient’s need for HCV treatment. Fibrosis 

is scored from F0 to F4, with 0 indicating no 

fibrosis and F4 indicating cirrhosis. 

Tools that may be used to determine the 

severity of chronic liver disease include biopsy, 

imaging, and serologic tests.

For HIV/HCV-coinfected patients, liver 

disease may progress quickly. A biopsy 

or other fibrosis test may be useful in 

determining the stage of disease and in 

planning whether or when to initiate HCV 

treatment. If the test reveals more advanced 

fibrosis or cirrhosis, treatment should be 

considered relatively urgently, using currently 

available therapeutics. Conversely, if the test 

reveals only mild-to-moderate fibrosis, it may 

be preferable to defer treatment and monitor 

the patient, particularly as more effective and 

more tolerable therapies are anticipated to 

become available within the next few years. 

Liver biopsy

Liver biopsy is used to define the degree 

of inflammation (the grade) and degree of 

fibrosis (the stage) to determine the need for 

HCV treatment. Biopsy has been the gold 

standard method, and is the main technique 

used in the United States. Liver biopsy 

carries some risk, primarily from bleeding 

(the risk of significant bleeding or fatality 

is approximately 1/10,000). Patients with 

severe thrombocytopenia or coagulopathy 

should not undergo liver biopsy. 

As HCV therapies evolve and demonstrate 

higher response rates, a biopsy may prove 

less of a determinant of when to initiate 

treatment than in years past. At this time, 

with few directly acting agents (DAA) 

available, biopsy may still be useful for 

determining whether a patient can safely 

wait for more effective regimens. 

Fibroscan

Several noninvasive tests to determine 

fibrosis have been developed. Fibroscan 

(elastography) is a radiology test used to 

assesses liver shear wave speed (expressed 

in meters per second) and equivalent 

stiffness (expressed in kilopascal) in a 

rapid, simple, noninvasive, and painless 

way. The FDA approved the Fibroscan in 

2013. For diagnosing cirrhosis (stage F4), 

the sensitivity and specificity were 87% and 

91%, respectively, whereas for diagnosing 

moderate stages of fibrosis (F2-F3), the 

sensitivity and specificity were 70% and 

84%, respectively. 

Serologic tests 

Several different scoring systems have 

been developed to estimate the degree of 

liver fibrosis based on serum biomarkers 

and other patient factors. For example, 

the Fibrosure test uses the measurements 

of alpha-2-macroglobulin, alpha-2-

globulin (haptoglobin), gammaglobulin, 

apolipoprotein A1, GGT, and total bilirubin, 

as well as the age and sex of the patient. The 

currently available serologic tests are not as 

accurate as liver biopsy in distinguishing 

different stages of fibrosis, and none of these 

have been FDA approved.
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Treatment

Overview of the Treatment of HCV

The goal of HCV treatment is to clear the 

HCV RNA from the bloodstream – making 

the virus undetectable – in order to slow or 

halt inflammation, fibrosis, and progression 

of liver disease, and to reduce risk of cirrhosis 

and HCC. Treatment success is defined as a 

sustained virological response (SVR). SVR 

is achieved when the HCV RNA becomes 

undetectable during treatment and remains 

undetectable after the completion of treatment. 

Originally, SVR was defined as the absence 

of HCV RNA 24 weeks (“SVR24”) after the 

completion of treatment. SVR12 (12 weeks 

after the end of treatment) is 99% predictive 

of SVR24, so recent studies often report this 

as the outcome measure. SVR correlates with 

clinical outcomes such as decreased risk of 

decompensation, decreased risk of HCC, and 

decreased risk of liver-related death. Most 

experts consider SVR to represent “cure” of 

HCV. It is important, however, to remember 

that this is a cure of the chronic viral hepatitis 

infection, but it is not the same as “curing” the 

damage to the liver. 

Pegylated interferon and ribavirin 

The standard of care in the treatment of 

chronic HCV from 2001 to 2011 was the 

combination of pegylated interferon (PEGIFN) alfa-2a and ribavirin, for both HCVmonoinfected and HIV/HCV-coinfected 

patients. Response rates varied by host and 

viral factors, among them HIV coinfection, 

HCV genotype, stage of liver disease, HCV 

viral load, race/ethnicity, and IL28B type. 

Overall, HCV-monoinfected genotype 1 

patients have had SVR rates of 42-46% and 

monoinfected genotype 2/3 patients have 

had SVR rates of 70-80% with PEG-IFN + 

ribavirin. HIV/HCV-coinfected patients have 

had much lower response rates, in the range of 

14-38%. Treatment was limited by these poor 

response rates as well as by multiple complete 

and relative contraindications to interferon 

or ribavirin, multiple side effects of both 

drugs but especially interferon, and the cost 

and complexity of care for both patients and 

providers.

Telaprevir and Boceprevir

In 2011, the HCV protease inhibitors 

boceprevir and telaprevir were approved 

for genotype 1 HCV. These were the first 

direct acting antivirals (DAAs) available 

for treatment of HCV. With use of these 

agents in combination with PEG-IFN and 

ribavirin, treatment response rates in HCVmonoinfected genotype 1 patients were much 

higher than with PEG-IFN + ribavirin alone. 

In HIV/HCV-coinfected patients, smaller 

studies of boceprevir and telaprevir (plus 

PEG-IFN and ribavirin) have shown SVRs in 

the range of 60-75%, substantially higher than 

with standard therapy. These triple-therapy 

regimens, however, are complex and burdened 

with adverse effects and drug interactions.

Sofosbuvir

Sofosbuvir is an HCV polymerase inhibitor 

that was FDA approved in late 2013 for 

treatment of HCV in both HIV-coinfected and 

HCV-monoinfected patients with genotypes 

1-4. It is approved for use with ribavirin alone 

(for genotypes 2 and 3) or with PEG-IFN + 

ribavirin (for most patients with genotypes 

1 and 4), using specific protocols. It also is 

being studied in combination with other HCV 

medications, including in several interferonfree regimens. Use of sofosbuvir-containing 

regimens has resulted in very high SVR rates 

(80% to >90%) with 12 or 24 weeks of therapy, 

in both treatment-experienced and treatmentnaive patients and in cirrhotic patients. Few 

significant drug-drug interactions with ARVs 

have been identified.
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Simeprevir

Simeprevir is a HCV protease inhibitor that 

was FDA approved in late 2013 for treatment 

of genotype 1 HCV, in combination with PEGIFN and ribavirin. Study data have shown SVR 

rates of 82% in treatment-naive genotype 1 

noncirrhotic patients and 58-65% in cirrhotic 

individuals treated with simeprevir + PEGIFN + ribavirin. Among patients with the 

IL28B CC type, 95% achieved SVR. Simeprevir 

also is being studied in interferon-free 

regimens. 

Simeprevir has markedly reduced efficacy in 

patients with the Q80K polymorphism, and 

screening for this is recommended before 

treatment. Simeprevir also has significant 

drug-drug interactions with some ARVs, 

in particular many protease inhibitors, 

nonnucleoside reverse transcriptase inhibitors, 

and the pharmacokinetic enhancer cobicistat.

Expansion of DAAs

In 2014-15, several additional HCV DAAs 

and combinations of DAAs are expected to be 

considered for FDA approval; many have the 

potential to be used in regimens that do not 

include interferon.

Treatment of acute HCV

As mentioned above, in the setting of acute 

HCV infection, RNA should be tested 

repeatedly for 12 weeks from the time of 

infection to ascertain whether spontaneous 

clearance will occur. If RNA is still present at 12 

weeks, treatment should be offered. 

With HIV/HCV-coinfected patients, as with 

HCV-monoinfected patients, early treatment 

of acute HCV infection yields a much higher 

rate of SVR than does treatment of chronic 

HCV infection. In three prospective trials of 

treatment for acute HCV in HIV-coinfected 

patients, using PEG-IFN + ribavirin for 24 or 

48 weeks, the SVR for genotype 1 HCV was 

55-75%, and 100% for genotype 3. By contrast, 

in the largest study of the same regimen for 

chronic HCV treatment in HIV-coinfected 

patients (n = 868), the SVR was about 29% 

for genotype 1 and 62% for genotype 2 or 3. 

Currently, there are no data on the efficacy of 

DAAs to treat acute HCV infection in HIVcoinfected patients. Given the relatively high 

SVR rates that result from treatment of acute 

HCV with pegylated interferon and ribavirin, 

and the absence of data in this setting, it is not 

routinely recommended to use DAAs in acute 

coinfection at this time. 

Treatment of chronic HCV

HIV coinfection is a strong indication for 

treatment of chronic HCV infection, because 

the risk of accelerated fibrosis and cirrhosis is 

higher for coinfected patients. HIV-infected 

patients with low CD4 cell counts should not 

be excluded from HCV treatment on the basis 

of CD4 count alone; this is true particularly for 

patients already on ART. For timing of HCV 

treatment, see “Timing of HCV treatment and 

HIV treatment,” below. Traditional treatment 

of chronic HCV infection in HIV/HCVcoinfected patients with PEG-IFN + ribavirin 

yields lower rates of SVR than does treatment 

of monoinfected patients (see above), but use of 

newer anti-HCV medications has improved the 

treatment outcomes in coinfected patients.

Patients with a high risk of progression to 

cirrhosis, including coinfected patients, 

should receive higher priority for treatment. 

Patients who have developed cirrhosis but 

remain compensated should be treated as soon 

as possible if they otherwise are candidates. 

Patients with decompensated liver disease 

should not receive HCV treatment (the likely 

risks of treatment outweigh potential benefits); 

appropriate candidates can be considered 

for liver transplantation. Many patients 

with minimal fibrosis may be best served by 

deferring treatment, pending availability of 

more effective and tolerable therapy options.

Current guidelines recommend treatment 

of HCV genotype-1-coinfected patients with 

PEG-IFN + ribavirin + an HCV protease 
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Coinfections, and Complications

inhibitor for 48 weeks; because of potential 

drug interactions between HCV protease 

inhibitors and antiretroviral medications, the 

selection of HCV protease inhibitor and ARV 

drugs must be made with great care (see “Drug 

Interactions,” below). HCV genotypes 2-6 

should be treated with PEG-IFN + ribavirin. 

However, as discussed above, the recent FDA 

approval of new DAA agents and the anticipated 

approval of others means that the paradigm 

for HCV treatment is in flux. It is anticipated 

that currently available and anticipated HCV 

drugs will be combined to construct a number 

of effective regimens (including all-oral and 

“interferon-free” regimens) that can be tailored 

to the treatment needs of particular patients. 

Based on current data, the emerging era of 

HCV treatment is expected to be one of higher 

response rates, lower side-effect profiles, and 

perhaps shorter courses of treatment. 

To determine an appropriate treatment 

regimen, consultation with a specialist is 

recommended.

HCV Directly Acting Antivirals: 

Classes and Agents

FDA approved:

Protease Inhibitors (NS3/4a)

• Boceprevir

• Telaprevir

• Simeprevir

Nucleoside Polymerase Inhibitors:

• Sofosbuvir

Classes with Agents under Investigation

• Protease Inhibitors (NS3/4a)

• Nucleoside Polymerase Inhibitors

• NS5A Inhibitors

• Nonnucleoside Polymerase Inhibitors

Drug Interactions

HCV protease inhibitors and other DAAs may 

have significant interactions with certain HIV 

ARVs, particularly with protease inhibitors, 

nonnucleoside reverse transcriptase inhibitors, 

and the pharmacokinetic booster cobicistat. 

Interactions between many DAAs and ARVs 

have not been studied. Known and expected 

drug-drug interactions need to be carefully 

considered before selecting an HCV treatment 

regimen. Consult with HIV, HCV, and clinical 

pharmacy specialists. Table 2 shows potential 

DAA-ARV interactions, based on currently 

available data. 
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Section 6: Comorbidities, 

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Table 2. Characteristics of Directly Acting Agents and Potential Interactions with ARVs

DAA Mechanism

Activity 

Against 

HCV 

Genotype

Barrier to 

Resistance Potential ARV Interactions

Telaprevir NS3/4A 

protease 

inhibitor

1 Low • Contraindicated with all protease inhibitors 

except atazanavir/ritonavir

• Contraindicated with elvitegravir/cobicistat 

• Requires increased dosage when 

administered with efavirenz

• No dosage adjustment when used with 

raltegravir

Boceprevir NS3/4A 

protease 

inhibitor

1 Low • Contraindicated with all protease inhibitors, 

and with efavirenz and elvitegravir/

cobicistat

Simeprevir NS3/4A 

protease 

inhibitor

1, 2, 4, 5, 6 Low • Concentrations decreased by efavirenz, 

and may be decreased by etravirine and 

nevirapine; should not be given with these 

NNRTIs

• Concentrations increased by darunavir/

ritonavir, ritonavir, and cobicistat; should 

not be given with any PI or cobicistat

• No clinically significant interactions with 

raltegravir, rilpivirine, tenofovir

Sofosbuvir NS5B RNA 

polymerase 

inhibitor

1-6 High • Concentrations decreased by tipranavir/

ritonavir

• No known clinically significant interactions 

with other ARVs

Adverse effects of treatment

IFN can cause fatigue, flulike symptoms, 

thrombocytopenia, nausea, depression, hair 

loss, weight changes, and many other potential 

side effects. IFN reduces total white blood cell 

counts, and can cause neutropenia. It also 

decreases CD4 cell counts, although the CD4 

percentage usually does not change. IFN can 

reduce HIV RNA somewhat (by approximately 

0.5 log10 copies/mL).

Ribavirin can cause a hemolytic anemia, 

sore throat, cough, and other side effects. 

Zidovudine and didanosine should be avoided 

with patients taking ribavirin, because of the 

risk of compounded toxicities (anemia with 

zidovudine, neuropathy, lactic acidosis, liver 

toxicity, and pancreatitis with didanosine). 

The side effects of boceprevir and telaprevir 

can include anemia, rash, and altered taste; 

telaprevir also can cause anorectal discomfort. 

The most commonly reported adverse effects 

of sofosbuvir + ribavirin regimens were 

fatigue, headache, insomnia, and nausea. In 

treatment arms containing sofosbuvir + PEGIFN + ribavirin, side effects were similar to 

those reported with PEG-IFN + ribavirin, with 

the exception of increased rates of fatigue and 

nausea. The addition of simeprevir to PEG-IFN 

+ ribavirin resulted in an increased incidence 

of rash including photosensitivity, pruritus, 

nausea, dyspnea, and hyperbilirubinemia. 

HCV treatment should not be given during 

pregnancy, and women receiving HCV 

treatment should avoid pregnancy. IFN 

may cause fetal growth abnormalities, and 
444 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

it is abortifacient in animals. Ribavirin is 

teratogenic, and both women and men must 

use two forms of contraception consistently 

during treatment with ribavirin and for 6 

months after discontinuation of treatment. 

Boceprevir and telaprevir are FDA Pregnancy 

Category B drugs but must be used with 

PEG-IFN and ribavirin, which are not 

recommended.

Timing of HCV treatment and HIV 

treatment

The decision of whether and when to treat 

HCV among people infected with HIV must be 

made on an individual basis. When coinfected 

patients require treatment for both infections, 

some experts begin with HIV treatment based 

on limited data that improved CD4 cell counts 

will enhance the response to HCV therapy, 

and this generally is recommended for patients 

with CD4 counts of <350 cells/μL. With 

patients who do not require ART urgently 

(e.g., because their CD4 counts are very high), 

consideration could be given to treating HCV 

first, with ART delayed until after completion 

of HCV treatment. This strategy is intended to 

simplify treatment and improve the tolerability 

of both therapies, though it brings the risk 

of HIV disease progression during HCV 

treatment. Patients already on ART generally 

should remain on ART throughout the course 

of HCV treatment, though regimens should 

be evaluated for adverse drug interactions 

with HCV drugs (e.g., with boceprevir and 

telaprevir). Consult with an HCV treatment 

expert to determine the appropriateness and 

timing of HCV treatment.

Some patients with HCV will experience 

worsening of hepatic function during ART, 

and liver function should be monitored closely. 

Some ARV medications are hepatotoxic and 

should be avoided or used cautiously; these 

include nevirapine, tipranavir, and high-dose 

ritonavir. Numerous other medications (e.g., 

fluconazole and isoniazid) are hepatotoxic and 

can pose problems for patients with impaired 

liver function.

Other care issues

Acute HAV or HBV infection in persons 

with chronic HCV can cause fulminant liver 

disease. All patients with HCV infection 

should be tested for immunity to HAV and 

HBV; patients who are not immune should be 

vaccinated.

Persons with HCV infection should be 

counseled to avoid exposure to hepatotoxins, 

including alcohol and hepatotoxic medications 

(e.g., acetaminophen in dosages >2 g per day, 

fluconazole, and isoniazid).

As appropriate, all persons with hepatitis C 

should receive individualized counseling on 

ways to reduce the risk of infecting others with 

HCV (including by unprotected sex, by sharing 

of injection drug equipment, other blood 

exposures [e.g., from sharing razors or tattoo 

equipment], and perinatal exposure).
Hepatitis C Infection | 445

Section 6: Comorbidities, 

Coinfections, and Complications

Patient Education

• Advise patients that most people with 

HCV will be asymptomatic for many 

years and may never develop symptoms. 

However, slow progression of fibrosis can 

be happening in the absence of symptoms 

and can progress to cirrhosis, so ongoing 

monitoring is important. 

• Patients can slow the development of fibrosis 

by avoiding alcohol and obesity, as fat in the 

liver can add to the liver damage. 

• As with HIV, patients must avoid passing 

HCV to others. Emphasize the importance 

of safer sex to protect themselves as well as 

their partners. Instruct patients not to share 

toothbrushes, dental appliances, razors, sex 

toys, tattoo equipment, injection equipment, 

or personal care items that may have blood 

on them. 

• Tell patients to discuss HCV with their sex 

partners and suggest that partners be tested 

for HCV. 

• Women who are pregnant or considering 

pregnancy should talk with a specialist in 

HIV and HCV to discuss ways of decreasing 

the risk of perinatal transmission. 

• HCV is not spread by coughing, sneezing, 

hugging, sharing food and water, or other 

casual contact. 

• HAV can cause severe illness, liver damage, 

or even death in people with HCV. Patients 

who are not immune to HAV need to receive 

the two-part hepatitis A vaccination series. 

• HBV can worsen liver function greatly if it 

is acquired in addition to HCV. Patients who 

are not immune to HBV need to receive the 

three-part hepatitis B vaccination series. If 

patients have been vaccinated in the past, 

they should have a blood test to confirm 

immunity. 

• HCV treatment aims to clear the HCV virus 

from the body. That reduces risk of cirrhosis, 

end-stage liver disease, hepatocellular 

carcinoma, and liver-related death. 

• HCV treatment is rapidly evolving and it is 

anticipated that several new regimens will be 

available over the next few years (2014-15). 

Each patient should talk to his or her health 

care provider about whether treatment is 

appropriate. 

• Standard HCV treatment until 2011 

included two drugs used together, pegylated 

interferon-alfa and ribavirin, for all patients 

being treated. In 2011, for genotype 1 

patients, boceprevir or telaprevir became 

available to be used to create a triple-therapy 

regimen. 

• In late 2013, simeprevir was FDA approved 

for use in combination with pegylated 

interferon and ribavirin for genotype 1 and 4 

patients and sofosbuvir was approved for use 

in combination with pegylated interferon 

and ribavirin for genotype 1 patients and for 

use with ribavirin alone (interferon-free) in 

genotype 2 or 3 patients and some genotype 

1 and 4 patients.

• Pegylated interferon can cause many side 

effects, including flulike symptoms, body 

aches, fevers, leukopenia, neuropathy, and 

depression. Most of these adverse effects are 

treatable with medications and resolve after 

therapy is completed.

• Ribavirin can cause side effects including 

rash, sore throat, and anemia.

• Multiple drug interactions are a concern 

for direct acting antivirals, including HIV 

medications. Drug-drug interactions need 

to be carefully considered before starting 

HCV treatment and choosing which HCV 

treatment is right for each patient. 

• It is essential that both men and women who 

are taking ribavirin should use two forms of 

contraception consistently during ribavirin 

therapy and for 6 months after completion of 

treatment.
446 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

References

• Armstrong GL et al. The prevalence of 

hepatitis C virus infection in the United 

States, 1999 through 2002. Ann Int Med 

2006;144:705-14. 

• Carrat F, Bani-Sadr F, Pol S, et al., ANRS 

HCO2 RIBAVIC Study Team. Pegylated 

interferon alfa-2b vs standard interferon 

alfa-2b, plus ribavirin, for chronic hepatitis 

C in HIV-infected patients: a randomized 

controlled trial. JAMA. 2004 Dec 

15;292(23):2909-13. 

• Chung RT, Andersen J, Volberding P, et al. 

Peginterferon Alfa-2a plus ribavirin versus 

interferon alfa-2a plus ribavirin for chronic 

hepatitis C in HIV-coinfected persons. N Engl 

J Med. 2004 Jul 29;351(5):451-9. 

• Dominguez S, Ghosn J, Valantin MA, et al. 

Efficacy of early treatment of acute hepatitis 

C infection with pegylated interferon and 

ribavirin in HIV-infected patients. AIDS. 

2006 May 12;20(8):1157-61. 

• Ly KN, Xing J, Klevens RM, et al. The 

increasing burden of mortality from viral 

hepatitis in the United States between 

1999 and 2007. Ann Intern Med. 2012 Feb 

21;156(4):271-8.

• National Institutes of Health. NIH 

Consensus Development Conference 

Statement: Management of Hepatitis C: 

2002. Available at consensus.nih.gov/2002/

2002HepatitisC2002116html.htm. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013. 

• Rein DB, Smith BD, Wittenborn JS, et al. The 

cost-effectiveness of birth-cohort screening 

for hepatitis C antibody in U.S. primary 

care settings. Ann Intern Med. 2012 Feb 

21;156(4):263-70.

• Torriani FJ, Rodriguez Torres M, Rockstroh 

JK, et al. Peginterferon alfa-2a plus ribavirin 

for chronic hepatitis C virus infection in HIVinfected patients. N Engl J Med. 2004 Jul 

29;351(5):438-50.

• U.S. Preventive Services Task Force. 

Screening for hepatitis C virus infection in 

adults: U.S. Preventive Services Task Force 

recommendation statement. Ann Intern 

Med. 2013 Sep 3;159(5):349-57. 

• van de Laar T, Pybus O, Bruisten S, et al. 

Evidence of a large, international network of 

HCV transmission in HIV-positive men who 

have sex with men. Gastroenterology. 2009 

May;136(5):1609-17.

• Weber R, Sabin CA, Friis-Møller N, et al. 

Liver-related deaths in persons infected with 

the human immunodeficiency virus: the 

D:A:D study. Arch Intern Med. 2006 Aug 

14-28;166(15):1632-41.
Herpes Simplex, Mucocutaneous | 447

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

The patient may complain of eruption of red, 

painful vesicles or ulcers (“fever blisters”) with 

or without an exudate in the mouth, on the lips 

(and occasionally in nares), on the genitals, or 

in the perianal area. The patient may complain 

of burning, tingling, or itching before eruption 

of the lesions. In the genital area, symptoms 

may be nonspecific without any eruption of 

lesions; most HSV type 1 and 2 infections are 

asymptomatic, yet virus still can be shed.

The vesicles will rupture and ulcerate, 

generally crusting over and healing in 

approximately 7-14 days. The lesions 

may be pruritic and are often painful. As 

immunosuppression progresses, the lesions 

may recur more frequently, grow larger or 

coalesce, and become chronic and nonhealing.

Perform a history, asking the patient about 

the symptoms described above, duration, 

associated symptoms, and history of oral or 

genital HSV infection.

O: Objective

Look for grouped vesicular or ulcerative lesions 

on an erythematous base on the mouth, anus, 

or external genitals, or ones that are visible on 

speculum or anoscopic examination. When 

immunosuppression is severe, lesions may 

coalesce into large, painful, and nonhealing 

ulcerations that spread to the skin of the 

thighs, lips, face, or perirectal region. These 

chronic erosive lesions may be confused with a 

chronic bacterial infection or decubitus ulcer, 

and should prompt consideration of acyclovirresistant HSV infection. Recurrent lesions may 

start atypically, first appearing as a fissure, 

pustule, or abrasion.

A: Assessment

A partial differential diagnosis includes the 

following: 

• Oral: Oral aphthous ulcers

• Genital: Chancroid, syphilis, cytomegalovirus, candidiasis, drug-related eruption, 

trauma

P: Plan

Diagnostic Evaluation

A clinical diagnosis of HSV can be made on 

the basis of the patient’s symptoms and clinical 

appearance only if vesicles and constitutional 

symptoms are present, but symptoms and 

signs may be variable, and primary syphilis 

always must be ruled out. Also, HSV-1 (rather 

than HSV-2) is increasingly the cause of 

initial episodes of anogenital herpes. For 

these reasons, current guidelines recommend 

laboratory testing to establish the diagnosis of 

HSV and to determine its type.

Herpes Simplex, Mucocutaneous

Background 

Herpes simplex virus (HSV) types 1 and 2 cause both primary and recurrent oral and genital 

disease. HSV usually appears as a vesicular eruption of the mucous membranes of the oral or 

perioral area, vulva, perianal skin, rectum, and occasionally the inguinal or buttock areas. The 

eruption develops into tender or painful ulcerated lesions that frequently are covered with a clear 

yellow crust. In some patients, however, the typical painful vesicular or ulcerative lesions may be 

absent. Persons with HIV disease and low CD4 cell counts have more frequent recurrences of HSV 

and more extensive ulcerations than do HIV-uninfected people. Persistent HSV eruption (lasting 

>1 month) is an AIDS-indicator diagnosis. HSV facilitates HIV transmission.
448 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

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For cell culture or polymerase chain reaction 

(PCR), obtain a specimen from a freshly 

opened vesicle or the base of an ulcer for 

culture confirmation. Note that lesions that are 

>72 hours old or are beginning to resolve may 

not show HSV in culture. Tzanck smears are 

not sensitive or specific.

PCR is more sensitive for detection of herpes 

DNA in ulcerative lesions, but is more 

expensive to perform and is less widely 

available than viral culture. If virologic 

test results are positive, typing should be 

performed to determine the type of HSV. 

Negative results do not rule out the possibility 

of HSV infection.

If cultures are negative, a sample can be taken 

from a fresh lesion for another culture or for 

PCR. In addition, type-specific serologic tests 

may be useful in the evaluation of symptomatic 

patients in whom a diagnosis of genital HSV 

is not clear. Current sexually transmitted 

disease (STD) guidelines also recommend 

that serologic testing be considered for HIVinfected individuals, for MSM at risk of HIV 

infection, and for those who present for STD 

evaluation if there is no history of past genital 

HSV diagnosis. Glycoprotein G (gG)-based 

serologic assays are recommended, as older 

assays do not reliably differentiate HSV-1 

antibody from HSV-2 antibody.

In any patient who presents with genital, anal, 

or oral ulceration, even if the suspicion of HSV 

is high, syphilis serologic testing (rapid plasma 

reagin [RPR], Venereal Disease Research 

Laboratory [VDRL], enzyme immunoassay 

[EIA], or chemiluminescent immunoassay 

[CIA]) should be done (see chapter Syphilis).

Treatment

Empiric antiviral treatment for new-onset 

suspicious lesions may be initiated in the 

absence of laboratory confirmation, especially 

if symptoms are significant. Dosage reduction 

of the antivirals is required for patients with 

renal impairment.

Note: treatment recommendations reflect 

current CDC/NIH/IDSA opportunistic 

infections guidelines; the CDC STD guideline 

recommendations are slightly different (see 

“References,” below).

Orolabial lesions (5-10 days) or genital 

lesions (5-14 days)

• Valacyclovir 1,000 mg PO BID 

• Famciclovir 500 mg PO BID 

• Acyclovir 400 mg PO TID

Severe mucocutaneous HSV disease

Treat initially with acyclovir 5 mg/kg IV Q8H 

until the lesions have started to regress, then 

an oral HSV antiviral agent (as above) until all 

lesions have healed.

Suppressive therapy

Consider suppressive therapy for patients 

with frequent or severe recurrences and those 

with HSV-2. Treatment may be continued 

indefinitely. If acyclovir is used, its dosage 

may need to be increased to 800 mg BID or 

TID for individuals whose HSV episodes are 

not adequately suppressed by 400 mg BID. 

Suppressive therapy using valacyclovir reduces 

the risk of HSV transmission between HIVuninfected heterosexual partners but the 

extent to which this is true in HIV-infected 

persons is unknown. Effective antiretroviral 

therapy (ART) also may reduce the frequency 

of HSV outbreaks.

• Valacyclovir 500 mg PO BID

• Famciclovir 500 mg PO BID

• Acyclovir 400 mg PO BID
Herpes Simplex, Mucocutaneous | 449

Section 6: Comorbidities, 

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Acyclovir-resistant HSV

The diagnosis of acyclovir-resistant HSV 

should be suspected if lesions fail to 

respond to 7-10 days of standard therapy 

and should be confirmed with culture and 

sensitivities. Cross-resistance to valacyclovir 

and ganciclovir will be present, and crossresistance to famciclovir is likely. The usual 

alternative treatment is foscarnet (40 mg/kg IV 

Q8H); other possibilities include IV cidofovir, 

topical imiquimod, topical trifluridine, and 

topical cidofovir. An infectious disease or HIV 

specialist should be consulted.

HSV During Pregnancy

Acyclovir appears to be safe and effective for 

use by pregnant women and remains the drug 

of choice. Few data are available on the use of 

valacyclovir and famciclovir during pregnancy 

but they appear to be safe.

It is important to avoid peripartum 

transmission of HSV. For women with 

recurrent or new genital HSV late in 

pregnancy, obstetric or infectious disease 

specialists should be consulted, and 

suppressive therapy with valacyclovir or 

acyclovir is recommended. All women should 

be evaluated carefully for symptoms and signs 

of genital HSV at delivery.

Patient Education

• Patients should be told that HSV has no 

cure, but treatment can decrease symptoms 

and recurrences. Treatment also has been 

shown to decrease shedding and HSV 

transmission in HIV-uninfected discordant 

couples, but it has not been studied in 

HIV-infected couples. Outbreaks and viral 

shedding may occur at intervals for the 

rest of their lives but frequency generally 

decreases with age of infection.

• HSV may be spread through kissing (if 

mouth or lips are infected) and sexual 

contact (oral, anal, or vaginal). Most HSV 

is transmitted when no genital lesions are 

present, so it is important that patients 

inform their sex partners of their herpes 

infection before sexual activity. Patients 

must avoid all sexual contact when lesions 

are visible, because a high volume of virus 

is present at those times. Correct use of 

condoms at each sexual encounter reduces 

the risk of HSV transmission.

• All patients with genital HSV should be 

encouraged to inform their partners.

• Episodic treatment is most effective when 

taken early in the outbreak, so patients not 

taking suppressive therapy should keep 

medication on hand and start treatment at 

the first signs of a prodrome or eruption.

• Genital HSV in a pregnant woman around 

the time of delivery can cause severe illness 

in the newborn. Women should inform 

their obstetrician and pediatrician if they 

have a history of HSV or are exposed to 

or infected with HSV during pregnancy. 

Pregnant women who do not have HSV 

should avoid sexual practices that facilitate 

HSV transmission in the third trimester 

with partners who have HSV, and men who 

have HSV should avoid sexual practices that 

facilitate HSV transmission with pregnant 

women in their third trimester who do not 

have HSV.
450 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

References

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 

17; 59 (No. RR-12):1-110. Available at 

www.cdc.gov/STD/treatment/2010. 

Accessed December 1, 2013.

• Cernik C, Gallina K, Brodell RT. The 

treatment of herpes simplex infections: an 

evidence-based review. Arch Intern Med. 

2008 Jun 9;168(11):1137-44.

• Lingappa JR, Celum C. Clinical and 

therapeutic issues for herpes simplex virus-2 

and HIV co-infection. Drugs. 2007;67(2):155-

74.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Strick LB, Wald A, Celum C. Management 

of herpes simplex virus type 2 infection 

in HIV type 1-infected persons. Clin 

Infect Dis. 2006 Aug 1;43(3):347-56.

• Wald A, Langenberg AG, Krantz E, et al. The 

relationship between condom use and herpes 

simplex virus acquisition. Ann Intern Med. 

2005 Nov 15;143(10):707-13.
Herpes Zoster/Shingles | 451

Section 6: Comorbidities, 

Coinfections, and Complications

Herpes Zoster/Shingles

Background

Shingles is a skin or mucosal infection caused by the varicella-zoster virus (VZV) that occurs along 

a dermatome and represents a reactivation of varicella (chickenpox). Zoster is common in patients 

with HIV infection, including apparently healthy individuals before the onset of other HIV-related 

symptoms. The incidence may be higher among patients with low CD4 cell counts and during the 4 

months after initiating potent antiretroviral therapy.

Zoster may be particularly painful or necrotic in HIV-infected individuals. Disseminated 

infection, defined as outbreaks with >20 vesicles outside the primary and immediately adjacent 

dermatomes, usually involves the skin and the visceral organs. Neurologic complications of zoster 

include encephalitis, aseptic meningitis, cranial nerve palsies, optic neuritis, transverse myelitis, 

and vasculitic stroke.

S: Subjective

The patient complains of painful skin 

blisters or ulcerations along one side of the 

face or body. Loss of vision may accompany 

the appearance of facial lesions. Pain in 

a dermatomal distribution may precede 

the appearance of lesions by many days 

(prodrome).

Assess the following during the history:

• Duration of pain or blisters (average of 2-3 

weeks if untreated)

• Location of pain or blisters; severity of pain

• History of chickenpox (usually in childhood)

O: Objective

Perform a skin and neurologic examination to 

include the following:

• Vesicular lesions with erythematous bases in 

a dermatomal distribution; may be bullous 

or hemorrhagic

• Necrotic lesions; may persist 

for as long as 6 weeks

• Dermatomal scarring (particularly in darkskinned individuals)

• Lesions in the eye area or tip of nose, 

along the trigeminal nerve; these represent 

ophthalmic nerve involvement, which 

requires immediate evaluation and IV 

treatment (see below)

A: Assessment

• Rule out other causes of vesicular skin 

eruptions (e.g., herpes simplex virus, severe 

drug reactions).

• Assess contact exposures (see below).

P: Plan

Diagnostic Evaluation

The diagnosis usually is clinical and is 

based on the characteristic appearance and 

distribution of lesions. If the diagnosis is 

uncertain, perform viral cultures or direct 

fluorescent antigen or polymerase chain 

reaction test of samples from a freshly opened 

vesicle or biopsy from the border of a lesion.

Treatment

• Treatment ideally should begin within 72 

hours of an outbreak or while lesions are not 

yet fully crusted and should be continued for 

7-10 days. Early treatment may attenuate a 

herpes zoster attack. 
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Localized dermatomal zoster

• Preferred therapy

• Valacyclovir 1 g PO TID

• Famciclovir 500 mg PO TID

• Alternative therapy

• Acyclovir 800 mg PO 5 times daily

• Dosage reductions of these drugs are 

required for patients with renal impairment.

• If new blisters are still appearing at 

the end of treatment, repeat course of 

PO therapy or consider IV treatment. 

Adjunctive corticosteroids aimed at 

preventing postherpetic neuralgia are not 

recommended.

• Consult an ophthalmologist immediately if 

lesions appear in the eye area or on the tip 

of the nose, or if the patient complains of 

visual disturbances, because VZV-related 

retinal necrosis can cause blindness. Because 

of the rapid progression associated with this 

diagnosis, hospitalization for administration 

of IV acyclovir and possibly foscarnet is 

recommended.

• VZV from zoster lesions is contagious, and 

contact or airborne spread from vesicle 

fluid may cause chickenpox in nonimmune 

people. If a zoster patient’s household 

includes a pregnant woman (HIV infected 

or uninfected) or an HIV-infected child, 

consult with a specialist immediately 

for advice on management of exposed 

household members. (See “Postcontact 

Chickenpox Prevention,” below.)

• Give analgesics for pain; narcotics may be 

required.

• Postherpetic neuralgia (PHN) is a common 

sequela of zoster. Antiviral therapy may 

reduce the risk of PHN, but PHN often 

requires special treatment for pain control. 

Treatment options include: 

• Nortriptyline 10-25 mg. To be taken at 

bedtime and increased by 25 mg every 3-5 

days to a maximum dosage of 150 mg QD 

until pain is controlled, assuming adverse 

effects remain tolerable. Other tricyclics 

may be used.

• Gabapentin 100-300 mg PO BID; this 

may be increased by 300 mg every 3 days 

until reaching 3,600 mg total daily dosage. 

Adjust gabapentin dosage in patients with 

kidney disease.

• Pregabalin 75 mg BID (or 50 mg TID) 

in patients with estimated creatinine 

clearance of >60 mL/minute; this may be 

increased to 300 mg total daily dosage 

over the course of a week as needed.

• Lidocaine 5% patches provide good local 

relief with minimal systemic absorption. 

Up to 3 patches may be applied 

simultaneously to the affected area for up 

to 12 hours in a 24-hour period.

• Capsaicin cream may be applied to the 

affected area TID or QID. Patients should 

wear gloves to apply the cream and wash 

their hands with soap and water afterward.

• Sustained-release opiates may be required.

(See chapter Pain Syndrome and Peripheral 

Neuropathy for more options and specific 

recommendations.)

Severe or unresponsive cases

• IV acyclovir may be indicated if: 

• The patient is severely 

immunocompromised

• The ophthalmic branch of the trigeminal 

nerve is affected (as noted above)

• Dissemination has occurred; visceral 

disease is suspected

• Lesions are extensive

• Lesions are not responsive to oral therapy

• Pain is intractable in the setting of active 

skin lesions

• The usual adult dosage is 10-15 mg/kg Q8H 

for 7-14 days based on clinical response; can 

switch to oral therapy when signs/symptoms 

are improving. Dosage reduction is required 
Herpes Zoster/Shingles | 453

Section 6: Comorbidities, 

Coinfections, and Complications

for patients with renal impairment. Refer to 

an infectious disease specialist.

• Acyclovir resistance may occur in patients 

previously treated with acyclovir or related 

drugs, and foscarnet may be required for 

effective treatment. Resistance should be 

suspected if lesions are not resolving after 10 

days of therapy or if they develop an atypical 

appearance. Such lesions should be cultured 

and drug sensitivities should be obtained.

Prevention

The vaccine for prevention of herpes zoster 

(Zostavax) has not been recommended by 

national guidelines for use in persons with 

HIV infection. Limited data in HIV-infected 

individuals with CD4 counts of >200 cells/

μL show safety and immunogenicity. The 

zoster vaccination may be considered for 

select patients >50 years of age with CD4 

counts of >200 cells/μL who have evidence 

of varicella immunity (if they have no 

evidence of varicella immunity, give the 

primary varicella vaccination). The vaccine 

is contraindicated in persons with AIDS 

or clinical manifestations of HIV. 

Postcontact Chickenpox Prevention

All HIV-infected susceptible persons, 

including pregnant women, who have close 

contact with a patient who has chickenpox or 

zoster must be treated to prevent chickenpox. 

Exposed individuals who have no history 

of chickenpox or shingles or no detectable 

antibody against VZV should be administered 

varicella-zoster immune globulin (VariZIG) 

as soon as possible, but at least within 10 

days after contact. Some experts also would 

recommend varicella vaccination for exposed 

patients with CD4 counts of ≥200 cells/

μL, or preemptive treatment with acyclovir 

or valacyclovir; these approaches have not 

been studied in HIV-infected persons. Even 

immunocompetent adults with primary VZV 

(chickenpox) can develop viral dissemination 

to the visceral organs. HIV-infected patients 

may develop encephalitis, pneumonia, or 

polyradiculopathy during primary varicella 

(chickenpox) or reactivated zoster (shingles).

Patient Education

• Patients should bathe the skin lesions in mild soap 

and water. For necrotic lesions, use warm, moist 

compresses 2-3 times a day to remove debris.

• Antibiotic ointments may help 

prevent secondary infection and 

keep dressings from sticking.

• Advise patients to take their medications 

as directed, and to contact the clinic if 

symptoms worsen.
454 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

References

• ACIP Adult Immunization Work Group, 

Bridges CB, Woods L, et al.; Centers for 

Disease Control and Prevention. Advisory 

Committee on Immunization Practices 

(ACIP) recommended immunization schedule 

for adults aged 19 years and older – United 

States, 2013. MMWR Surveill Summ. 2013 

Feb 1;62 Suppl 1:9-19.

• Benson C, Hua L, Andersen J, et al. Zostavax 

is generally safe and immunogenic in HIV+ 

adults virologically suppressed on ART: 

results of a phase 2, randomized, doubleblind, placebo-controlled trial. In: Program 

and abstracts of the 12th Conference on 

Retroviruses and Opportunistic Infections; 

March 5-8, 2012; Seattle. Abstract 96.

• Fishman S. Post-Herpetic Neuralgia (Oxford 

American Pocket Notes). Oxford University 

Press; 2008.

• Gebo KA, Kalyani R, Moore RD, et al. The 

incidence of, risk factors for, and sequelae 

of herpes zoster among HIV patients in the 

highly active antiretroviral therapy era. J 

Acquir Immune Defic Syndr. 2005 Oct 

1;40(2):169-74.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of 

Health, and the HIV Medicine Association 

of theInfectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.
Histoplasmosis | 455

Section 6: Comorbidities, 

Coinfections, and Complications

S: Subjective

Histoplasmosis may be difficult to diagnose 

because the symptoms are nonspecific. In 

addition, clinicians may not consider this 

diagnosis in low-prevalence areas.

Patients may experience fever, weight loss, 

fatigue, cough, and shortness of breath. They 

also may develop skin lesions, adenopathy, 

central nervous system (CNS) changes, 

oropharyngeal ulcers, nausea, diarrhea, and 

abdominal pain. Symptoms usually begin 

several weeks before patients present for care. 

On occasion, histoplasmosis presents abruptly 

as a sepsis-like syndrome.

Ask the patient about possible exposures, but 

note that absence of reported exposures does 

not rule out histoplasmosis. The following are 

associated with significant risk of exposure:

• Residence or travel in endemic areas (see 

above); in the United States, particularly the 

Ohio and Mississippi River Valleys

• Occupational history of farming or 

construction/remodeling

• Hobbies that involve contact with caves, bird 

roosts or nests, or farm areas

• Contact with soil having a high organic 

content and undisturbed bird droppings, 

such as that found around old chicken coops 

and bird roosts

Histoplasmosis

Background

Histoplasmosis is caused by Histoplasma capsulatum, a fungus that thrives in soil contaminated 

by droppings from birds and bats. In the United States, H. capsulatum is found most often along 

the Ohio and Mississippi River Valleys, in the central, mid-Atlantic, and south-central states, and 

from Alabama to southwest Texas. In highly prevalent areas, such as Indianapolis and Kansas City, 

more than 80% of the population has been exposed to Histoplasma through inhalation of airborne 

infectious elements. Histoplasmosis also is found in the Canadian provinces of Quebec and 

Ontario, Puerto Rico, Mexico, Central and South America, Africa, East Asia, and Australia.

The initial infection in most cases either produces no symptoms or manifests only as a mild flulike 

illness. However, immunosuppressed individuals may develop disseminated disease. Progressive 

disseminated histoplasmosis often represents a reactivation of latent infection, occurs late in the 

course of HIV disease (the CD4 count usually is <150 cells/μL), and is an AIDS-defining illness. 

Pulmonary histoplasmosis (without dissemination) may occur in people with higher CD4 counts. 

Within endemic areas, histoplasmosis accounts for 5% of opportunistic infections among patients 

with AIDS. In hyperendemic areas, the prevalence of histoplasmosis may reach 25% among AIDS 

patients. The incidence of histoplasmosis in the United States has declined with the use of effective 

antiretroviral therapy (ART).

Common clinical features that may be associated with histoplasmosis are shown in Table 1.
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Table 1. Common Clinical Manifestations of Histoplasmosis

Symptom 

Group

Percentage of 

Cases Examples

Constitutional 95% • Weight loss 

• Fever

• Fatigue

Gastrointestinal >10% • Splenomegaly 

• Hepatomegaly

• Diarrhea

• Abdominal pain

Respiratory 50-60% • Pneumonia • Pneumonitis

Hematologic >50% • Anemia 

• Leukopenia 

• Thrombocytopenia

Neurologic 15-20% • Meningitis, cerebritis 

• Encephalopathy 

• Focal parenchymal lesions

Septic 10-20% • Hypotension 

• Respiratory insufficiency 

• Renal or hepatic failure 

• Disseminated intravascular 

coagulopathy 

• High fever

Dermatologic <10% • Follicular, pustular, maculopapular, or erythematous lesions

O: Objective

Measure vital signs and document fever.

Perform a complete physical examination, with 

special attention to the lymph nodes, lungs, 

abdomen, skin, and neurologic system.

Common findings include enlargement of the 

liver, spleen, and lymph nodes. Skin lesions 

and oropharyngeal ulcers may be seen. 

A: Assessment

A partial differential diagnosis includes the 

following:

• Other deep-seated fungal infections, such as 

cryptococcosis and coccidioidomycosis

• Mycobacterial disease (Mycobacterium 

tuberculosis or Mycobacterium avium

complex)

• Pneumocystis pneumonia

• Lymphoma

P: Plan

Diagnostic Evaluation

• The H. capsulatum antigen test is sensitive 

and specific. The test is most sensitive 

for urine samples (>95% in disseminated 

disease), but can be used on serum (>85% 

sensitive in disseminated disease), bronchial 

fluids, or cerebrospinal fluid (CSF) 

specimens. Results may be obtained in a few 

days’ time. Urine antigen levels can be used 

to monitor the response to therapy.

• Cultures of blood, bone marrow, and 

specimens from other sources have 

reasonable sensitivity (about 85%), but 

obtaining results may take several weeks.

• Wright stain of the buffy coat of a blood 

specimen may reveal intracellular 

organisms.

• Biopsies of lymph nodes, liver, cutaneous 

lesions, and lungs may be diagnostic in 

up to 50% of cases; bone marrow can be 

stained with methenamine silver to show the 

organism within macrophages.
Histoplasmosis | 457

Section 6: Comorbidities, 

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• Meningitis can be challenging to diagnose. 

Diagnostically, Histoplasma antigen or antiHistoplasma antibodies can be detected in 

CSF in up to 70% of cases, whereas results 

for cultures are often negative. Nonspecific 

findings in the CSF include elevated protein 

and low glucose as well as a lymphocytic 

pleocytosis. A diagnosis of Histoplasma

meningitis should be considered if the 

patient has known disseminated disease and 

other more common etiologies of meningitis 

have been ruled out.

• Lactate dehydrogenase (LDH) and ferritin, 

although not specific, may be markedly 

elevated in disseminated disease.

• Complete blood count and chemistry panels 

may show pancytopenia, elevated creatinine, 

or abnormal liver function.

Treatment

Treatment consists of two phases: induction 

and chronic maintenance. Treatment should 

be continued for at least 12 months.

Severe disseminated histoplasmosis

Severe infection requires IV induction therapy 

with a lipid formulation of amphotericin; 

standard amphotericin is less effective and is 

associated with more adverse effects, but may 

be used as an alternative.

• Induction therapy (≥2 weeks or clinically 

improved):

• Preferred: Liposomal amphotericin B 

lipid formulation 3 mg/kg IV QD

• Alternatives: Amphotericin B lipid 

complex or amphotericin B cholesteryl 

sulfate complex 3 mg/kg IV QD 

• Maintenance therapy: After ≥2 weeks of 

therapy or improvement of the patient’s 

clinical status, therapy may be switched to 

itraconazole 200 mg PO TID for 3 days, then 

BID for at least 12 months of therapy. Liquid 

formulation of itraconazole is preferred.

Histoplasma meningitis

Amphotericin B must be used because itraconazole has poor penetration into the CNS:

• Induction therapy: Liposomal amphotericin 

B 5 mg/kg QD for 4-6 weeks

• Maintenance therapy: Itraconazole 200 mg 

PO BID or TID for ≥12 months and until 

abnormal CSF findings resolve

Mild to moderate disseminated 

histoplasmosis without CNS 

involvement

• Induction and maintenance therapy: 

Itraconazole 200 mg PO TID for 3 days 

followed by itraconazole 200 mg BID for ≥12 

months; liquid formulation of itraconazole 

is preferred

Pulmonary histoplasmosis in patients 

with CD4 counts of >300 cells/μL

Manage as for non-immunocompromised 

patients.

See “Potential ARV Interactions,” below, 

regarding azoles.

Long-term suppressive therapy

Long-term therapy must be given to prevent 

relapse after 12 months of initial treatment; 

preferred therapy consists of itraconazole 200 

mg PO QD. Fluconazole 800 mg QD is less 

effective but can be used as an alternative for 

patients who cannot tolerate or cannot obtain 

itraconazole. Voriconazole and posaconazole 

appear to be effective. (See “Potential ARV 

Interactions,” below, regarding azoles.)

Few data support the discontinuation of 

chronic maintenance therapy. One small 

study sponsored by the AIDS Clinical Trials 

Group demonstrated safety in discontinuing 

suppressive itraconazole therapy for patients 

who met the following criteria: had completed 

>1 year of itraconazole therapy, negative 

blood cultures, Histoplasma serum antigen 

<2 units, CD4 counts >150 cells/μL, and 

had been on ART for ≥6 months. Therefore, 

per U.S. Centers for Disease Control and 

Prevention guidelines, discontinuing 
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Section 6: Comorbidities, 

Coinfections, and Complications

suppressive therapy for any patient who 

meets these criteria can be considered. 

Suppressive therapy should be restarted if 

the CD4 count drops to <150 cells/μL.

Monitoring and relapse

Monitor either serum or urine Histoplasma

antigen, as well as clinical status, to evaluate 

response to therapy; a rise in the antigen 

level suggests relapse of histoplasmosis. 

A drug level of itraconazole should be 

measured at least once after 2 weeks of 

therapy as absorption of this drug can 

be erratic and interactions are expected 

between itraconazole and some ARVs.

In cases of treatment failure, both 

voriconazole and posaconazole have 

been successful in a few case reports; if 

treatment failure is suspected, an infectious 

disease specialist should be consulted.

Primary Prophylaxis

Currently, there are no studies that prove any 

survival benefit in using primary prophylaxis; 

however, prophylaxis with itraconazole 200 

mg PO QD can be considered for high-risk 

patients whose CD4 counts are <150 cells/μL 

(e.g., those with occupational exposure and 

those who reside in hyperendemic regions). 

HIV-infected patients with CD4 counts 

of <150 cells/μL should be educated about 

avoiding exposure.

Primary prophylaxis can be discontinued 

if the CD4 count remains ≥150 cells/

μL for 6 months on effective ART; 

prophylaxis should be restarted if the 

CD4 count drops to <150 cells/μL. 

Potential ARV Interactions

There may be significant drug-drug 

interactions between certain systemic 

antifungals, (particularly itraconazole, 

voriconazole, and posaconazole) and 

ritonavir-boosted protease inhibitors 

(PIs), nonnucleoside reverse transcriptase 

inhibitors (NNRTIs), elvitegravir/cobicistat, 

or maraviroc. Some combinations are 

contraindicated and others require dosage 

adjustment of the ARV, the antifungal, or 

both, and/or monitoring of drug levels. 

Check for adverse drug interactions before 

prescribing. See relevant tables in the U.S. 

Department of Health and Human Services 

Guidelines for the Use of Antiretroviral Agents 

in HIV-1-Infected Adults and Adolescents, or 

consult with an expert. 

Patient Education

• Histoplasmosis is not transmitted from 

person to person, so isolation is not 

necessary.

• Patients should take all their medications 

exactly as prescribed by their health care 

provider.

• Even with maintenance therapy, relapses can 

occur. Patients should contact their provider 

immediately if symptoms worsen.

• Persons with histoplasmosis should be 

treated with antiretroviral therapy.

• The azoles may cause birth defects. Women 

who are taking azole medications should 

avoid pregnancy. In addition, itraconazole 

and other azoles interact with some 

antiretrovirals and other medications; 

patients should tell their provider if they 

begin taking any new medications while 

receiving itraconazole.
Histoplasmosis | 459

Section 6: Comorbidities, 

Coinfections, and Complications

References

• Deepe GS Jr. Histoplasma Capsulatum. 

In: Mandell G, Bennett JE, Dolin R, eds. 

Principles and Practice of Infectious Diseases, 

6th ed. Philadelphia: Elsevier; 2005:3012-26.

• Goldman M, Zackin R, Fichtenbaum CJ, et 

al. Safety of discontinuation of maintenance 

therapy for disseminated histoplasmosis 

after immunologic response to antiretroviral 

therapy. Clin Infect Dis. 2004 May 

15;38(10):1485-9.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Wheat J. Histoplasmosis. In: Dolin R, 

Masur H, Saag M, eds. AIDS Therapy, 2nd 

Edition. Philadelphia: Churchill Livingstone; 

2003:511-521.

• Wheat J, Sarosi G, McKinsey D, et al. 

Practice guidelines for the management 

of patients with histoplasmosis. Infectious 

Diseases Society of America. Clin Infect Dis. 

2000 Apr;30(4):688-95.

Kaposi Sarcoma | 461

Section 6: Comorbidities, 

Coinfections, and Complications

Kaposi Sarcoma

Background

Kaposi sarcoma (KS) is an endothelial neoplasm that usually occurs as skin or oral lesions but may 

involve the internal organs. It is the most common AIDS-associated neoplasm and is an AIDSdefining disease. AIDS-associated KS is one of four types of KS, along with classic, endemic, and 

organ transplant-associated KS. Although the types vary in epidemiology and clinical presentation, 

all are associated with human herpesvirus type 8 (HHV-8), also known as KS-associated 

herpesvirus. The clinical manifestations of AIDS-associated KS (sometimes called epidemic KS) 

range in severity from mild to life-threatening. The progression of disease may be rapid or slow, but 

the overall prognosis is poor in the absence of treatment. The skin lesions of KS, even when they do 

not cause medical morbidity, may cause significant disfigurement and emotional distress.

AIDS-associated KS usually occurs in HIV-infected persons with advanced immunosuppression 

(CD4 count of <200 cells/μL), but may occur at any CD4 count. In the United States and Europe, 

KS occurs in all HIV risk groups, but most frequently among men who have sex with men (MSM). 

Risk factors for MSM include multiple sexual partners and a history of sexually transmitted 

diseases (STDs); risk factors for other groups have not been clearly identified. The transmission 

of HHV-8 is not well understood. Although experts believe HHV-8 is transmitted sexually, it 

apparently also passes from person to person by other routes.

The incidence of KS in resource-abundant countries has declined markedly since the early 1990s, 

in part because of the widespread availability of effective combination antiretroviral therapy 

(ART). In parts of sub-Saharan Africa, where endemic KS has long existed in people with normal 

immune function, the incidence of KS has risen sharply in people with HIV. ART appears to 

be effective in reducing the risk of AIDS-associated KS, particularly when initiated before the 

development of advanced immunosuppression.

S: Subjective

Skin Lesions

The cutaneous presentation of KS is the most 

common, occurring in 95% of cases. Lesions 

may occur anywhere on the skin. Common 

sites include the face (particularly under the 

eyes and on the tip of the nose), behind the 

ears, and on the extremities and torso. Lesions 

may be macules, papules, plaques, or nodules. 

At first, the lesions are small and may be flat. 

Their color may vary from pink or red to 

purple or brown-black (the latter particularly 

in dark-skinned individuals), and they are 

nonblanching, nonpruritic, and painless 

(lesions may become painful in the setting 

of immune reconstitution inflammatory 

syndrome [IRIS] associated with KS). Over 

time, the lesions often increase in size and 

number, darken, and rise from the surface; 

they may progress to tumor plaques (e.g., on 

the thighs or soles of the feet), or to exophytic 

tumor masses, which can cause bleeding, 

necrosis, and extreme pain.

Oral Lesions

Oral lesions may be flat or nodular and are red 

or purplish. They usually appear on the hard 

palate, but may develop on the soft palate, 

gums, tongue, and elsewhere. Oral lesions, 

if extensive, may cause tooth loss, pain, and 

ulceration.
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Section 6: Comorbidities, 

Coinfections, and Complications

Lymphedema

Lymphedema associated with KS usually 

appears in patients with visible cutaneous 

lesions, and edema may be out of proportion 

to the extent of visible lesions. Lymphedema 

also may occur in patients with no visible skin 

lesions. Common sites include the face, neck, 

external genitals, and lower extremities. A 

contiguous area of skin usually is involved. 

Lymph nodes may be enlarged.

Pulmonary KS

Pulmonary KS may be asymptomatic or cause 

intractable cough, bronchospasm, hemoptysis, 

chest pain, and dyspnea. The patient may 

exhibit difficulty breathing, bronchospasm, 

cough (sometimes with hemoptysis), and 

hypoxemia.

Gastrointestinal KS

Gastrointestinal KS may arise anywhere in 

the gastrointestinal tract. Patients usually are 

asymptomatic except in cases of intestinal 

obstruction or bleeding. KS may cause 

protein-losing enteropathy. Visceral disease 

is uncommon in the absence of extensive 

cutaneous disease.

During the history, ask about the symptoms 

noted above and associated characteristics, 

including the following:

• Duration of lesions

• Pain

• Frequency of new lesions

• Respiratory or gastrointestinal symptoms

• Edema or swelling

O: Objective

Physical Examination

Perform a careful physical examination, with 

particular attention to the following:

• Vital signs

• Skin (examine the entire skin surface 

including the scalp and conjunctiva)

• Oropharynx

• Extremities and external genitals (look for 

lesions, edema)

• Lymph nodes

Examine the lungs, abdomen, rectum, and 

other systems as indicated.

A: Assessment

The partial differential diagnosis depends on 

the type of symptoms present.

For cutaneous, oral, and lymph node 

presentations, consider the following:

• Bacillary angiomatosis

• Lymphoma

• Dermatofibromas

• Bacterial or fungal skin infections

• Venous stasis

For pulmonary symptoms, consider the 

following:

• Pneumocystis jiroveci pneumonia (PCP)

• Cytomegalovirus (CMV) pneumonia

• Pulmonary lymphoma (rare)

P: Plan

Diagnostic Evaluation

For cutaneous or oral KS, the diagnosis often 

is suggested by the appearance of skin or 

mucous membrane lesions. Biopsy of a lesion 

(or a suspect lymph node) is required to 

verify the diagnosis and rule out infectious or 

other neoplastic causes. Biopsy is particularly 
Kaposi Sarcoma | 463

Section 6: Comorbidities, 

Coinfections, and Complications

important if the lesions are unusual in 

appearance or if the patient has systemic or 

atypical symptoms.

If respiratory symptoms are present, obtain 

chest X-rays or computed tomography (CT) 

studies. The chest X-ray typically shows diffuse 

interstitial infiltrates, often accompanied by 

nodules or pleural effusion. Radiographic 

findings may be suggestive of KS, but cannot 

provide a definitive diagnosis. Bronchoscopy 

with visualization of characteristic 

endobronchial lesions usually is adequate for 

diagnosis.

For patients with gastrointestinal symptoms 

and suspected KS, perform endoscopy.

If the patient has fever or respiratory, 

gastrointestinal, or constitutional symptoms, 

evaluate for other infectious and malignant 

causes (e.g., by culture or biopsy) as suggested 

by the history and physical examination.

Treatment

Treatment of KS is not considered curative, 

and no single therapy is completely efficacious. 

ART is a key component of the treatment of KS 

and should be initiated promptly (or optimized 

to achieve complete HIV RNA suppression) for 

all persons with KS (for further information, 

see chapter Antiretroviral Therapy). KS often 

regresses and sometimes resolves in patients 

treated with effective ART. Some data suggest 

that protease inhibitors may have an anti-KS 

effect; however, non-PI-containing regimens 

also lead to KS regression; the role of specific 

antiretroviral agents beyond HIV control in 

KS remains unclear.

