U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau i

EDITED BY JEAN R. ANDERSON, MD

Associate Professor

Departments of Gynecology, Obstetrics, and Medicine

The Johns Hopkins University School of Medicine

Departments of Population and Family Health Sciences

The Johns Hopkins University School of Public Health
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

ii U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

Recommendations change rapidly in HIV care, so the care provider 

is cautioned that this edition is dated 2005. For the most current 

and continually updated HIV/AIDS treatment guidelines, contact 

AIDSinfo at:

http://www.aidsinfo.nih.gov

This Guide contains information relating to general principles of medical 

care which should not be construed as specific instructions for individual 

patients. Some of the information may cite the use of a particular drug 

in a dosage, for an indication, or in a manner other than recommended. 

Therefore, the manufacturer’s package inserts should be consulted for 

complete prescribing information. 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

HEALTH RESOURCES AND SERVICES ADMINISTRATION

HIV/AIDS BUREAU

PARKLAWN BUILDING, ROOM 7-13

5600 FISHERS LANE

ROCKVILLE MD 20857

http://www.hab.hrsa.gov

Publication date 2005
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau iii

FORWARD

A Guide to the Clinical Care of Women with HIV is a comprehensive clinical 

manual that addresses the primary care needs unique to women with 

HIV infection. The target audience is clinicians who provide primary care 

to women as well as those seeking a more in-depth understanding of how 

to care for women with HIV/AIDS. This 2005 edition of the guide, first 

published in 2001, has been updated and chapters have been added on 

international issues and nutrition.

A manual devoted specifically to the care of women with HIV is 

important. Because women are often challenged by social isolation, 

poverty, discrimination and lack of access to quality health care, they 

tend to be diagnosed later and to have poorer health status than men. 

They must contend with vulnerability related to reproductive and gender 

issues and domestic violence. Finally, women living with HIV are usually 

relied upon to meet the care needs of children and other family members, 

many of whom are also HIV-positive. 

DEDICATION

We want to acknowledge the women with HIV/AIDS who have been the 

inspiration for this Guide. Their strength is celebrated and their struggle 

is not forgotten. We offer this Guide as a tribute to them, and to the 

providers who have taken on this struggle and made it their own.

ACKNOWLEDGMENTS

A number of people made this Guide possible. Joan Holloway provided 

the framework for the Guide’s inception and development. Magda BariniGarcía, MD, MPH was the Project Officer who shepherded and oversaw the 

project. Helen Schietinger, the project manager, coordinated the production 

process and brought it to fruition. Laura Spofford designed the cover. For 

the 2005 edition, Patrice Lincoln was the typographer and designer and Bill 

Todd was the copyeditor and indexer. 
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

iv U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

For the 2005 Edition, 

the chapters were reviewed by the following experts:

Dawn Averitt 

Founder and CEO, The Well Project

Kirsten B. Balano, PharmD 

University of California, San Francisco

John G. Bartlett, MD

The Johns Hopkins University School of Medicine

Gail V. Berkenblit, MD, PhD 

The Johns Hopkins University School of Medicine 

Jonathan Ellen, MD

The Johns Hopkins University School of Medicine

Thurma McCann Goldman, MD 

HIV/AIDS Bureau, HRSA

Laura A. Guay MD

The Johns Hopkins University School of Medicine

Lisa Ruth Hirschhorn, MD 

Harvard University Medical School

Gregory M. Lucas, MD, PhD 

The Johns Hopkins University School of Medicine 

Mary E. McCaul, PhD

The Johns Hopkins University School of Medicine 

Howard L. Minkoff, MD 

State University of New York at Stonybrook School of Medicine

Helen Miramontes, RN, MSN, FAAN 

School of Nursing, University of California, San Francisco 

(Emeritus)

Ila Mulasi, MD

University of Maryland School of Medicine

Eula W. Pines, PhD, APRN, BC 

University of the Incarnate Word

Timothy R. Sterling, MD

Vanderbilt University School of Medicine

Glenn J. Treisman, MD, PhD 

The Johns Hopkins University School of Medicine

Ruth Ellen Tuomala, MD

Harvard University Medical School

Jonathan Zenilman, MD 

The Johns Hopkins University School of Medicine 
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau v

Contributing Authors

Silvia M. Abularach, MD, MPH

Assistant Professor

Department of Gynecology and Obstetrics

The Johns Hopkins University School of Medicine 

Baltimore, MD, U.S.

Carla S. Alexander, MD

Assistant Professor of Medicine

University of Maryland School of Medicine 

Baltimore, MD, U.S.

Jean R. Anderson, MD

Associate Professor 

Departments of Gynecology, Obstetrics, and Medicine

The Johns Hopkins University School of Medicine

Departments of Population and Family Health Sciences

The Johns Hopkins University School of Public Health

Baltimore, MD, U.S.

Barbara Aranda-Naranjo, PhD, RN, FAAN

Scanlon Endowed Chair in Values Based Health Care

Nursing and Health Studies

Georgetown University

Washington, DC, U.S.

Jared M. Baeten, MD, PhD

Department of Medicine

Massachusetts General Hospital

Boston, MA, U.S.

Patricia Barditch-Crovo, MD

Assistant Professor

Division of Infectious Diseases

The Johns Hopkins University School of Medicine 

Baltimore, MD, U.S. 

Magda Barini-García, MD, MPH

Senior Medical Advisor

HRSA Center for Quality 

HIV/AIDS Bureau, Health Resources and Services Administration

Rockville, MD, U.S. 

Victoria A. Cargill, MD, MSCE

Director of Minority Research, Director of Clinical Studies

Office of AIDS Research

National Institutes of Health 

Bethesda, MD, U.S.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

vi U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

Contributing Authors continued

Connie Celum, MD, MPH

Professor of Medicine and Adjunct Professor of Epidemiology

University of Washington

Seattle, WA, U.S.

Laura Cheever, MD, ScM

Deputy Associate Administrator

Chief Medical Officer

HIV/AIDS Bureau, Health Resources and Services Administration

Rockville, MD, U.S. 

Rachel Davis, RN, ACRN 

Field Nurse Case Manager 

Concentra Integrated Services, Inc. 

Pleasanton, TX, U.S.

Judith Y. Ellis, MS

Division of Training and Technical Assistance

HRSA Center for Quality

HIV/AIDS Bureau, Health Resources and Services Administration

Rockville, MD, U.S. 

Judith Feinberg, MD

Professor of Medicine

University of Cincinnati College of Medicine 

Cincinnati, OH, U.S.

Henry Francis, MD

Director, Center on AIDS and Other Medical Consequences 

of Drug Abuse (CAMCODA)

National Institute on Drug Abuse, National Institutes of Health 

Bethesda, MD, U.S.

Donna Futterman, MD

Professor of Clinical Pediatrics, Albert Einstein College of Medicine

Director, Adolescent AIDS Program, Montefiore Medical Center

Bronx, NY, U.S.

Monica Gandhi, MD, MPH

Assistant Professor

Division of Infectious Diseases

University of California, San Francisco 

San Francisco, CA, U.S.

Ruth M. Greenblatt, MD

Professor of Medicine, Epidemiology and Biostatistics 

University of California at San Francisco

San Francisco, CA, U.S.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau vii

Contributing Authors continued

Nancy A. Hessol, MSPH

Assistant Professor 

Department of Medicine

University of California, San Francisco 

San Francisco, CA, U.S. 

Dorothy Kasonde, MBCHB, MMed

Antiretroviral Consultant

JHPIEGO/Zambia

Lusaka, Zambia

Joyce Seiko Kobayashi, MD

Associate Professor

University of Colorado Health Sciences Center

Denver, CO, U.S. 

Rani Lewis, MD

Division Director for Maternal Fetal Medicine

Meharry School of Medicine

Nashville, TN, U.S.

Janine Maenza, MD

Clinical Assistant Professor 

Division of Allergy and Infectious Diseases, Department of Medicine

University of Washington

Seattle, WA, U.S.

Paul Pham, PharmD

Research Associate

Division of Infectious Diseases

The Johns Hopkins University School of Medicine 

Baltimore, MD, U.S.

Moses Pounds, PhD

Deputy Chief

Service Evaluation and Research Branch

Office of Science & Epidemiology

HIV/AIDS Bureau, Health Resources and Services Administration

Rockville, MD, U.S. 

Helen Schietinger, MA, ACRN

HIV Policy Analyst 

Washington, DC, U.S.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

viii U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

Contributing Authors continued

Suniti Solomon, MD

Founding Director

Y.R.Gaitonde (YRG) Centre for AIDS Research and Education

Chennai, India

Valdiléa Gonçalves Veloso Dos Santos, MD, MSc

Associate Researcher

Evandro Chagas Clinical Research Institute

Oswaldo Cruz Foundation

Rio Di Janiero, Brazil

Chia C. Wang, MD, MS

Assistant Professor 

Department of Medicine

Division of Infectious Diseases University of Washington 

Seattle, WA, U.S.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau ix

TABLE OF CONTENTS

 Abbreviations ................................................................................................x

I. Epidemiology and Natural History of HIV Infection in Women.............1

Nancy A. Hessol, MSPH, Monica Gandhi, MD, MPH, 

and Ruth M. Greenblatt, MD

II. Approach to the Patient .............................................................................35

Jean R. Anderson, MD

III. Prevention of HIV.......................................................................................47

Jared M. Baeten, MD, PhD, Chia C. Wang, MD, MS, 

and Connie Celum, MD, MPH 

IV. Primary Medical Care ................................................................................ 91

Judith Feinberg, MD and Janine Maenza, MD

V. Adherence to HIV Therapies ................................................................... 167

Laura W. Cheever, MD, ScM

VI. Gynecologic Problems.............................................................................. 177

Silvia M. Abularach, MD, MPH and Jean R. Anderson, MD

 Color Plates ............................................................................................... 231

VII. HIV and Reproduction ............................................................................. 241

Jean R. Anderson, MD

VIII. Addressing Cultural Issues to Improve Quality of Care ........................ 331

Barbara Aranda-Naranjo, PhD, RN, FAAN, Magda Barini-García, MD, MPH, 

Moses Pounds, PhD, and Rachel Davis, RN, ACRN

IX. Psychiatric Issues...................................................................................... 347

Joyce Seiko Kobayashi, MD

X. Substance Abuse........................................................................................ 377

Henry Francis, MD and Victoria A. Cargill, MD, MSCE

XI. Adolescents ................................................................................................ 405

Donna Futterman, MD

XII. Palliative Care and End-of-Life Care ....................................................... 419

Carla S. Alexander, MD

XIII. Occupational Exposure ............................................................................ 453

Rani Lewis, MD

XIV. Pharmacologic Considerations in HIV-Infected Pregnant Patients..... 469

Paul Pham, PharmD and Patricia Barditch-Crovo, MD

XV. Resources ................................................................................................... 547

Judith Y. Ellis, MS and Helen Schietinger, MA, ACRN

XVI. International Issues.................................................................................. 563

Dorothy Kasonde, MBCHB, MMed, Suniti Solomon, MD, 

Valdiléa Gonçalves Veloso dos Santos, MD, MSc, and Jean R. Anderson, MD

XVII.Nutrition Counseling, Care and Support................................................577

World Health Organization

 Index ..........................................................................................................599
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x U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

3TC Lamivudine

5-FU 5-fluorouracil

A-aDO2 Alveolar to arterial oxygen 

difference

ABC Abacavir

ACOG

American College 

of Obstetricians and 

Gynecologists

ADC AIDS dementia complex

ADR Adverse drug reaction

AFB Acid-fast bacilli

AFI Amniotic fluid index

AFP Alfa fetoprotein

AGC Atypical glandular cells

ALT Alanine aminotransferase

Anti-HBc Hepatitis B core antibody

Anti-HBs Hepatitis B surface 

antibody

AP Antepartum

APAP Acetaminophen

APV Amprenavir

ARV Antiretroviral

ASA Aspirin (acetylsalicylic acid)

ASC-H

Anal squamous 

intraepithelial lesions—

cannot exclude HSIL

ASCUS

Anal squamous 

intraepithelial lesions—

undetermined significance

ASIL Anal squamous 

intraepithelial lesions

ATV Atazanavir

AUC Area under the 

concentration-time curve

AZT Zidovudine

bDNA Branched DNA

bid 2 times daily

biw 2 times weekly

BMI Body mass index

BV Bacterial vaginosis

bx Biopsy

CASI Computer assisted selfinterviewing

ABBREVIATIONS

CBC Complete blood count

CBV Combivir

CDC Centers for Disease Control 

and Prevention

CEA Carcinoembryonic antigen

CES-D Center for Epidemiological 

Studies Depression scale

CI Confidence interval

CIN1, -2, -3 Cervical intraepithelial 

neoplasia, grade 1 (2, 3)

CLIA

Clinical Laboratory 

Improvements 

Amendments

Cmax Peak serum concentration

Cmin Trough serum 

concentration

CMV Cytomegalovirus

CNS Central nervous system

CPK Creatinine phosphokinase

CrCl Creatinine clearance

CSF Cerebrospinal fluid

CST Contraction stress test

CT Computed tomography

CVD Cardiovascular disease

CXR Chest x-ray

d Day

d/c Discontinue

d4T Stavudine

ddC Zalcitibine

ddI Didanosine

DEXA Dual-energy X-ray 

absorptiometry

DFA Direct fluorescent 

antibody

DLV Delavirdine

DMPA

Depomedroxyprogesterone 

acetate

DOT Directly observed therapy

DRESS Drug rash, eosinophilia, 

systemic symptoms

DS Double strength

dT Diphtheria/tetanus toxoid
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U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau xi

DVT Deep venous thrombosis

EBV Epstein-Barr virus

EC Enteric coated

EFV Efavirenz

ELISA Enzyme-linked 

immunosorbent assay

EM Electron microscopy

EMG Electromyelogram

ERCP Endoscopic retrograde 

cholangiopancreatography

ESR Erythrocyte sedimentation 

rate

ETOH Ethyl alcohol

FA Fluorescent antibody

FDA Food and Drug 

Administration

FSH Follicle stimulating 

hormone

FTA Fluorescent treponemal 

antibody

FTC Emtracitabine

FUO Fever of unknown origin

G6PD Glucose-6-phosphate 

dehydrogenase

GBS Group B Streptococci

GBV-C GB virus type C

GC Gonorrhea culture

G-CSF Granulocyte-colony 

stimulating factor

GI Gastrointestinal

GTT Glucose tolerance test

H&E Hematoxylin and eosin

HAART Highly active antiretroviral 

therapy

HAD HIV-associated dementia

HAV Hepatitis A virus

HBIG Hepatitis B 

immunoglobulin

HbsAg Hepatitis B surface antigen

HBV Hepatitis B virus

HCG Human chorionic 

gonadotropin

HCSUS HIV Cost and Services 

Utilization Study

HCV Hepatitis C virus

HDL High-density lipoprotein

HERS HIV Epidemiology 

Research Study

hgc Hard gel capsule

HLA Human leukocyte antigen

HPV Human papillomavirus

hr Hour

HRT Hormone replacement 

therapy

HSIL High-grade squamous 

intraepithelial lesion

HSV Herpes simplex virus

HTLV Human T-cell lymphotropic 

virus

IDSA Infectious Disease Society 

of America

IDU Injection drug use/user

IDV Indinavir

IgA Immunoglobulin A (E, G, 

M, etc.)

im Intramuscularly

INH Isoniazid

INR International 

normalization ratio

IP Intrapartum

IUD Intrauterine device

iv Intravenously

IVP Intravenous pyelogram

JC virus (Initials of index case of 

PML)

KOH Potassium hydroxide

KS Kaposi sarcoma

LAAM L-a-acetyl-methadol

LCR Ligase chain reaction

LDH Lactic dehydrogenase

LDL Low-density lipoprotein

LFT Liver function test

LIP Lymphoid interstitial 

pneumonia

ABBREVIATIONS continued
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xii U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

LP Lumbar puncture

LPV Lopinavir

LTS Long-term survival

MAC Mycobacterium avium 

complex

MCMD Minor cognitive-motor 

disorder

MDD Major depressive disorder

MDMA Methylenedioxymethamph

etamine (ecstasy)

MMR Measles, mumps and 

rubella

mo Month

MPA Medroxyprogesterone 

acetate

MRI Magnetic resonance 

imaging

MSM Men who have sex with 

men

MTCT Mother-to-child 

transmission

MTPA Methoxy (trifluoromethyl) 

phenylacetic acid

N/V/D Nausea/vomiting/diarrhea

N-9 Nonoxynol-9

NASBA Nucleic acid sequencebased amplification

NFV Nelfinavir

NIDU Non-injection drug use

NIH National Institutes of 

Health

NIMH National Institute of 

Mental Health

NNRTI Non-nucleoside reverse 

transcriptase inhibitor

NOS Not otherwise specified

NRTI Nucleoside reverse 

transcriptase inhibitor

NSAID Nonsteroidal antiinflammatory drug

NST Non-stress test

O&P Ova and parasites

OC Oral contraceptive

OI Opportunistic infection

OR Odds ratio

PACTG Pediatric AIDS Clinical 

Trials Group

PACTS

Perinatal AIDS 

Collaborative Transmission 

Study

PaO2 Partial pressure of oxygen

PCN Penicillin

PCP

Pneumocystis jiroveci 

(formerly carinii) 

pneumonia

PCR Polymerase chain reaction

PEP Postexposure prophylaxis

PGL Persistent generalized 

lymphadenopathy

PI Protease inhibitor

PID Pelvic inflammatory 

disease

PK Pharmacokinetic

PLWHA People living with HIV/

AIDS

PML Progressive multifocal 

leukoencephalopathy

PMTCT Prevention of mother-tochild transmission

po By mouth

PP Postpartum

PPD Purified protein derivative

PSN Predominantly sensory 

neuropathy

PTSD Post-traumatic stress 

disorder

PV Vaginally

qd 1 time daily

qm 1 time monthly

qod Every other day

qw 1 time weekly

ABBREVIATIONS continued
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U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau xiii

r/o Rule out

RIBA Recombinant immunoblot 

assay

RNA Ribonucleic acid

RPR Rapid plasma reagin

RT-PCR Reverse transcriptase 

polymerase chain reaction

RTV Ritonavir

sc Subcutaneously

sgc Soft gel capsule

SI Syncytium-inducing

SIL Squamous intraepithelial 

lesions

SIV Simian immunodeficiency 

virus

SMX Sulfamethoxazole

SOC States of Change behavior 

theory

SP Sulfadioxone 

pyrimethamine

sq Subcutaneous

SQV Saquinavir

SS Single strength

SSRI Selective serotonin 

reuptake inhibitor

STI Sexually transmitted 

infection

sx Symptom

TAM Thymidine-associated 

mutation

TB Tuberculosis

Td Tetanus/diphtheria

TDM Therapeutic drug 

monitoring

TE Toxoplasmic encephalitis

TIBC Total iron binding capacity

tid 3 times daily

tiw 3 times weekly

TMP Trimethoprim

TSH Thyroid-stimulating 

hormone

TSS Toxic shock syndrome

TST Tuberculin skin test

UNAIDS United Nations Program 

on AIDS

USPHS United States Public 

Health Service

VCT Voluntary counseling and 

testing

VDRL Venereal Disease Research 

Laboratory slide test

VZV Varicella zoster virus

WBC White blood cell

WHO World Health Organization

WIHS Women’s Interagency HIV 

Study

WITS Women and Infants 

Transmission Study

yr Year

ABBREVIATIONS continued
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xiv U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 1

A GUIDE ITO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

I. INTRODUCTION 

The successful introduction and spread of the human immunodeficiency virus (HIV) into the global human population has occurred 

for many reasons. The discovery and widespread use of penicillin and 

other antibiotics meant that there was treatment and cure for most 

sexually transmitted infections. The existence of these new drugs 

changed how people perceived risks associated with sexual activity. 

The development of hormonal contraceptives hastened the pace of 

change in sexual practices, as prevention of pregnancy without barrier 

methods became a possibility. Lifestyles were also changing: people 

were moving into regions that were previously uninhabited by man and 

long-distance travel became easier and much more common, allowing 

for greater social migration and sexual mixing. Although the virus may 

have been first introduced to humans earlier in the 20th century (most 

likely contracted from infected animals), it was in the 1970s that wider 

dissemination occurred. 

For industrialized countries, the first evidence of the AIDS epidemic was 

among groups of individuals who shared a common exposure risk. In 

the United States, sexually active homosexual men were among the first 

to present with manifestations of HIV disease, followed by recipients 

of blood or blood products, then injection drug users, and ultimately, 

children of mothers at risk. Women have represented an increasing 

proportion of reported AIDS cases in the United States, accounting for 

26% of adult cases in 2001 (CDC, 2002). Seventy-eight percent of AIDS 

cases in women are in African Americans and Hispanics, as compared 

with 52% of cases in men. 

In developing countries, the AIDS epidemic manifested quite differently,

both because the signs and symptoms were harder to distinguish from 

competing causes of morbidity and mortality, and because the epidemic 

was more generalized, instead of seemingly limited to certain “highrisk” groups. Worldwide, women now represent 50% of all adults living 

with HIV and AIDS (Table 1-1), and this proportion had been steadily 

increasing over time (UNAIDS, 2002). 

This chapter reviews the epidemiology of HIV/AIDS, beginning with 

how HIV is transmitted and the variables involved; the natural history 

of HIV infection in women — both without treatment and in the era of 

highly active antiretroviral therapy (HAART), and concludes with future 

issues regarding the HIV/AIDS epidemic.

I. EPIDEMIOLOGY AND NATURAL HISTORY OF

HIV INFECTION IN WOMEN

Nancy A. Hessol, MSPH, Monica Gandhi, MD, MPH, 

and Ruth M. Greenblatt, MD
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Epidemiology and Natural History of HIV Infection in Women

2 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

Table 1-1: Regional HIV/AIDS Statistics and Features, December 2002

Region Epidemic Started # Persons With Hiv Infection # Persons With New Hiv Infection Prevalence Among Adults Percent Of Infected Adults Who Are Women Main Modes Of Transmission For Adults

Sub-Saharan Africa Late 1970searly 1980s 29.4 million 3.5 million 8.8% 58% Heterosexual contact

North Africa and Mid-East Late 1980s 550,000 83,000 0.3% 55% Heterosexual contact, 

injection drug use,

South, South-East Asia Late 1980s 6.0 million 700,000 0.6% 36% Heterosexual contact, 

injection drug use

East Asia, Pacific Late 1980s 1.2 million 270,000 0.1% 24% Injection drug use, 

heterosexual contact, 

male/male sex

Latin America Late 1970searly 1980s 1.5 million 150,000 0.6% 30% Male/male sex, injection drug use, heterosexual 

contact

Caribbean Late 1970searly 1980s 440,000 60,000 2.4% 50% Heterosexual contact, male/male sex

Eastern Europe, 

Central Asia

Early 1990s 1.2 million 250,000 0.6% 27% Injection drug use

Western Europe Late 1970searly 1980s 570,000 30,000 0.3% 25% Male/male sex, injection drug use

North America Late 1970searly 1980s 980,000 45,000 0.6% 20% Male/male sex, injection drug use, heterosexual 

contact

Australia, New Zealand Late 1970searly 1980s 15,000 500 0.1% 7% Male/male sex

Total 42 million 5 million 1.2% 50%

Source: Modified from (UNAIDS, 2002).
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Epidemiology and Natural History of HIV Infection in Women

U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 3

I

II. HIV TRANSMISSION 

Epidemiologic studies have demonstrated that HIV is transmitted by 

three primary routes: sexual, parenteral (blood-borne), and perinatal. 

Virtually all cases of HIV transmission can be attributed to these 

exposure categories. Transmission rates from the infected host to the 

uninfected recipient vary by both mode of transmission and the specific 

circumstances. Because HIV is a relatively large virus, has a short half-life 

in vitro, and can only live within primates, HIV cannot be transmitted 

from casual (i.e., hugging or shaking hands) or surface (i.e., toilet seats) 

contact or from insect bites. 

A. MODES OF TRANSMISSION

Sexual transmission of HIV from an infected partner to an uninfected 

partner can occur through male-to-female, female-to-male, male-to-male, 

and female-to-female sexual contact. Worldwide, sexual transmission of 

HIV is the predominant mode of transmission (Quinn, 1996). Among U.S. 

women with AIDS, sexual transmission constitutes 41% of reported cases 

as of December 2001 (CDC, 2002). This 41% is probably an underestimate 

given that a large proportion of the women with AIDS who report no 

identifiable risk (an additional 17% of AIDS cases in women) are actually 

also infected via sexual transmission. While receptive anal and vaginal 

intercourse appear to present the greatest risk of infection (approximately 

0.1–3% and 0.1–0.2%, respectively, per episode), insertive intercourse 

(both anal and vaginal) has also been associated with HIV infection 

(approximately 0.06% and 0.1%, respectively, per episode) (Mastro, 1996; 

Vittinghoff, 1999). In addition, there have been a few case reports of 

male-to-male transmission from receptive oral intercourse with an HIVinfected male partner (approximately 0.04%-0.10% per contact) (Lifson, 

1990; Samuel, 1993; Vittinghoff, 1999; Page-Shafer, 2002) and female-tofemale transmission from oral-vaginal, oral-anal, sex toy–related, and 

digital intercourse (Marmor, 1986; Monini, 1996; Monzon, 1987; Perry, 

1989; Rich, 1993; Sabatini, 1983; Kwakwa, 2003). 

Parenteral transmission of HIV has occurred in recipients of blood 

and blood products, through transfusion of blood (estimated 95% risk 

of infection from transfusion of a single unit of HIV-infected whole 

blood [CDC, 1998a]) or clotting factors, in intravenous or injection drug 

users through the sharing of needles (approximately 0.67% risk per 

exposure [Kaplan, 1992]), in health care workers through needlesticks 

(approximately 0.3–0.4% risk per exposure, depending on the size 

and location of the inoculum [Tokars, 1993. Updated PHS guidelines, 

2001]), and, less commonly, mucous membrane exposure (0.09% risk 

per exposure (Updated PHS guidelines, 2001, Hessol, 1989). Among 

cumulatively reported AIDS cases in U.S. women through December 

2001, 39% had injection drug use as their exposure risk and 3% reported 

receipt of infected blood, blood products, or tissue (CDC, 2002). Parenteral 

transmission patterns vary by geographic region due to social and 

economic factors. For instance, in regions where the prevalence of HIV 
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Epidemiology and Natural History of HIV Infection in Women

4 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

infection is higher, the risk of occupational or nosocomial transmission of 

HIV is greater than in regions where there is lower prevalence (Consten, 

1995). The transmission risk is therefore related to the prevalence of 

HIV in the population as well as the frequency of exposure to infected 

body fluids and organs and the method of exposure (Fraser, 1995). In 

addition, many developing countries that have a high prevalence of HIV 

infection also lack the resources to implement universal precautions 

adequately (Gilks, 1998) and may experience a greater amount of 

transfusion-associated HIV transmission due to a lack of HIV antibody 

screening in some areas, a higher residual risk of contamination in 

blood supplies despite antibody screening (McFarland, 1997), and high 

rates of transfusion in some groups of patients. Recent data suggests 

that medical injections may account for a large number of previously 

unexplained HIV infections in the developing world (Gisselquist, et al. 

2002; Gisselquist, 2002; Rosenthal, 2001). 

Perinatal transmission can occur in utero, during labor and delivery, or postpartum through breast-feeding (Gwinn, 1996). Perinatal transmission rates 

average 25–30% (Blanche, 1989) overall in the absence of intervention, but 

vary by maternal stage of disease, use of antiretroviral therapy, duration 

of ruptured membranes, practice of breast-feeding, and other factors. 

In the United States as of December 2001, 91% of cumulative pediatric 

AIDS cases were attributed to perinatal transmission (CDC, 2002). More 

information on perinatal transmission can be found in Chapter VII on HIV 

and Reproduction. 

B. FACTORS FACILITATING TRANSMISSION

Transmission of HIV infection can be influenced by several factors, 

including characteristics of the HIV-infected host and the recipient, as 

well as the quantity and infectivity of the virus. A summary of factors 

affecting sexual transmission of HIV is presented in Table 1-2. 

INFECTIOUSNESS OF THE HOST

There is an association between the quantity of virus transmitted and 

the risk of HIV infection (Roques, 1993). Several studies have found 

that HIV-infected persons may be more likely to transmit the infection 

when viral replication is high, both during the initial stage of infection 

(Palasanthiran, 1993) and at more advanced stages of HIV disease (Laga, 

1989). People with high blood viral load are more likely to transmit 

HIV to recipients of blood, their sexual partners, and their offspring 

(Quinn, 2000; Vernazza, 1999; Gray, 2001). HIV has been quantified 

in semen (Coombs, 1998; Speck, 1999; Vernazza, 1997) and detected in 

female genital secretions (Ghys, 1997; Mostad, 1998), and virus in these 

locations may facilitate transmission. However, the association between 

infectivity and disease stage is not absolute; HIV-infected women may 

transmit virus to a first-born child but not to a second-born child (de 

Martino, 1991), and temporal studies of semen from HIV-infected men 

demonstrate waxing and waning viral titers over time (Krieger, 1991; 

Tindall, 1992). 
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Table 1-2: Biologic and Host-related Factors Affecting Sexual 

Transmission Of HIV 

Biologic Factor 

Host-related Infectivity Factors

Hiv Concentration 

In Genital 

Secretions

Infectiousness 

(Transmission)

Susceptibility 

(Acquisition)

Mutation of chemokinereceptor gene ? ? ▼▼▼

Late stage of HIV 

infection ▲▲ ▲▲▲ Not applicable

Primary HIV infection ▲▲ ▲▲ Not applicable

Anti-retroviral therapy ▼ ▼▼ ▼?

Local infection ▲▲ ▲ ▲▲

Presence of cervical 

ectopy* ▲▲ ▲? ▲▲

Presence of foreskin* ? ▲▲ ▲▲

Method of 

contraception

Barrier Not applicable ▼▼▼ ▼▼▼

Hormonal contraceptives ▲▲ ▲

▼			? ▲

▼			

Spermicidal agents ? ▼? ▲

▼			

Intrauterine devices ? ? ▲▲

Menstruation ? ▲▲ ▲

Factors that lower 

cervicovaginal pH* ▼? ▼? ▼?

Immune activation ▲? ▲ ▲

Genital tract trauma* ▲? ▲▲ ▲▲

Pregnancy ▲▲ ▲? ▲?

The degrees of positivity (▲ to ▲▲▲) and negativity (▼ to ▼▼▼) of the associations are indicated 

with arrows, with three arrows indicating a very strong association. The symbol ▲

▼				denotes that there 

is evidence in support of both a positive and negative association. A question mark (?) indicates an 

unknown or hypothesized association that is not currently supported by data. 

Source: Royce, 1997. Coptright New England Journal of Medicene. Reprinted with permission.

* More recent data reveal that use of microbicides containing nonoxynol-9 are associated with a higher 

susceptibility to HIV infection (Roddy, 1998). 

Factors that decrease viral titers, including antiretroviral therapy, may 

decrease but not eliminate the risk of HIV transmission (Hamed, 1993). 

Zidovudine has been shown to reduce vertical transmission from mothers 

to their fetus even when administered late in pregnancy or during labor 

(CDC, 1998b). (See Chapter VII on HIV and Reproduction.) Individuals 

receiving antiretroviral therapy have also shown reduced rates of HIV 

transmission to their sex partners (Musicco, 1994). Several studies have 

suggested that antiretroviral treatment reduces detection of HIV in 

female genital secretions (Cu Uvin, 1998) and the concentration of HIV 
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in semen (Gilliam, 1997; Gupta, 1997). Providers counseling patients 

on treatment should be clear that precautions to prevent transmission 

of the virus should be maintained because not all treatments reduce 

infectiousness, and transmissions have been reported among individuals 

with undetectable HIV RNA levels (European Collaborative Study Group, 

1999). The presence of HIV in seminal cells has been documented in 

some individuals receiving highly active antiretroviral therapy and with 

undetectable levels of HIV-RNA in plasma (Zhang, 1998).

Factors that increase the risk of exposure to blood, such as genital ulcer 

disease (Cameron, 1989; Plummer, 1991), trauma during sexual contact 

(Marmor, 1986), and menstruation of an HIV-infected woman during 

sexual contact (European Study Group, 1992; Nair, 1993; St Louis, 1993) 

may all increase the risk of transmission. 

Method of contraception also affects the likelihood of HIV transmission 

(Daly, 1994). There is overwhelming evidence that the correct 

and consistent use of latex condoms protects both men and women 

against HIV. 

SUSCEPTIBILITY OF THE RECIPIENT

Characteristics of the uninfected individual may increase the likelihood 

of infection for a given exposure to HIV. Specifically, inflammation 

or disruption of the genital or rectal mucosa (which can occur with 

sexually transmitted infections and trauma) and lack of circumcision in 

heterosexual men may increase the risk of infection (Cameron, 1989; 

Moses, 1994; Quinn, 2000). Sex during menstruation may increase a 

woman’s risk of acquiring HIV infection (Lazzarin, 1991) as may bleeding 

during sexual intercourse (Seidlin, 1993). In women, both ulcerative and 

nonulcerative sexually transmitted infections have been shown to be risk 

factors for acquiring HIV infection (Laga, 1993; Plummer, 1991). Cervical 

ectopy has been identified as a risk factor for acquisition of HIV infection 

in some (Nicolosi, 1994; Plourde, 1994) but not all (Mati, 1994) studies 

that have evaluated this condition. There is also some evidence that 

changes in the vaginal flora, as characterized by bacterial vaginosis, may 

facilitate acquisition of HIV (Sewankambo, 1997; Sturm-Ramirez, 2000). 

Nonbarrier contraceptive methods have also been investigated in 

association with risk of HIV acquisition. The most frequently studied 

methods of contraception have been oral contraceptives, injectable 

hormones, intrauterine devices, and nonoxynol-9 (Daly, 1994; Plummer, 

1998). (See Chapter III on Prevention of HIV.) Traditional vaginal agents, 

used in African women for sexual enhancement and self-treatment 

of vaginal symptoms, have also been investigated as potential cofactors 

for HIV transmission (Dallabetta, 1995). Use of hormonal contraceptives 

does not seem to be associated with increased susceptibility to HIV 

infection after adjustment for behavioral factors (Kiddugavu, 2003). 

The use of a popular vaginal and rectal microbicide, nonoxynol-9, 

has been shown to have no protective efficacy against the acquisition 
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of HIV (Roddy, 1998) and may even increase susceptibility to HIV 

infection due to mucosal barrier disruption, particularly with frequent 

use (Stephenson, 2000). The utility of other microbicidal agents for 

reducing the susceptibility to HIV infection is currently under active 

investigation.

There is increasing evidence that host genetic or immunologic factors 

may protect against HIV infection. This has been investigated in cohort 

studies of Nairobi sex workers (Willerford, 1993) and U.S. homosexual 

men (Dean, 1996), in which both sets of study subjects remained 

uninfected despite multiple sexual exposures to HIV. Individuals who 

are homozygous for a null allele of CCR5 are relatively resistant to 

sexually transmitted infection with HIV, indicating an important, though 

not absolute, role for this receptor in viral transmission. However, 

homozygous CCR5 mutations were not found among 14 hemophiliacs 

who remained uninfected with HIV after being inoculated repeatedly 

with HIV-contaminated Factor VIII concentrate from plasma during 

1980–1985 (Zagury, 1998). In this study, investigators found an 

overproduction of ß-chemokines in most of the uninfected individuals. 

VIRAL PROPERTIES

Several viral factors have been proposed to play a role in the 

transmissibility of HIV. These include phenotypic characteristics (e.g., 

envelope proteins required for transmission), genetic factors that control 

the replicative capacity and “fitness” of the virus, and resistance to 

antiretroviral drugs (Vernazza, 1999). 

Envelope sequences can define viral quasispecies that have been 

phenotypically arranged according to their ability to induce syncytia 

formation in infected T-cells (Paxton, 1998). It appears that the most 

commonly transmitted phenotype is the nonsyncytia-inducing, 

M-tropic viral strain, which is frequently found in those who have been 

recently infected. During the course of HIV infection the development 

of a more cytopathic, syncytia-inducing, T-tropic viral phenotype can 

be found and this is often a precursor to the development of AIDS. 

While some researchers have suggested that nonsyncytia-inducing 

isolates of HIV are preferentially transmitted (Roos, 1992), others 

have not been able to show preferential transmission of this isolate 

(Albert, 1995). 

Envelope sequences can also be used to define viral subtypes, or clades, 

and these subtypes may also influence the transmissibility of HIV. The 

distribution of HIV subtypes differs according to geographic region, 

with A, C, D, and E predominant in Sub-Saharan Africa and Asia and B 

predominant in the United States, the Caribbean, South America, and 

Western Europe (Hu, 1996). In one study, subtype E is reported to have 

greater tropism for Langerhans cells than subtype B (Soto-Ramirez, 1996) 

and may have a greater per-contact transmissibility. 
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The transmission characteristics of a viral strain that is resistant to 

certain antiretroviral agents may differ from transmission of wild-type 

virus. Recent data indicates that resistant virus may be transmitted less 

efficiently than wild-type virus (Leigh Brown, 2003), but further research 

on the characteristics of drug-resistant virus is underway.

III. NATURAL HISTORY AND HIV DISEASE PROGRESSION 

The natural history of HIV infection in adults has been extensively 

documented in the medical literature. The impact of sex on the 

manifestations and progression of HIV disease is still being investigated. 

HIV infects and induces cell death in a variety of human cell lines. 

T-helper lymphocytes (also known as CD4 cells) are a major target of 

viral infection, and circulating CD4 cells become steadily depleted from 

peripheral blood in most untreated infected persons. Thus quantification 

of CD4 cells in blood is a rather simple way of determining cumulative 

immunologic damage due to HIV. Profound CD4 cell depletion is unusual 

in persons who do not have HIV infection and is usually iatrogenic 

or associated with severe illnesses, such as chemotherapy-induced 

leukopenia (Aldrich, 2000). Other immunologic parameters become 

altered with HIV disease progression, and though often used for research 

purposes, they tend to be more difficult to measure and less reliable 

or more costly. The plasma HIV-RNA level or viral load quantifies the 

amount of virus circulating in the bloodstream and reflects the level of 

HIV replication.

Untreated HIV infection is a chronic illness that progresses through 

characteristic clinical stages; AIDS is an endpoint of HIV infection, 

resulting from severe immunologic damage, loss of an effective immune 

response to specific opportunistic pathogens, and tumors. AIDS is 

diagnosed by the occurrence of these specific infections and cancers or 

by CD4 cell depletion to less than 200/mm3. 

A. STAGING

HIV can cause a wide range of symptoms and clinical conditions that 

reflect the level of immunologic injury and different predisposing factors. 

Certain conditions tend to occur in association with each other and 

at specific CD4 cell counts. Staging systems for HIV disease facilitate 

clinical evaluation and therapeutic interventions, help determine the 

individual level of infirmity, and give prognostic information. Untreated 

HIV infection is a chronic illness that progresses through characteristic 

clinical stages that can be used to describe infirmity. Several groups have 

produced organized staging systems to facilitate clinical evaluation and 

planning therapeutic interventions. In industrialized countries, the most 

widely used system for classifying HIV infection and AIDS in adults 

and adolescents was published by the United States Centers for Disease 

Control and Prevention in 1992 (CDC, 1992). 
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The case definition (Table 1-3) begins first with confirmation of HIV 

infection via either serologic testing (combination of a screening method 

such as enzyme immunoassay and a more specific confirmatory test 

such as Western blot), or direct detection of HIV in patient tissue by viral 

culture, antigen detection, or other test such as polymerase chain reaction 

(PCR). The definition of each stage of illness is then based on two types of 

information: peripheral blood CD4 cell counts and clinical manifestations. 

CD4 cell counts are placed in three strata, ranging from relatively normal 

(>500 cells/mm3) to severe CD4 depletion (<200 cells/mm3). 

The clinical manifestations of HIV infection are also placed in three 

strata, generally in accordance with the level of immunologic dysfunction 

associated with the various conditions (Table 1-3). Category A includes 

persons who have minimal clinical findings, clinical findings that do not 

indicate immune injury (including absence of symptoms), generalized 

lymphadenopathy, or resolved acute HIV infection. Category B includes 

conditions that indicate the presence of a defect in cell-mediated 

immunity or conditions that appear to be worsened by HIV infection. 

Category C includes conditions that are considered AIDS defining, even 

in the absence of a CD4 cell count less than 200 cells/mm3 (CDC, 1992). 

The addition of specific laboratory measures, such as plasma HIV RNA 

level, improves prognostic value even after the occurrence of Category C 

conditions (Lyles, 1999). 

DEVELOPING WORLD

The CDC criteria require diagnostic testing and case confirmation 

methods that may not be available in developing countries, so several 

other sets of criteria have been proposed for these regions. Because 

lymphocyte subset quantitation is not widely available in many countries, 

the Global Program on AIDS of the World Health Organization (WHO) 

proposed a clinically based staging system that is more broadly applicable 

than the CDC system (WHO, 1993). The system uses clinical historical 

data, laboratory measures (optional), and indices of physical activity to 

assess level of infirmity to establish four clinical stages, summarized in 

Table 1-4. Laboratory measures include a single-assessment absolute CD4 

cell count, with the option of replacing this test with total lymphocyte 

count, both of which are placed in three strata. CD4 cell count is a better 

prognostic indicator than total lymphocyte count, but the two results 

correlate well (Brettle, 1993; Jacobson, 2003; Badri, 2003). 

Clinical history and functional measures are placed in four categories that 

range from asymptomatic to severe disease. In general, when compared 

with the CDC stages, the WHO system requires fewer diagnostic test data 

and fewer direct observations. The definition includes broader categories 

for conditions that may vary by region (e.g., disseminated infections with 

endemic mycoses, which are common in Southeast Asian AIDS patients 

but not in the United States or Europe). The inclusion of performance 

scale measures permits quantitative clinical assessment that is not 

dependent on laboratory resources. 
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Table 1-3: 1993 Revised Classification System for HIV Infection 

and Expanded Surveillance Case Definition for AIDS 

Among Adults And Adolescents

Cd4 Cell Category Clinical 

Category A 

Clinical 

Category B 

Clinical 

Category C

1. 500 cells/mm3 A1 B1 C1

2. 200–499 cells/mm3 A2 B2 C2

3. < 200 cells/mm3 A3 B3 C3

Category A Conditions Category B Conditions Category C Conditions

• No symptoms 

• Acute HIV infection (resolves) 

• Generalized lymphadenopathy 

• Bacillary angiomatosis 

• Oropharyngeal candidiasis 

• Vulvovaginal candidiasis:

persistent, frequent, or poorly 

responsive to therapy 

• Cervical intraepithelial neoplasia 

II or III 

• Constitutional symptoms: fever, 

diarrhea > 1 month 

• Oral hairy leukoplakia 

• Herpes zoster: multiple episodes 

or involving > 1 dermatome 

• Idiopathic thrombocytopenic 

purpura 

• Listeriosis 

• Pelvic inflammatory disease: 

particularly if complicated by 

tubo-ovarian abscess 

• Peripheral neuropathy

• Candidiasis of bronchi, trachea, 

lungs, or esophagus 

• Invasive cervical cancer 

• Coccidioidomycosis, 

disseminated or extrapulmonary 

• Cryptococcosis, extrapulmonary 

• Cryptosporidiosis (intestinal 

infection > 1 mo duration) 

• Cytomegalovirus disease 

(excluding liver, spleen or lymph 

nodes) 

• HIV-related encephalopathy 

• Herpes simplex: chronic ulcer 

> 1 mo duration, or bronchitis, 

pneumonitis, or esophagitis 

• Histoplasmosis: disseminated or 

extrapulmonary 

• Isosporiasis: > 1 mo duration 

• Kaposi’s sarcoma 

• Burkitt’s lymphoma 

• Immunoblastic lymphoma 

• Primary lymphoma of the brain 

• Mycobacterium avium complex

or M. kansasii: disseminated or 

extrapulmonary 

• M. tuberculosis: any site 

• Mycobacterium: other species or 

unknown species, disseminated 

or extrapulmonary 

• Pneumocystis carinii pneumonia 

• Recurrent pneumonia 

• Progressive multifocal 

leukoencephalopathy 

• Salmonella septicemia, recurrent 

• Toxoplasmosis of the brain 

• Wasting syndrome due to HIV 

Source: CDC, 1992.
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Table 1-4: The World Health Organization Clinical HIV 

Staging System and Proposed Modifications 

Laboratory Component Clinical Group

Cd4 Cell 

Count

Total 

Lymphocyte 

Count

1 2 3 4

A >=500 >=2000 A1 A2 A3 A4

B 200-499 1000-1999 B1 B2 B3 B4

C <200 <1000 C1 C2 C3 C4

Clinical Stage Clinical History Performance

Scale Criteria

Proposed 

Modifications

One:

Asymptomatic

1. Asymptomatic infection 

2. Persistent generalized 

lymphadenopathy

3. Acute retroviral infection

Normal 

functional level in 

performance scales

None

Two: Mild 

Disease

1. Unintentional weight loss less 

than 10% of body weight 

2. Minor mucocutaneous 

manifestations

3. Herpes zoster within the 

previous 5 years 

4. Recurrent upper respiratory 

infections

Performance scale 

level at which 

symptoms are 

present but patients 

are almost fully 

ambulatory

1. Substitution of weight 

loss with BMI 19–21 

kg/m2*

2. Specify addition of 

acute oral or genital 

ulcers as one of the 

minor mucocutaneous 

manifestations*

3. ESR ≤ 65 mm/hr defines 

Kigali stage II

4. ESR > 65 mm/hr defines 

Kigali stage III

Three: 

Moderate 

Disease

1. Unintentional weight loss 

greater than 10% of body 

weight 

2. Chronic diarrhea†

3. Prolonged intermittent or 

constant fever†

4. Oral candidiasis 

5. Oral hairy leukoplakia

6. Pulmonary tuberculosis 

developing within the previous 

year

7. Severe bacterial infections 

8. Chronic vulvovaginal 

candidiasis† or poorly 

responsive to therapy

Performance scale 

level at which 

patients remain 

in bed <50% of 

daytime, but more 

than normal

1. Suggest exclusion of 

oral candidiasis and 

pulmonary tuberculosis*

2. Recommend 

substitution of weight 

loss with BMI ≤ 19 

kg/m2*

3. Differentiation of 

ambulatory vs. 

hospitalized patients 

improved correlation 

with laboratory markers 

(Kassa, 1999) 

4. ESR ≤ 65 mm/hr defines 

Kigali stage II 

5. ESR > 65 mm/hr defines 

Kigali stage III 
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Table 1-4 (continued)

Clinical Stage Clinical History Performance

Scale Criteria

Proposed 

Modifications

Four: Severe 

Disease

1. HIV wasting syndrome 

defined as unexplained 

weight loss > 10% and 

either chronic diarrhea†

or chronic weakness† and 

unexplained fever 

2. Pneumocystis carinii

pneumonia

3. CNS toxoplasmosis 

4. Chronic cryptosporidial 

diarrhea†

5. Chronic isosporiasis with 

diarrhea†

6. Extrapulmonary 

cryptococcosis

7. Cytomegalovirus disease 

affecting organs other than 

the liver, spleen, or lymph 

nodes 

8. Visceral or chronic†

mucocutaneous Herpes 

simplex virus infection

9. Progressive multifocal 

leukoencephalopathy 

10. Any disseminated endemic 

mycosis

11. Candidiasis of the esophagus, 

trachea, bronchi, or lungs

12. Disseminated atypical 

Mycobacterium spp. infection 

13. Nontyphoidal Salmonella 

septicemia 

14. Extrapulmonary tuberculosis 

15. Lymphoma

16. Kaposi’s sarcoma 

17. HIV-related encephalopathy

Performance scale 

level at which 

patients remain 

in bed > 50% of 

daytime

1. Addition of oral 

candidiasis

2. Substitution of weight 

loss with BMI ≤ 19 

kg/m2*

3. Addition of chronic†

oral or genital ulcer

4. Addition of pulmonary 

tuberculosis

5. ESR > 65 mm/hr defines 

Kigali stage III

6. Addition of positive HIV 

serology‡

7. Addition of invasive 

cervical cancer‡

* Lifson, 1995.

† >1 mo duration.

‡ De Cock, 1993.

Source: WHO, 1993.

The four clinical stages in the WHO system correlated well with CD4 

cell counts and HIV RNA levels in a study of 750 Ethiopians (including 

336 women) by Kassa and others (Kassa, 1999). Other studies of patient 

populations have also demonstrated correlation of WHO clinical stage 

with CD4 cell count and clinical outcome (Morgan, 1997; 1998; Schechter, 

1995). When compared with the CDC staging, the WHO clinical stages 

demonstrated a high degree of specificity, but a lower level of sensitivity 

(35–65%) for HIV infection (Gallant, 1992; 1993). In particular all of the 

systems for disease staging are not perfectly sensitive and specific for 

HIV infection, but can be improved by the addition of HIV serologies 

(Ankrah, 1994; De Cock, 1991). Modifications (Table 1-4) have been 
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proposed that improve the prognostic accuracy of the WHO system. 

Based on observations made in a study of AIDS mortality among Rwandan 

women, Lifson and colleagues proposed minor modifications of clinical 

history definitions, replacement of body mass index (weight (kg) divided 

by height (m2)) for weight loss and use of erythrocyte sedimentation rate 

as a laboratory indicator of infirmity (Lifson, 1995). Body mass index 

was significantly better than percentage of body weight lost over two 

measurements taken in 1 year at predicting mortality. Both erythrocyte 

sedimentation rate and hematocrit were highly predictive of mortality 

over a 36-mo period of observation (Lifson, 1995). 

Other HIV-disease classifications, such as the Caracas definition proposed 

by the Pan American Health Organization (Rabeneck, 1996; Weniger, 

1992), have been proposed but have not been evaluated as extensively as 

the CDC and WHO systems. 

B. UNTREATED NATURAL HISTORY

PRIMARY OR ACUTE INFECTION

Acute HIV infection is a transient symptomatic illness that can be 

identified in 40–90% of cases of new HIV infection. It is characterized by 

a high rate of HIV replication, high titers of virus in blood and lymphoid 

organs (up to several million copies of HIV RNA per cubic millimeter of 

plasma), and initiation of an HIV-specific immune response. The amount 

of virus present in blood and tissues begins to fall after the appearance of 

cytotoxic (“killer”) lymphocytes that specifically react with HIV antigens; 

the vigor of this response varies among individuals and is associated with 

subsequent rate of disease progression (Cao, 1995). A pool of persistently 

infected CD4 cells (“latent reservoirs”) emerges early in the course of HIV 

infection and persists indefinitely (Chun, 1998). 

Symptoms have been identified 5–30 days after a recognized exposure to 

HIV (Schacker, 1998). The signs and symptoms of acute HIV infection 

are not specific; fever, fatigue, rash, headache, lymphadenopathy, 

pharyngitis, mild gastrointestinal upset, night sweats, aseptic meningitis, 

and oral ulcerations are most frequently reported. Because the clinical 

signs of acute HIV infection resemble those of many acute viral illnesses, 

the correct diagnosis is often missed. Because early treatment at the time 

of acute infection is actively being investigated (Rosenberg, 2000) (see 

Chapter IV on Primary Medical Care), early suspicion of and evaluation 

for HIV infection should be encouraged (Kahn, 1998). 

ESTABLISHED INFECTION

Regardless of whether the syndrome of acute HIV infection is recognized 

or not, after the HIV-specific immunological response begins to control 

the intensity of viremia, a so-called “viral set point” is established, which 

varies by individual. With exceedingly rare exceptions, the immunological 

response to HIV does not eliminate infection, but rather establishes 
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a steady state between viral replication and elimination (Henrad, 

1995). A variable level of viremia is attained that can be measured via 

quantification of the number of copies of HIV RNA present in blood (viral 

load). Although the viral load within the first 120 days of HIV infection 

is not of prognostic value (Schacker, 1998), most patients establish a 

relatively stable viral load after recovering from acute infection, and 

this viral set point is highly predictive of the rate of future progression 

of illness. In the case of a high viral load set point (i.e., values ranging 

up from 40000 copies/mm3), more rapid decline in CD4 cell counts and 

more rapid occurrence of Clinical Class B and C conditions will occur. 

Some patients have low viral load set points (below 500 copies/mm3), 

which indicates a better prognosis; no evidence of progression (CD4 cell 

depletion or HIV diseases) is seen for long periods of time in a small 

subset of patients (see section on long-term progression, below). The 

viral set point is likely influenced by several factors such as presence 

of other infections at the time of HIV exposure, genetic characteristics 

(particularly the type of HIV binding receptors present on lymphocytes), 

viral characteristics, age, and perhaps sex (see below) (Kahn, 1998). 

During the period of clinical stability, acute illnesses and other events 

that can stimulate the immune system, such as influenza, Herpes simplex

outbreaks, tuberculosis, and even routine vaccinations, have resulted in 

10–1000-fold increases in viral load; these increases are transient and 

most often resolve within 2 months (Stanley, 1996; Staprans, 1995). Thus, 

determination of viral load for prognostic purposes should not be done 

during or shortly after an acute illness. 

For most HIV-infected persons, viral quasispecies evolve over time. 

Transition for the nonsyncytia-inducing macrophage-tropic viral strains 

that are commonly present after transmission to syncytia-inducing Tlymphocyte tropic strains occurs in many hosts. While variation of viral 

quasispecies with time is usual, the mechanism by which this process 

occurs has not been defined. However, transitions in viral quasispecies 

and cellular tropism have been observed to coincide with key clinical 

events such as CD4 cell depletion and development of symptomatic 

illness. These virologic changes may reflect evolution of a virus 

that is tailored to an individual’s immune response or other genetic 

characteristics. Interventions that prevent evolution of quasispecies in a 

host may yield effective therapies in the future. 

The HIV RNA level in tissues does not correlate in a linear fashion 

with blood levels, so even in patients with undetectable plasma HIV 

RNA, intracellular and tissue HIV RNA can still be detected with 

more sophisticated techniques (Hockett, 1999). Thus HIV replication 

continues at varying pace among infected persons, even those who 

control viremia well. 
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HIV is also frequently present in the genital tract (Fiore, 1999; Iversen, 

1998), where expression of inflammatory mediators and lymphocyte 

receptors differ from blood and may influence the rate of viral replication 

and numbers of virions present (Anderson, 1998; Hladik, 1999). While 

the quantities of HIV present in cervicovaginal fluid are generally 

similar to those in blood (Hart, 1999; Shaheen, 1999), they differ in some 

individuals. The finding that HIV isolates from the lower genital tract can 

have different genotypic markers than blood isolates from a single host 

(Di Stefano, 1999; Shaheen, 1999) supports the concept that the lower 

genital tract sometimes functions as a separate virologic compartment. 

TIME COURSE

In most studies of seroconverters (persons for whom the date of the HIV 

infection can be estimated), 50–60% of adults will be diagnosed with an 

AIDS-defining condition within 10 years of infection (for the pre-HAART 

treatment era). Almost half of seroconverters will die (due to any cause) 

after 10 years of infection if the disease is left untreated (Vella, 1992). 

Increasing age is the factor most consistently associated with rate of 

progression and death in most groups of patients studied to date (Alioum, 

1998; UK Register of HIV Seroconverters Steering Committee, 1998; 

Pezzotti, 1999b; Prins, 1999). Date of infection also influences time from 

infection to an AIDS diagnosis, at least in some locations, demonstrating 

that even in the pre-HAART era, improvements in treatment have 

resulted in tangible benefits (Webber, 1998). 

LABORATORY INDICATORS AND PREDICTORS

A large number of laboratory tests have been evaluated as prognostic 

indicators in HIV infection. For the most part, the tests can be divided 

into three groups: A, measures of HIV replication; B, measures of 

immune function; and C, measures of inflammation. Group A is specific 

to HIV infection; Group B, when indicating severe CD4 cell depletion, is 

relatively specific to HIV infection; and Group C is generally not specific 

to HIV infection. Table 1-5 summarizes these laboratory measures, their 

outcomes, and their advantages and disadvantages. HIV RNA quantitation, 

performed on fresh or fresh-frozen plasma or serum, is a powerful and 

accurate prognostic indicator in HIV infection and is uniquely useful in 

determining response to antiretroviral therapy (Saag, 1996). In general 

the best measures of prognosis and staging include combinations of HIV 

RNA level, CD4 cell count, and perhaps lymphocyte function (cytotoxic 

lymphocyte response to HIV) (Spijkerman, 1997; Vlahov, 1998).
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Table 1-5: Laboratory Indicators of prognosis and/or stage of 

illness in HIV infection (blood specimen)

Group Test Interpretation 

in HIV Advantages Disadvantages

A HIV RNA level Higher level, 

greater rate of viral 

replication, poorer 

prognosis

Direct measure 

of current viral 

activity, excellent 

prognostic 

indicator. Useful 

as indicator 

of treatment 

response.

Requires freshly 

frozen and separated 

sample, expensive and 

technically demanding. 

(O’Brien, 1996; Saag, 

1996)

A P24 antigen 

level

Higher level indicates 

greater level of 

viremia, poorer 

prognosis

Simple and 

relatively 

inexpensive

Of less prognostic 

value than most other 

assays (Coombs, 1989; 

Fahey, 1990)

A Syncytiuminducing 

(SI) HIV 

phenotype

Emergence of 

SI strains is an 

independent 

predictor of 

progression to AIDS

An indicator of 

viral virulence for 

CD4 cells, adds 

to prognostic 

information 

provided by CD4 

and HIV RNA 

level

Requires viral culture 

or DNA assay, which 

is cumbersome and 

costly. (Koot, 1993)

B Lymphocyte 

count

Lymphopenia 

suggests greater 

immune injury

Indicates 

current status, 

cumulative over 

variable time

Nonspecific, can be 

influenced by large 

number of concurrent 

conditions and 

treatments

B CD4 subset 

(absolute 

count, % or 

CD8 ratio)

Depletion of CD4 

cells suggests 

immune injury and 

poorer prognosis, 

excellent prognostic 

indicator.

Indicates 

current status, 

cumulative over 

variable time, 

severe depletion 

relatively specific 

for HIV

Large range of 

variation (some 

introduced by 

differences among 

labs) expensive, must 

be performed on fresh 

(not frozen) specimen

B Lymphocyte 

markers of 

immunologic 

activation

Presence of 

specific sets of 

activation markers 

on lymphocytes, 

depending on type, 

indicates favorable 

or unfavorable 

prognosis. Excellent 

prognostic indicators.

Highly specific 

marker of long 

term stability or 

decline. 

Methods not 

standardized, costly 

and has limited 

availability. (Giorgi, 

1994)

B HIV-specific 

cytotoxic 

lymphocytes 

Strong cytotoxic 

responses to HIV 

indicate favorable 

prognosis.

Highly specific 

marker of long 

term stability.

Methods not 

standardized, costly 

and has limited 

availability. (Harrer, 

1996)

C B-2 

microglobulin

Higher B-2 

microglobulin levels 

associated with risk 

of progression

Simple to 

perform

General marker 

of inflammation, 

nonspecific. (Planella, 

1998)

C Neopterin Higher neopterin 

levels associated with 

risk of progression

Perhaps best 

prognostic 

indicator among 

group C. Simple 

to perform assay.

Not as good a 

prognostic indicator as 

CD4 cell count. (Fahey, 

1990)
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LONG-TERM NONPROGRESSORS

In untreated adults the median time from HIV infection to AIDS in 

developed countries is 8-10 years. However, approximately 8–15% of 

HIV-infected persons (most studies focus on men) remain symptomfree for much longer periods of time (Buchbinder, 1994; Munoz, 1995), 

a phenomenon that has been named long-term survival (LTS). These 

individuals are often called long-term nonprogressors. Among these 

individuals who remain clinically stable without treatment for 5–8 years, 

two groups can be discerned, those who have stable CD4 cell counts and 

those who have low CD4 cell counts but no AIDS-defining conditions 

(Schrager, 1994). Several factors have been found to be associated with 

longterm survival including host characteristics such as the presence of 

specific anti-HIV cytotoxic lymphocyte responses and viral characteristics 

such as defective genes and gene products (Kirchhoff, 1995). LTS patients 

tend to have consistently lower levels of HIV RNA after the period of acute 

infection, suggesting better control of viral replication (Vesanen, 1996). 