KS-associated IRIS has been described, and 

patients may experience painful enlarged 

lesions or progression of KS lesions during the 

first months of ART; they should be advised of 

this possibility.

Specific treatment of KS depends on 

various factors such as the number, extent, 

severity, and location of lesions; cosmetic 

considerations; and presence of visceral 

involvement. The goals of therapy may vary 

according to the clinical presentation and may 

include controlling symptoms, improving 

cosmetic appearance, reducing edema, 

eliminating pain, and clearing lesions. ART 

alone may be effective in mild-to-moderate 

KS. Local treatment (in conjunction with 

ART) may be given to patients who have 

bothersome symptoms from a few small 

lesions. Systemic therapy (in conjunction 

with ART) is needed for more extensive or 

more severe disease, including symptomatic 

visceral disease, widespread skin involvement, 

significant edema, and rapidly progressive KS. 

Consultation with a KS-experienced oncologist 

or dermatologist is recommended.

Local treatment of limited disease

Options for local treatment of limited disease 

include the following:

• ART with observation for response (limited, 

stable cutaneous disease may require no 

specific treatment)

• Intralesional chemotherapy (e.g., 

vinblastine)

• Radiation therapy, for localized or facial 

lesions (may cause mucositis when used for 

oropharyngeal lesions)

• Cryotherapy

• Laser therapy

Treatment of extensive or rapidly 

progressing disease

Extensive or rapidly progressing disease may 

include lymphedema, intraoral or pharyngeal 

disease that interferes with eating, painful or 

bulky lesions, and symptomatic pulmonary or 

visceral disease. Options for treatment include 

the following:

• Intralesional chemotherapy (e.g., 

vinblastine)

• Systemic chemotherapy (e.g., liposomal 

formulations of doxorubicin or 

daunorubicin, or paclitaxel)
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Section 6: Comorbidities, 

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• Numerous experimental agents are under 

evaluation

• Consultation with an oncologist is 

recommended for optimal treatment of 

extensive disease

Patient Education

• KS often responds to treatment. Educate 

patients that ART is a cornerstone of 

treatment; encourage them to start and 

adhere to ART.

• Swollen or edematous lesions increase the 

risk of cellulitis, whereupon lesions can 

become infected and progress rapidly. 

Advise patients to avoid injuring swollen 

or edematous lesions, to keep them clean, 

and to call their health care provider if 

lesions appear to be spreading or if swelling 

worsens.

• Advise patients to return to the clinic if 

respiratory or gastrointestinal symptoms 

develop.

• Patients may use cosmetic preparations to 

cover facial lesions. Refer patients to support 

groups or counseling services if they are 

having difficulty coping with their physical 

appearance.

References

• Gill J, Bourboulia D, Wilkinson J, et al. 

Prospective study of the effects of antiretroviral 

therapy on Kaposi sarcoma-associated 

herpesvirus infection in patients with and 

without Kaposi sarcoma. J Acquir Immune 

Defic Syndr. 2002 Dec 1;31(4):384-90.

• Jones JL, Hanson DL, Dworkin MS, et al. 

Incidence and trends in Kaposi’s sarcoma 

in the era of effective antiretroviral therapy. 

J Acquir Immune Defic Syndr. 2000 Jul 

1;24(3):270-4.

• Martinez V, Caumes E, Gambotti L, et al. 

Remission from Kaposi’s sarcoma on HAART 

is associated with suppression of HIV 

replication and is independent of protease 

inhibitor therapy. Br J Cancer. 2006 Apr 

10;94(7):1000-6.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Paparizos VA, Kyriakis KP, 

Papastamopoulos V, et al. Response of 

AIDS-associated Kaposi sarcoma to highly 

active antiretroviral therapy alone. J Acquir 

Immune Defic Syndr. 2002 Jun 1;30(2):257-8.
Molluscum Contagiosum | 465

Section 6: Comorbidities, 

Coinfections, and Complications

Molluscum Contagiosum

Background

Molluscum contagiosum is a viral infection of human epidermal keratinocytes, caused by a 

double-stranded DNA virus of the Poxviridae family. Molluscum appears as papules or nodules 

and sometimes is called “molluscum warts.” It is seen most frequently in HIV-uninfected 

children (up to 5% of children in the United States), in sexually active young adults, and in 

immunocompromised persons. It occurs in 5-18% of HIV-infected persons. Molluscum is benign 

but may cause extensive and cosmetically bothersome lesions, particularly in persons with 

advanced HIV infection.

Transmission occurs by person-to-person skin-to-skin contact (e.g., sexual activity, contact 

sports [especially wrestling], or simply touching) or via fomites (towels, bedclothes, clothing 

[including underwear], soft toys, shaving utensils, electrolysis equipment, tattooing tools, and 

sponges). The virus may be spread to other areas via self-inoculation (e.g., scratching, shaving, or 

touching a lesion).

In immunocompetent persons, the infection usually resolves spontaneously after 6-12 months, 

though genital lesions may remain longer. In HIV-infected persons, the lesions may be more 

extensive and persistent. There is a strong correlation between the degree of immunosuppression 

and the risk of molluscum infection, the number of lesions, and the ability of lesions to resist 

treatment.

S: Subjective

Patients complain of new papules on the trunk, 

axillae, antecubital and popliteal fossae, face, 

or genital/crural area. Papules of molluscum 

contagiosum may cause no symptoms but 

also can be intensely pruritic or tender to the 

touch. Ask patients whether others in the 

home (especially children and adolescents) or 

their sex partners have similar papules. Genital 

lesions are transmitted sexually; patients may 

recall seeing such lesions on the genitals of a 

previous partner.

Ask about fever or other systemic symptoms to 

evaluate for other causes of the papules.

O: Objective

Perform a thorough evaluation of the skin, 

genitals, and mouth. Molluscum commonly 

presents as multiple grouped lesions. The 

lesions are white, pink, or flesh colored; 

shiny, smooth surfaced, firm, pearly, and 

spherical (dome-shaped) papules (2-5 mm) 

or nodules (6-10 mm), with umbilicated, or 

dimpled, centers. Patients with HIV infection 

may develop giant lesions (>1 cm) or clusters 

of hundreds of small lesions. Occasionally, 

molluscum will have a polyp-like appearance. 

Lesions are usually found on the head, face, 

or neck or in the genital area, but may affect 

every part of the body except the palms and 

soles. Molluscum may occur inside the mouth, 

vagina, and rectum, and around the eyes. 

Lesions on the eyelids can cause conjunctivitis.
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A: Assessment

A partial differential diagnosis includes the 

following:

• Disseminated cryptococcosis

• Histoplasmosis skin lesions

• Penicillium marneffei

• Other fungal skin lesions

• Folliculitis

• Syphilis, condyloma acuminata, vulvar 

syringoma for multiple small molluscum 

genital lesions

• Squamous or basal cell carcinoma

P: Plan

Diagnostic Evaluation

The diagnosis of molluscum usually is based 

on the characteristic appearance of the 

lesions. Perform histologic or other laboratory 

testing to confirm the diagnosis or to exclude 

other infections or malignancies. Special 

staining will show keratinocytes containing 

eosinophilic cytoplasmic inclusion bodies. 

Electron microscopy will show poxvirus 

particles.

Treatment

Because molluscum does not cause illness and 

rarely causes symptoms, the treatment usually 

is undertaken primarily for cosmetic purposes. 

For individuals with large or extensive lesions, 

molluscum may be disfiguring or stigmatizing, 

and treatment may be important for their 

well-being. Treatment (particularly of genital 

lesions) can be considered in order to prevent 

transmission to others.

In HIV-infected patients, molluscum is difficult 

to eradicate and lesions often recur, particularly 

if immune suppression persists. Effective 

antiretroviral therapy may achieve resolution of 

lesions or significant improvement in the extent 

or appearance of molluscum and should be 

recommended for all.

Lesions that remain after weeks of 

antiretroviral therapy should be treated to 

prevent further spread. Refer complex cases to 

a dermatologist.

Choice of treatment modality is based on 

age, likelihood of compliance, number and 

size of lesions, and potential adverse effects 

of treatment. Therapeutic options include the 

following:

• Local excision: May be done by curettage, 

cryotherapy, electrocautery, or evisceration. 

Adverse effects include pain, irritation, 

soreness, and mild scarring. Repeated 

treatments are necessary. Curettage appears 

to be most efficacious (even for children) but 

is painful and requires anesthesia and a large 

time commitment over the course of several 

visits; it also has a risk of scarring. Relapse is 

common.

• Imiquimod 5% (Aldara): An immune 

response modifier; stimulates production of 

interferon-alfa and other proinflammatory 

cytokines, inducing a tissue reaction 

associated with viral clearance from the 

skin. Apply TIW for up to 16 weeks or 

QPM for 4 weeks. Clearing can take up to 3 

months. Limited studies; painless.

• Podophyllotoxin: Can be administered by 

a health care provider and washed off after 

1-4 hours. This treatment is caustic, may 

cause significant irritation, and has limited 

effectiveness. It is contraindicated for use 

during pregnancy. Patient-administered 

podophyllotoxin (Podofilox) may be a 

safer alternative to podophyllum. Adverse 

effects include burning, pain, inflammation, 

erosion, and itching.

• Cantharidin 0.7%: Can be applied by a 

health care provider. One study of 300 

children found that lesions cleared after two 

visits. This treatment may cause allergic 

reactions, stinging, and blistering. Do not 

use cantharidin around the eyes.
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Section 6: Comorbidities, 

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• Tretinoin (Retin-A) 0.1% cream: Can 

be applied to lesions BID. Adverse effects 

include drying, peeling, irritation, and 

soreness.

• Trichloroacetic acid: Can be administered 

by a health care provider. Controlling 

the depth of acid penetration is difficult. 

Adverse effects include pain and irritation; 

mild scarring is common.

• A combination of salicylic and lactic acid:

Response is highly variable and recurrence 

is common.

• Laser therapy: Safe, efficient, tolerable, and 

efficacious.

• Cidofovir 1-3% topical cream: Applied 

BID for 2 weeks, followed by a 30-day rest 

period and then two additional cycles. This 

treatment has been shown to be effective in 

several small studies and case reports, but it 

is expensive and difficult to compound. No 

systemic adverse effects are noted.

• Silver nitrate paste: May be used to burn 

each lesion individually.

Patient Education

• Molluscum infection is benign but may be 

distressing.

• Molluscum infection may be transmitted 

both sexually and nonsexually, through 

direct contact with lesions. Molluscum also 

can be transmitted indirectly by contact 

with infected objects.

• Latex condoms or barriers may not prevent 

transmission of genital molluscum.

• To prevent the spread of molluscum, instruct 

patients to take the following precautions: 

• Avoid close contact between their 

molluscum lesions and the skin, mouth, 

and genitals of other people.

• Avoid picking at, squeezing, or 

puncturing the lesions, as a lesion’s central 

plug is full of viral particles that can be 

spread easily by coming into contact 

with other parts of the body. In addition, 

lesions may become secondarily infected.

• Wash hands frequently.

• Keep fingernails short.

• Avoid shaving in areas with lesions 

because shaving could result in lesions 

spreading to other areas.

• Avoid sharing towels, bedclothes, 

clothing, shaving utensils, bathing 

equipment, or other objects that have been 

in contact with molluscum lesions.

• Wash all contaminated items in very hot, 

but not scalding, water.

• Cover lesions with clothing, if possible.
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References

• Binder B, Weger W, Komericki P, et al. 

Treatment of molluscum contagiosum with a 

pulsed-dye laser: pilot study with 19 children.

J Dtsch Dermatol Ges. 2008 Feb;6(2):121-5.

• Calista D. Topical cidofovir for severe 

cutaneous human papillomavirus and 

molluscum contagiosum infections in patients 

with HIV/AIDS: a pilot study. J Eur Acad 

Dermatol Venereol. 2000 Nov;14(6):484-8.

• Gould D. An overview of molluscum 

contagiosum: a viral skin condition. Nurs 

Stand. 2008 Jun 18-24;22(41):45-8.

• Isaacs SN. Molluscum contagiosum. 

In: UpToDate v14.1. 

• Simonart T, De Maertelaer V. Curettage 

treatment for molluscum contagiosum: a 

follow-up survey study. Br J Dermatol. 2008 

Nov;159(5):1144-7.

• Strauss RM, Doyle EL, Mohsen AH, et 

al. Successful treatment of molluscum 

contagiosum with topical imiquimod 

in a severely immunocompromised 

HIV-positive patient. Int J STD 

AIDS. 2001 Apr;12(4):264-6.

• Toro JR, Wood LV, Patel NK, et al. Topical 

cidofovir: a novel treatment for recalcitrant 

molluscum contagiosum in children infected 

with human immunodeficiency virus 1. Arch 

Dermatol. 2000 Aug;136(8):983-5.
Section 6: Comorbidities, 

Coinfections, and Complications

Mycobacterium avium Complex Disease | 469

Mycobacterium avium Complex Disease

Background

Mycobacterium avium complex (MAC) disease is an opportunistic infection caused by species 

of Mycobacterium that can produce severe illness in people with advanced AIDS but rarely 

affects others. The risk of disseminated MAC (DMAC) is directly related to the severity of 

immunosuppression. DMAC typically occurs in persons with CD4 counts of <50 cells/μL, and its 

frequency increases as the CD4 count declines. In the absence of antibiotic prophylaxis, DMAC 

occurs in up to 40% of AIDS patients with CD4 counts of <50 cells/μL. Antimicrobial therapy, 

especially if given in conjunction with antiretroviral therapy (ART) that achieves immune 

reconstitution, can be successful in treating MAC disease. Specific antimicrobial prophylaxis 

and effective ART also may be used to prevent MAC in patients with advanced AIDS (see chapter 

Opportunistic Infection Prophylaxis).

MAC organisms are common in the environment. They are found worldwide and have been 

isolated from soil, water, animals, birds, and foods. They usually enter the body through the 

respiratory or gastrointestinal tract and disseminate to cause multisystem infection, typically 

manifested by nonspecific symptoms and signs such as fever, sweats, weight loss, abdominal pain, 

fatigue, chronic diarrhea, and anemia and other cytopenias. MAC also can cause local disease 

such as central nervous system infection, lymphadenitis, soft-tissue or bone infections, and rarely, 

isolated pulmonary disease. Focal MAC disease is more common among patients on ART, whereas 

DMAC is the more common manifestation among those with low CD4 cell counts who are not on 

ART. Unlike Mycobacterium tuberculosis, Mycobacterium avium is not thought to be transmitted 

via person-to-person contact. In patients with subclinical or incompletely treated MAC who have 

recently started ART, an immune reconstitution inflammatory syndrome (IRIS) may occur with 

localized lymphadenitis or paradoxically worsening symptoms (see chapter Immune Reconstitution 

Inflammatory Syndrome).

S: Subjective

The patient complains of one or more of the 

following symptoms:

• Persistent or cyclic fever

• Night sweats

• Unintentional weight loss

• Anorexia

• Chronic diarrhea

• Weakness

• Fatigue

• Abdominal pain

• Lymph node enlargement

When taking the history, ask about the 

following:

• Any symptoms as described above, 

including duration and intensity; other 

symptoms of infection

• Whether the patient is taking MAC 

prophylaxis or ART

O: Objective

Perform a full physical examination with 

particular attention to the following:

• Vital signs (temperature, heart rate, blood 

pressure, respiratory rate)

• Weight (compare with previous 

measurements)
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• General appearance (cachexia, wasting, 

signs of chronic illness, jaundice, pallor)

• Lymph nodes (lymphadenopathy)

• Abdomen (hepatosplenomegaly, tenderness)

Review previous laboratory values, particularly 

the CD4 count (usually <50 cells/μL).

A: Assessment

Rule out other infectious or neoplastic causes 

of constitutional symptoms, anemia, or 

organomegaly. A partial differential diagnosis 

would include the following:

• M. tuberculosis infection

• Cytomegalovirus infection

• Lymphoma

• Bartonellosis

• Disseminated fungal infection

• Pyogenic abscess

• Other septicemia

P: Plan

Diagnostic Evaluation

Definitive diagnosis requires identification 

of MAC in blood or other normally sterile 

body fluids or tissues (M. avium cultured 

from sputum, bronchial washing, or stool may 

represent colonization rather than infection). 

Send blood for acid-fast bacilli (AFB) culture 

(sensitivity of a single blood culture for MAC 

bacteremia is 91%, sensitivity increases to 98% 

if two samples [drawn at different times] are 

sent). Because MAC may take weeks to grow in 

culture, ancillary studies should be performed. 

The following are not specific, but may be 

helpful in reaching a presumptive diagnosis:

• AFB smear 

• Complete blood count (CBC) for anemia, 

lymphopenia, and thrombocytopenia

• Serum alkaline phosphatase (often elevated 

in DMAC)

• Computed tomography (CT) scan of the 

chest and abdomen (intraabdominal 

and mediastinal lymphadenopathy or 

hepatosplenomegaly often are present)

If blood cultures are negative and MAC is 

suspected (or if results of blood cultures are 

pending), consider biopsy of the lymph nodes, 

bone marrow, liver, or bowel (via endoscopy) 

to detect DMAC by microscopic examination 

for AFB and culture. If the evidence suggests 

pulmonary MAC, consider bronchoscopy and 

bronchoalveolar lavage. Note that in MAC 

IRIS, MAC bacteremia usually is absent and a 

tissue-based diagnosis is required.

Perform additional studies as indicated to rule 

out other causes of the patient’s symptoms, 

including bacterial blood cultures, sputum 

for M. tuberculosis, Bartonella studies, lymph 

node cytology for lymphoma, and stool 

cultures, as appropriate.

Treatment

Because antimicrobial resistance develops 

quickly with single-drug therapy, multidrug 

regimens must be administered for DMAC.

Preferred regimens:

• Clarithromycin 500 mg BID + ethambutol 

15 mg/kg QD

• Azithromycin 500-600 mg QD + ethambutol 

15 mg/kg QD (see below)

Clarithromycin is the preferred cornerstone 

of MAC therapy, as it has been studied 

more extensively and is associated with 

more rapid clearance of MAC bacteremia. 

If clarithromycin cannot be tolerated or if 

there is concern regarding drug interactions, 

azithromycin may be substituted for 

clarithromycin, as above. Clarithromycin 

dosages should not exceed 1 g per day, as highdose clarithromycin has been associated with 

excess mortality.

Some experts recommend including a third 

agent for patients with more advanced HIV 

disease or higher MAC burden in blood 

cultures, and for those who are not receiving 
Mycobacterium avium Complex Disease | 471

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effective ART. The addition of rifabutin (300 

mg QD) has been associated with a mortality 

benefit in one study and with reduced 

emergence of mycobacterial resistance in 

two other trials; however, these studies were 

done before potent ART was available; the 

possible benefit of rifabutin in patients treated 

with effective ART has not been established. 

A fluoroquinolone (e.g., levofloxacin, 

moxifloxacin), amikacin, or streptomycin 

may be used instead of rifabutin as a third 

agent, or in addition to rifabutin as a fourth 

agent; however, studies have not confirmed the 

clinical benefit of these medications.

Because immune reconstitution is essential 

for controlling MAC, all patients who are not 

already receiving ART should begin ART, 

if possible. Current guidelines recommend 

initiation of ART after 2 weeks of MAC 

treatment, for patients who are not already on 

ART. This strategy may decrease the risk IRIS 

and it serves to forestall interactions between 

DMAC and ARV drugs and the additive 

toxicities of those medications. Patients who 

are receiving suboptimal ART should be 

changed to suppressive regimens, if possible.

Potential ARV Interactions

Clarithromycin and rifabutin have a number of significant drug interactions, including 

interactions with some commonly prescribed ARVs. These interactions should be reviewed 

prior to initiation of MAC therapy. Dosage adjustments or alternative medications may be 

required. Azithromycin does not have significant interactions with ARVs. 

Interactions of concern include the following:

Clarithromycin:

• Atazanavir may raise clarithromycin levels by 90%; some experts recommend using 

azithromycin in place of clarithromycin, or dosage reduction of clarithromycin by 50%. 

• Darunavir increases clarithromycin levels; alternative agent (azithromycin) or dosage 

reduction of clarithromycin is recommended for patients with renal impairment. 

• Lopinavir/ritonavir and other protease inhibitors may increase clarithromycin levels; 

alternative agent (azithromycin) or dosage reduction of clarithromycin is recommended for 

patients with renal impairment. 

• Efavirenz may lower clarithromycin levels; avoid this combination if possible.

• Etravirine may lower clarithromycin levels, while clarithromycin may in turn increase 

etravirine levels. Avoid this combination, if possible.

• Nevirapine may decrease clarithromycin levels and increase levels of its active metabolite. 

Avoid this combination, if possible.

• Elvitegravir/cobicistat may increase clarithromycin levels. Dosage reduction of 

clarithromycin is required for patients with renal insufficiency.

Protease inhibitor-based ART (e.g., lopinavir or darunavir) or integrase inhibitor-based ART 

may be the preferred HIV treatment for patients on MAC therapy, because of limited drug 

interactions associated with those ARV classes. 

Rifabutin has significant interactions with many drugs, including nonnucleoside reverse 

transcriptase inhibitors, protease inhibitors, and elvitegravir/cobicistat; therefore, dosage 

adjustments or alternative agents may be needed (for further information, see chapter 

Mycobacterium tuberculosis). 
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The patient should show clinical improvement 

within the first weeks of treatment. If there is 

not a response to treatment after 2-4 weeks, 

assess adherence, consider adding one or 

more drugs, and consider evaluation for 

other or additional causes of the patient’s 

symptoms. Repeat a blood culture with 

antimicrobial sensitivities for patients 

whose clinical status has not improved after 

4-8 weeks of treatment. Interpretation of 

MAC drug susceptibility testing should be 

undertaken in consultation with an infectious 

disease or HIV specialist, because laboratory 

evidence of drug resistance does not always 

correlate with clinical drug resistance.

If immune reconstitution inflammatory 

reactions are suspected, consider adding 

antiinflammatory medications, including 

corticosteroids if moderate to severe MAC IRIS 

symptoms do not improve with NSAIDs (see 

chapter Immune Reconstitution Inflammatory 

Syndrome).

Treatment of MAC generally is required for the 

remainder of the patient’s life in the absence 

of immune reconstitution with effective ART. 

It may be reasonable to discontinue MAC 

therapy if patients complete at least 12 months 

of MAC treatment, have no further symptoms, 

and demonstrate immune restoration in 

response to ART (an increase in CD4 counts 

to >100 cells/μL for at least 6 months). If MAC 

treatment is discontinued, the patient must be 

monitored carefully for any decrease in CD4 

cell count or recurrence of MAC symptoms. 

Treatment should be resumed if the CD4 count 

drops to <100 cells/μL or if symptoms recur.

Prevention

Primary prevention using azithromycin or 

clarithromycin should be initiated in persons 

with CD4 cell counts of <50 cells/μL. See 

chapter Opportunistic Infection Prophylaxis.

Patient Education

• Advise patients that antimycobacterial 

therapy alone will not eradicate MAC 

infection, but should decrease symptoms 

and improve quality of life. A response 

to treatment may take up to 4 weeks. If 

medications are discontinued, the disease 

almost always recurs, unless the CD4 count 

has increased to >50-100 cells/μL in response 

to ART.

• Patients must take all medicines exactly 

as prescribed. If doses are missed, or if the 

medication is stopped and restarted, MAC 

can develop resistance to the medications. 

If patients are having trouble taking the 

medications on schedule, they should 

contact their health care provider promptly.

• Advise patients that MAC IRIS is a common 

complication of effective ART and MAC 

therapy, and its occurrence in the course of 

treatment should be anticipated.

• Urge patients to contact the clinic 

immediately if they notice worsening of 

existing symptoms or the development of 

new symptoms.

• DMAC is an opportunistic infection of latestage HIV and it is indicative of profound 

immunosuppression. Some patients may 

not respond to MAC treatment or to ART. 

Because this is a life-threatening disease, 

clinicians should discuss advance directives 

and durable power of attorney with patients. 

Referral to a social worker, mental health 

clinician, or chaplain experienced in such 

issues may facilitate the discussion.
Mycobacterium avium Complex Disease | 473

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References

• Benson CA, Williams PL, Currier JS, 

et al.; AIDS Clinical Trials Group 223 

Protocol Team. A prospective, randomized 

trial examining the efficacy and safety 

of clarithromycin in combination with 

ethambutol, rifabutin, or both for the 

treatment of disseminated Mycobacterium 

avium complex disease in persons with 

acquired immunodeficiency syndrome. Clin 

Infect Dis. 2003 Nov 1;37(9):1234-43.

• Cabié A, Abel S, Brebion A, et al. 

Mycobacterial lymphadenitis after initiation 

of highly active antiretroviral therapy. 

Eur J Clin Microbiol Infect Dis. 1998 

Nov;17(11):812-3.

• Gordin FM, Sullam PM, Shafran SD, 

et al. A randomized, placebo-controlled 

study of rifabutin added to a regimen 

of clarithromycin and ethambutol for 

treatment of disseminated infection with 

Mycobacterium avium complex. Clin Infect 

Dis. 1999 May;28(5):1080-5.

• Horsburgh CR Jr, Gettings J, Alexander LN, 

et al. Disseminated Mycobacterium avium 

complex disease among patients infected with 

human immunodeficiency virus, 1985-2000.

Clin Infect Dis. 2001 Dec 1;33(11):1938-43.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Phillips P, Bonner S, Gataric N, et al. 

Nontuberculous mycobacterial immune 

reconstitution syndrome in HIV-infected 

patients: spectrum of disease and longterm 

follow-up. Clin Infect Dis. 2005 Nov 

15;41(10):1483-97.

• Race EM, Adelson-Mitty J, Kriegel GR, et al. 

Focal mycobacterial lymphadenitis following 

initiation of protease-inhibitor therapy 

in patients with advanced HIV-1 disease.

Lancet. 1998 Jan 24;351(9098):252-5.

Section 6: Comorbidities, 

Coinfections, and Complications

Mycobacterium tuberculosis | 475

Mycobacterium tuberculosis

Background 

In HIV-infected individuals, tuberculosis (TB) causes more deaths worldwide than any 

other condition. A biologic synergy exists between HIV and TB such that HIV-induced 

immunosuppression increases susceptibility to active TB infection, whereas active TB infection 

increases HIV progression and risk of death. The populations infected by these two pathogens 

overlap in many respects, creating epidemiologic synergy. Poverty, crowded living conditions, and 

inadequate interventions to reduce transmission and treat latent TB infection (LTBI) combine to 

enhance the transmission of both organisms.

In the United States, more than 60% of TB cases occur in foreign-born individuals, with the 

majority of these cases attributed to reactivation of LTBI. In 2010, only 8% of active TB cases 

occurred in patients known to be infected with HIV, and TB is a relatively infrequent AIDSdefining illness. Nevertheless, TB remains important to HIV clinicians in the United States 

because it can be highly infectious and challenging to diagnose, and because improper treatment 

may lead to drug resistance both in the infected patient and in individuals to whom that patient 

transmits. Although other conditions increase the risk of TB disease (e.g., malnutrition, diabetes, 

end-stage renal disease, pulmonary silicosis, and iatrogenic immunosuppressive drugs [especially 

inhibitors of tumor necrosis factor]), HIV infection remains an important risk factor.

TB is an infection caused by Mycobacterium tuberculosis (MTB) complex. These organisms grow 

slowly and can be identified only with special staining techniques, a trait that led to the name 

“acid-fast bacteria.” This chapter focuses on disease caused by M. tuberculosis; other chapters 

describe diagnosis and management of latent MTB infection (see chapter Latent Tuberculosis 

Infection) and diagnosis and management of disease caused by Mycobacterium avium (see chapter 

Mycobacterium avium Complex Disease).

MTB most often causes a chronic pneumonia, but it can affect organs other than the lungs as well. 

The lung destruction caused by MTB may create cavities, similar to abscesses; these contain huge 

numbers of organisms. TB is transmitted almost always by persons with active pulmonary TB who 

release large numbers of organisms in their sputum. Patients with smear-positive sputum are the 

most infectious; however, transmission from patients with AFB smear-negative, culture-positive 

sputum has been well documented. Extrapulmonary tuberculosis generally is not considered 

contagious. 

MTB organisms are inhaled and infect the lung. In most people, the initial lung infection is 

contained by an effective immune response. It usually is asymptomatic but leads to foci in the lung 

(and sometimes in other organs) of latent TB, which may reactivate and cause active TB disease 

years later. Shortly after the onset of infection with MTB, before its containment in the lung by 

the immune system, organisms can spread to other organs and establish latent infection in those 

areas as well. Reactivation in these other organs can lead to local disease (e.g., in the lymph nodes, 

meninges, bone, pericardium, peritoneum or intestine, and urogenital tract).

Persons with impaired immunity, such as persons with HIV-associated immunosuppression 

and very young children, are at high risk of developing progressive primary TB at the time of 

initial MTB infection. Primary progressive MTB usually causes pulmonary disease, but also can 
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cause meningitis or disseminated disease (blood, liver, spleen, lung, and other organs). Persons 

who have latent TB infection and then develop immunodeficiency are at high risk of developing 

reactivation disease. For example, compared with the <10% lifetime risk of developing active TB in 

immunologically normal persons, an HIV-infected person with latent TB has about a 10% chance 

each year of developing active disease. Even with immune reconstitution through antiretroviral 

therapy (ART) and a normalized CD4 cell count, HIV-infected patients remain at elevated risk of 

reactivation TB, compared with the background community risk of TB.

Classical pulmonary tuberculosis, with upper-lobe infiltrates and cavitary lesions, may occur in 

HIV-infected persons with relatively intact immunity. As the CD4 count decreases (particularly 

to <200 cells/μL), TB is more likely to manifest atypically in the chest (without cavitary disease) 

or with lower-lobe disease, adenopathy, pleural effusions, or interstitial or military infiltrates), 

and as extrapulmonary or multiorgan disease (particularly in lymph nodes, peritoneum, 

pericardium, and meninges). Granulomas may be seen in the tissues; in persons with advanced 

immunodeficiency, these may be poorly formed and non-caseating. Bone, joint, and urogenital 

TB are less-commonly associated with HIV-induced immunosuppression. Symptoms and signs 

in HIV-infected persons therefore can vary widely and can be difficult to distinguish from HIVrelated opportunistic infections and malignancies.

Appropriate use of modern chemotherapy with rifampin-containing TB treatment applied to drugsusceptible MTB disease cures at least 95% of these patients, including those with HIV coinfection. 

However, drug resistance seriously reduces the cure rate. Drug resistance usually is caused 

by improper or erratic treatment. It is spreading rapidly and becoming more severe. Effective 

diagnosis and cure of drug-susceptible TB not only reduces the disease burden in the individual 

and reduces further transmission, it also is crucial to avoiding drug resistance.

MTB resistance to a single drug may extend or complicate treatment but usually does not prevent 

successful treatment of TB. Resistance to both isoniazid and rifampin, with or without resistance 

to other first-line drugs, is called multidrug resistance (MDR), and it makes treatment especially 

difficult. Extreme drug resistance (XDR) occurs when, in addition to isoniazid and rifampin 

resistance, there is resistance to specific second-line drugs: a fluoroquinolone plus an injectable 

agent (kanamycin, amikacin, or capreomycin). Treatment of drug-resistant TB should be managed 

by experts or in consultation with experts. MDR TB is uncommon in the United States; it occurred 

in 1.3% of cases in 2010, and the great majority of these were foreign-born patients (82.6%). XDR is 

very rare in the United States, with only 4 cases reported in 2010.

Effective antiretroviral treatment (ART) is a critical component of the care of persons with TB, and 

ART should be initiated or optimized in all persons with active TB, regardless of their current CD4 

cell count.

This chapter will discuss the evaluation and management of TB in the United States and other 

high-income settings. For management of TB in resource-limited settings, see the relevant World 

Health Organization guidelines and other resources.
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S: Subjective

Persons with TB generally describe an illness 

lasting several weeks to months, associated 

with systemic features such as high fevers, 

night sweats, loss of appetite, and weight loss. 

These symptoms are nonspecific, but should 

raise the possibility of TB.

• Pulmonary TB presents with a chronic 

productive cough and sometimes with 

hemoptysis; shortness of breath occurs late 

in the disease course.

• TB adenitis presents with enlarged lymph 

nodes (usually asymmetric involvement 

in one region) that may suppurate and 

drain but usually are not painful, hot, or 

erythematous.

• TB meningitis presents with headache, 

gradual change in mental status, and at 

times with cranial nerve abnormalities such 

as double vision or decreased hearing.

• Disseminated TB may occur with systemic 

manifestations such as fever, sweats, and 

weight loss, with no localizing features.

Risk factors for TB infection include known 

prior contact with an active case, exposure in 

congregate settings (such as homeless shelters 

and prisons, but also in health care facilities), 

travel or residence in countries with high rates 

of endemic TB, and birth in a TB-endemic 

county (more than half of foreign-born 

individuals diagnosed with TB in the United 

States originated from one of the following five 

countries: Mexico, the Philippines, Vietnam, 

India, or China). In the United States, persons 

with active or past substance-use disorders and 

persons of color are more likely than others 

to have had exposure to TB. History of a prior 

positive tuberculin skin test (TST) or interferongamma release assay (IGRA) result provides 

evidence of previous TB exposure; however, up 

to 35% of patients with active TB will have a 

negative TST or IGRA result (see chapter Latent 

Tuberculosis Infection). Risks for active TB 

disease include any degree of HIV-associated 

immunosuppression, immunosuppression 

associated with other diseases (e.g., leukemia, 

lymphoma) or caused by medical therapies (e.g., 

tumor necrosis factor-alpha blockers such as 

etanercept), and malnutrition.

O: Objective

• Measure vital signs, including oxygen 

saturation.

• Measure weight; compare with previous 

values.

• Perform thorough physical examination 

with particular attention to the lungs, heart, 

abdomen, lymph nodes, skin, and neurologic 

system.

Systemic signs of chronic disease and 

inflammation are common, including cough, 

fever, night sweats (which may occur without 

awareness of the high fever that precedes 

them), and weight loss.

In patients with pulmonary TB, the breath 

sounds may be normal or focally abnormal; 

tachypnea and hypoxia occur only with 

extensive lung damage.

Extrapulmonary TB may present with focal 

adenopathy without local signs of inflammation, 

but perhaps with a draining sinus.

TB meningitis presents as subacute or 

chronic meningitis, with neck stiffness 

and changes in mental status. Symptoms 

may include cranial nerve palsies owing 

to inflammation at the base of the brain 

or increased intracranial pressure.

Pericardial disease can cause the pain 

and friction rub of pericarditis or signs of 

pericardial tamponade.

Infiltration of the bone marrow can produce 

pancytopenia.

Disseminated TB may cause diffuse 

adenopathy, hepatic or splenic enlargement, 

and abnormal liver function, although hepatic 

failure is rarely attributable to TB alone. 

Infection of the adrenal glands can cause 

adrenal insufficiency.
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A: Assessment

Note: If pulmonary TB is suspected, the 

patient should wear a mask while in the 

medical facility and the care provider 

should wear an N95 respirator during the 

examination to reduce transmission risk.

The differential diagnosis of TB is extensive 

and depends in part on the degree of 

immunosuppression (as indicated by the CD4 

cell count) of the individual. It includes a broad 

range of bacterial, mycobacterial, viral, and 

fungal infections in addition to noninfectious 

causes. A partial differential diagnosis of 

pulmonary TB includes the following:

• Bacterial pneumonia

• Pulmonary Mycobacterium pneumonia 

(nontuberculous)

• Pneumocystis jiroveci pneumonia (PCP)

• Cryptococcus neoformans pneumonia/

pneumonitis

• Pulmonary Kaposi sarcoma

• Toxoplasma pneumonitis

• Disseminated histoplasmosis

• Disseminated coccidioidomycosis

• Cytomegalovirus pneumonia

• Bronchogenic carcinoma

• Non-Hodgkin lymphoma

• Influenza

• Pulmonary embolus

• Chronic obstructive pulmonary disease

• Reactive airway disease

• Congestive heart failure

• Lactic acidosis

P: Plan

Diagnostic Evaluation

Initial evaluation

Suspected TB should be evaluated aggressively.

• During the initial evaluation, check 

complete blood count (CBC) and 

differential, sputum gram stain, sputum 

acid-fast bacilli (AFB) stain, culture, and 

nucleic acid amplification (NAA) test (see 

below), blood cultures, and chest X-ray.

• For patients with lymphadenopathy, 

consider fine-needle aspiration biopsy for 

bacterial and AFB stains and culture, and 

cytologic evaluation.

• For patients with meningitis or central 

nervous system (CNS) abnormalities, 

perform lumbar puncture (LP) and cerebral 

spinal fluid (CSF) analysis including cell 

count, protein, glucose, AFB smear and 

culture, and bacterial and fungal cultures.

• Computed tomography (CT) is 

recommended for all patients with HIV 

prior to LP, particularly if focal neurologic 

abnormalities are present.

• Perform other diagnostic tests as suggested 

by the clinical presentation.

Imaging

Pulmonary TB can be associated with any 

chest X-ray appearance, including a normal 

X-ray image. However, the chest X-ray 

classically demonstrates upper-lobe infiltrates 

with or without cavities. Patients with HIV 

infection (especially advanced HIV and low 

CD4 cell counts) are more likely to have 

atypical chest X-ray presentations, including 

absence of cavities, presence of lower-lobe 

disease, hilar or mediastinal adenopathy, and 

pleural effusions.

In disseminated TB, the chest X-ray may show 

a miliary pattern with small nodules (“millet 

seeds”) scattered throughout both lungs.
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AFB testing

TB should be diagnosed by identification of the 

organism in stained sputum smears or stains 

of tissue and confirmed by culture or NAA 

test. All positive cultures should undergo drug 

susceptibility testing. Proof of the diagnosis 

is important because other opportunistic 

diseases can mimic TB, and mycobacterial 

infections other than TB (e.g., MAC) can 

occur; these require different treatment. TB 

drug susceptibility testing is necessary to 

ensure appropriate treatment, to reduce the 

risk of developing further TB drug resistance, 

and to decrease the risk of transmission 

of drug-resistant TB. Three specimens of 

expectorated sputum should be sent for acidfast staining and mycobacterial culture. A 

presumptive diagnosis of pulmonary TB can 

be made if AFB are seen, but confirmation is 

required. Sputum induction with nebulized 

saline (e.g., by respiratory therapists) can be 

used for patients who do not have spontaneous 

sputum production. (Sputum induction has 

been successful in children, but for young 

children who cannot produce sputum, gastric 

lavage on three successive mornings can be 

performed to obtain swallowed sputum for 

smear [although false-positive results can 

occur] and culture.)

Current U.S. guidelines for treatment of 

opportunistic infections recommend NAA 

testing on at least one respiratory specimen 

(regardless of smear status) from each patient 

with signs and symptoms of pulmonary TB. 

The algorithm in Table 1 is recommended 

by the U.S. Centers for Disease Control and 

Prevention (CDC) for interpretation of NAA 

test results.

Table 1. Nucleic Acid Amplification Testing and Interpretation Algorithm

1. If the NAA result is positive and the AFB smear result is positive, presume the patient has TB and begin 

anti-TB treatment while awaiting culture results. The positive predictive value of FDA-approved NAA tests 

for TB is >95% in AFB smear-positive cases.

2. If the NAA result is positive and the AFB smear result is negative, use clinical judgment in deciding 

whether to begin anti-TB treatment while awaiting culture results and determine whether additional 

diagnostic testing is needed. Consider testing an additional specimen using NAA to confirm the NAA 

result. A patient can be presumed to have TB, pending culture results, if two or more specimens are NAA 

positive. 

3. If the NAA result is negative and the AFB smear result is positive, a test for inhibitors should be performed 

and an additional specimen should be tested with NAA. Sputum specimens (3-7%) might contain 

inhibitors that prevent or reduce amplification and cause false-negative NAA results. 

a. If inhibitors are detected, the NAA test is of no diagnostic help for this specimen. Use clinical judgment 

to determine whether to begin anti-TB treatment while awaiting results of culture and additional 

diagnostic testing.

b. If inhibitors are not detected, use clinical judgment to determine whether to begin anti-TB treatment 

while awaiting culture results and determine whether additional diagnostic testing is needed. A 

patient can be presumed to have an infection with non-TB mycobacteria if a second specimen is smear 

positive and NAA negative and has no inhibitors detected. 

4. If the NAA result is negative and the AFB smear result is negative, use clinical judgment to determine 

whether to begin anti-TB treatment while awaiting results of culture and additional diagnostic tests. 

Currently available NAA tests are not sufficiently sensitive (detecting 50-80% of AFB smear-negative, 

culture-positive pulmonary TB cases) to exclude the diagnosis of TB in AFB smear-negative patients 

suspected of having TB.

Adapted from U.S. Centers for Disease Control and Prevention. Updated Guidelines for the Use of Nucleic Acid Amplification Tests in the Diagnosis 

of Tuberculosis. MMWR Morb Mortal Wkly Rep. 2009 Jan 16;58(1):7-10. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5801a3.

htm. Acccesssed December 1, 2013.
480 | Guide for HIV/AIDS Clinical Care

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Sensitivity of the NAA tests in smear-positive 

specimens is high but decreases to 50-80% in 

smear-negative, culture-positive specimens. 

The rapid identification of MTB facilitates 

appropriate respiratory infection control 

precautions, contact tracing, and immediate 

treatment of MTB. NAA tests also are useful 

in making a presumptive diagnosis in smearnegative patients who are suspected to have 

active pulmonary TB, pending culture results. 

However, these tests can yield false-positive 

results, particularly with persons in whom 

pulmonary TB is unlikely. Also, false negatives 

can occur in both smear-positive and smearnegative patients. NAA testing is not available 

in all laboratories and in some it is restricted to 

AFB smear-positive specimens.

The Xpert MTB/RIF is a rapid NAA test 

that was recently reviewed by the FDA and 

allowed to be marketed the United States. 

This assay identifies TB and at the same time 

identifies rifampicin (RIF) resistance from 

a direct sputum sample. Data from highprevalence TB settings show a sensitivity of 

>98% for TB in smear-positive specimens. 

Sensitivity in smear-negative specimens is 

70% with a single test, and up to 90% with 

three tests, with a specificity of 99%. Other 

NAA tests can be used to rapidly identify 

clinically significant non-TB mycobacteria 

such as MAC and Mycobacterium kansasii. 

If a non-TB mycobacteria is diagnosed, 

respiratory precautions can be discontinued, 

and treatment for the specific or suspected 

organism can be started.

In patients with suspected pulmonary TB, 

negative sputum microscopy or NAA results 

do not rule out TB; and consideration should 

be given to starting empiric TB treatment 

while further evaluation is undertaken.

A diagnosis of extrapulmonary TB generally 

requires an examination of infected tissue 

or body fluid by microscopy and culture. 

NAA tests are approved for testing of sputum 

samples, but have been used on tissue and body 

fluids (such as CSF); specimens that are fresh 

or frozen generally are preferable to specimens 

preserved in formalin or a similar chemical. 

Specimens of organs with suspected TB can be 

obtained by peripheral lymph node aspiration, 

CT-guided or other guided aspiration and 

biopsy, liver biopsy, bone marrow biopsy, or 

thoracoscopy- or laparoscopy-guided biopsies 

of pleura or peritoneum. In some cases, 

surgery is required to obtain appropriate 

specimens. Blood cultures for mycobacteria 

(using appropriate mycobacterial media 

rather than standard blood culture media) 

may be positive in disseminated TB, 

particularly with advanced HIV disease; the 

technique is the same as in culturing blood 

for MAC organisms. Urine culture is used to 

diagnose renal TB, although this condition 

is rare among HIV-infected persons.

Initial growth of MTB on culture may occur 

within 3-8 weeks. A nucleic acid probe can 

confirm a positive culture as MTB within few 

days of culture growth; otherwise, speciation 

may take several weeks. Susceptibility testing 

generally takes 3-4 weeks after the initial 

culture growth, depending on what laboratory 

procedures are used. Rapid tests for diagnosis 

of drug resistance allow early identification 

of resistance and optimization of treatment. 

The Xpert MTB/RIF assay is available in the 

United States, and others (including line probe 

assays, nitrate reductase assay, and phagebased assays) are available in other countries. 

Some health departments have in-house 

assays for rifampin resistance. NAA tests for 

TB drug resistance are efficient at screening 

for resistance against drugs for which a single 

mutation (e.g., rifampin) or a few mutations 

(e.g., isoniazid) are responsible. Rapid assays to 

detect mutations that confer resistance to other 

first- and second-line drugs are in development.

Note that a positive TST or IGRA result 

confirms TB infection but does not prove 

active disease (see chapter Latent Tuberculosis). 
Mycobacterium tuberculosis | 481

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Similarly, a negative result may occur in up 

to 35% of HIV-infected persons with active 

TB and does not rule out TB disease. When 

a specific microbiologic diagnosis cannot 

be made or may be delayed (as with TB 

meningitis testing, for which CSF culture 

results may take weeks to obtain or may be 

negative), a positive TST or IGRA result can 

help support the diagnosis and implementation 

of therapy; however, a negative result on these 

tests does not rule out active TB.

Respiratory Precautions

Respiratory infection control precautions should 

be implemented for HIV-infected patients with 

an undiagnosed chronic cough or undiagnosed 

inflammatory infiltrate on chest X-ray. 

Individual institutions have specific guidelines 

that should be followed; patients usually are 

housed in single negative-pressure rooms and 

persons entering the rooms are required to 

wear protective respirators. Patients seen in the 

outpatient setting should wear a mask while 

in the medical facility, and providers should 

wear an N95 respirator when evaluating the 

patient. If three sputum smears yield negative 

results on AFB staining, or if a single deep 

specimen (bronchial lavage or tracheal aspirate) 

is smear negative, infectious TB is unlikely and 

respiratory precautions can be discontinued. 

Patients who are highly suspect for MTB and 

lack an alternative diagnosis may be kept on 

precautions and empiric treatment may be 

started, as transmission of TB from AFB smearnegative, culture-positive TB patients is well 

documented. Persons who have responded 

to treatment for an alternative diagnosis (e.g., 

bacterial pneumonia), and those who cannot 

produce the requisite three sputum samples, 

may be released from the TB precautions.

The impact of TB transmission is greater in a 

health care setting, where immunosuppressed 

persons may be exposed, than at home, 

where exposure has occurred prior to the TB 

evaluation. Of course, children younger than 

age 5 and immunosuppressed persons in the 

home are at increased risk.

Treatment

Treatment for TB should be instituted 

promptly when TB is considered likely and 

the proper specimens to prove the diagnosis 

have been obtained. It is ideal to have a 

positive smear result (and confirmation by 

NAA testing) prior to initiating treatment, 

but empiric treatment should be started 

while the initial specimens are collected from 

patients in whom the suspicion of TB is high, 

in severely ill persons, or in circumstances in 

which positive smear results are unlikely (e.g., 

suspected TB meningitis with AFB smearnegative CSF).

Randomized trials have demonstrated that 

ART decreases mortality in HIV-infected 

persons with active TB regardless of initial 

CD4 cell count; thus, effective ART should 

be initiated or optimized in everyone with 

TB/HIV coinfection; see “Coordinating with 

antiretroviral therapy,” below.

Adherence is the most important treatment 

issue once the decision to treat is made 

and an appropriate regimen is selected. It 

is the responsibility of the treating clinician 

to ensure that the patient completes a full 

course of therapy. Therefore, it is strongly 

recommended that patients be referred to 

public health departments for TB treatment. 

Health departments usually can provide free 

TB treatment and have specific resources 

and systems to promote adherence. It is 

recommended that all patients receive directly 

observed therapy (DOT), an approach by 

which the taking of every dose of anti-TB 

medication is observed and documented. 

Clinical trials have documented that DOT 

with enhancements to maximize adherence 

not only improves the rate of completion of 

therapy but also reduces mortality among 

HIV-infected TB patients. If a health 

department manages the TB treatment, the 

HIV clinician must coordinate with the health 

department for the following reasons: 1) to 

coordinate TB and HIV treatment regimens; 

2) to avoid or adjust for drug interactions; 3) 
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to assist the health department in avoiding 

diagnostic or treatment confusion in the 

event of immune reconstitution inflammatory 

syndrome (IRIS) or incident opportunistic 

diseases; and 4) to maximize adherence with 

the TB medications, ART, opportunistic 

infection treatment or prophylaxis, and any 

other medications.

Treatment consists of two phases: intensive 

and continuation. Several intermittent therapy 

regimens have been designed to simplify 

DOT; however, use of TIW and BIW regimens 

during the intensive phase of treatment have 

led to higher rates of treatment failure and 

resistance, as have weekly or BIW continuation 

phase regimens. Thus, daily (or 5-7 days 

per week) dosing by DOT is recommended 

during the intensive phase of treatment, 

and 5-7 days per week or TIW dosing is 

recommended during the continuation phase.

Preferred therapy (drugsusceptible pulmonary TB)

• Intensive Phase: Isoniazid + rifampin (or 

rifabutin) + pyrazinamide + ethambutol QD 

(5-7 days per week) for 8 weeks, by DOT

• Continuation Phase: isoniazid + rifampin 

or rifabutin 5-7 days per week or TIW

Table 2. Recommended Dosages of First-Line Antituberculosis Drugs for Adults

Drug Daily 3 Times Weekly

Isoniazid 5 mg/kg (usual dose 300 mg) 15 mg/kg (usual dose 900 mg)

Rifampin† 10 mg/kg (usual dose 600 mg) 10 mg/kg (usual dose 600 mg)

Rifabutin*

without HIV protease inhibitors, efavirenz, 

rilpivirine, or elvitegravir/cobicistat

5 mg/kg (usual dose 300 mg) 5 mg/kg (usual dose 300 mg)

with HIV protease inhibitors 150 mg 300 mg

with efavirenz 450-600 mg 450-600 mg

with elvitegravir/cobicistat* 150 mg 150 mg

Pyrazinamide

40-55 kg body weight 1,000 mg (18.2-25.0 mg/kg) 1,500 mg (27.3-37.5 mg/kg)

56-75 kg body weight 1,500 mg (20.0-26.8 mg/kg) 2,500 mg (33.3-44.6 mg/kg)

76-90 kg body weight 2,000 mg (22.2-26.3 mg/kg) 3,000 mg (33.3-39.5 mg/kg)

>90 kg body weight 2,000 mg# 3,000 mg#

Ethambutol

40-55 kg body weight 800 mg (14.5-20.0 mg/kg) 1,200 mg (21.8-30.0 mg/kg)

56-75 kg body weight 1,200 mg (16.0-21.4 mg/kg) 2,000 mg (26.7-35.7 mg/kg)

76-90 kg body weight 1,600 mg (17.8-21.1 mg/kg) 2,400 mg (26.7-31.6 mg/kg)

>90 kg body weight 1,600 mg# 2,400 mg#

† Rifampin is not recommended for patients receiving HIV protease inhibitors, etravirine, nevirapine, rilpivirine, or elvitegravir/cobicistat. Dolutegravir, raltegravir, and maraviroc require dosage adjustment. 

* Avoid coadministration of rifabutin with elvitegravir/cobicistat, if possible. If used together, consider therapeutic drug monitoring 

and dosage adjustment as indicated. Do not coadminister with rilpivirine.

# For patients weighing >90 kg, monitor for therapeutic response can consider therapeutic drug monitoring.

Adapted from Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of 

opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the 

National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.
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Four anti-TB drugs are administered for 

the first 2 months, then two drugs are 

administered for an additional 4 months 

(if the organism is susceptible to standard 

medications). The initial phase of TB treatment 

usually consists of isoniazid, rifampin or 

rifabutin (see below), pyrazinamide, and 

ethambutol; the continuation phase typically 

is simplified to isoniazid and rifampin. 

Pyridoxine (vitamin B6) at a dosage of 10-

50 mg QD usually is included to minimize 

the risk of isoniazid-induced peripheral 

neuropathy. If drug resistance or MDR is 

suspected, more drugs can be used initially, 

and treatment should be directed by experts. 

Resistance may be suspected among persons 

exposed to TB in countries with high rates of 

endemic resistance, those for whom previous 

treatment has failed, those who have been on 

and off treatment erratically, those who may 

have had a specific exposure to drug-resistant 

TB, and those who have been diagnosed 

during an outbreak. If drug susceptibility 

testing shows sensitivity to isoniazid and 

rifampin, ethambutol can be discontinued 

during the intensive phase. 

In certain circumstances, treatment duration 

is extended. In cavitary TB or TB in an HIVinfected person that remains sputum culture 

positive after 2 months of treatment, the twodrug continuation phase should be extended 

to 7 months for a total treatment course of 

9 months. For extrapulmonary TB in HIVinfected persons, a 6- to 9-month course of 

treatment is recommended. Exceptions include 

meningeal TB, which is treated for 9-12 

months. If cultures obtained prior to treatment 

demonstrate drug resistance, the regimen 

and the duration of therapy may need to be 

changed.

For TB meningitis or pericarditis, a course of 

corticosteroids may be given in addition to 

specific anti-TB therapy: dexamethasone 0.3-

0.4 mg/kg/day for 2-4 weeks then tapered over 

the course of 8-10 weeks or prednisone 1 mg/

kg/day for 3 weeks followed by a taper over the 

course of 3-5 weeks. For adrenal insufficiency, 

replacement corticosteroids should be given.

Considerations During pregnancy

Pyrazinamide has not been formally proven 

safe for use during pregnancy; however, it is 

used during pregnancy in many countries 

and there have been no reports of problems. 

Some health departments in the United States 

avoid the use of pyrazinamide for pregnant 

women and extend the continuation phase to 7 

months, whereas others prescribe the standard 

regimens shown in Table 2 during pregnancy. 

Streptomycin and certain second-line drugs 

should be avoided during pregnancy. HIVinfected women in the United States are 

instructed not to breast-feed, so there usually 

are no issues regarding TB treatment of HIVinfected women during breast-feeding. ART 

should be started as early as possible; consult 

with an expert.

Coordinating with Antiretroviral 

Therapy

ART and TB treatment must be coordinated 

for both to be successful. ART is strongly 

recommended for all adults and adolescents 

with active TB, and both randomized and 

nonrandomized trials have demonstrated 

reduction in mortality when ART is combined 

with anti-TB chemotherapy.

The optimal timing of ART initiation in 

relation to TB treatment has been established 

with several randomized controlled trials. 

Adults and adolescents with active TB and 

CD4 counts of <50 cells/μL should start ART 

within 2 weeks of starting TB treatment. All 

patients with CD4 counts of ≥50 cells/μL 

should start ART within 8-12 weeks of starting 

TB therapy, but those who have CD4 counts 

of 50-200 cells/μL and severe disease should 

start within 2-4 weeks, if possible. Further, 

current HHS ARV guidelines recommend 

consideration of early ART (within 2-4 weeks) 
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Section 6: Comorbidities, 

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for patients with CD4 counts of >200 cells/μL 

and severe disease. In all cases, TB treatment 

should be started immediately.

Timing of ART initiation in CNS TB infection 

is not clear. In one randomized trial, there was 

not a mortality benefit to starting ART at 2 

weeks after TB treatment initiation compared 

with starting after 2 months of TB treatment, 

and more severe adverse events occurred in the 

earlier ART arm. Given the capacity for close 

monitoring that exists in the United States, 

many experts recommend initiating ART as 

with non-CNS TB.

Although paradoxical immune response (i.e., 

IRIS, see below) appears to be more common 

in patients who start ART earlier in the course 

of TB treatment, IRIS generally is not fatal.

Drug-drug interactions

Drug interactions between TB medications 

and ARVs may require dosage adjustments 

or modifications in treatment (see Table 3). 

Rifampin is a potent inducer of cytochrome 

P450 enzymes and has many clinically 

important drug interactions. It reduces 

the blood levels of nonnucleoside reverse 

transcriptase inhibitors (NNRTIs), protease 

inhibitors (PIs), integrase inhibitors, and 

the CCR5 antagonist maraviroc, but does 

not affect nucleoside/nucleotide reverse 

transcriptase inhibitors (NRTIs) or the fusion 

inhibitor enfuvirtide. Triple-nucleoside 

regimens can be administered safely during 

rifampin treatment but are less potent than 

first-line ARV combinations and generally 

are not recommended. Current guidelines 

recommend the use of efavirenz plus a 

two-drug NRTI backbone if cotreatment 

with rifampin is planned (see Table 3). 

Efavirenz blood levels may be reduced 25% 

by concomitant rifampin, but the majority 

of available clinical data suggest that that the 

standard efavirenz dosage of 600 mg/day is 

appropriate for rifampin coadministration, 

particularly in African-American and Asian 

populations. Limited clinical data support 

the use of nevirapine at standard dosages 

in combination with rifampin. This is not a 

favored approach because nevirapine levels 

are reduced up to 50% when combined with 

rifampin. In one study, 20% of patients on 

ARV and TB treatment with rifampin had 

trough nevirapine levels that were below target, 

although they achieved the same rates of HIV 

RNA suppression as did patients on efavirenz. 

Plasma levels of the integrase inhibitors 

raltegravir and dolutegravir also are reduced 

when they are given with rifampin but the 

interaction can be overcome by increasing the 

dosage of the integrase inhibitor; few clinical 

data are available on the use of integrase 

inhibitors with rifampin.

To avoid rifampin-ARV interactions, rifabutin 

typically is used in place of rifampin. Rifabutin 

has fewer marked effects on the pharmacokinetics of other drugs, although its own blood 

concentrations can be affected by certain 

ARVs. Dosing recommendations for rifabutin 

with ARVs are found in Table 3. Acquired 

rifamycin resistance has been reported with 

coadministration of rifabutin with protease 

inhibitors, leading to the recommendation 

that the rifabutin dosage be at least 150 mg 

daily when given with ritonavir-boosted PIs 

and that monitoring of serum rifabutin levels 

be considered. Rifabutin is expensive; some 

public health systems do not provide rifabutin 

as part of TB treatment and it often is not 

available in resource-limited countries. The 

FDA characterizes rifabutin in pregnancy 

category B: it has been safe in animal studies 

of pregnancy but has not been proven safe for 

humans. For pregnant women who require 

both TB and ARV therapy, the use of rifabutin 

rather than rifampin allows the use of nonefavirenz-based ARV regimens.

Persons who are already on ART when TB 

treatment is begun must have their ARV 

regimens reassessed; the appropriate dosages 

of rifampin or rifabutin must be chosen or the 

ARV regimen must be modified, at least until 

completion of TB treatment (see Table 3).
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Table 3. Interactions Between Antiretroviral Medications and Rifampin or 

Rifabutin: Contraindicated Combinations and Dosage Adjustments*

Antiretroviral

Agent Rifampin

Rifabutin*

(Preferred in combination with PIs))

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz** ↓ efavirenz AUC; use standard efavirenz 

dosage 600 mg QD with monitoring for 

virologic efficacy (consider 800 mg QD if 

weight >60 kg).

Use standard efavirenz dosage. Increase 

rifabutin to 450-600 mg daily. 

Etravirine ↓ etravirine levels expected; do not 

coadminister.

Etravirine without ritonavir-boosted PI: 

rifabutin 300 mg QD. 

Etravirine with a boosted PI: avoid, or 

consider therapeutic drug monitoring or 

rifabutin.

Nevirapine ↓ nevirapine levels; avoid if possible. If 

used, initiate nevirapine at 200 mg BID 

(no lead-in dosage); do not use nevirapine 

extended-release formulation.

↓ nevirapine and ↑ rifabutin levels. No 

dosage adjustment recommended; use 

cautiously.

Rilpivirine ↓ rilpivirine levels; do not coadminister. ↓ rilpivirine levels; do not coadminister.

Protease Inhibitors

All protease 

inhibitors

↓ protease inhibitor levels; do not 

coadminister.

↑ rifabutin levels; adjust rifabutin dosage 

to 150 mg QD. Monitor for anti-TB efficacy, 

consider therapeutic drug monitoring.