For example, viral growth in peripheral mononuclear cells taken from LTS 

patients was markedly less than in perhipheral blood mononuclear cells 

taken from healthy HIV-uninfected donors (Cao, 1995).

SEX EFFECTS

Concerns about sex-based differences in the course of HIV infection 

were expressed early in the epidemic. Women appeared to have more 

rapid progression of illness than men and to present with a different 

constellation of opportunistic conditions than men. However, current 

data suggests that the incidence and distribution of HIV-related illnesses 

are similar by sex, with the exception of Kaposi’s sarcoma, which is 

uncommon in women, and gynecologic manifestations of HIV. When 

sophisticated statistical methods were applied that controlled for the 

tendency of women to receive less care and to present with more 

advanced disease, sex-based differences in HIV disease course appeared 

to be eliminated. In general the predictors of the rate of HIV disease 

progression and survival among women are the same as in men. CD4 

cell count depletion and higher HIV RNA level are strong predictors 

of progression and survival in women (Anastos, 1999b). Several recent 

reports, however, describe sex-based differences in HIV RNA level and 

in rate of CD4 cell depletion; women had HIV RNA levels 30–50% lower 

than men who had comparable CD4 cell counts (Bush, 1996; Evans, 1997; 

Farzadegan, 1998). Similar results occurred when analysis was restricted 

to seroconverters or when HIV culture was used to quantify viremia 

rather than RNA assays (Lyles, 1998; Sterling, 1999; Sterling, 2001). A 

recent epidemiologic review of 13 studies, 4 of which were longitudinal, 

confirmed these findings, which were unchanged after adjustment for 

potential confounding variables, such as age, race, mode of transmission, 

and antiretroviral treatment (Gandhi, 2002). Intuitively, lower levels of 

circulating HIV RNA, which suggest lower steady-state levels of viremia, 

should be associated with better outcome. However, the lower HIV RNA 
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level seen in women does not appear to provide benefit in terms of 

disease progression or survival. Viral load differences tend to dissipate 

several years after seroconversion and rates of progression to AIDS are 

similar by sex (Sterling, 1999; Sterling, 2001) when examined in men and 

women followed from seroconversion. [Studies have also suggested that 

CD4 cell counts are higher in women at onset of AIDS (Prins, 1999) but 

that CD4 cell depletion may occur more rapidly in women as compared 

to men (Anastos, 2000).]

Determination of the effect of sex on the rate of progression, time until 

occurrence of an AIDS-defining condition, and death is a complicated 

process. Unless the date of HIV infection can be established, duration of 

infection becomes a significant unknown factor in studies. In addition, 

particularly in developed countries, HIV-infected women and men differ 

by more than just their biologic sex. Women tend to have lower income, 

be un- or underinsured for health care, be members of minority ethnic 

groups, have been born in Africa, have used injection drugs or cocaine, or 

to have a sexual partner who has done so, all of which are risk factors for 

poor health in general. In most studies women have shorter duration of 

infection prior to AIDS and death than men, but these differences tend to 

disappear when CD4 cell count and drug use are taken into consideration 

(Alioum, 1998; UK Register of HIV Seroconverters Steering Committee, 

1998; Pezzotti, 1999a; Santoro-Lopes, 1998). Several studies have reported 

an excess proportion of infections or deaths due to bacterial infection, 

often pneumonia (Feldman, 1999), among women compared with men 

(Melnick, 1994; Weisser, 1998).

Factors that influence disease progression are summarized in Table 1-6.

Table 1-6: Factors that influence rate of HIV-disease progression

Host Factors Effect Notes Reference

Age Increasing age 

associated with more 

rapid progression

Increasing age at 

the time of infection 

is consistently 

associated with rate 

of progression to 

AIDS and survival 

after AIDS diagnosis

(UK, 1998; 

Del Amo, 

1998; van 

Benthem, 

1998)

Sex Lower HIV RNA level 

among women, 

without progression 

benefit (Sterling 2001).

(Sterling, 

2001)

Race No consistent effect in 

various studies

(Del Amo, 

1998)

Chemokine 

receptor 

and ligand 

mutations: 

CCR5, CCR2, 

SDF-1

Homozygous mutation 

protective versus 

primary infection, 

heterozygotes appear 

to have slower 

progression

These mutations are 

much more common 

among Caucasians

(Winkler, 

1998; 

Zimmerman, 

1997; 

Martin, 

1998)
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Table 1-6 Factors that influence rate of HIV-disease progression (continued)

Host Factors Effect Notes Reference

HLA Type HLA differences 

associated with 

differing HIV RNA 

levels and rate of 

progression

Not currently of 

clinical utility, may 

provide clues to 

immunopathogenesis

(Saah, 

1998)

HIV risk 

behavior

Higher CD4 cell counts 

in persons with a 

history of IDU

This effect seen in 

several studies

(Brettle, 

1995)

Viral Factors Effect Notes Reference

Clade/location Mixed evidence, 

possible impact of viral 

subtype (or clade) on 

rate of progression

No clinical application 

currently

(Prins, 

1999; 

(Kanki, 

1999)

Mutations Mutation of viral 

genes can produce 

attenuated viral strains 

that are associated 

with slowed disease 

progression

Mutation resulting in 

attenuation appears 

relatively rare.

(Deacon, 

1995; 

Learmont, 

1999)

Clinical 

Indicators

Effect Notes Reference

Oral candidiasis 

and hairy 

leukoplakia

The presence of oral 

candidiasis or hairy 

leukoplakia suggests 

HIV infection and 

progression to impaired 

immunological 

function. Oral 

candidiasis adds to the 

predictive value of HIV 

RNA in persons with 

low CD4 cell counts

Accuracy of diagnosis 

varies with clinician 

experience, but oral 

manifestations are 

particularly useful 

prognostic indicators 

in resource-poor 

environments and 

important points 

of HIV recognition 

world-wide

(Carre, 

1998; 

Greenspan, 

1996)

C. NATURAL HISTORY IN HAART ERA

INDUSTRIALIZED COUNTRIES

In countries that are able to provide highly active antiretroviral therapy 

(HAART), HIV-associated morbidity and mortality have declined 

significantly (Michaels, 1998; Miller, 1999a; Miller 1999b; Palella, 1998; 

Pezzotti, 1999b). (See Primary Medical Care in Chapter IV for more 

information.) These population findings, based on regional surveillance 

systems, were preceded by a multitude of clinical trials that demonstrated 

clinical and virologic benefits of HAART (Bartlett, 1996; Collier, 1996; 

Deeks, 1997; Hammer, 1997). Despite the promise and documented 

benefits of HAART, clinical progression continues to occur among 

recipients, particularly among persons who received antiretroviral 
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treatment before initiation of HAART (Ledergerber, 1999). Viral resistance 

to HAART components can occur via several mechanisms, which for 

the most part involve mutation of viral target proteins (Richman, 1996; 

Schapiro, 1999). The emergence of antiretroviral resistance is a function 

of several factors: prior treatment, pre-treatment level of viremia, drug 

levels (adherence to medication regimens, bioavailability of medications, 

adequate dosing), and specifics of the regimen (Gulick, 1998; Ledergerber, 

1999; Shafer, 1998). Multiple daily doses, side effects, and, in some 

cases, dietary restrictions aggravate the problem of achieving optimal 

drug levels because protease inhibitor agents are relatively poorly 

bioavailable. Suppression of viral replication and prevention of resistance 

are directly related to the levels of antiretroviral medications. Persistent 

viral replication provides an opportunity for resistant mutations to occur, 

and selective pressure to support the continued presence of such mutants 

(Condra, 1998; Feinberg, 1997; Wong, 1997). Besides clinical treatment 

failure, emergence of antiretroviral resistance is now associated with 

transmission of resistant virus to previously uninfected persons, a 

finding that could portend significant limits to the effectiveness of 

these treatments in populations over long periods of time (Boden, 1999; 

Brodine, 1999; Yerly, 1999; Grant, 2002). 

DEVELOPING COUNTRIES

The high cost of antiretroviral drugs and the need for clinical and 

laboratory services for monitoring response to and efficacy of these 

treatments has greatly restricted provision of HAART in the developing 

world. Thus the reductions in morbidity and gains in survival in HIV 

patients that have been demonstrated in many industrialized countries 

do not consistently extend to developing countries in which the majority 

of HIV cases occur worldwide. A consensus statement regarding 

provision of these therapies has been released based on meetings 

held in Dakar and Abidjan during 1997. The key recommendations 

of conference participants include: efforts must be made to expand 

provision of antiretroviral therapy; antiretroviral therapy only makes 

sense in the setting of effective AIDS control programs; funding must 

be sustained to provide uninterrupted treatment and continuity of 

care; care providers must be trained in use of the treatments and basic 

patient rights; resources for assessment of efficacy and tolerance must 

be available; sentinel monitoring for resistance pattern determination 

should be available; 3-drug combination regimens should be used when 

possible; treatment of pregnant women to prevent perinatal transmission 

must be a priority; and new drug development should focus on less 

costly medications (International AIDS Society, 1999). In December 

2002, the World Health Organization launched a new initiative called “A 

Commitment to Action for Expanded Access to HIV/AIDS Treatment” 

to promote international cooperation in expanding access to HIV 

treatments to resource-poor settings.
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IV. FUTURE ISSUES 

A. GLOBAL IMPACT

The HIV/AIDS epidemic continues to spread without full control in any 

country. Over 58 million people have been infected worldwide. By the end 

of 2002, the United Nations Program on AIDS (UNAIDS) estimated that 42 

million people were living with HIV, a figure that includes 19.2 million adult 

women (UNAIDS, 2002) (Table 1-1). In 2002 it is estimated that 5 million 

new HIV infections occurred, with 2 million of these occurring in women. 

After steady increases of the prevalence of disease among women during 

the 1990s, currently 46% of all persons over the age of 15 living with HIV 

are women. Globally, AIDS is now the fourth leading cause of mortality; 3.1 

million deaths have been attributable to AIDS in 2002 alone, of which 1.2 

million occurred in women. The notable improvements in AIDS mortality 

reported in North America and Europe, in association with the introduction 

of highly active combination antiretroviral therapies, do not extend to most 

of the world’s cases, which occur in regions where this expensive type of 

treatment is not available. 

More than 95% of HIV-infected people live in the developing world, most 

in Sub-Saharan Africa. Seventy percent of infections that occurred during 

2002 took place in this epicenter. The region has also experienced 83% of 

all AIDS deaths. Unfortunately, prior projections of the epidemic course in 

southern Africa underestimated the incidence of infection by half (Balter, 

1998). Improved data have revealed that the prevalence rates in southern 

Africa are staggering: 20–26% of adults (aged 15–49 yr) are infected; in 

some regions 20–50% of pregnant women are infected and are likely to 

transmit infection to one third of their offspring. In four southern African 

countries, HIV prevalence in adults now exceeds 30%: Botswana (38.8%), 

Lesotho (31%), Swaziland (33.4%), and Zimbabwe (33.7%). The declining 

mortality rate and population growth taking place in other regions cannot 

be extended to Sub-Saharan Africa, because of the extent of AIDS mortality 

(Bongaarts, 1998). AIDS has now surpassed malaria as the leading cause of 

death in this region (Balter, 1999). Life expectancy will fall from 64 to 47 yr 

by 2015. AIDS will cost, on an average, 17 yr of life expectancy in the 9 SubSaharan countries with a >10% prevalence of HIV infection among adults. 

The child mortality rates in this region are also elevated by AIDS; rates are 

approximately double that expected without the HIV epidemic (UNAIDS, 

2002). Within 1 yr, 2400 Zimbabweans will succumb to AIDS per week, 

many in the prime of life, many leaving dependent children as orphans (up 

to 1 in 5 children are likely to become orphans). The former United States 

Surgeon General, David Satcher, notes that “the progress of decades of work 

immunizing children, controlling diseases, and improving nutrition is being 

negated by HIV” (Satcher, 1999). 

In Asia, the epidemic has a mixed pattern that includes countries with 

slow growth in HIV prevalence, countries with some success in control 

efforts, and regions that appear to be experiencing explosive epidemics. 
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Currently 7.2 million Asians are infected with HIV. Rapidly accelerating 

epidemics are occurring in China, Cambodia, Vietnam, and India. For 

instance, the US Intelligence Council estimates that 20 to 25 million 

people in India will be infected by the year 2010. Whereas urban areas 

were initially of greatest concern in many countries, recent information 

has revealed very active epidemics in specific rural areas (up to 2% of the 

general population), which are hosts to large proportions of the region’s 

population. 

Although the outlook for AIDS in Asia is bleak, there is also cause 

for hope. Growth of the epidemic in the Philippines is notably slow 

(Jacobs, 1999). Thailand has been successful in reducing the incidence 

of infection in sentinel population groups (such as members of the 

military and pregnant women) using a combination of good surveillance, 

effective policy response, and implementation of educational and 

condom promotion programs. The incidence of HIV infection among 

pregnant women in Thailand has dropped from a peak of 2.4% in 1995 to 

1.7% in 1997 (Phoolchareon, 1998). However, ongoing political upheaval 

and cuts to the national HIV prevention budget may modify this pattern 

of success in the near future. 

In the Americas the epidemic continues to grow in specific subgroups. 

In the United States, as summarized earlier in this chapter, the highest 

incidence of infection is occurring among poor women, particularly 

among women of color. Increasing rates of HIV incidence in men who 

have sex with men have been reported from large urban centers in the 

US over the past several years [Chen, 2002; Koblin, 2003]. In Mexico the 

incidence of infection among men who have sex with men continues to 

be high, whereas in Brazil and the Caribbean heterosexual transmission 

is increasing. At surveillance sites in the Dominican Republic and Haiti 

the prevalence of HIV infection among pregnant women has reached 8% 

(UNAIDS, 2002). 

Rapid spread of infection among injection drug users in Eastern Europe 

and Central Asia is likely to foreshadow a large number of cases among 

women and increasing prevalence of perinatal transmission. The 

introduction of HIV into these high-risk populations has been paralleled 

by tremendous increases in the incidence of syphilis and other sexually 

transmitted infections. 

B. CONTAINING THE EPIDEMIC

Control of the HIV epidemic should be a worldwide health priority. Complex 

interactions of social, economic, and cultural factors have preceded AIDS 

with epidemics of other sexually transmitted infections, and now hinder 

control of HIV itself. Global disparities in economic status have limited 

efforts to control sexually transmitted infections that are much simpler to 

diagnose and treat than HIV. The effect of limited monetary resources is 

compounded by stigmatization of HIV and sexually transmitted infections 

that affect willingness to seek care, social support of afflicted individuals, 
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and health policy decision making. Traditional cultural values regarding 

the role of women also tend to intensify the problems. Lack of acceptance 

of the right of women to make decisions about childbearing and work 

outside the home limits options for individuals who wish to reduce the 

risk of infection via sexual exposures. Economic independence is a crucial 

factor enabling women to make decisions for themselves. The options for 

employment outside of sex work, for divorced or widowed women, in 

many societies are quite restricted. These fundamental values may directly 

conflict with efforts to empower women to avoid the risk of HIV and other 

sexually transmitted infections (Gollub, 1999). 

To control the HIV epidemic, societies need to make commitments that 

may require an uncomfortable loss of highly valued cultural norms. 

Without social acceptance and encouragement, behaviorally mediated risk 

reduction strategies may not assume full efficacy. Vaccination is, at present, 

an optimal but unavailable solution. The prospects for development of an 

effective vaccine in the near future are not promising. Thus we have good 

cause to fear for the effects of HIV on women worldwide, and to increase 

our attention to this enormous problem as we enter the 21st century and 

the third decade of the HIV pandemic. 

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34 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 35

II

A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

The woman with HIV infection is indistinguishable from most women 

seen in primary care today. Women with HIV cover the spectrum of age, 

color, geography, education, cultural background, and income level, and 

have all of the health and lifestyle concerns any other woman has, in 

addition to those related to HIV. She is often asymptomatic, and may not 

know she is infected. She is frequently a mother and a caretaker for other 

family members. The issues most important to her will be those shaped 

by her personal circumstances — HIV is part of these circumstances, but 

her own perception of how big a part will vary from woman to woman 

and from time to time. The health care provider–patient relationship 

begins with where the individual woman is. To be most effective, it must 

become a partnership based on mutual trust and respect.

This chapter reviews general guidelines for interaction with all patients, 

highlighting points that are particularly relevant to women with HIV 

infection, and provides an overview of the initial and ongoing medical 

and psychosocial evaluation.

I. GENERAL GUIDELINES

A. COMMUNICATION

The initial interaction of patient and provider should begin with 

introductions and from there, it should be highlighted with clear and 

nonjudgmental communication. Language and terminology used should 

be sensitive, inoffensive, and easily understood by the patient. This will 

vary depending on the patient’s age, cultural background, and level of 

education. Translation will be needed for women unable to adequately 

understand or express themselves in the language of the medical 

provider.

Whenever possible, questions should be asked in an open-ended manner, 

including questions about behavior and treatment adherence, and the 

woman should be given permission to be honest and to acknowledge 

failure in terms of relapse or nonadherence. She should be given 

adequate time and opportunity to ask questions and express concerns.

Women undergoing gynecologic exams often feel special anxiety, 

vulnerability, embarrassment, or simply fear of discomfort or the 

discovery of pathology. This anxiety and vulnerability may be particularly 

pronounced in women with history of sexual abuse, rates of which are 

increased in some popluations of women living wth HIV. It is important 

II. APPROACH TO THE PATIENT

Jean R. Anderson, MD
36 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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to adequately prepare each woman verbally for the exam, and visually 

as well, if possible, showing her charts, models, or equipment (such as 

specula), which may demystify the whole process. Explain what will be 

done and why, as well as the degree of discomfort to be expected. During 

the exam tell her what you are going to do before doing it, describe what 

you see or feel, and reassure her when findings are normal.

Do not underestimate the importance of nonverbal communication. 

Facial expression and body posture are often far more articulate than 

words, and the most effective providers are sensitive to these cues and 

use their own body language with care. Maintaining frequent eye contact 

encourages the patient’s candor, builds rapport and trust, helps allay 

embarrassment and fear, and conveys your interest and attention. The 

gynecologic exam may need to be postponed until a subsequent visit in 

some women in order to develop trust and to ensure there is adequate 

time for those with special anxiety about the exam.

Patients should be given written instructions on how to reach their 

providers when there are problems or questions and how to make 

appointments. Whenever possible, written information about HIV and 

its treatment, and other health issues, should be available to supplement 

face-to-face discussions.

B. RESPECT

Every person deserves respect. Do not be condescending, patronizing, or 

judgemental. Under no circumstances should a patient ever be treated as 

a sexual object, particularly when assessing risk behaviors or performing 

the pelvic exam. Although different circumstances may dictate different 

levels of formality, addressing the patient by her first name (without her 

express consent) or, especially, by terms of familiarity (e.g., “honey” or 

“dear”) is usually inappropriate and often offensive.

Respect for the individual includes respect for her beliefs and values. 

The use of complementary therapies among HIV-infected individuals is 

common and should be respected, not ridiculed, even while discouraging 

potentially harmful remedies and emphasizing the proven effectiveness 

of currently recommended regimens.

C. SENSITIVITY

Sensitivity is essential to gather and impart important information, to 

foster trust, and to ensure ongoing follow-up. It requires attention to 

how words are used and questions are asked, and to a great deal that 

is unspoken. Responding to a patient’s fear, anxiety, denial, or anger is 

inevitably part of the health provider’s role and requires consideration 

of more than a disease process, but of a whole person and the entire 

context of her life. Any chronic and life-threatening disease carries with 

it an enormous burden of vulnerability and loss of control. Anything the 
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II

provider can do to give back some control to the woman will help ease 

that burden. The importance of adherence to antiretroviral regimens for 

optimal effectiveness and to reduce the development of drug resistance 

has been well established. Allowing the patient to be involved in 

choosing her treatment regimen when possible will allow her values 

and lifestyle (job schedule, etc.) to be considered and is believed to 

enhance adherence. Understanding her cultural background enhances 

your sensitivity. For example, involvement of the patient’s spouse or 

mother during visits may be particularly important and reassuring for 

Hispanic women.

D. CONFIDENTIALITY

Confidentiality is a major cornerstone of the therapeutic relationship. 

It carries special meaning for HIV-infected individuals who have 

experienced discrimination in the workplace and other settings, 

stigmatization, and occasional abandonment by friends or family. HIVpositive women may be particularly vulnerable to these effects because 

of lower economic status, cultural traditions and general societal beliefs 

about the role of women, minority status, and child care or other 

caretaking responsibilities. Information about a patient’s HIV status or 

details about her medical condition should be kept strictly confidential 

by providers and shared only with the express permission of the woman 

herself. At the same time she should be encouraged and assisted in 

disclosing her status to others who need to know, i.e., sexual partners and 

health care providers. It is important to note that all states are required to 

report cases of AIDS and some also have mandatory HIV reporting. The 

need to report and the safeguards (such as anonymous reporting in some 

states) which are in place should be discussed with each woman.

II. EVALUATION OF THE HIV-INFECTED WOMAN

A. TEAM APPROACH

Because of the medical and social complexity of HIV disease, a team 

approach to the care of women with HIV is essential and care should 

be both coordinated and integrated with different members of the 

team. Furthermore, as the time available for the primary care provider 

to spend with each patient becomes increasingly limited, the role of 

other team members in assistance with education and support becomes 

even more important. Expertise needed includes HIV medical expertise 

(including management of antiretroviral regimens), gynecology, 

nursing, counseling, and social service assistance/case management. 

Throughout the course of HIV infection, multidisciplinary medical 

collaborations should be available for evaluation and management of 

the varied medical problems associated with HIV. The use of peer 
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counselors may be especially helpful as women deal with negotiating 

safer sexual practices, contraception and other reproductive concerns, 

medication adherence, and other issues where similar cultural 

background and personal experience with HIV may facilitate education 

and candid discussion.

B. HIV EXPERIENCE

Care by a medical provider with HIV experience is one of the few 

specific provider or health care system-related factors that has been 

shown to prolong the life of HIV-infected individuals (Kitahata, 1996; 

Laine, 1998). This is increasingly important as antiretroviral treatment 

becomes steadily more complicated and recommendations change 

almost monthly. Awareness of drug interactions and strategies to avoid 

the development of antiretroviral resistance are but two issues that have 

a significant impact on both the short- and long-term health of the HIVpositive individual. Primary providers with little or no HIV experience 

should link with providers with HIV expertise to provide optimal care 

by referral or regular consultation. If a woman requires referral to an 

HIV expert, it is important that the primary care provider assure the 

woman that she is not being abandoned; furthermore, as women live 

longer with HIV, the primary care provider’s involvement in caring for 

other medical conditions remains critical for the overall health of the 

woman. Current U.S. Public Health Service treatment guidelines, several 

as living documents with regular online updating, can be accessed at 

http://www.aidsinfo.nih.gov. The Health Resources and Services 

Administration also supports the AIDS Education and Training Centers 

warmline (1-800-933-3413), which is a resource for clinical providers 

needing expert consultation.

C. CULTURAL SETTING AND BACKGROUND

The ability to give optimal patient care depends on an understanding of 

where the patient “begins,” her traditions and beliefs. These affect her 

understanding of health and disease and her acceptance of conventional 

medical treatment, as well as possible reliance on alternative or 

complementary therapies. These also affect her view of herself as a 

woman, her role and responsibilities in society, and issues related to 

childbearing and contraception. Potential barriers to care that may be 

encountered include difficulties in speaking, understanding, or reading 

English, culturally based fears and mistrust of the health care system, 

and undocumented immigration status.The role of cultural sensitivity in 

the care of HIV-positive women will be more fully addressed in Chapter 

VIII on Psychosocial and Cultural Considerations.
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D. SPECIAL POPULATIONS

In addition to cultural setting or background, women living with HIV/

AIDS may have other life circumstances that require special approaches 

to care and unique sensitivity. These include incarcerated women; 

women with alcohol or drug addiction; women with psychiatric illness; 

lesbians and transgendered women; women who are victims of domestic 

violence; and others. Certain circumstances may arouse strong emotions 

in care providers because of the provider’s own background or beliefs. It 

is essential that the provider be willing and able to separate themselves 

from whatever personal connotations or associations they may assign to 

certain lifestyles or life circumstances, and provide care that is unbiased, 

sensitive, kind, and empathetic. If this is not possible, the patient should 

be referred to another provider who can give such care. 

E. SPIRITUALITY

The spiritual dimension of a person’s life encompasses her beliefs 

and values and what gives her life meaning and a sense of wholeness 

(Puchalski, 2000). Spirituality is important throughout life, during both 

health and illness, and an individual’s beliefs and values can have a 

profound effect on the way she views illness and its treatment. Some 

women may view HIV as a punishment and this belief may lessen their 

acceptance of treatment or may put them at risk of nonadherence. Major 

spiritual questions that often arise during illness are:

• What gives my life meaning?

• Why is this thing happening to me?

• How will I survive this loss?

• What will happen to me when life ends?

It is important that the health care provider consider spirituality as an 

important component of physical, emotional, and mental health, assess 

the woman’s beliefs, and learn what is important to her. The spiritual 

history should include specific questions about the patient’s faith or 

beliefs, the importance and influence of these in her life, her involvement 

in a spiritual or religious community and its importance to her, and how 

the health care provider can help address these issues as part of her health 

care. Spirituality should be addressed as an ongoing issue, and referrals 

to ministers, priests, rabbis, other spiritual guides, or similar community 

resources can be an important component of care. The provider’s own 

spiritual beliefs can be a source of strength personally and can enhance 

the patient-provider relationship, but should not be imposed on the 

patient — her own beliefs should be respected.

F. IDENTIFYING SUPPORT SYSTEMS AND DISCLOSURE

During the initial evaluation, the HIV-infected woman’s social and 

emotional support system should be identified and reinforced, and updated 

information about this support system should be obtained at each visit. To 

whom has she disclosed her HIV status and what was the response? Many 
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HIV-positive women experience feelings of guilt and shame, or are fearful 

of violence or abandonment, and so are reluctant to trust anyone with 

knowledge of their infection or their feelings about it. Many communities 

still attach enormous stigma to HIV and the individual woman’s fears about 

ostracism and abandonment should be openly addressed. Their sense of 

isolation is harmful to both their physical and emotional well-being, and 

may result in avoiding clinic visits and nonadherence to drug therapy. The 

use of peer advocates or support groups may offer additional support for 

many women with HIV.

Special issues involve disclosure to sexual partners, children, and other 

health care providers. Disclosure to those individuals who may be at 

risk for transmission of HIV from the patient should be encouraged and 

barriers to disclosure, such as fear of violence, should be identified and 

addressed. The provider should offer assistance with disclosure when 

appropriate. Disclosure of a mother’s HIV status to her children, who may 

or may not be infected themselves, is a personal decision and should be 

honored. The provider should discuss the various considerations in this 

decision and offer assistance if needed.

G. LIMITED RESOURCE SETTINGS

Currently, in limited resource settings the foundations of HIV care are 

services to provide basic medical care, treat sexually transmitted infections 

(STIs), identify HIV infection through voluntary counseling and testing 

(VCT), and provide primary and secondary HIV prevention services, 

including prevention of mother-to-child transmission. Prevention and 

treatment of TB and other opportunistic infections are needed as 

patients with HIV become more immunosuppressed, but require greater 

resources in terms of medications, laboratory monitoring, patient and 

provider education and training, and community engagement. In 

settings with few resources the ability to use antiretroviral drugs is still 

limited by issues of cost, accessibility, and health care infrastructure, 

but this is beginning to change with the growing global consensus that 

there is a moral imperative to provide these life-sustaining therapies. The 

Clinical Services Pyramid (Figure 2-1) (JSI/WEI Center for HIV/AIDS. 

2001) illustrates the inter-relatedness of the community, laboratory 

infrastructure, and patient and provider education that is essential at all 

levels of HIV care. These components of the health care system must 

exist and be strengthened for both prevention and care and treatment 

services to succeed and use of anti-retroviral therapy (ARV) to reach 

those most in need. 
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II

Figure 2-1

Patient and Provider Education

Clinical Services Pyramid

Community Support

Prevention/Treatment

ART

Lab Capacity

TB OIs

VCT

Basic

Medical

Services

MTCT STI

Treatment

Source: John Snow, Inc./World Education, Inc. Center for HIV/AIDS. Boston, MA 2001.

H. MEDICAL EVALUATION

INITIAL EVALUATION

The initial evaluation of an HIV-infected woman should include a 

comprehensive medical assessment, including a detailed HIV history: 

date of diagnosis, possible routes of exposure, HIV-related symptoms 

or opportunistic infections, previous antiretroviral or prophylactic 

therapies, disclosure history, and support systems (see above). Prior 

antiretroviral treatments should be documented in as much depth as 

possible, including specific medications, length of treatment, side effects 

or complications, response, results of resistance testing, if done, and 

adherence. Current employment, relationship status and child care 

responsibilities, insurance status, and drug and alcohol abuse must all 

be considered in decision making about further therapeutic regimens. 

A comprehensive gynecologic history should be obtained, including 

menstrual history, sexual practices, contraception and condom use 

history, previous sexually transmitted and other genital tract infections, 

prior abnormal Pap smears, and other gynecologic illnesses or symptoms. 

The initial physical examination should include a baseline pelvic exam 

with Pap smear and other studies as needed based on history and physical 

findings. Various studies (Anderson, 1989; Frankel, 1997; Minkoff, 1999) 

have found that both prevalence and incidence of gynecologic problems 

are high in HIV-infected women throughout their disease course.
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This initial assessment should take place over several closely spaced visits. 

This will allow the woman and her clinical care team to become familiar 

with one another and to develop the trust and partnership that will form 

the foundation of her ongoing care. This is particularly important for 

the woman with newly diagnosed HIV, who is often struggling with the 

shock, fear, denial, and despair that accompany the discovery of a lifethreatening illness; she should be given the opportunity to assimilate 

information about HIV and her own clinical status in small bites.

FOLLOW-UP VISITS

Follow-up visits should be scheduled at intervals based on the woman’s 

HIV clinical, immunologic, and virologic status; other medical or 

comorbid conditions, including substance abuse or mental illness; and 

other individual needs for counseling or psychosocial support. CD4 cell 

counts and HIV-RNA levels should be monitored at 3–4-month intervals 

and more often if results suggest inadequate or failing therapeutic 

response, or with development of clinical signs or symptoms. At each 

interval visit the woman should be questioned about new symptoms, 

side effects, adherence with medications, and psychosocial issues and 

concerns. Last menstrual period should be documented, as well as 

current sexual activity and interval use of condoms and contraception. 

Risk behaviors should be reassessed at regular intervals because sexual 

and drug-use patterns may vary, and safe practices should be reinforced 

through positive prevention counseling. (CDC, 2001). Pelvic examination 

should be repeated at least annually, and more frequently with history 

of abnormal Pap smears, unsafe sexual practices, exposure to STIs, or 

development of gynecologic signs or symptoms. STI screening should be 

performed when the patient reports recent or ongoing high-risk sexual 

activity. Pelvic examination every 6 months may be considered in women 

with clinically advanced disease, low CD4 cell counts, and/or high 

viral loads because their incidence of certain HIV-related gynecologic 

problems may be increased. The medical and gynecologic evaluation of 

the HIV-infected woman is described in more detail in Chapter IV on 

Primary Medical Care and Chapter VI on Gynecologic Problems.

I. FAMILY-CENTERED CARE

HIV is a disease of families. Not only may the woman be infected, but 

her husband or partner and children may also be living with HIV. Even 

when other family members are not infected, they are deeply affected 

by the presence of chronic and life-threatening illness within the family, 

possible fears of transmission of infection, and often stigma. The HIVpositive woman may neglect her own care while providing care to sick 

family members or to her children. The provider should encourage all 

HIV-positive family members to receive appropriate care and should help 

enlist family support for the infected woman by providing information 
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and education about HIV and updates on the woman’s condition (with 

II

her permission) and by assistance in identifying support systems for the 

entire family.

J. EDUCATION AND COUNSELING

Despite the dramatic advances in therapy, decreases in mortality and 

hospitalizations, and overall improvement in quality of life, HIV remains a 

life-threatening and often life-ending disease with no cure on the horizon. 

For women it is often enveloped by poverty; isolation; person, partner, or 

community drug use; and the competing priorities of children and family. 

Mental illness, substance abuse, or domestic violence may complicate the 

clinical picture. Not dissimilar to diabetes, modern management of HIV 

disease requires a basic understanding of HIV infection and an intense 

personal involvement in one’s own care — taking multiple medications 

on fairly strict schedules, food requirements, recognizing and managing 

side effects, etc. Unlike most other chronic medical conditions, HIVpositive individuals remain infectious for the rest of their lives and 

must learn about and become empowered to change behaviors that 

put themselves or others at risk. This learning process is ongoing 

and lifelong and requires continuous reinforcement. It should aim to 

correct misconceptions and myths and should recognize that relapses 

in unsafe sexual or drug-using behaviors and at least episodic problems 

with adherence are the norm rather than the exception. Peer advocates 

(HIV-affected women from similar cultural backgrounds) can be effective 

members of the clinical team to help educate patients, advocate for them, 

and provide counseling as needed.

K. ACCESS TO CARE

A recent report from the HIV Cost and Services Utilization Study, using 

a national sample representative of the adult U.S. population infected 

with HIV and in ongoing care, found significant variations in service 

utilization and receipt of medication. Women were more likely than 

men to use the Emergency Department and to be hospitalized and were 

less likely to have received antiretroviral therapy including a protease 

inhibitor or nonnucleoside reverse transcriptase inhibitor by early 1998. 

Other predictors for poor access to care included racial or ethnic minority 

status and lack of insurance (Shapiro, 1999). If women with HIV are to 

benefit equally from the advances in understanding and management of 

this infection, attention must be paid at the individual, community, and 

societal levels to the factors hindering equal access to care: stigma and 

isolation, lack of empowerment, competing concerns (e.g., food, housing, 

care for other family members), child care, transportation, insurance, 

violence against women, and many more.
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III. THE CHRONIC CARE MODEL

The Chronic Care Model (http://www.improvingchroniccare.org) was 

developed and refined by experts in chronic illness management to 

encourage high quality chronic disease care. It can be applied to a 

number of chronic illnesses, including HIV/AIDS. The Model identifies 

the key elements in the system of care that can help patients be healthier, 

providers more satisfied and that can help reduce costs of care throughout 

the system. These elements include (Figure 2-2):

A. COMMUNITY-RESOURCES AND POLICIES: 

Community programs can support and extend the care for individuals 

with HIV/AIDS. They can provide resources and support, promote better 

self-care, and play a broader role in advocacy for patients and for health 

policies that can better support the lives of individuals with HIV/AIDS.

B. HEALTH SYSTEM-ORGANIZATION OF HEALTH CARE

The health system caring for patients with HIV/AIDS should be organized 

in such a way that there is flexibility and ability to change, that there are 

appropriate resources and support for providers and patients, and that 

there is an emphasis on prevention and maintenance, rather than crisisoriented care.

C. DECISION SUPPORT

Treatment decisions should be founded on evidence-based guidelines. 

Clinical providers for individuals with HIV/AIDS need ongoing education 

and training to remain current, because of the rapid changes in knowledge 

and practice. Primary care providers for patients also should be kept 

informed and involved when patients are referred for specialist care.

D. DELIVERY SYSTEM DESIGN

The health care delivery system should be proactive and should focus 

on keeping patients as healthy as possible. This requires determining 

what care is needed, clear delineation of roles different members of the 

team play in care, ensuring that team members have current information 

about patient status, and facilitating follow-up as a part of standard care. 

E. SELF-MANAGEMENT SUPPORT

Successful HIV care depends on a well-informed and motivated patient. 

Although care providers are responsible for appropriate prescribing of 

antiretroviral drugs and can facilitate adherence, ultimately the woman 

herself must take the medications properly and return for regular care 

and follow-up. It is essential that patients be given the tools to better care 

for themselves, including information about how to take medications, 

recognition of adverse effects, and tools to minimize or prevent side effects. 
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Patients should have a central role in making decisions about their care 

II

and in problem-solving; this will foster a sense of collaboration, trust, and 

responsibility. Patient involvement in self-management of other chronic 

diseases has been shown to reduce emergency and other outpatient visits, 

decrease health distress, and improve self-efficacy (Bodenheimer, 2002)

F. CLINICAL INFORMATION SYSTEMS

Information systems are essential to track individual patients and populations of 

patients with HIV/AIDS, and clinical information technology can help prevent 

serious errors in care, such as medication errors (Bates, et al, 1998). A metaanalysis of published reports of interventions used in management of patients 

with other chronic illnesses found that education of providers and feedback and 

reminders to providers significantly increased provider adherence to treatment 

guidelines and improved disease control (Weingarten, 2002).

Figure 2-2

Functional and Clinical Outcomes

Overview of the Chronic Care Model

Community

Resources and Policies

1. Health System

Organization of Health Care

2.

Decision

Support

Delivery 5.

System

Design

Self- 4.

Management

Support

3. Clinical

Information

Systems

6.

Prepared,

Proactive

Practice Team

Informed,

Activated

Patient

Productive

Interactions

Source: Wagner, 1998. Copyright American College of Physicians. Reprinted with permission. 

Available at http://www.improvingchroniccare.org.
46 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Bates DW, Leape LL, Cullen DJ,et al. Effect of computerized physician 

order entry and team intervention on prevention of serious medication 

errors. JAMA 1998;280:1311-1316.

Bodenheimer T, Lorig K, Holman H, Grumbach K. Patient self-management 

of chronic disease in primary care. JAMA 2002;288:2469-2475.

CDC. Revised guidelines for HIV counseling, testing and referral. MMWR 

2001;50:RR-19:1-58.

Frankel R, Selwyn P, Mezger J, Andrews S. High prevalence of gynecologic 

disease among hospitalized women with human immunodeficiency 

virus infection. Clin Infect Dis 25:706–12, 1997.

Kitahata M, Koepsell T, Deyo R, et al. Physicians’ experience with the 

acquired immunodeficiency syndrome as a factor in patients’ survival. 

N Engl J Med 334:701–6, 1996.

Laine C, Markson L, McKee L. The relationship of clinic experience with 

advanced HIV and survival of women with AIDS. AIDS 12: 417–24, 1998.

Minkoff HL, Eisenberger-Matityahu D, Feldman J, Burk R, Clarke L. Prevalence and incidence of gynecologic disorders among women infected with 

human immunodeficency virus. Am J Obstet Gynecol 180: 824–36, 1999.

Puchalski CM, et al. Taking a spiritual history allows clinicians to understand 

patients more fully. J Palliative Care 3:129-37, 2000.

Shapiro MF, Morton SC, McCaffrey DF, et al. Variations in the care of HIVinfected adults in the United States: Results for the HIV Cost and Services Utilization Study. JAMA 281:2305–15, 1999.

Wagner EH. Chronic disease management: What will it take to improve care 

for chronic illness? Effective Clinical Practice 1:2-4, 1998.

Weingarten S, Henning J, Badamgarav E et al. Interventions used in disease 

management programmes for patients with chronic illness-which ones 

work? Meta-analysis of published reports. BMJ 2002;325:925-942.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 47

III

A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

I. INTRODUCTION

Two decades into the human immunodeficiency virus (HIV) epidemic, 

scientists and clinicians on both the biomedical and behavioral fronts 

continue to be faced with daunting challenges. While scientists have made 

progress in vaccine development and in understanding the complexities 

of the viral-host immune response, highly effective, widely available 

biomedical preventive measures are still in developmental stages. 

Thus, there remains a critical need to identify and implement effective 

behavioral strategies and to more effectively address the complex forces 

that fuel the heterosexual HIV epidemic, including poverty, migration of 

populations, social and cultural disruption, gender discrimination, and 

stigma about sexually transmitted infections (STIs) and HIV.

Many of the measures that women can take to prevent acquisition of 

STIs and HIV have been known for the past decade: abstaining from 

intercourse, selecting low-risk partners, negotiating partner monogamy, 

and male condom use. However, the high rates of incident HIV infections 

among women in many parts of the world and the rising incidence 

among women in the United States are a testament to prevention 

barriers facing women in heterosexual relationships. Women are often 

unaware of their partners’ infection status or level of risk and, in many 

cases, are unable to insist on abstinence or to negotiate sexual safety 

with their partners. Importantly, in many parts of the world, prevalence 

figures suggest that girls are exposed to HIV earlier than boys (UNAIDS/

WHO, 2003). Young girls are often emotionally immature, economically 

disadvantaged, and socially inexperienced, making them vulnerable to 

sexual relationships that may expose them to HIV and to other sexually 

transmitted infections that can potentiate HIV transmission. Women in 

economically disadvantaged nations and in socially marginalized groups 

in the industrialized world may have less access to medical care for 

treatment of STIs and contraception, and may also not feel empowered 

to negotiate for condom use, abstinence, or monogamy within their 

sexual relationships. Thus, culturally sensitive interventions that target 

both behavioral and biologic risk factors for HIV are necessary to reduce 

transmission to women and girls.

This Guide is about the care of women who are already HIV-infected, and 

therefore the focus of this chapter is not on primary prevention strategies 

such as abstinence aimed at women who are not infected. The vast 

majority of women with HIV have become HIV-positive through sexual 

activity, and require assistance in behavioral strategies to negotiate safer 

sex within existing relationships or, a much more challenging objective 

in this case, to negotiate abstinence.

III. PREVENTION OF HIV

Jared M. Baeten, MD, PhD, Chia Wang, MD, MS, 

and Connie Celum, MD, MPH
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This chapter discusses issues regarding HIV testing, including risk 

assessment and pre- and posttest counseling, and then reviews models 

of behavioral intervention strategies for HIV prevention, published 

behavioral intervention trials, and some practical aspects of counseling 

women on how to reduce sexual risk behavior. Biologic cofactors that 

may increase risk and thus may be targets for intervention are briefly 

examined. Finally, new approaches to HIV and STI prevention, including 

microbicides, vaccines, and postexposure antiviral medication are 

reviewed. The important issues of substance abuse and strategies for 

changing drug use behavior are not addressed in this chapter, but are 

reviewed extensively in Chapter X.

II. RISK ASSESSMENT FOR STI/HIV INFECTIONS

 Unprotected sex increases a woman’s risk of HIV infection, based 

in large part on her partner(s)’ risk behaviors.

Just as most people would find celibacy an impractical means of 

reducing sexual risk, many individuals may find changing other specific 

sex behaviors difficult or unacceptable. Although some sexual behaviors 

may be less “mainstream” than others, it is important to remember 

that participation in such behaviors does not necessarily reflect a lack 

of morals or willpower, but rather different perceptions of enjoyable 

and common sex behavior. Furthermore, sexually active women may 

not realize that they are practicing behaviors that put them at risk for 

HIV infection. Because of the heterogeneous nature of sexual practices, 

individual risk assessment is crucial in any attempt to reduce risk of HIV 

by changing sex behavior. In pre- and posttest HIV counseling, individual 

risk assessment provides a framework in which to conduct further 

behavioral intervention and identifies patients appropriate for HIV and 

STI screening. Guidelines for physicians and other care practitioners 

recommend that HIV and STI risk assessment be conducted for every 

patient (Phillips, 2003); however, most primary care physicians do not 

routinely incorporate questions about sexual behavior into routine 

patient care.

Clinician discomfort and fear of embarrassing or offending the 

patient when discussing sex are impediments to conducting 

effective risk assessment.

In such circumstances, the clinician may find it more acceptable 

to “frame” the discussion by explaining the routine nature of such 

questions, thus demonstrating that the patient is not singled out 

because of mannerisms, appearance, or ethnicity. One approach may 

be to emphasize the importance of this information for patient care: “To 

be able to provide the best care for you today, we need to understand 

your risk for certain infections by talking about your sexual practices.” 

Another may be to allude to the universality of many concerns: “Many 

women find it difficult to get their men to wear condoms; has this been 

a problem for you?” (Curtis, 1999).
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As with any type of medical history taking, open-ended questions 

probably serve as the most effective means of 

eliciting information when taking a sexual history.

Language should be clear, easy to understand, nonoffensive, and 

nonjudgmental. Many clinicians prefer closed-ended questions when 

they are functioning under time pressures. In such cases, a questionnaire 

that the patient completes in the waiting room may be a preferred tool. 

Whenever possible, however, clinician-patient interaction serves as the 

ideal forum for sexual risk assessment.

 Many clinicians are not familiar with risk factors for HIV 

infection specifically relevant to women.

Risk factors for HIV infection in male homosexuals and intravenous drug 

users have been well described. In contrast, factors that may increase risk 

in women, such as a history of unwanted pregnancy, or an incarcerated 

sex partner, are less specific and less well recognized. Although some risk 

factors for women can be derived from epidemiologic studies, such as 

history of “high-risk STIs” (i.e., gonorrhea or syphilis), crack cocaine use, 

and injection drug use, some women are at risk through monogamous 

partner relationships with their HIV-infected husbands. A rare case of 

female-to-female sexual transmission of HIV, possibly through sharing 

sex toys, was recently reported (Kwakwa, 2003). Therefore, identifying 

risk behaviors in women requires a careful and skilled clinician. In 

many cases, a low threshold for recommending HIV testing is necessary. 

Important risk topic areas to cover are listed in Table 3-1.

Table 3-1: Risk Assessment for STI/HIV for Women

Number of sex partners in the previous year________, and lifetime: ________

Sex with: ❏ men, ❏ women, ❏ or both 

Type of sexual practices: ❏ vaginal intercourse ❏ anal intercourse ❏ oral sex 

❏ use of sex toys ❏	other (specify) ______________

History of abnormal Pap smear: ❏ yes, or ❏	no

History of sexually transmitted infection: ❏ yes, or ❏	no

History of using: ❏ intravenous drugs, ❏ sharing needles, 

❏ use of crystal methamphetamines, or ❏ crack cocaine

History of a sex partner who was incarcerated: ❏ yes, or ❏	no

History of alcohol or drug abuse: ❏ yes, or ❏	no

Does she feel that her sex partner(s) puts her at risk? ❏ yes, or ❏	no

How does the woman protect herself from HIV/AIDS?

___________________________________________________________________

How does the woman protect herself from unplanned pregnancy?

___________________________________________________________________

Is there anything else that she feels she should mention to ensure good medical care?

___________________________________________________________________
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III. HIV COUNSELING AND TESTING

 There are clear benefits to HIV testing.

For a woman, knowledge of her serostatus is essential to prevent vertical 

transmission to her infant and horizontal transmission to her partners, 

and to seek medical care for herself. With the proven efficacy of several 

peri-partum antiviral regimens to reduce vertical transmission rates and 

medical therapy to improve survival among HIV-infected individuals, 

including in resource-poor settings, there are even stronger reasons to 

urge sexually active women to seek HIV testing for themselves and their 

partners. Unfortunately, most women at risk for HIV infection remain 

unaware of their HIV status (Kitahata, 2002).

Routine provision of HIV testing may be most effective.

Selective screening strategies have targeted intravenous drug users, STI 

clinic attendees, and economically disadvantaged individuals (Phillips, 

2003). The advantage of selective screening is cost-savings, particularly 

in low-prevalence parts of the world. Many experts favor a universal 

recommendation for HIV screening, at least for pregnant women. The 

advantage of universal screening is not only increased detection rates, 

but perhaps also increased test acceptance. Screening using an optout approach, under which testing is done routinely unless actively 

declined, significantly increases HIV testing rates among pregnant 

women (Stringer, 2001). Opt-out testing at antenatal clinics in Africa 

is being promoted as a key strategy to increase uptake of interventions, 

such as short-course antiretrovirals, for prevention of mother-to-child 

HIV transmission (Bassett, 2002). In the United States, the Centers 

for Disease Control and Prevention (CDC) has recently recommended 

that HIV-1 screening of all pregnant women become part of routine 

care (CDC, 2003). Universal screening removes the stigma of HIV 

testing by eliminating any targeted testing based on sexual orientation, 

socioeconomic status, or race. When HIV testing is stigmatized, women 

in high-risk groups may be reluctant to identify themselves. Thus, for 

the general population, current U.S. guidelines recommend routine 

offering of voluntary testing in all settings where HIV prevalence is 

>1% or where there is increased risk of acquiring or transmitting 

HIV, regardless of setting prevalence (CDC, 2003). Offering routine 

HIV testing is cost-effective under certain circumstances and could 

lead to earlier identification of infected individuals and linkage to HIV 

treatment. However, routine offering of HIV testing in high-prevalence 

areas to hospitalized patients and those presenting to emergency care 

settings has not been widely adopted. On the other hand, the cost of 

universal HIV testing is significantly higher than voluntary, selective 

screening strategies, and there are both practical and ethical issues in 

implementing universal screening, even in perinatal care.
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A. PRE- AND POSTTEST HIV COUNSELING

 The counseling that occurs before and after HIV testing has three 

principal goals (celum, 1999):

1. to provide counseling about risk reduction for HIV-negative 

persons,

2. to identify HIV-infected persons for clinical interventions, and

3. to provide counseling to HIV-positive persons about potential 

transmission.

The components of HIV pretest and posttest counseling are 

outlined in Table 3-2

Pretest counseling should include discussion about the basic facts of 

HIV infection, the acquired immunodeficiency syndrome (AIDS), and 

HIV testing. However, in most situations, emphasis should be placed 

less on didactic material than on individualized discussion of risk and 

risk-reduction unless the patient has very limited understanding of HIV/

AIDS. Posttest counseling should reinforce these concepts in the context 

of the test result. Regardless of the test result, resources and referrals 

for the patient and/or her partner should be provided. For patients at 

risk for domestic violence, the potential domestic turmoil that a positive 

test result can elicit should be emphasized. This issue will be further 

addressed in the section on ethnic and gender considerations.

Make use of an opportunity to provide client-centered counseling

Any time spent with the patient, however short, provides an opportunity 

for the clinician to conduct individualized counseling about recognizing 

and reducing high-risk sexual behaviors. Patients who present with 

concerns or symptoms of STIs are usually also at risk or concerned about 

risk for STI, including HIV. In the context of a negative HIV test, the 

posttest counseling session provides a valuable opportunity to develop 

a risk-reduction plan in a woman who has identified herself as someone 

who is concerned about risk and may be at high risk. Many clinicians 

may find it effective to deliver the negative test result in the context of 

a “second chance,” thus emphasizing that current behaviors are unsafe 

and can be changed.
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Table 3-2: Components of HIV Pre- and Posttest Counseling

Pretest Counseling

• Assess understanding of HIV transmission and natural history; psychological 

stability; social support; impact of a positive result

• Discuss likelihood and meaning of positive, negative, and indeterminate 

test results*

• Discuss provisions made at the site for confidentiality. (In the United States, 

some states have name-based reporting of HIV, and clients should be 

informed about the availability of anonymous testing)

• Ensure that follow-up is available

• Emphasize the importance of obtaining test results

• Discuss risk-reduction plan and referral to other services

• Obtain informed consent for HIV antibody testing

* For patients who identify a high-risk exposure, the clinician should explain that tests 

are generally positive within 3 mo of exposure. Therefore, repeat testing should be 

recommended 3 mo after exposure, if the initial test is negative.

Posttest Counseling

• Ensure that the client is ready to receive results

• Disclose and interpret results:

 For HIV-seronegative persons:

- Readdress and reinforce risk reduction plan

- Discuss the need for repeat testing for those with recent (<3 mo) exposure or 

ongoing risk behavior

 For persons with indeterminate HIV-1 Western blots:

- Discuss prevalence of and risk factors for indeterminate test results

- For persons with p24 bands and persons with high-risk behavior:

• Discuss the possibility of acute HIV infection and need 

for repeat testing in 1, 3, and 6 mo

• Perform HIV polymerase chain reaction, if available, to 

confirm infection status and determine viral load

 For HIV-seropositive persons:

- Differentiate between being HIV-infected and having AIDS

- Emphasize the importance of early clinical intervention, if available, and make 

medical referral

- Counsel patient that he/she is HIV-positive and discuss ways to avoid 

transmitting HIV to others

- Assess need for psychological support and provide referral, if appropriate and 

if available

- Assess possibility of domestic violence and provide referral, if necessary and if 

available

 - Ensure that the patient has follow-up
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B. RAPID TESTS

 Rapid tests are a good alternative in many settings.

After all, HIV testing is only of value if patients return for their test 

results and posttest counseling. Many testing programs in the United 

States use an initial enzyme-linked immunosorbent assay (ELISA) with 

confirmation through Western blot. In less developed areas, two ELISAs 

run in sequence are often used. With both protocols, the patient is 

required to return to the clinic 1–2 wk after testing for results. In 1995, 

25% of persons testing HIV-positive and 33% of persons testing HIVnegative at publicly funded HIV testing sites in the United States failed 

to return for test results (CDC, 1998a). Similar low return rates have been 

described in many developing-country settings.

Rapid testing for HIV would result in substantial cost savings and 

circumvent patient no-show rates (Spielberg, 1996). A number of 

rapid tests, defined as requiring less than 2 hr, are available. The 

World Health Organization (WHO) has developed alternative testing 

strategies using sequential rapid tests, thus obviating the need for 

expensive and delayed confirmatory testing (UNAIDS, 2002). Some 

tests require as little as 5 min, use blood obtained from a finger-stick, 

and can be performed easily by clinical staff using only minimal 

laboratory facilities. Most tests are 95–100% sensitive and specific. One 

rapid test (OraQuick Rapid HIV-1 Antibody Test) has been approved 

by the FDA with a waiver from the Clinical Laboratory Improvements 

Amendments (CLIA) regulations, allowing it to be used outside of 

traditional laboratory settings. Thus, HIV rapid testing is expected to 

become more feasible and widely-adopted in the United States. The CDC 

is currently conducting demonstration projects to promote the use of 

rapid testing outside of usual clinical settings, including in correctional 

facilities, non-medical venues, and during labor and delivery for 

women who did not receive antenatal testing (CDC, 2003). The CDC 

has published recommendations that clients receive the results of rapid 

HIV tests on the day of testing. Patients who test negative can be given 

a definitive negative result without a return visit. For patients who test 

positive, it is recommended that they be informed that their screening 

test was positive, and that they should return to receive a confirmed test 

result.

In the United States, rapid testing is most appropriate in areas of high 

prevalence where clinic return rates are low (STI clinics, emergency 

departments) or an HIV diagnosis will influence immediate management 

decisions (postexposure prophylaxis, unknown HIV status in a pregnant 

woman presenting to Labor & Delivery). Rapid and other alternative 

testing methods (e.g., home testing, oral fluid and urine testing, 

telephone collection of test results) are being explored as strategies to 

increase HIV testing among high-risk populations. In many ways, rapid 
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testing is most appropriate in economically disadvantaged countries 

where HIV seroprevalence is high, laboratory resources are limited, and 

patient travel to and from clinic may be very inconvenient. The use of 

rapid tests has increased substantially over the past few years and has 

become a key component of HIV prevention and treatment programs 

in many developing countries (e.g., initiatives for prevention of motherto-child transmission and general population voluntary counseling and 

testing).

Rapid tests may result in unwanted test results

Some have expressed concern that rapid HIV testing may not offer 

patients sufficient time to digest counseling information and to decide 

whether they truly desire to know their HIV status. In some settings, 

women in particular may find it difficult to decline unwanted HIV testing, 

in part due to cultural injunctions against refusing a test offered by a 

health care worker perceived as an authority figure. Thus, the principal 

components of HIV testing must remain the same for rapid testing as for 

traditional screening programs. Regardless of how HIV testing is done, 

patients must be informed of the nature of the test and the risks and 

benefits of knowing their HIV status. They should consent voluntarily to 

the testing procedures, be informed that they can refuse testing, and have 

their confidentiality strictly preserved. Finally, they should be told that 

refusal of testing will not lead to denial of usual clinical services. 

C. IMPACT OF HIV COUNSELING AND TESTING ON PREVENTION

What is the evidence that HIV testing may change risk behavior? 

The literature in this area is difficult to synthesize, largely because of 

evolving counseling practices, varying lengths of follow-up, and lack 

of randomized trials with well-defined endpoints. Older studies from 

the United States did not demonstrate a substantial effect. In one 

observational study from Baltimore from the early 1990s, both HIVpositive and HIV-negative patients had high rates of STIs 6–23 mo after 

receiving HIV test results and posttest counseling (Zenilman, 1992). A 

second study found HIV testing was associated with a moderate decrease 

in gonorrhea incidence among patients in Miami who tested HIVpositive but with a moderate increase among those testing HIV-negative 

(Otten, 1993). These findings suggest that learning of a positive HIV 

test result may have a modest effect on sexual risk-taking. The studies 

also raise important concerns about the effectiveness of HIV testing 

and counseling in impacting sexual risk-taking, and about potential 

disinhibition after receiving a negative test result. However, guidelines 

and training for HIV-1 counseling have improved over the past decade, 

and thus it is difficult to know the impact that current counseling 

procedures may have on subsequent sexual behavior.

A more recent large study conducted in Kenya, Tanzania, and Trinidad 

randomly assigned individuals and couples to either HIV voluntary 

counseling and testing or basic health information (Voluntary HIV-1 
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Counseling and Testing Efficacy Study Group, 2000). This trial found that 

counseling and testing resulted in a significant decline in unprotected 

intercourse with non-primary partners by both male and female study 

participants. Newly-identified HIV-infected participants were more likely 

than HIV-uninfected participants to reduce episodes of unprotected 

intercourse. Among couples, unprotected intercourse reduced more in 

those in which one or both members were diagnosed with HIV compared 

with those in which both members were HIV-uninfected.

Other studies of HIV counseling and testing among couples have 

demonstrated similarly encouraging results. Among 149 HIV-discordant 

couples in Zaire, HIV counseling and testing was followed by a dramatic 

increase in consistent condom use (from <5% to >70%) and a low rate 

of HIV transmission (3% after 100 person-years of follow-up) (Kamenga, 

1991). A recent study of 963 discordant couples from Zambia reported 

a sustained increase in condom use from <3% to >80% after joint 

voluntary counseling and testing (Allen, 2003). The authors concluded 

that couples’ counseling and testing should be a top HIV prevention 

priority. Overall, modeling studies suggest that voluntary counseling and 

testing is a highly cost-effective HIV prevention strategy (Creese, 2002). 

IV. BEHAVIORAL INTERVENTION MODELS

Over the past 20 years, there has been a growing appreciation that 

behavioral interventions should be based on deterministic models 

of sexual behavior. These models provide us with guidance on the 

determinants of high risk sexual behavior, and allow us to develop 

interventions and measurements for those key determinants. A number 

of behavioral models are used in HIV/STI prevention research and 

interventions, including those listed below. 

• The Health Belief Model, the Social Cognitive Theory, the 

Theory of Reasoned Action, and the Stages of Change Theory 

(Bandura, 1996; Fishbein, 1999) have been developed to explain 

determinants of human behavior change. These models all have in 

common the theory that perceived risks and benefits of behavioral 

change predict the likelihood of behavior change and can guide the 

approach to behavioral interventions. These models are described 

and contrasted in Table 3-3.

• The AIDS Risk Reduction Model integrates the concepts of the abovementioned theoretical models into a framework providing 

information, motivation, and behavioral skills specific to AIDS risk 

reduction (Catania, 1990; Fisher, 1992). With this model, counselors 

help patients to identify sexual behaviors that put them at risk for 

acquiring HIV, formulate plans to change these behaviors, and take 

action to realize these plans.
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Table 3-3: Behavioral Theories Relevant to Sexual Risk 

Reduction Counseling

Health Belief Model

Adopting health-protective behavior depends on a person feeling personally 

threatened by a disease with serious negative consequences, and feeling that the 

benefits of making the behavior change will outweigh the costs of not changing.

Social Cognitive Theory

Adopting health-protective behavior depends on a person believing that he or 

she has the ability to change (self-efficacy) and that the benefits of making the 

behavior change will outweigh the costs of not changing.

Theory of Reasoned Action

Adopting health-protective behavior depends on a person’s strength of intention 

to perform that behavior. The strength of the intention is based on the person’s 

overall positive or negative attitude toward performing the behavior, based on 

perceived outcomes, as well as whether the person believes that important family 

members and friends believe that he or she should alter behavior.