Integrase Inhibitors

Dolutegravir ↓ dolutegravir levels; increase dolutegravir 

to 50 mg BID for integrase-naive patients 

(avoid if integrase resistance).

No dosage adjustment.

Elvitegravir/

cobicistat

↓ elvitegravir and cobicistat levels 

expected; do not coadminister

↓ elvitegravir and ↑ rifabutin levels; do not 

coadminister.

Raltegravir Increase raltegravir dosage to 800 mg BID; 

monitor for virologic response.

No dosage adjustment.

CCR5 Receptor Antagonists

Maraviroc ↓ maraviroc levels; coadministration not 

recommended. If maraviroc must be 

used: Without a strong CYP 3A4 inhibitor: 

maraviroc 600 mg BID. With a strong CYP 

3A4 inhibitor: maraviroc 300 mg BID.

Possible ↓ maraviroc levels. Without a 

strong CYP 3A4 inhibitor: maraviroc 300 

mg BID. With a strong CYP 3A4 inhibitor: 

maraviroc 150 mg BID.

Fusion Inhibitors

Enfuvirtide No dosage adjustment. No dosage adjustment.

Note: Rifapentine should not be coadministered with NNRTIs, PIs, or maraviroc. 

* If available, rifabutin may be substituted for rifampin when TB treatment and ART are combined.

** Avoid use of efavirenz during early pregnancy and with women who may become pregnant while on therapy. Both 

rifampin and rifabutin significantly reduce estrogen and progestin levels for women on hormonal contraceptives; 

efavirenz raises estrogen levels moderately. Two forms of birth control, including one barrier method and either a 

mid- to high-dose hormonal contraceptive or an intrauterine device, are recommended most often.

Adapted from Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of 

opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the 

National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at aidsinfo.nih.gov/

guidelines. Accessed December 1, 2013.
486 | Guide for HIV/AIDS Clinical Care

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Monitoring for efficacy

Ideally, every dose of anti-TB therapy is 

observed and documented by a health care 

agent or responsible individual, particularly 

during the intensive phase. Patients’ adherence 

should be evaluated by a health care team 

member at least weekly during the initial 

phase of treatment and at least weekly or 

monthly during the continuation phase. If 

gaps in medication use occur, the cause must 

be evaluated and a plan to improve adherence 

must be implemented.

In treatment of pulmonary TB, monthly 

sputum specimens should be obtained for 

smear and culture until two sequential 

specimens are sterile on culture. Patients with 

extrapulmonary and disseminated TB usually 

are monitored clinically and with imaging 

studies. Biopsies are not repeated but other 

specimens (CSF and other body fluids) may be 

obtained for repeat AFB smear and culture. 

Monitoring of patients with extrapulmonary 

and disseminated TB should be done in 

consultation with an expert.

Immune reconstitution 

inflammatory syndrome

Patients on treatment for active TB who 

begin ART may experience a paradoxical 

increase in signs and symptoms of TB (fever, 

dyspnea, increased cough, enlarging lymph 

nodes, worsening chest X-ray findings, 

increased inflammation at other involved 

sites, or enlargement of CNS tuberculomas). 

These often are attributable to an enhanced 

immune response against remaining MTB 

organisms that occurs because of immunologic 

improvement from ART. IRIS may occur at 

any point from within 2 weeks up to several 

months after ART is initiated. TB treatment 

failure (potentially owing to an inappropriate 

treatment regimen, inadequate adherence, 

or drug resistance) must be ruled out, and 

the possibility of drug toxicity should be 

considered. In addition, new presentation 

of opportunistic infection or malignancies 

should be considered. Paradoxical IRIS is a 

clinical diagnosis, and it can be made only 

after alternative diagnoses are excluded. If IRIS 

is diagnosed, TB and HIV treatment should 

be continued and symptoms can be managed 

with nonsteroidal antiinflammatory drugs or, 

in severe cases, with corticosteroids. Many 

experts recommend the use of corticosteroids 

particularly in the case of TB IRIS involving 

the CNS (see chapter Immune Reconstitution 

Inflammatory Syndrome).

Adverse effects of anti-TB 

medications

Anti-TB medications may have significant 

adverse effects. The most important adverse 

reactions reported for the commonly used antiTB medications are listed in Table 4. The most 

frequent toxicities of first-line TB medications 

include hepatic enzyme elevations. Before 

initiating TB treatment, conduct a complete 

blood count with platelet count, serum 

creatinine count, liver function tests 

(aspartate aminotransferase [AST], alanine 

aminotransferase [ALT], bilirubin, alkaline 

phosphatase), and hepatitis B and C serology. 

Newly diagnosed TB patients with unknown 

HIV status should be tested for HIV infection.

Patients should be monitored monthly with 

a symptom review to assess possible toxicity, 

and laboratory tests should be performed 

if symptoms suggest adverse effects. For 

patients with liver disease, it may be prudent 

to perform routine laboratory monitoring 

after 1 month on treatment and every 3 

months thereafter. Persons with symptoms 

and aminotransferase elevations ≥3 times 

the upper limit of normal, and asymptomatic 

persons with aminotransferase elevations ≥5 

times the upper limit of normal, should have 

therapy interrupted and should be managed 

thereafter in consultation with an expert.

Patients should be monitored for isoniazidinduced peripheral neuropathy; this adverse 
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effect is rare if pyridoxine is administered 

with isoniazid, as recommended. Testing of 

visual acuity and red-green color vision is 

recommended at the start of therapy with 

ethambutol. Persons on standard ethambutol 

dosages with normal baseline examinations 

should be asked monthly about visual 

disturbances. Patients on higher ethambutol 

dosages and those who have been on 

ethambutol for more than 2 months should 

have periodic eye examinations for acuity and 

color discrimination.

Table 4. Adverse Events Associated with Common Anti-TB Medications

Medication Common Toxicity Rare Toxicity

First-Line Agents

Isoniazid Transient transaminase elevation, 

hepatitis, positive antinuclear 

antibody (ANA)

Peripheral neurotoxicity, lupus-like syndrome, CNS 

effects, hypersensitivity, rash, monoamine poisoning

Rifampin Transient bilirubin elevation, 

transaminase elevations, anorexia, 

nausea, vomiting, hepatitis, redorange discoloration of urine and 

tears

Acute renal failure, shock, thrombocytopenia, 

rash, “flu” syndrome from intermittent doses, 

pseudomembranous colitis, pseudoadrenal crisis, 

osteomalacia, hemolytic anemia

Rifabutin Elevated liver function tests, 

nausea, red-orange discoloration 

of urine and tears

Cytopenias, uveitis, rash

Ethambutol Optic neuritis Skin rash, joint pains, peripheral neuropathy

Pyrazinamide Joint pains, gout, hepatitis Gastrointestinal symptoms, skin 

rash, sideroblastic anemia

Streptomycin Auditory and vestibular nerve 

damage, renal injury

Rash

Second-Line Agents

Moxifloxacin Nausea, diarrhea, dizziness Tendon rupture, hepatoxicity, renal damage, 

prolonged QT interval, skin reactions

Amikacin/

Kanamycin

Auditory, vestibular, renal injury

Adapted from American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of Tuberculosis. MMWR Recomm 

Rep. 2003 Jun 20;52(RR-11):1-77; and Harries A, Maher D, Gramm S; World Health Organization. HIV/TB: A Clinical Manual, 2nd Edition.

Geneva: World Health Organization; 2004:131-2. 
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Patient Education

• All patients with TB-positive sputum or 

bronchoscopy specimens can infect others 

with TB. All close contacts, especially 

children, should be screened for TB as soon 

as possible and given medication to prevent 

(or treat) active disease.

• The health department will be notified of 

each TB case and will provide the required 

follow-up care.

• Patients must take all medicines exactly 

as prescribed. If doses are missed, or if the 

medication is stopped and restarted, the TB 

bacteria can develop resistance to even the 

best medications and become even more 

dangerous. If patients are having trouble 

taking the medication on schedule, they 

should contact their health care provider 

immediately.

• If patients become ill, if their skin or eyes 

turn yellow, or if their urine darkens to a 

“cola” color, they should contact their health 

care provider immediately.

• Patients must keep all follow-up 

appointments. Blood tests will be done 

regularly to ensure that the liver is working 

well, and patients will be checked for 

medication adverse effects. They should 

show their health care provider all 

medications, vitamins, and supplements 

they are taking so that the provider can 

check for drug interactions.

• Rifampin and rifabutin will make urine, 

sweat, and tears turn orange; this is not 

harmful. They will cause staining of plastic 

contact lens; patients should avoid wearing 

contact lenses if they are taking rifamycins.

• Rifampin and rifabutin may cause birth 

control pills to become ineffective. An 

alternative method of contraception should 

be used when the patient is undergoing 

treatment.

• The use of alcohol should be avoided during 

treatment with TB drugs to avoid the risk of 

liver damage.
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References

• Abdool Karim SS, Naidoo K, Grobler A, et 

al. Integration of antiretroviral therapy with 

tuberculosis treatment. N Engl J Med. 2011 

Oct 20;365(16):1492-501.

• Abdool Karim SS, Naidoo K, Grobler A, et 

al. Timing of initiation of antiretroviral drugs 

during tuberculosis. N Engl J Med. 2010 Feb 

25;362(8):697-706.

• American Thoracic Society; Center for 

Disease Control and Prevention; Infectious 

Diseases Society of America. Treatment of 

Tuberculosis. MMWR Recomm Rep. 2003 

Jun 20;52(RR-11):1-77. Available at www.cdc.

gov/mmwr/preview/mmwrhtml/rr5211a1.

htm. Accessed December 1, 2013.

• Blanc FX, Sok T, Laureillard D, et al.; 

CAMELIA (ANRS 1295-CIPRA KH001) 

Study Team. Earlier versus later start of 

antiretroviral therapy in HIV-infected adults 

with tuberculosis. N Engl J Med. 2011 Oct 

20;365(16):1471-81.

• Centers for Disease Control and Prevention. 

Trends in tuberculosis – United States, 2011.

MMWR Morb Mortal Wkly Rep. 2012 Mar 

23;61(11):181-5.

• Centers for Disease Control and Prevention. 

Updated guidelines for the use of nucleic 

acid amplification tests for the diagnosis of 

tuberculosis. MMWR Morb Mortal Wkly 

Rep. 2009 Jan 16;58(1):7-10.

• Havlir D. International randomized 

trial of immediate vs. early ART in HIV+ 

patients treated for TB: ACTG 5221 

STRIDE study. In: Program and abstracts 

of the 18th Conference on Retroviruses 

and Opportunistic Infections; February 

27-March 2, 2011; Boston. [Oral abstract].

• Mandell G, Bennett JE, Dolin R, et al. 

Mandell, Douglas, and Bennett’s Principles 

and Practice of Infectious Diseases, 7th 

Edition. Philadelphia: Churchill Livingstone 

Elsevier; 2010.

• Manosuthi W, Sungkanuparph S, 

Tantanathip P, et al; N2R Study Team. A 

randomized trial comparing plasma drug 

levels and efficacies between 2 nonnucleoside 

reverse transcriptase-inhibitor therapies in 

HIV-infected patients receiving rifampin: 

the N2R study. Clin Infect Dis. 2009 Jun 

15;48(12):1752-9.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Török ME, Yen NT, Chau TT, et al. Timing of 

initiation of antiretroviral therapy in human 

immunodeficiency virus (HIV)-associated 

tuberculous meningitis. Clin Infect Dis. 2011 

Jun;52(11):1374-83.

Pelvic Inflammatory Disease | 491

Section 6: Comorbidities, 

Coinfections, and Complications

Pelvic Inflammatory Disease

Background 

Pelvic inflammatory disease (PID) is the syndrome resulting from the ascent of microorganisms 

from the vagina and cervix to the uterine endometrium, fallopian tubes, ovaries, or contiguous 

abdominal structures. Many episodes of PID go unrecognized, because of lack of symptoms 

or mild, nonspecific symptoms (e.g., dyspareunia, abnormal bleeding, and vaginal discharge). 

Infecting organisms may include Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT), 

which are sexually transmitted, as well as anaerobic bacteria (Gardnerella vaginalis or Haemophilus 

influenzae), gram-negative rods (Escherichia coli), Streptococcus agalactiae, gastrointestinal flora, 

and mycoplasmas (Mycoplasma hominis). It is thought that PID generally is caused by sexually 

transmitted diseases (STDs) and that additional organisms become involved after infection spreads 

and protective immunological barriers are disrupted.

Between 20% and 40% of women with cervical chlamydial infection and 10-20% of women with 

gonococcal infection eventually develop PID, but accurate estimates of the incidence of PID and 

infertility resulting from GC and CT are difficult to obtain. Hospitalizations for PID declined 

steadily throughout the 1980s and 1990s but remained relatively constant between 2000 and 2006, 

at approximately 80,000 annually.

PID is co-epidemic with HIV among some urban populations of reproductive age. Data on PID 

outcomes among HIV-infected women are limited. Many studies have documented no difference 

in length or severity of lower abdominal pain, vaginal discharge, fever, abnormal vaginal bleeding, 

or low back pain between HIV-infected and HIV-uninfected women with PID. However, there is a 

higher rate of tubo-ovarian abscesses and severe salpingitis and pyosalpinx among HIV-infected 

women.

Clinical presentation may include salpingitis, endometritis, tubal and ovarian abscess, and pelvic 

peritonitis, although PID may present with subtle or mild symptoms even in HIV-infected women. 

Long-term complications of PID may include infertility, ectopic pregnancy, pelvic adhesions, 

and chronic pain. After a single episode of PID, a woman’s risk of ectopic pregnancy increases 

sevenfold. Approximately 13% of women are infertile after a single episode of PID, 25-35% after 

two episodes, and 50-75% after three or more episodes.

Diagnosis of PID usually is based on clinical findings, and providers should maintain a low 

threshold for diagnosing and promptly treating this disease, as it can wreak havoc on a woman’s 

reproductive health. All women who are diagnosed with PID should be tested for GC and CT.

S: Subjective

The patient may complain of mild-to-moderate 

lower abdominal pain and tenderness, pain 

with intercourse, vaginal discharge, fever, 

chills, heavy menstrual bleeding, or other 

abnormal vaginal bleeding. 

Inquire about the following during the history:

• Symptoms listed above, and duration

• Sexual history including new sex partner(s) 

and episodes of unprotected sex

• Last menstrual period

• Previous diagnosis of gonorrhea or 

chlamydia

• Previous abdominal or gynecologic surgery

• History of recent intrauterine device (IUD) 

placement (the risk of PID associated with 

IUD use is confined primarily to the first 3 

weeks after insertion)
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O: Objective

Check vital signs with special attention to 

temperature (may be elevated or normal).

Perform a focused physical examination. 

Check abdomen (bowel sounds, distention, 

rebound, guarding, masses, suprapubic and 

costovertebral angle [CVA] tenderness); 

perform complete pelvic examination looking 

for abnormal bleeding or discharge; uterine, 

adnexal, or cervical motion tenderness; pelvic 

masses or adnexal enlargement.

A: Assessment

A partial differential diagnosis includes the 

following:

• Pregnancy, uterine or ectopic

• Ruptured or hemorrhagic ovarian cyst

• Dysmenorrhea

• Appendicitis

• Pyelonephritis

• Diverticulitis

• Irritable bowel syndrome

• Cystitis

• Uterine fibroids/leiomyomas

• Ovarian torsion

• Mittelschmerz

• Kidney stones

• Pyelonephritis

P: Plan

Diagnostic Evaluation

A diagnosis of PID usually is based on clinical 

findings; however, the following can support 

a diagnosis and help rule out other causes of 

abdominal pain:

• Pregnancy test

• Nucleic acid amplification tests (NAAT) or 

culture for GC and CT

• Microscopic examination of saline 

preparation of vaginal secretions

Often, diagnosis must be made and treatment 

initiated on the basis of clinical criteria. Current 

guidelines identify “minimal criteria” found 

on pelvic examination in patients with PID: 

• Cervical motion tenderness, or

• Uterine tenderness, or

• Adnexal tenderness

The following signs support a diagnosis of PID: 

• Oral temperature >101°F (>38.3°C)

• Abnormal cervical or vaginal 

mucopurulent discharge

• Presence of abundant numbers of white 

blood cells on saline microscopy of vaginal 

secretions (this also can detect concomitant 

infections such as bacterial vaginosis and 

trichomoniasis)

• Elevated erythrocyte sedimentation rate (ESR)

• Elevated C-reactive protein (CRP)

• Laboratory documentation of cervical 

infection with GC or CT (the absence of 

infection from the lower genital tract, 

where samples are usually obtained, 

does not exclude PID and should not 

influence the decision to treat)
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Definitive diagnosis may be 

made on the basis of:

• Endometrial biopsy with histopathologic 

evidence of endometritis

• Transvaginal sonogram or other imaging 

showing thickened, fluid-filled tubes with 

or without free pelvic fluid or tubo-ovarian 

complex

• Laparoscopic abnormalities 

consistent with PID

Treatment

Because clinical diagnostic criteria for PID are 

not always conclusive, presumptive diagnosis 

and early empiric treatment is common. The 

positive predictive value of a clinical diagnosis 

is 65-90%.

Empiric therapy for PID should be started in 

women who have one or more of the minimal 

criteria, plus pelvic or lower abdominal pain 

and risk factors for PID (sexually active 

young women, women at risk of STDs), unless 

another cause for the symptoms is identified.

Treatment considerations

Antimicrobial regimens must be broadly 

effective against likely pathogens (see below). 

HIV-infected women appear to respond as 

well to standard antibiotic regimens as do 

HIV-uninfected women. It is not known 

whether HIV-infected women with advanced 

immunosuppression should be treated 

more aggressively; decisions about whether 

to use oral or parenteral therapy must be 

individualized.

In the United States and elsewhere GC 

commonly is resistant to fluoroquinolone; 

thus, this class of antibiotics is no longer 

recommended for treatment of PID.

No evidence suggests that IUDs should be 

removed in women diagnosed with PID. 

However, caution should be used if the IUD 

remains in place, and close clinical follow-up is 

recommended.

The goals of treatment include the following:

• Alleviate the pain and systemic malaise 

associated with infection

• Achieve microbiological cure

• Prevent development of permanent 

tubal damage with associated 

problems, such as chronic pelvic pain, 

ectopic pregnancy, and infertility

• Prevent the transmission of 

infection to others

Indications for hospitalization of patients with 

PID include the following:

• Unsure diagnosis; surgical emergency 

cannot be excluded

• Pregnancy

• Patient does not respond clinically (within 

72 hours) to oral antimicrobial therapy

• Tubo-ovarian abscess

• Severe illness with nausea and vomiting or 

high fever

• Inability to follow or tolerate outpatient 

regimen
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Pregnancy

If the patient is pregnant, aggressive treatment 

is essential to prevent preterm delivery, 

fetal loss, and maternal morbidity. Some 

medications should be avoided to reduce the 

risk of fetal toxicity; these include doxycycline 

and gentamicin. Hospitalization for parenteral 

antibiotic therapy is recommended.

Antibiotic Regimens

Recommended Oral/Outpatient Regimens

• Ceftriaxone 250 mg IM in a single dose + 

doxycycline 100 mg PO BID for 14 days, 

with or without metronidazole 500 mg PO 

BID for 14 days

• Cefoxitin 2 g IM in a single dose and 

probenecid 1 g PO concurrently in a single 

dose + doxycycline 100 mg PO BID for 14 

days, with or without metronidazole 500 mg 

PO BID for 14 days

• Other parenteral third-generation 

cephalosporin (e.g., ceftizoxime or 

cefotaxime) + doxycycline 100 mg PO BID 

for 14 days, with or without metronidazole 

500 mg PO BID for 14 days

Alternative Oral Regimens

If parenteral cephalosporin therapy is not 

feasible, consult with an expert. Limited 

evidence supports the use of amoxicillin/

clavulanic acid with doxycycline, and 

azithromycin with or without metronidazole 

or ceftriaxone. Because of the prevalence 

of fluoroquinolone-resistant GC, use of 

fluoroquinolones is no longer recommended 

but may be considered, with or without 

metronidazole, if the community prevalence 

is low, the patient’s risk of gonorrhea is low, 

and follow-up can be assured if the GC test 

result is positive. For more information, see the 

CDC Sexually Transmitted Diseases Treatment 

Guidelines (see “References,” below).

Recommended Parenteral Regimens

• Cefotetan 2 g IV Q12H + 

doxycycline 100 mg PO BID

• Cefoxitin 2 g IV Q6H + 

doxycycline 100 mg PO BID

• Clindamycin 900 mg IV Q8H + gentamicin 

loading dose IV or IM (2 mg/kg of body 

weight), followed by a maintenance dose 

(1.5 mg/kg) Q8H; single daily dosing 

(3-5 mg/kg) may be substituted

Alternative Parenteral Regimen

• Ampicillin/sulbactam 3 g IV Q6H + 

doxycycline 100 mg PO BID

Women who are started on oral antibiotics 

but do not respond within 72 hours should 

be reevaluated to confirm the diagnosis of 

PID and should be administered parenteral 

therapy on either an outpatient or inpatient 

basis. Patients who are treated with parenteral 

antibiotics usually can be transitioned to 

oral antibiotics within 24 hours of clinical 

improvement.

Follow-Up

• Patients should show significant clinical 

improvement within 3 days of initiation 

of therapy (e.g., improvement in fever, 

abdominal tenderness, and uterine, 

adnexal, and cervical motion tenderness). 

If the patient has not improved, consider 

hospitalization, additional diagnostic 

testing, or surgical intervention. Patients 

who are hospitalized for treatment initially 

may be switched to an oral regimen and be 

discharged on oral therapy after they have 

improved clinically.

• Evaluate sex partners and offer them 

treatment if they had sexual contact with 

the patient during the 60 days preceding 

the patient’s onset of symptoms. Treat 

empirically for both chlamydia and 

gonorrhea.

• If the GC or CT test results are positive, 

rescreening for GC and CT 3 months after 

therapy is recommended. Provide education 

about sexual risk reduction. Instruct patients 
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Section 6: Comorbidities, 

Coinfections, and Complications

to use condoms with every sexual contact 

to prevent reinfection with GC and CT, to 

prevent other STDs, and to prevent passing 

HIV to sex partners.

• Studies of patients treated for CT infection 

show reinfection rates as high as 13% within 

4 months of treatment, highlighting the 

need for follow-up and partner treatment.

Patient Education

• Instruct patients to take all of their 

medications. Advise patients to take 

medications with food if they feel nauseated, 

and to contact the clinic promptly if they 

experience vomiting or are unable to take 

their medications.

• Sex partners from the previous 60 days 

need to be tested for CT, GC, and syphilis 

(as well as HIV, if uninfected) and treated 

empirically, as soon as possible, with a 

regimen effective against GC and CT, even 

if they have no symptoms. Advise patients 

to inform their partners that they need to be 

tested and treated. Otherwise, they may be 

reinfected.

• Advise patients to avoid sexual contact until 

the infection has been cured.

• Provide education about sexual risk 

reduction. Instruct patients to use condoms 

with every sexual contact to prevent 

becoming reinfected, to prevent other STDs, 

and to prevent passing HIV to sex partners.

• Advise patients that PID can recur, and that 

they should contact the clinic if symptoms 

such as pain or fever develop.

• Patients must not drink beer, wine, or 

any other alcoholic beverage while taking 

metronidazole, and for at least 24-48 hours 

after the last dose. Metronidazole may cause 

a disulfiram-like reaction, resulting in severe 

nausea and vomiting. Note that patients 

taking ritonavir capsules may experience 

symptoms caused by the small amount of 

alcohol in the capsules; advise patients to 

contact the clinic if nausea and vomiting 

occur.

References

• Abularach S, Anderson J. Gynecologic 

Problems. In: Anderson JR, ed. A Guide 

to the Clinical Management of Women 

with HIV. Rockville, MD: Health 

Resources and Services Administration, 

HIV/AIDS Bureau; 2005. Available at 

hab.hrsa.gov/deliverhivaidscare/files/

clinicalcareguide2005.pdf. Accessed 

December 1, 2013.

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. MMWR 2010 Dec 17; 

59 (No. RR- 12):1-110. Available at www.

cdc.gov/STD/treatment/2010. Accessed 

December 1, 2013.

• Cohn SE, Clark RA. Sexually transmitted 

diseases, HIV, and AIDS in women. In: The 

Medical Clinics of North America, vol. 87; 

2003:971-995.

• Handsfield HH, Sparling PF. Gonococcal 

Infections. In: Goldman L, Ausiello D, eds. 

Cecil Medicine; 23rd edition. Philadelphia: 

Saunders Elsevier; 2007.

• Handsfield HH, Sparling PF. Neisseria 

Gonorrhoeae. In: Mandell GL, Bennett 

JE, Dolin R, eds. Mandell, Douglas, and 

Bennett’s Principles and Practice of Infectious 

Diseases. Vol. 7. New York: Churchill 

Livingstone; 2010.

• Trigg BG, Kerndt PR, Aynalem G. 

Sexually transmitted infections and pelvic 

inflammatory disease in women. Med Clin 

North Am. 2008 Sep;92(5):1083-113, x.

Pneumocystis Pneumonia | 497

Section 6: Comorbidities, 

Coinfections, and Complications

Pneumocystis Pneumonia

Background

Pneumocystis jiroveci pneumonia (previously called Pneumocystis carinii pneumonia, and still 

abbreviated PCP), is caused by an unusual fungus, P. jiroveci. Many humans appear to be infected 

in childhood, but clinical illness occurs only in people with advanced immunosuppression, either 

through new infection or reactivation of latent infection. More than 90% of PCP cases occur in 

patients with CD4 counts of <200 cells/μL. Cases of PCP in otherwise healthy young men who 

have sex with men were among the first recognized manifestations of AIDS, in 1981. The organism 

can affect many organ sites, but pneumonia is by far the most common form of disease. In the 

United States, the incidence of PCP has declined sharply since the use of prophylaxis and effective 

antiretroviral therapy (ART) became widespread, but PCP is still many patients’ initial presenting 

opportunistic infection, and it is a significant cause of morbidity and mortality among HIVinfected patients.

S: Subjective

The patient reports fever, shortness of breath, 

particularly with exertion, nonproductive 

cough, night sweats, weight loss, or fatigue. 

Typically, the symptoms worsen over the 

course of days to weeks. Pleuritic pain and 

retrosternal pain or burning also may be 

present. There may be minimal symptoms 

early in the disease course of PCP.

Ask the patient about fever, fatigue, and weight 

loss, which may be present for weeks, with 

gradual worsening of shortness of breath. PCP 

may present less commonly with acute onset 

symptoms of fevers, chills, sweats, dyspnea, 

and cough.

Note: Given the possibility of HIV-associated 

tuberculosis (TB), patients with cough should 

be kept in respiratory isolation until TB is 

ruled out. 

O: Objective

Perform a full physical examination, with 

particular attention to the following:

• Vital signs, including temperature, heart 

rate, blood pressure, respiratory rate, oxygen 

saturation at rest and after exertion (there is 

often a sharp drop in oxygen saturation with 

exertion)

• Appearance

• Lung examination

Patients may appear relatively well, or acutely 

ill. Tachypnea may be pronounced, and 

patients may exhibit such a high respiratory 

rate (e.g., >30 breaths per minute) that they are 

unable to speak without stopping frequently to 

breathe. Chest examination may be normal, or 

reveal only minimal rales, although coughing 

is common on deep inspiration. Cyanosis may 

be present around the mouth, in the nail beds, 

and on mucous membranes. Cough is either 

unproductive, or productive of a thin layer of 

clear or whitish mucus. 

A: Assessment

A partial differential diagnosis 

includes the following:

• Pneumococcal pneumonia

• Other bacterial pneumonias

• TB

• Influenza Lymphocytic interstitial 

pneumonitis

• Bronchitis

• Cytomegalovirus (CMV) pneumonitis

• Histoplasmosis
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• Other fungal pneumonia, especially 

cryptococcosis

• Pulmonary Kaposi sarcoma

• Mycobacterium avium complex

• Asthma, chronic obstructive 

pulmonary disease

• Congestive heart failure

• Pulmonary hypertension

P: Plan

Diagnostic Evaluation

• CD4 cell count: Check records for a recent 

CD4 count (CD4 is <200 cells/μL in >90% of 

PCP cases). Note that a CD4 count obtained 

in the setting of acute illness (e.g., when the 

patient presents with pneumonia) may be 

substantially lower than the usual baseline, 

and may be difficult to interpret. 

• Pulse oximetry at rest and after exercise: 

Oxygen desaturation with exercise suggests 

an abnormal alveolar-arterial O2 gradient 

(A-a gradient). 

• Arterial blood gas (ABG): Hypoxemia is 

common, as is elevation in A-a gradient. 

Generally, PO2 levels and A-a gradient are 

associated with disease severity. Poorer 

outcomes are seen with PO2 <70 mm Hg and 

A-a gradient >35 mm Hg. 

• Lactate dehydrogenase (LDH): Elevated 

serum LDH (>300-500 IU/L) is common. 

• Chest X-ray: Typically shows bilateral 

interstitial infiltrates, but atypical patterns 

with cavitation, lobar infiltrates, nodules, 

or pneumothorax may occur, and chest 

X-ray findings may be normal in some cases. 

Upper-lobe predominance is common if the 

patient is receiving aerosolized pentamidine 

for PCP prophylaxis. 

• Thin-section chest computed tomography 

(CT) scan: May show patchy ground-glass 

opacities; in a patient with clinical signs or 

symptoms of PCP, these are suggestive but 

not diagnostic of PCP. 

• Sputum induction: The patient inhales 

saline mist to mobilize sputum from the 

lungs. The respiratory therapist collects 

expectorated sputum, which is stained 

and examined for P. jiroveci organisms. 

This technique is useful because of its 

noninvasive approach, but it requires an 

experienced technician, and is not available 

at all centers. Sensitivity varies widely (10-

95%), depending on the expertise level of 

the staff at a particular center. (If there is 

any chance that the patient has TB, sputum 

induction should be performed in a confined 

space in a negative pressure area or near 

an exhaust fan vented safely outside, and 

samples should be sent for acid-fast bacilli 

[AFB] smear and culture.) 

• Bronchoscopy with bronchoalveolar lavage 

(BAL): Definitive diagnosis usually can be 

made through detection of organisms in 

BAL fluid obtained during bronchoscopy. 

Sensitivity is >95% at centers with an 

experienced staff. BAL fluid can be evaluated 

for bacteria, mycobacteria, and fungi, as well 

as for P. jiroveci. Polymerase chain reaction 

(PCR) testing increasingly is used; its 

specificity has not been well established.

• Transbronchial biopsy: May be performed 

if BAL is not diagnostic and if lung disease 

is progressive despite treatment, to look for 

diagnoses other than PCP. Open lung biopsy 

rarely is performed.
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Treatment

Presumptive treatment often is initiated on 

the basis of clinical presentation, chest X-ray 

findings, and ABG results, while definitive 

diagnostic tests are pending. The standard 

and alternative treatment regimens are shown 

below. Duration of treatment is 21 days for all 

regimens.

Trimethoprim-sulfamethoxazole (TMPSMX, Bactrim, Septra, cotrimoxazole) is the 

drug of choice, administered IV or PO for 21 

days (a typical PO dose is 2 double-strength 

tablets taken TID). Adverse effects of TMPSMX (e.g., rash, fever, leukopenia, anemia, 

gastrointestinal intolerance, hepatotoxicity, 

hyperkalemia) are common, mostly mild, and 

usually “treated through” successfully. Patients 

who have had previous reactions to sulfa 

drugs also may be desensitized successfully 

(see chapter Sulfa Desensitization). TMP-SMX 

requires dosage adjustment for patients with 

renal insufficiency.

Pentamidine has similar efficacy to TMPSMX but greater toxicity (nephrotoxicity, 

pancreatitis, glucose dysregulation, cardiac 

arrhythmias). It usually is reserved for patients 

with severe disease who require IV therapy.

Adjunctive corticosteroids

Adjunctive corticosteroids should be given 

if the patient’s PO2 is <70 mm Hg (breathing 

room air) or the A-a gradient is ≥35 mm Hg. 

Corticosteroids should be given as early as 

possible (preferably before or with the first 

dose of antibiotic therapy) and within 36-72 

hours of the start of anti-PCP therapy: 

• Prednisone 40 mg BID days 1-5; 40 mg 

QD on days 6-10; 20 mg QD on days 11-21. 

Alternatively, IV methylprednisolone can be 

given, at 75% of the prednisone dosage.

Moderate to Severe PCP

Preferred therapy

• TMP-SMX (TMP 15-20 mg/kg/day + SMX 75- 100 mg/kg/day) IV in divided doses Q6H or Q8H (switch to PO 

after clinical improvement) 

Alternative therapy

• Pentamidine 4 mg/kg IV QD (dosage reduction to 3 mg/kg QD may be needed if toxicities develop)

• Clindamycin 600 mg IV or 900 mg IV Q8H (or 300 mg PO Q6H or 450 mg PO Q8H) + primaquine* base

30 mg PO QD

Mild to Moderate PCP

Preferred therapy

• TMP-SMX (TMP 15-20 mg/kg/day + SMX 75- 100 mg/kg/day) PO, in divided doses TID

• TMP-SMX double-strength (DS), 2 tablets TID

Alternative therapy

• Dapsone* 100 mg PO QD + TMP 15 mg/kg/day PO in 3 divided doses 

• Clindamycin (300 mg PO Q6H or 450 mg PO Q8H) + primaquine* base 30 mg PO QD

• Atovaquone 750 mg PO BID with food

* Test for G6PD deficiency before use (most common among patients of African or Mediterranean descent); caution with use in patients 

with GCPD deficiency.
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Other therapy notes

• Patients started on IV therapy can be 

switched to a PO treatment regimen to 

complete the 3-week course when they are 

afebrile, have improved oxygenation, and are 

able to take oral medications.

• For patients not already on ART, ART 

generally should be started within 2 weeks of 

initiating treatment for PCP. 

• Paradoxical worsening of PCP resulting 

from presumed immune reconstitution 

inflammatory syndrome (see chapter 

Immune Reconstitution Inflammatory 

Syndrome) has been reported; monitor 

patients for worsening symptoms after ART 

initiation.

• Consultation with HIV experts is advisable 

when initiating of ART in the setting of PCP.

Treatment failures

The average time to clinical improvement for 

hospitalized patients is 4-8 days, so premature 

change in therapy should be avoided. For 

patients who fail to improve on appropriate 

therapy, it is important to exclude other 

diagnoses, rule out fluid overload, and consult 

an infectious disease specialist. 

Secondary Prophylaxis

Anti-PCP prophylaxis (chronic maintenance 

therapy) should be given to all patients who 

have had an episode of PCP. Prophylaxis 

should be continued for life, unless immune 

reconstitution occurs as a result of ART and 

the CD4 count has been >200 cells/μL for more 

than 3 months.

In patients with stable CD4 count of >200 

cells/μL on effective ART, it is recommended 

that PCP prophylaxis be discontinued 

because it offers little clinical benefit but may 

cause drug toxicity, drug interactions, and 

selection of drug-resistant pathogens, plus it 

adds to the cost of care and to the patient’s 

pill burden.

If PCP occurred at a CD4 count of >200 cells/

μL, it is recommended to continue prophylaxis 

for life despite immune reconstitution; 

however, data to support this approach are 

limited.

Prophylactic therapy

Preferred:

• TMP-SMX DS, 1 tablet PO QD, or 1 singlestrength tablet PO QD

Alternative:

• TMP-SMX DS: 1 tablet PO TIW (e.g., 

Monday, Wednesday, Friday)

• Dapsone* 100 mg PO QD, or 50 mg PO BID

• Dapsone* 50 mg PO QD + pyrimethamine 

50 mg PO once weekly + leucovorin 25 mg 

PO once weekly

• Dapsone* 200 mg PO + pyrimethamine 75 

mg + leucovorin 25 mg, all once weekly

• Aerosolized pentamidine 300 mg once 

monthly, via Respirgard II nebulizer (note: 

does not prevent toxoplasmosis) (Warning: 

May increase the risk of extrapulmonary 

pneumocystosis, pneumothorax, and 

bronchospasm.)

• Atovaquone 1,500 mg PO QD (with or 

without pyrimethamine 25 mg PO QD + 

leucovorin 10 mg PO QD)

* Use with caution in G6PD deficiency.

Primary Prophylaxis

• Primary prophylaxis against PCP should 

be given to all HIV-infected patients with a 

CD4 count of <200 cells/μL, CD4 percentage 

of <14%, or a history of oral candidiasis; see 

chapter Opportunistic Infection Prophylaxis.
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Patient Education

• Patients should be instructed to take all 

medications exactly as prescribed.

• Patients should call their health care 

provider if symptoms worsen.

• Patients being treated with TMP-SMX or 

dapsone who develop rash, fever, or other 

new symptoms should call their provider to 

be evaluated for a drug reaction.

• Patients should understand that taking antiPCP prophylaxis is extremely important 

for preventing repeat episodes of illness. 

Patients should not stop taking these 

medicines without talking with their health 

care provider, and should not let their supply 

of medications run out.

• Patients should be counselled about the 

importance of ART in restoring immune 

system function to reduce the likelihood of 

illness and death from PCP and other OIs.

References

• Leoung GS. Pneumocystosis and HIV.

In: Coffey S, Volberding PA, eds. HIV 

InSite Knowledge Base [textbook online]; 

San Francisco: UCSF Center for HIV 

Information; April 2005. Available at 

hivinsite.ucsf.edu/InSite?page=kb00&doc=kb-05-02-01.

• Masur H. Pneumocystosis. In: Dolin R, 

Masur H, Saag MS, eds. AIDS Therapy, 2nd 

Edition. Philadelphia: Churchill Livingstone; 

2003:403-418.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Zolopa A, Andersen J, Powderly W, et al. 

Early antiretroviral therapy reduces AIDS 

progression/death in individuals with acute 

opportunistic infections: a multicenter 

randomized strategy trial. PLoS One. 

2009;4(5):e5575.

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Progressive Multifocal 

Leukoencephalopathy

Background

Classic PML

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central 

nervous system (CNS) caused by reactivation of latent infection with JC virus, a polyomavirus that 

infects and lyses oligodendrocytes. Demyelination can occur along any part of the white matter, 

and often does so at multiple sites (hence the term multifocal). The severity of symptoms increases 

as demyelination progresses.

Among HIV-infected patients, PML occurs classically and most frequently in those with CD4 

counts of <200 cells/μL who are not receiving antiretroviral therapy (ART), but it can occur in 

patients with higher CD4 counts and in those on suppressive ART. Patients typically present with 

multiple focal deficits of the cerebrum and brainstem, such as cognitive decline, focal weakness, 

and cranial nerve palsies, with one focal deficit often predominating. Symptoms typically progress 

over the course of several weeks. Imaging studies show noninflammatory, nonenhancing white 

matter lesions, without mass effect, with an anatomical location that maps to deficits on the 

neurological examination. A presumptive diagnosis of PML often can be made on the basis of 

the patient’s clinical presentation and results of neuroimaging studies. Cerebrospinal fluid (CSF) 

often tests positive for JC virus DNA by polymerase chain reaction (PCR), although brain biopsy is 

sometimes needed for definitive diagnosis.

Among untreated patients, the interval between the first manifestation of neurologic symptoms 

and death may be as short as 3-4 months. Although the prognosis for patients with PML has 

improved with the use of potent ART, there is no specific treatment for PML, and mortality rates 

remain high. Patients who survive PML are likely to have permanent neurologic deficits.

Inflammatory PML

Whereas PML in the absence of ART usually is not an inflammatory condition, initiation of 

ART may cause an immune reconstitution inflammatory syndrome, involving new or worsening 

neurologic deficits and inflammatory changes seen on brain imaging and biopsy specimens. 

(See chapter Immune Reconstitution Inflammatory Syndrome.) The initiation of ART in a patient 

with late-stage HIV-related disease may even reveal previously undetected PML. Although 

many patients with inflammatory PML improve or at least stabilize, some suffer exacerbation of 

symptoms, rapid progression of disease, cerebral edema, herniation, and death. 
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S: Subjective

The patient or a caregiver may note symptoms 

such as weakness, gait abnormalities, 

difficulties with speech, visual changes, 

altered mental status, personality changes, 

and seizures. Hemianopia, ataxia, dysmetria, 

and hemiparesis or hemisensory deficits 

often are seen. The onset is likely to be 

subacute, with progression over the course 

of weeks, though neurologic disturbances 

may become profound. PML is not associated 

with headache or fever (except in cases of 

immune reconstitution PML); this may help 

to distinguish it from other opportunistic 

illnesses of the CNS.

O: Objective

• Measure vital signs.

• Perform a full physical examination, 

including a thorough neurologic and 

mental status evaluation. Look for focal or 

nonfocal neurologic deficits, particularly 

cranial nerve abnormalities, visual field 

defects, weakness, gait abnormalities, and 

abnormalities in cognitive function, speech, 

or affect; deficits are likely to be multiple. 

The patient typically is alert.

• Review previous laboratory values, 

particularly CD4 count (usually <200 cells/

μL in patients with PML).

A: Assessment

Rule out other causes of the patient’s 

neurologic changes. A partial differential 

diagnosis includes the following:

• CNS lymphoma

• Toxoplasmosis

• HIV encephalopathy

• HIV dementia

• Other (non-HIV) forms of dementia

• Cerebrovascular disease

• Neurosyphilis

• CNS opportunistic infection (e.g., 

tuberculosis, cryptococcosis, and 

cytomegalovirus)

• Multiple sclerosis

P: Plan

Diagnostic Evaluation

Presumptive diagnosis of PML often is made 

on the basis of clinical presentation, brain 

imaging, and laboratory tests. 

Definitive diagnosis requires detection 

of JC virus DNA in CSF of patients with 

radiographic and clinical findings consistent 

with PML or a brain biopsy and identification 

of characteristic pathological changes. 

Definitive diagnosis should be attempted in all 

patients, if possible, and particularly in those 

patients for whom the diagnosis is unclear.

Radiographic Studies

CNS imaging may reveal changes typical of 

PML, but is nonspecific. Magnetic resonance 

imaging (MRI) is more sensitive than 

computed tomography (CT) for detecting 

PML. Classic PML presents as single or 

multiple hypodense lesions in the subcortical 

white matter, with no surrounding edema. On 

MRI, lesions show increased T2 signal and 

little or no enhancement with gadolinium. On 

CT, PML lesions typically are nonenhancing. 

In some patients, and particularly in 
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patients taking ART, PML lesions may show 

inflammatory changes, such as enhancement, 

and there may be cerebral edema.

CSF Evaluation

• CSF cell count, protein level, and glucose 

level generally are normal or show mild 

pleocytosis and slightly elevated protein.

• JC virus PCR assays are approximately 75-

85% sensitive (lower in patients on ART); 

detection of JC virus in a patient whose 

clinical presentation and radiographic 

imaging results are consistent with PML is 

adequate to make a diagnosis. A negative 

result with JC virus PCR does not rule out 

PML.

Other Studies

• Other diagnostic tests should be performed 

as indicated to rule out other potential 

causes of the patient’s symptoms.

• A brain biopsy should be considered if the 

diagnosis is unclear.

Treatment

• There is no specific treatment for JC virus. 

Potent ART with maximal virologic 

suppression and effective immune 

reconstitution is the only treatment that may 

be effective for patients with PML. Even with 

ART, however, mortality rates approach 40-

50%, and neurologic deficits are unlikely to 

be reversed.

• Initiate ART for patients who are not already 

receiving treatment. It is not clear whether 

antiretroviral agents with good CNS 

penetration are more effective than those 

that are less likely to cross the blood-brain 

barrier.

• For patients who are on ART with 

incomplete virologic suppression, change 

the ART regimen appropriately to achieve 

virologic suppression, if possible. (See 

chapter Antiretroviral Therapy.)

• If symptoms are caused by immune 

reconstitution, consider adding 

corticosteroids (e.g., dexamethasone or 

methylprednisolone) to help decrease 

inflammation.

• The following agents have been proposed as 

specific therapy for PML, but have not been 

shown to be effective by prospective studies 

and are not recommended for treatment: 

cidofovir, cytarabine, and topotecan. Few 

data exist to assess the potential benefit 

of interferon-alfa and inhibitors of the 

serotonergic 5-HT2a receptor.

• Depending on the patient’s cognitive 

and physical status, he or she may need a 

care provider in the home to assure that 

medications are taken on schedule.

• The patient is likely to need supportive care 

for personal hygiene, nutrition, safety, and 

prevention of accidents or injury; refer as 

indicated.

Patient Education

• Most patients diagnosed with PML will need 

supportive treatment for an undetermined 

period of time, and hospice referral should 

be considered if the patient does not show 

clinical improvement in response to ART.

• If the patient is receiving ART, be sure that 

caregivers, family members, and friends are 

taught about the medications and are able to 

help the patient with adherence.

• When a diagnosis of PML has been 

established or suspected, initiate a 

discussion of plans for terminal care 

(including wills, advanced directives, and 

supportive care and services) with the 

patient and family members or caregivers.
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References

• Aksamit AJ. Review of progressive multifocal 

leukoencephalopathy and natalizumab. 

Neurologist. 2006 Nov;12(6):293-8.

• Koralnik IJ. New insights into progressive 

multifocal leukoencephalopathy. Curr Opin 

Neurol. 2004 Jun;17(3):365-70.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Wyen C, Lehmann C, Fatkenheuer G, et 

al. AIDS-related progressive multifocal 

leukoencephalopathy in the era of HAART: 

report of two cases and review of the 

literature. AIDS Patient Care STDS. 2005 

Aug;19(8):486-94.
Seborrheic Dermatitis | 507

Section 6: Comorbidities, 

Coinfections, and Complications

Seborrheic Dermatitis

Background 

Seborrheic dermatitis is one of the most common skin manifestations of HIV infection. It occurs in 

3-5% of the general HIV-uninfected population but in up to 85-95% of patients with advanced HIV 

infection. Among HIV-infected individuals, seborrheic dermatitis often begins when their CD4 

counts drop to the 450-550 cells/μL range. The disease is more likely to occur among young adults 

(because they have oilier skin) and males, and is more common in areas with cold, dry winter air. 

It is rarely found in African blacks, unless the person is immunocompromised. It is more common 

during times of mental stress and severe illness.

Seborrheic dermatitis is a scaling, inflammatory skin disease that may flare and subside over time. 

It is characterized by itchy reddish or pink patches of skin, accompanied by greasy flakes or scales. 

It most commonly occurs in the scalp and on the face, especially at the nasolabial folds, eyebrows, 

and forehead, but also may develop on the ears, chest, upper back, axillae, and groin. Dandruff 

is considered to be a mild form of seborrheic dermatitis. Occasionally, seborrheic dermatitis 

may be severe, may involve large areas of the body, and may be resistant to treatment. Severe 

manifestations are more likely with advanced HIV infection.

The etiology of seborrheic dermatitis is not entirely clear. Malassezia yeast (formerly called 

Pityrosporum ovale), a fungus that inhabits the oily skin areas of 92% of humans, is the most likely 

culprit. This same yeast also is thought to cause tinea versicolor and Pityrosporum folliculitis. 

Overgrowth of the Malassezia yeast in the oily skin environment, failure of the immune system to 

regulate the fungus, and the skin’s inflammatory reaction to the yeast overgrowth appear to be the 

chief factors that cause the dermatitis.

S: Subjective

The patient complains of a new rash, 

sometimes itchy, or of “dry skin” that will 

not go away despite the application of topical 

moisturizers.

O: Objective

Perform a thorough evaluation of the skin 

with special attention to the scalp, medial 

eyebrows, eyelashes and eyelids, beard and 

other facial hair areas, nasolabial folds, 

postauricular areas, the concha of the auricle, 

glabella, umbilicus, central chest, back, axillae, 

and groin. Seborrheic dermatitis appears as 

white to yellow greasy or waxy flakes over 

red or pink patches of skin; however, discrete 

fine scales may indicate a mild form of the 

disease. Around the eyes, seborrheic dermatitis 

can cause eyelid erythema and scaling. The 

distribution usually is symmetrical.

A: Assessment

The diagnosis of seborrheic dermatitis is based 

on the characteristic appearance. A partial 

differential diagnosis includes psoriasis, atopic 

dermatitis, contact dermatitis, erythrasma, 

tinea capitis (can be present on the scalp 

without hair loss), rosacea, and rarely, 

dermatomyositis. 

P: Plan

Treatment

• Initiate antiretroviral therapy (ART) for 

patients not on ART
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• Specific treatments are divided into 

three types: antimycotic (first choice), 

antiinflammatory (second choice), and 

keratolytic. Shampoos may be used on the 

entire body, with avoidance of eyes and 

mucous membranes. 

• Topical antifungal medications: The azoles 

and ciclopirox have been well studied 

and shown to have both antifungal 

and antiinflammatory activity. Various 

preparations are available; selection can be 

based on cost and availability. Antifungals 

may be used in combination with topical 

corticosteroid therapy (see below). Effective 

antifungals include but are not limited to the 

following: 

• Ketoconazole (Nizoral) 2% cream or 

shampoo; ketoconazole is one of the most 

widely studied of all topical treatments 

• Bifonazole ointment, miconazole cream 

(Monistat), terbinafine (Lamisil) 1% 

solution or cream, or clotrimazole 

(Lotrimin) 1% cream, lotion, or solution 

• Ciclopiroxolamine (Loprox) 1% shampoo, 

gel, or cream

• Zinc pyrithione (keratolytic/antifungal) 

shampoo or cream

• Topical corticosteroids generally are 

effective and may be used in combination 

with topical antifungal therapy (see above). 

Low-potency agents (e.g., hydrocortisone 

1%) rather than high-potency corticosteroids 

(e.g., betamethasone dipropionate, 

triamcinolone), are recommended, especially 

for the face, to reduce the risk of adverse 

effects associated with all corticosteroids 

(e.g., atrophy, telangiectasias, and perioral 

dermatitis). Corticosteroid shampoos also 

may be considered for scalp involvement. 

• Selenium sulfide/sulfur preparations (the 

most common is selenium sulfide shampoo). 

• Whole coal tar, crude coal tar extract: 

shampoos, creams, and gels. 

• Lithium succinate or lithium gluconate 

ointment, available in some countries as a 

combination of lithium succinate 8% and 

zinc sulfate 0.05% (may have antifungal or 

antiinflammatory effects). Not for use on the 

scalp. 

• Honey, 90% diluted with warm water, may 

be used to treat seborrheic dermatitis and 

dandruff. 

• Azelaic acid, 15% gel or 20% cream, has 

sebosuppressive, antimicrobial, antifungal, 

and antiinflammatory activity (also used for 

acne and rosacea). 

• Noncorticosteroid topical 

immunomodulators (calcineurin inhibitors): 

• Tacrolimus

• Pimecrolimus

• Oral therapy may be used for patients 

who are refractory to topical treatment 

(may interact with protease inhibitors 

and nonnucleoside reverse transcriptase 

inhibitors; check for possible drug-drug 

interactions with antiretroviral and other 

medications before prescribing). There 

are limited data regarding the efficacy of 

systemic medication. 

• Fluconazole 300 mg once weekly for

2 weeks

• Itraconazole 200 mg QD for 7 days

• Ketoconazole 200 mg QD for no more 

than 4 weeks

• Terbinafine 250 mg QD for 4 weeks
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Potential adverse effects:

• With all topical products: skin burning, 

stinging, dryness; allergic or contact 

dermatitis. Tar shampoos may discolor light 

hair, leave an oily film on hair, and leave 

an odor. Coal tar may be carcinogenic; use 

shampoo no more than twice a week, leave 

on skin or hair for 5 minutes, and rinse well.

• Topical corticosteroids may cause skin 

atrophy, telangiectasias, folliculitis, striae, 

and excessive hair growth. Risk of adverse 

effects can be mediated by using product 

infrequently, diluting the product, or 

limiting the amount of time the product is 

on the skin. 

• With oral therapy, monitor for hepatotoxicity.

Patient Education

• Although topical and oral medicines can 

relieve symptoms, recurrence is common. 

Effective antiretroviral therapy should 

be considered to control the effects of 

HIV on the immune system and thereby 

decrease exacerbations and the severity 

of seborrheic dermatitis associated with 

immunosuppression. 

References

• Bikowski J. Facial seborrheic dermatitis: 

A report on current status and therapeutic 

horizons. J Drugs Dermatol. 2009 

Feb;8(2):125-33.

• Dunic I, Vesic S, Jevtovic DJ. Oral 

candidiasis and seborrheic dermatitis in 

HIV-infected patients on highly active 

antiretroviral therapy. HIV Med. 2004 

Jan;5(1):50-4.

• Faergemann J, Bergbrant IM, Dohse M, et 

al. Seborrhoeic dermatitis and Pityrosporum 

(Malassezia) folliculitis: characterization of 

inflammatory cells and mediators in the skin 

by immunohistochemistry. Br J Dermatol. 

2001 Mar;144(3):549-56.

• Gupta AK, Bluhm R. Seborrheic dermatitis. 

J Eur Acad Dermatol Venereol. 2004 

Jan;18(1):13-26; quiz 19-20.

• Gupta AK, Ryder JE, Nicol K, et al. 

Superficial fungal infections: an update on 

pityriasis versicolor, seborrheic dermatitis, 

tinea capitis, and onychomycosis. Clin 

Dermatol. 2003 Sep-Oct;21(5):417-25.

• Levin NA. Beyond spaghetti and meatballs: 

skin diseases associated with the Malassezia 

yeasts. Dermatol Nurs. 2009 JanFeb;21(1):7-13, 51; quiz 14.

• Naldi L, Rebora A. Clinical practice: 

seborrheic dermatitis. N Engl J Med. 2009 

Jan 22;360(4):387-96.

• Rigopoulos D, Paparizos V, Katsambas A. 

Cutaneous markers of HIV infection. Clin 

Dermatol. 2004 Nov-Dec; 22(6):487-98.

• Waldroup W, Scheinfeld N. Medicated 

shampoos for the treatment of seborrheic 

dermatitis. J Drugs Dermatol. 2008 

Jul;7(7):699-703.

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Section 6: Comorbidities, 

Coinfections, and Complications

Sinusitis

Background 

Sinusitis is defined as an inflammation involving the membrane lining of any sinus, and it occurs 

more frequently in people with HIV infection than in the general population. It commonly occurs 

as part of a viral upper respiratory infection (URI), and usually is self-limited. Bacterial sinusitis 

usually occurs as a secondary complication of a viral URI, which causes decreased patency of the 

nasal ostia, decreased nasal ciliary action, and increased mucus production. Acute sinusitis is 

defined as lasting up to 4 weeks, whereas chronic sinusitis persists for at least 12 weeks.

HIV-infected patients are susceptible to sinusitis for a number of reasons related to their 

immunosuppression. Pathophysiologic mechanisms for this susceptibility may include 

proliferation of lymphatic tissue contributing to nasal obstruction, defects in B-cell and T-cell 

immunity owing to HIV, and defects in production of immunoglobulins, specifically IgE, resulting 

in an exaggerated allergic response in the nasal mucosa. As in the general population, the most 

common pathogens causing acute bacterial sinusitis are Streptococcus pneumoniae, Moraxella 

catarrhalis, and Haemophilus influenzae. However, HIV-infected patients have a greater incidence 

of sinusitis caused by Staphylococcus aureus and Pseudomonas aeruginosa. The bacterial causes 

of chronic sinusitis are not well defined, but may involve more polymicrobial and anaerobic 

infections. In patients with severe immunosuppression, particularly those with CD4 counts of ≤50 

cells/μL, sinusitis may be caused by Aspergillus and other fungal pathogens. 

S: Subjective

The patient may complain of facial pain, 

frontal or maxillary headache, postnasal drip, 

or fever.

Ask the patient about specific symptoms, the 

duration and progression of symptoms, and 

treatments attempted.

• Fever

• Facial pain or pressure, headache; positional 

pain (worse when patient bends forward)

• Purulent or bloody nasal discharge

• Postnasal drip

• Nasal congestion

• Recent URI

• Malaise

• Chronic cough

• Maxillary tooth pain

• Ear pressure

• History of chronic sinusitis, seasonal 

allergies, antibiotic allergies, atopy

• Tobacco use, inhaled recreational drugs

O: Objective

• Document vital signs.

• Perform a careful physical examination 

focusing on the head and face, neck, and 

lungs. Examine the nose, mouth, ears, and 

sinuses. 

• Look for nares inflammation and 

drainage from sinus ostia.

• Examine the tympanic membranes and 

external auditory canals. 
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• Evaluate the oropharynx for mucus 

drainage, lesions, and exudates.

• Check the teeth and gums for tenderness 

and erythema.

• Palpate for tenderness over frontal and 

maxillary sinus cavities.

• Examine the face and orbits for swelling 

or erythema.

• Perform cranial nerve examination.

• Auscultate the chest for abnormal lung 

sounds.

A: Assessment

A partial differential diagnosis includes the 

following:

• Allergic rhinitis

• Sinus blockage by other lesions such as 

Kaposi sarcoma or lymphoma (particularly 

if the CD4 count is <200 cells/μL) or fungal 

infections (if the CD4 count is <50 cells/μL) 

• Dental abscess, caries

• Meningitis

• Vasculitis

• Trauma

P: Plan

Diagnostic Evaluation

Uncomplicated acute sinusitis usually is a 

clinical diagnosis. There are no symptoms, 

physical findings, or tests that reliably 

distinguish bacterial from viral sinusitis. 

Patients generally can be assumed to have 

bacterial sinusitis if symptoms do not resolve, 

or if they worsen, over the course of 7-10 

days. Any patient with high fever or severe 

or unusual symptoms should be evaluated 

urgently for other causes of illness. 

Imaging studies usually are not indicated for 

uncomplicated acute sinusitis. In patients 

with a poor response to empiric antibiotic 

therapy for acute bacterial sinusitis, worsening 

symptoms, and those with suspected chronic 

sinusitis, computed tomography (CT) scans 

of the paranasal sinuses are the best initial 

radiologic study. Standard X-rays (sinus series) 

can detect cloudiness or air-fluid levels and 

will show mucosal thickening (a nonspecific 

finding in HIV-infected individuals).

Cultures of nasal aspirates are not useful 

for diagnosis, because nasal fluids do not 

accurately represent pathogens in the 

paranasal sinuses. Sinus aspirate cultures will 

give definitive diagnosis of a specific organism 

in the majority of cases; this may be considered 

in complicated cases. Definitive diagnosis of 

invasive fungal sinusitis requires tissue for 

culture.

Treatment

Treatment is multimodal. For viral sinusitis, 

treatment is based on symptom suppression; 

for bacterial sinusitis, an antibiotic can be 

added to other therapies, e.g., if symptomatic 

treatment has not resulted in improvement 

after 10 days.

• Nasal irrigation with saline solution 1-2 

times daily (solution should be prepared 

from sterile or bottled water)

• Nasal steroid (e.g., budesonide, fluticasone, 

mometasone, or triamcinolone) (see 

“Potential ARV Interactions,” below) 

• Nonsteroidal antiinflammatory drugs 

(NSAIDs): ibuprofen or other 

• Mucolytic agent: guaifenesin 

• Cough suppressant as needed 

• Antihistamine: chlorpheniramine or other

• Decongestant: e.g., ephedrine, 

pseudoephedrine
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If acute bacterial sinusitis is suspected (e.g., 

symptoms have not improved within 10 days), 

treat as above and add an antibiotic for a 5-7 

day course of therapy:

• Amoxicillin/clavulanate (Augmentin) 

825/125 mg PO BID or 500/125 mg PO TID 

(more effective against resistant species 

of pneumococcus and H. influenza than 

amoxicillin)

• Doxycycline 100 mg PO BID

• Levofloxacin 500 mg QD or moxifloxacin 

400 mg QD

For chronic sinusitis, administer multimodal 

treatments as listed above for 3-4 weeks. 

The value of antibiotics in chronic sinusitis 

is unclear; consider especially if a trial of 

antibiotics has not been undertaken.