Stages of Change Theory

Adoption of new behavior involves five distinct stages:

1. Precontemplative Does not see need to do target behavior

2. Contemplative Sees a need to do target behavior, but is ambivalent

3. Ready for Action Ready to do target behavior soon, or has already started

4. Action Doing target behavior consistently 3–6 mo

5. Maintenance Doing target behavior consistently >6 mo

• The Stage of Change (SOC) behavioral theory proposes that the 

process of behavioral change occurs along a continuum of five 

fundamental stages (Table 3-3) (Coury-Doniger, 1999). The stages 

can be used to tailor the counselor’s approach to an individual by 

assessing where an individual is on that continuum for a specific 

behavior. For example, an individual with multiple partners 

who sees no need to use condoms consistently would be in the 

Precontemplative stage. In contrast, a woman in a mutually 

monogamous relationship who sees the need to know her partner’s 

HIV status, but fears angering her partner by this request, would 

be in the Action stage. A counselor’s approach to these two patients 

would be different. For the first individual, counseling directed 

at recognition of risk would be most appropriate, whereas for the 

second woman, communication and goal-setting skills should be 

emphasized. Importantly, individuals do not always move forward 

linearly along this continuum, but may “relapse” and move forward 

and backward between the stages. At the Rochester STI clinic, 

clinicians who have formally incorporated the SOC model in 

their risk assessment and counseling of STI clients report a high 

degree of satisfaction with the SOC model as a diagnostic tool that 

guides their specific counseling interventions with a client (CouryDoniger, 1999).
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V. PUBLISHED BEHAVIORAL INTERVENTION TRIALS

Several well-designed randomized controlled trials have been conducted to 

assess the efficacy of various behavioral intervention strategies, and most 

conclude that such interventions result in decreased sexual risk-taking 

(primarily unprotected sex) and, in some studies, STI and HIV incidence. 

In contrast to didactic education sessions, behavioral interventions focus 

on recognizing risk and formulating effective risk reduction strategies. 

Knowledge alone does not motivate change. To translate this concept 

into an issue many of us have experienced, consider the issue of weight 

reduction and diet modification. Despite widespread knowledge about 

the adverse health effects of eating fatty foods, adhering to a diet is 

notoriously difficult. Similarly, knowledge about STIs and HIV is not 

enough to implement change in sexual behavior.

Randomized controlled studies using STI incidence as an outcome provide 

objective evidence of health-related endpoints, thus representing the most 

valid measurement of an intervention’s efficacy. Five such trials, all 

conducted in the United States, examined the efficacy of behavioral 

intervention strategies using STI incidence as an outcome measure 

(Table 3-4). All five studies used similar intervention approaches 

incorporating education, motivation, and development of a concrete 

plan for behavioral change. Sessions were structured as individual or 

group counseling.

Behavioral interventions can lead to lower rates of 

STI acquisition

As shown in Table 3-4, results of these studies varied. The discrepancy in 

reported outcomes may be related to several factors. The sample sizes of 

the National Institute of Mental Health (NIMH) study (NIMH, 1998) and 

CDC-funded Project RESPECT (Kamb, 1998) study were large, providing 

excellent ability to detect even a modest effect of the intervention. In the 

San Francisco study (Boyer, 1997), for example, the sample size provided 

only 45% power to detect the approximate 20% change in STI incidence 

detected in the RESPECT study. However, an appreciable effect of the 

intervention was detected in the San Antonio study (Shain, 1999) despite a 

sample size of only 617. In this study, ethnic-specific tools and counselors 

were used, thus perhaps enhancing the effect of the intervention. Indeed, 

in this study, a 49% decreased STI incidence was detected after 12 mo, 

compared with a 20% decrease reported in the RESPECT study. Finally, 

adherence to behavioral session schedule and follow-up with STI exam 

are crucial elements affecting study validity. The NIMH, RESPECT, and 

San Antonio studies all reported higher adherence rates and follow-up 

rates compared to the Houston (Branson, 1998) and San Antonio studies, 

thus providing increased ability to measure the effectiveness of the 

intervention.
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Table 3-4: Results of Large Randomized Trials of Behavioral Interventions Conducted in the United States

National Institute of Mental Health (Multicenter)

Project RESPECT 

Study Group 

(Multicenter)

University of Texas (San Antonio)

Centers for Disease Control and Prevention (Houston)

University of California (San Francisco)

Population Inner city clinics in multiple cities/men and women 

screened with questionnaire(74% African American, 25% Hispanic,58% female)

 Inner city clinics in multiple cities/men and women screened with questionnaire (59% African American, 19% Hispanic,43% female)

Public health clinics/women with nonviral STI (69% Mexican American, 30% African American, 100% female)

 Medical Center STI clinic (90% African American, 44% female)

STI clinic/men and women (46% African American, 16% Hispanic, 37% female)

Sample size 3706 5758 617 964 399Intervention type

 Small group Individual Small group Small group Individual

Number of sessions

 7 biweekly sessions of 90–120 min each

 2 or 4 weekly sessions of 60 min each

 3 weekly sessions of 3–4 hr each

 4 biweekly sessions and a booster group session at 2 mo

 4 weekly sessions of 60 min each

Control group 1 hr didactic AIDS education 2 didactic 5-min AIDS education sessions 1 standard 15-min session 2 standard 20-min sessions 1 standard 15-min sessionAdherence rates 63% attended 

≥6 sessions

 82% attended all sessions

 75% attendedall sessions 

 47% attended ≥ 4 sessions 

 48% attended all sessions 

 Number of STI exams

 1 (at 12 mo) 2–4 (at 3, 6, 9, 12 mo, 3 and 

9 mo optional)

 2 (at 6 and 12 mo) 4 (at 2, 6, 9, and 12 mo) 2 (at 3 and 5 mo)

Follow-up rates 82% 81% at least 1, 51% all 4 90% 72% at least 1 visit, 47% all 4 72% at least 1 visit, 52% bothFindings in intervention group compared to control group

• Improved self-reported 

prevention efforts

• Fewer STI symptoms• No difference in STI 

incidence 12 mo after intervention, determined by chart review, STI exam

• 30% lower STI incidence 

after 6 mo

• 20% lower STI incidence 

after 12 mo

• 2 session and 4 session 

interventions had equivalent results

• 34% lower STI incidence 

after 6 mo

• 49% lower STI incidence 

after 12 mo

• Self-reported risky sexual 

behavior and incidence of STIs were similar between intervention and control groups

• No change in STI incidence• Improved self-reported 

prevention efforts in men

• No improvement in selfreported prevention efforts 

in women

Cited behavioral intervention models

• Risk reduction counseling, 

model not specified

• Theory of Reasoned Action• Social Cognitive Theory

• AIDS Risk Reduction Model • AIDS Risk Reduction Model • AIDS Risk Reduction Model
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Even brief (two 20-min) counseling sessions can result in lower 

STI rates and can be incorporated into clinical settings

The 20-min Project RESPECT counseling sessions may be most applicable 

to busy practitioners interested in conducting effective behavioral 

counseling. This study demonstrated that individual “brief” counseling, 

involving two sessions of 20 min each, was as effective in reducing STI 

incidence as four “enhanced” 1-hr sessions. Both intervention arms, 

the two 20-min and four 1-hr counseling sessions, were superior to a 

didactic message. The first of the two brief 20-min sessions focused on 

recognizing HIV risk and barriers to risk reduction. After working with 

the client to agree on an achievable risk reduction plan, the counselors 

concluded the sessions by identifying a small risk reduction step that 

could be achieved before the second session. At the second session, 

counselors reviewed progress and barriers in achieving the behavioral 

goal, and helped to clients to arrive at a long-term risk reduction plan. 

Although the four 1-hr “enhanced” sessions also included recognizing 

risk and formulating risk reduction plans, more energy was focused 

on key theoretical behavioral elements such as self-efficacy, attitudes, 

and social norms underlying risk behavior. The fact that the brief two 

20-min counseling sessions demonstrated equivalent efficacy to 4 hr of 

counseling is encouraging to practitioners who would like to integrate 

effective HIV counseling into busy clinical settings. A follow-up study 

of the efficacy of a brief counseling intervention in the context of rapid 

HIV testing is being conducted by the CDC (Respect II) which will be 

relevant given the increased use of rapid testing both in the U.S. and in 

resource-poor settings. 

Behavioral intervention studies in resource-poor settings

Several early studies among female commercial sex workers in 

developing country-settings demonstrated that condom promotion 

activities were accompanied by reduced high-risk sexual activity and a 

decrease in HIV and STI incidence. More recently, sustained reductions 

in HIV incidence among sex workers, paralleled by changes in sexual 

behavior, have been noted in several countries. Encouragingly, a few 

countries (e.g., Thailand, Uganda) have reported reduced HIV prevalence 

in the general population as well during the last few years, accompanied 

by secular changes in sexual behavior. Unfortunately, very few 

controlled trials of sexual behavior interventions to prevent HIV and STI 

transmission have been conducted in resource-poor settings. Recently, 

a large community randomized trial examined the effects of behavioral 

intervention or behavioral intervention coupled with improved STI 

services compared with routine government health services on HIV and 

STI transmission in the Masaka district of rural Uganda (Kamali, 2003). 

Behavioral interventions focused on knowledge acquisition, skill and 

attitude development, and motivational support and were accomplished 

through community-level approaches including public meetings, 

drama productions, informational leaflets, and individual discussions. 
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Communities randomized to the behavioral intervention experienced a 

lower incidence of HSV-2, and those randomized to STI services as well 

had reduced transmission of gonorrhea and syphilis. In both intervention 

arms, an increase in condom use was noted. Disappointingly, however, 

neither intervention arm saw a reduction in HIV incidence compared 

with the control arm, though HIV incidence in both the intervention and 

control communities was lower than the investigators expected, likely 

related to the secular change in HIV transmission that appears to be 

occurring in Uganda.

Some on-going studies are examining sexual behavior among adolescents, 

among whom HIV incidence is particularly high in many countries. 

Additionally, in light of gender differences in sexual decision making in 

many settings, other intervention trials are targeting behavioral change 

in men as a way to reduce heterosexual HIV spread. Given the high 

incidence of HIV in many developing countries, behavioral interventions 

to prevent heterosexual HIV transmission continue to be desperately 

needed.

VI. PRACTICAL ASPECTS OF COUNSELING PATIENTS ABOUT 

SEXUAL RISK REDUCTION

All of this information may seem overwhelming to the health care 

provider who has no special training in behavioral theory. However, the 

underlying principle is one that can be applied by any practitioner in 

any setting: counseling should be individualized to the person receiving 

the counseling. Any attempt to accomplish individualization of approach 

would be superior to simply providing a didactic message. Some practical 

aspects of counseling are listed in Table 3-5 and discussed below. 

Table 3-5: Practical Aspects of Counseling

• Focus the counseling session on risk reduction topics

• Listen and react to the patient

• Don’t stick to a practiced script

• Avoid overambitious risk reduction plans; focus on realistic goals

• Give the patient a written documentation of the risk reduction plan

• Use culturally sensitive and ethnic-specific language and terminology, when 

available and appropriate

• Consider issues specifically relevant to women
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 Focus the counseling session

The cornerstone of the counseling session is to focus the session on 

the patient’s recent sexual activities, their perception of their risk, and 

motivation to reduce their risk of HIV/STI exposure, redirecting the 

patient to this topic whenever necessary. Clinicians and counselors 

may become distracted by providing excessive information about 

scientific data and principles in response to patient questioning. Such 

information is probably more effectively dispensed in pamphlet form 

or by referral to other patient information sources. In addition, women 

at risk for STIs including HIV frequently come to clinic with multiple 

complicating issues, including poverty, domestic violence, substance 

abuse, and child care problems. Often the counselor begins to feel 

responsible for addressing all of these issues and discouraged by the fact 

that many of them seem so insurmountable. Furthermore, the patient 

may be uncomfortable discussing her own risk, and may therefore be 

emotionally invested in distracting the counselor from that subject. 

For these reasons, it is important for the counselor to remember that 

the goal during the limited interaction period with the woman is to 

directly address, and hopefully impact, risky sexual behavior. Some 

appropriate topics are listed in Table 3-6. Other longstanding issues 

may not be easily solvable, and may be more appropriately referred to 

a social worker, substance abuse counselor, or mental health counselor.

Table 3-6: Appropriate Risk Reduction Topics

• Enhance self-perception of risk

- Identify risk behavior

 - Assess level of concern

- Identify ambivalent feelings about risk

• Explore specifics of most recent risk

- Identify specific risk details

- Assess patient acceptable risk level

- Address ability to communicate with partner

- Identify situations that make the patient vulnerable to risk

- Identify triggers of high-risk behavior

- Assess patterns of risk behavior

 • Review previous risk reduction experience

- Identify successful attempts at risk reduction

- Identify obstacles to risk reduction

- Synthesize risk patterns

- Summarize and reflect patient risk

- Address risk in context of patient’s life

- Convey concerns and urgency regarding risk

- Support and encourage the patient to action

Source: Adapted from Kamb ML, 1998.
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 Listen and react

At the same time, it is important to listen and react to the patient. It 

is a human quality that we enjoy talking and thinking about ourselves. 

A counseling technique of summarizing a patient’s descriptions and 

viewpoints about her risk is an extremely effective communication 

tool. In an effort to be nonjudgmental, counselors may find themselves 

nodding supportively to just about any statement that the patient may 

make. Instead, sometimes direct and clear feedback from the counselor 

about self-destructive behavior may communicate more effectively the 

importance of reducing risk (Figure 3-1). For example, if a patient is 

describing an evening during which she had sex with multiple men 

while using crack cocaine, it may be more appropriate for the counselor 

to respond with emphasis that such behavior is dangerous. It would also 

be important to explore the emotional or physical needs leading to such 

risky sexual behavior and to identify potential alternatives to fulfilling 

such needs.

Don’t stick to a practiced script

In an effort to focus, some counselors may restrict themselves to a 

practiced script and thus squander opportunities to effectively impact 

risk behavior. Specific counseling scenarios a provider might encounter 

are described below:

- references to suicide: “I could have killed myself”

- self-deprecating comments: “I was so stupid”

- overacceptance of risk: “Even if I would have known he was HIVpositive, I wouldn’t have used a condom”

- inappropriate behavior: giggling, putting feet up on the table

Such statements are usually pleas from patients for a direct and honest 

response, and taking such opportunities to acknowledge and problemsolve risky behavior is important in establishing the objectives of the 

session. Inappropriate patient behavior such as excessive giggling, angry 

postures, or demonstrations of boredom, should also elicit comment 

and questions from the counselor. Overlooking such behavior in an 

effort to be professional, polite, or focused detracts from the ability to 

communicate.

Avoid overambitious risk reduction plans

The most common error made by counselors is to develop an 

overambitious risk reduction goal, particularly during sessions in which 

good rapport has been developed. In many cases, counselors may 

convince themselves that the woman has acknowledged her risk to such 

a degree that she is now ready to eliminate any subsequent episodes of 

unprotected sex. Such goals are likely unrealistic. Behavioral specialists 

favor extremely concrete goals, such as “On Friday night I am going to ask 

my partner to wear a condom.” Even modest goals, such as stopping at a 

drug store and purchasing condoms on the way home from the session, 

may be suggested. Other possible goals are listed in Table 3-7.
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Figure 3-1: Listen and React to the Patient

React to what a woman tells you. Use words and body language to 

express yourself.

Last night, I did cocaine and 

had sex with

five guys at the party.

I see . . . well . . . that 

doesn’t sound 

like safe behavior.

Last night, I got totally high 

and I had sex with

five guys at the party.

That’s terribly risky! I’m 

very worried 

about you!

Instead of...

Try
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Table 3-7: Examples of Concrete Individualized Risk Reduction 

Plans

Type of Plan Description

1. Patient will talk about HIV/STI 

concern/risk to partner/friends

- Disclosure or communication with partner

- Disclosure or communication with peers

- Disclosure or communication with others

2. Patient plans to get herself 

tested or have partners 

tested for HIV/STIs before 

having sex

- Patient will test herself again to ensure uninfected

- Have partner tested for HIV/STI

- Use condoms until partner tested for HIV/STI

- Abstain from sex until partner tested for HIV/STI

3. Patient plans to reduce, 

change, or eliminate at-risk 

partner(s)

- Break up with high-risk partner(s)

- Eliminate a particular type of high-risk partner 

(prostitute, anonymous partner)

- Patient will have fewer partners

4. Patient will change the type 

of partners she has

- Patient will get to know partners better before 

having sex

- Patient will remain monogamous with one 

partner for 3 mo

- Patient will abstain from sex for 3 mo

5. Patient plans to change use 

of alcohol and drugs

- Decrease/eliminate alcohol/drug use when 

having sex

- Generally decrease/eliminate a specific drug/alcohol

- Change venue where needles/drugs/alcohol used

- Do not share needles (exchange or obtain new)

- Clean needles or only share with known HIVnegative partner

6. Patient plans to increase 

condom use or increase 

situations that she 

uses condoms

- Talk to partner(s) about using condoms

- Buy condoms or have them more available

- Sex with condoms more often

- Use condoms with all partners (vaginal/anal sex)

- Use with all non-main partner (vaginal/anal sex)

- Use condoms with main partner (vaginal/anal sex)

7. Patient plans to change the 

kind of sex she will have

- Have oral sex instead of vaginal or anal sex

- Have mutual masturbation or petting (no 

penetrative sex)

8. Patient plans to make 

changes in the situations she 

is in that are associated with 

risky behavior

- Eliminate going to particularly risky place 

(bar, park)

- Reduce number of times going to particularly 

risky place

- Substitute behavior; go to gym, movies, etc.

Source: Adapted from Kamb ML, 1998, and from Beth Dillon, Project RESPECT training materials.
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Put it in writing

Furnishing written documentation of patient goals reinforces verbal 

instructions and provides additional motivation.

Use time wisely

The question then remains: what amount of time is necessary to effect 

a behavioral intervention? The Project RESPECT study demonstrated 

successful intervention with two 20-min sessions within 10 days of each 

other. An ongoing follow-up study, RESPECT 2, compares a single 1-hr visit 

with rapid HIV testing to the two 20-min sessions. In busy clinics, where care 

for genital tract infections and other medical problems may be occurring 

simultaneously with patient counseling, clinicians may not feel that they 

have sufficient time to counsel effectively. However, in many cases, 

patients spend much more time waiting in the reception area or in the 

exam room than they actually do with the clinician. Optimizing use of 

patient time by providing educational materials during waiting periods 

may allow the clinician to limit the amount of didactic information 

dispensed in the clinic and to spend more time in interactive behavioral 

modification. A self-assessment of the counseling session will allow 

clinicians to measure their counseling skills. Goals for the counseling 

session include exploring behaviors most associated with risk, identifying 

a reasonable risk reduction plan, and assessing the patient support 

system. A reasonable checklist for a behavioral intervention session is 

shown in Table 3-8.

Table 3-8: A Checklist for the Behavioral Intervention Counseling 

Session

❏ Explored behaviors most associated with risk

❏	Identified behaviors most amenable to change

❏ Identified reasonable change step

❏ Developed the change step into a plan for action

❏ Problem-solved obstacles to the plan

❏ Confirmed with patient that the plan is reasonable

❏ Assessed patient’s support system

❏ Identified referral resource, if necessary and available

❏ Reviewed date, time, and goals for next visit

❏ Recognized behavior change as a challenge

Source: Adapted from Kamb ML, 1998, and from Beth Dillon, Project RESPECT training materials.
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VII. ETHNIC AND GENDER CONSIDERATIONS IN RISK 

REDUCTION COUNSELING

 Language, visual materials, and descriptive terms sensitive to 

specific cultures and ethnicities may be important in improving 

communication techniques.

Ethnographic data from the San Antonio study found that African 

American women in their study population displayed an emphasis on 

infectious disease prevention, referring to sharing eating utensils as 

“eating behind” and sharing needles as “fixing behind.” The authors 

suggested that use of terms such as having sex “behind” someone 

might be an effective means of communicating the concept of unsafe 

sexual practices in their study population. In contrast, people of Asian 

background often conceptualize the human body of being made up of 

“hot” and “cold” components and may think of disease processes such 

as STIs as “hot.” Referring to a condom as “cold” may emphasize the 

effectiveness of such preventative measures. Finally, some studies have 

shown that the use of visual tools enhances verbal communication in 

Spanish. It is important to recognize, however, that such colloquialisms 

or cultural preferences may vary between regions, socioeconomic strata, 

and religions. If used in the wrong setting, approaches designed for one 

ethic group may offend another, and detract from the counselor’s ability 

to communicate. In the absence of a validated communication tool, the 

counselor should take their cues from the patient.

Some counseling concerns are particularly relevant to women.

In many economically disadvantaged areas of the world, poverty 

engenders oppression of women. When education and jobs are scarce, 

many economies preferentially educate and employ men, thus leaving 

women financially dependent on their husbands, vulnerable to “sugar 

daddies,” and bartering sex for food and clothing either in informal 

relationships or in a structured brothel setting. Many cultures sanction a 

family structure in which the mother of the husband lives in the home 

and is responsible for directing household activities and ensuring the wellbeing of her son. Many cultures also may place more value on men than 

on women, and may mythologize male prowess and discourage condom 

use. Finally, many societies do not recognize the legal rights of women 

in custody battles, thus leaving women tied to their husbands if they 

wish to remain with their children. In conditions in which women are 

economically and emotionally dependent on men, women often neglect 

their basic human rights. Such barriers may be extremely daunting to 

counselors, and the temptation may be to attempt to debunk societal 

inequalities or to degenerate into a “male-bashing” session. In such cases, 

the basic tenets of behavioral counseling should be recalled; focus on 

risk and tailor the session to the readiness of the woman for behavioral 

change. Clear, feasible risk reduction plans should be formulated, usually 

involving self-education about risk and recognition of responsibility to 

reduce risk.
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Domestic violence may need to be addressed.

Domestic violence continues to be a prevalent problem, affecting 20-30% 

of households in the United States and possibly even higher numbers in 

other parts of the world. Younger women and those with or at-risk for 

HIV may be particularly likely to experience domestic violence (Maman, 

2002). One study from the early 1990’s from Kenya found that only 66 

(27%) of 243 HIV infected pregnant women informed their partners of 

their results, of whom 11 were subsequently chased from their home, 7 

were beaten, and 1 committed suicide (Temmerman, 1995). Only one 

third of women in that research setting returned to receive their HIV 

results when the testing protocol was later changed to allow women the 

option of not knowing their HIV status. As voluntary HIV counseling 

and testing programs become more available in many part of the world, 

support must be given to women living in abusive relationships so that 

they can negotiate choices that will have positive effects on their health 

and that of their children. Anecdotal reports from voluntary counseling 

and testing centers in several African countries suggest that HIV testing 

of couples is associated with less partner violence, especially in recent 

years as HIV testing has become more common.

Fear of domestic violence may also impede a woman’s ability to 

assert her rights in a relationship to reduce her risk of HIV infection. 

Counselors must realize that such fear may be entirely reasonable, and 

that counseling patients about domestic violence may be beyond their 

area of expertise. Whenever possible, appropriate patients should be 

referred to domestic violence centers. At the same time, counselors can 

help patients formulate risk reduction plans in the setting of domestic 

violence. The counselor must approach the issue of HIV testing while 

mentioning and indeed, when appropriate, emphasizing the possibility 

of domestic violence and social stigma. Although counselors must 

encourage disclosure in order to avoid the potential of infecting an 

uninfected partner, they must remember that the safety of the patient 

is their first priority. Unfortunately, only increased availability and 

acceptance of widespread testing and recognition of seroprevalence will 

succeed in destigmatizing HIV infection. Meanwhile, on the individual 

level, care must be taken to help the woman identify ways to reduce her 

risk of physical harm and excessive emotional stress while at the same 

time initiating the process of recognizing and reducing risk behavior.

VIII SEXUALLY TRANSMITTED INFECTIONS AND THE RISK 

OF HIV INFECTION

Sexually transmitted infections (STIs) increase susceptibility 

to HIV infection

The fact that STIs are important cofactors for HIV acquisition has been well 

established by prospective studies from a variety of populations examining 

risk factors for seroconversion. In such studies, women with genital ulcer 

disease, gonococcal or chlamydial cervicitis, or trichomoniasis were at 
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2–4-fold increased risk for HIV infection. However, study design issues, 

including small sample sizes and potential confounding by sexual behavior, 

have limited the ability of these observational studies to fully determine 

the magnitude of risk that STIs pose for HIV acquisition (Røttingen, 2001). 

Moreover, even the best-designed prospective studies have been unable 

to separate STIs acquired at the same time as HIV (perhaps reflecting 

increased infectiousness of an HIV-infected partner) from those present 

prior to HIV acquisition that could increase susceptibility. Because of 

obvious ethical limitations, randomized trials that deny individuals STI 

treatment cannot be conducted. Thus, as detailed below, community 

intervention trials of improved STI services or mass STI treatment have 

been conducted to determine the impact of STIs on population-wide HIV 

transmission. 

Vaginal infections may also increase HIV susceptibility

Several studies, including well-controlled prospective investigations, 

have demonstrated that disturbances in the normal microbial flora of 

the vagina may increase HIV risk. One study among women attending 

an antenatal clinic in Malawi found that those with bacterial vaginosis 

(defined by vaginal pH >4.5, homogeneous vaginal discharge, presence 

of clue cells, and positive amine odor) were 2–4 times more likely to 

acquire HIV during pregnancy and postnatally over an average follow-up 

of more than 2.5 years (Taha, 1998). A second prospective study from 

Kenya found that HIV incidence was 2-fold higher among nonpregnant 

women with abnormal flora on Gram’s stain of vaginal fluid or with 

negative vaginal cultures for Lactobacillus species, which are the hydrogen 

peroxide–producing gram-positive rods that dominate the normal vaginal 

ecosystem (Martin, 1999). An earlier report from this same cohort of 

Kenyan women found that Candida vaginitis also increased HIV risk ~2-

fold (Martin, 1998). 

Genital herpes may contribute substantially to HIV spread

A number of recent studies have highlighted the possible role of genital 

herpes infection (primarily due to HSV-2) in facilitating HIV transmission 

worldwide. As noted above, genital ulcer disease has long been regarded 

as a strong risk factor for HIV acquisition. Over the last two decades, 

HSV-2 has become the major cause of genital ulcer disease in many 

populations, and HSV-2 seroprevalence has increased substantially as 

well. A meta-analysis found chronic HSV-2 infection to be associated with 

a 2-fold increase in the risk of HIV acquisition among the best designed 

studies (Wald, 2002). Recent studies suggest that primary HSV-2 infection 

may be associated with even greater HIV risk (del Mar Pujades Rodriguez, 

2002). Compellingly, one large survey study from Africa concluded that 

country-to-country differences in the prevalence of HSV-2 may be one 

of the principal causes of differential HIV spread across that continent 

(Auvert, 2001). Studies of suppressive antiviral therapy against HSV-2 to 

prevent HIV transmission are underway and may provide a relatively 

inexpensive and simple intervention to decrease HIV acquisition, 

infectiousness, or both. 
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Community randomized trials of STI treatment offer 

conflicting results

Observational studies have demonstrated clear and consistent evidence 

that STIs and other genital tract infections increase HIV susceptibility. 

This conclusion was supported by the results of a trial conducted in 

the Mwanza region of Tanzania that randomly allocated communities 

to improved syndromic management of STIs or to routine government 

health care services (Grosskurth, 1995). Syndromic STI management 

resulted in a 40% decrease in new HIV infections in the intervention 

communities. In contrast, in the Rakai district of Uganda, a community 

randomized trial of mass antibiotic treatment for STIs, given at 10-

month intervals, failed to demonstrate a reduction in HIV seroincidence 

(Wawer, 1999). One principal reason for the disparate results of these two 

trials is likely related to the stage of the epidemic in the two locations 

(Grosskurth, 2000). In Mwanza, the baseline HIV prevalence was 4%, 

indicating an early phase of the epidemic. In Rakai, the epidemic was 

at a more mature phase, with a baseline prevalence of 16%. Experts 

concluded that the core group of high-risk individuals, who are crucial to 

epidemic transmission and who are most likely to have concurrent STIs, 

was already HIV-saturated in Rakai, thus minimizing the impact of the 

intervention. Recently, a third trial, from the Masaka district of Uganda, 

demonstrated no effect of syndromic STI management on HIV incidence 

in the context of a mature HIV epidemic (Kamali, 2003). These results 

confirm that it is not the type of intervention but rather the stage of the 

epidemic in an area that permits a community-wide impact of better STI 

services. Subsequent analysis suggested that an important difference 

between the three studies was the prevalence of curable STIs, which 

was significantly higher in Mwanza than in Rakai or Masaka, which may 

explain the larger impact that STI treatment had on HIV transmission in 

that study (Orroth, 2003). In all the studies, the effect of herpes treatment 

was not assessed, since medications against genital herpes were not part 

of the interventions, though a large proportion of STI episodes in all three 

trials were likely a result of herpes outbreaks. Nevertheless, STIs clearly 

increase individual-level risk of HIV acquisition, and STI treatment 

should remain an important part of reducing HIV risk for individuals 

and populations, even in areas where HIV is already well-established. 

STI treatment remains one of the most cost-effective HIV prevention 

strategies for resource-poor settings (Creese, 2002).

How should we counsel women at risk for STIs and HIV?

Important issues in counseling women at risk for STIs and HIV are 

presented in Table 3-9. Reducing the prevalence and incidence of 

STIs should reduce the susceptibility to HIV transmission. Measures 

to reduce STIs include female and male condom use, seeking early 

diagnosis and treatment of genital tract symptoms, and frequent STI 

screening and should be a part of HIV prevention in the United States 

as well as in developing countries (CDC, 1998b). Infections such as 

yeast vaginitis and bacterial vaginosis are not sexually transmitted, 
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but arise from disruption of a woman’s genital tract flora. For this 

reason, these infections are often underemphasized in programs to 

diagnose and treat genital tract infections. However, these are relatively 

common conditions, and thus they may be responsible for a substantial 

fraction of HIV infections in some populations. Clinicians should 

diagnose and have a low threshold to treat both bacterial vaginosis and 

Candida vaginitis in women with high-risk sexual behavior. Vaginal 

douching, which has no therapeutic benefit, may increase the risk of 

developing bacterial vaginosis and pelvic inflammatory disease and 

should be strongly discouraged. Preventable risk factors for Candida 

vaginitis include uncontrolled diabetes mellitus, antibiotics, and highestrogen oral contraceptives. Other possible risk factors that are less 

well documented include wearing poorly ventilated clothing, use of 

low-estrogen oral contraceptives, frequent swimming, feminine hygiene 

sprays, and use of spermicidal jelly.

Finally, women with a history of genital herpes or with serologic 

evidence of herpes simplex virus type 2 infection should be taught how 

to recognize prodromes and recurrences. Suppressive herpes antiviral 

therapy should be considered in women with frequent recurrences who 

report high-risk sexual behavior (CDC, 2002).

Table 3-9: Measures to Reduce STIs

• Encourage male and female condom use

• Encourage seeking medical care early for diagnosis and treatment of genital 

tract symptoms

• Routine screening for genital tract infections, including chlamydia cervicitis, 

yeast vaginitis, and bacterial vaginosis among sexually active women

• Discourage douching

• Educate women about risk factors for yeast vaginitis

• Teach how to recognize genital herpes recurrences and prodromes and offer 

antiviral treatment to shorten or suppress recurrences

IX. CONDOMS AND PREVENTION OF HIV INFECTION

Readers of history may know that decorative penile covers have been 

mentioned in Egyptian writings as far back as 1350 BC. In 1564, the Italian 

anatomist, Fallopius, described the concept of a penile barrier for the 

prevention of venereal disease. The famous romancer, Casanova, is said 

to have protected himself with sheets of sheep intestine. Since that time, 

technology has allowed the production of latex male condoms and, more 

recently, polyurethane male condoms and female condoms. Important 

issues to discuss while counseling women on use of male and female 

condoms are listed in Table 3-10 and discussed below.
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Table 3-10: Important Issues for Patients Being 

Counseled on Condom Use

• Store in a cool, dry place, such as a bedroom drawer

- Avoid excessive humidity, such as in a bathroom

- Avoid excessive heat, such as in a wallet carried in a trouser pocket

- Avoid exposure to direct sunlight

• Use appropriate spermicide or lubricating jelly

- Mineral–oil–containing compounds, such as petroleum jelly, cooking oils, shortening, 

or lotions can weaken latex

• Use male condom properly

- Use male condom at the onset of male arousal, even before penetration

- Make sure that the male condom is unrolled to extend completely to the penis base

- Use enough lubrication to prevent excessive friction that might lead to breakage

- Hold the male condom at the base during withdrawal to prevent slippage

• Use female condom properly

- The inner ring must be placed completely onto the cervix or the condom may twist

- Additional lubrication may be needed to prevent the condom from twisting

- Care must be taken not to insert the penis between the condom and vaginal wall

- The outer ring may need to be held in place to keep the condom from slipping into 

the vagina or anus

- During anal intercourse, the insertive partner may have to keep thrusts shallow, 

because the condom is not as long as the rectum. It also might be advisable to 

remove the inner ring for anal sex to reduce likelihood of rectal bleeding.

A. MALE CONDOMS

Male condoms prevent transmission of many STIs

The literature on the role of barrier contraception as protection against 

STIs is vast and the reported degree of protection against specific STIs 

varies from paper to paper. A distillation of available data produces the 

conclusion that, of available barrier methods that have been adequately 

tested, latex male condoms provide substantial protection against 

infection with HIV and most other STIs, and are currently the most 

reliable protective measure. In a workshop reviewing the scientific 

evidence on condom effectiveness, the U.S. National Institutes of Health 

concluded that consistent condom use reduces a woman’s risk of HIV 

by at least 85% (NIAID, 2001). Moreover, some studies have reported no 

seroconversions at all among consistent condom users despite repeated 

coital exposure (Carlin, 1995). A significant increase in condom use, and 

a lower than anticipated rate of new HIV infections, followed voluntary 

HIV counseling and testing of HIV discordant couples in one African 

study (Allen, 1992). In terms of other STIs, male condoms may be less 

reliably protective against transmission of herpes and human papilloma 

viruses.
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 Latex male condoms must be stored and used properly

Male condom failures are more likely caused by postmanufacture 

defects secondary to latex deterioration than to manufacturing defects. 

Latex male condoms have proved impermeable to HIV in vitro. In 

contrast, natural membrane (“skin”) condoms have been shown to be 

permeable to small amounts of HIV and other infectious agents, and 

are not recommended for disease prevention. Transmission of HIV that 

occurs with use of latex male condoms is likely due to technical failures 

or improper usage rather than to manufacturing defects. Since 1987, 

the Food and Drug Administration in the United States has maintained 

a high level of quality by limiting the number of defective condoms 

to four per 1000 count batch. Patients should be counseled that stored 

male condoms should be replaced often because temperature, light, 

and animal pests all can contribute to latex deterioration and decreased 

effectiveness. In clinical studies, breakage rates range from 0.5% to 7% 

(Stratton, 1993). Studies reporting higher breakage rates tended to include 

populations from underdeveloped areas or those who participated in anal 

intercourse.

Male condoms must be used properly to be effective.

Using oil-based lubricating materials such as petroleum jelly, cooking 

oils, shortening, or lotions during intercourse weakens latex and 

promotes breakage. Common errors that patients should be cautioned 

about include delaying condom use until just before full penetration, 

failure to extend the condom all the way to the penis base, insufficient 

application of a water-based lubricant, and failure to hold the condom at 

the base during withdrawal.

 Polyurethane male condoms may be a future alternative

Acceptability of male condom use is limited by complaints of decreased 

male sensitivity and limitation of sexual enjoyment by both men and 

women. Polyurethane has been hailed as an attractive alternative to latex 

because of increased tensile strength that should, theoretically, allow for 

a thinner condom wall translating into increased penile sensation. A male 

polyurethane condom, Avanti, has been popular since its introduction 

in late 1994, but after increasing numbers of complaints of condom 

breakage, the manufacturers have changed specifications to produce 

a thicker condom labeled “Intended for Latex Sensitive Condom Users 

Only.” Breakage rates, patient acceptability, and the ability of this product 

to protect against STI and HIV infection are yet to be demonstrated.

B. FEMALE CONDOMS

Also made of polyurethane, the female condom has been available for 

use in the United States since 1993 (Bounds, 1997) and offers women 

more control over use than with the male condom. The female condom 

is a sheath, closed at one end, with flexible rings at both ends (Figure 

3-2). The device is inserted into the vagina by compressing the closedend ring and pushing against the cervix, while the outer ring covers 
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the labia (Figure 3-3). Only one female condom is currently available, 

marketed under the name “Reality” in the United States and Canada and 

“Femidom” in other parts of the world. Limited data are available on the 

efficacy of the female condom in preventing HIV and STIs, although most 

experts have extrapolated from the data on male latex and polyurethane 

condoms to conclude that, if used properly, female condoms would be 

impermeable to most viruses and other microorganisms. In a study 

sponsored by the United Nations Programme on HIV/AIDS (UNAIDS), 

female commercial sex workers in Thailand were randomized into a 

group instructed to consistently use male condoms, and a group given 

the option to use female condoms if the male refused to wear a condom 

(Fontanet, 1998). Both groups reported universal male or female condom 

use rates of approximately 97%, although 9% of the women in the “option 

group” used the female condom. Before introduction of the female 

condom, women in the study population were experiencing an average 

of two STIs per year (trichomoniasis, chlamydial infection, gonococcal 

infection, genital ulcer disease). This rate was surprisingly high, 

particularly given the high rate of reported condom use, and may be due 

to overreporting of condom use or STIs acquired from their husbands or 

nonpaying partners. Nevertheless, the group randomized to the option to 

use either type of condom demonstrated a 24% decrease in the incidence 

of STI compared with the male condom–only group. Importantly, 

female condoms were reportedly well accepted by both the women and 

their clients. Condom tears occurred less frequently with the female 

condom than the male condom. A recent study found that the female 

condom acts as an effective barrier for the vast majority of uses, and 

exposures to semen become less frequent with greater user experience 

(Macaluso, 2003).

Figure 3-2 : The Female Condom

Source: The Female Health Company. Chicago, IL.
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Figure 3-3: Female Condom Insertion and Positioning

STEP 1

Inner ring is squeezed for 

insertion.

STEP 2

Sheath is inserted, 

similarly to a tampon.

STEP 3

Inner ring is pushed up 

as far as it can go with 

index finger.

STEP 4

Female condom is in 

place

Index Finger

Inner 

Ring

Open End

Inner Ring

Open 

End

Vaginal 

Canal

Cervix

Uterus

Inner 

Ring

Open 

End

Inner 

Ring

Open End

 Source: Adapted from Reality brand female condom literature.
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C. ACCEPTABILITY OF MALE AND FEMALE CONDOMS

Factors influencing condom use are presented in Table 3-11. These factors 

are complex, and often differ between men and women. Surveys have 

shown that both men and women are influenced by perceived social 

norms and attitudes about condom use, and by the recognition that 

condoms may prevent STIs. Ability to obtain condoms without excessive 

cost or embarrassment, ease of using the condom, and preservation of 

pleasurable sexual sensation are clearly concerns for both men and 

women. Acceptability of the male condom for both men and women is 

increased by normal appearance and feel, lack of odor, lack of slippage, 

the presence of a reservoir tip, and spermicidal lubrication. Men may 

be more likely to use the male condom if they feel that the woman may 

perceive them as being more sensitive and caring if they do so. Women, 

on the other hand, have complained that the interruption of foreplay 

negatively affects the acceptability of the male condom. For the female 

condom, both men and women have complained about the aesthetic 

appearance of the external ring, and the noise during intercourse. The 

fact that the female condom is made of polyurethane and not latex may 

increase its acceptability, particularly among latex-allergic users. Women 

have reported that inserting the female condom interrupts foreplay. 

Interestingly, in several surveys, more women have said that they would 

be likely to use the female condom again than have said that they liked 

using it, suggesting that women may be willing to sacrifice comfort and 

pleasure during sex for protection against STIs and pregnancy. Many 

women have also strongly expressed a preference for a female-controlled 

device to prevent STIs. Finally, in surveys, pregnancy prevention is more 

important to women than to men, and most women feel that both the 

male and female condom may be inferior to other contraceptive methods 

(Grady, 1999).

D. SPECIAL CONSIDERATIONS FOR WOMEN WHO HAVE SEX WITH WOMEN

Discussion of recommendation of protective sexual practices should not 

be limited to exclusively heterosexual women. Sexual transmission of 

HIV between women has been described. The use of barriers such as 

dental dams should be recommended for oral-genital contact, particularly 

in HIV discordant relationships. Sexual activity should be avoided during 

menstruation or when there are symptoms of genital tract infection. 

The sharing of sex toys contaminated with blood was implicated in a 

recently described case of female-to-female sexual transmission of HIV 

(Kwakwa, 2003).
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Table 3-11: Factors Associated with Condom Use and Non Use

Condoms in General Important to 

Men

Important to 

Women

 Negative image of condom use associated with 

disease, promiscuity, and distrust of sex partner ■ ■

 Actual and perceived social norms governing 

condom use ■ ■

 Perceived ability to protect against sexually 

transmitted infections ■ ■

 Ease of obtaining or purchase ■ ■

 Ease of putting on or in ■ ■

 Slippage during intercourse ■ ■

 Adequate lubrication ■ ■

 Sensation during intercourse ■ ■

Male Condoms Important to 

Men

Important to 

Women

Normal appearance and feel ■ ■

Lack of odor ■ ■

Reservoir tip ■ ■

 Spermicide coating ■ ■

 Interruption of foreplay ■

 Inferior contraceptive method ■

 Perception that partner may believe user is 

sensitive and caring ■

Female Condoms Important to 

Men

Important to 

Women

 Aesthetic appearance of external ring ■ ■

 Noise during intercourse ■ ■

 Polyurethane material ■ ■

 Interruption of foreplay ■

Female controlled device ■

 Inferior contraceptive method ■

Source: Adapted from Grady. 1999.
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X. OTHER FORMS OF CONTRACEPTION AND THE RISK 

OF HIV INFECTION

The role of hormonal contraceptives in HIV transmission 

is controversial

The association between hormonal contraception and HIV infection has 

been the subject of controversy. Because of the unique considerations 

that contribute to contraceptive choice, a clinical trial randomizing 

a woman to contraception or placebo is probably not feasible. Thus, 

although many studies presenting data on the association have been 

published, all are population surveys or observational studies. The 

reported effects of oral contraceptives on HIV susceptibility are widely 

divergent, ranging from protective, to no effect, to an increased risk. A 

meta-analysis on the subject reported that the use of oral contraceptives 

may be associated with a small increased risk of HIV infection (Wang, 

1999). When the results of all 28 published studies were combined, a 

pooled odds ratio of 1.2 (95% confidence interval 0.99–1.42) was found. 

This pooled risk estimate increased with increasing study quality, 

suggesting that a true association, albeit small, does exist. In addition, 

two prospective studies found that use of the injectable contraceptive 

depo-medroxyprogesterone acetate (Depo-Provera) was associated with 

increased risk of HIV infection. One, conducted among 779 commercial 

sex workers in Mombasa, Kenya, found women using Depo-Provera were 

at a 2-fold increased risk of acquiring HIV compared with women using no 

contraceptive method, after controlling for differences in sexual behavior, 

condom use, and STIs (Martin, 1998). Insufficient data exist on other 

hormonal contraceptive methods to reach a conclusion about the effect 

on a woman’s susceptibility to HIV. A large observational study currently 

being conducted among family planning clinic attenders in Zimbabwe, 

Uganda, and Thailand is examining the relationship between hormonal 

contraceptive use and HIV acquisition in a lower-risk population of 

women, with preliminary results expected in 2004.

Other contraceptive methods and HIV acquisition

Cervical barrier contraceptive devices, such as the diaphragm or 

cervical cap, have been postulated as potentially protective against 

HIV (Moench, 2001). Evidence supporting this hypothesis comes from 

laboratory investigations suggesting the cervical epithelium is particularly 

susceptible to HIV infection and observational studies that found lower 

rates of cervical STIs, like gonorrhea, among women who used the 

diaphragm. However, cervical barrier devices do not cover much of the 

vagina and thus still would result in significant mucosal exposure to HIV. 

A large randomized trial of the diaphragm to decrease HIV acquisition 

will be conducted in Africa. If successful, cervical barriers would be a 

discreet, easy, female-controlled method to prevent HIV infection.
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The use of spermicides as a sole method for HIV prevention should 

be discouraged. The most well-studied vaginal spermicidal product is 

nonoxynol-9 (N-9). A large meta-analysis of several controlled trials 

concluded that N-9 provides no protection from HIV (summary relative 

risk 1.12, 95% confidence interval 0.88-1.42) or other STIs and slightly 

increases the risk of genital ulceration (Wilkinson, 2002). This last finding 

may be of particular concern to women at high risk of HIV. In the largest 

randomized trial of N-9, conducted among commercial sex workers in 

several developing countries, a nearly 2-fold increased HIV risk was 

seen among the subset of women who used the product several times 

per day (Van Damme, 2002). Overall, N-9 is not recommended for HIV 

prevention, especially among high-risk women. 

Data on the relationship between the use of intrauterine devices (IUDs) 

and HIV acquisition is sparse. In general, IUDs are not recommended 

for women at high risk for STIs because of possible increased risk of 

pelvic inflammatory disease, though IUDs are a safe, long-lasting, and 

effective contraceptive method for lower-risk women. Like many other 

contraceptive methods, IUDs provide no barrier protection and thus would 

be unlikely to decrease HIV risk. A theoretical increase in HIV risk has 

been hypothesized due to the foreign body reaction and accompanying 

intrauterine inflammation associated with IUD use. In addition, use of 

non-progestin releasing IUDs are associated with longer and heavier 

menses, which may increase risk of transmission bidirectionally.

Female sterilization by tubal ligation has no effect on male-to-female 

HIV transmission. Additionally, HIV has been acquired vaginally by 

women who have had hysterectomies. Early penile withdrawal, while 

theoretically reducing the innoculum size, has not been studied and 

should not be recommended. Although the exact effect of vasectomy 

on the ability to transmit HIV from male to female is unknown, HIV 

has been cultured from the ejaculate of HIV-infected vasectomized men 

(Anderson, 1991).

Contraception and prevention of infection are separate issues

The issue of contraception for sexually active woman of reproductive 

age is obviously complex. The importance of preventing unwanted 

pregnancies is clear. Any counselor working with women is familiar 

with the issue of controlling and planning family size while taking 

into account economic factors, maternal health, and social pressures. 

Hormonal contraception is one of the most effective means to prevent 

pregnancy. The message conveyed to women must be that contraception 

and protection against STIs, including HIV, are separate considerations. 

Regardless of which method women choose for pregnancy prevention, 

counselors must emphasize that male and female condoms are the only 

methods proven to prevent STI transmission.

The effectiveness of various contraceptive methods in reducing risk of 

HIV infection is summarized in Table 3-12.
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Table 3-12: Contraception and prevention of HIV-1 infection

Method May 

Increase Risk*

No Effect or 

Insufficient 

Data*

Protective — 

Strong Evidence

Male condom ■

Female condom ■

Intrauterine device ■

Diaphragm ■

Cervical cap ■

Tubal ligation ■

Vasectomy ■

Early penile 

withdrawal ■

Oral contraceptives ■

Depo-Provera ■

* Counsel that condoms should be used to prevent HIV-1 infection.

XI. NEW APPROACHES TO HIV AND STI PREVENTION: 

MICROBICIDES, VACCINES, AND POSTEXPOSURE 

PROPHYLAXIS

Given the difficulties that many women encounter in negotiating 

condom use, other prevention strategies under the control of women 

have been sought, such as topical microbicides. Although microbicides 

have generated considerable enthusiasm, progress in this area has been 

relatively slow. Most of the research in microbicides over the past 10 years 

has focused on safety and efficacy of nonoxynol-9 (N-9). Unfortunately, 

as reviewed in section X, N-9 is unlikely to provide significant protection 

from HIV or STIs and may increase the likelihood of HIV transmission 

to high-risk women (Van Damme, 2002; Wilkinson, 2002). Policy 

organizations such as the CDC and WHO have recently circulated 

advisories to discourage use of N-9 for STI and HIV prevention.

Although the concept of topical microbicides is promising, the 

process of developing and testing new microbicidal products for 

safety and ultimately efficacy in preventing HIV in clinical trials 

will take a number of years

A number of new topical microbicidal products are in early clinical 

trials, and many more are in preclinical development (McCormack, 

2001). These include agents with broad-spectrum activity (acidic buffers 

such as BufferGel, surfactants such as C31G, and natural Lactobacillus 

suppositories), inhibitors of viral entry (such as PRO2000, carrageenan, 

and dextrin sulfate), and inhibitors of viral replication (such as gel 

formulations of antiretroviral medications, including tenofovir). Efficacy 
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trials of topical microbicides face many challenges, including issues of 

compliance, product safety and acceptability, and the potential for sexual 

behavior to change as a result of product use. Moreover, microbicide 

studies have faced difficulty in the development of biologically inert but 

physically identical placebos for use in efficacy trials, as even inactive gel 

placebos may provide some degree of HIV protection simply as a result 

of their physical or barrier properties.

Vaccines hold the most promise for preventing the largest 

number of HIV infections transmitted sexually, perinatally, 

or through drug use

Only one HIV prophylactic vaccine has completed efficacy testing. 

This vaccine, which used a recombinant HIV subtype B gp120 protein 

developed by the VaxGen corporation, provided essentially no reduction 

in HIV acquisition in a large trial conducted in North America and Europe 

(McCarthy, 2003). A similar trial of a bivalent HIV subtype B/E construct 

among Thai injection drug users also failed to prevent HIV acquisition. 

Overall, the necessary components of an immunogen that could 

induce protection against infection are not yet completely understood. 

Clues have emerged from dissecting the properties of immunity that 

offer protection against other pathogens, and also those that arise in 

individuals infected with HIV. Primate studies, using the related simian 

immunodeficiency virus (SIV) or SIV/HIV chimeric virus constructs, 

have provided important information about how the virus establishes 

itself during early infection as well as about the immunologic potential 

of candidate vaccines. In addition, studies of persons demonstrating 

unusual control of HIV infection (e.g., who remain uninfected despite 

repeated HIV exposure or who demonstrate long-term nonprogression 

although infected with HIV) suggest there are unique host defense 

characteristics, particularly cellular immunity, that might be able to be 

replicated by a vaccine. 

Our understanding of the mechanism of action of other effective viral 

vaccines and of HIV pathogenesis is guiding HIV vaccine development. 

Most licensed vaccines prime host immunity to control initial infection 

more efficiently, rather than provide sterilizing immunity. Protection 

is commonly mediated by induction of antibodies that block infection, 

which allows time for antigen-specific T cells to mature and overtake 

any cells that do become infected. However, HIV preferentially targets 

T helper cells and often establishes latent infection within them. Thus, 

a vaccine must induce sufficient immunity to block such HIV “seeding” 

or prevent viral reemergence from latently infected cells. Unfortunately, 

HIV is not easily neutralized by antibody, so vaccine strategies that 

use recombinant proteins, like in the effective hepatitis B vaccine, are 

unlikely to be successful for HIV (as demonstrated by the unsuccessful 

HIV recombinant gp120 subunit vaccine). Most experts believe that 

regimens priming both the cellular and humoral immune arms are 

the best candidates for protection. Considerable research into cellular 

immunity against HIV has been conducted over the past few years, 
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and vaccine constructs that induce cell-mediated responses, at least 

in a moderate proportion of individuals, have been developed. These 

generally consist of poorly replicating viral or bacterial vectors (e.g., 

vaccinia, canarypox, adenovirus, salmonella) expressing a selection of 

HIV gene products, such as gag, pol, env, nef, or a variety of isolated Tcell epitopes. Alternative strategies include naked DNA vaccines, which 

can induce some degree of cellular and antibody-mediated immunity 

and have the advantage of being considerably more stable in tropical 

climates. 

The development of an effective HIV vaccine faces several additional 

challenges. The remarkable ability of HIV to undergo genetic change 

suggests that vaccines based on individual viral strains, especially 

laboratory adapted strains, may not induce immunity with sufficient 

flexibility to prevent a new infection. The predominance of distinct HIV 

subtypes in different regions of the world may complicate development 

of a single universal HIV vaccine, although cross-clade cellular immune 

responses have been demonstrated in human immunogenicity trials. 

Moreover, since HIV transmission occurs predominantly by sexual 

contact, protection will likely require mucosal as well as systemic 

immunity. Finally, a number of logistic and ethical considerations 

relevant to the conduct of HIV vaccine research have been raised, 

including the need for unbiased counseling towards risk reduction for 

vaccine participants, the obligation to provide HIV care to individuals 

infected during a trial, and the commitment to rapidly provide vaccine to 

at-risk communities should an effective candidate be found.

Numerous clinical studies of various HIV vaccine constructs have been 

conducted, are in progress, or are planned. On-line updated lists of trials of 

HIV vaccines are maintained by the International AIDS Vaccine Initiative 

(www.iavi.org) and the HIV Vaccine Trials Network (www.hvtn.org). 

Postexposure prophylaxis (PEP) may reduce the likelihood of HIV 

infection after a high-risk exposure

Theoretically, PEP can prevent HIV transmission either by blocking initial 

viral infection of cells or by inhibiting viral dissemination, thus allowing 

for immune clearance of a small number of already infected cells. The 

data for efficacy of antiretrovirals as PEP comes primarily from a single 

case-control study of health care workers who experienced occupational 

HIV exposures, mostly though needlestick injuries. Those who received 

zidovudine had an 80% lower likelihood of becoming infected, though this 

study was limited by a small sample size, retrospective design, and other 

potential sources of bias. The rationale for PEP after sexual exposure is 

largely that the probability of infection after a single unprotected sexual 

exposure is similar to that after a needlestick exposure (i.e., ~0.1%, 

though slightly higher for receptive anal intercourse) (Katz, 1998; USPHS, 

1998). Animal models suggest that PEP may be effective for mucosal and 

needle exposures, particularly when used within 24–48 hr. Ethical and 

pragmatic considerations make it unlikely that a randomized trial of PEP 

will be conducted. The effectiveness of PEP is likely to be influenced by 
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time to initiation of treatment, duration of treatment, size of inoculum, 

and drug resistance profile of the virus in the source individual. While 

the risks and benefits of PEP for sexual exposure remain to be fully 

defined, studies suggest that provision of PEP for nonoccupational 

exposures is feasible (Kahn, 2001). Recently, some have suggested that 

routine antiretroviral chemoprophylaxis, with relatively safe agents such 

as nevirapine or tenofovir, be tested as an HIV prevention strategy for 

individuals at particularly high risk (e.g., commercial sex workers in high 

HIV prevalence settings) (Youle, 2003).

Individual providers who are approached by anxious patients who have 

recently had a high-risk sexual exposure must weigh the likelihood of HIV 

infection in the contact, antiretroviral treatment history if the contact is 

known to be HIV-infected, specific nature and timing of the exposure 

(since initiation of PEP within 48 hr may be important), and possible 

risks of drug toxicity or side effects in choosing whether to use PEP and 

which drugs to prescribe. CDC guidelines recommend 2–3 antiretroviral 

medications, depending on the intensity of the exposure, for 4 weeks for 

occupational exposures having at least moderate HIV risk (CDC, 2001). 

A similar approach has been adopted by many providers when selecting 

a regimen for “sexual PEP.” The source partner’s likelihood of resistant 

virus, based on treatment history, stage of disease, and viral load, can 

be factored into the choice of a PEP regimen. Other considerations 

should include evaluation for other STIs, emergency contraception when 

appropriate, and possible indication for hepatitis B vaccination. Informed 

consent is recommended when administering PEP.

PEP should not be administered routinely, with exposures at low risk of 

transmission, or when care is sought after 72 hr from the time of exposure. 

Situations in which PEP should be especially considered include condom 

breakage with serodiscordant couples and sexual assault. PEP is not a 

substitute for risk reduction and should not be considered a form of 

primary HIV prevention. Individuals presenting for possible PEP should 

have reinforcement of the importance of initiating, resuming, or improving 

risk reduction activities. Providers are requested to report nonoccupational 

PEP use to a national registry maintained by the CDC at (877) 448-1737 or 

http://www.hivpepregistry.org.

XII. PREVENTION MESSAGES FOR HIV-INFECTED WOMEN 

While this chapter has largely focused on factors that may increase 

a woman’s risk of acquiring HIV, prevention messages are equally 

important for women who are already HIV-infected. Studies have shown 

that women with HIV are concerned about factors that may increase 

their infectiousness to their sexual partners and children. In general, 

the central messages for preventing sexual HIV transmission apply to 

HIV-infected women as well as to those who are uninfected and at risk 

through their or their partners’ behaviors. These include the importance 

of knowing one’s HIV status and that of one’s sexual partners, the ability 
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for behavioral change to prevent transmission, and the potential for 

consistent condom use to significantly reduce HIV risk. Issues relevant 

to the prevention of mother-to-child transmission of HIV are covered in 

chapter VII.

Perhaps not surprisingly, many factors that increase the risk of HIV 

acquisition also appear to increase HIV infectiousness (reviewed in 

Baeten, 2003). Because of logistical limitations, relatively few studies 

have been conducted to assess the risk that HIV-infected women pose 

to susceptible sexual partners. However, numerous studies have now 

demonstrated that HIV shedding in genital secretions is likely a reliable 

marker of infectiousness, based on good biologic plausibility that 

factors that increase genital HIV shedding increase HIV transmission 

and on strong agreement between correlates of HIV transmission in 

epidemiologic studies and correlates of genital shedding of HIV. Thus, 

most studies of factors that influence the infectiousness of women with 

HIV have examined HIV shedding in the genital tract. 

Plasma viral load is the strongest predictor of HIV infectiousness

In a large study of HIV-discordant couples from Uganda, HIV plasma 

viral load was the principal predictor of heterosexual transmission and 

demonstrated a clear dose-response effect (Quinn, 2000). The rate of 

transmission from female index cases to their uninfected male partners 

was similar to that from male index cases to uninfected female partners, 

suggesting that HIV-infected women are no less likely to transmit 

the virus than are infected men. The results of this study were not 

necessarily surprising—higher viral load is a strong risk factor for motherto-child HIV transmission and HIV shedding in genital tract secretions. 

Epidemiologic studies suggest that individuals with primary HIV 

infection and advanced HIV disease, which are both characterized by high 

systemic and genital viral burdens, are more likely to transmit the virus 

to sexual partners. The only study to assess the effect of antiretroviral 

therapy on sexual HIV transmission found that men taking zidovudine 

monotherapy were at 50% decreased risk of transmitting HIV to female 

partners (Musicco, 1994). Given the dramatic reductions in plasma viral 

load and in the risk of mother-to-child HIV transmission that result from 

combination antiretroviral therapy, it is likely that effective regimens 

would significantly decrease a woman’s risk of transmitting HIV to sexual 

partners. However, studies have shown that genital HIV shedding may 

not be fully suppressed among individuals on therapy, even those with 

undetectable plasma viral loads, suggesting that antiretroviral therapy 

may not completely eliminate transmission risk.

STIs and other genital tract infections increase the risk of 

HIV transmission

Numerous studies have demonstrated that genital ulcer disease, cervical 

infections, and vaginal infections increase HIV shedding in the female 

genital tract, and that successful treatment reduces shedding (Baeten, 

2003). In areas where antiretroviral therapy is not available, control 
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of STIs should be a primary intervention to decrease sexual HIV 

transmission. Moreover, in all settings, STI screening and treatment 

may reduce HIV infectiousness among persons who do not qualify for 

antiretroviral therapy (e.g., those with CD4 counts >200–350) or even 

among those who are on therapy, since these infections may stimulate 

genital viral replication even in the context of good systemic HIV 

suppression. Recent studies have found that genital herpes shedding 

is associated with increased HIV shedding, suggesting that suppressive 

therapy for HSV may reduce HIV infectiousness. Studies to determine 

the efficacy of HSV therapy to decrease HIV shedding and transmission 

are planned. 

Contraception, menstruation, and HIV infectivity

Oral and injectable hormonal contraception were associated with 

increased genital HIV shedding in two cross-sectional studies from Kenya 

(Mostad, 1997). No published prospective studies have yet assessed the 

effect of initiation of hormonal contraception or duration of hormonal 

contraceptive use on genital HIV shedding over time. Very little information 

is available from epidemiologic studies on the relationship between 

hormonal contraceptive use and HIV transmission risk. Thus, there is no 

recommendation against use of hormonal contraception by HIV-infected 

women. Given the importance of preventing unintended pregnancies, 

effective methods of contraception should be strongly encouraged, and 

condom use should be promoted as well as an adjunct method to decrease 

HIV infectiousness. 