If symptoms persist or worsen, refer patients to 

an otolaryngologist for further evaluation and 

treatment.

Potential ARV Interactions

Protease inhibitors (PIs) (particularly 

ritonavir-boosted PIs) or cobicistat may 

increase serum glucocorticoid levels if 

used concurrently with nasal steroids. 

Fluticasone (e.g., Flonase) nasal spray or 

inhaler should not be used with ritonavirboosted PIs or cobicistat, and should be 

avoided, if possible, in patients taking 

unboosted PIs. Budesonide (Rhinocort 

Aqua) nasal spray also should be avoided 

with ritonavir-boosted PIs or cobicistat. 

Interactions between PIs or cobicistat and 

other nasal steroids have not been well 

studied, though available data suggest 

that beclomethasone has no clinically 

significant interaction with protease 

inhibitors.

Patient Education

• Instruct patients in the correct use of 

medications used to treat sinusitis, including 

proper technique for nasal irrigation, as 

required.

• Advise patients that drinking eight glasses 

(8-12 oz each) of fluid daily helps to keep the 

mucus thin enough to drain from the sinus 

passages.

• Instruct patients to take antibiotics on 

schedule until the entire prescription is 

gone in order to prevent recurrence of the 

infection. Advise patients to call or return 

to clinic for swelling of the face or swelling 

around the eyes, increased facial tenderness, 

new or worsening fever, or other concerning 

symptoms.

References

• Chow AW, Benninger MS, Brook I, 

et al.; Infectious Diseases Society of 

America. IDSA clinical practice guideline 

for acute bacterial rhinosinusitis in 

children and adults. Clin Infect Dis. 2012 

Apr;54(8):e72-e112.

• Gilbert DN, Moellering RC Jr., Eliopoulos 

GM, et al. The Sanford Guide to 

Antimicrobial Therapy, 35th Edition. Hyde 

Park, VT: Antimicrobial Therapy Inc.; 2005.

• Gurney TA, Lee KC, Murr AH. 

Contemporary issues in rhinosinusitis and 

HIV infection. Curr Opin Otolaryngol Head 

Neck Surg. 2003 Feb;11(1):45-8.

• Lee KC, Tami TA. Otolaryngologic 

Manifestations of HIV. In: Coffey S, 

Volberding PA, eds. HIV InSite Knowledge 

Base [textbook online]. San Francisco: 

UCSF Center for HIV Information; 

1998. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-13. 

Accessed December 1, 2013.

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Section 6: Comorbidities, 

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Syphilis

Background 

Syphilis is a sexually transmitted disease (STD) 

caused by the spirochete Treponema pallidum. It 

is a complex disease with protean variations that 

can mimic many common infections or illnesses. 

HIV infection may alter the natural history and 

management of syphilis, causing a more rapid course 

of illness, higher risk of neurologic complications, 

and potentially greater risk of treatment failure with 

standard regimens. Because many individuals with syphilis have no symptoms, or have symptoms 

that subside without treatment, sexually active individuals at risk of syphilis should receive regular 

screening for syphilis, as well as for other STDs.

There has been a resurgence of syphilis in the United States, particularly among men who have sex 

with men (MSM). This trend is concerning, because syphilis can have major health consequences 

if it is undetected and untreated, and because it increases the risk of HIV transmission. Risk 

assessment should be conducted at each patient visit for unprotected sex (including oral, anal, and 

vaginal sex), multiple sex partners, and use of recreational drugs (methamphetamine and cocaine, 

in particular, are associated with high-risk sexual practices among MSM). Sexually active persons 

with HIV who are at risk of acquiring syphilis should be screened at least annually, as discussed 

below. MSM with multiple partners should be tested every 3-6 months.

The natural history of untreated syphilis infection is divided into stages based on length of infection.

Primary Syphilis

Primary syphilis usually manifests after an incubation period of 1-3 weeks from exposure and is 

characterized by a painless self-limiting ulcer (chancre) at the site of inoculation, which usually 

occurs during sexual contact. The organism disseminates shortly after exposure via the lymphatics 

to the bloodstream and beyond. HIV-infected individuals often have multiple or atypical syphilitic 

lesions that could be misidentified. Some patients have no primary lesion, or have a primary 

lesion that is not visible. Associated regional lymphadenopathy can occur. Without treatment, the 

primary lesion generally lasts a few days to a few weeks. Individuals sometimes have a resolving 

chancre concurrently with a rash of secondary syphilis.

Secondary Syphilis

Secondary syphilis usually develops 2-8 weeks after initial infection and is caused by ongoing 

replication of the spirochete at disseminated sites of infection that may involve multiple organ 

systems but most commonly involves the skin and mucous membranes. Rash is the most common 

presenting symptom; skin lesions may be macular, maculopapular, papular, or pustular, or they 

may appear as condyloma lata (which may look like condyloma acuminata caused by human 

papillomavirus). The rash often appears on the trunk and extremities and may involve the 

palms and soles of feet. Constitutional symptoms, lymphadenopathy, arthralgias, and myalgias 

are common and neurologic or other symptoms may occur. In the absence of treatment, the 

manifestations of secondary syphilis last days to weeks, then usually resolve to the latent stages.

HRSA HAB Performance 

Measures

Percentage of adult patients with a diagnosis of HIV who had a test for syphilis

performed within the measurement year

(Adult and Adolescent measure)
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Latent Syphilis

Latent syphilis follows resolution of secondary syphilis. As in HIV-uninfected individuals, latent 

syphilis is asymptomatic and the diagnosis is determined by positive serologic tests. Latent syphilis 

is further classified as “early latent” if the infection is known to be <1 year in duration, “late latent” 

if the infection is known to be >1 year in duration, or “latent syphilis of unknown duration” if the 

duration of infection is not known.

Late or Tertiary Syphilis

Late or tertiary syphilis is caused by chronic infection with progressive disease in any system 

causing serious illness and death in untreated patients. The most common manifestations include 

cardiovascular syphilis, gummatous syphilis, and the late forms of neurosyphilis (tabes dorsalis 

and general paresis) (see the “Neurosyphilis” section, below).

Neurosyphilis

Neurosyphilis can occur at any time after initial infection, owing to early spread of the spirochete 

to the central nervous system (CNS) in approximately 30-40% of patients. The vast majority of 

these patients has no neurologic signs or symptoms and clears this site of infection. The early 

forms of neurosyphilis occur within weeks to a few years after infection, including during the 

secondary stage of syphilis. Early neurosyphilis can manifest as syphilitic meningitis (symptoms 

may include headache, confusion, nausea, vomiting, and a stiff neck); cranial nerve abnormalities 

(particularly extraocular or facial muscle palsies, causing visual changes, and facial weakness, 

tinnitus, and hearing loss) also may be present. The second manifestation of early neurosyphilis 

is meningovascular syphilis, which presents with stuttering stroke symptoms owing to increasing 

inflammation of the cerebral arteries causing intermittent occlusion. Ocular syphilis (uveitis, retinitis, 

retinal detachment, and other eye abnormalities) may occur early after infection with or without the 

early forms of neurosyphilis. Although these early forms of neurosyphilis, including ocular syphilis, 

occur in patients without HIV, they may be more common among HIV-infected individuals.

S: Subjective

Symptoms depend on the site of initial 

infection, the stage of disease, and whether 

neurosyphilis is present. Symptoms are not 

present in most patients.

If symptoms are present, the patient may 

experience the following: 

• Painless sore(s), ulcer(s), or abnormal lesions 

in the genital area, vagina, anus, or oral 

cavity

• New rash, usually on the trunk, often on 

extremities, soles of the feet, or palms

• Wart-like growths, mucus patches, or patchy 

hair loss

• Fever, malaise, swollen glands, arthralgias, 

myalgias

• Neurosyphilis: vision changes, eye pain, 

tinnitus, hearing loss, headaches, dizziness, 

facial weakness, motor or sensory loss, altered 

mental status, changes in personality or affect, 

lightning-rod pains in the lower extremities

Conduct a targeted history of patients at risk 

of syphilis, those who are contacts to a case, 

or those with positive syphilis serologies, 

asking about symptoms listed above, including 

duration; inquire about other or associated 

symptoms. Ascertain the following:

• Previous diagnosis of syphilis, stage, 

treatment (including facility where 

diagnosed and treated), and last titer result

• New sex partners in past 90 days (for 

primary or secondary syphilis)

• Date of last negative syphilis test, and where 

obtained

• Pregnancy status
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O: Objective

Check for fever, document other vital signs.

Perform a complete examination including the 

following:

• Skin and mucosal areas (including the palms 

and soles, genitals, perianal area): chancre/

ulcers, abnormal lesions, rash, condyloma 

lata, patchy hair loss

• Oropharynx: chancres, mucus patches, 

condyloma lata

• Lymph nodes

• Ophthalmic examination (including 

slit-lamp examination for persons with 

ocular complaints; uveitis, retinitis, retinal 

detachment)

• Neurologic examination (mental status, 

cranial nerves [including visual acuity], 

sensory, motor, reflexes, coordination, 

gait): abnormal mental status, visual 

acuity changes, extraocular movement 

abnormalities, neurosensory hearing loss, 

facial palsy, paraesthesias, sensory or motor 

loss, hyperactive reflexes, ataxia

A: Assessment

Because syphilis has a wide range of 

manifestations, the differential diagnosis is 

broad. It is important to consider syphilis as 

a possible cause of many presenting illnesses. 

A partial differential diagnosis includes the 

following:

• Other causes of maculopapular rashes: 

pityriasis, tinea versicolor, drug eruption, 

folliculitis, scabies, psoriasis, acute HIV 

infection

• Other causes of genital ulcerative disease: 

herpes simplex virus (HSV), chancroid, 

trauma, other skin infections (e.g., those 

caused by Staphylococcus or Candida)

• Other causes of ocular disease; 

cytomegalovirus (CMV) retinitis, CMV 

immune reconstitution uveitis, HSV keratitis

• Other causes of neurologic disease: Bell 

palsy, CNS lymphoma, toxoplasmosis, other 

causes of meningitis, stroke

• Other causes of systemic symptoms (e.g., 

fever, malaise, adenopathy): acute HIV 

infection, acute hepatitis, other infections or 

malignancies

P: Plan

Diagnostic Evaluation

Darkfield examination and direct 

fluorescent antibody

Darkfield examination, direct fluorescent 

antibody (DFA), or polymerase chain reaction 

(PCR) testing of a sample from suspicious 

genital or anal chancres or moist dermatologic 

lesions (not oral lesions) are definitive tests for 

syphilis, although these are not available in 

most clinic settings.

Serologic tests

Nontreponemal tests (rapid plasma reagin 

[RPR] or Venereal Disease Research Laboratory 

[VDRL]) traditionally have been used as initial 

serologic tests for syphilis. Because false-positive 

results may occur, particularly in the setting 

of HIV infection, positive nontreponemal test 

results must be confirmed with a treponemal 

test. Treponemal antibody tests (TP-PA [T. 

pallidum particle agglutination], EIA [enzyme 

immunoassay], or CIA [chemiluminescence 

immunoassay]) should be used to confirm a 

positive nontreponemal test. Many high-volume 

laboratories have begun to use a treponemal 

test as an initial screen for syphilis infection, 

followed by a quantitative nontreponemal 

test, to reduce the workload from the titration 

required for nontreponemal titers. The 

FTA-ABS (fluorescent treponemal antibody 

absorption) may lack specificity and is no longer 

recommended as the gold standard treponemal 

test.

Nontreponemal tests may be falsely negative 

in primary and secondary syphilis, before a 

sufficient antibody response has developed; 
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treponemal tests may be slightly more sensitive 

and should be ordered if the nontreponemal 

test result is negative in a patient with signs 

or symptoms suggestive of primary or 

secondary syphilis. Another possible cause of 

a false-negative nontreponemal result is the 

prozone phenomenon, seen when antibody 

concentrations are very high (usually in 

secondary syphilis) and the specimen is not 

diluted sufficiently. If serologic test results 

are negative and suspicion of syphilis is high, 

request that the laboratory perform additional 

dilutions on nontreponemal test specimens; 

if the diluted serum is nonreactive, perform 

other diagnostic tests (e.g., biopsy).

A nontreponemal test titer should be obtained 

on the day of treatment to use in determining 

response to treatment; a fourfold change 

in titer is considered a significant change. 

Although fluctuating titers after treatment 

in HIV-infected patients have been seen, a 

sustained (>2 weeks) fourfold increase in titer 

raises concerns about reinfection or treatment 

failure. Note that the same nontreponemal test 

should be used consistently for a single patient; 

RPR titers cannot be compared with VDRL 

titers.

Cerebrospinal fluid evaluation

HIV-infected patients with neurologic or 

ocular signs or symptoms of syphilis or 

tertiary syphilis should undergo lumbar 

puncture (LP) for cerebrospinal fluid (CSF) 

analysis. CSF evaluation also is indicated for 

patients in whom treatment for early syphilis 

fails (see below). Routine CSF evaluation is not 

indicated for HIV-infected patients who have 

syphilis without neurologic or ophthalmic 

signs or symptoms. CSF analysis should 

include the following: 

• CSF-VDRL: This test is specific but not 

very sensitive; a positive result is diagnostic 

but a negative result does not rule out 

neurosyphilis.

• Leukocytes: Elevated white blood cell count 

(>10 cells/μL) is suggestive but not specific. 

Note that mononuclear pleocytosis (up to 

5-20 cells/μL) is not uncommon in patients 

with HIV infection, particularly those with 

higher CD4 cell counts; a threshold of >20 

cells/μL may improve the specificity of the 

neurosyphilis diagnosis.

• Some recommend checking CSF FTA-ABS. 

This is very sensitive but not very specific; a 

negative result indicates that neurosyphilis 

is highly unlikely.

Other testing

All patients who test positive for syphilis 

should be tested for gonorrhea and chlamydia, 

with sampling sites based on sexual practices 

and exposures (oropharyngeal, urethral, 

cervical or vaginal, or anorectal testing). 

Patients not known to be HIV infected also 

should be tested for HIV. 

Treatment

Treatment of syphilis in HIV-infected 

individuals essentially is the same as in 

HIV-uninfected individuals, and depends 

on stage and the presence or absence of 

neurosyphilis. It is important to follow patients 

closely to assure the success of treatment. 

For further information, see the Centers for 

Disease Control and Prevention (CDC) STD 

treatment guidelines or the CDC/NIH/IDSA 

opportunistic infection (OI) guidelines (see 

“References,” below). 

An RPR or VDRL test should be sent on the 

day of treatment; the titer will be the reference 

point for assessing treatment efficacy (see 

“Follow-Up,” below). 

Early syphilis

(<1 year in duration [i.e., primary, secondary, 

and early latent]; no neurologic signs or 

symptoms)

• Preferred therapy: benzathine penicillin G, 

2.4 million units IM (single dose) 
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• Alternative therapy: (for patients with 

penicillin allergy) note that penicillin is 

strongly preferred; consider allergy testing 

and desensitization to penicillin; alternative 

therapies are not as well proven in HIVinfected individuals; close monitoring for 

treatment response is recommended

• Doxycycline 100 mg PO BID for 14 days 

• Tetracycline, 500 mg PO QID for 14 days* 

• Ceftriaxone, 1 g IM or IV QD for 10-14 

days 

* Proposed in the STD guidelines; not mentioned in the OI 

guidelines

Treatment failures and resistance have been 

reported in patients treated with azithromycin 

(2 g, single dose); the STD and OI guidelines 

state that this regimen should not be used 

to treat MSM or pregnant women. For 

other patients, both guidelines state that 

azithromycin should be considered only when 

treatment with penicillin or doxycycline is not 

feasible, and with close follow-up.

Late latent syphilis

(>1 year in duration or of unknown duration; 

no neurologic signs or symptoms)

• Preferred therapy: Benzathine penicillin 

G, 2.4 million units IM weekly for 3 

consecutive weeks (7.2 million units in total)

• Alternative therapy: For penicillinallergic patients, refer for desensitization 

to penicillin. As an alternative, some 

specialists consider doxycycline 100 mg PO 

BID for 28 days, although efficacy in HIVinfected individuals is not proven. Referral 

to infectious disease specialist and close 

clinical monitoring are required.

Tertiary syphilis

Consult with specialists.

Neurosyphilis

(syphilis at any stage with neurologic or ocular 

symptoms, or CSF abnormalities consistent 

with neurosyphilis in patients who fail 

treatment)

Ideally, patients should be hospitalized and 

given 2 weeks of penicillin IV under close 

observation. Penicillin-allergic patients should 

be referred for desensitization, if possible. 

• Preferred therapy: aqueous crystalline 

penicillin G, 18-24 million units IV per 

day (3-4 million units Q4H [or continuous 

infusion] for 10-14 days).

• Alternative therapy (requires strict 

adherence with therapy): 

• Procaine penicillin 2.4 million units IM 

per day, plus probenecid 500 mg PO QID, 

both for 10-14 days

• Some experts consider use of ceftriaxone 

2 g IM or IV QD for 10-14 days with close 

clinical monitoring

• Most experts recommend administration of 

benzathine penicillin, 2.4 million units IM 

weekly for 3 weeks, after completion of the 

standard 10- to 14-day course of therapy for 

neurosyphilis.

• Recheck CSF leukocyte count every 6 

months until the cell count normalizes 

(if CSF pleocytosis was present at initial 

evaluation). If the leukocyte count is not 

lower at 6 months, consider retreatment 

(consult with a specialist). Normalization of 

serum RPR may predict normalization of 

CSF parameters.

Note: A Jarisch-Herxheimer reaction may 

occur after initial syphilis treatment, especially 

in primary, secondary, or even latent syphilis. 

This self-limited treatment effect should 

not be confused with an allergic reaction to 

penicillin. It usually begins 2-8 hours after 

the first dose of penicillin and consists of 

fever, chills, arthralgias, malaise, tender 

lymphadenopathy, and intensification of rash. 

It resolves within 24 hours and is best treated 
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with rest and acetaminophen. Patients should 

be warned about the possibility of a JarischHerxheimer reaction.

Pregnancy

Pregnant women should be treated with 

penicillin, using a regimen appropriate for 

the stage of infection (see above). Additional 

treatment may be indicated in early syphilis; 

consult with a specialist. Penicillin-allergic 

pregnant women should be referred for 

desensitization to penicillin. Doxycycline and 

tetracycline may cause fetal toxicity and should 

not be used during pregnancy. Azithromycin 

and erythromycin do not have adequate 

efficacy in treating pregnant women or their 

fetuses and should not be used. The efficacy 

of ceftriaxone during pregnancy has not been 

studied adequately.

Women treated during the second half of 

pregnancy are at risk of contractions, early 

labor, and fetal distress if they develop a 

Jarisch-Herxheimer reaction; thus, they 

should be advised to seek obstetric attention 

if they develop fever or contractions, or note a 

decrease in fetal movement.

Sex partners

Syphilis is transmitted sexually only when 

mucocutaneous lesions of syphilis are 

present; this is uncommon after the first year 

of infection. Nevertheless, sex partners of a 

patient who has syphilis in any stage should be 

evaluated. For patients with primary syphilis, 

that means partners within the previous 3 

months plus the duration of the lesion; for 

patients with secondary syphilis, partners 

within the previous 6 months plus the duration 

of signs; for patients with early latent syphilis, 

partners within the past 1 year.

• Persons exposed within 90 days preceding 

the diagnosis of primary, secondary, or 

early latent syphilis should be treated 

presumptively, as they may be infected with 

syphilis even if they are seronegative. 

• Persons exposed more than 90 days before 

the diagnosis of primary, secondary, or 

early latent syphilis should be treated 

presumptively if serologic test results are not 

available immediately and their follow-up 

is in doubt. Otherwise, they should receive 

serologic testing and be treated appropriately 

if the test result is positive.
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Follow-Up

All HIV-infected patients treated for early 

syphilis should be evaluated clinically and 

serologically at 3, 6, 9, 12, and 24 months (at 

6, 12, 18, and 24 months for latent syphilis) to 

rule out treatment failure. Treatment success is 

determined by a fourfold decrease (equivalent 

to two dilutions) in RPR or VDRL titer by 

6-12 months (for primary and secondary 

syphilis) or 12-24 months (for latent syphilis) 

of treatment. Patients whose titers do not 

decrease appropriately could have experienced 

treatment failure or may have been reinfected. 

Any patient with apparent treatment failure 

should undergo an LP for CSF analysis and be 

re-treated as appropriate. 

For patients with neurosyphilis, current 

guidelines recommend that, if a CSF 

pleocytosis was present initially, the CSF cell 

count should be checked every 6 months until 

it decreases. If the CSF cell count is not normal 

after 2 years, retreatment for neurosyphilis 

should be considered.

After syphilis treatment that results in at least 

a fourfold decrease in RPR or VDRL titer, 

a sustained fourfold increase in titer most 

commonly reflects reinfection; the patient 

should be evaluated carefully for possible 

reexposure and treated for new infection if 

appropriate. If reinfection is unlikely, CSF 

testing should be done and appropriate 

treatment should be given. For patients with 

persistently high or fluctuating titers after CSF 

examination and appropriate re-treatment, 

consult with a specialist.

Some patients retain reactive (usually at low 

titer) nontreponemal test results after successful 

treatment for syphilis. In these “serofast” 

individuals, reinfection with syphilis is indicated 

by a rise in test titer of at least fourfold.

Risk-reduction counseling

All patients with syphilis should receive risk 

evaluation and risk-reduction counseling. 

Evaluate each patient’s sexual practices with 

regard to risk of acquiring STDs and of 

transmitting HIV. Work with the patient to 

reduce sexual risks. 

Patient Education

• Instruct patients to go to clinic for treatment 

at the intervals recommended. If patients 

are given oral antibiotics (penicillin-allergic 

individuals), instruct them to take their 

medications exactly as prescribed.

• Warn patients about the possibility of a 

Jarisch-Herxheimer reaction after an initial 

dose of penicillin and advise them about 

self-management of associated symptoms 

(e.g., acetaminophen or aspirin at usual 

doses, fluids, and rest).

• Instruct patients about the required followup laboratory and clinical evaluations 

necessary to document adequate treatment. 

Emphasize the need for regular evaluation of 

treatment efficacy.

• Sex partners from the previous 3-6 months 

(sometimes longer, depending on the stage 

of syphilis) need to be evaluated and treated 

as soon as possible, even if they have no 

symptoms. Advise patients to inform their 

partners that they need to be tested and 

treated. Ask patients whether they would 

like assistance with partner notification 

and refer to the local health department for 

partner services, if available.

• Syphilis is a reportable communicable 

disease in the United States. Inform patients 

that they may be contacted to verify 

adequate treatment and assist with partner 

notification and treatment.

• Provide education about sexual risk 

reduction. Review sexual practices and 

support patients in using condoms with 

every sexual contact to prevent becoming 

reinfected with syphilis or infected with 

other STDs, and to prevent passing HIV to 

sex partners. 
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References

• Centers for Disease Control and Prevention. 

Sexually Transmitted Diseases Treatment 

Guidelines, 2010. Available at www.cdc.gov/

STD/treatment/2010. Accessed December 1, 

2013.

• Marra CM, Maxwell CL, Smith SL, et al. 

Cerebrospinal fluid abnormalities in patients 

with syphilis: association with clinical and 

laboratory features. J Infect Dis. 2004 Feb 

1;189(3):369-76.

• Marra CM, Maxwell CL, Tantalo L, et 

al. Normalization of cerebrospinal fluid 

abnormalities after neurosyphilis therapy: 

does HIV status matter? Clin Infect Dis. 

2004 Apr 1;38(7):1001-6.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Paz-Bailey G, Meyers A, Blank S, et al. A 

case-control study of syphilis among men 

who have sex with men in New York City: 

association with HIV infection. Sex Transm 

Dis. 2004 Oct;31(10):581-7.

• Peterman TA, Heffelfinger JD, Swint EB, et 

al. The changing epidemiology of syphilis. Sex 

Transm Dis. 2005 Oct;32(10 Suppl):S4-10.

• Pope V. Use of treponemal tests to screen for 

syphilis. Infect Med. 2004 21(8); 399-404. 

• Torian LV, Makki HA, Menzies IB, et al. 

HIV infection in men who have sex with 

men, New York City Department of Health 

sexually transmitted disease clinics, 1990-

1999: a decade of serosurveillance finds that 

racial disparities and associations between 

HIV and gonorrhea persist. Sex Transm Dis. 

2002 Feb;29(2):73-8.
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Toxoplasmosis

Background 

Toxoplasma gondii is a common intracellular protozoan that preferentially infects the central 

nervous system (CNS). In immunodeficient patients it may cause encephalitis; it also can cause 

local disease such as chorioretinitis and pneumonia. Clinical disease usually occurs through 

reactivation of latent infection in patients who have CD4 counts of <100 cells/μL. Toxoplasma 

seroprevalence varies widely, from 11% in the United States to 75% in some European countries, 

and even higher in certain resource-limited countries. In the absence of prophylaxis, toxoplasmic 

encephalitis occurs in more than 30% of patients with advanced HIV infection who are 

seropositive for T. gondii. There have been case reports of CNS toxoplasmosis in the setting of 

immune reconstitution on antiretroviral therapy (ART); see chapter Immune Reconstitution 

Inflammatory Syndrome.

Toxoplasma has an infectious reservoir in almost all animals; humans acquire infection either 

through ingestion of tissue cysts contained in undercooked meat (usually pork, lamb, or beef) or 

oocysts on contaminated vegetables or through exposure to cat feces containing oocysts. There is 

no transmission by person-to-person contact.

CNS toxoplasmosis is an AIDS-defining condition that can be progressive and fatal. However, 

antimicrobial therapy, especially if given in conjunction with ART that results in immune 

reconstitution, can be successful in treating toxoplasmosis. Specific prophylaxis and effective ART 

also may be used to prevent toxoplasmosis in patients with advanced AIDS who have latent T. 

gondii infection (as demonstrated by the presence of anti-Toxoplasma immunoglobulin G [IgG] 

antibodies; see chapter Preventing Exposure to Opportunistic and Other Infections).

S: Subjective

The patient may complain of subacute onset 

of dull, constant headache, fever, visual 

changes or other focal neurologic symptoms, 

confusion, or disorientation. Seizures may 

occur. Caregivers may report subtle alterations 

in mental status or mood.

Take a careful history from the patient and 

caregivers about the symptoms listed above 

and their duration, progression, and severity. 

Inquire about other related symptoms. Ask 

whether the patient is taking Toxoplasma

prophylaxis or ART.

O: Objective

• Measure vital signs (temperature, heart rate, 

blood pressure, respiratory rate).

• Perform a full physical examination 

including a thorough neurologic 

examination, looking for focal or nonfocal 

neurologic deficits, particularly weakness, 

cranial nerve abnormalities, visual field 

defects, gait disturbances, and abnormalities 

in speech, cognitive, or affective functions.

• Review previous laboratory values, 

particularly the following: 

• CD4 count (usually <50-100 cells/μL in 

patients with toxoplasmosis)

• Toxoplasma IgG (>95% of patients with 

toxoplasmosis have positive IgG)

A: Assessment

Rule out other infectious or neoplastic causes 

of headache, fever, and neurologic changes. 
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A partial differential diagnosis includes the 

following: 

• CNS lymphoma

• Cryptococcal meningitis

• Progressive multifocal 

leukoencephalopathy (PML)

• Tuberculous meningitis

• Brain abscesses of bacterial, fungal, or 

mycobacterial etiologies

• Herpes simplex virus or cytomegalovirus 

(CMV) encephalitis

• Primary HIV encephalopathy

• AIDS dementia complex

• Cerebrovascular accident secondary to 

hemorrhage, hypoxia, or emboli from 

vegetative endocarditis

• Neurosyphilis

• Other causes of chorioretinitis such as CMV, 

HIV, and cryptosporidiosis

P: Plan

Diagnostic Evaluation

Definitive diagnosis requires identification 

of T. gondii in tissue biopsy or body fluid 

samples from a patient with a compatible 

clinical presentation. Brain biopsy usually is 

not performed if toxoplasmosis is strongly 

suspected; instead, presumptive diagnosis 

is made on the basis of clinical presentation, 

laboratory and imaging tests, and response to 

therapy. Brain biopsy should be considered for 

patients who do not respond to therapy and for 

those whose diagnosis is unclear.

• Serum Toxoplasma IgG antibody test results 

are positive in nearly all patients with 

toxoplasmic encephalitis. A negative IgG test 

result makes the diagnosis very unlikely but 

does not rule it out. (Antibody titer changes 

are uncommon in reactivation disease and 

are not useful in making a diagnosis.)

• CNS imaging with computed tomography 

(CT) typically shows multiple contrastenhancing mass lesions, but may show 

a single lesion or no lesions. Magnetic 

resonance imaging (MRI) is more sensitive 

than CT for CNS toxoplasmosis. Other 

imaging studies, such as single photon 

emission CT (SPECT), may be useful in 

distinguishing toxoplasmic lesions from 

CNS lymphoma.

• If possible, cerebrospinal fluid should be 

checked for T. gondii by polymerase chain 

reaction (PCR).

• Other diagnostic tests should be performed 

as indicated to rule out other potential 

causes of the patient’s symptoms.

• Patients with toxoplasmic encephalitis 

typically respond quickly to treatment. If 

clinical improvement is not seen after 10-14 

days of appropriate treatment, or if clinical 

worsening is seen in the first week, consider 

brain biopsy for alternative diagnoses.

Treatment

Treatment consists of two phases: acute 

therapy and chronic maintenance therapy. 

If possible, consult with an expert on the 

management of toxoplasmosis.

Presumptive treatment often is begun on 

the basis of clinical presentation, positive 

Toxoplasma IgG, and results of brain imaging 

studies. If patients do not respond quickly 

to treatment, other diagnoses should be 

considered. The following recommendations 

are based on treatment guidelines published 

by the Centers for Disease Control and 

Prevention, National Institutes of Health, and 

HIV Medicine Association/Infectious Diseases 

Society of America (see “References,” below).

Acute Therapy

Acute therapy should be given for at least 

6 weeks, and until the patient has shown 

improvement by clinical and radiographic 

measures.
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Preferred

• Pyrimethamine 200 mg PO as a single 

loading dose, then 50 mg (<60 kg body 

weight) or 75 mg (>60 kg body weight) QD + 

sulfadiazine 1,000 mg (<60 kg body weight) 

or 1,500 mg (>60 kg body weight) PO Q6H + 

folinic acid (leucovorin) 10-25 mg QD

Dosage adjustments to the lower end of 

therapeutic range of pyrimethamine and 

sulfadiazine may be considered for patients 

who have significant bone marrow suppression 

despite folinic acid supplementation. Monitor 

patients carefully for cytopenias, especially if 

they are taking other agents that cause bone 

marrow suppression, such as zidovudine, 

valganciclovir, and ganciclovir.

Note: Patients at risk of G6PD deficiency 

should be checked for G6PD deficiency before 

starting pyrimethamine.

Alternative

• Pyrimethamine + folinic acid (administered 

as described above) + clindamycin 600 mg 

PO or IV Q6H; recommended for patients 

with significant allergic reactions to sulfa 

medications

• Trimethoprim-sulfamethoxazole (TMPSMX) 5 mg/kg TMP and 25 mg/kg SMX PO 

or IV BID. TMP-SMX can be considered 

when the availability of other regimens is 

limited or when patients need IV therapy

• Atovaquone 1,500 mg PO BID 

+ pyrimethamine + folinic acid 

(pyrimethamine and folinic acid as 

described above)

• Atovaquone 1,500 mg PO BID + sulfadiazine 

1,000-1,500 mg PO Q6H (sulfadiazine 

dosing as above)

• Atovaquone 1,500 mg PO BID

• Pyrimethamine + leucovorin (dosing as 

above) + azithromycin 900-1,200 mg PO QD 

Note: The regimens that contain sulfadiazine, 

TMP-SMX, or atovaquone also are effective in 

preventing Pneumocystis jiroveci pneumonia 

(PCP), so patients on these regimens do not 

need additional PCP prophylaxis.

Adjunctive corticosteroids (e.g., 

dexamethasone 4 mg PO or IV Q6H) may be 

indicated for patients with CNS mass effect or 

edema. Use is based on clinical judgment and 

should be discontinued as soon as it is feasible 

to do so.

Anticonvulsant therapy should be given to 

patients with a history of seizures (but not to 

those who have not had seizures).

Ventilatory support may be necessary if severe 

CNS symptomatology is present.

Chronic Maintenance Therapy

After at least 6 weeks of initial therapy 

and significant clinical and radiologic 

improvement, chronic maintenance therapy 

can be considered.

Preferred

• Pyrimethamine 25-50 mg PO QD + 

sulfadiazine 2,000-4,000 mg PO daily in 2-4 

divided doses + folinic acid 10-25 mg PO 

QD (also effective as PCP prophylaxis)

Alternative

• Pyrimethamine 25-50 mg PO QD + 

clindamycin 600 mg PO Q8H + folinic acid 

10-25 mg PO QD

• TMP-SMX double-strength 1 tablet PO BID

• Atovaquone 750-1,500 mg PO BID + 

pyrimethamine 25-50 mg PO QD (+ folinic 

acid 10-25 mg PO QD) 

• Atovaquone 750-1,500 mg PO BID + 

sulfadiazine 2,000-4,000 mg PO daily in 

2-4 divided doses (also effective as PCP 

prophylaxis)

• Atovaquone 750-1,500 mg PO BID

For patients who complete acute therapy 

successfully, have resolution of signs and 

symptoms of toxoplasmosis, and have immune 
526 | Guide for HIV/AIDS Clinical Care

Section 6: Comorbidities, 

Coinfections, and Complications

reconstitution (with CD4 counts >200 

cells/μL) for more than 6 months on ART, 

it is reasonable to consider discontinuing 

maintenance therapy. Some specialists would 

require resolution of CNS lesions on radiologic 

studies before discontinuation of therapy. 

Patients must be observed for recurrence of 

symptoms, and treatment should be restarted 

if the CD4 count decreases to <200 cells/μL.

Considerations During Pregnancy

All pregnant women should be tested for T. 

gondii. If the result is positive, evaluate the 

pregnant woman for signs or symptoms of 

toxoplasmosis and the neonate for evidence of 

congenital infection. Perinatal transmission 

usually occurs only with acute maternal 

infection, but in advanced HIV, it may occur 

with reactivation of chronic infection. If T. 

gondii infection occurs during pregnancy, 

consult with maternal-fetal and infectious 

disease specialists. Treatment for pregnant 

women is the same as for nonpregnant adults 

(see above). Note that sulfadiazine taken at 

the time of delivery may increase the risk of 

neonatal hyperbilirubinemia and kernicterus.

Patient Education

• Advise patients that antimicrobial therapy 

alone will not eradicate toxoplasmosis, 

but should decrease symptoms and 

improve quality of life. If medications are 

discontinued, the disease is likely to recur, 

unless the CD4 count increases to >100-200 

cells/μL in response to ART.

• Inform patients that suppressive therapy 

must be continued to prevent recurrence. 

The duration of this therapy may be lifelong.

• It is essential for patients to take all 

medicines exactly as prescribed. If doses are 

missed, or if the medications are stopped 

and restarted, Toxoplasma can develop 

resistance to the medications. If patients are 

having trouble taking the medication on 

schedule, they should contact their health 

care provider immediately.

• Educate patients about the benefits of ART 

in strengthening the immune system and 

preventing opportunistic infections such as 

toxoplasmosis.

• Advise patients to contact the clinic 

promptly if symptoms worsen or if new 

symptoms develop.

• Toxoplasmosis is a late-stage HIV 

opportunistic infection that indicates 

profound immune suppression. Some 

patients may not respond to treatment or 

to ART. As with any patient who is at risk 

of a life-threatening HIV-related disease, 

clinicians should discuss advance directives 

and durable power of attorney with patients. 

Referral to a social worker, mental health 

clinician, or chaplain experienced in such 

issues may facilitate this discussion.

References

• Liesenfeld O, Wang SY, Remington 

JS. Toxoplasmosis in the Setting of 

AIDS. In: Merigan TC, Bartlett JG, 

Bolognesi D, eds. Textbook of AIDS 

Medicine, 2nd Edition. Baltimore: 

Williams and Wilkins; 1999:225-259.

• Panel on Opportunistic Infections in 

HIV-Infected Adults and Adolescents. 

Guidelines for the prevention and treatment 

of opportunistic infections in HIV-infected 

adults and adolescents: recommendations 

from the Centers for Disease Control and 

Prevention, the National Institutes of Health, 

and the HIV Medicine Association of the 

Infectious Diseases Society of America. 

Available at aidsinfo.nih.gov/guidelines. 

Accessed December 1, 2013.

• Subauste CS. Toxoplasmosis and 

HIV. In: Coffey S, Volberding PA, 

eds. HIV InSite Knowledge Base

[textbook online]. San Francisco: 

UCSF Center for HIV Information; 

2006. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-05-04-03. 

Accessed December 1, 2013.
Adverse Reactions to HIV Medications | 527

Section 7: ARV Interactions and 

Adverse Events

Adverse Reactions to HIV Medications

Kirsten Balano, PharmD

Background

Clinicians and patients face many challenges associated with antiretroviral therapy (ART). These 

include making decisions about when to start therapy, what regimen to start, when to change 

medications, and how to switch if a regimen is failing. Although clinical research guides the 

selection of antiretroviral (ARV) regimens, it is important to remember that the best regimen for 

any patient is the regimen that individual is willing and able to take. No regimen, no matter how 

potent, will be effective if the patient does not take it properly. Adherence to ART is one of the 

most important predictors of treatment efficacy. Although many factors may interfere with proper 

adherence to ART, adverse reactions to the medications are among the most important. In one 

trial, patients experiencing adverse events were 13 times less likely than those not experiencing 

adverse events to have the highest levels (95-100%) of adherence. Monitoring and managing 

adverse reactions to ARVs are crucial to establishing a successful HIV regimen.

Although adverse reactions are common and often predictable, their management must be 

individualized. Several factors will affect the management of adverse reactions, including comorbid 

conditions, the patient’s other current medications, the availability of alternative medications, and 

the patient’s history of medication intolerance. In some cases, the patient’s report of the severity 

of adverse effects can be inconsistent with the clinical interpretation (i.e., some patients may 

overemphasize symptoms, whereas others underemphasize them), and this must be considered 

when determining the management of adverse reactions.

Using a case-based approach, this chapter suggests strategies for the evaluation and management 

of adverse effects, and it reviews several of the most commonly noted adverse effects in patients 

starting an ARV regimen. It is not intended as a comprehensive guide to adverse effects. For 

detailed information regarding assessment of symptoms, see the complaint-specific chapters found 

in section Common Complaints of this manual. For information on common adverse reactions 

to ARV agents and to medications used to prevent and treat opportunistic infections, see chapter 

Antiretroviral Therapy and the Antiretroviral Reference Tables in this manual. In each case of 

suspected medication adverse effects, the patient should be evaluated for other possible causes of 

the symptoms. Consultation with an HIV expert can help in determining the best management 

strategy when symptoms may have multiple and overlapping causes.

S: Subjective

A pregnant woman presents 3 weeks after 

starting a new ARV regimen. She complains 

of fatigue, nausea, and rash. Her current ARV 

medications are nevirapine (NVP) plus a 

fixed-dose combination of zidovudine (ZDV) 

and lamivudine (3TC) (i.e., Combivir). This 

was selected on the basis of her pregnancy, her 

preferences, and her past treatment history. She 

also is taking trimethoprim-sulfamethoxazole 

(TMP-SMX) as prophylaxis against PCP. 

Although she reports that she had not missed 

any doses of her medications and she likes the 

low pill burden of this regimen, she does not 

want to continue because she has been feeling 

so sick that she cannot adequately care for her 

children. She is asking to stop her ARV therapy 

because of “too many side effects.”

The patient should be evaluated in the clinic 

for her complaints about adverse effects. 
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Section 7: ARV Interactions and 

Adverse Events

O: Objective 

The following are suggestions for this 

evaluation; they are not intended to be 

a complete review of the workup and 

management of each symptom or objective 

finding. For more-detailed information, refer 

to the complaint-specific chapters of this 

manual, as noted above.

Vital signs: Fever may indicate a 

hypersensitivity reaction (HSR) or acute 

hepatitis attributable to medications, or 

an immune reconstitution inflammatory 

syndrome in relation to an opportunistic 

infection in the setting of early ART 

therapy. See chapter Fever for a more 

complete discussion about fever workup and 

considerations. Tachycardia or hypotension 

may suggest anemia, HSR, dehydration, 

infection, or another illness.

Physical examination: Pay special attention 

to the skin (rash, pallor), mucous membranes, 

and liver (enlargement or tenderness). 

Positive physical examination findings 

should be evaluated for severity and extent of 

involvement.

Laboratory tests: Check the complete blood 

count when monitoring drugs that may 

cause bone marrow toxicity (e.g., anemia, 

neutropenia). Perform a complete metabolic 

panel including electrolytes and liver 

function tests (LFTs). If the history suggests 

pancreatitis, evaluate amylase and lipase.

Other studies: Perform as indicated by 

symptoms and examination (e.g., chest X-ray if 

respiratory symptoms are present).

A: Assessment

Step 1: Clarify the patient’s reports of 

adverse reactions by requesting the following 

information for each symptom the patient 

describes:

• Characterize the symptoms by asking about 

severity, onset, timing, and frequency. It is 

helpful to have the patient describe whether 

the symptoms have been improving or 

worsening over time.

• Ask whether the patient has tried any 

remedies to alleviate the symptoms and 

whether they were helpful.

• Explore how the patient is currently taking 

the regimen. Closed-end questions (e.g., 

“What are your current medications?” “How 

often do you take them?” “How many pills 

of each medicine do you take?” and “Do you 

take your medicines with or without food?”) 

can be helpful in determining whether 

the patient has been taking medications 

correctly. Incorrect administration of 

medications (e.g., taking higher dosages 

than recommended) can lead to adverse 

effects and often is overlooked by providers.

Step 2: Assess the severity of the reaction 

against the need to continue the current 

regimen. For this assessment, it is important 

to have an understanding of the relative 

availability of alternative ARV regimens. Also 

try to determine the patient’s risks of adverse 

reactions to specific medications. A review of 

the patient’s clinical status, treatment history, 

resistance tests, and other testing is important.

• Most adverse effects are self-limited 

and mild-to-moderate in severity. With 

supportive care, patients often are able 

to continue their current medications. 

This is particularly true with regard to 

gastrointestinal symptoms (e.g., nausea, 

vomiting, bloating, diarrhea). Supportive 

care for gastrointestinal adverse effects 

includes reminding the patient to take 

medications with food (if appropriate), 

suggesting the use of symptomatic remedies 

(e.g., ginger-containing beverages or foods 

to relieve nausea [see “Nausea,” below]), and 

prescribing medications such as antiemetics 

or antidiarrheals if needed. Other symptoms 

that can be monitored carefully with 

supportive care include fatigue, malaise, 

mild rashes, abdominal pain, and bloating.
Adverse Reactions to HIV Medications | 529

Section 7: ARV Interactions and 

Adverse Events

• More severe reactions often require 

discontinuation of the offending medication. 

These include fever, liver function 

abnormalities, rash with mucous membrane 

involvement, or severe systemic symptoms. 

• Determining which medication in a 

multidrug regimen is causing the reaction 

is often challenging because it is common 

for patients to concurrently take several 

medications with overlapping toxicities.

• Some patient factors affect the risk of 

particular adverse drug effects. For example, 

patients with higher CD4 cell counts at 

the time that nevirapine is initiated have a 

greater risk of hepatotoxicity (specifically, 

women with CD4 counts of >250 cells/μL or 

men with CD4 counts of >400 cells/μL), and 

patients with the HLA-B*5701 allele have 

higher rates of abacavir HSR. In patients 

with these risk factors, these drugs should be 

avoided.

• It is important to consider the possibility 

that non-ARV medications in the patient’s 

regimen could be causing the adverse 

effects. This could include medications 

given as prophylaxis (or treatment) for 

opportunistic infections (e.g., TMP-SMX), 

or medications to treat other comorbidities. 

Even with patients who have been on other 

non-ARV medications for months or years, 

initiation of a new ARV regimen (e.g., one 

with potent hepatic CYP 450 inhibition or 

induction effects) may alter serum levels 

of these other medications (see chapter 

Drug-Drug Interactions with HIV-Related 

Medications). For example, an increase in 

anxiety symptoms after starting a new ARV 

regimen could be attributable to altered drug 

concentrations of a chronic antidepressant 

or antianxiety medicine caused by an ARV, 

not to the new ARV medications themselves.

• The threshold for stopping a medication 

depends in part on the availability of 

alternative agents for the individual patient. 

Some patients have limited alternatives 

because their virus is resistant to other 

ARVs or because they have not tolerated 

certain ARVs in the past. For patients who 

develop significant adverse effects when 

starting their first ARV regimen, consider 

substituting alternative ARV medications 

(chosen with efficacy considerations in 

mind) that are better tolerated as early as 

possible to prevent nonadherence arising 

from a desire to avoid the adverse effects. For 

these situations, single-drug substitutions 

often improve tolerance and make it more 

likely that long-term viral suppression will 

be achieved.

• Some patients may refuse to attempt 

symptomatic treatment or to make 

substitutions in the ARV regimen. Although 

treatment interruptions generally should be 

avoided, in certain situations it may be best 

to discontinue all ARVs and return to an 

adherence-readiness assessment (see chapter 

Adherence) to determine when to restart 

ART and what medications to restart (see 

chapter Antiretroviral Therapy).

Gathering Additional Subjective and 

Objective Information

For the patient who reported nausea, fatigue, 

and rash 3 weeks after starting nevirapine and 

ZDV/3TC (Combivir) (see above), additional 

history, physical examination, and laboratory 

work yielded the following information:

• Nausea: This has been present since she 

started ART 3 weeks ago. She has had 

difficulty taking the ARVs with food, 

because of nausea. No actual vomiting or 

other abdominal pain has occurred. She 

has not tried any remedies. The nausea is 

not worsening and perhaps has improved 

slightly over the past few days.

• Fatigue: This has been present since she 

started ARVs 3 weeks ago. She is able to 

exercise and perform normal daily activities.

• Vital signs: Normal, with no fever or signs 

of hemodynamic changes.
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Section 7: ARV Interactions and 

Adverse Events

• Skin: Skin and conjunctival pallor is noted, 

along with mild-to-moderate maculopapular 

rash on the trunk, back, and extremities. 

These are associated with slight itching, but 

no pain. No mucous membrane involvement 

is noted. The rash has been present for 6 

days, with slight improvement over the past 

day.

• Abdomen: Nontender, with 

normal liver size.

• Complete blood count: Normal, except for a 

slight increase in mean corpuscular volume 

(MCV), probably from ZDV therapy and not 

indicating macrocytic anemia.

• LFTs: Normal.

• Pretreatment laboratory results: CD4 

count of 190 cells/μL, HLA-B*5701 negative.

Assessing Availability of 

Alternative Regimens

A clarified ARV history yielded the following 

information. The patient took ZDV for 5 

months during another pregnancy a few years 

ago, and she recalls similar feelings of nausea 

and fatigue that caused her distress at the 

time. She was able to continue ZDV through 

the end of her pregnancy. She has taken 

several ritonavir-boosted protease inhibitors 

briefly in the past; she did not tolerate these 

and subsequently has refused treatment with 

protease inhibitors. The resistance test done 

prior to initiation of ART shows no significant 

ARV resistance. She has no comorbidities. The 

patient has a number of treatment options, but 

these may be limited by tolerance issues (e.g., 

protease inhibitor intolerance).

Summary Assessment

The patient’s symptoms are mild and are 

most likely related to starting ARV therapy, 

although pregnance also can have associated 

nausea and fatigue. The laboratory evaluation 

does not reveal significant abnormalities 

(e.g., anemia, transaminitis). In particular, 

the symptoms, signs, and laboratory work 

are not consistent with HSR, hepatotoxicity, 

or other serious adverse effects. Thus, no 

additional workup is needed at this time. 

Careful monitoring is important because, if 

symptoms do not improve over the next few 

days, the patient should have a more extensive 

workup for other possible causes of the 

symptoms. If other causes of her symptoms 

are ruled out and she is unable to tolerate 

supportive care, alternative ARV medications 

(e.g., tenofovir, abacavir, an integrase inhibitor, 

or perhaps an unboosted protease inhibitor) 

could be substituted for medications in her 

current regimen, keeping in mind the need to 

maintain efficacy of the overall regimen and 

the recommendations for ART in pregnancy 

(see chapter Reducing Perinatal HIV 

Transmission).

P: Plan 

A suggested treatment plan for the mild 

adverse effects exhibited by the patient 

described above is as follows: 

Fatigue

Fatigue is a common adverse effect among 

patients who are starting ART. It is usually 

self-limited, and, with reassurance that 

symptoms should improve over a few weeks, 

most patients are able to continue their 

regimens without any changes. If fatigue 

does not resolve within the first weeks of 

treatment, it is important to rule out other 

causes of fatigue, including depression. For 

ZDV-containing regimens, clinicians should 

rule out ZDV-induced anemia, especially when 

patients are taking other medications that can 

cause bone marrow toxicity (e.g., TMP-SMX). 

Some patients experience fatigue from ZDV 

even without anemia. If fatigue persists for 

several weeks or becomes debilitating, and 

other causes are ruled out, consider replacing 

ZDV in this regimen. Patients taking regimens 

containing efavirenz also may complain of 

fatigue. With efavirenz, the fatigue often 

is related to sleep disturbances and other 
Adverse Reactions to HIV Medications | 531

Section 7: ARV Interactions and 

Adverse Events

central nervous system (CNS) effects of this 

medication. Efavirenz-related CNS adverse 

effects, including fatigue, are likely to resolve 

over a period of days to weeks. Toxicities can 

be minimized by ensuring that patients take 

efavirenz on an empty stomach (1 hour before 

or 2 hours after eating). (See chapter Fatigue.)

Nausea

Nausea is another common adverse effect 

described by patients starting a new ARV 

regimen. As with fatigue, it usually is 

self-limited, and patients without other 

systemic symptoms, acute hepatitis, HSR, 

or pancreatitis usually can continue their 

regimens. Supportive care often helps patients 

to continue their regimens. For example, 

patients should take their medications with 

food, unless contraindicated for the ARV. 

Small, frequent snacks may be helpful for 

patients with significant nausea. Clinical trials 

have suggested that ginger extract may relieve 

nausea symptoms. Patients can take ginger 

(available in a variety of forms, including 

ginger ale, tea, cookies, and candies) or 

antiemetics.

Among the medications that the patient 

described above is taking, ZDV is the most 

likely culprit to cause persistent nausea. If 

nausea symptoms continue for several weeks 

despite taking the ARVs with food, using 

ginger, or taking other antiemetics, and if 

other underlying causes are ruled out, consider 

replacing ZDV in this regimen. (See chapter 

Nausea and Vomiting.)

Rash

Rash is a common adverse effect of certain 

ARVs and many other medications. It may 

present with a wide range of severity, as 

follows:

• Mild rash with no other related symptoms, 

resolving over the course of days or weeks

• Moderate rash, may be accompanied by 

systemic symptoms (e.g., fever, liver function 

abnormalities, myalgias)

• Life-threatening rashes (e.g., StevensJohnson syndrome, toxic epidermal 

necrolysis) associated with pain, mucous 

membrane involvement, fever, liver function 

changes, and myalgias

If a patient is taking two or more medications 

that have rash as a possible adverse effect, it 

may be difficult to determine which medicine 

is the most likely cause of the rash. In the case 

of the patient described above, the rash most 

likely is related to one of two medications. 

Her rash currently is mild, but drug rash can 

range from mild to severe and life-threatening 

(including Stevens-Johnson syndrome).

• Nevirapine 

• Mild nevirapine rash: usually a selflimited reaction that can be treated 

symptomatically

• Moderate to severe nevirapine rash, 

with or without hepatitis: requires 

discontinuation of nevirapine

• TMP-SMX reaction: may be mild or severe, 

and onset may be delayed

• Other reactions: can be caused by other 

medications, by immune reconstitution 

inflammatory effects, contact dermatitis, 

folliculitis, and other causes

If the clinician discontinues all of the suspect 

medications and the rash resolves, the patient 

will be relieved, but the clinician will not be 

able to determine which medication caused 

the rash. In cases of mild rash, it is reasonable 

to try to identify the offending agent by 

discontinuing one medication at a time (a 

substitution should be made for a discontinued 

ARV, to maintain regimen potency). This 

situation would require careful clinical 

judgment or consultation with an expert 

regarding the advantages or disadvantages of 

discontinuing each of the suspect medications.
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Adverse Events

Other Adverse Reactions

Patients may describe any number of adverse 

effects after starting new medications. 

Although some adverse effects are caused 

directly by the medications themselves, some 

symptoms may occur simply in the process 

of starting ART. The start of ART may 

precipitate a significant psychological shift in a 

patient’s perception of self, in living with HIV 

infection, and in daily routine. In particular, 

patients who have kept their HIV infection 

distant from their “everyday” lives may notice 

significant psychological changes as they take 

medications every day, go to the pharmacy to 

pick up medications, and make frequent visits 

to the clinic for evaluation and laboratory 

work. Some patients become depressed upon 

realizing that the severity of their illness 

now requires them to be on treatment. 

These psychological adjustments can cause 

significant symptoms that should be assessed 

and managed in a manner similar to the way 

in which pharmacologic adverse reactions are 

managed.

These psychological effects can be considered 

“process” effects from starting ART rather 

than adverse effects of the ARV medications 

themselves. As with the self-limited adverse 

effects of early-stage ARV therapy, process 

effects should become more tolerable over time 

as the medication regimen becomes routine for 

the patient. One of the most common process 

effects is fatigue. Many patients hope that 

their ARV regimen will give them increased 

energy and health, and they become frustrated 

when they notice increasing fatigue after 

starting the regimen. These patients must 

be evaluated to rule out common adverse 

effects that contribute to fatigue (e.g., anemia, 

hepatitis, lactic acidosis). Equally important, 

especially for patients beginning a new 

regimen, symptoms of fatigue could indicate 

depression or signal that the “process” of 

taking medications is emotionally difficult. 

Counseling, peer support, and antidepressant 

medications can be used to treat this type of 

fatigue. Often, once patients realize that some 

of the goals of treatment are being achieved 

(e.g., the CD4 cell count increases, the HIV 

viral load becomes undetectable, or symptoms 

of HIV infection resolve), they recognize the 

benefits of ARV medications, and their fatigue 

or other adverse symptoms associated with the 

process of starting the regimen may lessen.

This discussion has focused on the adverse 

reactions to ARV medications that patients 

are most likely to describe as they start a new 

regimen. Patients and providers also need to 

consider counseling about and management 

of long-term toxicities such as lipodystrophy, 

renal dysfunction, peripheral neuropathy, 

cardiac disease, diabetes, and dyslipidemia. As 

these long-term toxicities continue to challenge 

providers and patients alike, clinical trials and 

expert guidelines will provide support and 

information.

Clinicians are encouraged to report adverse 

reactions to medications to the U.S. Food 

and Drug Administration (FDA) MedWatch 

program by telephone at 800-FDA-1088, via 

fax at 800-FDA-0178, via the Internet at www.

fda.gov/Safety/MedWatch/HowToReport/, or 

by mail at MedWatch HF-2, FDA, 5600 Fishers 

Lane, Rockville, MD 20857.
Adverse Reactions to HIV Medications | 533

Section 7: ARV Interactions and 

Adverse Events

Patient Education

• All medications have potential to cause 

adverse reactions, which are defined as 

negative, unintended effects of medication 

use.

• Advise patients to report any adverse 

reaction to their medical care provider as 

soon as possible.

• Before starting a new medication, medical 

care providers or pharmacists should 

counsel patients about the most common 

adverse effects and about any remedies that 

are available to minimize the severity of 

those effects.

• Advise patients to talk to their provider 

or pharmacist before starting any new 

medications (including over-the-counter 

medications and herbs) because some 

drugs may interact with ARVs or other 

medications and can increase side effects or 

cause unwanted reactions.

• Nausea is one of the most common adverse 

effects. Counsel patients that nausea can be 

minimized by taking medications with food 

(if indicated, as some medications should 

be taken on an empty stomach) or by using 

ginger-based food or beverages (e.g., ginger 

ale, tea, cookies). If these measures do not 

work, patients should talk with their medical 

care provider; they may need medications to 

treat the symptoms.

• Counsel patients that they should not stop 

taking any medications unless instructed to 

do so by their medical care provider.

References

• Calmy A, Hirschel B, Cooper DA, et al. 

A new era of antiretroviral drug toxicity.

Antivir Ther. 2009;14(2):165-79.

• Ickovics JR, Cameron A, Zackin R, et al. 

Consequences and determinants of adherence 

to antiretroviral medication: results from 

Adult AIDS Clinical Trials Group protocol 

370. Antivir Ther. 2002 Sep;7(3):185-93.

• Montessori V, Press N, Harris M, et al. 

Adverse effects of antiretroviral therapy 

for HIV infection. CMAJ. 2004 Jan 

20;170(2):229-38.

• Panel on Antiretroviral Guidelines 

for Adults and Adolescents. Table 13: 

Antiretroviral Therapy-Associated Common 

and/or Severe Adverse Effects. In: Guidelines 

for the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013

• Roca B. Adverse drug reactions to 

antiretroviral medication. Front Biosci. 2009 

Jan;14:1785-92.

Drug-Drug Interactions with HIV-Related Medications | 535

Section 7: ARV Interactions and 

Adverse Events

Drug-Drug Interactions with 

HIV-Related Medications

Kirsten Balano, PharmD

Background

Drug-drug interactions are common concerns of patients with HIV and their health care 

providers. The issues involved in evaluating drug interactions are complex. Although many 

questions can be articulated simply (e.g., “What antidepressant is least likely to have drug 

interactions with antiretroviral medications?”), the responses to these questions involve more 

complex concerns (e.g., “In choosing an antidepressant for my patient with HIV, I must consider 

efficacy, adverse effects, and tolerability as well as drug interactions.”).

This complexity is increased because antiretroviral (ARV) agents, particularly protease inhibitors 

(PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), the pharmacokinetic booster 

cobicistat, and the CCR5 antagonist maraviroc, can cause or be affected by alterations in the 

activity of the cytochrome (CYP) P450 enzyme system in the liver, as well as by other mechanisms 

of drug metabolism. Interactions between an ARV and another drug (whether another ARV or a 

different type of medication) may result in an increase or a decrease in the serum levels of either 

the ARV or the interacting drug, potentially changing the effectiveness or the toxicity risk of 

substrate drugs. Understanding drug-drug interactions is challenging because of several factors, 

including the following: 

• Different drugs affect different P450 enzymes.

• Some medications have dosage-related responses that influence their effects on P450 enzymes.

• Formal pharmacokinetic studies on drug combinations are limited.

• Even when pharmacokinetic data exist for specific drug combinations, the clinical significance 

of any changes in pharmacokinetic parameters may not be clear.

• Patients taking ARVs often have complex drug regimens. Patients typically are taking three or more 

medications that could influence interactions. Pharmacokinetic studies that evaluate the clinical 

significance of drug interactions involving more than two medications are less likely to be available.

• Other metabolic pathways of medications such as P-glycoprotein (P-gp) and UDPglucuronosyltransferase (UGT)-1A1, can be altered by drug interactions. The integrase inhibitors 

dolutegravir and raltegravir, for example, are metabolized by UGT-1A1. 

• Some drug interactions involve effects on absorption or drug availability rather than 

metabolism. For example, the PI atazanavir and the NNRTI rilpivirine require gastric acidity for 

absorption; integrase inhibitor activity is impaired by polyvalent cations (e.g., iron, aluminum, 

calcium, and magnesium, and antacids, laxatives, supplements, and other preparations that 

contain them).