The effect of the diaphragm or cervical cap on HIV shedding and 

transmission is unknown. Cervical secretions tend to have significantly 

higher viral concentrations than vaginal secretions, potentially suggesting 

that cervical barrier devices may decrease transmission risk. However, 

women who have had hysterectomies can shed significant amounts of 

virus in the vagina, so even complete removal of cervical secretions does 

not eliminate HIV risk. One study from Kenya demonstrated that IUDs 

are a safe method of contraception for some HIV-infected women (Sinei, 

1998), and a secondary analysis found no increase in HIV shedding in 

cervical secretions after IUD insertion. 

Several studies have now demonstrated that the quantity of HIV shed in 

the genital tract varies over the course of the menstrual cycle (Coombs, 

2003). Shedding appears to be lowest during the peri-ovulatory period 

and highest near the time of menstruation, which is in agreement with 

epidemiologic studies that found increased transmission risk for male 

partners of infected women who had unprotected intercourse during 

menses. However, these results are difficult to translate into a prevention 

message since HIV is shed to some degree throughout the menstrual cycle, 

and some women may shed high quantities of virus at all times. Overall, 

recommendations to women with HIV should stress the importance of 

consistent condom use to decrease HIV transmission risk.
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 New interventions to decrease HIV transmission risk

There remains a great need for simple, inexpensive interventions to 

prevent and treat HIV among individuals living in resource-poor settings. 

Several observational studies suggested that micronutrient deficiencies 

increased HIV infectivity and accelerated disease progression. However, 

subsequent randomized trials of micronutrients, conducted among HIVinfected African women among whom the prevalence of nutritional 

deficiencies was high, failed to demonstrate any substantial benefit 

of supplementation with vitamin A or other vitamin and mineral 

preparations (Baeten, 2002; Baeten, 2003). Vaginal microbicides offer a 

potentially promising strategy to decrease HIV transmission risk, since 

these products may decrease the infectiousness of virus shed into the 

genital tract. An effective therapeutic vaccine against HIV (i.e., one 

that could reduce systemic and genital viral burden among infected 

individuals) could significantly slow the global spread of the epidemic. 

No therapeutic vaccine has yet demonstrated clinical efficacy, though 

research in this area is continuing.

XIII. CONCLUSIONS

Prevention of HIV remains a critical priority, particularly amidst 

increasing complacency related to enthusiasm about more effective 

treatments for HIV. The most effective available strategies for prevention 

are HIV counseling and testing, behavioral interventions to become 

abstinent or to reduce risk-taking, and condoms. STI treatment decreases 

individual-level risk of acquiring and transmitting HIV and has been 

shown to be an effective population-wide intervention in some settings. 

Topical microbicides may provide a prevention strategy directly under the 

control of women, although N-9 has not been shown to have significant 

efficacy against HIV transmission in commercially available spermicidal 

concentrations. New microbicide products are early in preclinical and 

clinical trial testing. Development of an effective HIV vaccine will likely 

be essential to controlling the global epidemic, and a number of candidate 

vaccines are undergoing clinical testing at this time. Lastly, postexposure 

prophylaxis is occasionally being prescribed for high-risk exposures, 

although there are very few data on safety and efficacy. While these new 

strategies are being tested, providers must continue risk assessments to 

identify women at risk for acquiring or transmitting HIV and assist them 

in reducing their risk through setting achievable risk reduction plans.
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IV

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I. INTRODUCTION

No field in medicine today is moving as swiftly as that of HIV/AIDS. The 

speed at which new developments occur and the rapidity with which 

they are superseded by newer data are nothing short of breathtaking. 

As a consequence, most studies are typically out of date at the time 

of publication. Because of the rapid turnover of key information, this 

chapter focuses on the essential principles of care for the HIV-infected 

woman. “Cutting-edge” treatment strategies currently being studied will 

be mentioned but not described in detail. To be truly useful, we indicate 

the general directions in which this field is moving and how to access 

updated information.

Several studies have demonstrated that positive clinical outcomes 

are a function of the clinician’s experience in caring for HIV-infected 

individuals (Kitahata, 1996). Nonspecialists are urged to seek expert 

advice and consultation whenever there is any question about the best 

way to manage a specific patient. This is especially important in the 

setting of antiretroviral treatment failure and in advanced HIV disease 

when patients are vulnerable to multiple simultaneous opportunistic 

processes.

There is as yet no compelling evidence that the clinical course of HIV 

infection in women differs significantly from that in men, with the 

obvious exception of the associated gynecologic conditions and obstetric 

issues (described elsewhere, see Chapters VI and VII). Although recent 

data have indicated that women may have lower HIV viral loads than 

men with an equivalent degree of immunosuppression, this does not 

appear to confer benefit in terms of overall survival or complicationfree survival (see Chapter I: Epidemiology and Natural History of HIV 

Infection in Women). At present, the approach to management of HIVinfected women and men is the same. With prolonged survival now 

possible, general preventive strategies and health maintenance, such as 

smoking cessation, control of hypertension, minimizing cardiovascular 

risk factors, and routine screening for malignancy (cervical, breast, 

colon), are all part of routine care for HIV-seropositive adults.

IV. PRIMARY MEDICAL CARE

Judith Feinberg, MD, and Janine Maenza, MD
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II. INITIAL EVALUATION

A. HISTORY

A comprehensive database is valuable to the primary caregiver in 

assessing the patient’s current status and in formulating a management 

plan. It is critical to remember that most patients are anxious and 

frightened at their initial encounter for HIV care; the ability to empathize, 

to share knowledge without being patronizing, to provide reassurance, 

and to remain nonjudgmental are essential to gaining the patient’s 

trust and to obtaining accurate information (see Chapter II: Approach 

to the Patient). In addition to all the usual aspects of history-taking, the 

following areas are of particular importance in HIV disease and deserve 

special attention.

• HIV diagnosis: When did you first test positive for HIV? Why were 

you tested? This neutral, open-ended start permits the patient to 

ask questions about HIV risk behaviors and possible route(s) 

of transmission, including sexual partners and practices and 

alcohol/drug use behaviors. If the patient can identify the source 

of new infection, it is valuable to know if the source patient has 

been treated for HIV, as the acquisition of drug-resistant infection 

has increasingly been reported. Was the patient ever tested for 

HIV before? If prior test(s) were negative, it is valuable to assess 

whether HIV has been relatively recently acquired by looking for 

evidence of the acute seroconversion syndrome within the past 

6–9 mo. These symptoms are classically those of seronegative 

mononucleosis — fever, aches, pharyngitis, lymphadenopathy, 

and frequently rash, although the range of possible clinical 

manifestations of acute HIV infection is very broad. 

• HIV treatment history: If the patient has already been treated 

for HIV disease, then it is extremely valuable to know the patient’s 

pretherapy CD4 cell count, HIV viral load, and specific treatment 

history. What was her prior antiretroviral therapy, including 

duration? Were there any difficulties with adherence, response 

to therapy, adverse effects, or history of treatment-limiting 

intolerance to any agent? Was resistance testing done and, if so, 

are results available? It is important to determine what, if any, 

obstacles she has experienced in taking antiretroviral therapy as 

prescribed (see Chapter V on Adherence). Has she had any HIVassociated diagnoses and was she treated for these conditions? Has 

she taken any opportunistic infection prophylaxis? Has she ever 

been hospitalized? If so, was it for an HIV-related problem?

• History of sexually transmitted infections and other infectious 

diseases: Including syphilis, gonorrhea, herpes simplex, pelvic 

inflammatory disease, anogenital warts; tuberculosis (PPD status, 

exposure to active case, prior prophylaxis or treatment for active 

disease); hepatitis A, B, or C; prior vaccinations, including those for 

childhood illnesses, hepatitis A and/or B, pneumococcal infection 
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and influenza; history of chicken pox or shingles; complete 

gynecologic history (see Chapter VI on Gynecologic Problems), 

including most recent evaluation, Pap smear, and results.

• History of other medical diagnoses: With particular attention 

to hypertension, type 2 diabetes, cardiovascular disease, 

premalignant or malignant conditions.

• Sexual practices: Including use of condoms (male and/or female 

versions) and/or other forms of birth control, consistency of use; 

number of current partners and their HIV status (if known); sexual 

activity with men, women, or both; history of trading sex (oral or 

intercourse) for drugs or money; history of anal sex.

• Presence of HIV-associated signs and symptoms: Fatigue, lymphadenopathy,

weight loss, skin problems, bacterial pneumonia, thrush (oral, 

vaginal), as well as signs/symptoms more typical of advanced HIV 

disease, including fevers, night sweats, persistent diarrhea, severe 

headache, respiratory symptoms (especially progressive dyspnea on 

exertion and cough, whether productive or nonproductive), mental 

status changes, difficulty swallowing, midline substernal discomfort 

with swallowing, and visual changes, particularly the presence of 

floaters or visual field deficits.

• Mental health history: Past and current problems, evidence of 

depression (trouble sleeping, early awakening, change in appetite, 

loss of interest in usual activities, anhedonia).

• Family history: Age and health of children, including HIV test 

results if performed; HIV in other family members; other medical 

diagnoses, especially hypertension, type 2 diabetes, cardiovascular 

disease, malignancy in family members.

• Medications taken regularly: Including prescription and overthe-counter remedies; history of and attitude toward regular 

medication use; use of alternative (nontraditional) medications for 

HIV or other conditions; drug allergies.

• Social history: Place of birth, where patient was raised, where 

and with whom patient lives and relationship to others in the 

household; childcare responsibilities; history of domestic violence; 

pets, especially reptiles (risk of salmonellosis) and kittens (risk of 

toxoplasmosis); extent of formal education; occupational history 

and potential toxic exposures; travel history; cigarette, alcohol, and 

illicit drug use in the past or continuing; misuse of prescription 

medications.

• Sources of support: To whom has the patient disclosed her 

diagnosis and what were their reactions? Are there friends or 

family to whom disclosure seems possible either now or perhaps 

in the future? Are other family members HIV-positive? Are family 

or friends able to care for the patient’s children in the event of 

illness? Does she have a job and, if so, does it provide health 

insurance?
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Just as important as the information that the clinician obtains in 

the history-taking process is the information about HIV disease 

that is shared with the patient. Counseling and education are 

important elements of the therapeutic bond with the caregiver, 

but because this entails an enormous amount of information, it 

is best broached initially and then reintroduced and reinforced at 

appropriate intervals.

Many patients are in a state of shock following diagnosis, or may 

be suffering from situational depression or fear of their partner’s 

response. Be kind. Be patient. Schedule enough time (1 hr) for the 

initial visit. Make sure the patient knows your purpose is to support 

her and care for her. Another key bond is the one between the 

patient and the office/clinic nurse, which should be encouraged. 

Ensure that she has a path to reach you or the nurse for any 

questions, complaints, or symptomatic therapy, especially when 

starting antiretroviral therapy.

It is important to convey information in lay language at a level 

of complexity appropriate to the patient’s level of comprehension 

(remembering that formal educational levels may not necessarily 

correlate with the patient’s ability to understand complicated medical 

concepts). These include the following areas.

• HIV pathogenesis: What are CD4 lymphocytes and why are they 

important? How does HIV infection affect CD4 cells?

• Natural history of HIV disease: How is “AIDS” different from 

“HIV infection” (or “HIV disease”)? What is the typical time course 

between acquisition of HIV and the development of HIV-associated 

problems? AIDS?

• Monitoring the activity of HIV disease: What do CD4 cell counts 

and HIV viral load tests measure? How are they used, and how 

often will they be repeated?

• Goals of HIV disease management: To maintain or improve 

the patient’s immune system, control HIV replication; avoiding 

or minimizing side effects of medications; preventive care 

(vaccinations, opportunistic infection prophylaxis, periodic Pap 

smears, other appropriate screening tests).

• Principles of HIV treatment: Describe the available viral targets 

and classes of drugs used, and the value of combination therapy in 

preserving health and prolonging life. Underscore the importance 

of adherence.

• Preventing spread of HIV infection: Notifying sexual partners 

and drug use contacts, safer sexual practices, safer needle use 

including needle exchange programs, ready availability of bleach 

in the household for cleaning up blood, appropriate wound care for 

accidental injuries, reassurance about the difficulty of transmitting 

HIV to casual contacts and to family members even in the close 

context of everyday family life.
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Last, because a diagnosis of HIV infection means a chronic, lifethreatening disease and still carries a social stigma, the clinician plays a 

key role in exploring mental health and psychosocial needs, helping the 

patient identify potential sources of support, and referring the patient for 

additional medical, psychiatric, and/or social services.

B. PHYSICAL EXAMINATION

The examination may yield clues to specific HIV-associated conditions. 

Vital signs should be tracked carefully, particularly temperature and 

weight. The discovery of hypertension, largely ignored in the past, should 

trigger appropriate attempts at control, including weight loss, reduction 

of salt intake, and medication if necessary. Special attention should be 

paid to the following areas.

• General: Evidence of wasting, often prominent at the temples; fat 

redistribution syndromes including the development of a buffalo 

hump, enlarged breasts, and truncal obesity, which may coexist 

with or be separate from marked subcutaneous fat loss in the 

extremities, face, and buttocks.

• Eyes: The conjunctival surfaces should be examined for the 

purplish spots of Kaposi’s sarcoma (KS) and for petechiae. 

Fundoscopy may reveal “cotton wool” spots (microinfarcts of the 

retinal nerve fiber layer due to occlusion of retinal capillaries). 

These must be differentiated from the typical ‘eggs and ketchup’ 

appearance of the infiltrates and hemorrhages caused by 

cytomegalovirus (CMV) retinitis in patients with very advanced 

HIV disease; visual field deficits are common in CMV retinitis and 

may be uncovered with simple field testing by confrontation.

• Oropharynx: Oral examination often yields the earliest physical 

evidence of HIV infection with thrush (white plaques on buccal 

mucosa or posterior pharynx that are readily scraped with a 

tongue blade) and oral hairy leukoplakia (furry white plaques 

most often found on the lateral margins of the tongue that cannot 

be scraped off); purplish spots or plaques on mucosal surfaces, 

including the area under the tongue, typically indicate Kaposi’s 

sarcoma but may also be consistent with bacillary angiomatosis. 

No examination of an HIV-infected person, regardless of disease 

stage, should be considered complete without a careful assessment 

of the oropharynx.

• Lymph nodes: Nontender or minimally tender generalized 

adenopathy may wax and wane and most often is related to 

HIV infection itself, but may also indicate lymphoma. Regional 

adenopathy is more frequently associated with local pathology, 

such as intrathoracic adenopathy in tuberculosis or abdominal 

adenopathy in disseminated Mycobacterium avium complex 

(MAC) infection. Extremely tender lymph nodes should trigger 

an evaluation for the etiology.
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• Lungs: Fine, dry “cellophane” rales are classic for Pneumocystis 

carinii pneumonia (PCP), but are a late finding and may be absent.

• Hepatosplenomegaly: Organomegaly typically reflects 

disseminated infection with MAC, tuberculosis, or histoplasmosis, or 

may be a sign of lymphoma.

• Pelvic examination:

- External genitalia/perineum: Sores or ulcers are usually 

indicative of sexually transmitted infections, especially herpes 

simplex virus (HSV) or syphilis. In very immunosuppressed 

patients, ulcers may be caused by other opportunistic pathogens, 

such as CMV, or may represent aphthous ulcers. Condyloma 

acuminata may appear as small, fleshy papules or may be 

exuberant, florid growths reaching several centimeters in 

diameter; other human papillomavirus-associated lesions may be 

recognized only with magnification and/or application of acetic 

acid. Raised and pigmented lesions may represent premalignant 

changes (vulvar intraepithelial neoplasia).

- Speculum and bimanual pelvic examination: Abnormal 

vaginal discharge can be caused by various forms of vaginitis 

(yeast, bacterial vaginosis, or trichomoniasis) or cervicitis. Pap 

smears should be obtained to rule out cervical dysplasia. Cervical 

motion, and uterine and adnexal tenderness suggest possible 

pelvic inflammatory disease. (Gynecologic exam is discussed in 

detail in Chapter VI.)

• Neurologic: Motor deficits may reflect space-occupying lesions 

of the central nervous system (CNS) such as toxoplasmosis, CNS 

lymphoma, and progressive multifocal leukoencephalopathy, 

or may be due to neurosyphilis. Symmetrical, distal sensory 

deficits (especially decrease or loss of vibratory or proprioceptive 

sensation), typically affecting the feet more than the hands, 

indicate peripheral neuropathy, which may be due to HIV itself 

or to drug toxicity from the dideoxy nucleoside analogues. Poor 

short-term memory, diminished concentration, and sensorimotor 

retardation are the hallmarks of AIDS dementia complex (HIV 

encephalopathy). Dysphoric mood or flat affect may reveal 

depression.

• Skin: Like the oropharynx, careful examination of the skin often 

yields early clues about HIV infection, and should be performed 

regularly. Early manifestations include pruritic papular eruptions 

that may be bacterial folliculitis, eosinophilic folliculitis, or scabies. 

Pearly papules, often with central umbilication, are typical of 

molluscum contagiosum. A painful vesicular rash may be HSV but 

in a dermatomal distribution is usually shingles (varicella-zoster 

virus). Seborrheic dermatitis may be severe and appears as scaly, 

erythematous areas on the face, especially the nasolabial fold and 

eyebrows, or may be confined to the scalp and hairline. Psoriasis is 

another common scaling lesion. Purplish macules or plaques may 

be either KS or bacillary angiomatosis, similar to their appearance 

on mucosal surfaces; however, in dark-skinned individuals, KS may 

appear more brown than purple.
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III. LABORATORY TESTING

A. INITIAL DIAGNOSIS

Because of the advances made in HIV treatment, with associated 

decreases in HIV-related morbidity and mortality; concerns about 

possible increases in HIV incidence; and the new availability of a simple 

rapid HIV test (Oraquick), the CDC recommends that voluntary HIV 

testing be made a routine part of medical care for all patients in high 

HIV-prevalence clinical settings and for those with risks for HIV in low 

HIV-prevalence clinical settings. (CDC, 2003).

HIV infection is usually diagnosed by serologic tests that detect antibody 

to the virus. Infection may also be detected by nucleic acid-based assays 

that either measure the number of copies of the virus in plasma (RNA 

polymerase chain reaction [PCR]) or detect the virus in cells (DNA). 

Informed consent, with pre- and posttest counseling, is legally mandatory 

for performing HIV serologic tests in most locations, and should be 

procured at all times when the test is offered.

• Serology: The most common method of HIV detection is with an 

enzyme-linked immunosorbent assay (ELISA) test for screening, 

followed by confirmation with a Western blot. For a positive 

Western blot, the Centers for Disease Control and Prevention 

(CDC) and Association of State and Territorial Public Health 

Laboratory Directors require a band pattern indicating antibodies 

to two of the following proteins: p24, gp41, and gp120/160. A 

serologic test may be reported as positive if the ELISA is positive 

and Western blot criteria are met. The test may also be reported 

as indeterminate if the ELISA is positive, but only a single band 

is detected by Western blot. Serologic tests generally become 

positive 3–12 wk after infection occurs. The interpretation of an 

indeterminate test during this window period may be clarified 

by a quantitative virology assay with a PCR-based technique 

(see below). An indeterminate test may reflect the process 

of seroconversion, but may also be a constant finding in an 

uninfected individual. Causes of indeterminate results include:

- seroconversion;

- advanced HIV infection with decreased titers of p24 antibodies 

(rare)(seroreversion);

- autoantibodies due to autoimmune or collagen vascular diseases 

or malignancy;

- cross-reactive alloantibodies from pregnancy, blood transfusions, 

or organ transplantation; and

- previous receipt of an experimental HIV vaccine.

 When indeterminate results are obtained, risk assessment is 

important, since women in low-risk categories with indeterminate 

tests are unlikely to be infected and can be reassured. 

Nevertheless, after indeterminate test results, repeat testing should 

be performed at 1, 2, and 6 months, and precautions should be 
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taken to prevent HIV transmission to others until seroconversion 

is ruled out. In general, patients with indeterminate tests who are 

in the process of seroconversion usually have positive Western 

blots within 1 month. In high-risk patients or in other situations 

where seroconversion is suspected HIV nucleic acid amplification 

(HIV-DNA PCR, HIV-RNA PCR) may be considered and has high 

sensitivity during acute infection, often before antibodies to the 

virus have developed.

 The window period before seroconversion and 

agammaglobulinemia are possible causes of false-negative results.

 Although infection with HIV-2 (more common in West Africa) and 

HIV-1 subtype O have been associated with indeterminate and 

false negative results on earlier generation serologic tests, most 

currently used assays will detect these infections.

 Accuracy of HIV serologic testing is quite high (>99% sensitivity 

and specificity), but the predictive value of a positive or negative 

test depends on the seroprevalence of HIV in the patient 

population. In a low prevalence population, the rate of falsepositive results of combined ELISA and Western blot testing 

is <.001%. The frequency of indeterminate results in a low 

prevalence population is .02%.

• Viral detection

- Nucleic acid amplification. May be used to clarify the diagnosis 

of HIV infection in acute infection, during the window period 

(after exposure, before seroconversion), when serologic tests are 

indeterminant, or with neonatal infection.

> Plasma HIV RNA. Routinely used to monitor the course and 

treatment of HIV infection (see below). The three most common 

techniques are reverse transcriptase polymerase chain reaction 

(RT-PCR), a branched DNA (bDNA) technique, and nucleic acid 

sequence-based amplification (NASBA). These tests report the 

number of copies of virus per milliliter of plasma. The assays are 

considered equally reliable, but vary somewhat in lower levels 

of detection and dynamic range. Lower limits of detection for 

standard tests are 100–400 copies/mL, but ultrasensitive assays are 

available that can detect as few as 20–50 copies/mL. Sensitivity 

is 90–95% overall, but is increased to 98–100% with CD4 counts 

<200/mm3. False-positive rates are 2–3%, usually with low HIV 

RNA titers (Rich, 1999).

> DNA PCR. A qualitative test used to detect intracellular virus, 

and primarily used for viral detection with neonatal infection and 

with indeterminant serology. Sensitivity is >99% at all stages of 

infection and specificity is approximately 98%.

- Viral isolation. Qualitative or quantitative cultures are used 

primarily for diagnosis in neonatal HIV infection, and for more 

in-depth viral analysis. The procedure is expensive and labor 

intensive. Sensitivity is 95–100%.
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• Alternative tests

- Home testing: Home Access Express Test is the only available 

home test for HIV as of May 2003. Filter paper with a blood 

sample obtained with a lancet is mailed in to a laboratory in a 

coded, anonymous process. Dried blood samples are tested by 

the same ELISA and Western blot tests used on venous blood. 

Sensitivity and specificity approach 100%. Results are provided 

by phone (a recorded message for those with negative results, 

counseling for those with positive results).

- Rapid tests: The OraQuick Rapid HIV Test provides results 

in 10–20 minutes. Sensitivity approaches 100%; specificity 

is also >99%, but positive results should be confirmed with 

standard serology. Rapid tests may prove useful in STI clinics or 

emergency rooms (where patients often do not return for tests 

results) or on labor and delivery wards for high-risk pregnant 

women who have not previously been tested.

- Saliva test: The OraSure test uses ELISA and Western blot testing 

to detect antibodies to HIV in saliva. Sensitivity and specificity 

are similar to that with standard serology. This test is useful for 

people with poor venous access or those who want HIV testing, 

but refuse blood tests.

- Urine test: The only currently available urine test (Calypte 

HIV-1 Urine EIA) is licensed for screening only and must 

be administered by a physician; a positive result requires 

confirmation by another method.

B. BASELINE LABORATORY EVALUATION

After the diagnosis of HIV has been confirmed, a baseline laboratory 

evaluation is needed to establish the stage of disease, and exposure 

to other infectious diseases (Table 4-1). In addition, routine tests of 

hematology, chemistry, and lipid profiles are needed at baseline, because 

HIV and other concomitant illness may affect these values, and detected 

abnormalities may also have an impact on the choice of therapy for the 

individual patient.

• CD4 lymphocyte count: The hallmark of HIV infection is the 

progressive decline in CD4+ (helper) T lymphocytes. Normal 

laboratory ranges for CD4 lymphocyte counts are usually 500–

1400/mm3. CD4 counts may drop precipitously at the time of 

primary HIV infection, and then usually rebound to near-baseline 

levels. The natural history of HIV then involves a progressive 

loss of CD4 cells, averaging 30–60 cells/yr (Figure 4-1). The risk 

of opportunistic infections increases with declining counts. (See 

Chapter I on Epidemiology and Natural History.)
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 Knowledge of the baseline CD4 count is of vital importance in 

assessing the patient: staging of HIV infection (Table 1-3 in 

Chapter I), recommendations for antiretroviral treatment (see 

Section IV. C), and prophylaxis against specific opportunistic 

infections (see Section V. A) are based on the degree of 

immunosuppression as quantified by the CD4 count.

 Many factors may cause variability in the CD4 count. These 

include:

- interlaboratory variations;

- seasonal and diurnal variation (lowest levels at noon, highest in 

the evening)

- the use of corticosteroids (decreases values)

- intercurrent illness (decreases values)

- HTLV-1 coinfection (increases values).

In addition, because the CD4 count is a value derived by 

determining the percentage of white blood cells that are 

lymphocytes, and then the percentage of lymphocytes that are CD4 

receptor-positive, there may be variation in other white blood cell 

compartments (as may occur in pregnancy) that leads to variations 

in the CD4 count. Because the CD4 percentage is the directly 

measured value and the absolute CD4 count is the calculated one, it 

is more useful and accurate to focus on the CD4 percentage to assess 

trends in this important parameter.

Table 4-1: Baseline Laboratory Evaluation

❏		Confirm HIV diagnosis (usually with ELISA and Western blot)

❏		CD4 count

❏		Viral load

❏		Chemistry panel: including liver and renal function

❏		Hematology panel: including white blood cell count differential

❏		Lipid profile: total cholesterol, HDL, LDL, triglycerides

❏		Serologies: syphilis, toxoplasmosis, CMV, varicella-zoster virus (if no history of 

chickenpox or shingles), hepatitis A, hepatitis B, hepatitis C

❏		PPD

❏		G6PD (in selected patients)

❏		Pap smear/STI screening
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Figure 4-1: Natural History of HIV Infection without the Use of Antiretroviral Therapy

120011001000

900800700600500400300200100

0

Weeks Years

1/5121/2561/1281/641/321/161/81/41/20

107106105104103102

Lymphocyte Count (cells/mmm CD4 + T 3)

Culturable Plasma Viremia (dilutional titer)

HIV RNA Copies per mL Plasma

Death

Opportunistic

diseases

Constitutional

symptoms

Primaryinfection

+/-Acute HIV syndromeWide dissemination of virusSeeding of lymphoid organs

Clinical latency

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11

Source: Fauci, 1996. Copyright American College of Physicians. Reprinted with permission.
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• Quantitative virology/viral load assays: The HIV RNA level or 

“viral load” is also of pivotal importance in assessing the HIVinfected patient. Whereas the CD4 count indicates the current 

degree of immunosuppression, the viral load indicates the rapidity 

with which the disease is likely to progress: higher viral loads have 

repeatedly been shown to be associated with a more rapid rate of 

disease progression (Figure 4-2). Recent studies have shown that 

women have lower viral loads than men at comparable CD4 cell 

counts, although these viral load differences tend to disappear 

several years after seroconversion and they have not been 

associated with slower disease progression or longer survival 

(see Chapter I: Epidemiology and Natural History of HIV 

Infection in Women).

 The most commonly used methods to quantify HIV RNA are RTPCR, bDNA, and NASBA techniques (see Viral Detection, above). 

Standard tests have lower limits of detection of 100–400 copies/

mL, but current ultrasensitive assays can detect as few as 20 

copies/mL. Although results of different viral load assays correlate, 

absolute values differ and there is no standard multiplication factor 

to translate between results in the different assays. Therefore, 

the same assay should be used to follow an individual patient 

longitudinally. Intraperson variability on viral load assays is <.5 

log, but this degree of variability is important to consider when 

determining clinical significance of a reported change in viral load 

values for an individual patient.

 Indications for plasma HIV RNA testing are shown in Table 4-2. It 

is also critical to repeat any HIV RNA result that is being used as 

the basis for a change in patient management.

• Hematology and chemistry panels: The effects of HIV and 

related infections may involve hematologic, renal, or hepatic 

abnormalities. A complete blood count is necessary at baseline 

to evaluate for leukopenia, anemia, and thrombocytopenia. In 

addition, the total white blood cell count and lymphocyte count 

are needed to calculate an absolute CD4 count. A chemistry 

panel that includes an evaluation of renal and hepatic function is 

also necessary: HIV-associated nephropathy may be indicated by 

elevations in blood urea nitrogen/creatinine, and the effects of 

viral hepatitis, alcohol, or medications may cause abnormalities 

of liver function tests. Any of these findings provide important 

information in their own right, but will also have an impact on the 

patient’s options for antiretroviral therapy.