• Other influences on medication activity include food-drug interactions, protein binding, and 

altered intercellular activation of medications.
536 | Guide for HIV/AIDS Clinical Care

Section 7: ARV Interactions and 

Adverse Events

Information on various drug-drug interactions 

is available in guidelines and via the Internet 

(see “Resources,” below). Such resources can 

provide data regarding two-drug combinations, 

but rarely consider all the complexities outlined 

above. What follows, therefore, is a suggested 

approach to considering drug-drug interactions 

in managing HIV-infected patients and making 

patient-specific decisions, illustrated by a case 

study.

S: Subjective

A new patient arrives for a clinic intake 

appointment. The patient receives medical care 

from a local infectious disease physician who 

treats only a handful of HIV-infected patients. 

The patient was recently released from hospital 

with a discharge diagnosis of pneumonia and 

Mycobacterium avium complex (MAC). The 

patient is not yet taking ARVs, but needs to 

start ART promptly, along with an adherence 

support program. The patient has other 

medical problems, including hyperlipidemia, 

erectile dysfunction, diabetes, depression, 

gastroesophageal reflux disease (GERD), 

and herpes. The clinician wants to review 

the patient’s medication list to check for any 

potential drug-drug interactions. 

O: Objective

Review the patient’s pharmacy records for 

current medications, and ask about use of overthe-counter (OTC), herbal or natural products, 

and dietary supplements. As requested, the 

patient has brought in all medications from 

home for review. The current medication list 

includes the following:

• Clarithromycin 500 mg BID

• Ethambutol 1,000 mg QD

• Rifabutin 300 mg QD 

• Trimethoprim-sulfamethoxazole (TMPSMX) (Septra, Bactrim) double-strength, 1 

tablet QD

• Lovastatin 20 mg QD

• Metformin 500 mg BID

• Bupropion 150 mg QD

• Acyclovir 400 mg BID

• Omeprazole 20 mg QD (patient buys OTC 

for heartburn)

• Milk thistle (silymarin) (patient takes as 

needed for energy and liver health)

A: Assessment 

Step 1: Identify interactions and classify them 

as follows:

• Definite interactions

• Probable interactions

• Possible interactions

Definite Drug Interactions

A drug interaction is definite if a high level 

of evidence is available regarding the drug 

combination, the clinical significance of the 

interaction is well understood, and consensus 

exists regarding the management strategy (e.g., 

whether dosage adjustments are required, or 

concurrent use is contraindicated). Common 

definite interactions for HIV patients include 

the following: 

• Certain combinations of HIV agents (e.g., 

certain PIs or integrase inhibitors with 

NNRTIs, maraviroc with PIs or NNRTIs, 

tenofovir with atazanavir)

• Rifamycins and PIs, NNRTIs, cobicistat, or 

maraviroc

• Statins with PIs or cobicistat

• Erectile dysfunction agents and PIs or 

cobicistat

• Methadone and certain PIs or NNRTIs

• Fluticasone and PIs or cobicistat

Probable Drug Interactions

A drug interaction is probable if the limited 

available evidence suggests that an interaction 

may occur, even if the clinical outcome or 

significance may not be clearly established. 

Effective management of a probable interaction 
Drug-Drug Interactions with HIV-Related Medications | 537

Section 7: ARV Interactions and 

Adverse Events

is based on assessment and clinical judgment 

about the risks and benefits of a particular 

combination for each patient. Examples 

of probable interactions with HIV-related 

medications include the following: 

• Antidepressants and PIs or NNRTIs

• Oral contraceptives and PIs or cobicistat

• Warfarin and PIs, NNRTIs, or cobicistat

• Proton pump inhibitors (PPIs) or H-2 

blockers and atazanavir or rilpivirine

• Polyvalent cations (e.g., calcium, iron, 

cation-containing antacids) and integrase 

inhibitors

• Certain antifungal agents and PIs, 

NNRTIs, or cobicistat (except in the case of 

voriconazole, for which definite information 

on interactions is available)

• Certain antiepileptic medications and PIs, 

NNRTIs, or cobicistat

Possible Drug Interactions

Possible drug interactions may be difficult to 

distinguish from probable drug interactions, 

but in these cases, only theoretical evidence 

is available. The proper management of such 

interactions requires weighing the risks and 

benefits of the combination and making sound 

clinical judgments. Examples of possible drug 

interactions with HIV medications include the 

following: 

• Herbal products and PIs, NNRTIs, or 

cobicistat (except in the case of St. John’s 

wort, for which definite information on 

interactions is available)

• Antidiabetic medications and PIs or 

NNRTIs

• Antipsychotic agents and PIs, NNRTIs, or 

cobicistat

Memorizing all the potential drug interactions 

is impossible. It is possible, however, to 

remember a few commonly encountered 

drug combinations that have the potential for 

clinically significant interactions. It is also 

important to recognize that PIs (particularly 

ritonavir), NNRTIs, and cobicistat very 

commonly interact with other medications. 

The above examples of definite, probable, and 

possible interactions are reasonable “red flag” 

drug combinations that can be recalled easily. 

In addition, certain Internet resources allow 

providers to submit all of a patient’s current 

medications and planned additions (e.g., 

atazanavir/ritonavir as part of a new ARV 

regimen) and receive information on potential 

interactions (see “Resources,” below). Finally, 

consultation with clinical pharmacists can 

aid in identifying and classifying potential 

interactions.

P: Plan 

Step 2: The patient described above will start 

an ARV regimen of atazanavir/ritonavir + 

tenofovir + emtricitabine. The PI may cause 

problematic drug-drug interactions with some 

of the patient’s preexisting medications, and 

tenofovir interacts with atazanavir. Develop 

a plan for management when these ARVs are 

added. For this patient, the following definite 

interactions should be of concern:

• Rifabutin and atazanavir/ritonavir

• Lovastatin and atazanavir/ritonavir

• Tenofovir and atazanavir

• Clarithromycin and atazanavir/ritonavir

Refer to available references for management 

suggestions. Such references include the 

following: 

• U.S. Department of Health and Human 

Services. Guidelines for the Use of 

Antiretroviral Agents in HIV-1-Infected 

Adults and Adolescents (aidsinfo.nih.gov/

guidelines), relevant tables

• HIV InSite Database of Antiretroviral Drug 

Interactions (hivinsite.ucsf.edu/interactions)

• University of Liverpool HIV Drug 

Interaction Charts (www.hivdruginteractions.org)
538 | Guide for HIV/AIDS Clinical Care

Section 7: ARV Interactions and 

Adverse Events

• Clinical Care Options (www.clinicaloptions.

com/HIV.aspx)

Most of these resources include specific dosage 

adjustments or alternative agents to consider 

when managing these drug combinations. The 

suggestions for this patient are as follows:

• Rifabutin levels are increased by atazanavir/

ritonavir. The rifabutin dosage should be 

decreased to 150 mg daily with standard 

atazanavir/ritonavir dosing. Alternatively, 

discuss with the patient’s primary care 

provider whether rifabutin is important to 

the current MAC regimen or whether the 

patient could be treated adequately with just 

clarithromycin + ethambutol to avoid the 

above-cited interactions.

• Lovastatin levels are increased substantially 

by atazanavir/ritonavir; concurrent use 

with a PI can lead to potentially fatal 

rhabdomyolysis. Lovastatin should be 

discontinued when atazanavir/ritonavir is 

initiated. To manage hyperlipidemia, the 

patient should be switched to a statin whose 

metabolism is less affected by these PIs, 

such as pravastatin or low-dose atorvastatin 

(simvastatin, also is contraindicated for use 

by patients who take a PI).

• Tenofovir can decrease plasma 

concentrations of unboosted atazanavir, but 

can be administered safely with ritonavirboosted atazanavir.

• Clarithromycin levels are increased by 

atazanavir/ritonavir; concurrent use can 

lead to QTc prolongation. If clarithromycin 

is co-administered with atazanavir/ritonavir, 

its dosage should be reduced by 50%.

Although this patient’s current medication 

list does not contain an erectile dysfunction 

agent, the patient should be educated about the 

definite interactions and dosage adjustments 

recommended for patients using those agents 

with PIs. Some patients may obtain erectile 

dysfunction agents outside the care of their 

physician and, if unaware of the interactions 

and suggested dosage adjustments, may be at 

risk of life-threatening consequences.

The following probable or possible interactions 

should be considered if PIs are begun, 

including:

• Omeprazole with atazanavir/ritonavir

• Bupropion with atazanavir/ritonavir

• Milk thistle with atazanavir/ritonavir

The web-based resources and other references 

listed above include some information about 

these potential interactions. The following are 

suggestions:

• Omeprazole: PPIs and H2-blockers 

decrease serum levels of atazanavir, even 

when boosted with ritonavir, but the 

clinical significance of this interaction has 

not been demonstrated. In general, it may 

be best to avoid concomitant use of these 

acid-blocking medications with atazanavir 

by either discontinuing the GERD 

medication or switching to another ARV. 

Unboosted atazanavir should not be used 

with PPIs. For patients without evidence of 

ARV resistance in whom coadministration 

of these medications is judged unavoidable, 

atazanavir/ritonavir may be used, but 

doses of omeprazole should not exceed 20 

mg and must be taken at least 12 hours 

prior to taking atazanavir/ritonavir. Note 

that tenofovir also can lower atazanavir 

levels, so increasing atazanavir to 400 mg/

day with ritonavir 100 mg/day could be 

considered.

• Bupropion and milk thistle: Specific 

management or dosage adjustments based 

on data are not available. This patient should 

be monitored for increased or decreased 

effects of bupropion and educated about 

potential interactions with milk thistle. 

Clinical judgment and decision making 

with the primary care provider and other 

specialists (e.g., psychiatrists) may be 

required.
Drug-Drug Interactions with HIV-Related Medications | 539

Section 7: ARV Interactions and 

Adverse Events

Consultation with clinical pharmacy services 

may assist in evaluating the potential 

significance of drug interactions and 

developing management strategies.

Patient Education

• Instruct patients that HIV medications, 

in particular PIs, NNRTIs, cobicistat, 

and maraviroc, have a high potential for 

significant drug interactions.

• Tell patients to bring all their medicines, 

including any herbal, nutritional, and 

dietary supplements and OTC remedies, 

with them to all medical appointments. If 

they cannot bring the actual containers with 

them, they should bring a list of current 

prescribed medications, supplements, and 

OTC medications.

• Patients should have their primary care 

provider or pharmacist review any newly 

prescribed medications along with their 

current list of medicines. This is especially 

important if another physician prescribes a 

new medication.

• Patients should not “borrow” medications 

from friends or family. Assure patients that 

if they have a problem that needs medical 

treatment, their primary care provider will 

discuss it and choose the safest treatments 

for them.

• Tell patients that, if they are considering 

buying a new nutritional or herbal 

supplement or an OTC product, they should 

consult their pharmacist or primary care 

provider about interactions with drugs on 

their current medication list.

• Not all drug interactions are cause for alarm. 

Some drug combinations are safe for certain 

people, but less safe for others. Warn patients 

not to stop taking any medicines without the 

advice of their primary care provider.

Resources

• HIV InSite Database of Antiretroviral Drug 

Interactions (hivinsite.ucsf.edu/interactions)

• University of Liverpool HIV Drug 

Interaction Charts (www.hivdruginteractions.org/)

• Clinical Care Options (www.clinicaloptions.

com/HIV.aspx)

References

• Dickinson L, Khoo, S, Back D. 

Pharmacokinetics and drug-drug interactions 

of antiretrovirals: an update. Antiviral Res. 

2010 Jan;85(1):176-89.

• Liedtke MD, Lockhart SM, Rathbun 

RC. Anticonvulsant and antiretroviral 

interactions. Ann Pharmacother. 2004 

Mar;38(3):482-9.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Piscitelli SC, Gallicano KD. Interactions 

among drugs for HIV and opportunistic 

infections. N Engl J Med. 2001 Mar 

29;344(13):984-96.

• Rainey PM. HIV drug interactions: the good, 

the bad, and the other. Ther Drug Monit. 

2002 Feb;24(1):26-31.

• Sheehan NL, Kelly DV, Tseng AL, et 

al. Evaluation of HIV drug interaction 

web sites. Ann Pharmacother. 

2003 Nov;37(11):1577-86.

• Soodalter J, Sousa M, Boffito M. Drug-drug 

interactions involving new antiretroviral 

drugs and drug classes. Curr Opin Infect Dis. 

2009 Feb;22(1):18-27.

Antiretroviral Medications and Hormonal Contraceptive Agents | 541

Section 7: ARV Interactions and 

Adverse Events

Antiretroviral Medications and 

Hormonal Contraceptive Agents

Background

Few pharmacokinetic or clinical studies have examined interactions between antiretroviral (ARV) 

medications and hormonal contraceptives, but it is known that certain protease inhibitors (PIs) 

and nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well as the boosted integrase 

inhibitor combination elvitegravir/cobicistat, do interact with hormonal contraceptives. These 

interactions may increase the risk of medication failure or medication adverse effects of either the 

ARV or the contraceptive. There are no known interactions between hormonal contraceptives and 

nucleoside analogues or the CCR5 antagonist.

Oral Contraceptives

All oral contraceptives currently marketed in the United States, with the exception of progestinonly pills (which contain norethindrone), contain both ethinyl estradiol and a progestin 

(desogestrel, drospirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone 

acetate, norgestimate, or norgestrel). The oral contraceptives ethinyl estradiol and norethindrone 

may interact in complex ways with PIs and NNRTIs. The mechanism of these interactions 

may be multifactorial and includes the activity of these agents on cytochrome P450 enzymes. 

Pharmacokinetic studies have shown changes (either increases or decreases) in levels of ethinyl 

estradiol and norethindrone in women who are taking certain PIs, NNRTIs, or elvitegravir/

cobicistat. Other studies have shown decreases in levels of amprenavir (the active agent of 

fosamprenavir) in women taking oral contraceptives.

The clinical significance of these drug interactions has not been evaluated thoroughly, but may 

cause oral contraceptive failure, ARV failure, or medication toxicity, depending on whether drug 

levels are lowered or raised by the interacting drug. The consequences of decreased hormone 

levels may include an increased risk of pregnancy, so an alternative or additional method of 

contraception is commonly recommended. The consequences of decreased ARV levels may include 

virologic failure and development of resistance mutations. The consequences of a higher level of 

hormones may include risk of thromboembolism, breast tenderness, headache, nausea, and acne.

The available pharmacokinetic data are summarized in Table 1. For further discussion of oral and 

non-oral contraceptives for HIV-infected women, see chapter Health Care of HIV-Infected Women 

Through the Life Cycle.
542 | Guide for HIV/AIDS Clinical Care

Section 7: ARV Interactions and 

Adverse Events

Table 1. Interactions Between Antiretroviral Agents and Oral Contraceptives

Key to symbols:

 Use alternative/additional method or 

do not administer together 

! Use with caution  Safe to use in combination or no 

dosage adjustment necessary

Antiretroviral 

Agent

Pharmacokinetic Changes 

with Oral Contraceptives Comments

Protease Inhibitors

Atazanavir 

(ATV, Reyataz) 

(unboosted)

• EE AUC ↑ 48% 

• NE AUC ↑ 110%

! • OC should contain ≤30 mcg EE. Monitor for 

side effects, or use alternative method.

ATV/r • EE AUC ↓ 19%

• 17-deacetyl norgestimate 

(active metabolite of NG) 

AUC ↑ 85%

! • OC should contain ≥35 mcg EE.

• OCs containing progestins other than 

norethindrone or norgestimate have not 

been studied.

Darunavir (DRV, 

Prezista) DRV/r

• EE AUC ↓ 44%

• NE AUC ↓ 14%

 • Use alternative or additional method of 

contraception. 

Fosamprenavir 

(FPV, Lexiva)

• EE Cmin ↑ 32%

• NE Cmin ↑ 45%; AUC ↑ 18%

• Amprenavir AUC ↓ 22% 

• Amprenavir Cmin ↓ 20% 

 • Data are derived from studies with 

amprenavir (the active metabolite of FPV).

• Risk of ARV failure and of EE or NE adverse 

effects: do not coadminister fosamprenavir 

with OCs.

• Use alternative method of contraception.

FPV/r • EE AUC ↓ 37%

• NE AUC ↓ 34%

 • Risk of contraceptive failure and of ritonavir 

adverse effects.

• Use alternative method of contraception.

Indinavir (IDV, 

Crixivan)

• EE AUC ↑ 24% 

• NE AUC ↑ 26%

 • No dosage adjustment is recommended.

• Monitor for EE or NE adverse effects.

IDV/r • No data  • Risk of contraceptive failure; use alternative 

or additional method of contraception.

Lopinavir/r 

(LPV/r, Kaletra)

• EE AUC ↓ 42% 

• NE AUC ↓ 17% 

 • Risk of contraceptive failure; use alternative 

or additional method of contraception.

Nelfinavir (NFV, 

Viracept)

• EE AUC ↓ 47% 

• NE AUC ↓ 18% 

 • Risk of contraceptive failure; use alternative 

or additional method of contraception.

Ritonavir (RTV, 

Norvir)

• EE AUC ↓ 40%  • Risk of contraceptive failure; use alternative 

method of contraception.

Saquinavir (SQV, 

Invirase)/r

• No data; theoretic EE ↓

• SQV kinetics not affected 

by OC

 • Risk of contraceptive failure; use alternative 

or additional method of contraception.

Tipranavir (TPV, 

Aptivus)/r

• EE AUC ↓ 48%

• NE no significant change 

 • Risk of contraceptive failure; use alternative 

or additional method of contraception.
Antiretroviral Medications and Hormonal Contraceptive Agents | 543

Section 7: ARV Interactions and 

Adverse Events

Antiretroviral 

Agent

Pharmacokinetic Changes 

with Oral Contraceptives Comments

Nonnucleoside Reverse Transcriptase Inhibitors

Efavirenz (EFV, 

Sustiva)

• EE AUC no significant 

change

• 17-deacetyl norgestimate 

(active metabolite of NG)

AUC ↓ 64%

• LN AUC ↓ 58-83%

• NE: AUC ↓ predicted

 • Decrease in progestin levels: risk of 

contraceptive failure [including failure 

of emergency contraception (Plan B)]; 

use alternative or additional method of 

contraception. 

Etravirine (ETR, 

Intelence)

• EE AUC ↑ 22%

• NE AUC ↓ 5%

 • No dosage adjustment is necessary.

Nevirapine (NVP, 

Viramune)

• EE AUC ↓ 20% 

• NE AUC ↓ 19%

 • Risk of contraceptive failure; use alternative 

or additional method of contraception.

Rilpivirine (RPV, 

Edurant)

• EE AUC ↑ 14%

• NE no significant change

 • No dosage adjustment is necessary.

CCR5 Antagonist

Maraviroc (MVC, 

Selzentry) 

• No significant effect on 

EE or LN

 • No dosage adjustment is necessary.

Integrase Inhibitor

Dolutegravir 

(DTG, Tivicay)

• No significant change in 

EE AUC or NG AUC

 • No dosage adjustment is necessary

Elvitegravir

(EVG, Stribild)

• NE AUC ↓ 25%, Cmin ↓ 44%

• NG AUC, Cmax, Cmin ↑ >2-fold

! • Risk of NG adverse effects (not fully known; 

may include venous thrombosis); consider 

alternative method of contraception.

Raltegravir (RAL, 

Isentress)

• No significant change in 

EE AUC or NG AUC

 • No dosage adjustment is necessary.

Abbreviations: AUC = area under the time-concentration curve (drug exposure); C max = maximum concentration; C min = minimum 

concentration; EE = ethinyl estradiol; LN = levonorgestrel; NE = norethindrone; NG = norgestimate; OC = oral contraceptive; RTV = 

ritonavir; /r = low-dose ritonavir

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected 

adults and adolescents. Department of Health and Human Services. Available at aidsinfo.nih.gov/guidelines.

Non-Oral Hormonal 

Contraceptives 

Hormonal contraceptives using delivery 

methods other than oral include the following:

• Products containing both progestin and 

estrogen components: transdermal patch, 

vaginal ring

• Products containing a progestin 

alone (medroxyprogesterone acetate, 

levonorgestrel, norelgestromin, or 

etonogestrel): subcutaneous or IM injection, 

intrauterine system, implantable device

There has been little research on the 

interactions between ARVs and most of 

these agents. Theoretically, interactions with 

ARVs would be less likely with contraceptive 

methods that have primarily local action and 

minimal systemic absorption, and for injection 

or transdermal delivery systems, since firstpass metabolism is avoided. However, caution 

is still warranted, as this assumption has not 

been proven.
544 | Guide for HIV/AIDS Clinical Care

Section 7: ARV Interactions and 

Adverse Events

Because the transdermal patch and vaginal 

ring contain ethinyl estradiol, women 

who take ARVs that increase or decrease 

serum estradiol levels (see Table 1) are 

advised to use an alternative (or additional) 

contraceptive method. Small studies of depomedroxyprogesterone acetate (DMPA, or 

Depo-Provera) have shown no significant 

interactions between DMPA and nelfinavir, 

efavirenz, or nevirapine. Interactions between 

DMPA and other ARVs have not been 

studied, but DMPA’s interactions with PIs 

and NNRTIs would be expected to be similar 

to those of norethindrone (see Table 1). For 

other non-oral hormones, pending further 

study, an alternative (or additional) method of 

contraception should be considered.

References

• Anderson MS, Wenning L, Moreau A, et al. 

Effect of raltegravir on the pharmacokinetics 

of oral contraceptives. In: Program 

and abstracts of the 47th Interscience 

Conference on Antimicrobial Agents and 

Chemotherapy; September 17-20, 2007; 

Chicago. Abstract A-1425.

• Bounds W, Guillebaud J. Observational 

series on women using the contraceptive 

Mirena concurrently with anti-epileptic and 

other enzyme-inducing drugs. J Fam Plann 

Reprod Health Care. 2002 Apr;28(2):78-80.

• Carten M, Kiser J, Kwara A, et al. 

Pharmacokinetic interactions between 

the hormonal emergency contraception, 

levonorgestrel, and efavirenz. In: Program 

and abstracts of the 17th Conference on 

Retroviruses and Opportunistic Infections. 

February 16-19, 2010; San Francisco. 

Abstract 934.

• Chu JH, Gange SJ, Anastos K et al. 

Hormonal contraceptive use and the 

effectiveness of highly active antiretroviral 

therapy. Am J Epidemiol. 2005 May 

1;161(9):881-90.

• Cohn SE, Park JG, Watts DH, et al.; 

ACTG A5093 Protocol Team. Depomedroxyprogesterone in women on 

antiretroviral therapy: effective contraception 

and lack of clinically significant interactions. 

Clin Pharmacol Ther. 2007 Feb;81(2):222-7.

• Gupta S. Non-oral hormonal contraception. 

Curr Ob Gyn. 2006 Feb;16(1):30-8.

• Heikinheimo O, Lehtovirta P, Suni J, et al. 

The levonorgestrel-releasing intrauterine 

system (LNG-IUS) in HIV-infected women – 

effects on bleeding patterns, ovarian function 

and genital shedding of HIV. Hum Reprod. 

2006 Nov;21(11):2857-61.

• Implanon [package insert]. Kenilworth, NJ: 

Schering-Plough; 2009.
Antiretroviral Medications and Hormonal Contraceptive Agents | 545

Section 7: ARV Interactions and 

Adverse Events

• Joshi AS, Fiske WD, Benedek IH, et al. Lack 

of a pharmacokinetic interaction between 

efavirenz (DMP 266) and ethinylestradiol 

in healthy female volunteers. In: Program 

and abstracts of the 5th Conference on 

Retroviruses and Opportunistic Infections; 

February 1-5, 1998; Chicago. Abstract 348.

• Kearney BP, Mathias A. Lack of 

effect of tenofovir disoproxil fumarate 

on pharmacokinetics of hormonal 

contraceptives. Pharmacotherapy. 2009 

Aug;29(8):924-9.

• Mayer K, Poblete R, Hathaway B, et al. 

Efficacy, effect of oral contraceptive, and 

adherence in HIV infected women receiving 

Fortovase (saquinavir) soft gel capsule thrice 

and twice daily regimens. In: Program and 

abstracts of the XIII International AIDS 

Conference; July 9-14, 2000; Durban, South 

Africa. Abstract TuPeB3226.

• McNicholl I. Database of Antiretroviral 

Drug Interactions. HIV InSite. San 

Francisco: UCSF Center for HIV 

Information. Available at hivinsite.ucsf.edu/

interactions. Accessed December 1, 2013.

• Mitchell HS, Stephens E. Contraception 

choice for HIV positive women. Sex Transm 

Infect. 2004 Jun;80(3):167-73.

• Nanda K, Amaral E, Hays M, et al. 

Pharmacokinetic interactions between 

depot medroxyprogesterone acetate and 

combination antiretroviral therapy. Fertil 

Steril. 2008 Oct;90(4):965-71.

• Ouellet D, Hsu A, Qian J, et al. Effect of 

ritonavir on the pharmacokinetics of ethinyl 

oestradiol in healthy female volunteers. Br J 

Clin Pharmacol. 1998 Aug;46(2):111-6.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Scholler-Gyure M, Debroye C, Aharchi 

F, et al. No effect of TMC125 on the 

pharmacokinetics of oral contraceptives. 

In: Program and abstracts of the 8th 

International Congress on Drug Therapy 

in HIV Infection; November 12-16, 2006; 

Glasgow. Abstract P277.

• Sekar VJ, Lefebvre E, Guzman SS, et al. 

Pharmacokinetic interaction between ethinyl 

estradiol, norethindrone and darunavir with 

low-dose ritonavir in healthy women. Antivir 

Ther. 2008;13(4):563-9.

• Sevinsky H, Eley T, He B, et al. Effect 

of efavirenz on the pharmacokinetics of 

ethinylestradiol and norgestimate in healthy 

female subjects. In: Program and abstracts 

of the 48th Interscience Conference on 

Antimicrobial Agents and Chemotherapy; 

October 25-28, 2008; Washington. Abstract 

A-958.

• Tackett D, Child M, Agarwala S, et 

al. Atazanavir: a summary of two 

pharmacokinetic drug interaction studies in 

healthy subjects. In: Program and abstracts 

of the 10th Conference on Retroviruses and 

Opportunistic Infections; February 10-13, 

2003; Boston. Abstract 543.

• Watts DH, Park JG, Cohn SE, et al. Safety 

and tolerability of depot medroxyprogesterone 

acetate among HIV-infected women on 

antiretroviral therapy: ACTG A5093. 

Contraception. 2008 Feb;77(2):84-90.

Pain Syndrome and Peripheral Neuropathy | 547

Section 8: Neuropsychiatric 

Disorders

Pain Syndrome and 

Peripheral Neuropathy

Background 

The International Association for the Study of Pain defines pain as “an unpleasant sensory and 

emotional experience associated with actual or potential tissue damage or described in terms of 

such damage.” Pain is subjective, it is whatever the patient says it is, and it exists whenever the 

patient says it does. Pain is a common symptom in people with HIV infection, especially those 

with advanced disease. It occurs in 30-60% of HIV/AIDS patients and can diminish their quality of 

life significantly. Like cancer patients, HIV patients experience an average of 2.5 to 3 types of pain 

at once. Pain in HIV-infected patients may have many causes (as discussed below). 

Pain is significantly undertreated, especially among HIV-infected women, because of factors 

ranging from providers’ lack of knowledge about the diagnosis and treatment of pain to patients’ 

fear of addiction to analgesic medications. Pain, as the so-called fifth vital sign, should be assessed 

at every patient visit. 

Peripheral Neuropathy

Pain from HIV-associated peripheral neuropathy is particularly common, and may be debilitating. 

Peripheral neuropathy is clinically present in approximately 30% of HIV-infected individuals and 

typically presents as distal sensory polyneuropathy (DSP). It may be related to HIV itself (especially 

at CD4 counts of <200 cells/μL), to medication toxicity (e.g., from certain nucleoside analogues 

such as stavudine or didanosine), or to the effects of chronic illnesses (e.g., diabetes mellitus). 

Patients with peripheral neuropathy may complain of numbness or burning, a pins-and-needles 

sensation, shooting or lancinating pain, and a sensation that their shoes are too tight or their feet 

are swollen. These symptoms typically begin in the feet and progress upward; the hands also may 

be affected. Patients may develop difficulty walking because of discomfort, or because they have 

difficulty feeling their feet on the ground. Factors associated with increased risk of peripheral 

neuropathy include the following: 

• Previous peripheral neuropathy

• Low CD4 count (<200 cells/μL)

• Previous AIDS-defining opportunistic 

infection or neoplasm

• Vitamin B12 deficiency

• Exposure to stavudine or didanosine

• Use of other drugs associated with 

peripheral neuropathy (e.g., isoniazid, 

dapsone, metronidazole, hydroxyurea, 

thalidomide, linezolid, ribavirin, vincristine)

• Use of other neurotoxic agents (e.g., alcohol)

• Diabetes mellitus

Patients should be assessed carefully before the introduction of a potentially neurotoxic medication 

(including stavudine or didanosine), and the use of these medications for patients at high risk of 

developing peripheral neuropathy should be avoided. 
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S: Subjective

Self-report is the most reliable method to 

assess pain.

The patient complains of pain. The site and 

character of the pain will vary with the 

underlying cause. Ascertain the following 

from the patient:

• Duration, onset, progression

• Distribution, symmetry

• Character or quality (e.g., 

burning, sharp, dull)

• Intensity

• Severity (using the 0-10 scale; see Figure 1)

• Neurologic symptoms (e.g., weakness, 

cranial nerve abnormalities, bowel or 

bladder abnormalities)

• Exacerbating or relieving factors

• Response to current or past pain 

management strategies

• Past medical history (e.g., AIDS, diabetes 

mellitus)

• Psychosocial history

• Substance abuse and alcohol use history 

(amount, duration)

• Medications, current and recent 

(particularly zalcitabine, didanosine, 

stavudine, and isoniazid)

• Nutrition (vitamin deficiencies)

• Meaning of the pain to the patient

Measuring the severity of the pain: Have 

the patient rate the pain severity on a 

numeric scale of 0-10 (0 = no pain; 10 = worst 

imaginable pain), a verbal scale (none, small, 

mild, moderate, or severe), or a pediatric 

faces pain scale (when verbal or language 

abilities are absent). Note that pain ratings >3 

usually indicate pain that interferes with daily 

activities. Use the same scale for evaluation of 

treatment response.

Figure 1. Faces Pain Rating Scale (0-10)

Quick screen for peripheral neuropathy: Ask 

about distal numbness and check Achilles 

tendon reflexes. Screening for numbness and 

delayed or absent ankle reflexes has the highest 

sensitivity and specificity among the clinical 

evaluation tools for primary care providers. 

For a validated screening tool, use the ACTG 

Brief Peripheral Neuropathy Scale (BPNS) 

to scale and track the degree of peripheral 

neuropathy (see www.hiv.va.gov/provider/

manual-primary-care/peripheral-neuropathy.

asp#S4.2X).

O: Objective

Measure vital signs (increases in blood 

pressure, respiratory rate, and heart rate can 

correlate with pain). Perform a symptomdirected physical examination, including a 

thorough neurologic and musculoskeletal 

examination. Look for masses, lesions, and 

localizing signs. Pay special attention to 

sensory deficits (check for focality, symmetry, 

and distribution [such as “stocking-glove”]), 

muscular weakness, reflexes, and gait. Patients 

with significant motor weakness or paralysis, 

especially if progressive over days to weeks, 

should be evaluated emergently.

To evaluate peripheral neuropathy: Check 

ankle Achilles tendon reflexes and look for 

delayed or absent reflexes as signs of peripheral 

neuropathy. Distal sensory loss often starts 

with loss of vibratory sensation, followed by 

loss of temperature sensation, followed by 

onset of pain. Findings are usually bilateral 

and symmetric.

 0 1 2 3 4 5 6 7 8 9 10
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Section 8: Neuropsychiatric 

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A: Assessment

Pain assessment includes determining the type 

of pain, for example, nociceptive, neuropathic, 

or muscle spasm pain.

Nociceptive pain occurs as a result of tissue 

injury (somatic) or activation of nociceptors 

resulting from stretching, distention, or 

inflammation of the internal organs of the 

body. It usually is well localized; may be 

described as sharp, dull, aching, throbbing, 

or gnawing in nature; and typically involves 

bones, joints, and soft tissue.

Neuropathic pain occurs from injury to 

peripheral nerves or central nervous system 

structures. Neuropathic pain may be described 

as burning, shooting, tingling, stabbing, or like 

a vise or electric shock; it involves the brain, 

central nervous system, nerve plexuses, nerve 

roots, or peripheral nerves. It is associated with 

decreased sensation and hypersensitivity.

Muscle spasm pain can accompany spinal 

or joint injuries, surgeries, and bedbound 

patients. It is described as tight, cramping, 

pulling, and squeezing sensations.

Although pain in HIV-infected patients 

can result from opportunistic infections, 

neoplasms, or medication-related neuropathy, 

it is important to include non-HIV-related 

causes of pain in a differential diagnosis. Some 

of these other causes may be more frequent in 

HIV-infected individuals. A partial list for the 

differential diagnosis includes: 

• Anorectal carcinoma

• Aphthous ulcers

• Appendicitis 

• Arthritis, myalgias 

• Candidiasis, oral or esophageal 

• Cholecystitis 

• Cryptococcal disease 

• Cytomegalovirus colitis 

• Dental abscesses 

• Gastroesophageal reflux disease (GERD) 

• Ectopic pregnancy 

• Herpes simplex 

• Herpes zoster 

• Kaposi sarcoma 

• Lymphoma 

• Medication-induced pain syndromes (e.g., 

owing to growth hormone, granulocyte 

colony-stimulating factor) 

• Medication-induced peripheral neuropathy 

(e.g., owing to didanosine, stavudine, 

isoniazid, vincristine) 

• Other causes of peripheral neuropathy: 

diabetes, hypothyroidism, B12 deficiency, 

syphilis, cryoglobulinemia (especially in 

patients with hepatitis C coinfection) 

• Mycobacterium avium complex 

• Myopathy 

• Pancreatitis 

• Pelvic inflammatory disease 

• Toxoplasmosis

P: Plan

Perform a diagnostic evaluation based on the 

suspected causes of pain.

Treatment

Treatment should be aimed at eliminating 

the source of pain, if possible. If symptomatic 

treatment of pain is needed, begin treatment 

based on the patient’s pain rating scale, using 

the least invasive route. The goal is to achieve 

optimal patient comfort and functioning 

(not necessarily zero pain) with minimal 

medication adverse effects. Use the three-step 

pain analgesic ladder originally devised by 

the World Health Organization (WHO); see 

Figure 2.
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Nonpharmacologic interventions

The following interventions can be used at any 

step in the treatment plan: 

• A therapeutic provider-patient relationship 

• Physical therapy 

• Exercise 

• Relaxation techniques 

• Guided imagery 

• Massage 

• Biofeedback 

• Reflexology 

• Acupuncture 

• Thermal modalities (hot and cold 

compresses or baths) 

• Transcutaneous electrical nerve 

stimulation (TENS) 

• Spiritual exploration 

• Prayer 

• Deep breathing 

• Meditation 

• Enhancement of coping skills 

• Self-hypnosis 

• Humor 

• Distraction

• Hobbies

Pharmacologic interventions

Principles of pharmacologic pain 

treatment

• The dosage of the analgesic is adjusted to 

give the patient adequate pain control.

• The interval between doses is adjusted so 

that the pain control is uninterrupted. It 

can take 4-5 half-lives before the maximum 

effect of an analgesic is realized.

• Chronic pain is more likely to be controlled 

when analgesics are dosed on a continuous 

schedule rather than “as needed.” Sustainedrelease formulations of opioids should be 

used whenever possible.

• For breakthrough pain, use “as needed” 

medications in addition to scheduled-dosage 

analgesics. When using opiates for both 

scheduled analgesia and breakthrough 

pain, a good rule of thumb is to use 10% of 

the total daily dosage of opiates as the “as 

needed” opiate dose for breakthrough pain.

• Oral administration has an onset of 

analgesia of about 20-60 minutes, 

tends to produce more stable 

blood levels, and is cheaper.

• Beware of the risk of prolonged 

analgesic half-lives in patients with 

renal or hepatic dysfunction.

• Caution when using combination 

analgesics that are coformulated with 

ingredients such as acetaminophen, 

aspirin, or ibuprofen. Determine the 

maximum daily dosage of all agents.

The following three steps are adapted from the 

WHO analgesic ladder. Agents on higher steps 

are progressively stronger pain relievers but 

tend to have more adverse effects.
Pain Syndrome and Peripheral Neuropathy | 551

Section 8: Neuropsychiatric 

Disorders

Figure 2. Pharmacologic Approaches to Pain Management: WHO Three-Step Ladder

Step 3: Severe Pain

Morphine

Hydromorphine

Methadone

Levorphanol

Fentamyl

Oxycodone

±Nonopioid analgesics

±Adjuvants

Step 2: Moderate Pain

APAP or ASA+

Codeine

Hydrocodone

Oxycodone

Dhydrocodeine

Tramadol (not available 

with ASA or APAP)

±Adjuvants

Step 1: Mild Pain

Aspirin (ASA)

Acetaminophen (APAP)

Nonsteroidal 

anti-inammatory drugs 

(NSAIDs) 

±Adjuvants

Adapted from World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health 

Organization; 1990.

Note: “Adjuvants” refers either to medications that are coadministered to manage an adverse effect of an opioid or to so-called adjuvant 

analgesics that are added to enhance analgesia.

Step 1: Nonopiates for mild pain 

(pain scale 1-3)

• The most common agents in this step 

include acetaminophen (650-1,000 mg 

PO Q6H as needed) and nonsteroidal 

antiinflammatory drugs (NSAIDs) such as 

ibuprofen 600-800 mg PO TID with food, 

and cyclooxygenase-2 (COX-2) inhibitors 

such as celecoxib and rofecoxib.

• A proton-pump inhibitor (such as 

omeprazole) can decrease the risk of 

gastrointestinal bleeding when using 

NSAIDs.

• Acetaminophen has no effect on platelets 

and no antiinflammatory properties; avoid 

use in patients with hepatic insufficiency, 

and in general limit to 4 g per day in acute 

use (or 2 g per day for patients with liver 

disease). Monitor liver function tests in 

chronic use.

• NSAIDs and acetaminophen can be used 

together for synergism.

• Note that COX-2 inhibitors have been 

associated with an increased risk of 

cardiovascular events and should be used 

with caution.
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Section 8: Neuropsychiatric 

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Step 2: Mild opiates with or without 

nonopiates for moderate pain (pain 

scale 4-6)

• Most agents used to treat moderate pain 

are combinations of opioids and Step 

1 agents. The most common agents are 

acetaminophen combined with codeine, 

oxycodone, or hydrocodone. Codeine can 

be dosed as codeine sulfate, separately from 

acetaminophen. Beware of acetaminophen 

toxicity in these combination drugs.

• Other agents include buprenorphine (partial 

opiate agonist).

• Tramadol (Ultram) is a centrally acting 

nonopiate that can be combined with 

NSAIDs. As with opiates, it is prone 

to abuse. Tramadol lowers the seizure 

threshold; avoid use for patients with a 

seizure history. Avoid coadministration 

with selective serotonin reuptake 

inhibitors (SSRIs) and monoamine 

oxidase inhibitors (MAOIs) because 

of the risk of serotonin syndrome.

Step 3: Opioid agonist drugs for severe 

pain (pain scale 7-10)

• Morphine is the drug of choice in this 

step. Start with short-acting morphine 

and titrate the dosage to adequate pain 

control, then divide the 24-hour total 

in half to determine the dosing for 

the sustained-release morphine, given 

Q12H. When converting from IV to 

PO morphine, PO dosage is about two 

to three times the parenteral dosage.

• Other agents used are oxycodone, 

hydromorphone, fentanyl, levorphanol, 

methadone, codeine, hydrocodone, 

oxymorphone, and buprenorphine.

• Avoid meperidine because of the increased 

risk of delirium and seizures.

• Around-the-clock, sustained-release PO 

dosing will achieve optimum pain relief.

• Patients unable to take PO therapy may use 

transdermal fentanyl patches or do rectal 

administration of sustained-release tablets 

such as long-acting morphine. Note that the 

onset of analgesia with fentanyl patches can 

take more than 12 hours, and the analgesic 

effect can last more than 18 hours after the 

patch is removed.

• Anticipate and treat complications and 

adverse effects of opioid therapy, such 

as nausea, vomiting, and constipation. 

Constipation often leads to nausea and 

can be prevented with prophylactic stool 

softeners (such as docusate) and stimulant 

laxatives (such as senna).

Adjunctive treatments

The addition of antidepressant medications 

can improve pain management, especially 

for chronic pain syndromes. These agents, 

and anticonvulsants, usually are used to treat 

neuropathic pain (discussed in more detail 

below), but should be considered for treatment 

of other chronic pain syndromes as well.

Treatment of neuropathic pain

Assess the underlying etiology, as discussed 

above, and treat the cause as appropriate. 

Review the patient’s medication list for 

medications that can cause neuropathic pain. 

Discontinue the offending agents, if possible. 

For patients on stavudine or didanosine, 

in particular, switch to another nucleoside 

analogue if suitable alternatives exist, or at 

least consider dosage reduction of stavudine 

to 30 mg BID (consult with an HIV expert). 

For patients on isoniazid, ensure that they are 

taking vitamin B6 (pyridoxine) regularly to 

avoid isoniazid-related neuropathy.

Nonpharmacologic interventions for 

neuropathic pain

The nonpharmacologic interventions 

described above can be useful in 

treating neuropathic pain.
Pain Syndrome and Peripheral Neuropathy | 553

Section 8: Neuropsychiatric 

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Pharmacologic interventions for 

neuropathic pain

Follow the WHO ladder of pain management 

described above. If Step 1 medications are 

ineffective, consider adding antidepressants, 

anticonvulsants, or both before moving on to 

opioid treatments.

Antidepressants

Antidepressant medications often exert 

analgesic effects at dosages that are lower than 

those required for antidepressant effects. As 

with antidepressant effects, optimum analgesic 

effects may not be achieved until several weeks 

after starting therapy.

• Tricyclic antidepressants (TCAs): Note that 

ritonavir and other protease inhibitors, and 

the pharmacokinetic booster cobicistat, may 

increase the level of TCAs, so start at the 

lowest dosage and titrate up slowly. Dosages 

may be titrated upward every 3-5 days, as 

tolerated. In general, TCAs are best avoided 

in elderly patients. 

• Nortriptyline (Pamelor): Starting dosage 

is 10-25 mg QHS. Usual maintenance 

dosage is 20-150 mg QHS.

• Desipramine (Norpramin): Starting 

dosage is 25 mg QHS. Usual maintenance 

dosage is 25-250 mg QHS. 

• Imipramine: Starting dosage is 25 mg 

QHS. Usual maintenance dosage is 25-300 

mg QHS. 

• Amitriptyline (Elavil): Starting dosage 

is 10-25 mg QHS. Usual maintenance 

dosage is 25-150 mg QHS. Amitriptyline 

has the highest rate of adverse effects 

among the TCAs, so other agents typically 

are preferred. 

Adverse effects include sedation, 

anticholinergic effects (e.g., dry mouth, 

urinary retention), altered mental status, QT 

prolongation, arrhythmias, and orthostatic 

hypotension. Monitor TCA levels and EKG at 

higher dosage levels. There is a significant risk 

of overdose if taken in excess. 

• SSRIs: See chapter Major Depression and 

Other Depressive Disorders for dosing, side 

effects, and drug interactions associated 

with this class of agents. SSRIs are less 

effective than TCAs in treating chronic pain. 

• Venlafaxine (Effexor): Starting dosage is 

37.5 mg daily. Usual maintenance dosage 

is 75-300 mg daily in divided doses or by 

extended-release formulation (Effexor XR). 

Note that there are limited data on using 

venlafaxine for patients with HIV infection. 

• Duloxetine (Cymbalta): Starting dosage 

is 30-60 mg daily. Dosages of >60 mg per 

day are rarely more effective for either 

depression or pain treatment. Note that 

there are limited data on using duloxetine 

for patients with HIV infection. 

Anticonvulsants

The following agents may be effective for 

neuropathic pain:

• Gabapentin (Neurontin): Considered 

first-line for HIV sensory neuropathy for 

its tolerability. Starting dosage is 100-300 

mg QHS; may be increased every 3-5 days 

to BID or TID to achieve symptom relief. 

Monitor response and increase the dosage 

every 1-2 weeks by 300-600 mg/day. Usual 

maintenance dosage is 1,200-3,600 mg/day 

in divided doses. Adverse effects include 

somnolence, dizziness, fatigue, weight gain, 

and nausea. To discontinue, taper over the 

course of 7 or more days. 

• Pregabalin (Lyrica): Starting dosage is 

25-50 mg TID; may be increased by 25-50 

mg per dose every 3-5 days as tolerated to 

achieve symptom relief. Maximum dosage 

is 200 mg TID. Adverse effects are similar to 

those of gabapentin. To discontinue, taper 

over the course of 7 or more days. 

• Lamotrigine (Lamictal): Starting dosage 

is 25 mg QOD; titrate slowly to 200 mg BID 

over the course of 6-8 weeks to reduce the 

risk of rash (including Stevens-Johnson 

syndrome). Adverse effects include sedation, 
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Section 8: Neuropsychiatric 

Disorders

dizziness, ataxia, confusion, nausea, blurred 

vision, and rash. Note that lopinavir/

ritonavir (Kaletra) may decrease lamotrigine 

levels; higher dosages may be needed. To 

discontinue, taper over the course of 7 or 

more days. 

• Although phenytoin and carbamazepine 

have some effectiveness in treating 

neuropathy, they have significant drug 

interactions with protease inhibitors 

and nonnucleoside reverse transcriptase 

inhibitors, and their use with HIV-infected 

patients is limited. Topiramate and 

valproic acid have been used for migraine 

prophylaxis and anecdotally may be useful 

for treating peripheral neuropathy, but 

have not been well-studied in HIV-related 

neuropathies.

Topical therapy 

• Capsaicin cream (0.075%, 0.1%): Capsaicin 

inhibits the secretion of substance P and 

has been found to be effective for the 

management of pain associated with 

arthritis and neuropathy. It may be applied 

BID or TID. Patients must be instructed to 

wash their hands well after applying to avoid 

spreading the residual cream to sensitive 

areas such as the nose or eyes. It may cause 

burning.

Treatment of Muscle Spasm Pain

Stretching, heat, and massage may help the 

pain of muscle spasm. This pain also can 

respond to muscle relaxants such as baclofen, 

cyclobenzaprine, tizanidine, benzodiazepines, 

as well as intraspinal infusion of local 

anesthetics for spinal injuries.

Substance Abuse, HIV, and Pain

Some health care providers hesitate to treat 

pain in patients with current or past substance 

abuse because of concern about worsening 

these patients’ dependence on opioids or 

suspicion that such patients are seeking pain 

medications for illicit purposes. However, the 

following points should be considered: 

• Many patients with current or past 

substance abuse do experience pain, and this 

pain should be evaluated by care providers 

and treated appropriately. 

• Failure to distinguish among addiction, 

tolerance, and dependence can lead to 

undertreatment of chronic pain by health 

care providers. 

• Addiction (substance abuse) is a complex 

behavioral syndrome characterized by 

compulsive drug use for the secondary gain 

of euphoria. 

• Pharmacologic tolerance refers to the 

reduction of effectiveness, over time, of a 

given dosage of medication. 

• Physical dependence is the consequence of 

neurophysiologic changes that take place in 

the presence of exogenous opioids. 

• Aberrant use of pain medications, 

if it develops, is best managed by an 

interdisciplinary team of providers from 

HIV clinical care, psychiatry, psychology, 

pharmacy, social services, and drug 

addiction management. 

• Drug-drug interactions between 

certain antiretroviral medications and 

methadone can decrease methadone serum 

concentrations (see chapter Drug-Drug 

Interactions with HIV-Related Medications). 

If this occurs, methadone dosages may need 

to be increased to prevent opiate withdrawal. 

• As part of chronic pain management in 

patients with substance abuse, consider 

establishing a written pain-management 
Pain Syndrome and Peripheral Neuropathy | 555

Section 8: Neuropsychiatric 

Disorders

contract to be signed by the clinician and the 

patient. The contract should: 

• Clearly state limits and expectations for 

both the patient and provider. 

• Identify a single clinician responsible for 

managing the pain regimen. 

• Tell the patient what to do if the pain 

regimen is not working. 

• Describe the procedure for providing 

prescriptions (e.g., one prescription given 

to the patient, in person, for a limited 

period of time, such as 1 month). 

• List the rules for dealing with lost 

medications or prescriptions. 

Patient Education

• Pain management is part of HIV treatment, 

and patients should give feedback to allow 

the best treatment decisions. If pain persists 

for more than 24 hours at a level that 

interferes with daily life, patients should 

inform their health care provider so that 

the plan can be changed and additional 

measures, if needed, can be tried.

• Patients should not expect full pain relief in 

most cases, but enough relief that they can 

perform their daily activities.

• “Mild” pain medications (e.g., NSAIDs, 

aspirin, acetaminophen) usually are 

continued even after “stronger” medications 

are started because their mechanism of 

action is different from that of opiates. This 

combination of pain medication has additive 

effects, so that pain may be controllable with 

a lower narcotic dosage.

• Patients taking “around-the-clock” 

medications should take them on schedule. 

Those taking “as needed” medications 

should take them between doses only if they 

have breakthrough pain.

• Patients who are prescribed opiates should 

be advised to take no more than the 

prescribed dosages. Misuse or inappropriate 

use can result in overdose.

• Opiates may cause severe constipation. 

Patients must remain hydrated and will 

likely need stool softeners, laxatives, or other 

measures. They should contact their health 

care provider promptly if constipation 

occurs.

• Patients taking opiates should avoid driving 

and operating machinery.
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Section 8: Neuropsychiatric 

Disorders

References

• American Academy of HIV Medicine. Pain 

Management. In: AAHIVM Fundamentals of 

HIV Medicine (2007 ed.). Washington, DC: 

American Academy of HIV Medicine; 2007.

• Association of Nurses in AIDS Care. Pain. 

In: Kirton C, ed. Core Curriculum for HIV/

AIDS Nursing, 2nd Edition. Thousand Oaks, 

CA: Sage Publications; 2003;143-155.

• Breitbart W. Suicide Risk and Pain in Cancer 

and AIDS. In: Chapman CR, Foley KM, eds. 

Current and Emerging Issues in Cancer Pain: 

Research and Practice. New York: Raven 

Press; 1993;49-66.

• Cherry CL, Wesselingh SL, Lal L, et al. 

Evaluation of a clinical screening tool for 

HIV-associated sensory neuropathies. 

Neurology. 2005 Dec 13;65(11):1778-81.

• Gonzalez-Duarte A. Robinson-Papp J, 

Simpson DM. Diagnosis and management 

of HIV-associated neuropathy. Neurol Clin. 

2008 Aug;26(3):821-32, x.

• Hahn K, Arendt G, Braun JS, et al. A 

placebo-controlled trial of gabapentin for 

painful HIV-associated sensory neuropathies.

J Neurol. 2004 Oct;251(10):1260-6.

• McArthur J, Brew B, Nath A. Neurological 

complications of HIV infection. Lancet 

Neurol. 2005 Sep;4(9):543-55.

• O’Neill WM, Sherrard JS. Pain in human 

immunodeficiency virus disease: a review. 

Pain. 1993 Jul;54(1):3-14.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Singer EJ, Zorilla C, Fahy-Chandon B, et al. 

Painful symptoms reported by ambulatory 

HIV-infected men in a longitudinal study.

Pain. 1993 Jul;54(1):15-9.

• Slaughter A, Pasero C, Manworren R. 

Unacceptable pain levels. Am J Nurs. 2002 

May;102(5):75, 77.

• Swica Y, Breitbart W. Treating pain in 

patients with AIDS and a history of substance 

use. West J Med. 2002 Jan;176(1):33-9.

• Weinreb NJ, Kinzbrunner BM, Clark M. 

Pain Management. In: Kinzbrunner BM, 

Weinreb NJ, Policzer JS, eds. 20 Common 

Problems: End-of-life Care. New York: 

McGraw Hill Medical Publishing Division; 

2002:91-145.

• U.S. Department of Health and Human 

Services. A Guide to the Clinical Care of 

Women with HIV – 2013 Edition. Rockville, 

MD: U.S. Department of Health and Human 

Services; 2013. Available at hab.hrsa.gov/

deliverhivaidscare/files/womenwithaids.pdf. 

Accessed March 1, 2013.

• U.S. Department of Health and Human 

Services. Management of Cancer Pain. 

Rockville, MD: Department of Health and 

Human Services; 1994.

• World Health Organization. Cancer Pain 

Relief and Palliative Care, Report of a WHO 

Expert Committee. Geneva: World Health 

Organization; 1990.
Section 8: Neuropsychiatric 

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HIV-Associated Neurocognitive Disorders | 557

HIV-Associated Neurocognitive 

Disorders

Background 

HIV is a neurotropic virus that directly invades the brain shortly after infection. HIV replicates in 

brain macrophages and microglia, causing inflammatory and neurotoxic host responses. HIV may 

cause cognitive, behavioral, and motor difficulties. These difficulties may range in severity from 

very mild to severe and disabling.

The American Academy of Neurology (AAN) recognizes three categories of HIV-associated 

neurocognitive disorder (HAND) (see Table 1, below). 

• Asymptomatic neurocognitive impairment (ANI) is determined by neurocognitive testing 

and is not apparent clinically. 

• Mild neurocognitive disorder (MND) is a diagnosis of exclusion; it may be made clinically if 

neurocognitive testing is not available, and it involves mild functional impairment. 

• HIV-associated dementia (HAD) involves moderate to severe functional impairment. 

[In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) section on cognitive disorders, 

MND correlates with mild neurocognitive disorder, and HAD with major neurocognitive disorder.]

Both MND and HAD are AIDS-defining conditions (listed as “Encephalopathy, HIV Related” in 

the classification system used by the U.S. Centers for Disease Control and Prevention), and they are 

risk factors for death. Neurocognitive disorders associated with HIV are among the most common 

and clinically important complications of HIV infection. However, they are diagnoses of exclusion, 

and other medical causes must be ruled out.

Risk factors for developing an HIV-associated neurocognitive disorder include the following:

• Older age

• Female gender

• More advanced HIV disease (including CD4 count of <100 cells/μL, wasting)

• High plasma HIV RNA (viral load)

• Comorbid conditions (especially anemia and infection with cytomegalovirus, human 

herpesvirus 6, and JC virus)

• History of injection drug use (especially with cocaine)

• History of delirium

With the advent of ART, HAD prevalence has declined and MND prevalence has increased. 
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As people with HIV live longer and become older, the risk of developing cognitive impairment 

increases. The use of effective antiretroviral therapy (ART) that maintains the plasma HIV RNA 

at undetectable or low values is important for preventing and treating HIV-related neurocognitive 

disorders. In people with neurocognitive impairment, however, there may be some benefit in 

using antiretroviral (ARV) agents that penetrate the CNS. However, recent research suggests 

that neuroinflammation rather than the HIV viral load in the CNS is primarily responsible for 

cognitive impairment in HIV-infected individuals. In choosing an ART regimen, it is important to 

take into consideration resistance testing, CNS penetration, and adherence issues.

Minor Neurocognitive Disorder

MND is characterized by mild impairment in functioning and may escape diagnosis by the 

clinician. The onset and course of MND can vary dramatically. The more demanding the activities 

of a particular individual, the more likely that person would be to notice the difficulties in 

functioning.

HIV-Associated Dementia

HAD is characterized by symptoms of cognitive, motor, and behavioral disturbances. There is 

often a progressive slowing of cognitive functions, including concentration and attention, memory, 

new learning, sequencing and problem solving, and executive control. HAD also can present with 

behavioral changes, which mainly take the form of apathy, loss of motivation, poor energy, fatigue, 

and social withdrawal. Motor changes, including slowing, clumsiness, unsteadiness, increased 

tendon reflexes, and deterioration of handwriting may occur.

S: Subjective

If a neurocognitive disorder is suspected, 

obtain a history of the patient’s symptoms (see 

below). Whenever possible, obtain a parallel 

history of the patient’s past history and recent 

mental status changes from significant others 

or caretakers.

Patient self-reports of cognitive problems 

and bedside cognitive status tests may be 

insensitive, particularly to subtler forms of 

impairment. Often, other people may observe 

changes in the person’s behavior or mood that 

indicate some change in cognitive functioning.

To help clarify factors that may be causing the 

changes in mental status, inquire about the 

following:

• Acuity of onset

• Recent changes or events

• Medications, particularly new medications

• Drug and alcohol use

• Symptoms of opportunistic illnesses, other 

infections

• HIV history, including duration, CD4 cell 

count, HIV viral load, history of ART

• History of other medical and psychiatric 

disorders
Section 8: Neuropsychiatric 

Disorders

HIV-Associated Neurocognitive Disorders | 559

Table 1. AAN Criteria for HIV-Associated Neurocognitive Disorder

HIV-Associated Asymptomatic Neurocognitive Impairment (ANI)

• Acquired impairment in cognitive functioning, involving at least two ability domains, documented by 

performance of at least 1 SD below the mean for age-education-appropriate norms on standardized 

neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: 

verbal/language; attention/working memory; abstraction/executive; memory (learning; recall); speed of 

information processing; sensory-perceptual, motor skills.

• The cognitive impairment does not interfere with everyday functioning.

• The cognitive impairment does not meet criteria for delirium or dementia.

• There is no evidence of another preexisting cause for the ANI.

Mild Neurocognitive Disorder (MND)

• Acquired impairment in cognitive functioning, involving at least two ability domains, documented by 

performance of at least 1 SD below the mean for age/education-appropriate norms on standardized 

neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: 

verbal/language, attention/working memory, abstraction/executive, memory (learning and recall), speed 

of information processing, sensory–perceptual and motor skills. 

• The cognitive impairment produces at least mild interference in daily functioning (at least one of the 

following): 

• Self-report of reduced mental acuity, inefficiency in work, homemaking or social functioning 

• Observation by knowledgeable others that the individual has undergone at least mild decline in 

mental acuity with resultant inefficiency in work, homemaking, or social functioning

• The cognitive impairment does not meet criteria for delirium or dementia.

• There is no evidence of another pre-existing cause for the mild neurocognitive disorder. If the individual 

with suspected mild neurocognitive disorder also satisfies criteria for a severe episode of major 

depression with significant functional limitations or psychotic features, or substance dependence, the 

diagnosis of mild neurocognitive disorder should be deferred to a subsequent examination conducted at 

a time when the major depression has remitted or at least 1 month after cessation of substance use.

HIV-Associated Dementia (HAD)

• Marked acquired impairment in cognitive functioning, involving at least two ability domains; typically 

the impairment is in multiple domains, especially in the learning of new information, slowed information 

processing and defective attention/concentration. The cognitive impairment must be ascertained by 

neuropsychological testing with at least two domains being 2 standard deviations or greater below that 

of demographically corrected means. 

• The cognitive impairment produces marked interference with day-to-day functioning (work, home life 

and social activities).

• The pattern of cognitive impairment does not meet criteria for delirium. 

• There is no evidence of another, pre-existing cause for the dementia (e.g., other CNS infection, CNS 

neoplasm, cerebrovascular disease, pre-existing neurologic disease or severe substance abuse 

compatible with CNS disorder).

Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 

2007 Oct 30;69(18):1789-99.

Additionally, the AAN specifies that, for 

patients with severe depression or substance 

dependence who are suspected of having 

HAD, the neurocognitive assessment should 

be deferred until the depression or substance 

use is in remission. 

Although the AAN criteria include assessment 

via neuropsychological testing, in the absence 

of such testing, it is acceptable to make a 

presumptive diagnosis of MND or HAD on 

the basis of clinical signs and symptoms once 

all other possible causes of changes in mental 

function have been ruled out.
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Section 8: Neuropsychiatric 

Disorders

O: Objective

• Check temperature and other vital signs 

(MND and HAD are not associated with 

fever).

• Perform a complete physical examination 

with special attention to signs of 

opportunistic illnesses.

• Perform a thorough neurological 

examination, including funduscopy. Rule 

out focal neurologic deficits.

• Perform Mini-Mental State Examination 

(note that this is not sensitive for HIVassociated neurocognitive disorders; 

negative results do not rule out these 

conditions).

Consider a neuropsychological screening test 

such as the Modified HIV Dementia Scale (see 

Figure 1), International HIV Dementia Scale, 

or the Montreal Cognitive Assessment. Others 

are noted in “Laboratory and Diagnostic 

Evaluation,” below.

A: Assessment

A differential diagnosis includes the following 

medical conditions, which may present with 

cognitive changes or delirium: 

• Substance use: intoxication or withdrawal 

from alcohol, opioids, stimulants, etc.

• Psychiatric disorders, especially major 

depression

• Metabolic or systemic disorders, including 

hepatic encephalopathy, vitamin B12 

or folate deficiency, uremia, endocrine 

disorders (e.g., hypogonadism)

• Central nervous system (CNS) 

opportunistic infections, such as 

cytomegalovirus encephalitis, cryptococcal 

meningitis, tuberculous meningitis, CNS 

toxoplasmosis, and progressive multifocal 

leukoencephalopathy (PML)

• Systemic infections

• Brain tumors, including CNS lymphoma 

and metastatic disease

• Other causes of cognitive impairment and 

dementia (e.g., neurosyphilis, substanceinduced dementia, vascular dementia, 

brain injury, Alzheimer disease, and 

hydrocephalus)

• Medication adverse effects: ARV 

medications (especially efavirenz), 

psychotropic medications, interferon, 

anticholinergics, and others

• Poisoning with toxic substances

P: Plan

Laboratory and Diagnostic Evaluation

A change in the mental status of an HIV-infected 

person should prompt a thorough search for 

underlying biological causes. As noted above, 

HIV-related neurocognitive disorders are 

diagnoses of exclusion, and other causes of 

the patient’s symptoms should be ruled out.

Perform the following tests:

• Laboratory tests: Complete blood count, 

electrolytes and creatinine, liver function, 

thyroid function, vitamin B12, rapid plasma 

reagin (RPR) or Venereal Disease Research 

Laboratory (VDRL).

• Toxicology tests if substance use is suspected 

(e.g., opioids, ethanol, amphetamines).

• Brain imaging studies (computed 

tomography [CT] scan or magnetic 

resonance imaging [MRI]); rule out spaceoccupying masses and other lesions; cortical 

atrophy may be seen in advanced HAD; this 

finding is not specific.

• Cerebral spinal fluid (CSF) tests if CNS 

infection is suspected.

• Consider tests for neurocognitive 

impairment as noted in the table below; 

most of these can be found on the website of 

the New York State Department of Health 

AIDS Institute at www.hivguidelines.org/

clinical-guidelines/hiv-and-mental-health.

• Refer to an HIV-experienced 

neuropsychologist, neurologist, or 

psychiatrist, if available.
Section 8: Neuropsychiatric 

Disorders

HIV-Associated Neurocognitive Disorders | 561

Figure 1. Modified HIV Dementia Scale

Maximum Score Score Exercise

N/A N/A Memory/Registration: State four words for the patient to recall (dog, hat, 

green, peach), pausing 1 second between each. Then ask the patient to 

restate all four.

6 ( ) Psychomotor Speed: Ask the patient to write the alphabet in upper case 

letters horizontally across the page; record time: seconds.

≤21 sec = 6

21.1 - 24 sec = 5

24.1 - 27 sec = 4

27.1 - 30 sec = 3

30.1 - 33 sec = 2

33.1 - 36 sec = 1

> 36 sec = 0

4 ( ) Memory Recall: Ask the patient to restate the four words from Memory/

Registration above. Give one point for each correct response. For words 

not recalled, prompt with a “semantic” clue, as follows: animal (dog); piece 

of clothing (hat), color (green), fruit (peach). Give 1/2 point for each correct 

after prompting. 

2 ( ) Construction: Copy the cube below; record time: seconds.

(<25 sec = 2; 25 – 35 sec = 1; >35 sec = 0)

Maximum score: 12 points; a score of <7.5 points suggests possible HAD (note, this test is not specific)

Adapted from McArthur JC. Minor cognitive motor disorder: Does it really exist? Hopkins HIV Rep. Nov 1996;8(4):8. 
562 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

 Table 2. Tests for Identifying and Staging HIV-Related Neurocognitive Impairment 

HIV Dementia Scale • Screens for the memory and attention deficits and psychomotor 

slowing that are typical of HAD

• Requires training to administer and, therefore, may not be ideal 

for a clinic setting

Modified HIV Dementia Scale • Designed specifically for use by non-neurologists and, therefore, 

may be more useful than the HIV Dementia Scale for a primary 

care setting

• Requires approximately 5 minutes to administer

• See Figure 1, above 

Mental Alternation Test • Useful for assessing patients with early dementia, who will show 

impairments in timed trials

Memorial Sloan-Kettering (MSK) 

Scale

• Can be used for assessing severity

• Combines the functional impact of both cerebral dysfunction 

(dementia) and spinal cord dysfunction (myelopathy); the two 

entities can be separated and staged independently

Trail Making Test, Parts A and 

B (from the Halstead-Reitan 

Neuropsychological Battery)

• May be used as a screening tool, but results require 

interpretation by a neuropsychologist

• May be used at the bedside to track a patient’s response to ART 

over time

Grooved Pegboard (dominant and 

nondominant hand)

• May be used as a screening tool and does not require literacy

Treatment

There are no specific treatments for HIVassociated neurocognitive disorders, but 

ART may reverse the disease process, and 

a number of therapies may be helpful. The 

treatment of MND and HAD ideally utilizes a 

multidisciplinary approach that may involve 

HIV specialists, neurologists, psychiatrists, 

psychologists, nurse practitioners, social 

workers, substance-use counselors, case 

managers, and others.

Neurocognitive impairment in patients 

with HIV infection often is multifactorial. 

In addition to treating HIV-associated 

neurocognitive disorders themselves, it is 

important to correct, as much as possible, all 

medical conditions that may adversely affect 

the brain (e.g., psychiatric comorbidities, 

endocrinologic abnormalities, adverse 

medication effects). For patients using alcohol 

or illicit or nonprescribed drugs, implement 

strategies to reduce their use; these agents can 

further impair cognition.

Pharmacologic Management of HIVAssociated Neurocognitive Disorders

• ART: Maximal suppression of HIV 

replication via ART may partially or fully 

reverse HIV-associated neurocognitive 

disorders, and ART is the treatment of 

choice for both treatment and prevention of 

HIV-associated neurocognitive disorders, 

including dementia. In general, ART 

regimens that effectively suppress HIV 

RNA in the serum also suppress HIV in the 

CNS. However, ARV medications vary in 

their ability to penetrate the blood-brain 

barrier and, therefore, in their ability to act 

directly on the HIV in the CNS. Limited 

data suggest that using ARVs with good CNS 

penetration may be important in treating or 

preventing neurocognitive disorders, and 

some experts recommend the use of these 

ARVs, if otherwise appropriate, for patients 

with HIV dementia. ARVs with the best 

CNS penetration include the nucleoside 

reverse transcriptase inhibitors (NRTIs) 
Section 8: Neuropsychiatric 

Disorders

HIV-Associated Neurocognitive Disorders | 563

abacavir, emtricitabine, and zidovudine 

(AZT, ZDV); the nonnucleoside reverse 

transcriptase inhibitor (NNRTI) nevirapine; 

the protease inhibitors (PIs) indinavir/

ritonavir and lopinavir/ritonavir; and the 

CCR5 antagonist maraviroc. The integrase 

inhibitor raltegravir has reasonably good 

CNS penetration. There currently is no role 

for testing levels of HIV RNA in the CSF 

outside research settings.

• Stimulants: Stimulant medications (e.g., 

methylphenidate, dextroamphetamine) 

have been used as palliative agents to help 

manage symptoms of fatigue, decreased 

concentration, and memory deficits among 

patients with MND and HAD. Starting 

dosages of both is 5 mg/day; maximum 

dosage is 60 mg/day. The response to 

stimulants is idiosyncratic and varies from 

patient to patient; begin with the lowest 

dose of 5 mg QAM and titrate upward as 

needed. If BID dosing is required as a result 

of afternoon fatigue, the afternoon dose 

should be taken before 2 p.m. to prevent 

interference with sleep. Consider referral to 

a psychiatrist or neurologist for evaluation 

and initiation of treatment; after a stable 

dosage is achieved, treatment may be 

continued. These medications should be 

used with caution for patients who have a 

history of stimulant abuse.

• For comorbid depression, consider 

prescribing antidepressant medications as 

for other medically ill HIV-infected patients 

(see chapter Major Depression and Other 

Depressive Disorders).

• Antipsychotic medications may be useful 

in treating agitation and hallucinations but 

should be used for patients with dementia 

only when nonpharmacologic measures 

are insufficient for patient management; 

consult with a psychiatrist. All antipsychotic 

medications increase the risk of death 

in elderly patients with dementia. Start 

antipsychotic medications at the lowest 

possible dosage and increase slowly as needed.

• Many agents are being studied for either 

their neuroprotective effects or their 

therapeutic effects on HIV-associated 

neurocognitive disorders. The data are 

not sufficient at present to make specific 

recommendations. Patients with dementia 

often are sensitive to medication side effects; 

follow closely.

• Benzodiazepines have been shown 

to increase confusion and decrease 

concentration, and generally should be 

avoided.

Nonpharmacologic Management of 

MND and Mild HAD

• Encourage patients to remain appropriately 

active

• Explain the benefits of structured routines

• Encourage good nutrition

• Use strategies to minimize use of alcohol 

and illicit drugs

• Use memory aids such as lists

• Simplify complex tasks, especially drug 

regimens

• When giving instructions, do the following: 

• Repeat information

• Write instructions to provide structure for 

patients and caregivers

• Ask patients to express the information 

and instructions in their own words

• Adherence to medical regimens, including 

ART, often is particularly difficult for 

patients with neurocognitive disorders. 

Encourage use of medication adherence 

tools such as pill boxes, alarms, and, if 

available, packaged medications (e.g., blister 

packs) or prefilled medi-sets. Encourage 

patients to enlist adherence support from 

family members and friends.

• Cognitive skills building can be helpful 

(e.g., reading, solving puzzles, intellectual 

conversation).
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Section 8: Neuropsychiatric 

Disorders

Nonpharmacologic Management of 

Moderate to Severe HAD

The strategies noted above should be utilized, 

but additional measures are needed.

Management of patients with severe or latestage HAD requires an evaluation of their 

safety and a determination of the environment 

and level of supervision that are needed. The 

clinician should attend to the following:

• Help determine whether patients can be left 

alone at home or whether doing so would 

present the risk of them wandering away or 

sustaining an injury in the home (e.g., from 

the use of an appliance such as the oven).

• For patients who cannot be left alone at 

home, assess options for support (e.g., 

help from family members or paid home 

attendants).

• Utilize fall prevention strategies.

• For patients who smoke, decide whether 

smoking can be done safely; if smoking is 

deemed unsafe, consider smoking cessation 

programs or supervision.

• If lesser measures fail, explore options for 

placement in a skilled nursing facility.

Additional helpful strategies for managing 

patients who are confused, agitated, or 

challenged by their experience include the 

following:

• Keep their environments familiar to the 

extent possible (e.g., in terms of objects, 

people, locations).

• Redirect or distract patients from 

inappropriate behavior.

• Remain calm when patients become 

confused or agitated; refrain from 

confronting an agitated patient; reorient 

confused or agitated patients.

• Provide a clock and calendar in the room to 

help keep patients oriented to time and to 

day of the week.

• Provide lighting that corresponds with day 

and night.

• Emphasize routines.

• Ensure that patients who require eyeglasses 

or hearing aids wear them to help lessen 

confusion and disorientation.

• Prepare patients for any planned changes.

• Ensure that patients are receiving their 

prescribed medications.

• Protect wandering patients.

• Supervise any cigarette smoking.

• Offer activities that keep patients’ minds 

alert.

• Educate family members about the nature of 

dementia and methods for helping patients 

maintain activities of daily living.

• Suggest that patients or their family 

members make arrangements for financial, 

health, and other matters in the event they 

become unable to make decisions about their 

affairs (e.g., advance health care directives, 

durable powers of attorney, wills).

Patient Education

• Advise patients that ART can be effective 

in preventing and treating HIV-related 

neurocognitive impairment.

• Inform patients and family members of 

the many other strategies that may aid in 

managing neurocognitive impairment. 

Such strategies may help patients maintain 

the highest possible level of skills and 

independence.

• Family members and significant others 

can be important sources of support (e.g., 

by providing assistance with medication 

adherence).

• Advise patients with advanced HAD that 

placement in a residential facility may be the 

best option for ensuring their safety.
Section 8: Neuropsychiatric 

Disorders

HIV-Associated Neurocognitive Disorders | 565

References

• American Academy of Neurology. 

Nomenclature and research case definitions 

for neurologic manifestations of human 

immunodeficiency virus-type 1 (HIV-1) 

infection. Report of a Working Group of the 

American Academy of Neurology AIDS Task 

Force. Neurology. 1991 Jun;41(6):778-85.

• Antinori A, Arendt G, Becker JT, et 

al. Updated research nosology for HIVassociated neurocognitive disorders. 

Neurology. 2007 Oct 30;69(18):1789-99.

• Brew B, Pemberton L, Cunningham P, et 

al. Levels of human immunodeficiency virus 

type 1 RNA in cerebrospinal fluid correlate 

with AIDS dementia stage. J Infect Dis. 1997 

Apr;175(4):963-6.

• Cherner M, Cysique L, Heaton RK, 

et al.; HNRC Group. Neuropathologic 

confirmation of definitional criteria for 

human immunodeficiency virus-associated 

neurocognitive disorders. J Neurovirol. 

2007;13(1):23-8.

• Cohen MA, Gorman JM. Comprehensive 

Textbook of AIDS Psychiatry. New York: 

Oxford University Press; 2008.

• Evers S, Rahmann A, Schwaag S, et al. 

Prevention of AIDS dementia by HAART 

does not depend on cerebrospinal fluid drug 

penetrance. AIDS Res Hum Retroviruses.

2004 May;20(5):483-91.

• Goodkin K, Fernandez F, M Forstein, 

et al. A perspective on the proposal for 

neurocognitive disorder criteria in DSM-5 

as applied to HIV-associated neurocognitive 

disorders. Neuropsychiatry (London). 2011 

Oct 1;1(5):431-440.

• McArthur JC, McClernon DR, Cronin 

MF, et al. Relationship between human 

immunodeficiency virus-associated dementia 

and viral load in cerebrospinal fluid and 

brain. Ann Neurol. 1997 Nov;42(5):689-98.

• New York State Department of Health AIDS 

Institute. Mental Health Care for People 

with HIV Infection: Clinical Guidelines for 

the Primary Care Practitioner. Available at 

www.hivguidelines.org/clinical-guidelines/

hiv-and-mental-health. Accessed December 

1, 2013.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Power C, Selnes OA, Grim JA, et al. HIV 

dementia scale: a rapid screening test. 

J Acquir Immune Defic Syndr Hum 

Retrovirol. 1995 Mar 1;8(3):273-8.

• Price RW, Epstein LG, Becker JT, et al. 

Biomarkers of HIV-1 CNS infection and 

injury. Neurology. 2007 Oct 30;69(18):1781-8.

• Rippeth JD, Heaton RK, Carey CL, et 

al.; HNRC Group. Methamphetamine 

dependence increases risk of 

neuropsychological impairment in HIV 

infected persons. J Int Neuropsychol Soc. 

2004 Jan;10(1):1-14.

• Schifitto G, Navia BA, Yiannoutsos CT, 

et al.; Adult AIDS Clinical Trial Group 

(ACTG) 301; 700 Teams; HIV MRS 

Consortium. Memantine and HIV-associated 

cognitive impairment: a neuropsychological 

and proton magnetic resonance spectroscopy 

study. AIDS. 2007 Sep 12;21(14):1877-86.

• Shiu C, Barbier E, Di Cello F, et al. HIV1 gp120 as well as alcohol affect bloodbrain barrier permeability and stress 

fiber formation: involvement of reactive 

oxygen species. Alcohol Clin Exp Res. 2007 

Jan;31(1):130-7.

Major Depression and Other Depressive Disorders | 567

Section 8: Neuropsychiatric 

Disorders

Major Depression and Other 

Depressive Disorders

Background

Major depression is the most prevalent psychiatric 

comorbidity among people with HIV infection and 

commonly has a significant impact on health. The 

etiology may be multifactorial, as with depression 

in HIV-uninfected persons, but HIV infection may 

bring additional complexity. A diagnosis of HIV may 

cause a psychological crisis, but also may complicate 

underlying psychological or psychiatric problems (e.g., 

preexisting depression, anxiety, or substance abuse). Direct viral infection of the central nervous 

system (CNS) can cause several neuropsychiatric syndromes. In addition, both HIV-related 

medical conditions and HIV medications can cause or contribute to depression.

Patients with untreated depression experience substantial morbidity and may become selfdestructive or suicidal. They are at continuing risk of engaging in unsafe behaviors that may lead to 

HIV transmission and poor adherence to care and treatment.

Major depression in persons with comorbid medical illness, including HIV infection, has been 

associated with the following:

• Decreased survival

• Impaired quality of life

• Decreased adherence to antiretroviral therapy (ART)

• Increased risk behaviors

• Suicide

• Longer hospital stays and more frequent medical visits (e.g., emergency room, medical clinics)

• Higher treatment costs

HRSA HAB Performance Measures

Percentage of patients aged 12 years and 

older screened for clinical depression

on the date of the encounter using an 

age-appropriate standardized depression 

screening tool AND, if positive, a followup plan is documented on the date of the 

positive screen 

(Adult and Adolescent measure)

Stress and depressive symptoms, especially 

when they occur jointly, are associated 

with diminished immune defenses in HIVinfected individuals, and severe depression 

is associated with higher mortality rates. 

Anxiety symptoms are common among people 

with major depression (see chapter Anxiety 

Disorders). Psychotic symptoms may occur 

as a component of major depression and are 

associated with an increased risk of suicide. 

Even one or two symptoms of depression 

increase the risk of an episode of major 

depression.

All clinicians should do the following:

• Maintain a high index of suspicion for 

depression and screen frequently for mood 

disorders.

• Elicit any history of psychiatric diagnoses or 

treatment.

Rule out medical conditions that may cause 

mood or functional alterations.
568 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

Refer for psychiatric evaluation and 

psychosocial support, including, as 

appropriate, to substance abuse counselors and 

domestic violence service providers. 

A screening test for depression such as the 

Patient Health Questionnaire-2 (PHQ-2) 

should be administered yearly or whenever 

a patient’s complaints or symptoms suggest 

depressive disorders.

Depression is diagnosed, as in HIV-uninfected 

individuals, according to the criteria of the 

Diagnostic and Statistical Manual of Mental 

Disorders (DSM)-5.

Major Depression

The patient may complain of either or both of 

two cardinal symptoms: 

• Diminished interest or pleasure in activities

• Depressed mood, sadness

If either or both of these are present, other 

complaints may be used to diagnose major 

depression, including the following:

• Decreased ability to concentrate

• Appetite changes with weight changes 

(increase or decrease)

• Fatigue or loss of energy

• Feelings of worthlessness or guilt

• Insomnia or hypersomnia

• Psychomotor agitation or retardation

• Recurrent thoughts of death or suicide 

The diagnosis of major depression is made 

if five of the above symptoms occur on most 

days for at least 2 weeks. Depressed mood or 

diminished interest or pleasure must be one of 

the five symptoms present. 

Other subjective symptoms of depression may 

include the following:

• Hopelessness

• Helplessness

• Irritability or anger

• Somatic complaints in addition to those 

noted above

Other Depressive Disorders 

• Persistent depressive disorder: A new DSM 

category that subsumes dysthymia and 

chronic major depressive disorder. This is 

another very common depressive disorder 

found among HIV-infected patients. 

Treatments for major depression and 

persistent depressive disorder are similar. 

Dysthymia has been characterized by more 

chronic but less severe symptoms than those 

Patient Health Questionnaire-2 (PHQ-2)

Over the past 2 weeks, how often have you been 

having little interest or pleasure in doing things? 

0 = Not at all

1 = Several days

2 = More than half the days

3 = Nearly every day

Over the past 2 weeks, how often have you been 

feeling down, depressed, or hopeless?

0 = Not at all

1 = Several days

2 = More than half the days

3 = Nearly every day

Calculate the total point score: 

Score interpretation: Patient Health 

Questionnaire-2 (PHQ-2) 

Score Probability 

of major 

depressive 

disorder (%)

Probability of 

any depressive 

disorder (%)

1 15.4 36.9

2 21.1 48.3

3 38.4 75.0

4 45.5 81.2

5 56.4 84.6

6 78.6 92.9
Major Depression and Other Depressive Disorders | 569

Section 8: Neuropsychiatric 

Disorders

found in major depression. The diagnosis 

is made when a person has had a depressed 

mood for most of the day, for more days 

than not, for at least 2 years. While 

depressed, the patient exhibits two or more 

of the following symptoms:

• Poor appetite or overeating

• Insomnia or hypersomnia

• Low energy or fatigue

• Low self-esteem

• Poor concentration or difficulty making 

decisions

• Feelings of hopelessness

In addition, the symptoms must cause 

clinically significant distress or impairment 

in functioning, and there can have been no 

major depressive episode during the first 

two years of the disturbance. 

• Bipolar disorder: Major depression may be 

a manifestation of bipolar disorder. Bipolar 

disorder should be ruled out before giving 

an antidepressant to a patient with major 

depression, as bipolar disorder usually 

requires the use of mood stabilizers before, 

or instead of, beginning antidepressant 

medications (antidepressant therapy 

may precipitate a manic episode). Bipolar 

disorder should be suspected if a patient 

has a history of episodes of high energy 

and activity with little need for sleep, has 

engaged in risky activities such as buying 

sprees and increased levels of risky sexual 

behavior, or has a history of taking mood 

stabilizers (lithium and others) in the 

past. If bipolar disorder is suspected, refer 

the patient to a psychiatrist for further 

evaluation and treatment. 

• Other forms of depression include 

adjustment disorder with depressed mood 

(acute reaction to a life crisis, such as the loss 

of a job), premenstrual dysphoric disorder, 

disruptive mood dysregulation disorder, and 

depressive disorder not otherwise specified. 

S: Subjective

• Inquire about the symptoms listed above, 

and about associated symptoms.

• Take a careful history of the timing and 

duration of symptoms, their relationship to 

life events (e.g., HIV testing, loss of a friend, 

onset of physical symptoms), and any other 

physical changes noted along with the mood 

changes.

• Elicit personal and family histories of 

depression, bipolar disorder, or suicidal 

behavior.

• Probe for suicidal thoughts, plans, and 

materials to execute the plans (see chapter 

Suicide Risk).

• Inquire about hallucinations, paranoia, and 

other symptoms.

• Ask about current and past medication use 

and substance abuse. 

O: Objective

Perform mental status examination, including 

evaluation of affect, mood, orientation, 

appearance, agitation, or psychomotor 

slowing; perform thyroid examination, 

inspection for signs of self-injury, and 

neurologic examination if appropriate. 

A: Assessment

Partial Differential Diagnosis

Rule out nonpsychiatric causes of symptoms, 

which may include the following: 

• Hypothyroidism or hyperthyroidism

• Hypotestosteronism (hypogonadism) – very 

common with HIV disease in both men and 

women

• Other endocrine disorders such as Addison 

disease

• Substance-induced mood disorder 

(intoxication or withdrawal)

• Medication adverse effects (e.g., from steroids, 

efavirenz, isoniazid, or interferon-alfa)
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Section 8: Neuropsychiatric 

Disorders

• HIV dementia or minor cognitive motor 

disorder

• HIV encephalopathy

• Neurosyphilis

• Opportunistic illnesses affecting the 

CNS (e.g., toxoplasmosis, cryptococcal 

disease, CNS cytomegalovirus, progressive 

multifocal leukoencephalopathy)

• Vitamin B12, folate (B6), zinc, vitamin A, or 

vitamin D deficiency

P: Plan

Evaluation

The diagnosis is based on clinical criteria as 

indicated above. Rule out medical and other 

causes. An initial screening includes the 

following:

• Complete blood count, electrolytes, 

creatinine, blood urea nitrogen (BUN), 

glucose

• Thyroid function tests (thyroid stimulating 

hormone [TSH], T4)

• Vitamin B12, vitamin D, and folate levels

• Testosterone (both in men and women)

• Other tests as suggested by history and 

physical examination

Treatment

Refer immediately for psychiatric evaluation or 

treatment if the patient is: 

• Hopeless

• Suicidal (see chapter Suicide Risk)

• Displaying psychotic symptoms

• Debilitated or functionally impaired by 

severe symptoms

• Not responding to treatment 

The combination of psychotherapy and 

antidepressant medication is more effective 

than either treatment modality alone. Social 

support interventions (e.g., communitybased HIV support groups) also can help; 

refer to available resources. Patients should 

be encouraged to discontinue alcohol or 

substance use, and should be referred for 

treatment as indicated.

Psychotherapy

Individual psychotherapy with a skilled, 

HIV-experienced mental health professional 

can be very effective in treating depression. 

Several specific types of individual and 

group psychotherapies for depression (e.g., 

interpersonal therapy, cognitive-behavioral 

therapy, behavioral activation, supportive 

psychotherapy, coping effectiveness) have 

been shown to be effective for HIV-infected 

individuals. 

Pharmacotherapy

For most patients, a selective serotonin 

reuptake inhibitor (SSRI) or a serotoninnorepinephrine reuptake inhibitor (SNRI) 

is the most appropriate initial treatment 

for depression. For patients who experience 

treatment failure with these agents (or have 

an incomplete response) at a customary 

therapeutic dosage, consultation with a 

psychiatrist is recommended.

When selecting antidepressant medications, 

consider their side effect profiles as a 

means to manage other symptoms the 

patient may be experiencing. For example, 

activating antidepressants (taken in the 

morning) may help patients who complain 

of low energy; antidepressants that increase 

appetite may be useful for patients with 

wasting syndrome; sedating antidepressants 

(taken at bedtime) may help patients with 

insomnia. Medications that may be lethal 

if overdosed (e.g., tricyclic antidepressants) 

should not be prescribed to patients for 

whom suicidality may be a concern.

The information below describes specific 

antidepressant medications, with information 

on dosage and possible adverse effects. 
Major Depression and Other Depressive Disorders | 571

Section 8: Neuropsychiatric 

Disorders

Most antidepressants should be started at 

low dosages and gradually titrated upward 

to avoid unpleasant side effects that might 

lead to nonadherence. Antidepressant 

effect usually is not noticed until 2-4 

weeks after starting a medication. If there 

is no improvement in symptoms in 2-4 

weeks, and there are no significant adverse 

effects, the dosage may be increased.

A therapeutic trial consists of treatment for 4-6 

weeks at a therapeutic dosage. If the patient’s 

symptoms have not improved, an increase 

in dosage or a switch to another medication 

should be considered. Patients who remain 

depressed should be referred to a psychiatrist.

Monitor all patients closely after starting 

them on antidepressant medications. 

Depressive symptoms may continue to 

worsen while on medication; improved 

energy is the initial effect of antidepressants, 

whereas hopelessness and sadness improve 

later. In addition, some young persons are 

at risk of worsening depression caused by 

antidepressants. Black-box warnings advise 

that antidepressants may cause increased risk 

of suicidality in children, adolescents, and 

young adults (<24 years of age) with major 

depressive or other psychiatric disorders, 

especially during the first month of treatment.

Medications should be continued for 6-9 

months beyond the resolution of symptoms, 

to reduce the risk of recurrence. After 

this time, treatment may be tapered down 

gradually if the patient wishes, with careful 

monitoring for depressive symptoms. 

The risk of recurrence is higher if the first 

depressive episode is inadequately treated 

or if the patient has had multiple depressive 

episodes. For patients with recurrent 

depression, consider long-term maintenance 

antidepressant treatment. See “Discontinuing 

antidepressant medication,” below.

Potential ARV Interactions

Interactions may occur between certain 

ARVs and agents used to treat depression. 

Some combinations may be contraindicated 

and others may require dosage adjustment. 

Refer to medication interaction resources or 

consult with an HIV expert, psychiatrist, or 

clinical pharmacist before prescribing.

Some ARV medications (particularly protease 

inhibitors [PIs]) and the pharmacokinetic 

booster cobicistat may affect the 

metabolism of some antidepressants via 

cytochrome P450 interactions. For example, 

ritonavir can significantly increase serum 

levels of tricyclic antidepressants, increasing 

the risk of tricyclic toxicity. In the case of 

most other antidepressants, interactions 

with ARVs generally are not clinically 

significant, but most antidepressants used 

concomitantly with PIs or cobicistat should 

be started at low dosages and titrated 

cautiously to prevent antidepressant adverse 

effects and toxicity. On the other hand, 

some PIs may decrease levels of paroxetine, 

sertraline, and bupropion, and efavirenz 

also lowers sertraline and bupropion levels; 

these antidepressants may require upward 

titration if used concurrently with interacting 

ARVs. Further information is presented under 

individual agents and classes, below.

For patients who are starting ARV 

medications (particularly PIs) or cobicistat 

and are on a stable antidepressant regimen, 

monitor carefully for adverse effects and 

for efficacy of the antidepressant; dosage 

adjustments may be required. 

The available antidepressant medications 

(SSRIs and SNRIs), including therapeutic 

dosages and possible positive and negative 

effects, are listed in Table 1.
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Section 8: Neuropsychiatric 

Disorders

Table 1. SSRI and SNRI Antidepressant Medications and 

Possible Positive and Negative Effects

Medication/Usual 

Dosage Possible Positive Effects Possible Negative Effects

SSRIs No anticholinergic or cardiovascular 

effects, nonfatal in overdose; may help 

treat anxiety

• Sexual dysfunction (men and 

women)

• Serotonin withdrawal syndrome if 

discontinued abruptly

Citalopram (Celexa): 

10-60 mg QD

May have lower risk of significant drugdrug interactions than other SSRIsMild nausea, possible sedation

Escitalopram (Lexapro): 

10-20 mg QD

May have lower risk of significant drugdrug interactions than other SSRIsMild nausea, possible sedation

Fluoxetine (Prozac): 

10-40 mg QD

Rarely sedating, often energizing, lower 

risk of SSRI withdrawal syndrome if 

discontinued abruptly

Insomnia, agitation, nausea, headache, 

sexual dysfunction in men and 

women, long half-life

Paroxetine (Paxil): 

10-40 mg QD

May be sedating (for patients 

experiencing sedation with paroxetine, 

dose at bedtime; can be useful with 

depression-associated insomnia)

Insomnia, agitation (for patients 

experiencing these effects, administer 

dose in mornings), nausea, headache, 

higher risk of SSRI withdrawal 

syndrome, weight gain

Sertraline (Zoloft): 

50-200 mg QD

May have lower incidence of significant 

drug-drug interactions compared with 

fluoxetine and paroxetine

Insomnia, agitation, nausea, headache

SNRIs • Nausea, headache, nervousness, 

sexual dysfunction (men and 

women)

• Serotonin withdrawal syndrome if 

discontinued abruptly

Duloxetine (Cymbalta): 

30-60 mg QD

May be used also for pain management 

and neuropathy; may have lower risk 

of significant drug-drug interactions 

compared with SSRIs

Nausea, somnolence

Venlafaxine (Effexor): 

37.5-75 mg BID or TID

OR

Venlafaxine XR (Effexor 

XR): 75-375 mg QD

May have lower risk of significant drugdrug interactions compared with SSRIsHypertension (monitor blood pressure 

at higher dosages)

Higher risk of SSRI/SNRI withdrawal 

syndrome

Desvenlafaxine (Pristiq): 

50 mg QD

May have lower risk of significant drugdrug interactions compared with SSRIsHigher risk of SSRI/SNRI withdrawal 

syndrome
Major Depression and Other Depressive Disorders | 573

Section 8: Neuropsychiatric 

Disorders

Other agents

• Bupropion (Wellbutrin and others): 

Bupropion is available in immediate-release 

form (requires TID dosing), sustainedrelease (SR) (requires BID dosing), or 

extended-release (XL) (QD dosing) 

formulations. At higher bupropion dosages, 

there is an increased risk of seizures, and 

this drug is contraindicated in patients 

who have risk factors for seizures. For 

patients taking PIs, caution should be used 

as the dosage approaches 300-400 mg per 

day because of possible increases in levels 

of bupropion (however, tipranavir and 

efavirenz may decrease bupropion levels). 

Bupropion may have an activating effect, 

which some patients may experience as 

agitation, insomnia, or both, and also may 

have an appetite suppressant effect. It usually 

does not cause sexual dysfunction, and 

therefore may be helpful for individuals with 

depression who experience adverse sexual 

effects with other antidepressant agents.

• Mirtazapine (Remeron): (15-45 mg QPM) 

May have lower risk of significant drugdrug interactions compared with SSRIs; 

can be useful when weight gain and sleep 

induction are needed. Potential adverse 

effects include sedation, increased appetite, 

weight gain, constipation, and dry mouth. 

Note that the higher dosages may result 

in increased activation owing to increased 

norepinephrine (NE) receptor antagonism.

• Tricyclics: Tricyclic antidepressants may be 

effective, but generally are not recommended 

for treatment of depression because they 

have a higher risk of adverse effects than 

do SSRIs and SNRIs. They also are more 

dangerous (potentially fatal) in overdose. 

Adverse effects include anticholinergic 

effects, sedation, and cardiac conduction 

abnormalities. Levels of tricyclics are 

increased by ritonavir, so lower dosages may 

be needed for patients taking ritonavir or 

ritonavir-boosted PIs. 

Routine monitoring of blood levels of 

tricyclics should be performed on patients 

receiving higher doses (e.g., 100 mg per 

day; 50 mg for nortriptyline), those on 

concurrently on ritonavir, and those 

with risk factors for cardiac conduction 

abnormalities. A routine electrocardiogram 

should be performed before prescribing 

tricyclics, and this class of drugs should not be 

prescribed to patients with cardiac conduction 

problems. 

The adverse effects of tricyclics can be used to 

treat insomnia or diarrhea, for example, and 

tricyclics can be effective for neuropathic pain.

• Imipramine (Tofranil): FDA indications 

for depression and chronic pain. The full 

recommended dosage for either problem 

is 150-300 mg QHS. Starting dosage: 25-

75 mg PO QHS.

• Doxepin (Sinequan): FDA indications for 

depression and anxiety at adult dosages of 

150-300 mg QHS. Starting dosage: 25-75 

mg PO QHS.

• Three other available tricyclics have an 

FDA indication for depression only: 

nortriptyline (Pamelor) at dosages of 50-

150 mg QHS; desipramine (Norpramin) 

at dosages of 50-200 mg a day; and 

protriptyline (Vivactil) at dosages of 5-10 

mg, either TID or QID.

• Tricyclics need to be started at low 

dosages and titrated gradually. Lower 

dosages (or alternative agents) often are 

more appropriate for patients who are 

elderly, medically ill, or taking ritonavir 

or a ritonavir-boosted PI. 
574 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

• Trazodone: a highly sedating 

antidepressant that is rarely used at 

an antidepressant dosage. Rather, it is 

often given at lower dosage for insomnia 

associated with depression, at a dosage 

of 25-50 mg 1-2 hours before bedtime. 

Ritonavir and other PIs can increase 

trazodone levels significantly; start at low 

dosage and use the lowest effective dosage; 

monitor for adverse effects.

• Nefazodone (Serzone): an antidepressant 

that usually should be avoided in people 

with HIV infection. Little information on 

interactions with ARVs is available, but 

it appears that nefazodone may increase 

levels of maraviroc and saquinavir, and 

that ritonavir may increase nefazodone 

levels. It has a black-box warning for severe 

liver toxicity. If the patient has ever had 

liver toxicity from the drug, restarting it is 

contraindicated. 

• St. John’s wort: an herbal antidepressant 

that can significantly decrease serum 

concentrations of PIs, NNRTIs, and 

maraviroc; it is contraindicated for use by 

patients taking those ARVs. 

Treatment may involve antidepressant 

combinations, including psychostimulants; 

consult with a psychiatrist. 

Discontinuing antidepressant 

medication

Antidepressant medication generally 

should be continued for at least 6 months 

following resolution of a first episode of major 

depression. Longer term, and even indefinite, 

maintenance treatment may be necessary 

for people with recurrent major depression. 

When discontinuing antidepressants, it is 

important to taper them gradually to avoid 

withdrawal symptoms or rebound depression. 

Abrupt discontinuation of SSRI and SNRI 

antidepressants often precipitates unpleasant 

withdrawal symptoms such as confusion, 

agitation, irritability, sensory disturbances, 

and insomnia. This is particularly true for 

paroxetine and venlafaxine. Fluoxetine, 

because of its long half-life, is uncommonly 

associated with withdrawal symptoms.

Brain stimulation treatments 

There are a variety of brain stimulation 

treatments that usually are reserved for 

patients who have inadequate responses to 

medication. Electroconvulsive therapy (ECT) 

is the best known of these treatments and, 

despite the stigma associated with it, is more 

effective than antidepressant medication. 

Newer brain stimulation treatments also are 

available. These treatments require referral to 

the specialty care locations that offer them. 

Antidepressant medication often is used for 

maintenance after stabilization with ECT, but 

for some people, maintenance ECT is needed 

to prevent the relapse of depression.
Major Depression and Other Depressive Disorders | 575

Section 8: Neuropsychiatric 

Disorders

Patient Education

• Providers should explain to patients that 

illness (physical or emotional) is not a 

character flaw or a moral or spiritual 

weakness. It is a common aspect of HIV 

infection. Sadness is a normal part of life, 

but major depression always is abnormal 

and often can be alleviated with medication, 

psychotherapy, or both.

• Providers should help patients identify the 

symptoms of depression and the factors 

that led them to seek treatment. Patients 

will need to monitor themselves for 

recurrences or exacerbations and get help if 

the symptoms recur. Patients should be told 

to contact providers if they notice changes 

in their sleep, appetite, mood, activity level, 

or concentration, or if they notice fatigue, 

isolation, sadness, or feelings of helplessness.

• When starting an antidepressant 

medication, patients should expect that 

it will take 2-4 weeks for them to notice 

any improvement. Their symptoms 

should continue to decrease over the 

following weeks. If they do not have much 

improvement in symptoms, providers 

may choose to adjust the dosage of the 

medication or to change medications. 

Patients must continue taking their 

medications so that the symptoms of 

depression do not return.

• Providers should let patients know that St. 

John’s wort can lower levels of ARVs and 

cannot be taken if they are on ART.

• Antidepressants typically are given for a 

long time, usually for a year or longer, to 

help patients with the chemical imbalances 

associated with major depression. Patients 

should be told that they should not suddenly 

stop antidepressants they have been taking 

for a long time, and that these medications 

need to be discontinued gradually.

• Some patients develop problems with 

sexual function while they are taking 

antidepressants. They should report any 

problems to their prescribers. (Note: 

Providers should let patients know that 

sexual well-being is fundamental to quality 

of life and can be talked about and addressed 

in the clinical setting.)
576 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

References

• American Psychiatric Association. 

Diagnostic and Statistical Manual of Mental 

Disorders (5th ed.). Arlington, VA: American 

Psychiatric Publishing; 2013.

• Himelhoch S, Medoff DR, Oyeniyi G. 

Efficacy of group psychotherapy to reduce 

depressive symptoms among HIV-infected 

individuals: a systematic review and metaanalysis. AIDS Patient Care STDS. 2007 

Oct;21(10):732-9

• Ickovics JR, Hamburger ME, Vlahov D, 

et al.; HIV Epidemiology Research Study 

Group. Mortality, CD4 cell count decline, and 

depressive symptoms among HIV-seropositive 

women: longitudinal analysis from the HIV 

Epidemiology Research Study. JAMA. 2001 

Mar 21;285(11):1466-74.

• Leserman J, Petitto JM, Perkins DO, et 

al. Severe stress, depressive symptoms, and 

changes in lymphocyte subsets in human 

immunodeficiency virus-infected men. A 

2-year follow-up study. Arch Gen Psychiatry. 

1997 Mar;54(3):279-85.

• Maye TJ, Vittinghoff E, Chesney MA, et al. 

Depressive affect and survival among gay and 

bisexual men infected with HIV. Arch Intern 

Med. 1996 Oct 28;156(19):2233-8.

• New York State Department of Health AIDS 

Institute. Mental Health Care for People with 

HIV Infection: Clinical Guidelines for the 

Primary Care Practitioner. Available at www.

hivguidelines.org/clinical-guidelines.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Schatzberg AF, Nemeroff CB, eds. 

Essentials of Clinical Psychopharmacology.

Washington: American Psychiatric Press; 

2006.

• Sikkema KJ, Hansen NB, Ghebremichael 

M, et al. A randomized controlled trial of 

a coping group intervention for adults with 

HIV who are AIDS bereaved: longitudinal 

effects on grief. Health Psychol. 2006 

Sep;25(5):563-70.

• Stober DR, Schwartz JAJ, McDaniel JS, et 

al. Depression and HIV disease: prevalence, 

correlates and treatment. Psych Annals. 

1997;27(5):372-377.

• Wainberg ML, Faragon J, Cournos F, 

et al. Psychiatric Medications and HIV 

Antiretrovirals: A Guide to Interactions for 

Clinicians, 2nd Edition. Laminated booklet 

produced by the New York/New Jersey AIDS 

Education and Training Center, U.S. Health 

Resources and Services Administration; 2008.
Suicide Risk | 577

Section 8: Neuropsychiatric 

Disorders

Suicide Risk 

Background

Transient suicidal thoughts are common for some people 

throughout the course of HIV disease and often do not indicate 

significant risk of suicide. However, persistent suicidal thoughts 

with associated feelings of hopelessness and intent to die are 

very serious and must be assessed promptly and carefully. 

Compared with people at high risk of suicide who are not HIV 

infected, people living with HIV have significantly increased 

frequency and severity of both suicidal ideation and thoughts of 

death. The risk of suicide is especially high for patients who are 

depressed and for those at pivotal points in the course of HIV 

infection. Stigma, quality of life concerns, and issues regarding 

disclosure may be contributing factors.

Suicidality may be the direct physiological result of HIV (e.g., owing to the impact of HIV in 

the brain), a reaction to chronic pain, or an emotional reaction to having a chronic and lifethreatening illness (e.g., major depression as a result of physical illness or psychiatric side effects 

caused by medications used to treat HIV infection and associated comorbidities). Many events may 

trigger suicidal thoughts among people with HIV. Such events include learning of their positive 

HIV status, disclosing to family and friends, starting antiretroviral therapy (ART), noticing the 

first symptoms of infection, having a decrease in CD4 cell count, undergoing a major illness or 

hospitalization, receiving an AIDS diagnosis, losing a job, experiencing major changes in lifestyle, 

requiring evaluation for dementia, and losing a significant relationship.

Evaluation of suicide risk must be included as part of a comprehensive mental health evaluation 

for HIV-infected patients. Note that asking patients about suicidal thoughts does not increase their 

risk of suicide. 

Risk factors for suicide attempts include the following: 

HRSA HAB Performance 

Measures

Percentage of patients aged 

12 years and older screened 

for clinical depression on the 

date of the encounter using an 

age-appropriate standardized 

depression screening tool AND, 

if positive, a follow-up plan is 

documented on the date of the 

positive screen 

(Adult and Adolescent measure)

• Previous suicide attempts 

• Abandonment by or isolation from, 

family, friends, or significant others 

• Age >45 for men, >55 for 

women; or teen years 

• Male gender 

• Gay sexual orientation 

• Transgender 

• Any acute change in health status; 

worsening of HIV-related illness 

or other physical illnesses 

• Family history of completed suicide 

• Alcohol and other substance 

misuse, abuse, or dependence 

• Relapse into drug use after 

significant recovery 

• Severe anxiety, depression, psychotic 

disorder, or other mental health disorder 

• Domestic violence 

• Social isolation (e.g., being single, 

divorced, or alone, or experiencing 

the death of a spouse) 

• Multiple losses or recent stressors 

• Financial difficulty, unemployment 
578 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

• Hopelessness and lack of pleasure 

• Impulsivity 

• Pain 

• Perception of poor prognosis 

• Perception of poor social support 

• Planning for death

• Stigmatization associated with 

illness, sexual orientation, substance 

use history, or other factors 

• Fear of HIV-associated dementia 

Protective factors include the following:

• Strong psychosocial support 

• Evidence of good coping mechanisms 

• Cultural and religious beliefs against suicide 

• Reasons for living 

• No specific plan for suicide

S: Subjective

The patient expresses or exhibits, or a 

personal care giver discloses, the following: 

• Active suicidal ideation with intent and plan, 

such as giving away significant personal 

belongings, saying goodbye, acquiring the 

means (e.g., gun, pills), writing a suicide note 

• Depressed mood, hopelessness, agitation, 

intoxication with alcohol or other drugs 

• Passive withdrawal from therapy or medical 

care or decreased adherence (e.g., stopping 

medications, missing appointments) 

• A desire for HIV disease to progress more 

rapidly 

Inquire about the following during the 

history (again, note that asking patients about 

suicidal thoughts does not increase their risk of 

suicide):

• Previous suicide attempt(s) – one of the best 

predictors of eventual death by suicide 

• Friend or family member who has 

committed suicide 

• Personal or family history of depression 

• Previous episode of psychosis 

• Presence of risk factors described above 

Probe for other depressive symptoms 

and the immediacy of potential suicidal 

intent. Sample questions may include the 

following: 

• “It sounds as if you’re in great pain. Have 

you ever thought that life is not worth 

living?” 

• “Do you often think of death?” 

• “Do you think about hurting yourself?” 

• “How might you do that?” 

• “Do you have a plan?” Ask whether the 

patient has access to the components of the 

plan (e.g., gun, pills) 

• “Is this something you feel you might do?” 

• “What would prevent you from doing this?” 

• “Have you ever attempted suicide? What did 

you do?”

O: Objective

• Perform a mental status examination and 

suicide assessment.

• Look for signs of self-inflicted injuries such 

as wrist lacerations or neck burns.

• Look for signs of depression, agitation, or 

intoxication.
Suicide Risk | 579

Section 8: Neuropsychiatric 

Disorders

A: Assessment

See chapter Major Depression and Other 

Depressive Disorders for differential diagnosis 

of possible causes of depression and suicidality. 

P: Plan

Evaluation

Evaluate the patient for depression, risk 

factors for suicide, and contributing 

psychiatric illnesses or situational 

stressors. Determine the immediacy of 

potential suicidal intent. If a mental health 

professional is available on site or can be 

summoned, an urgent consultation often is 

helpful in making these determinations. 

Treatment

• If the patient exhibits active suicidal 

ideation with a plan, hospitalize 

the patient immediately, preferably 

in a psychiatric facility.

• If suicidal thoughts are passive, refer for 

evaluation for specific psychiatric disorders 

and refer for psychotherapy with an HIVexperienced mental health provider. 

• Encourage the patient to contact you 

or another specified clinician for 

help, or to go to a hospital if suicidal 

ideation worsens or patient worries 

about acting upon suicidal thoughts. 

• Note that making a contract with a patient 

against suicide is not recommended; 

research shows it is not effective, and it 

can provide a false sense of security. 

• Inform patients about local suicide 

prevention resources, including suicide 

hotlines, emergency response (e.g., 911), 

and local emergency departments. 

• Contact the patient between appointments. 

Enlist the help of significant others (if the 

patient agrees); invite them to accompany 

the patient on the next visit and see all 

of them together. Consider a support 

group or peer referral, if available. 

• Consider dispensing medications on a 

weekly basis for the following purposes: 

• Monitoring emotional status 

and treatment adherence 

• Preventing the availability of 

lethal doses of medications 

• Perform appropriate follow-up. In 

consultation with a skilled mental health 

provider, be sure that the patient is 

receiving appropriate ongoing treatment for 

underlying or persisting psychiatric illness. 

Assess at each visit for adherence to mental 

health care and for recurrence of symptoms. 

Patient Education

• Suicidal ideation and severe depression are 

not normal aspects of HIV infection, and 

usually can be treated effectively.

• Patients should report suicidal thoughts to 

their health care provider.

• Inform patients about local suicide 

prevention resources, including suicide 

hotlines, emergency response (e.g., 911), and 

local emergency departments. 
580 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

References

• Cournos F, Lowenthal D, Cabaniss D. 

Clinical Evaluation and Treatment Planning: 

A Multimodal Approach. In: Tasman A, Kay 

J, Lieberman JA, et al., eds. Psychiatry, Third 

Edition. Hoboken, NJ: John Wiley & Sons; 

2008;525-45. 

• Gielen AC, McDonnell KA, O’Campo 

PJ, et al. Suicide risk and mental health 

indicators: Do they differ by abuse and HIV 

status? Women’s Health Issues. 2005 MarApr;15(2):89-95. 

• Goldstein RB, Black DW, Nasrallah A., 

et al. The prediction of suicide: Sensitivity, 

specificity and predictive value of a 

multivariate model applied to suicide among 

1906 patients with affective disorders. Arch 

Gen Psychiatry. 1991 May;48(5):418-22. 

• Kelly B, Raphael B, Judd F, et al. Suicidal 

ideation, suicide attempts, and HIV infection.

Psychosomatics. 1998 Sep-Oct;39(5):405-15. 

• Kessler RC, Borges G, Walters EE. 

Prevalence of and risk factors for lifetime 

suicide attempts in national comorbidity 

survey. Arch Gen Psychiatry. 1999 

Jul;56(7):617-26. 

• Komiti A, Judd F, Grech P, et al. Suicidal 

behaviour in people with HIV/AIDS: a review.

Aust N Z J Psychiatry. 2001 35(6):747-57. 

• Mountain Plains AIDS Education and 

Training Center. HIV and Suicide: Risk 

Assessment and Intervention. 2007. 

• New York State Department of Health AIDS 

Institute. Mental Health Care for People 

with HIV Infection: Clinical Guidelines for 

the Primary Care Practitioner. Available at 

www.hivguidelines.org/clinical-guidelines. 

Accessed December 1, 2013.

• Robertson K, Parsons TD, Van Der Horst C, 

et al. Thoughts of death and suicidal ideation 

in nonpsychiatric human immunodeficiency 

virus seropositive individuals. Death Stud. 

2006 Jun;30(5):455-69. 

• Roy A. Characteristics of HIV patients who 

attempt suicide. Acta Psychiatr Scand. 2003 

Jan;107(1):41-4. 

• Wainberg ML. Mental Health Issues in 

HIV-Positive Patients. Presentation at the 3rd 

annual Mountain-Plains AIDS Education 

and Training Center Faculty Development 

Conference, Keystone, CO. Mountain Plains 

AIDS Education and Training Center; 2005.
Anxiety Disorders | 581

Section 8: Neuropsychiatric 

Disorders

Anxiety Disorders 

Background

Anxiety symptoms are common and can develop or 

recur for many reasons, including a patient’s worries 

about HIV infection and treatment, or issues unrelated 

to HIV. Symptoms can range from mild distress to fullblown anxiety disorders. Symptoms of anxiety can mimic 

symptoms of physical illness, and an appropriate workup 

should be performed to rule out other illnesses. Use of illicit 

drugs (e.g., amphetamines, cocaine) or alcohol can cause or 

substantially worsen anxiety symptoms; all patients should 

be screened for substance use.

Anxiety disorders include generalized anxiety disorder, 

specific phobia, and social phobia; related disorders include 

posttraumatic stress disorder (PTSD) and panic disorder. This chapter focuses primarily on anxiety 

symptoms and generalized anxiety disorder. See chapters Panic Disorder and Posttraumatic Stress 

Disorder for further information about these conditions. 

HRSA HAB Performance 

Measures

Percentage of patients aged 

12 years and older screened 

for clinical depression on the 

date of the encounter using an 

age-appropriate standardized 

depression screening tool AND, 

if positive, a follow-up plan is 

documented on the date of the 

positive screen

(Adult and Adolescent measure)

S: Subjective

The criteria for a diagnosis of generalized 

anxiety disorder include unrealistic or 

excessive worry about two or more life 

circumstances for ≥6 months, and at least 

three of the following subjective complaints:

• Restlessness or feeling keyed-up or on edge 

• Difficulty concentrating or mind going 

blank 

• Irritability 

• Muscle tension 

• Being easily fatigued 

• Sleep disturbance (difficulty falling or 

staying asleep, or restless, unsatisfying sleep)

Other subjective complaints may include the 

following:

• Shortness of breath or smothering sensations 

• Palpitations or accelerated heart rate 

• Dizziness or lightheadedness 

• Exaggerated startle response 

• Trembling, twitching, or feeling shaky 

• Dry mouth 

• Flushes or chills 

• Frequent urination 

• Muscle aches or soreness 

• Nausea, diarrhea, or other abdominal 

distress 

• Skin rashes 

• Sweating or cold, clammy hands 

• Trouble swallowing or “lump in the throat” 

Ask about the symptoms indicated above, and 

about the following: 

• Anxiety patterns (e.g., constant or 

intermittent; timing, duration, precipitants) 

• Onset: sudden or gradual 

• Caffeine intake 

• Recreational drug or alcohol use (current

or recent) 

• Concomitant illnesses (e.g., cardiac, 

pulmonary, endocrine)
582 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

• Family history of similar problems 

• Medications, supplements, and herbal 

preparations 

• History of previous episodes 

• Recent stressors 

• Sleep disturbances

• Other physical symptoms 

O: Objective

Measure vital signs, with particular attention 

to heart rate (tachycardia) and respiratory rate 

(shortness of breath, hyperventilation).

Perform a physical examination, 

including mental status and neurologic, 

cardiopulmonary, and thyroid examinations.

A: Assessment

A differential diagnosis may include the 

following medical conditions: 

• Substance use (e.g., amphetamines, cocaine) 

• Substance or medication withdrawal (e.g., 

alcohol, benzodiazepines) 

• Excessive caffeine intake 

• Electrolyte imbalances 

• Heart disease, arrhythmias 

• Hyperthyroidism 

• Hypoglycemia 

• Immune disorders 

• Respiratory disease, hypoxia 

• Medication adverse effects (e.g., with 

efavirenz, isoniazid, corticosteroids, 

theophylline, or stimulants) 

• Sleep disturbances or sleep deprivation 

• Allergic reactions 

• Anemia 

• Central nervous system (CNS) or 

opportunistic infections or malignancies 

• Systemic or other infections 

• Vitamin B12 deficiency 

P: Plan

Diagnostic Evaluation

Perform the following tests: 

• Blood glucose, electrolytes 

• Thyroid function tests (TSH, T4) 

• Electrocardiogram (EKG) if patient has 

shortness of breath or palpitations 

• Arterial blood gases (if difficulty breathing is 

not self-limited) 

• Other tests as indicated by symptoms and 

physical examination 

Treatment

Once medical disorders have been ruled out, 

and the diagnosis of an anxiety disorder is 

established, several options are available: 

Psychotherapy

Options include cognitive-behavioral therapy, 

interpersonal therapy, exposure therapy, 

a stress-management group, relaxation 

therapy, visualization, guided imagery, 

supportive psychotherapy, and psychodynamic 

psychotherapy. Long-term psychotherapy may 

be indicated if experienced professionals are 

available and the patient is capable of forming 

an ongoing relationship. If possible, refer to 

an HIV-experienced therapist. The type of 

psychotherapy available to the patient often 

depends on the skills and training of the 

practitioners in a given health care system or 

region. In addition, the patient may be referred 

to available community-based support.

Pharmacotherapy

Medications, with or without psychotherapy, 

may alleviate symptoms of anxiety. Patients 

with advanced HIV disease, like geriatric 

patients, may be more vulnerable to the CNS 

effects of certain medications. Medications 

that affect the CNS should be started at low 
Anxiety Disorders | 583

Section 8: Neuropsychiatric 

Disorders

dosage and titrated slowly. Similar precautions 

should apply to patients with liver dysfunction. 

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) 

and serotonin-norepinephrine reuptake 

inhibitors (SNRIs) are effective in treating 

patients with anxiety. They are favored for 

long-term use when a specific anxiety disorder 

is present and persistent. These medications do 

not cause tolerance or pose a risk of addiction. 

Below is a list of antidepressants approved 

by the U.S. Food and Drug Administration 

(FDA) for specific anxiety disorders, and 

their usual recommended dosages. FDA 

recommendations are based on availability of 

specific study data, but all SSRIs (regardless 

of whether they have an FDA indication for 

anxiety) may be helpful for a broad range of 

anxiety disorders.

Common adverse effects of SSRIs and SNRIs 

include sexual dysfunction, sleep disturbance, 

and nausea. For patients who are medically 

ill, these medications should be started at low 

dosage and titrated up slowly; a low dosage 

may be effective. These medications also 

should be down-tapered slowly; SSRI/SNRI 

discontinuation syndrome may occur if they 

are discontinued abruptly. 

See chapter Major Depression and Other 

Depressive Disorders for further information 

about antidepressant medications, including 

adverse effects. 

SSRI antidepressants: 

• Fluoxetine (Prozac): FDA indication for 

panic disorder with a recommended 

dosage of 20 mg QD. Also recommended 

for obsessive-compulsive disorder, but 

higher dosages are needed, sometimes up 

to 80 mg daily.

• Escitalopram (Lexapro): FDA indication 

for generalized anxiety disorder at a 

dosage of 10 mg QD.

• Citalopram (Celexa): Does not have 

specific FDA indications for anxiety 

disorders. Suggested dosage: start at 10 

mg QD and titrate as needed; maximum 

dosage: 60 mg daily.

• Paroxetine (Paxil): FDA indications for 

obsessive-compulsive disorder and panic 

disorder both at a recommended dosage 

of 40 mg QD. Also indicated for social 

anxiety disorder at a dosage of 20-40 mg 

daily. Usual starting dosage: 10 mg daily.

• Sertraline (Zoloft): FDA indications for 

panic disorder and PTSD at dosages of 

50-200 mg QD. Usual starting dosage: 25 

mg daily.

SNRI antidepressants:

• Venlafaxine timed-release formulation 

(Effexor XR): FDA indication for 

generalized anxiety disorder, at 

recommended dosages of 75-225 mg per 

day. Note: There is a risk of hypertension 

at the higher dosages of venlafaxine; 

monitor blood pressure.

• Duloxetine (Cymbalta): FDA indication 

for generalized anxiety disorder at a 

recommended dosage of 60 mg QD.

Other antidepressants:

• Some sedating antidepressants are 

effective, nonaddictive agents that are 

helpful when taken at bedtime for both 

insomnia and anxiety symptoms. These 

include trazodone 25-100 mg QHS or 

imipramine (Tofranil) 25 mg QHS. Note 

that imipramine and other tricyclics 

must be used with caution but are not 

contraindicated for use by patients taking 

ritonavir (including ritonavir-boosted 

protease inhibitors [PIs]).

• Gabapentin (Neurontin), which 

sometimes is used as a mood stabilizer, 

may be given at dosages of 200-400 mg 

BID to QID and may help to diminish 

anxiety.
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Section 8: Neuropsychiatric 

Disorders

Anxiolytics

Short-term use of benzodiazepines sometimes 

is appropriate for mild and brief situational 

anxiety symptoms, even without the presence 

of a specific anxiety disorder. For longer-term 

use, non-benzodiazepines (e.g., buspirone [see 

below], SSRIs, or SNRIs) are preferred.

• Buspirone (BuSpar) is a nonaddictive 

anxiolytic. Start at 5 mg PO TID. If 

symptoms persist, the dosage can be 

increased by 5 mg per dose each week to a 

maximum of 10-15 mg TID (for a total daily 

dosage of 30-45 mg). It will take several 

weeks for patients to notice a decrease in 

anxiety; low-dose benzodiazepines may 

be used during this interval. The major 

potential adverse effects of buspirone are 

dizziness and lightheadedness.

• Consider intermediate half-life 

benzodiazepines such as lorazepam (Ativan) 

0.5 mg PO Q8H or oxazepam (Serax) 10 mg 

PO Q6H if buspirone is not tolerated or to 

alleviate anxiety symptoms until buspirone 

takes effect. Longer-acting benzodiazepines 

such as clonazepam (Klonopin) also may be 

useful at dosages of 0.25-0.5 mg PO BID.

• Benzodiazepines generally should be used 

only for acute, short-term management 

because of the risk of tolerance and 

physiologic dependence. These risks are even 

more problematic for patients with a history 

of addiction. 

Potential ARV Interactions

Interactions may occur between certain 

ARVs and agents used to treat anxiety. Some 

combinations may be contraindicated and 

others may require dosage adjustment. Refer 

to medication interaction resources or consult 

with an HIV clinical pharmacist, HIV specialist, 

or psychiatrist before prescribing.

Antidepressants

• Some ARV medications (particularly 

PIs) and the pharmacokinetic booster 

cobicistat may affect the metabolism of 

some antidepressants via cytochrome 

P450 interactions. For most SSRIs and 

SNRIs, interactions with ARVs generally 

are not clinically significant; in the case of 

tricyclics, their levels may be significantly 

increased by ritonavir. On the other hand, 

some PIs may decrease levels of paroxetine 

and sertraline, and efavirenz also lowers 

sertraline levels. See chapter Major 

Depression and Other Depressive Disorders

for further information. 

Anxiolytics

• PIs, nonnucleoside reverse transcriptase 

inhibitors (NNRTIs), and cobicistat 

may raise blood concentrations of 

many benzodiazepines. Consider 

using a benzodiazepine metabolized 

by glucuronidation (e.g., lorazepam, 

oxazepam), particularly in patients 

with liver disease. For benzodiazepines 

metabolized by the CYP system (e.g., 

clonazepam), start at low dosages and 

titrate slowly. Given the very long half-life 

of both the parent drug and its metabolites, 

diazepam is best avoided in patients 

receiving ART. Other CNS depressants 

and alcohol should be avoided in patients 

taking these benzodiazepines. 

• Midazolam (Versed) and triazolam 

(Halcion) are contraindicated for 

use with all PIs and with cobicistat, 

delavirdine, and efavirenz. 

• Buspirone levels may be increased by 

ritonavir-boosted PIs and cobicistat, and 

may be decreased by CYP inducers. Monitor 

patients for adverse effects and for efficacy.
Anxiety Disorders | 585

Section 8: Neuropsychiatric 

Disorders

Patient Education

• Behavioral interventions can help to reduce 

anxiety, but may take practice. Patients 

should seek help from a therapist or another 

experienced source.

• Advise patients that misuse of alcohol 

or illicit drugs can cause or substantially 

worsen anxiety symptoms; advise patients 

to decrease or eliminate use. Refer for 

substance abuse treatment if indicated.

• Inform patients that they may develop 

problems with sexual function because of 

antianxiety medications. Patients should 

report any problems to their prescribers. 

(Note: Providers should let patients know 

that sexual well-being is fundamental to 

quality of life and can be talked about and 

addressed in the clinical setting.)

References

• American Psychiatric Association. 

Diagnostic and Statistical Manual of Mental 

Disorders (5th ed.). Arlington, VA: American 

Psychiatric Publishing; 2013.

• New York State Department of Health AIDS 

Institute. Mental Health Care for People 

with HIV Infection: Clinical Guidelines for 

the Primary Care Practitioner. Available at 

www.hivguidelines.org/clinical-guidelines. 

Accessed December 1, 2013.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Wainberg ML, Faragon J, Cournos F, 

et al. Psychiatric Medications and HIV 

Antiretrovirals: A Guide to Interactions 

for Clinicians, 2nd Edition. Laminated 

booklet produced by the New York/

New Jersey AIDS Education and 

Training Center, U.S. Health Resources 

and Services Administration; 2008.

Panic Disorder | 587

Section 8: Neuropsychiatric 

Disorders

Panic Disorder

Background

Panic disorder is an anxiety disorder whose essential feature is the presence of recurrent, 

unexpected panic attacks. Panic attacks are discrete, sudden-onset episodes of intense fear 

or apprehension accompanied by specific somatic or psychiatric symptoms (e.g., palpitations, 

shortness of breath, fear of losing control). A patient is diagnosed as having panic disorder when he 

or she has experienced such attacks, and at least one of the attacks has been followed by ≥1 month 

of persistent concern about additional attacks, worry about the implications or consequences of the 

attack, or a significant change in behavior related to the attack.

The symptoms of panic disorder usually begin in late adolescence to the mid-30s and may coincide 

with the presentation of major depressive disorder, social phobia, or generalized anxiety disorder. 

Panic disorder can interfere with the ability to conduct activities of daily living. Patients with panic 

disorder have an increased incidence of suicide.

Symptoms may mimic those of various physical illnesses or be caused by other medical conditions 

(e.g., hyperthyroidism, brain tumors, adrenal tumors, heart arrhythmias, hypoglycemia, anemia). 

Substance or alcohol intoxication or withdrawal also may cause panic symptoms. Patients with 

panic symptoms should be evaluated for other causative conditions.

Major depressive disorder occurs in 50-65% of people with panic disorder. Major depression 

may precede or follow the onset of panic disorder. Patients with panic disorder therefore should 

be screened for depression initially and periodically thereafter (see chapter Major Depression 

and Other Depressive Disorders). Anxiety also commonly is experienced by persons with panic 

disorder; see chapter Anxiety Disorders for further information about this condition. 

S: Subjective

The patient complains of discrete periods of 

intense fear or discomfort in which four or 

more of the following symptoms developed 

abruptly and reached a peak within 10 

minutes: 

• Shortness of breath or smothering sensation 

• Sweating 

• Trembling or shaking 

• Dizziness, lightheadedness, faintness, or 

feeling of unsteadiness 

• Numbness or tingling sensations 

• Chest pain or discomfort 

• Palpitations or accelerated heart rate 

• Hot flashes or chills 

• Sensation of choking 

• Depersonalization or derealization 

• Fear of dying 

• Fear of going crazy or losing control 

• Nausea or abdominal distress

Other subjective complaints may include the 

following:

• Apprehension about the outcome of routine 

activities and experiences 

• Anticipation of a catastrophic outcome 

from a mild physical symptom or from 

medication side effects 

• Discouragement and demoralization

Panic attacks are, by definition, selflimited and they peak quickly. Symptoms 

that persist continuously for longer 

periods suggest other causes. 
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Section 8: Neuropsychiatric 

Disorders

Ask about the symptoms indicated above and 

about the following: 

• Frequency, duration, and onset of panic 

episodes 

• Possible precipitants, (e.g., settings in which 

attacks occur), situations (e.g., being alone 

outdoors), relationship to food or hunger 

• Current medications, herbal products, and 

supplements; recent medication changes 

• Multiple visits to health care providers with 

complaints suggesting panic attacks 

• Family history of mood and psychiatric 

illnesses, particularly anxiety and panic 

• Use of recreational drugs (especially 

stimulants such as cocaine or 

amphetamines), alcohol (current and recent), 

and caffeine 

• Sleep disturbances 

• Concomitant illnesses (e.g., endocrine, 

cardiac, pulmonary) 

• Any associated or concurrent symptoms that 

could suggest a medical etiology 

• Screen for depression (see chapter Major 

Depression and Other Depressive Disorders)

O: Objective

Measure vital signs, with particular attention 

to heart rate (tachycardia) and respiratory 

rate (shortness of breath, hyperventilation). 

Perform a complete physical examination, 

including thyroid, cardiac, pulmonary, and 

neurologic evaluation. 

During actual panic attacks, patients may have 

increases in heart rate, respiratory rate, or 

systolic blood pressure. 

A: Assessment

A differential diagnosis may include the 

following conditions:

• Congestive heart failure, myocardial 

ischemia, arrhythmias 

• Hyperthyroidism 

• Intoxication with or withdrawal 

from psychoactive substances (e.g., 

amphetamines, cocaine, hallucinogens, 

caffeine, medications) 

• Hypoglycemia 

• Hypoxia 

• Hyperparathyroidism 

• Medication side effects 

• Pheochromocytoma 

• Adrenal disorders, Cushing syndrome, 

electrolyte abnormalities 

• Respiratory infection 

• Seizure disorder 

• Vestibular dysfunction 

• Allergic reactions 

• Posttraumatic stress disorder 

• Social phobia or specific phobia (specific 

phobia is a response to a specific stimulus, 

whereas a patient with panic attacks is 

unsure when they will recur and what will 

trigger them) 

• Agoraphobia

• Obsessive-compulsive disorder 

• Separation anxiety disorder
Panic Disorder | 589

Section 8: Neuropsychiatric 

Disorders

P: Plan

Diagnostic Evaluation

Perform the following tests:

• Electrolytes, blood glucose 

• Thyroid function tests (thyroid stimulating 

hormone [TSH], T4) 

• Arterial blood gases if the patient has 

persistent shortness of breath 

• Electrocardiogram if chest pain or other 

cardiac symptoms are present 

• Other tests as indicated by symptoms and 

physical examination

Treatment

Once other diagnoses have been ruled out, 

consider the following treatments:

Psychotherapy

Options include cognitive-behavioral therapy, 

interpersonal therapy, exposure therapy, 

a stress-management group, relaxation 

therapy, visualization, guided imagery, 

supportive psychotherapy, and psychodynamic 

psychotherapy. Long-term psychotherapy 

may be indicated if experienced professionals 

are available and the patient is capable of 

forming an ongoing relationship. If possible, 

refer to an HIV-experienced therapist. The 

type of psychotherapy selected often will 

depend on the skills and training of the 

practitioners available in a given health 

care system or region. In addition, refer 

the patient to available community-based 

support. Emergency referrals may be needed 

for the most anxious patients and those with 

comorbid depression.

Pharmacotherapy

Patients with advanced HIV disease and 

geriatric patients may be more vulnerable to 

the central nervous system (CNS) effects of 

certain medications. Medications that affect 

the CNS should be started at low dosage and 

titrated slowly. Similar precautions should 

apply to patients with liver dysfunction. 

Options 

A number of medications have an approved 

indication by the U.S. Food and Drug 

Administration (FDA) for panic disorder. 

These include the serotonin reuptake 

inhibitors (SSRIs), serotonin-norepinephrine 

reuptake inhibitor (SNRI) venlafaxine 

extended-release, and benzodiazepines listed 

below. For most patients, SSRIs are preferable 

to benzodiazepines for the treatment of panic 

disorder because they do not have the potential 

for addiction and they do not pose the same 

level of risk if drug interactions cause an 

elevation of their levels. Other medications 

used to treat anxiety disorders, such as SNRIs 

may be considered, and some of them are less 

likely to interact with ARV medications. See 

chapter Anxiety Disorders for descriptions of 

these medications.

SSRI antidepressants approved for panic 

disorder include the following: 

• Fluoxetine (Prozac), recommended dosage 

20 mg PO QD (usual starting dosage 10 mg 

daily) 

• Paroxetine (Paxil), recommended dosage 

40 mg PO QD (usual starting dosage 10 mg 

daily) 

• Sertraline (Zoloft), recommended dosage 

50-200 mg PO QD (usual starting dosage 25 

mg daily) 

SNRI antidepressant approved for panic 

disorder:

• Venlafaxine (Effexor XR), recommended 

dosage 75-225 mg PO QD (usual starting 

dosage 37.5 mg daily)

Benzodiazepines approved for panic disorder 

include the following:

• Clonazepam (Klonopin), recommended 

dosage 0.5-2 mg PO BID 

• Alprazolam (Xanax), recommended 

dosage 0.5-3 mg PO TID or Xanax XR at 

a recommended dosage of 3-6 mg PO QD; 

start at low dosage, may increase every 3-4 

days in increments of ≤ 1 mg/day if tolerated
590 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

Potential ARV Interactions

Interactions may occur between certain 

ARVs and agents used to treat panic. Some 

combinations may be contraindicated and 

others may require dosage adjustment. Refer 

to medication interaction resources or consult 

with an HIV expert or clinical pharmacist before 

prescribing.

Some ARV medications (particularly protease 

inhibitors [PIs]) and the pharmacokinetic 

booster cobicistat may affect the metabolism of 

some SSRIs via cytochrome P450 interactions. 

These generally are not clinically significant, 

but SSRIs used concomitantly with PIs or 

cobicistat should be started at low dosages and 

titrated cautiously to prevent antidepressant 

adverse effects and toxicity. On the other hand, 

some PIs may decrease levels of paroxetine and 

sertraline, and efavirenz also lowers sertraline 

levels; these antidepressants may require 

upward titration if used concurrently with 

interacting ARVs.

PIs and cobicistat can significantly elevate 

the levels of clonazepam and alprazolam, 

resulting in the potential for severe sedation or 

respiratory depression. For patients receiving 

clonazepam or alprazolam, it is recommended 

that these medications be used at the lowest 

dosages for the shortest duration possible. 

Patient Education

• Inform patients that behavioral 

interventions can help to reduce the 

frequency and severity of panic attacks.

• Some antidepressants and antianxiety 

medications can prevent or reduce the 

severity of panic attacks.

• Advise patients that they may develop 

problems with sexual function because of 

the medications. Patients should report 

any problems to their prescribers. (Note: 

Providers should let the patient know that 

sexual well-being is fundamental to quality 

of life and can be talked about and addressed 

in the clinical setting.)

References

• American Psychiatric Association. 

Diagnostic and Statistical Manual of Mental 

Disorders (5th ed.). Arlington, VA: American 

Psychiatric Publishing; 2013.

• New York State Department of Health AIDS 

Institute. Mental Health Care for People 

with HIV Infection: Clinical Guidelines for 

the Primary Care Practitioner. Available at 

www.hivguidelines.org/clinical-guidelines. 

Accessed December 1, 2013.

• Panel on Antiretroviral Guidelines for 

Adults and Adolescents. Guidelines for 

the use of antiretroviral agents in HIV-1-

infected adults and adolescents. Department 

of Health and Human Services. Available 

at aidsinfo.nih.gov/guidelines. Accessed 

December 1, 2013.

• Wainberg ML, Faragon J, Cournos F, 

et al. Psychiatric Medications and HIV 

Antiretrovirals: A Guide to Interactions 

for Clinicians, 2nd Edition. Laminated 

booklet produced by the New York/

New Jersey AIDS Education and 

Training Center, U.S. Health Resources 

and Services Administration; 2008.
Posttraumatic Stress Disorder | 591

Section 8: Neuropsychiatric 

Disorders

Posttraumatic Stress Disorder

Francine Cournos, MD; and Milton Wainberg, MD

Background

Symptoms of posttraumatic stress disorder (PTSD) can develop after exposure to a traumatic 

event. A traumatic event may be a single instance, such as a car accident or experience of a natural 

disaster, or an ongoing pattern of events, such as continuous neglect, physical or sexual abuse, 

or chronic exposure to war or violent conflict. PTSD causes intrusive memories, hyperarousal, 

and psychological numbing or avoidance, among other symptoms. It may impair an individual’s 

psychological and physical functioning, decreasing immune system function and increasing 

susceptibility to illness. Untreated PTSD can increase the risk of HIV transmission or acquisition 

and worsen the course of HIV treatment.

Individuals with PTSD may experience depression, anxiety, social isolation, impairments in trust 

and attachments, and feelings of anger, and PTSD often coexists with depression, anxiety, or other 

psychiatric illnesses. PTSD may be associated with increased risk-taking behavior (e.g., substance 

abuse, unsafe sex).

The rate of PTSD among individuals with HIV infection (in whom the lifetime prevalence 

is possibly as high as 42%) is higher than that of the general population (1.3%-7.8%). Women 

experience PTSD at a higher rate than men. The likelihood of developing PTSD increases in 

relation to the severity of or proximity to the traumatic event. A history of traumatic experiences 

may increase an individual’s risk of developing PTSD after a new trauma. Although a diagnosis of 

HIV may trigger PTSD symptoms, a history of trauma or abuse often is present as well. A personal 

or family psychiatric history may increase the likelihood of developing PTSD.

PTSD is diagnosed, as in HIV-uninfected individuals, according to the criteria of the Diagnostic 

and Statistical Manual of Mental Disorders (DSM)-5 (see “References,” below). It is treatable 

through diverse therapies and psychopharmacology.

S: Subjective

The following reflect DSM-5 diagnostic 

criteria; include them in the history.

• The person experienced, witnessed, or was 

confronted with an event or events that 

involved actual or threatened death, serious 

injury, or sexual violence, or a threat to the 

physical integrity of self or others.

• The person’s response involved intense fear, 

helplessness, or horror.

• The person complains of persistently 

reexperiencing the event in one or more of 

the following ways: 

• Recurrent and intrusive distressing 

recollections of the event, including 

images, thoughts or perceptions

• Recurring distressing dreams of the event

• Acting or feeling as if the traumatic 

event were recurring (includes a sense 

of reliving the experience, illusions, 

hallucinations and dissociative flashback 

episodes, including those that occur when 

awakening or intoxicated)

• Intense psychological distress at exposure 

to internal or external cues that symbolize 

or resemble an aspect of the traumatic 

event

• Physiological reactivity on exposure to 

internal or external cues that symbolize or 

resemble an aspect of the traumatic event
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Section 8: Neuropsychiatric 

Disorders

• The person makes efforts to avoid thoughts 

or reminders of the trauma.

• The person has disturbances in mood or 

cognition that began or worsened after the 

traumatic event.

Other complaints may include the following:

• Overwhelming emotions caused by 

memories of the event

• Emotional numbness

• Disruptions in consciousness, memory, or 

identity

• Depersonalization (i.e., a feeling of watching 

oneself act, while having no control over a 

situation)

• Derealization (i.e., alteration in the 

perception or experience of the external 

world so that it seems strange or unreal)

• Feelings of estrangement from others

• Episodes of lost time

The patient may experience the following:

• Recurrent distressing recollections of the 

event

• Recurrent distressing dreams of the event

• Illusions/hallucinations of the event actually 

occurring

• Psychological distress triggered by cues 

reminiscent of the event

• Avoidance of thoughts, feelings, or 

conversation associated with the event

• Avoidance of activities, places, or people 

associated with the event

• Inability to recall important aspects of the 

event

• Diminished interest in significant activities

• Detachment

• Restricted range of affect

• Difficulty falling or staying asleep

• Irritability or outbursts of anger

• Difficulty concentrating

• Hypervigilance

Ask about the duration of symptoms (PTSD is 

characterized by symptoms that last for more 

than 1 month).

Also screen for the following:

• Clinical depression

• Anxiety disorders

• Alcohol or other substance-use disorders

O: Objective

• Check vital signs, with particular attention 

to heart rate (tachycardia) and respiratory 

rate (shortness of breath, hyperventilation).

• Perform a physical examination, including 

mental status and neurologic examination 

(tremor, hyperreflexia, focal abnormalities).

• Look for signs of physical trauma or sexual 

assault.

A: Assessment

A differential diagnosis may include the 

following: 

• Substance use (e.g., amphetamines, cocaine) 

• Substance withdrawal (e.g., alcohol, 

benzodiazepines) 

• Electrolyte imbalances 

• Excessive caffeine intake 

• Hyperthyroidism 

• Medications effects (e.g., efavirenz, 

isoniazid, steroids, theophylline) 

• Allergic reactions 

• Head trauma 

• Hypoglycemia 

• Sleep disturbances or sleep deprivation 

• Central nervous system (CNS) or 

opportunistic infections or malignancies 
Posttraumatic Stress Disorder | 593

Section 8: Neuropsychiatric 

Disorders

• Systemic or other infections 

• Respiratory disease 

• Heart disease, arrhythmias 

• Anemia 

• Vitamin B12 deficiency

P: Plan

Evaluation

Perform the following tests:

• Complete blood count, electrolytes, 

creatinine, blood urea nitrogen, glucose 

• Thyroid function tests (thyroid stimulating 

hormone [TSH], T4) 

• Vitamin B12 levels 

• Other tests as suggested by history and 

physical examination 

Treatment

Once other diagnoses have been ruled out and 

the diagnosis of PTSD is established, several 

treatment options are available. 

Psychotherapy

Options include individual cognitivebehavioral therapy, cognitive processing 

therapy, exposure therapy, eye movement 

desensitization and reprocessing, interpersonal 

therapy, a stress-management group, 

relaxation therapy, visualization, guided 

imagery, supportive psychotherapy, and other 

forms of therapy. Long-term psychotherapy 

may be indicated if experienced professionals 

are available and the patient is capable of 

forming an ongoing relationship. If possible, 

refer to an HIV-experienced therapist. The 

specific psychotherapy often depends on the 

skills and training of the practitioners available 

in a given health care system or region. 

In addition, refer the patient to available 

community-based support.

Pharmacotherapy

Antidepressants 

Most antidepressants should be started at low 

dosages and gradually titrated upward to avoid 

unpleasant side effects. Therapeutic effects may 

not be noticed until 2-4 weeks after starting 

a medication. If there is no improvement in 

symptoms in 2-4 weeks, and there are no 

significant adverse effects, the dosage may be 

increased. Before prescribing a medication, 

always remember to check for drug-drug 

interactions, particularly with concurrent 

antiretrovirals (ARVs). See “Potential ARV 

Interactions,” below, and chapter Major 

Depression and Other Depressive Disorders for 

further information about antidepressants, 

including possible adverse effects and 

interactions with ARVs.

• Selective serotonin reuptake inhibitors

(SSRIs) have the strongest evidence for 

efficacy and tolerability for PTSD and are 

first-line medication treatment. Two SSRI 

antidepressants have a specific indication 

for PTSD approved by the U.S. Food and 

Drug Administration (FDA): sertraline 

(Zoloft) at recommended dosages of 50-200 

mg QD (usual starting dosage: 25 mg daily) 

and paroxetine (Paxil) at recommended 

dosages of 20-50 mg QD (usual starting 

dosage: 25 mg daily). Other SSRIs include 

fluoxetine (Prozac), citalopram (Celexa), and 

escitalopram (Lexapro).

• The serotonin norepinephrine reuptake 

inhibitor (SNRI) antidepressants such 

as venlafaxine (Effexor), desvenlafaxine 

(Pristiq), and duloxetine (Cymbalta), as 

well as the antidepressant mirtazapine 

(Remeron), are second-line treatments 

if SSRIs prove ineffective or are not well 

tolerated.

• Tricyclic antidepressants (TCAs) may be 

employed if the individual has had a good 

response to them in the past and they do not 

cause severe side effects, or if the individual 
594 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

has failed to respond to or cannot tolerate 

SSRIs or SNRIs. TCAs in low dosages also 

may be used for sleep; see chapter Insomnia.

Anxiolytics

Antianxiety medications have not been 

shown to be effective treatments for PTSD 

when used alone but may be effective, as 

adjunctive therapy, in reducing anxiety 

symptoms. Benzodiazepines can reduce 

anxiety rapidly, often within hours, but 

may have counterbalancing side effects 

early in the course of their use that include 

sedation and incoordination. In addition, 

physical dependency may develop in patients 

who use them for more than a few weeks. 

Benzodiazepines are not recommended for 

people who have a history of alcohol abuse or 

dependence. Benzodiazepines ideally would 

be used only briefly and intermittently to quell 

acute and severe anxiety symptoms. Levels of 

many benzodiazepines may be increased by 

certain protease inhibitors and nonnucleoside 

reverse transcriptase inhibitors; see “Potential 

ARV Interactions,” below.

Buspirone (BuSpar) is a nonaddictive 

anxiolytic. It usually must be taken for at least 

1-2 weeks before anxiety symptoms begin 

to lessen. Starting dosage is 5 mg PO TID. If 

symptoms persist, the dosage can be increased 

by 5 mg per dose each week to a maximum of 

10-15 mg PO TID (for a total daily dosage of 

30-45 mg). Low-dose benzodiazepines may 

be used during the initial weeks of buspirone 

therapy, until the effects of buspirone are 

felt. The major potential adverse effects of 

buspirone are dizziness and lightheadedness. 

Anticonvulsants

Mood stabilizers such as valproate (Depakote), 

carbamazepine (Tegretol), lamotrigine 

(Lamictal), and topiramate (Topamax) may be 

added for patients with a partial response to an 

antidepressant. They may be helpful for those 

who have considerable irritability, anger, or 

hostility, as well as those with reexperiencing 

symptoms (e.g., flashbacks, intrusive 

memories). Gabapentin (Neurontin) 200-400 

mg BID or QID sometimes helps to diminish 

anxiety. Treatment with these agents usually 

should be done by or in consultation with a 

psychiatrist.

Antipsychotics

Older and newer antipsychotics (aripiprazole, 

olanzapine, paliperidone, quetiapine, 

risperidone, and ziprasidone) may be suitable 

for individuals with psychotic features of 

PTSD or those who have a comorbid psychotic 

illness. These medications also may be helpful 

for some individuals who have not benefited 

from medications indicated for PTSD. 

Adverse effects may include dyslipidemia, 

hyperglycemia, weight gain, and sudden 

cardiac death. Consultation with a psychiatrist 

is recommended.

Other medications

A variety of other medications have been 

used as adjunctive treatment when insomnia 

and nightmares persist despite adequate 

use of psychotropic medications. Research 

is still quite limited, but suggests that the 

antihypertensive drugs clonidine (Catapres) 

and prazosin (Minipress) may help with the 

insomnia and nightmares of PTSD.

Patients with advanced HIV disease and 

geriatric patients may be particularly 

vulnerable to the CNS effects of certain 

medications. Medications that affect the CNS 

should be started at low dosage and titrated 

slowly. Similar precautions should apply to 

patients with liver dysfunction.
Posttraumatic Stress Disorder | 595

Section 8: Neuropsychiatric 

Disorders

Potential ARV Interactions

Interactions may occur between certain 

antiretrovirals and agents used to treat PTSD. 

Some combinations may be contraindicated 

and others may require dosage adjustment. 

Refer to medication interaction resources 

or consult with an HIV expert or pharmacist 

before prescribing.

Antidepressants

• Levels of many SSRIs and SNRIs may be 

increased or decreased by certain protease 

inhibitors (PIs) or NNRTIs and by the 

pharmacokinetic booster cobicistat. These 

interactions generally are not clinically 

significant, but most agents should 

be started at low dosages and titrated 

cautiously while monitoring efficacy 

and adverse effects. See chapter Major 

Depression and Other Depressive Disorders.

• Tricyclic levels can be increased 

substantially by ritonavir and cobicistat. If 

they are used for patients taking ritonavir, 

ritonavir-boosted PIs or cobicistat, they 

should be started at low dosage, patients 

should be followed closely, and tricyclic 

levels should be monitored.

Anxiolytics

• PIs, cobicistat, and nonnucleoside reverse 

transcriptase inhibitors may raise blood 

concentrations of many benzodiazepines. 

If benzodiazepines are used, they should 

be started at low dosage, and other 

CNS depressants should be avoided. 

Consult with a clinical pharmacist before 

prescribing. See chapters Anxiety Disorders

and Insomnia for additional information. 

• Midazolam (Versed) and triazolam 

(Halcion) are contraindicated for use 

with all PIs or cobicistat and with 

delavirdine and efavirenz.

• Buspirone levels may be increased by 

ritonavir-boosted PIs or cobicistat and may 

be decreased by CYP inducers. Monitor 

patients for adverse effects and for efficacy.

Anticonvulsants

• Most anticonvulsants may have significant 

interactions with certain ARVs and 

other medications; check for drug-drug 

interactions before prescribing.

Antipsychotics

• Potential interactions vary according to the 

specific medications used; consult with a 

pharmacist or psychiatrist.

Patient Education

• Explain to patients that illness (physical or 

emotional) is not a character flaw or a moral 

or spiritual weakness.

• Inform patients that both behavioral 

interventions and medication can be very 

helpful in treating PTSD. If one strategy is 

not successful, many others are available.

• Advise patients that psychiatric medications 

are often given for a long time, usually for a 

year or longer.

• Advise patients that, when they start taking 

an antidepressant medication for PTSD, 

they should expect that it will take 2-4 

weeks for them to notice any improvement. 

Their symptoms should continue to 

decrease over the following weeks. If 

they do not have much improvement in 

symptoms, providers may choose to adjust 

the dosage of the medication or to change 

medications. Patients must continue taking 

their medications so that symptoms do not 

return.

• Advise patients that they may develop 

problems with sexual function because of 

psychiatric medications. They should report 

any problems to their prescribers. 
596 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

References

• American Psychiatric Association. 

Diagnostic and Statistical Manual of Mental 

Disorders (5th ed.). Arlington, VA: American 

Psychiatric Publishing; 2013.

• Cohen M, Hoffman RG, Cromwell C, et al. 

The prevalence of distress in persons with 

human immunodeficiency virus infection. 

Psychosomatics. 2002 Jan-Feb;43(1):10-5.

• Essock SM, Dowden S, Constantine NT, et 

al.; Five-Site Health and Risk Study Research 

Committee. Risk factors for HIV, hepatitis B, 

hepatitis C among persons with severe mental 

illness. Psychiatr Serv. 2003 Jun;54(6):836-41.

• McNicholl I. HIV InSite Database 

of Antiretroviral Drug Interactions. 

San Francisco: UCSF Center for HIV 

Information. Available at hivinsite.ucsf.edu/

insite?page=ar-00-0. Accessed December 1, 

2013.

• New York State Department of Health AIDS 

Institute. Mental Health Care for People 

with HIV Infection: Clinical Guidelines for 

the Primary Care Practitioner. Available at 

www.hivguidelines.org/clinical-guidelines. 

Accessed December 1, 2013.

• New York State Department of Health AIDS 

Institute. Trauma and Post-Traumatic Stress 

Disorder in Patients with HIV/AIDS; 2007. 

Available at www.hivguidelines.org/clinicalguidelines. Accessed December 1, 2013.

• van Liempt S, Vermetten E, Geuze E, 

et al. Pharmacotherapeutic treatment of 

nightmares and insomnia in posttraumatic 

stress disorder: an overview of the literature.

Ann N Y Acad Sci. 2006 Jul;1071:502-7.
Insomnia | 597

Section 8: Neuropsychiatric 

Disorders

Insomnia

Background

Insomnia is a common accompaniment to HIV infection, especially as the disease progresses 

and complications worsen. Once present, insomnia tends to be chronic, unlike the transient 

disturbances of sleep that are a normal part of life. Most insomnia related to HIV can be 

characterized by the amount, quality, or timing of sleep. Insomnia may cause progressive fatigue 

and diminished functioning. 

S: Subjective

The patient may complain of the following:

• Difficulty initiating sleep

• Early-morning awakening

• Mind-racing thoughts (e.g., “I can’t turn off 

my thoughts.”)

• Difficulty maintaining sleep

• Nonrestorative sleep (i.e., although the 

amount of sleep is adequate, the patient does 

not feel rested upon awakening)

• Nighttime restlessness

Ask about the symptoms above, and about the 

following: 

• Determine the patient’s bedtime sleep habits; 

request additional history from a sleep 

partner, if possible

• Try to quantify how long the patient actually 

sleeps each night

Ask about the following:

• Alcohol and recreational drug use

• Caffeine intake (quantity, times of day)

• Nightmares, life stressors

• Concurrent medications that may cause 

insomnia as an adverse effect (e.g., efavirenz, 

corticosteroids, pseudoephedrine, and 

decongestants)

• Medications (prescription or over-thecounter) or supplements used to promote 

sleep

• Shift work, exercise, nighttime reflux or 

heartburn, snoring, and periods of apnea 

(not breathing)

• Collar size (size >16 more often associated 

with sleep apnea)

Screen for depression and anxiety.

O: Objective

Perform a general symptom-directed physical 

examination, including evaluation of body 

habitus, neurologic status, and mental status.

A: Assessment

A partial differential diagnosis includes the 

following:

• Alcohol intake (interferes with sleep 2-4 

hours after ingestion, may cause nocturnal 

awakening)

• Caffeine intake

• Recreational drug use

• Anxiety disorder

• Major depression (insomnia is a primary 

symptom)

• Transient insomnia related to acute stress

• Cognitive impairment

• Disturbance of the sleep/wake cycle because 

of excessive time in bed or inadequate sleep 

hygiene (e.g., noise in the bedroom)

• Medication adverse effects (e.g., from 

steroids, efavirenz)
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Section 8: Neuropsychiatric 

Disorders

• Other identifiable sleep disorders (e.g., obstructive sleep apnea, periodic leg movements)

• Pain

• Underlying systemic medical conditions that 

can interfere with sleep, such as delirium, 

lung disease, congestive heart failure, renal 

failure, diarrhea, and incontinence

P: Plan

Evaluation

The diagnosis usually is based on history. A 

sleep evaluation (including polysomnography) 

may be indicated when a physiologic cause 

(e.g., obstructive sleep apnea) is suspected or 

insomnia is severe.

Treatment

Treat underlying illnesses that may be causing 

or contributing to insomnia.

• Manage correctible medical conditions that 

may interfere with sleep.

• Treat depression and anxiety disorders. 

These are very common contributors to 

insomnia among people with HIV infection. 

See chapters Major Depression and Other 

Depressive Disorders, Anxiety Disorders, and 

Panic Disorder.

• If the patient is suspected of having sleep 

apnea, periodic limb movements in sleep, or 

restless limb syndrome, refer to a specialist 

in sleep medicine for evaluation.

The following options are available for 

treatment: 

Behavioral strategies

• To correct deleterious sleep habits, patients 

should do the following: 

• Establish a bedtime routine.

• Avoid stimuli before bedtime.

• Avoid vigorous exercise within 3-4 hours 

of bedtime.

• Reduce or eliminate daytime napping.

• Avoid eating, reading, watching TV, or 

working in bed.

• Wake up at the same time each day 

regardless of total hours of sleep.

• Have a dark, cool, quiet, comfortable 

environment conducive to sleep.

• Place the bedroom clock out of sight.

• If unable to fall sleep after 15-20 minutes, 

the patient should get up, go into another 

room for nonstimulating activity in dim 

light (such as reading), and not go back to 

bed until sleepy.

• The patient should discontinue use of 

caffeine, central nervous system stimulants, 

alcohol, and tobacco, with tapering if 

necessary, to avoid withdrawal symptoms.

• Teach or refer the patient for relaxation 

techniques.
Insomnia | 599

Section 8: Neuropsychiatric 

Disorders

Pharmacotherapy

Choosing a pharmacologic agent for 

insomnia

A number of medications may be effective in 

treating insomnia. In selecting a medication 

for an individual patient, consider the 

following about a specific medication:

• Is it likely to improve symptoms that may be 

contributing to the patient’s insomnia (e.g., 

depression, anxiety, psychosis, neuropathic 

pain)?

• Does it pose risks to the patient based 

on comorbid medical conditions (e.g., 

benzodiazepines should not be given 

to patients with sleep apnea, tricyclic 

antidepressants should not be given to 

patients with cardiac conduction problems)?

• Does it have adverse interactions with other 

medications (e.g., zolpidem [Ambien], 

zaleplon [Sonata], and eszopiclone [Lunesta] 

should be used with caution in patients 

taking protease inhibitors [PIs])?

• Is it the optimal agent for a patient with a 

current or past history of alcohol or sedative 

abuse/dependence?

• Is it affordable (e.g., formulary or co-pay 

issues)?

Treatment considerations

There are limited data to guide the frequency 

(nightly, intermittently, as needed) and 

duration (brief, intermediate, long-term) of 

hypnotic medications. Hypnotics should be 

prescribed at the lowest effective dosage for 

the shortest possible period. The greater the 

degree of physical illness, the more likely the 

patient will need a low dosage of a hypnotic 

agent. When long-term treatment is necessary, 

benzodiazepines pose the greatest risk of 

tolerance, abuse, and dependence.

Possible adverse effects of all hypnotics include 

excess sedation, daytime grogginess, impaired 

judgment, behavior changes, and disruption 

of the sleep architecture. In addition, persons 

taking hypnotics may engage in overnight 

activities or behaviors without being fully 

awake, and may not remember these activities 

afterwards (e.g., walking, driving, eating); they 

also may have impairment in cognition and 

motor skills the next morning. 

Interactions may occur between certain 

antiretrovirals (ARVs) and agents used to 

treat insomnia. Some combinations may be 

contraindicated and others may require dosage 

adjustment. Refer to medication interaction 

resources or consult with an HIV expert, 

psychiatrist, or pharmacist before prescribing.
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Section 8: Neuropsychiatric 

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Agents with FDA-Approved Indications for Insomnia

Antihistamines 

• The antihistamines diphenhydramine, doxylamine, and hydroxyzine, given at doses of 25-50 mg QHS, 

can be used for sleep. Adverse anticholinergic effects often interfere with long-term use.

Antidepressants 

• Trazodone, 25-50 mg; maximum dose: 200 mg QHS. 

• Trazodone, a triazolopyridine derivative antidepressant and sedative, is the only antidepressant 

with a U.S. Food and Drug Administration (FDA) indication for insomnia, and it is widely 

used for this purpose. However, levels may be increased by ritonavir-boosted PIs and by the 

pharmacokinetic booster cobicistat. Do not use with saquinavir/ritonavir; use lower dosages for 

patients receiving other PIs or cobicistat. Trazodone may (rarely) cause priapism. Trazodone can be 

used for an indefinite period of time as it is not associated with tolerance or addiction.

Non-benzodiazepine hypnotics (agonists of the benzodiazepine receptor)

• Zolpidem (Ambien) 5 mg for women, 5-10 mg for men, 5 mg for geriatric patients; zolpidem-CR 

(Ambien-CR) 6.25 mg for women, 6.25-12.5 mg for men; zaleplon (Sonata) 5-10 mg; and eszopiclone 

(Lunesta) 2-3 mg QHS. 

• These newer hypnotic agents are benzodiazepine receptor agonists with shorter half-lives than 

benzodiazepines and may be less likely to result in day-after drowsiness. They may have decreased 

addiction potential compared with benzodiazepine hypnotics. Higher doses and extendedrelease formulations appear to increase the risk of next-morning impairment. Patients should be 

advised to use these hypnotics on an as-needed basis rather than nightly; it is easier for patients to 

discontinue a drug that they are not taking every day. The inhibition of CYP 3A4 enzyme activity 

by PIs or cobicistat may increase levels of these benzodiazepine receptor agonists, particularly 

eszopiclone; this may cause excessive sedation or respiratory depression.

Melatonin agonists

• Ramelteon (Rozerem), 8 mg QHS. 

• The first of a new class of melatonin agonists to receive FDA approval, ramelteon may have some 

advantages over sedative/hypnotic agents, such as reduced dependence and overuse. However, 

it may have severe adverse reactions, including hypersensitivity reactions such as anaphylaxis and 

angioedema. Long-term interactions with ARV agents are unknown.

Benzodiazepine hypnotics

• A number of benzodiazepines have FDA-approved indications for the short-term treatment of 

insomnia. They carry a risk of addiction and residual drowsiness the following day.

• Metabolized by glucuronidation; predicted to have few drug interactions with ARVs: 

• Temazepam (Restoril) 7.5-30 mg; intermediate half-life

• Lorazepam (Ativan), 1-2 mg; intermediate half-life.

• Metabolized by CYP 34A; PIs and cobicistat may prolong their duration, resulting in excessive daytime 

somnolence. These may be most beneficial for use with patients whose insomnia is associated with 

anxiety: 

• Flurazepam (Dalmane) 15-30 mg

• Quazepam (Doral) 7.5-15 mg

• Estazolam (ProSom) 1-2 mg

• Clonazepam (Klonopin) at a dose of 0.5-2 mg has been approved for treatment of periodic leg 

movements. PIs and cobicistat may prolong its duration and increase risk of adverse effects; start at 

low dosage and titrate slowly.

• Triazolam (Halcion), another approved agent for insomnia, is contraindicated for use with all PIs, some 

nonnucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine, efavirenz), and cobicistat because 

of potentially life-threatening reactions (e.g., respiratory depression)
Insomnia | 601

Section 8: Neuropsychiatric 

Disorders

Agents Used for Sedating Side Effects (no FDA indication for insomnia)

Antidepressants 

• Tricyclic antidepressants at doses of 10-50 mg can be beneficial for sleep, but they have longer halflives than short-acting hypnotic agents, and potential adverse effects include cardiac dysrhythmias 

and pulmonary complications. Tricyclics generally should be avoided for geriatric patients. Levels of 

tricyclics are elevated by ritonavir and by cobicistat, and lower dosages may be needed for patients 

taking ritonavir or ritonavir-boosted PIs or cobicistat. Routine testing of tricyclic blood levels should 

be performed on patients receiving higher doses (e.g., 100 mg per day; 50 mg for nortriptyline), those 

concurrently on ritonavir, and those with risk factors for cardiac conduction abnormalities. A routine 

electrocardiogram should be performed before prescribing tricyclics, and this class of drugs should 

not be prescribed to patients with cardiac conduction problems. However, tricyclic antidepressants 

also have characteristics that may benefit some patients, including treatment of chronic pain, 

promotion of weight gain, and reduction of diarrhea. Amitriptyline (Elavil) and doxepin (Sinequan) are 

the most sedating of the tricyclic antidepressants and therefore are the drugs in this class most often 

used for sleep.

• The tetracyclic antidepressant mirtazapine (Remeron) is sedating and has been effective in treating 

insomnia at low dosages (7.5-15 mg). Higher dosages may result in increased activation owing to 

increased norepinephrine (NE) receptor antagonism.

• The selective serotonin reuptake inhibitor (SSRI) antidepressants are not sufficiently sedating to 

be used as sleeping agents, but when insomnia is caused by depression, sleep will improve as the 

depression lifts.

Anticonvulsants

• Gabapentin (Neurontin) can be useful for patients with insomnia and has been demonstrated to 

be particularly beneficial for patients with alcohol and other substance-use disorders; it is widely 

prescribed for neuropathic pain.

Patient Education

• Instruct patients in behavioral interventions 

that can help to reduce insomnia.

• Additional interventions are available when 

behavioral interventions are not sufficient.

• Patients should be warned strongly about 

risks associated with medications used 

to treat insomnia, including the risk of 

sleepwalking and other overnight activities 

and next-morning impairment in cognition 

and coordination.

• Patients should report new or worsening 

symptoms to their health care provider. 

These may be not only signs of worsening 

insomnia, but also of symptoms of anxiety, 

depression, medications, or changes in 

medical conditions 

References

• FDA Drug Safety Communication: Risk 

of next-morning impairment after use 

of insomnia drugs; FDA requires lower 

recommended doses for certain drugs 

containing zolpidem (Ambien, Ambien 

CR, Edluar, and Zolpimist). January 10. 

2013. Available at www.fda.gov/Drugs/

DrugSafety/ucm334033.htm.

• Ford DE, Kamerow DB. Epidemiologic 

study of sleep disturbances and psychiatric 

disorders. An opportunity for prevention? 

JAMA. 1989 Sep 15;262(11):1479-84.

• Insomnia and HIV: A Biopsychosocial 

Approach. In: Comprehensive Textbook of 

AIDS Psychiatry; Cohen MA, Gorman JM, 

eds. New York: Oxford University Press; 

2008;163-72.
602 | Guide for HIV/AIDS Clinical Care

Section 8: Neuropsychiatric 

Disorders

• Kuppermann M, Lubeck DP, Mazonson PD, 

et al. Sleep problems and their correlates in a 

working population. J Gen Intern Med. 1995 

Jan;10(1):25-32.

• McNicholl I. HIV InSite Database 

of Antiretroviral Drug Interactions. 

San Francisco: UCSF Center for HIV 

Information. Available at hivinsite.

ucsf.edu/insite?page=ar-00-02. 

Accessed December 1, 2013.

• Ohayon MM, Roth T. Place of chronic 

insomnia in the course of depressive and 

anxiety disorders. J Psychiatr Res. 2003 JanFeb;37(1):9-15.

• Reid S, Dwyer J. Insomnia and HIV 

infection: a systematic review of prevalence, 

correlates, and management. Psychosom 

Med. 2005 Mar-Apr;67(2):260-9.

• Schutte-Rodin S, Broch L, Buysse D, et al. 

Clinical guideline for the evaluation and 

management of chronic insomnia in adults. J 

Clin Sleep Med. 2008 Oct 15;4(5):487-504.

• Sleep and Sleep-Wake Disorders. In: 

Psychiatry, 3rd Edition. Tasman A, Kay J, 

Lieberman JA, et al., eds. London: J. Wiley & 

Sons, 2008:1626-57.

• Sleep and Wakefulness Disorders. In: The 

Merck Manual of Diagnosis and Therapy, 

18th ed.; Beers MH, Porter RS, Jones TV, 

eds. Whitehouse Station, NJ: Merck & Co.; 

2006:1834-40.

• Wainberg ML, Faragon J, Cournos F, 

et al. Psychiatric Medications and HIV 

Antiretrovirals: A Guide to Interactions 

for Clinicians, 2nd ed. Laminated booklet 

produced by the New York/New Jersey AIDS 

Education and Training Center, Health 

Resources and Services Administration; 2008.
Oral Health | 603

Section 9: Oral Health

Oral Health

Background

Examination of the oral cavity should be 

included in both the initial and interim 

physical examination of all HIV-infected 

patients. Patients with lesions suspected 

to be oral manifestations of HIV disease 

should be referred to an oral health expert 

with experience in treating oral lesions 

associated with HIV/AIDS. Other oral 

lesions may be a sign of a systemic disease, 

a side effect of medications, or a result of 

poor oral hygiene.

The following is an overview of conditions 

commonly seen in patients with HIV 

infection. See chapters Oral Hairy 

Leukoplakia, Oral Warts, Oral Ulceration, 

and Necrotizing Ulcerative Periodontitis 

and Gingivitis for more information about 

those conditions. 

Xerostomia (Dry Mouth)

HRSA HAB Performance Measures

Percentage of HIV-infected oral health patients who 

had a dental and medical health history (initial or 

updated) at least once in the measurement year

Percentage of HIV-infected oral health patients who 

had a dental treatment plan developed and/or 

updated at least once in the measurement year

Percentage of HIV-infected oral health patients who 

received oral health education at least once in the 

measurement year

Percentage of HIV-infected oral health patients who 

had a periodontal screen or examination at least 

once in the measurement year

Percentage of HIV-infected oral health patients with 

a Phase 1 treatment plan that is completed within 

12 months

S: Subjective

The chief complaint may be a dry, “sticky,” or 

possibly a burning sensation in the mouth, or 

an inability to “taste” food. The patient may 

present with difficulty swallowing.

O: Objective

The oral mucosal tissues appear dry and 

sometimes “shiny” in appearance. The lips 

may be dry and cracked, and the tongue is dry. 

Dental decay may be present on the cervical 

portion of the teeth (near the gingival margin 

or “gumline”). Oral candidiasis (thrush) may 

or may not be present.

A: Assessment

The differential diagnosis for the cause 

of xerostomia includes but is not limited 

to medication side effects (e.g., from 

anticholinergics), systemic diseases (e.g., 

Sjögren syndrome), adverse effects of radiation 

therapy, and salivary gland diseases.

P: Plan

Identify the cause of xerostomia and modify, if 

possible. Treat with artificial saliva products or 

oral lubricant products (e.g., Salivart, Biotene 

Oral Balance Dry Mouth Relief Moisturizing 

Gel, TheraSpray). Discourage sucking on hard 

candies with sugar that can promote caries 

(dental decay). Encourage patients to use 

sugar-free gums and candies to help promote 

salivary function. Promote good oral hygiene 

with flossing and brushing with a fluoride 
604 | Guide for HIV/AIDS Clinical Care

Section 9: Oral Health

toothpaste, and encourage regular (every 

3-4 months) dental recall visits. Severe cases 

of xerostomia may be treated by prescribing 

cholinergic stimulants such as pilocarpine 

(Salagen).

Burning Mouth Syndrome; 

Atrophic Glossitis

S: Subjective

The patient may complain of a constant 

burning sensation in the mouth or a numbness 

or tingling feeling of the tongue. Eating 

certain foods or spices may trigger the burning 

sensation. The patient also may complain of 

dry mouth or a metallic taste in the mouth.

O: Objective

The tongue and oral mucosal tissues may be 

normal in appearance or there may be a slight 

redness on the tip and lateral margins of the 

tongue. In other cases, the tongue may appear 

“bald,” owing to the loss of papillae on the 

dorsal surface, and it may be “beef red” in color.

A: Assessment

Possible systemic etiologies include nutritional 

and vitamin deficiencies (atrophic glossitis), 

chronic alcoholism, medication adverse 

effects, diabetes mellitus, and gastric 

reflux. Local etiologies include denture 

irritation, oral habits such as tongue or 

cheek biting, and excessive use of certain 

toothpastes or mouthwashes. Psychological 

factors and nerve damage also may cause 

burning mouth. Erythematous candidiasis 

also can present as a burning sensation.

P: Plan

Identify the cause of the burning sensation, if 

possible, by review of the medical history and 

by performing diagnostic tests as indicated 

(e.g., complete blood count, biopsy, or oral 

cytological smears). Once the underlying 

cause is identified, treatment may be as simple 

as changing a dentifrice or eliminating the 

identified irritant, or the condition may 

require systemic treatment.

Recurrent Aphthous 

Ulceration (RAU)

S: Subjective

The patient complains of a painful ulcer or 

ulcers in the mouth that recur.

O: Objective

The typical appearance of an aphthous ulcer 

is a “red raised border with a depressed, 

necrotic (white-to-yellow pseudomembrane) 

center.” Aphthous ulcers tend to present on 

nonkeratinized or nonfixed tissues such as the 

buccal mucosa or posterior oropharynx and 

may be small or large, solitary or in clusters, 

and can resemble intraoral herpetic lesions 

(although herpetic lesions tend to present 

on keratinized tissues such as the roof of the 

mouth and gingival tissues).

A: Assessment

The differential diagnosis includes traumatic 

ulcers and herpes simplex virus ulcers.

P: Plan

The diagnosis usually is based on appearance. 

For further information, see chapter Oral 

Ulceration.
Oral Health | 605

Section 9: Oral Health

Recurrent Herpes Simplex

S: Subjective

The patient complains of a locally painful ulcer 

or ulcers on the lips or intraoral areas.

O: Objective

Herpes lesions are located on the lips, gingival 

tissues, or the hard palate. They may appear as 

small vesicular lesions that rupture, forming 

small ulcers. They may rupture and coalesce 

into larger lesions.

A: Assessment

The differential diagnosis includes aphthous 

ulcer and traumatic ulcer.

P: Plan

The diagnosis usually is based on appearance. 

For further information, see chapters 

Oral Ulceration and Herpes Simplex, 

Mucocutaneous.

Periodontal Disease

The medical evaluation of patients with 

HIV infection should include assessment 

of periodontal health. Whereas the same 

type of plaque-induced periodontal diseases 

can be seen in both immunocompetent and 

immunosuppressed individuals, periodontal 

disease in HIV-infected patients can be a 

marker of HIV disease progression. In the 

HIV-infected patient with periodontal disease, 

it is important to distinguish whether the 

periodontitis represents an acute/aggressive 

or chronic presentation unique to those with 

HIV disease. In addition, it is important 

to determine whether the patient has an 

inflammatory oral disease process that may 

further compromise his or her health.

Various illnesses and systemic factors (e.g., 

diabetes mellitus, hormonal abnormalities, 

medications, and malnutrition) can complicate 

the clinical presentation of periodontal disease. 

If significant periodontal disease is suspected, 

refer to an experienced dentist for diagnosis 

and treatment. Gingivitis (gum disease), a 

milder form of periodontal disease, usually is 

reversible with proper professional and home 

oral health care. For further information 

on necrotizing ulcerative periodontitis or 

necrotizing ulcerative gingivitis, see chapter 

Necrotizing Ulcerative Periodontitis and 

Gingivitis.

S: Subjective

The patient may complain of red, swollen, or 

painful gums, which may bleed spontaneously 

or with brushing; chronic bad breath or bad 

taste in the mouth; loose teeth or teeth that are 

separating; or a “bite” that feels abnormal.

O: Objective

Examine the gingival tissues. Periodontitis 

appears as localized or generalized gingival 

inflammation. The gingivae appear bright 

red or reddish-purple, ulcerated, or necrotic. 

Spontaneous gingival hemorrhage and 

purulent discharge may be evident around the 

teeth, especially if pressure is applied to the 

gingivae. Gingiva may be pulling away from 

the teeth. Fetor oris may be present.

A: Assessment

The differential diagnosis includes gingivitis, 

periodontitis, trench mouth, and oral 

abscesses. Diagnosis usually is based on 

appearance. Patients with severe or recalcitrant 

disease should be referred to an oral health 

care provider for definitive diagnosis and 

treatment.
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Section 9: Oral Health

P: Plan

Treatment may include:

• Warm saline rinses

• Daily brushing and flossing

• Antimicrobial mouth rinse (e.g., Listerine, 

chlorhexidine)

• Antibiotic therapy

For further information, see chapter 

Necrotizing Ulcerative Periodontitis and 

Gingivitis.

Dental Caries Caused 

by Methamphetamine 

and Cocaine Use

Dental decay seen in individuals who smoke 

methamphetamine or crack cocaine, or use 

cocaine orally, often is referred to as “meth 

mouth.” 

S: Subjective

The chief complaint may be pain in one or 

more teeth. However, if the condition is 

chronic, the patient may not complain of pain.

O: Objective

In meth mouth, the enamel on all teeth or 

multiple teeth is grayish-brown to black in 

color (owing to decay), and appears “soft” (this 

has been described as a “texture less like that 

of hard enamel and more like that of a piece of 

ripened fruit”). Oral mucosal tissues appear 

dry as a result of decreased salivary flow. The 

gingiva appears red or inflamed, and there 

may be spontaneous bleeding of the gingiva 

around the teeth.

Another pattern of dental decay can be seen 

in cocaine users who rub the drug along the 

gingiva in order to test its strength or purity. 

This can lead to localized dryness of the 

gingival tissues. Consequently, plaque sticks 

to the cervical portion of the teeth in the area 

where the cocaine is rubbed, resulting in dental 

caries along the cervical portion of the teeth.

A: Assessment

The differential diagnosis includes other causes 

of caries.

P: Plan

Refer to a dentist for appropriate care, which 

may involve restorative, endodontic therapy, 

periodontal care, and oral surgery. In severe 

cases, extraction of the involved teeth and 

replacement with a partial or complete denture 

may be necessary. Encourage proper oral 

hygiene; evaluate sucrose intake.

Oral Cancer

S: Subjective

Oral malignancies may be symptomatic or 

asymptomatic. Data suggest two distinct 

pathways for the development of oropharyngeal 

cancer: one driven predominantly by the 

carcinogenic effects of tobacco or alcohol 

(or both), the other by genomic instability 

induced by human papillomavirus.

The patient may complain of a mouth sore that 

fails to heal or that bleeds easily, or a persistent 

white or red (or mixed) patch. The patient may 

note a lump, thickening, or soreness in the 

mouth, throat, or tongue; difficulty chewing 

or swallowing food; difficulty moving the jaw 

or tongue; chronic hoarseness; numbness of 

the tongue or other areas of the mouth; or 

a swelling of the jaw, causing dentures to fit 

poorly or become uncomfortable.
Oral Health | 607

Section 9: Oral Health

O: Objective

Perform a thorough evaluation of the 

oropharynx, as well as lymph nodes in the 

head and neck. Suspicious lesions may occur 

on the lips, tongue, floor of the mouth, palate, 

gingiva, or oral mucosa, and may appear as an 

ulcer or a soft-tissue mass or masses that can 

be pink, reddish, purple, white, or mixed red 

and white. The lesion typically is indurated and 

may be painful. It may enlarge rapidly between 

examinations.

A: Assessment

The differential diagnosis includes oral 

squamous cell carcinoma, lymphoma, Kaposi 

sarcoma, traumatic ulcer, hyperplasia, and 

hyperkeratosis.

P: Plan

An ulcerated lesion or symptom described 

above that is present for 2 weeks or longer 

should be evaluated promptly by a dentist 

or physician. If cancer is suspected, a biopsy 

should be obtained to make a definitive 

diagnosis. Treatment will be based on the 

specific diagnosis.

Bruxism

S: Subjective

The patient may complain of chronic facial or 

jaw pain, sensitive teeth, earache, or waking 

up with a headache or facial pain. Often, the 

patient is not aware that he or she is clenching 

or grinding the teeth. Bruxism very often is a 

result of increased stress or anxiety, causing 

the patient consciously or unconsciously to 

clench or grind the teeth. However, some 

people may be “nighttime bruxers” and grind 

their teeth while sleeping, often loudly enough 

to wake others sleeping in the same room.

O: Objective

Perform a focused evaluation of the 

oropharynx, jaw, and facial muscles. The teeth 

may appear shortened, flattened, or worn down 

as a result of chronic grinding or clenching of 

the teeth. There may be hyperkeratotic lesions 

on the inside of cheeks as a result of chronic 

grinding or biting. There may be tenderness 

with palpation of facial muscles.

A: Assessment

The differential diagnosis includes other causes 

of facial or jaw pain, such as caries, dental 

abscesses, and trauma.

P: Plan

Refer the patient to a dentist for treatment. 

Treatment may include wearing a bite guard 

or psychological or behavioral management 

therapy.

Oral Piercing

S/O/A: Subjective/Objective/

Assessment

Jewelry worn in piercings in the tongue, lips, or 

cheeks can chip or fracture the teeth. Chronic 

rubbing of jewelry against the gingiva can cause 

the gingiva to recede, leading to periodontal 

problems. (These complications occur apart 

from procedure- or technique-associated 

complications associated with body piercing, 

such as inflammation and infection, bleeding, 

and transmission of bloodborne pathogens.)

P: Plan

Refer the patient to a dentist for treatment. 

Recommend plastic tongue jewelry as opposed 

to metal to prevent fracture of teeth. Removal 

of the jewelry may be warranted.

Section 9: Oral Health
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Section 9: Oral Health

Maxillary Tori; 

Mandibular Tori

S: Subjective

The patient may complain of a “lump” in the 

roof or floor of the mouth, or behind the lower 

front teeth.

O: Objective

Exostosis of normal bone (covered by oral 

mucosal tissue) can appear as a nodular or 

lobulated protuberance centrally located on 

the hard palate (maxillary tori) or unilaterally 

or bilaterally located behind the mandibular 

incisors (mandibular tori). This develops 

slowly and the patient may become aware 

of exophytic growth only if the area is 

inadvertently traumatized.

A: Assessment

Differential diagnosis includes other benign or 

malignant lesions, including oral cancer.

P: Plan

No treatment is indicated unless the exostosis 

interferes with speech or swallowing, or 

removal is needed for fabrication of dentures 

or a partial denture. Tori are a variation of 

normal anatomy.

References

• Cherry-Peppers G, Daniels CO, Meeks V, et 

al. Oral manifestations in the era of HAART. 

J Natl Med Assoc. 2003 Feb;95(2 Suppl 

2):21S-32S. 

• DePaola LG. The Importance of Oral Health in 

HIV Disease. NUMEDIX. 2003; 4(2):68-69. 

• Ibsen O, Phelan J. Oral Pathology for the 

Dental Hygienist; 4th ed. Philadelphia: W.B. 

Saunders; 2004. 

• Mayo Foundation for Medical Education 

and Research. Canker Sore (March 24, 

2012); Cold Sore (May 23, 2012); Bad Breath

(December 18, 2012); Bruxism/Teeth 

Grinding (May 19, 2011); Burning Mouth 

Syndrome (February 7, 2013); and Trench 

Mouth (April 9, 2013). Available at www.

mayoclinic.com. Accessed December 1, 2013.

• National Institutes of Health, National 

Institute of Dental and Craniofacial 

Research. Dry Mouth. Bethesda, MD: 

National Oral Health Information 

Clearinghouse; June 1999. NIH Publication 

#99-3174. Available at www.nidcr.nih.gov/

OralHealth/Topics/DryMouth/DryMouth.

htm. Accessed December 1, 2013.

• National Institutes of Health, National 

Institute of Dental and Craniofacial 

Research. TMD/TMJ: Temporomandibular 

Disorders. Bethesda, MD: National Oral 

Health Information Clearinghouse; May 

2005. NIH Publication #94-3487. Available 

at www.nidcr.nih.gov/OralHealth/Topics/

TMJ/TMJDisorders.htm. Accessed 

December 1, 2013.

• Newland JR, Meiller TF, Wynn R, et al. Oral 

Soft Tissue Diseases: A Reference Manual 

for Diagnosis and Management; 2nd ed.

Hudson, OH: Lexi-Comp; 2002. 

• Nittayananta W, ed. Oral Manifestations of 

HIV Infection: Current Update with Asian 

Focus. Bangkok; 2004.
Oral Ulceration | 609

Section 9: Oral Health

Oral Ulceration

Background 

Oral ulcerations appear as necrotic or eroded areas on the oral mucosa, including the tongue. 

Most such lesions are idiopathic (aphthous) or of viral etiology (e.g., herpes simplex virus [HSV]; 

rarely herpes zoster [VZV]). Oral ulcerations may be caused by fungal, parasitic, or bacteriologic 

pathogens; malignancy; or other systemic processes. This chapter will focus on herpetic and 

aphthous ulcers.

Herpetic ulcerations tend to appear on keratinized tissues such as the hard palate or gingiva. 

Recurrent aphthous ulcers tend to manifest on nonkeratinized tissues such as buccal mucosa, soft 

palate, and lingual (bottom) surface of the tongue, and, by definition, recur.

S: Subjective

The patient complains of painful ulcerated 

areas in mouth. He or she may have difficulty 

eating, drinking, swallowing, or opening the 

mouth, and may complain of sore throat.

Inquire about previous occurrences of 

oral ulcerative disease as well as ulcerative 

gastrointestinal diseases, including HSV, 

cytomegalovirus (CMV), or histoplasmosis. 

Ask about recent sexual exposures. Inquire 

about recent trauma or burns. Note current 

medications and any recent changes in 

medications; obtain history of tobacco 

(smoked and chewed) and alcohol use.

O: Objective

Look for red or white-bordered erosions or 

ulcerations varying in size from 1 mm to 2 cm 

on the buccal mucosa, oropharynx, tongue, 

lips, gingiva, and hard or soft palate. Lesions 

caused by HSV tend to be shallow and occur 

on keratinized tissues. HSV lesions may 

appear as clusters of vesicles that may coalesce 

into ulcerations with scalloped borders. 

Aphthous ulcers present with a white or gray 

pseudomembrane surrounded by a halo of 

inflammation.

A: Assessment

Rule out syphilis and other suspected 

pathogens as well as trauma, seizure, and other 

physical injury.

P: Plan

Diagnostic Evaluation

The diagnosis of HSV and aphthous ulcers 

usually is made on the basis of characteristic 

lesions. Location, duration, and recurrence 

are key elements in determining the nature 

of the oral ulcer. As mentioned previously, 

HSV-related ulcers most often present on 

keratinized fixed tissues; aphthous ulcers 

appear on nonfixed tissues such as buccal 

mucosa, and have a tendency to recur. Check 

the absolute neutrophil count (ANC), as a low 

count (<500 cells/μL) may be associated with 

nonresponsive ulcerative disease. If diagnosis 

is uncertain, it is possible to perform HSV 

culture or polymerase chain reaction (PCR) 

testing on oral ulcerations that appear on 

keratinized tissues or the dorsal and lateral 

surfaces of the tongue, scraping near the 

margin of the lesion or unroofing a fresh 

vesicle, if available, and scraping the base. 

The sensitivity of HSV testing decreases when 

collections are taken from older, resolving 

herpetic areas; herpetic lesions >72 hours old 

usually will not yield a positive culture.
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Section 9: Oral Health

If other diagnoses are suspected, perform 

culture or biopsy as indicated. Also perform 

biopsy for ulcers that do not respond to 

therapy (in nonneutropenic patients).

Note that syphilis is very common among 

some HIV-infected populations. For patients 

in whom primary syphilis (manifested by an 

oral chancre) is suspected, perform (or refer 

for) darkfield examination; check Venereal 

Disease Research Laboratory (VDRL) or rapid 

plasma reagin (RPR) results (note that VDRL 

or RPR results may be negative in primary 

syphilis); see chapter Syphilis for further 

information. It is worth noting that, whereas 

chancres are described as painless, open sores 

in the mouth usually are associated with some 

degree of pain.

Treatment

If HSV culture is positive, or if HSV is strongly 

suspected owing to the appearance of the 

lesions or the patient’s history, treat with 

HSV antiviral medication (e.g., valacyclovir, 

famciclovir, or acyclovir) while waiting for 

results of culture. Do not use topical steroids 

without a concomitant oral HSV antiviral if 

the lesion is of possible herpetic etiology. Refer 

to chapter Herpes Simplex, Mucocutaneous for 

more information regarding management and 

treatment of HSV lesions.

Recalcitrant minor aphthous ulcerations 

should be treated with topical corticosteroids 

(e.g., fluocinonide 0.05% or clobetasol 0.05% 

ointments mixed 1:1 with Orabase). For 

multiple small lesions or lesions in areas 

where topical ointments are difficult to apply, 

consider dexamethasone elixir (0.5 mg/5 

mL); the patient is to rinse TID with 5 mL for 

1 minute, then expectorate. As with all oral 

topical steroids, patients should not drink 

or eat for 30 minutes after rinsing. Continue 

treatment for 1 week or until lesions resolve.

In some cases, recurrent aphthous ulcers 

may respond to one of the various “magic 

mouthwashes” that contain combinations 

of antibiotic, antifungal, corticosteroid, 

antihistamine, and anesthetic medication. 

The inclusion of an antihistamine (e.g., 

diphenhydramine) or an anesthetic (e.g., 

lidocaine) may be helpful in treating pain 

associated with these ulcers.

For large or extensive aphthous ulcers, 

systemic corticosteroids may be needed: 

prednisone 40-60 mg PO daily for 1 week 

followed by a taper should prove beneficial. If 

this is ineffective, refer for biopsy to rule out 

CMV, other infection, or neoplastic disease. 

For patients with major oral aphthous ulcers 

that are recalcitrant to other therapies, 

thalidomide 200 mg daily for 2 weeks may be 

considered. Thalidomide is teratogenic and 

should not be used for women of childbearing 

potential without thorough patient education 

and two concomitant methods of birth control. 

Consult with an expert.

Pain control may be needed in order for the 

patient to maintain food intake and prevent 

weight loss. Most of the topical treatments 

noted above will ease pain as well as treat 

the ulcer. Additional considerations for pain 

control include the following:

• Oral anesthetics: Various products are 

available, including gels (e.g., Gelclair, an 

adherent oral rinse that acts as an oral 

bandage), viscous liquids, and sprays (e.g., 

benzocaine, lidocaine). These may be applied 

topically or swished and expectorated. They 

will provide temporary relief, but may lead 

to a temporary loss of taste sensation.

• Systemic: If topical treatments are 

inadequate, consider systemic analgesics 

(e.g., nonsteroidal antiinflammatory drugs 

or opiates). Refer to chapter Pain Syndrome 

and Peripheral Neuropathy.
Oral Ulceration | 611

Section 9: Oral Health

Assess nutritional status and consider adding 

liquid food supplements, if indicated. Suggest 

soft, nonspicy, or salty foods if the ulcer 

is interfering with food intake. Refer to a 

registered dietitian if client is experiencing 

pain, problems eating, or weight loss.

Refer to an oral health specialist or an HIVexperienced dentist as needed.

Patient Education

• Advise patients to report any oral pain or 

difficulty swallowing to their health care 

provider.

• Instruct patients in the application of topical 

ointments, and indicate that they may 

require assistance if the lesion is difficult for 

them to see on their own.

• It is important for patients to maintain good 

nutrition and food intake while their oral 

ulcers heal. Advise them to eat soft, bland 

foods, and refer to a nutritionist if they have 

difficulty. 

• Antiretroviral therapy should be initiated or 

optimized to improve immune function in 

patients with recurrent aphthous ulcers.

References

• Greenspan D. Oral Manifestations 

of HIV. In: Coffey S, Volberding 

PA, eds. HIV InSite Knowledge Base

[textbook online]; San Francisco: UCSF 

Center for HIV Information; June 

1998. Available at hivinsite.ucsf.edu/

InSite?page=kb-00&doc=kb-04-01-14. 

Accessed December 1, 2013.

Oral Warts | 613

Section 9: Oral Health

Oral Warts

Background 

Oral warts are caused by human papillomavirus (HPV) and may appear anywhere within the 

oral cavity or on the lips. They occur more frequently and more extensively in people with HIV 

infection than in those with normal immune function, especially in patients with advancing 

immune suppression (CD4 counts of <200-300 cells/μL). Oral warts may be refractory to 

therapy. The frequency of oral warts may increase, at least temporarily, in patients treated with 

antiretroviral therapy.

It should be noted that HPV infection is strongly associated with oropharyngeal cancer among 

subjects with or without the established risk factors of tobacco and alcohol use, although oral 

warts normally are not caused by the HPV types that are associated with oncogenic changes. One 

analysis of stored samples suggests that the percentage of all oropharyngeal cancers that are HPVpositive has increased from about 20% to 60% since about 1980. Researchers also have reported 

that HPV-related oral cancers were among the most responsive to chemotherapy and radiation. 

S: Subjective

The patient notices raised lesions in the mouth 

or on the lips. Warts are not painful unless 

they have been traumatized.

O: Objective

Examine the oral cavity carefully for 

abnormalities. Wart lesions may vary in 

appearance from smooth, small, and slightly 

raised lesions to cauliflower-like or spiked 

masses with prominent folds or projections. 

They may be single or multiple.

Review recent CD4 counts. In patients with oral 

warts, the CD4 count usually is <300 cells/μL.

A: Assessment

A partial differential diagnosis includes: 

squamous cell carcinoma, lichen planus, and 

traumatic hyperkeratinized areas resulting 

from cheek biting or tongue thrusting.

P: Plan

Diagnostic Evaluation

• The diagnosis of oral warts usually is based 

on the appearance of the lesions. If lesions 

are unusual in appearance, are ulcerated, 

or have grown rapidly, perform biopsy to 

rule out cancer. If there is suspicion of other 

causes, perform other diagnostic evaluations 

as indicated.

• HPV may be demonstrated with electron 

micropsy or in situ hybridization; this 

testing is not routinely required.

• Observation of these lesions is important 

because of the potential, however minimal, 

for development of squamous cell 

carcinoma.
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Section 9: Oral Health

Treatment

• Treatment is difficult, as these lesions 

tend to recur. Treatment options include 

cryosurgery and surgical or laser excision. 

Care must be taken when using laser 

excision, as HPV can survive in an aerosol. 

Extraoral lesions (lip or corner of mouth) 

may be treated with topical agents such as 

podofilox topical solution (Condylox) or 

fluorouracil 5% topical (Efudex). Imiquimod 

5% cream (Aldara) may help to prevent 

recurrence once the lesions have resolved. 

• Refer to an oral health specialist or dentist 

for treatment.

Patient Education

• Instruct patients to comply with regular 

dental and medical care regimens.

• Instruct patients to use medications exactly 

as prescribed.

References

• Greenspan D, Canchola AJ, MacPhail LA, 

et al. Effect of highly active antiretroviral 

therapy on frequency of oral warts. Lancet. 

2001 May 5;357(9266):1411-2.

• King MD, Reznik DA, O’Daniels CM, et al. 

Human papillomavirus-associated oral warts 

among human immunodeficiency virusseropositive patients in the era of highly active 

antiretroviral therapy: an emerging infection.

Clin Infect Dis. 2002 Mar 1;34(5):641-8.
Oral Hairy Leukoplakia | 615

Section 9: Oral Health

Oral Hairy Leukoplakia

Background 

Oral hairy leukoplakia (OHL) is an oral infection caused by Epstein-Barr virus (EBV). It appears 

as white corrugated lesions (sometimes “hairy” in appearance) primarily on the lateral aspects of 

the tongue. The infection may spread across the entire dorsal surface onto the ventral surface of 

the tongue, and occasionally may be found on buccal mucosa. It is common in people with HIV 

infection, particularly in those with advanced immunosuppression (CD4 count <200 cells/μL), and 

may serve as a marker of HIV.

S: Subjective

The patient notices new, white lesions on the 

tongue that cannot be wiped off or removed by 

scraping or brushing. The OHL lesions usually 

are asymptomatic, but occasionally may 

cause alteration in taste, discomfort, or other 

symptoms.

O: Objective

Perform a focused examination of the 

oropharynx. OHL appears as unilateral or 

bilateral white plaques or papillary lesions on 

the lateral, dorsal, or ventral surfaces of the 

tongue or on buccal mucosa. The lesions may 

vary in appearance from smooth, flat, small 

lesions to irregular, “hairy” or “verrucous” 

lesions with prominent vertical folds or 

projections.

A: Assessment

A partial differential diagnosis for OHL 

includes:

• Oral candidiasis

• Squamous cell carcinoma

• Geographic tongue

• Lichen planus

• Smoker’s leukoplakia

• Epithelial dysplasia

• White sponge nevus

• Irritation leukoplakia

P: Plan

Diagnostic Evaluation

A presumptive diagnosis of OHL usually is 

made on the basis of the clinical appearance 

of the lesions. OHL often is confused with 

candidiasis; the diagnosis of OHL should be 

considered for lesions that do not wipe away, 

as would be the case for pseudomembranous 

candidiasis. Definitive diagnosis of OHL 

requires biopsy and demonstration of EBV. 

• Perform biopsy of lesions only if they are 

ulcerated or unusual in appearance, to 

distinguish OHL from cancer or other 

causes.

Treatment

• Because OHL usually is asymptomatic, 

specific treatment generally is not necessary. 

• Immune system reconstitution through 

antiretroviral therapy will resolve OHL; 

encourage initiation of HIV treatment if the 

patient is not yet on antiretroviral therapy.

• If specific treatment is required, the 

following options may be considered. 

Relapse is common after discontinuation of 

treatment. 

• Acyclovir 800 mg PO 5 times per day for 

2 weeks; famciclovir and valacyclovir may 

be considered.

• Topical tretinoin (Retin-A) 0.025-0.05% 

solution, podophyllin 25% in tincture of 

benzoin, and other treatments also have 

been used.
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Section 9: Oral Health

• For relapse of severe OHL, consider 

maintenance therapy with high-dose 

acyclovir, famciclovir, or valacyclovir.

• For severe symptomatic cases, surgical 

treatment (e.g., cryosurgery, excision) may 

provide temporary resolution.

• Candidiasis may be present concurrently; 

treat candidiasis if it is present (see chapter 

Candidiasis, Oral and Esophageal).

Patient Education

• Advise patients that OHL rarely is a problem 

in itself, but may be a marker of HIV 

progression.

• Encourage patients to start antiretroviral 

therapy.

• Advise patients to contact their care 

providers if new symptoms develop.

• Instruct patients to comply with regular 

dental and medical care regimens.

References

• Agbelusi GA, Wright AA. Oral lesions as 

indicators of HIV infection among routine 

dental patients in Lagos, Nigeria. Oral Dis. 

2005 Nov;11(6):370-3.

• Coogan MM, Greenspan J, Challacombe 

SJ. Oral lesions in infection with human 

immunodeficiency virus. Bull World Health 

Organ. 2005 Sep;83(9):700-6.

• Greenspan JS, Greenspan D. Oral 

Complications of HIV Infection. In: Sande 

MA and Volberding PA, eds. Medical 

Management of AIDS, 6th ed. Philadelphia: 

WB Saunders; 1999:157-169.

• Kufe DW, Pollock RE, Bast RC Jr., et al., eds. 

Cancer Medicine, 6th ed. Lewiston, NY: BC 

Decker Inc.; 2003.

• Shiboski CH, Patton LL, Webster-Cyriaque 

JY, et al.; Oral HIV/AIDS Research Alliance, 

Subcommittee of the AIDS Clinical Trial 

Group. The Oral HIV/AIDS Research 

Alliance: updated case definitions of oral 

disease endpoints. J Oral Pathol Med. 2009 

Jul;38(6):481-8.
Necrotizing Ulcerative Periodontitis and Gingivitis | 617

Section 9: Oral Health

Necrotizing Ulcerative 

Periodontitis and Gingivitis

Background 

Necrotizing ulcerating periodontitis (NUP) is a marker of severe immunosuppression that affects 

gingival tissues (gums) and extends to the underlying bone or periodontium. It may or may not 

be distinct from necrotizing ulcerative gingivitis (NUG), which is considered to be confined to 

the gingiva. This discussion will focus primarily on NUP, but the microbial profiles and treatment 

recommendations for these two periodontal diseases are similar.

NUP in HIV-infected individuals is believed to be an endogenous infection that progresses to 

necrosis of the gingiva. Pathogens may include anaerobic bacteria and fungi. NUP usually presents 

as “blunting” or ulceration of the interdental papillae, but rapidly progresses to destruction of 

underlying alveolar bone. It usually is associated with severe pain and spontaneous bleeding. 

Several case reports have described extensive destruction leading to exfoliation of teeth within 

3-6 months of onset, with sequestration of necrotic alveolar bone and necrotic involvement of the 

adjacent mandible and maxilla. Patients may present with concomitant malnutrition resulting 

from inability to take food by mouth. The prevalence of NUP in the HIV-infected population has 

been reported as 0-5%. NUP is the most serious form of periodontal disease associated with HIV.

S: Subjective

The patient complains of painful, 

spontaneously bleeding gums, diminished 

or metallic taste, bad breath, or loose teeth 

(with a prevalence toward anterior teeth and 

first molars). “Deep jaw pain” is a common 

complaint and may reflect extension to 

adjacent mucosa.

O: Objective

Examine the oral cavity carefully. NUP and 

NUG present with fiery red, ulcerated gingival 

tissues, and grayish exudate. Teeth may be 

very loose or missing and there will be a fetid 

odor from the mouth. The ulcerated tissues 

can extend past the attached gingiva to the 

adjacent mucosa. Necrosis of adjacent bone 

also is common.

A: Assessment

The differential diagnosis includes other causes 

of gingival ulceration, such as herpes simplex 

virus, herpes zoster, and cytomegalovirus. (See 

relevant chapters on these conditions.)

P: Plan

Treatment

Treatment usually is divided into the acute 

phase and the maintenance phase. The 

primary concern in the acute phase is pain 

control. For the maintenance phase, treatment 

is directed toward reducing the burden of 

potential pathogens, preventing further tissue 

destruction, and promoting healing.

• For uncomplicated NUP or NUG, the 

primary care provider should prescribe 

an antimicrobial rinse (see below), 

antibiotic therapy (see below), medications 

for pain management, and nutritional 

supplementation; the patient should be 

referred to a dental health care professional.

• Chlorhexidine gluconate rinse (0.12%) twice 

daily after brushing and flossing (an alcoholfree preparation is preferred).
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Section 9: Oral Health

• Antibiotic therapy (preferably narrow 

spectrum, to leave gram-positive aerobic 

flora unperturbed). 

• Metronidazole is the drug of choice, 500 

mg PO BID for 7-10 days.

• If the patient cannot tolerate 

metronidazole: clindamycin 150 mg QID 

or amoxicillin-clavulanate (Augmentin) 

875 mg PO BID for 7-10 days, if no 

hypersensitivity or allergy to either drug 

exists.

• Refer to a dentist for the following: 

• Removal of plaque and debris from the 

site of infection and inflammation.

• Debridement of necrotic hard and soft 

tissues, with a 0.12% chlorhexidine 

gluconate or povidone-iodine lavage.

• Regular deep cleaning.

Patient Education

• Advise the patient of the following: Good 

oral hygiene is critical for arresting gingival 

infection and tooth loss. Avoid smoking 

and try to eliminate emotional stress. When 

primary stabilization is achieved, resume 

daily brushing and flossing after every meal. 

This may be difficult during the acute phase, 

but it is very important to keep the mouth 

as clean as possible. Nutrition education 

and supplements (liquid diet, plus vitamins/

minerals) are recommended.

• Frequent professional cleaning (every 

3 months) may be needed during the 

maintenance phase.

• Patients taking metronidazole should not 

drink alcohol for at least 24-48 hours after 

taking the last dose, in order to avoid severe 

nausea and vomiting from a disulfiram-like 

reaction.

• Instruct patients not to drink or eat for 30 

minutes after rinsing with chlorhexidine.

• HIV (and hepatitis C) may (rarely) be 

transmitted from bleeding gums during 

“deep kissing” or other activities (oralgenital contact). Advise patients/clients to 

avoid exposing partners to HIV by taking all 

necessary precautions, including abstinence 

from risky activities until this condition is 

healed and stable (no oozing of oral fluids).

References

• American Academy of Periodontology, 

Committee on Research, Science and 

Therapy. Periodontal Considerations in the 

HIV-Positive Patient. Chicago: American 

Academy of Periodontology; 1994.

• Coogan MM, Greenspan J, Challacombe 

SJ. Oral lesions in infection with human 

immunodeficiency virus. Bull World Health 

Organ. 2005 Sep;83(9):700-6.

• Greenberg MS, Glick M, eds. Burket’s Oral 

Medicine: Diagnosis and Treatment, 10th 

Edition. Hamilton, Ontario: BC Decker; 

2003:61-63.

• Greenspan D, Greenspan J, Schiodt M, 

et al. AIDS and the Mouth. Copenhagen: 

Munksgaard; 1990:106.

• Kroidl A, Schaeben A, Oette M, et al. 

Prevalence of oral lesions and periodontal 

diseases in HIV-infected patients on 

antiretroviral therapy. Eur J Med Res. 2005 

Oct 18;10(10):448-53.

• Petersen PE. The World Oral Health Report 

2003: continuous improvement of oral health 

in the 21st century-the approach of the WHO 

Global Oral Health Programme. Community 

Dent Oral Epidemiol. 2003 Dec;31:28-29.

• Petersen PE, Bourgeois D, Ogawa H, et al. 

The global burden of oral diseases and risks to 

oral health. Bull World Health Organ. 2005 

Sep;83(9):661-9.

• Reznik DA. Oral manifestations of HIV 

disease. Top HIV Med. 2005 Dec-2006 

Jan;13(5):143-8.
Web-Based Resources | 619

Section 10: Resources

and References

Web-Based Resources

Background 

The care and management of HIV-infected patients is a rapidly evolving field. Keeping up to date 

with clinical information about HIV care has in the past required attendance at national and 

international conferences. With the increasing availability of the Internet, clinicians and patients 

are able to access the most current advances through Web coverage, without requiring travel or 

time away from work.

The challenge of using Internet resources is in determining which websites are accurate and 

current. Check for dates of authorship, the credentials of the site sponsors and authors, and how 

well supported any recommendations or analysis may be. Be aware of any possible commercial 

bias. Finally, it is important to remember that information on these sites does not replace clinical 

judgment or consultation with HIV experts.

Listed below is a selection of useful and accurate Internet sites. Many of these websites also link 

out to additional information resources, and many allow users to subscribe to receive updates via 

email. Many providers find it helpful to review sites geared toward patients, in order to maintain 

familiarity with patients’ concerns and patient-based information resources.

Resources for Clinicians

• AIDSInfo (aidsinfo.nih.gov)

Official repository for HIV/AIDS 

information from the U.S. Public Health 

Service. Content includes national clinical 

trial information, drug and vaccine 

overviews, fact sheets for patients, and a 

clinical guidelines portal that includes the 

following: 

• Adult and Adolescent ARV Guidelines

• Adult and Adolescent OI Prevention and 

Treatment Guidelines

• Perinatal Guidelines

• Pediatric ARV Guidelines

• Pediatric OI Prevention and Treatment 

Guidelines

• Guidelines on Care for HIV-Infected 

Residents Displaced from Disaster Areas 

• Preexposure Prophylaxis (PrEP) 

Guidelines

• Occupational Postexposure Prophylaxis 

(PEP) Guidelines

• Nonoccupational Postexposure 

Prophylaxis (nPEP) Guidelines

• Recommendations for Hormonal 

Contraception

• HIV Counseling, Testing, and Referral 

Guidelines

• Guidelines on Incorporating HIV 

Prevention into Medical Care

• TARGET Center

(careacttarget.org)

The central source of Ryan White training 

and technical assistance, including clinical 

care resources funded by HRSA’s HIV/AIDS 

Bureau. 

• AIDS Education and Training Centers 

National Resource Center

(www.aidsetc.org)

Clinical training resources, including 

curricula, self-study, and slide sets, including 

slides for all national guidelines. 
620 | Guide for HIV/AIDS Clinical Care

Section 10: Resources

and References

• National HIV/AIDS Clinicians’ 

Consultation Center (www.nccc.ucsf.edu)

An AIDS Education and Training 

Centers clinical resource for health care 

professionals, with contact information for 

the Warmline, PEPline, and Perinatal HIV 

Hotline. 

• Aidsmap (www.aidsmap.com)

London-based HIV/AIDS news and 

treatment information site. Patient 

information is written at both lower and 

higher literacy levels. International focus. 

• Clinical Care Options for HIV

(clinicaloptions.com)

Continuing Medical Education (CME) 

materials related to HIV/AIDS, including 

conference reviews. 

• HIV InSite (hivinsite.ucsf.edu)

Major HIV/AIDS portal from the University 

of California San Francisco. Includes HIV 

InSite Knowledge Base, updated ARV 

information, including an ARV interactions 

database, global country profiles, and links 

out to other useful sites. 

• HIV Drug Resistance Database

(hivdb.stanford.edu)

Information on resistance mutations to 

antiretroviral medications from Stanford 

University. 

• HIV Web Study

(depts.washington.edu/hivaids)

Northwest AETC, University of 

Washington. Dozens of online clinical cases 

featuring downloadable tables, charts, and 

images. 

• International Training and Education 

Center on HIV (www.go2itech.org)

The international AETC. Website features 

extensive database of international HIV/

AIDS training materials. 

• International Antiviral Society-USA

(www.iasusa.org)

ARV resistance mutations charts and “Cases 

on the Web” online CME courses. 

• Journal Watch: HIV/AIDS Clinical Care

(www.jwatch.org/hiv-aids-clinical-care)

From the publishers of the New England 

Journal of Medicine, Journal Watch features 

updates and analysis online or via a weekly 

email newsletter. 

• Medscape HIV/AIDS Topic Area

(www.medscape.com/hiv?src=pdown)

CME materials related to HIV/AIDS, 

including conference coverage, news, and 

special features. 

• VA National HIV/AIDS Program

(www.hiv.va.gov)

Comprehensive information portal for 

providers. Also has a section for veterans 

and patients. 

• Women, Children, and HIV

(www.womenchildrenhiv.org)

Expert-selected, evidence-based information 

on prevention of mother-to-child 

transmission of HIV, care of women and 

children with HIV, and related topics.
Web-Based Resources | 621

Section 10: Resources

and References

Resources for Patients 

and the Community

• AIDS.gov (aids.gov)

AIDS.gov provides access to Federal HIV/

AIDS information through a variety of new 

media channels, and supports the use of 

new media tools by Federal and community 

partners to improve domestic HIV programs 

serving minority and other communities 

most at-risk of, or living with, HIV. 

• AIDS.org (www.aids.org)

Online home of AIDS Treatment News.

• AIDS InfoNet (www.aidsinfonet.org)

Comprehensive collection of fact sheets 

on clinical topics, available in English and 

Spanish, in print-friendly and downloadable 

formats. Regularly updated. 

• AIDSmeds (aidsmeds.com)

Information regarding HIV-related 

medications for patients, including drug 

interactions calculator. 

• AIDS Project Los Angeles (www.apla.org)

Fact sheets, newsletters, and program 

information. Some information in Spanish. 

• The Body (www.thebody.com)

Major HIV information resource geared 

toward patients and the community. 

• Gay Men’s Health Crisis (www.gmhc.org)

Patient and program information from one 

of the oldest community organizations. 

Some information in Spanish. 

• Project Inform (www.projectinform.org)

Comprehensive information and advocacy 

information geared toward individuals 

infected and affected by HIV. 

• San Francisco AIDS Foundation

(www.sfaf.org)

AIDS 101, BETA treatment newsletter, and 

prevention and program information. Some 

information in Spanish. 

• The Well Project

(www.thewellproject.org/en_US)

Health resources for women diagnosed with 

HIV and AIDS. 

Sulfa Desensitization | 623

Section 10: Resources

and References

Sulfa Desensitization

Background 

Trimethoprim-sulfamethoxazole (TMP-SMX), also known as Septra, Bactrim, and cotrimoxazole, is 

a key antibiotic for prophylaxis and treatment of several HIV-related illnesses. It is the most effective 

prophylaxis and the first-line treatment for Pneumocystis jiroveci pneumonia (PCP). In addition, 

it is effective in preventing toxoplasmosis encephalitis in severely immunocompromised patients 

who have evidence of previous exposure (see chapter Opportunistic Infection Prophylaxis), and it is 

effective against certain bacterial infections. TMP-SMX is quite inexpensive, which is a rarity in the 

field of HIV treatment. Because of its effectiveness and availability, it is used widely throughout the 

world. However, adverse reactions to TMP-SMX and other sulfa drugs occur in a high proportion 

of HIV-infected patients (roughly 25%), and such reactions may limit treatment options.

Desensitization to TMP-SMX should be considered when there are no reasonable or available 

alternatives and the patient has not experienced severe reactions (e.g., Stevens-Johnson syndrome 

or toxic epidermal necrolysis) to sulfa drugs. Several methods of desensitizing patients with 

previous reactions to TMP-SMX have been tried. These methods vary in starting dosage and 

length of dosage escalation, but success rates are around 80% in most cases and may be higher in 

patients with CD4 counts of <200 cells/μL.

S: Subjective

The patient reports a previous adverse reaction 

to sulfa drugs, such as erythema, pruritus, or 

rash. The patient has no history of anaphylaxis, 

Stevens-Johnson syndrome, or toxic epidermal 

necrolysis, and no reaction involving 

vesiculation, desquamation, ulceration, 

exfoliative dermatitis, etc.

O: Objective

CD4 count <200 cells/μL, or other important 

indication for TMP-SMX.

A: Assessment

Reaction to sulfa, possibly reversible with 

desensitization protocol.

P: Plan

Begin 9- to 13-day desensitization protocol, 

starting with pediatric oral suspension, which 

contains 40 mg of TMP and 200 mg of SMX 

per 5 mL (1 teaspoon). Gradually increase the 

dosage according to the protocol.

If there is any concern about the severity of 

a previous reaction, have the patient take the 

initial morning dose in the clinic so that the 

patient may be monitored for 3-4 hours before 

going home. (This assumes that emergency 

treatment, including IV access materials, 

IV fluids, epinephrine, antihistamines, and 

steroids, are readily available.)

Many experts recommend treatment with an 

antihistamine medication starting 1 day before 

initiation of the desensitization regimen and 

continuing daily until the dosage escalation is 

completed.

More rapid desensitization protocols are 

available (see “References,” below) for patients 

urgently needing treatment with TMP-SMX.

Desensitization Regimen

Use commercially available pediatric 

suspension (containing TMP 8 mg and SMX 

40 mg per mL [40 mg/200 mg per 5 mL]), 

followed by double-strength tablets, as follows:
624 | Guide for HIV/AIDS Clinical Care

Section 10: Resources

and References

Table 1. Sulfa Desensitization Regimen

Days Dosage (TMP/SMX) Volume or Tablet

1-3 8 mg/40 mg 1 mL

4-6 16 mg/80 mg 2 mL

7-9 40 mg/200 mg 5 mL (or 1/2 single-strength tablet)

9-12 80 mg/400 mg 1/2 double-strength tablet (or 1 single-strength tablet)

13 and thereafter 160 mg/800 mg 1 double-strength tablet

Note: These day ranges are approximate; patients can be advanced more quickly or more slowly, depending 

on their reactions to the dosages.

In the event of mild reaction: If the patient experiences a mild reaction or itching (i.e., mild morbilliform 

rash without fever, systemic symptoms, or mucosal involvement), the dosage can be reduced to the last 

tolerated step or continued at the same dosage for an additional day, while simultaneously treating the rash 

or reaction. Antihistamines or antipyretics may be used to treat symptoms of mild reactions. If the reaction 

diminishes, the patient may advance to the next dosage (consider more gradual increase of dosages); if the 

reaction worsens or if systemic symptoms develop, TMP-SMX should be discontinued. 

In the event of severe reaction: The desensitization regimen should be discontinued and the patient 

should be treated appropriately for the reaction. 

Patient Education

For home desensitization regimen

• Explain the benefits of using TMP-SMX. Be 

sure the patient understands and is able to 

follow these instructions: 

• The patient should measure the dose 

carefully and take it each morning, 

followed by a glass (6-8 oz) of water. (The 

patient should do a demonstration, if 

possible, using an oral syringe that will be 

used for the actual measuring at home.)

• TMP-SMX can cause severe illness unless 

close attention is paid to any problems that 

may occur. It is extremely important for the 

patient to check his/her body temperature 

each afternoon. If the temperature is more 

than 100.5°F by mouth, the patient should 

stop taking the drug and contact the clinic. 

Note: If shaking chills occur, the body 

temperature should be checked as soon as 

the shaking stops, and the patient should 

contact the clinic.

• If the patient develops a rash, blisters on the 

skin or in the mouth, or vomiting, he or she 

should stop taking TMP-SMX and go the 

clinic or emergency room immediately. The 

skin should be checked each evening, and 

any time itching occurs.

• If mild itching or a faint rash occurs, 

diphenhydramine (Benadryl) 25-50 mg PO 

can be taken Q4H as needed. If itching or 

rash persists, continue with the same dosage 

for an additional day; the patient should 

contact the clinic if there are questions or 

concerns.

• The patient should contact the clinic for 

alternative dosage instructions in the event 

of persistent itching without rash.

• Other adverse events should be reported 

immediately.
Sulfa Desensitization | 625

Section 10: Resources

and References

For all desensitized patients

• Desensitization may be effective only as long 

as the allergic individual is continuously 

exposed to the drug. After desensitization 

is complete, continue with the daily dosage. 

If the drug is stopped (even for a few days), 

the entire regimen may have to be repeated, 

as patients may have a recurrence of the 

adverse reaction.

References

• Carr A, Penny R, Cooper DA. Efficacy 

and safety of rechallenge with low-dose 

trimethoprim-sulfamethoxazole in previously 

hypersensitive HIV-infected patients. AIDS. 

1993 Jan;7(1):65-71.

• Conant M, Dybul M. Trimethoprimsulfamethoxazole hypersensitivity 

and desensitization in HIV disease. 

In: Program and abstracts of the VIII 

International Conference on AIDS/III 

STD World Congress; July 19-24, 1992; 

Amsterdam. Abstract PO-B-3291.

• Leoung GS, Stanford JF, Giordano MF, et al. 

Trimethoprim-sulfamethoxazole (TMP-SMZ) 

dose escalation versus direct rechallenge for 

Pneumocystis carinii pneumonia prophylaxis 

in human immunodeficiency virus-infected 

patients with previous adverse reaction 

to TMP-SMZ. J Infect Dis. 2001 Oct 

15;184(8):992-7.

• Nguyen MT, Weiss PJ, Wallace MR. Twoday oral desensitization to trimethoprimsulfamethoxazole in HIV-infected patients. 

AIDS. 1995 Jun;9(6):573-5.

• Piketty C, Gilquin J, Kazatchkine MD. 

Efficacy and safety of desensitization to 

trimethoprim-sulfamethoxazole in human 

immunodeficiency virus-infected patients. J 

Infect Dis. 1995 Aug;172(2):611.

• Rich, JD, Sullivan, T, Greineder, 

D, Kazanjian, PH. Trimethoprim/

sulfamethoxazole incremental dose regimen 

in human immunodeficiency virus-infected 

persons. Ann Allergy Asthma Immunol 

1997; 79:409.

• Torgovnick J, Arsura E. Desensitization to 

sulfonamides in patients with HIV infection. 

Am J Med. 1990 May;88(5):548-9.

• White MV, Haddad ZH, Brunner E, 

et al. Desensitization to trimethoprim 

sulfamethoxazole in patients with 

acquired immune deficiency syndrome and 

Pneumocystis carinii pneumonia. Ann 

Allergy. 1989 Mar;62(3):177-9.

Antiretrovirals Available in the United States and Mexico | 627

Section 10: Resources

and References

Antiretrovirals Available in the 

United States and Mexico

Brand and Generic Names of ARVs in the United States and Mexico

This chart was developed to facilitate continuity of care for people living with HIV who may 

receive care in both the United States and Mexico. Although most HIV medications are available in 

both countries, some are sold under different brand names.

Antirretrovirales Disponibles 

en los Estados Unidos Antiretrovirals Available in Mexico

Generic Brand Name Genérico Nombre Comercial

Nucleoside/Nucleotide Analogues (NRTIs) Inhibidores de la Trascriptasa Reversa 

Análogos a Nucleósidos (ITRAN)

Abacavir* Ziagen Abacavir* Ziagenavir

Didanosine* Videx Didanosina* Videx

Emtricitabine Emtriva Emtricitabina* Emtriva

Lamivudine* Epivir Lamivudina* Epivir/3TC

Stavudine* Zerit Estavudina* Zerit

Tenofovir Viread Tenofovir Viread

Zidovudine* Retrovir Zidovudina* Retrovir

Nonnucleoside Reverse Transcriptase 

Inhibitors (NNRTIs)

Inhibidores de la Trascriptasa Reversa 

No Nucleósidos (ITRNN)

Delavirdine Rescriptor No disponible/not available

Efavirenz Sustiva Efavirenz Stocrin

Etravirine Intelence Etravirina Etravirina

Nevirapine* Viramune Nevirapina* Viramune

Rilpivirine Edurant No disponible/not available

Protease Inhibitors (PIs) Inhibidores de Proteasa (IP)

Atazanavir Reyataz Atazanavir Reyataz

Darunavir Prezista Darunavir* Prezista

Fosamprenavir Lexiva Fosamprenavir Telzir

Indinavir Crixivan Indinavir Crixivan

Lopinavir/Ritonavir Kaletra Lopinavir/Ritonavir Kaletra

Nelfinavir Viracept Fuera de mercado/off market

Ritonavir Norvir Ritonavir Norvir

Saquinavir (hard-gel 

caps)

Invirase Saquinavir (cápsula de 

gel duro)

Invirase

Tipranavir Aptivus Tipranavir Aptivus
Section 10: Resources

and References

628 | Guide for HIV/AIDS Clinical Care

Section 10: Resources

and References

Antirretrovirales Disponibles 

en los Estados Unidos Antiretrovirals Available in Mexico

Generic Brand Name Genérico Nombre Comercial

Chemokine Coreceptor Antagonists Inhibidores de Acoplamiento

Maraviroc Selzentry Maraviroc Celsentri

Fusion Inhibitors Inhibidores de Fusion

Enfuvirtide (T20) Fuzeon Enfuvirtida* Fuzeon

Integrase Inhibitors Inhibidores de Integrasa

Dolutegravir Tivicay No disponible/not available

Elvitegravir ** No disponible/not available

Raltegravir Isentress Raltegravir Isentress

Fixed-Dose Combinations Combinaciones en Tableta Única

Efavirenz + tenofovir + 

emtricitabine

Atripla Efavirenz + tenofovir + 

emtricitabina

Atripla

Lamivudine + 

zidovudine*

Combivir Lamivudina + 

zidovudina

Combivir

Rilpivirine + tenofovir + 

emtricitabine

Complera No disponible/not available

Abacavir + lamivudine Epzicom Abacavir + lamivudina Kivexa

Elvitegravir + 

cobicistat + tenofovir + 

emtricitabine

Stribild No disponible/not available

Zidovudine + lamivudine 

+ abacavir

Trizivir Zidovudina + lamivudina 

+ abacavir

Trizivir

Tenofovir + 

emtricitabine

Truvada Tenofovir + 

emtricitabina

Truvada

* Available as generic/Disponible en forma genérica

** Available only in fixed-dose combination (Stribild)

Sources / Fuentes:

• Guía de Manejo Antirretroviral de las Personas que Viven con el VIH/SIDA, Quinta Edición. Secretaría de Salud, Consejo Nacional 

para la Prevención y Control del SIDA (CONASIDA); Subsecretaría de Prevención y Promocin de la Salud, Centro Nacional 

para la Prevención y el Control del VIH/SIDA (CENSIDA). México 2012. Available at www.censida.salud.gob.mx/. Accessed 

December 1, 2013.

• FDA-Approved and Investigational Antiretrovirals. HIV InSite [website]. Available at hivinsite.ucsf.edu/InSite?page=md-rr-13. 

Accessed December 1, 2013.

• Lista de Medicamentos antiretrovirales. Centro Nacional para la Prevención y el Control del VIH/SIDA. Available at aidsetc.

org/resource/us-mexico-antiretroviral-drug-chart. Accessed December 1, 2013.

References

• U.S./Mexico Border AETC Steering 

Team. U.S.-Mexico Antiretroviral 

Drug Chart. August 2010. Available 

at aidsetc.org/aidsetc?page=etresdisplay&resource=etres-285. Accessed 

December 1, 2013.
Antiretroviral Reference Tables | 629

Section 10: Resources

and References

Section 10: Resources

and References

Antiretroviral Reference Tables

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected 

adults and adolescents. Department of Health and Human Services. Available at aidsinfo.nih.gov/guidelines. Accessed December 1, 2013.

Table 5a. Antiretroviral Regimens Recommended for Treatment-Naive Patients 

Preferred Regimens (Regimens with optimal and durable efficacy, favorable tolerability and toxicity profile, and 

ease of use) The preferred regimens for non-pregnant patients are arranged by chronological order of FDA 

approval of components other than nucleosides and, thus, by duration of clinical experience.

NNRTI-based Regimens Comments 

• EFV/TDF/FTC (AI) 

PI-based Regimens (in alphabetical order)

• ATV/r + TDF/FTC (AI)

• DRV/r (once daily) + TDF/FTC (AI)

INSTI-based Regimen (in order of drug 

approval)

• RAL + TDF/FTC (AI)

• EVG/COBI/TDF/FTC (AI)

• DTG + ABC/3TC (AI)

• DTG + TDF/FTC (AI)

Preferred Regimen1 for Pregnant Women

• LPV/r (twice daily) + ZDV/3TC1 (AI)

EFV:

• Teratogenic in nonhuman 

primates. A regimen that 

does not include EFV should 

be strongly considered in 

women who are planning to 

become pregnant or who are 

sexually active and not using 

effective contraception. 

TDF:

• Should be used with caution 

in patients with renal 

insufficiency.

ATV/r: 

• Should not be used in 

patients who require >20 mg 

omeprazole equivalent per 

day. Refer to Table 15a for 

dosing recommendations 

regarding interactions 

between ATV/r and acidlowering agents.

EVG/COBI/TDF/FTC:

• Should not be started in 

patients with an estimated 

CrCl <70 mL/min, and 

should be changed to an 

alternative regimen if the 

CrCl falls below 50 mL/min

• Should not be used with 

other ARV drugs or with 

nephrotoxic drugs

• COBI is a potent CYP 3A 

inhibitor. It can increase 

the concentration of other 

drugs metabolized by this 

pathway. Refer to Tables 

15d and 16c for drug 

interaction information 

on concomitantly 

administered drugs.

Once-daily LPV/r is not 

recommended in pregnant 

women.

Alternative Regimens (Regimens that are effective and tolerable but have potential disadvantages compared 

with preferred regimens. An alternative regimen may be the preferred regimen for some patients.)

NNRTI-based Regimens (in alphabetical order)

• EFV + ABC/3TC (BI)

• RPV/TDF/FTC (BI)

• RPV + ABC/3TC (BIII)

PI-based Regimens (in alphabetical order)

• ATV/r + ABC/3TC (BI)

• DRV/r + ABC/3TC (BIII)

• FPV/r (once or twice daily) + 

ABC/3TC or TDF/ FTC (BI)

• LPV/r (once or twice daily) + 

ABC/3TC or TDF/ FTC (BI)

INSTI-based Regimen

• RAL + ABC/3TC (BIII)

Comments 

RPV:

• Not recommended in 

patients with pretreatment 

HIV RNA >100,000 copies/mL

• Higher rate of virologic 

failures reported in patients 

with pre-ART CD4 count 

of <200 cells/μL who are 

treated with RPV + 2 NRTIs

• Contraindicated for use with 

protein pump inhibitors 

(PPIs)

ABC: 

• Should not be used in 

patients who test positive 

for HLA-B*5701 

• Use with caution in 

patients with high risk of 

cardiovascular disease 

or with pretreatment 

HIV-RNA >100,000 

copies/mL (see text)

Note: 3TC may substitute for FTC or vice versa. 1 For more detailed recommendations on antiretroviral use in an HIV-infected pregnant woman, refer to Recommendations for Use of 

Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the 

United States. Available at aidsinfo.nihi.gov/guidelines. Accessed December 1, 2013.

Abbreviations:

INSTI = integrase strand transfer inhibitor 

NNRTI = non-nucleoside reverse 

transcriptase inhibitor 

NRTI = nucleos(t)ide reverse transcriptase inhibitor 

PI = protease inhibitor 

ABC = abacavir 

ATV = atazanavir 

3TC = lamivudine 

COBI = cobicistat

ddI = didanosine 

DRV = darunavir 

DTG = dolutegravir

EFV = efavirenz 

EVG = elvitegravir

FPV = fosamprenavir

FTC = emtricitabine 

LPV = lopinavir

NVP = nevirapine

r = low dose ritonavir 

RAL = raltegravir

SQV = saquinavir 

TDF = tenofovir 

ZDV = zidovudine
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Section 10: Resources

and References

Table 5b. Other Antiretroviral Regimens for Treatment-Naive Patients 

Regimens that may be selected for some patients but are less satisfactory than preferred or 

alternative regimens listed in Table 5a. 

NNRTI-based Regimens 

• EFV + ZDV/3TC

• NVP + (ABC/3TC or TDF/FTC 

or ZDV/3TC)

• RPV + ZDV/3TC

PI-based Regimens 

• (ATV or ATV/r or DRV/r or FPV/r 

or LPV/r or SQV/r) + ADV/3TC

• ATV + ABC/3TC

• SQV/r + (ABC/3TC or TDF/FTC)

INSTI-based Regimen 

• RAL + ZDV/3TC 

CCR5 Antagonist-Based Regimens 

• MVC + (ABC/3TC or TDF/FTC 

or ZDV/3TC) 

Comments

NVP:

• Should not be used in patients with moderate to severe 

hepatic impairment (Child-Pugh B or C).1

• Should not be used in women with pre-ART CD4 counts of 

>250 cells/μL or in men with pre-ART CD4 counts of >400 

cells/μL.

• Use with caution when coadministered with ABC; both NVP 

and ABC can cause HSR within the first few weeks after 

initiation of therapy.

ZDV:

• Can cause bone marrow suppression, myopathy, 

lipoatrophy, and rarely, lactic acidosis with hepatic 

steatosis.

ATV/r:

• Generally preferred over unboosted ATV.

MVC

• Perform tropism testing before initiation of therapy; may be 

considered for patients who have only CCR5-tropic virus.

SQV/r:

• Not recommended for patients with:

• Pretreatment QT interval >450 msec

• Refractory hypokalemia or hypomagnesemia

• Concomitant therapy with other drugs that prolong QT 

interval

• Complete AV block

Note: 3TC may substitute for FTC or vice versa. 1 Refer to Appendix B, Table 7 for the criteria for Child-Pugh classification.

Abbreviations: 3TC = lamivudine; ABC = abacavir; ATV = atazanavir; ATV/r = atazanavir/ritonavir; AV = atrioventricular; COBI = cobicistat; ddI = didanosine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; 

EVG = elvitegravir; FPV = fosamprenavir; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; 

msec = millisecond; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; 

RAL = raltegravir; RTV = ritonavir; SQV = saquinavir; SQV/r = saquinavir/ritonavir; TDF = tenofovir; ZDV = zidovudine
Antiretroviral Reference Tables | 631

Section 10: Resources

and References

Table 6. Advantages and Disadvantages of Antiretroviral Components Recommended as

Initial Antiretroviral Therapy 

ARV 

Agent(s) Advantages Disadvantages

Nonnucleoside Reverse Transcriptase Inhibitors (in alphabetical order)

NNRTI Class 

Advantages:

• Long half-lives

NNRTI Class Disadvantages:

• Greater risk of resistance at the time of treatment failure than with 

PIs

• Potential for cross-resistance

• Skin rash

• Potential for CYP450 drug interactions (see Tables 14, 15b, and 16b)

• Transmitted resistance more common than with PIs

EFV • Virologic responses 

noninferior or 

superior to most 

comparators to date

• Once-daily dosing

• Coformulated with 

TDF/FTC 

• Neuropsychiatric side effects

• Teratogenic in nonhuman primates. Several cases of neural tube 

defect in infants born to women who were exposed to EFV in the 

first trimester of pregnancy reported. EFV use should be avoided in 

women with potential for pregnancy and is contraindicated in the 

first trimester.

• Dyslipidemia

NVP • No food 

requirement

• Fewer lipid effects 

than EFV

• Once-daily dosing 

with extendedrelease tablet 

formulation

• Higher incidence of rash, including rare but serious hypersensitivity 

reactions (Stevens-Johnson syndrome or toxic epidermal 

necrolysis), than with other NNRTIs

• Higher incidence of hepatotoxicity, including serious and even fatal 

cases of hepatic necrosis, than with other NNRTIs

• Contraindicated in patients with moderate or severe (Child-Pugh B 

or C) hepatic impairment

• Some data suggest that ARV-naive patients with high pre-NVP CD4 

counts (>250 cells/μL for females, >400 cells/μL for males) are at 

higher risk of symptomatic hepatic events. NVP is not recommended 

in these patients unless benefit clearly outweighs risk.

• Early virologic failure of NVP + TDF (FTC or 3TC) in small clinical trials 

RVP • Once-daily dosing

• Coformulated with 

TDF/FTC

• Smaller pill size than 

coformulated TDF/

FTC/EFV or TDF/FTC/

EVG/COBI

• Compared with EFV:

• Fewer 

discontinuations 

for central 

nervous system 

adverse effects

• Fewer lipid 

effects

• Fewer rashes

• Smaller pill size

• Not recommended for use in patients with pre-ART HIV RNA 

>100,000 copies/mL because the rate of virologic failures is higher 

in these patients

• Higher rate of virologic failures observed in patients with pre-ART 

CD4 count of <200 cells/μL

• More NNRTI-, TDF-, and 3TC-associated mutations at virological 

failure than with regimen containing EFV + two NRTIs

• Meal requirement

• Absorption depends on lower gastric pH. (See Table 15a for 

detailed information regarding interactions with H2 antagonists 

and antacids.)

• Contraindicated with PPIs

• RPV-associated depression reported

• Use RPV with caution when coadministered with a drug having 

known risk of torsades de pointes.
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Section 10: Resources

and References

ARV 

Agent(s) Advantages Disadvantages

Protease Inhibitors (in alphabetical order)

PI Class Advantages:

• Higher genetic 

barrier to resistance 

than NNRTIs and RAL

• PI resistance at the 

time of treatment 

failure uncommon 

with RTV-boosted PIs

PI Class Disadvantages:

• Metabolic complications such as dyslipidemia, insulin resistance, 

and hepatotoxicity

• Gastrointestinal adverse effects

• CYP3A4 inhibitors and substrates: potential for drug interactions 

(more pronounced with RTV-based regimens)

(See Tables 14 and 15a.)

ATV (unboosted)• Fewer adverse 

effects on lipids 

than other PIs

• Once-daily dosing

• Low pill burden

• Good 

gastrointestinal 

tolerability

• Signature mutation 

(I50L) not associated 

with broad PI crossresistance

• Indirect hyperbilirubinemia sometimes leading to jaundice or 

scleral icterus

• PR interval prolongation: generally inconsequential unless ATV 

combined with another drug with similar effect

• Unboosted ATV should not be coadministered with TDF, EFV, or 

NVP (see ATV/r).

• Nephrolithiasis, cholelithiasis

• Skin rash

• Food requirement

• Absorption depends on food and low gastric pH (See Table 15a for 

detailed information regarding interactions with H2 antagonists, 

antacids, and PPIs.)

ATV/r) • RTV boosting: 

higher trough ATV 

concentration and 

greater antiviral 

effect

• Once-daily dosing

• Low pill burden

• More adverse effects on lipids than unboosted ATV

• More hyperbilirubinemia and jaundice than unboosted ATV

• Food requirement

• Absorption depends on food and low gastric pH (See Table 15a for 

interactions with H2 antagonists, antacids, and PPIs)

• RTV boosting is required with TDF and EFV. With EFV, use ATV 400 

mg and RTV 100 mg, once daily (PI-naive patients only).

• Should not be coadministered with NVP.

• Nephrolithiasis, cholelithiasis

DRV/r • Once-daily dosing

• Potent virologic 

efficacy

• Skin rash

• Food requirement

FPV/r • Twice-daily dosing 

resulted in efficacy 

comparable to LPV/r

• Once-daily dosing 

possible with RTV 

100 mg or 200 mg 

daily

• No food effect

• Skin rash

• Hyperlipidemia

• Once-daily dosing results in lower amprenavir concentrations than 

twice-daily dosing

• For FPV 1,400 mg + RTV 200 mg: requires 200 mg of ritonavir and 

no coformulation

• Fewer data on FPV 1,400 mg + RTV 100 mg dose than on DRV/r and 

ATV/r
Antiretroviral Reference Tables | 633

Section 10: Resources

and References

ARV 

Agent(s) Advantages Disadvantages

Protease Inhibitors (in alphabetical order) continued

LPV/r • Coformulated

• No food 

requirement

• Greater CD4 T-cell 

count increase than 

with EFV-based 

regimens

• Requires 200 mg per day of RTV

• Lower drug exposure in pregnant women – may need dosage 

increase in third trimester

• Once-daily dosing not recommended in pregnant women

• Once-daily dosing results in lower trough concentration than 

twice-daily dosing

• Possible higher risk of myocardial infarction associated with 

cumulative use of LPV/r

• PR and QT interval prolongation have been reported. Use with 

caution in patients at risk of cardiac conduction abnormalities or 

receiving other drugs with similar effect.

SQV/r • Similar efficacy but 

less hyperlipidemia 

than with LPV/r

• Highest pill burden among available PI regimens (6 pills per day)

• Requires 200 mg of RTV

• Food requirement

• PR and/or QT interval prolongations in a healthy volunteer study

• Pretreatment ECG recommended

• SQV/r is not recommended for patients with any of the following 

conditions:

• Congenital or acquired QT prolongation

• Pretreatment ECG >450 msec

• On concomitant therapy with other drugs that prolong QT 

interval

• Complete atrioventricular block without implanted pacemakers

• Risk of complete atrioventricular block
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Section 10: Resources

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ARV 

Agent(s) Advantages Disadvantages

Integrase Strand Transfer Inhibitors (in alphabetical order)

DTG • Once daily dosing 

if no resistance to 

integrase inhibitors

• Virologic response 

noninferior to RAL, 

superior to DTV/r 

and EFV

• Inhibits tubular secretion of creatinine and can decrease CrCL 

without affecting renal glomerular function

• May cause headache or sleep disturbance

EVG • Coformulation with 

COBI/TDF/FTC

• Once-daily dosing

• Noninferior to EFV/

TDF/FTC and ATV/r + 

TDF/FTC

• COBI is a potent CYP3A4 inhibitor, which can result in significant 

interactions with CYP3A substrates.

• COBI inhibits active tubular secretion of creatinine and can 

decrease CrCl without affecting renal glomerular function.

• Has potential for new onset or worsening off renal impairment

• Only recommended for patients with baseline CrCl >70 mL/min; 

therapy should be discontinued if CrCl decreased to <50 mL/min

• Lower genetic barrier to resistance than 

with boosted PI-based regimens

• Food requirement

RAL • Virologic response 

noninferior to EFV

• Fewer drug-related 

adverse events and 

lipid changes than 

with EFV

• No food effect

• Fewer drug-drug 

interactions than 

with EVG/COBI/

TDF/FTC-, PI-, 

NNRTI- MVC-based 

regimens

• Twice-daily dosing

• Lower genetic barrier to resistance than with boosted PI-based 

regimens

• Increase in creatine kinase, myopathy, and rhabdomyolysis have 

been reported

• Rare cases of severe hypersensitivity reactions (including StevensJohnson syndrome and toxic epidermal necrolysis) have been 

reported

CCR5 Antagonist

MVC • Virologic response 

noninferior to EFV 

in post-hoc analysis 

of MERIT study (See 

text.)

• Fewer adverse 

effects than EFV

• Requires viral tropism testing before initiation of therapy, which 

results in additional cost and possible delay in initiation of therapy

• In the MERIT study, more MVC-treated than EFV-treated patients 

discontinued therapy owing to lack of efficacy

• Less long-term experience in ART-naive patients than with boosted 

PI- or NNRTI-based regimens

• Limited experience with dual NRTIs other than ZDV/3TC

• Twice-daily dosing

• CYP 3A4 substrate: dosing depends on presence or absence of 

concomitant CYP3A4 inducer(s) or inhibitor(s)

Section 10: Resources

and References
Section 10: Resources

and References

Antiretroviral Reference Tables | 635

ARV 

Agent(s) Advantages Disadvantages

Dual-Nucleoside Reverse Transcriptase Inhibitor Pairs (in alphabetical order)

ABC/3TC • Virologic response 

noninferior to 

ZDV/3TC

• Better CD4 T-cell 

count responses 

than with ZDV/3TC

• Once-daily dosing

• Coformulation

• No food effect

• No cumulative TAMmediated resistance

• Potential for abacavir hypersensitivity reaction in patients with 

HLA-B*5701

• Inferior virologic responses when compared with TDF/FTC in patients with baseline HIV RNA >100,000 copies/mL in ACTG 5202 

study; however, this was not seen in the HEAT study

• Some observational cohort studies show increased potential for 

cardiovascular events, especially in patients with cardiovascular 

risk factors

TDF/FTC • Better virologic 

responses than 

with ABC/3TC 

in patients with 

baseline HIV RNA 

>100,000 copies/mL 

in ACTG 5202 study; 

however, this was 

not seen in the HEAT 

study

• Active against HBV; 

recommended dualNRTI for HBV/HIV 

coinfection

• Once-daily dosing

• No food effect

• Coformulated (TDF/

FTC, EFV/TDF/FTC, 

EVG/COBI/TDF/FTC, 

and RPV/TDF/FTC)

• No cumulative TAMmediated resistance

• Potential for renal impairment, including proximal tubulopathy 

and chronic renal insufficiency

• Early virologic failure of NVP + TDF + (FTC or 3TC) in small clinical 

trials

• Potential for decrease in bone mineral density

ZDV/3TC • Coformulated 

(ZDV/3TC and 

ZDV/3TC/ABC)

• No food effect 

(although better 

tolerated with food)

• Preferred dual NRTI 

in pregnant women

• Bone marrow suppression, especially anemia and neutropenia

• Gastrointestinal intolerance, headache

• Mitochondrial toxicity, including lipoatrophy, lactic acidosis, 

hepatic steatosis

• Compared with TDF/FTC, inferior in combination with EFV

• Less CD4 increase compared with ABC/3TC

• Twice-daily dosing

Abbreviations: /r = ritonavir boosted; 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; d4T = stavudine; ddI = didanosine; DRV = darunavir; DTG = 

dolutegravir; ECG = electrocardiogram; EFV = efavirenz; EVG = elvitegravir; FPV = fosamprenavir; FTC = emtricitabine; HPV = hepatitis B 

virus; LPV = lopinavir; MVC = maraviroc; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase 

inhibitor; NVP = nevirapine; PI = protease inhibitor; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SQV 

= saquinavir; TAM = thymidine analogue mutation; TDF = tenofovir; ZDV = zidovudine