• Other serologies:

- Syphilis: High rates of coinfection with other STIs necessitate 

routine syphilis serology in all HIV-infected patients. A reactive 

nontreponemal assay (RPR or VDRL) must be confirmed with 

the treponemal-specific FTA or MTPA. Cerebrospinal fluid 

evaluation is indicated in HIV-infected persons with latent 

syphilis, treatment failure (when a nontreponemal test does 

not decline 4-fold within 6–12 mo after treatment), and those 

patients with neurologic signs or symptoms.
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Figure 4-2: Likelihood of Developing AIDS within 3 Years

90.0%80.0%70.0%60.0%50.0%40.0%30.0%20.0%10.0%

0.0%

MACS bDNA:

RT-PCR:

>30K

>55K

10K-30K

20K-55K

3K-10K

7K-20K

501-3K

1500-7K

> 500

<1500

< 200201-350351-500501-750>750

3.7% 2.0% 2.0%

2.0%

32.6% 32.6%

42.9%

64.4%

85.5%

40.1%

9.5%

3.2%

8.1%

8.1%

8.1%

16.1%

16.1%

40.1%

Plasma Viral Load 

(copies/mL)

Source: Adapted from Mellors, 1997. Copyright American College of Physicians. Reprinted with permission.
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Table 4-2: Indications for Plasma HIV RNA Testing*

Clinical Indication Information Use

Syndrome consistent 

with acute HIV infection

Establishes diagnosis 

when HIV antibody 

test is negative or 

indeterminate

Diagnosis†

 Initial evaluation of 

newly diagnosed HIV 

infection

Baseline viral load “set 

point”

Decision to start or defer 

therapy

Every 3–6 mo in patients 

not on therapy

Changes in viral load Decision to start therapy

2–8 wk after initiation of 

antiretroviral therapy

Initial assessment of drug 

efficacy

Decision to continue or 

change therapy

3–6 mo after start of 

therapy

Maximal effect of 

therapy

Decision to continue or 

change therapy

Every 3–6 mo in patients 

on therapy

Durability of antiretroviral 

effect

Decision to continue or 

change therapy

Clinical event or 

significant decline in 

CD4+ T cells

Association with 

changing or stable viral 

load

Decision to continue, 

initiate, or change 

therapy

* Acute illness (e.g., bacterial pneumonia, tuberculosis, HSV, PCP, etc.) and immunizations can cause 

increase in plasma HIV RNA for 2–4 wk; viral load testing should not be performed during this time. 

Plasma HIV RNA results should usually be verified with a repeat determination before starting or making 

changes in therapy.

† Diagnosis of HIV infection made by HIV RNA testing should be confirmed by standard 

methods such as Western blot serology performed 2–4 mo after the initial indeterminate or negative test.

Source: DHHS, 2005.

- Toxoplasmosis: Serologic evidence of latent toxoplasmosis 

infection, as detected by Toxoplasma gondii IgG, may be 

relevant for decisions on prophylaxis, evaluation of neurologic 

symptoms in patients with advanced immunosuppression, and 

avoidance of exposure in those who have not been previously 

infected. There is great worldwide variation in the prevalence 

of latent toxoplasma infection: in the United States the rate is 

approximately 30%.

- CMV: Latent CMV infection is present in most HIV-infected 

adults. Knowledge of CMV antibody status can guide the 

medical provider to the use of CMV-negative blood products if 

transfusions are required.

- Varicella: In patients who do not have a known history of 

chickenpox or shingles, varicella serology should be obtained. 

The knowledge that a patient is varicella IgG-negative is 

important in the event of a subsequent exposure: postexposure 

prophylaxis with varicella immune globulin could then be given.
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- Hepatitis: Hepatitis A serology will identify those who are not 

immune, and are therefore vaccine candidates. Hepatitis A 

vaccine should be given to patients with hepatitis C co-infection, 

other chronic liver disease, and perhaps to all HIV-infected 

patients. Hepatitis B serologies should be performed routinely: 

hepatitis B surface antigen (HBsAg) and hepatitis B core or 

surface antibodies (anti-HBc and anti-HBs) allow determination 

of active hepatitis (HBsAg-positive) and of those who are not 

immune to hepatitis B (anti-HBc-negative, anti-HBs-negative). 

Hepatitis B vaccination is then recommended in those who are 

not immune; and antiviral therapy, such as lamivudine (which 

has anti-hepatitis B activity), can be considered in those who are 

HBsAg-positive. Hepatitis C virus (HCV) serology (anti-HCV IgG) 

is also routinely recommended. Recombinant immunoblot assays 

(RIBA) for HCV are used to confirm the diagnosis if a screening 

ELISA is positive. HCV RNA, as detected by RT-PCR or bDNA 

assay, can also be used to confirm the diagnosis and allows 

determination of active HCV infection. Knowledge of hepatitis 

C antibody status is needed to guide therapeutic decision for 

possible HCV treatment and may also be relevant for decisions 

regarding antiretroviral therapy and other potentially hepatotoxic 

agents, and frequency of assessment of liver function tests 

during such therapy (see Table 4-3).

Table 4-3: Laboratory Tests for Hepatitis Viruses

Hepatitis Virus Laboratory Test Interpretation

A Anti-HAV IgM Recent HAV infection

Anti-HAV IgG Immunity to HAV

B HBsAg Current (acute or chronic) HBV 

infection

HBeAg Current HBV infection with high 

risk of infectivity

Anti-HBc Past or present HBV infection

Anti-HBs Immunity to HBV (past infection 

or after vaccination)

C Anti-HCV IgG 

(ELISA)

Past or present HCV infection

Anti-HCV IgG (RIBA) Confirms HCV ELISA

HCV RNA Current HCV infection

• Tuberculosis: A baseline PPD should be obtained in all patients 

who do not have a history of a positive PPD in the past. A positive 

PPD is considered >5mm induration in the setting of HIV 

infection.

• Glucose-6-phosphate dehydrogenase: A relative deficiency of 

glucose-6-phosphate dehydrogenase (G6PD) may be found in up 

to 2% of African American women and an absolute deficiency is 

occasionally found in women of Mediterranean descent. Absolute 
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G6PD deficiency predisposes to hemolytic anemia upon exposure 

to certain medications, including several that are commonly used 

in HIV treatment: dapsone, sulfonamides, primaquine. A relative 

deficiency is not usually clinically significant. Baseline testing 

in selected patients is helpful so that these agents may be safely 

administered at a later date without needing to determine G6PD 

levels at that point.

• Lipid profile: Many antiretroviral agents have been 

associated with the development of hypertriglyceridemia and 

hypercholesterolemia. A baseline fasting lipid profile should be 

performed to determine total cholesterol, triglycerides, highdensity lipoprotein (HDL), and low-density lipoprotein (LDL) 

levels before beginning any antiretroviral therapy.

• Pap smear/STI screening: A Pap smear should be obtained, 

and testing done for gonorrhea and Chlamydia (see Chapter VI 

Gynecologic Problems).

C. INTERVAL MONITORING

In an asymptomatic patient not taking antiretroviral therapy with a high 

(> 500/mm3) CD4 count, follow-up every 6 mo may be appropriate. 

For those patients who are symptomatic and/or receiving antiretroviral 

therapy, visits should occur at least every 3 mo. For those who have 

just initiated or changed antiretroviral therapy, follow-up in 4–6 wk 

may be appropriate. Laboratory evaluation at each of these visits should 

routinely include the following: complete blood count with differential, 

CD4 lymphocyte count, and viral load. Chemistry panels may be done 

less frequently (every 6 mo) in a patient with prior normal values who 

remains clinically stable.

Hematology and chemistry values are needed to monitor possible 

medication toxicities, complications of HIV, and other possible illnesses. 

The CD4 count and viral load allow assessment of disease progression 

and effects of antiretroviral therapy. In following the CD4 count over 

time, it is important to recognize the causes of variability discussed above. 

Use of the CD4 percentage, rather than absolute CD4 count, may help 

eliminate some of this variability to clarify CD4 response to medications. 

In interpreting viral load changes over time, the variability of tests results 

must be noted: .3–.5 log. In a patient who previously had a viral load 

below the limit of detection of the assay being used (“undetectable”), who 

now has quantifiable virus, a repeat test should be performed as soon as 

possible, rather than waiting until routinely scheduled follow-up.

The frequency with which lipid profiles are checked will vary by individual 

patient characteristics. In patients not taking antiretroviral therapy, a baseline 

lipid profile should be done with the initial evaluation or before beginning 

antiretroviral therapy. The profile should include total cholesterol, HDL, 
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LDL, and triglycerides. If the baseline is normal and the patient is not on 

antiretroviral therapy, there is no need for interval monitoring beyond 

that which would be done in an HIV-uninfected adult. In patients taking 

combination antiretroviral therapy, general guidelines are:

1. Get a baseline lipid profile (fasting) before starting therapy.

2. Follow total cholesterol with routine chemistry panels.

3. Obtain a complete fasting lipid profile annually or if the total 

cholesterol begins to increase on routine testing.

4. Follow complete lipid profiles every 3–6 mo for patients in 

whom a lipid abnormality has been detected, both before starting 

any antihyperlipidemic therapy and once such therapy has been 

started.

Recommendations for management of hyperlipidemia may be found at 

http://www.americanheart.org.

Annual monitoring of syphilis serology for reactivation or new infection 

is generally recommended. PPDs should also be checked annually if 

the patient belongs to a population with high epidemiologic risk of 

tuberculosis.

Baseline data and interval monitoring may be followed by the use of a 

flow sheet such as the one developed at the Johns Hopkins Outpatient 

HIV Clinic (Figure 4-3).
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Figure 4-3: Patient Intake Flow Sheet

Attach Label Race Risk

Provider

Site: ( ) Moore Clinic ( ) GSS ( ) Country

Hopkins Function

( ) 1° Care ( ) Specialty ( ) Consultation

Other PCP

DATES

1° Infection HIV+ Confirmation 1st JHH visit

AIDS AIDS Reported Psychosocial Nutrition

BASELINE DATA

HBsAg HBsAb anti-HCV total HAV

Toxo CMV VZC G6PD

Baseline 

lipids: 

T Chol. HDL Chol LDL Chol TG

IMMUNIZATIONS

Pneumovax (q 5 yr) dT (q 10 yr)

HBV #1 (mo. 0) #2 (mo. 1) #3 (mo. 6)

HAV #1 (mo. 0) #2 (mo. 6)

ONGOING HEALTH CARE MAINTENANCE

Years

Full Physical Exam

PPD (annual if at risk)

RPR (annual)

Ophtho exam (CD4 < 50)

Occ. Bld (age 50+, annual)

Flex. Sig./Colonoscopy

GC/Chlamydia

Flu vaccine (annual)

Other

Women:

Pap Smear (annual)

Mammogram

Birth control review (annual)

Men:

PSA (consider 50+, annual)

MISCELLANEOUS

Advance Directives (dates discussed, location of documents)

Family/Contacts (names, contact info)

Case Manager

Home Care
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Figure 4-3: Patient Intake Flow Sheet (continued)

Attach Label Allergies:

Baseline wgt:

Height:

Date Wgt CD4 CD4% VL Antiretroviral 

Therapy

OI 

Proph/Rx

Events, Resistance 

Test Results, etc.

Johns Hopkins Outpatient HIV Clinic. Baltimore, MD. Reprinted with permission. 
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IV. ANTIRETROVIRAL THERAPY

A. GENERAL PRINCIPLES

Three characteristics of HIV infection have significant implications 

for antiretroviral therapy (see Chapter VII HIV and Reproduction for 

discussion of antiretroviral therapy in pregnancy).

1. Between the time of initial infection and the development of 

clinical disease there is progressive immunosuppression as 

evidenced by a decline in CD4 lymphocyte counts.

2. Viral replication is extremely rapid: the half-life of HIV in plasma 

is less than 48 hr and there is turnover of up to 1 billion virions 

per day (Ho, 1995).

3. HIV has a high degree of inherent genetic mutability: mutations 

that may confer resistance to antiretroviral therapy arise rapidly.

Thus, there is a rationale for initiating antiretroviral therapy before 

the onset of symptoms (i.e., to prevent immunosuppression), and 

therapy must be maintained to prevent viral replication. Strategies of 

antiretroviral therapy have therefore evolved to prevent the development 

of viral resistance. Although monotherapy with any of the antiretroviral 

agents will increase CD4 count, the clinical benefit of such therapy is 

very limited, largely because of the development of viral resistance. 

Combination antiretroviral therapy has been shown to have superior 

effectiveness in controlling viral replication and in limiting the emergence 

of resistant virus. These effects translate into greater clinical benefit: 

combination therapy reduces the risk of HIV progression and death. In 

addition, patients with levels of circulating virus that are below 400–500 

copies/mL (the limit of detection in the past few years), but greater than 

20–50 copies/mL (the limit of detection in the newest generation of tests) 

will experience virologic failure sooner that those with viral loads below 

20–50 copies/mL (Raboud, 1998). Therefore, achievement of the lowest 

possible viral load should be a guiding principle in the selection of a 

treatment regimen.

The specific combination of antiretroviral therapy selected for a patient 

must take into account many factors. These include the specific side 

effects, dosing schedules, drug-drug interactions of different medications, 

and history of antiretroviral therapy. See Chapter XIV on Pharmacologic 

Considerations in HIV-infected Pregnant Patients for information on 

highly active antiretroviral therapy in pregnancy and Chapter XV 

on Resources for sources of complete updated information on 

antiretroviral therapy.
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IV

B. ANTIRETROVIRAL AGENTS

NUCLEOSIDE ANALOGUES

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were 

the first class of agents shown to be effective in the treatment of HIV 

infection. The target enzyme for this group of drugs is HIV reverse 

transcriptase, an RNA-dependent DNA polymerase (see Figure 4-4).

Figure 4-4: Sites of Action of Antiretroviral Agents

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1. Site of Action of NRTIs: Incorporate into DNA and block reverse transcriptase

2. Site of Action of NNRTIs: Bind to reverse transcriptase

3. Site of Action of PIs: Bind to protease to inhibit viral protein cleavage and 

therefore release of virus from cell

4. Site of Action of Fusion Inhibitors: Interact with virus to inhibit virus-cell fusion

Seven NRTIs are currently licensed in the United States: zidovudine 

(AZT), didanosine (ddI), zalcitibine (ddC), stavudine (d4T), lamivudine 

(3TC), abacavir, (ABC) and emtricitabine (FTC). There are also 3 

combination NRTIs (Combivir, Trizivir, Epzicom), a nucleotide reverse 

transcriptase inhibitor (tenofovir) and a nucleoside-nucleotide reverse 

transcriptase inhibitor combination (Truvada) (Table 4-4).
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Table 4-4: Nucleoside/Nucleotide Analogue Reverse Transcriptase 

Inhibitors

Generic Name Trade 

Name Standard Dosing Common Side Effects

Zidovudine (AZT) Retrovir 200 mg tid or 300 mg 

bid (2–6 pills/day)

Anemia, nausea, 

headache

Didanosine (ddI) Videx/Videx 

- EC

200 mg bid or 400 mg 

qd (125 mg bid if <60 

kg) (1–4 pills/day)

GI symptoms 

(diarrhea), peripheral 

neuropathy, 

pancreatitis

Zalcitibine (ddC) Hivid 0.75 mg tid (3 pills/day) Peripheral neuropathy, 

pancreatitis

Stavudine (d4T) Zerit 40 mg bid (30 mg bid if 

<60 kg) (2 pills/day)

Peripheral neuropathy, 

pancreatitis 

Lamivudine 

(3TC)

Epivir 150 mg bid or 300 mg 

qd 

(1–2 pills/day)

Headache

Lamivudine/

zidovudine

Combivir 1 pill bid As for 3TC and AZT

Abacavir Ziagen 300 mg bid 

(2 pills/day)

Hypersensitivity,* rash, 

GI symptoms

Abacavir/

lamivudine/

zidovudine

Trizivir 1 pill bid As per abacavir 

(including 

hypersensitivity), 3TC, 

and AZT

Tenofovir 

disoproxil 

fumarate

Viread 300 mg qd 

(1 pill/day)

GI symptoms

Emtricitabine Emtriva 200 mg qd 

(1 pill/day)

Headache, nausea, 

diarrhea, rash

Abacavir/

lamivudine

Epzicom 1 tablet qd As for 3TC and 

abacavir

Emtricitabine/

tenofovir DF

Truvada 1 tablet qd As for FTC and TDF

* 3-4% of patients will develop a hypersensitivity reaction to abacavir with symptoms that include fever, 

rash, myalgias. Rechallenge with abacavir after hypersensitivity reaction may be life-threatening and 

should never be done.

In addition to the side effects listed for each medication, lactic acidosis 

with hepatic steatosis is a rare but potentially life-threatening toxicity 

with the use of NRTIs.

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) noncompetitively 

inhibit HIV reverse transcriptase by binding to a site distant from the 

enzyme’s active site. Three NNRTIS are currently available in the United 

States: nevirapine, delavirdine, and efavirenz (Table 4-5).
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Table 4-5: Nonnucleoside Reverse Transcriptase Inhibitors

Generic Name Trade Name Standard Dosing Common Side 

Effects

Nevirapine Viramune 200 mg qd x 14 

days, then 200 

mg bid 

(2 pills/day)

Rash, hepatitis

Delavirdine Rescriptor 400 mg tid 

(12 pills/day)

Rash

Efavirenz Sustiva 600 mg qd 

(qhs 

administration 

may limit CNS 

side effects) (1 or 

3 pills/day)

Headache, 

dizziness, 

cognitive effects, 

rash

PROTEASE INHIBITORS

Protease inhibitors (PIs) prevent maturation of virus protein by 

competitively inhibiting HIV protease, an enzyme essential for viral 

protein cleavage. When this enzyme is blocked, immature, noninfectious 

virus particles are produced. The other important properties that protease 

inhibitors share include their limited central nervous system penetration 

and their metabolism by the cytochrome P450 enzyme system and 

resultant multiple drug-drug interactions (Table 4-6).

Table 4-6: Protease Inhibitors

Generic Name Trade Name Standard Dosing Common Side 

Effects

Saquinavir 

(hard gel 

capsules)

Invirase 600 mg tid 

(9 pills/day)

Diarrhea, nausea, 

abdominal discomfort

Saquinavir 

(soft gel 

capsules)

Fortovase 1200 mg tid 

(18 pills/day)

Diarrhea, nausea, 

abdominal discomfort

Ritonavir Norvir 600 mg bid 

(12 pills/day)

Nausea, abdominal 

discomfort, 

circumoral 

paresthesias

Indinavir Crixivan 800 mg q8h 

(6 pills/day)

Nephrolithiasis, GI 

symptoms

Nelfinavir Viracept 750 mg tid 

(or 1250 mg bid) (4–10 

pills/day)

Diarrhea

Amprenavir Agenerase 1200 mg bid 

(16 pills/day)

GI symptoms, rash
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Table 4-6: Protease Inhibitors (continued)

Lopinavir/

ritonavir

Kaletra Lopinavir 400 mg/ ritonavir 

100mg (3 capsules or 5mL) 

bid 

(6 capsules/day)

Diarrhea, nausea, 

abdominal discomfort

Atazanavir Reyataz 400 mg qd 

(2, 200 mg capsules/day) 

300 mg qd 

(2, 150 mg capsules/day) if 

combined with ritonavir 100 

mg qd (1 capsule/day)

Nausea, diarrhea, 

unconjugated 

hyperbilirubinemia

Fosamprenavir Lexiva 1400 mg bid (2, 700 mg 

tablets twice daily) 1400 mg 

qd (2, 700 mg tablets/day) 

if combined with ritonavir 

200 mg qd (2 capsules/

day) 700 mg bid (1, 700 

mg tablet twice daily) if 

combined with ritonavir 

100 mg bid (1 capsule 

twice daily) Adjustment of 

ritonavir dose needed when 

fosamprenavir plus ritonavir 

are administered with 

efavirenz

GI symptoms, 

headache, rash

In addition to the medication-specific side effects listed here, a number of 

abnormalities are associated with protease inhibitors as a class. Patients 

taking protease inhibitors may develop serum lipid abnormalities 

(hyperlipidemia, hypertriglyceridemia), redistribution of body fat 

(lipodystrophy), and/or glucose intolerance.

FUSION INHIBITORS

Fusion inhibitors interact with HIV directly, rather than with the host 

cell. This interaction prevents fusion of HIV to the cell. The first fusion 

inhibitor, enfuvirtide (T-20, Fuzeon) was licensed in the U.S. in March 

2003. Enfuvirtide must be given by subcutaneous injection (twice daily). 

The most common side effect is local injection site reactions.

C. ADVERSE CLINICAL EVENTS ASSOCIATED WITH ANTIRETROVIRAL THERAPY

There are several significant adverse clinical events that have been 

associated with use of antiretroviral therapy. In some cases these are 

drug specific, while in others an increased risk of a specific adverse 

event appears to involve an entire class of antiretroviral drugs. 

The complications discussed below are of particular clinical significance 

or concern. In general, decisions about management, including future 

antiretroviral management, should be made in consultation with an 

HIV expert. 
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1. Lactic Acidosis/Hepatic Steatosis: This is a rare but life-threatening 

complication associated with use, often prolonged, of NRTIs and 

appears to more commonly seen in women. The initial clinical 

signs and symptoms are nonspecific and may include nausea 

and vomiting, diarrhea, anorexia, abdominal pain, generalized 

weakness, myalgias, ascending neuromuscular weakness, and 

hepatomegaly. In addition to elevated lactate levels, laboratory 

evaluation may reveal elevated liver function tests, creatine 

phosphokinase, lipase, and amylase or increased anion gap. There 

are technical difficulties associated with serum lactate testing and 

routine testing is not recommended. However, providers should 

have a low threshold for measuring serum lactate in the presence 

of suggestive signs or symptoms or other associated laboratory 

abnormalities. When interpreting serum lactate levels, levels of 

2-5 mmol/dL are considered elevated and need to be correlated 

with symptoms; levels >5mmol/dL are abnormal; and levels 

> 10 mmol/dL indicated serious and possibly life-threatening 

situations. Antiretroviral treatment should be stopped if clinical 

and laboratory manifestations of lactic acidosis occur. 

2. Hepatotoxicity: Hepatotoxicity, defined as a 3–5 fold increase 

in serum transaminases, may occur with or without clinical 

hepatitis. It has been reported with all NNRTIs and PIs and may 

be present with lactic acidosis associated with NRTI use. Most 

patients with hepatotoxicity are asymptomatic. Nevirapine has 

the greatest potential for causing hepatotoxicity (up to 12%) 

and this complication appears to be more common in women 

(Martinez, 2001; Bartlett, 2003). Nevirapine-associated hepatitis 

might also be part of a hypersensitivity syndrome, associated 

with other symptoms such as skin rash, fever, and eosinophilia. 

In a recent retrospective analysis of controlled and uncontrolled 

clinical trials, women with CD4 cell counts > 250 cells/mm3, 

including pregnant women, receiving chronic treatment for 

HIV infection, were at significantly higher risk (12-fold) of 

hepatotoxicity. In some cases hepatic injury progressed despite 

discontinuation of treatment and fatalities have occurred. 

(Boehringer-Ingelheim, 2004). Approximately two-thirds of 

nevirapine-associated clinical hepatitis occurs within the first 12 

weeks of treatment and the greatest risk for severe hepatotoxicity 

in the recent analysis occurred in the first six weeks of treatment 

and was often associated with rash. However, risk continues 

after this time and patients should be closely monitored for the 

first 18 weeks of treatment. Initial presentation may include 

nonspecific gastrointestinal and flu-like smptoms, and liver 

enzyme abnormalities may or may not be present. However, this 

syndrome can progress rapidly to fulminant hepatic failure. A twoweek lead-in dosing with 200 mg once daily before dose escalation 

to 200 mg twice daily is recommended to reduce the incidence of 

hepatotoxicity. Many clinicians advise close monitoring of clinical 

symptoms and liver enzymes after starting nevirapine (e.g., every 

2 weeks for the first month, then monthly for the first 12 weeks, 
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and every 1–3 months thereafter). Nevirapine should not be used 

in future regimens in women who experience severe liver toxicity 

while taking nevirapine. PI-associated hepatotoxicity can occur 

any time during the treatment course. Risk factors for liver toxicity 

include hepatitis B or C infection, alcohol abuse, baseline elevated 

liver enzymes, stavudine (d4T) use, and concomitant use of other 

hepatotoxic agents (DHHS, 2003; http://AIDSinfo.nih.gov) . 

3. Hyperglycemia: Hyperglycemia has been reported in 3–17% 

of patients on PI-containing antiretroviral regimens (DHHS, 

2003. http://AIDSinfo.nih.gov). Preexisting diabetes may be 

exacerbated. Although routine use of glucose tolerance testing is 

not recommended, patients should be advised about symptoms of 

hyperglycemia (i.e., polydipsia, polyphagia, polyuria) and fasting 

blood glucose measurements should be considered at 3–4 month 

intervals during the first year of PI treatment for patients with no 

prior history of diabetes. Patients with preexisting diabetes should 

be monitored closely. 

4. Lipodystrophy (Fat Maldistribution Syndromes): Recognition 

of fat maldistribution syndromes has increased in the era of 

combination antiretroviral therapy; they are characterized by 

fat wasting (lipoatrophy) or fat accumulation. The absence of 

standard case definitions makes it difficult to estimate prevalence. 

Lipodystrophy might be associated with serum dyslipidemias, 

glucose intolerance, or lactic acidosis (Joffe, 2001; Carr, 1998). 

Fat accumulation is most commonly seen in the abdomen, the 

dorsocervical fat pad, and the breasts. This complication has 

been most associated with use of PI-containing regimens and 

prevalence increases with duration of therapy (Miller, 1998). 

Lipoatrophy most commonly affects the face and extremities and 

risk has been reported to increase with long-term NRTI exposure 

(Mallal, 1999). Women seem particularly prone to developing 

truncal obesity (increased abdominal girth, increased breast size). 

The etiology of these syndromes is unknown and at the present 

time, there is no clearly effective therapy. Women who perceive 

significant changes in body habitus related to their antiretroviral 

regimen may be at increased risk for nonadherence. It may be 

useful to obtain some standard measurements, such as minimum 

waist, maximum hip, and neck circumference at an early visit, 

before antiretroviral therapy is started. It is important to question 

the patient at regular intervals about any perceived changes 

in body shape or changes in clothing and brassiere size, and 

anthropomorphic measurements may be repeated to document 

any changes. 

 Detailed descriptions of medications, drug-drug interactions, and 

medication use in pregnancy may be found in Chapter XIV on 

Pharmacologic Considerations in HIV-infected Pregnant Patients.
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5. Hyperlipidemia: Combination antiretroviral therapy, primarily 

regimens containing protease inhibitors, has been associated with 

elevation in total serum cholesterol and low-density lipoprotein 

(LDL) and in increases in fasting triglycerides (Thiebaut 2000; 

Romeu 1999). Therapeutic intervention may be needed and, 

although data remain inconclusive, lipid elevations seen with 

antiretroviral therapy may be associated with increased risk of 

cardiovascular complications. Indications for monitoring and 

treatment of antiretroviral-associated dyslipidemias are the same 

as among uninfected persons (Adult Treatment Panel III, 2001), 

although patients with additional risks for atherosclerotic disease 

should be especially closely monitored (Dube 2000). Low-fat diet, 

regular exercise, control of hypertension, and smoking cessation 

should be routinely recommended for all patients, including those 

treated with antiretroviral agents. When treatment is indicated, 

statins are generally considered first-line therapy, although 

potential drug-drug interactions between statins and PIs must be 

kept in mind and agents that are less affected by the inhibitory 

effect of PIs via the cytochrome P450 system are preferred (e.g., 

pravastatin). If lipid elevations are severe or do not respond to 

other therapy, a change in antiretroviral regimen may be indicated, 

such as replacement of the PI component with an NNRTI. 

6. Bone Disorders: There is evidence that avascular necrosis 

involving the hips and decreased bone density (osteopenia, 

osteoporosis) may be linked to combination antiretroviral therapy 

regimens in adults and children (Tebas 2000; Scribner 2000). 

Diagnosis of osteonecrosis is generally made with CT or MRI 

ordered in response to complaints of pain. Diagnosis of osteopenia 

or osteoporosis is made with bone densitometry (dual energy Xray absorptiometry or DEXA; quantitative ultrasound). Losses in 

bone mineralization appear to be more common in PI-containing 

regimens (Tebas 2000). Women are at increased risk for decreased 

bone density and adequate intake of calcium and vitamin D and 

appropriate weight-bearing exercise should be recommended. 

There are no recommendations for routine monitoring of 

bone density among asymptomatic HIV-infected persons, but 

additional risk factors, including estrogen deficiency (e.g., 

menopausal women), alcohol or tobacco abuse, sedentary lifestyle 

or immobilization, Caucasian or Asian race, wasting, and thin 

body habitus, should prompt consideration of screening. When 

significant decreases in bone density are recognized, treatment 

with bisphosphonates, raloxifene, or calcitonin may be indicated. 

7. Rash: Skin rash most commonly occurs with NNRTI-containing 

regimens, and is most frequent and most severe with nevirapine. 

Most cases are mild to moderate and occur within the first 

weeks of therapy. Women appear to be at increased risk for 

more serious skin rashes (Bersoff-Matcha, 2001). More serious 

cutaneous manifestations (e.g., Stevens-Johnson Syndrome and 

toxic epidermal necrosis) should result in prompt and permanent 

discontinuation of NNRTI or other offending agents. A severe 
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and potentially life-threatening syndrome consisting of drug 

rash, eosinophilia, and systemic symptoms (DRESS) has been 

described (Bourezane, 1998). Outside of the NNRTI drug class, 

skin rash occurs most frequently with abacavir and amprenavir. 

If rash is determined to be from an abacavir-associated systemic 

hypersensitivity reaction, then abacavir should be discontinued 

and not restarted. Amprenavir is a sulfonamide and should be 

used with caution in patients with history of sulfa allergy. 

D. TREATMENT GUIDELINES

The Department of Health and Human Services (DHHS) Panel on 

Clinical Practices for Treatment of HIV Infection continuously updates 

treatment guidelines. Updated recommendations are available at 

http://www.aidsinfo.nih.gov. The guidelines detail indications for 

therapy in chronically infected patients, recommendations for initial 

therapy, considerations for changes in therapy, and possible regimens 

for such changes (Table 4-7).

Table 4-7: Indications for Initiating Antiretroviral Therapy for the 

Chronically HIV-1 Infected Patient

Clinical 

Category

CD4+ Cell Plasma HIV 

RNA

Recommendation

Symptomatic 

(AIDS or severe 

symptoms)

Any value Any value Treat

Asymptomatic, 

AIDS

CD4+ cells 

<200/mm3

Any value Treat

Asymptomatic CD4+ cells 

>200/mm3 but 

≤ 350/mm3

Any value Treatment should be offered, 

although controversial.*

Asymptomatic CD4+ T cells 

>350/mm3

>100,000 

(by RT-PCR 

or bDNA)

Some experienced clinicians 

recommend initiating therapy, 

recognizing that the 3-year 

risk for untreated patients to 

develop AIDS is >30%; in the 

absence of increased levels of 

plasma HIV RNA, other clinicians 

recommend deferring therapy 

and monitoring the CD4+ T cell 

count and level of plasma HIV 

RNA more frequently; clinical 

outcome data after initiating 

therapy are lacking.

Asymptomatic CD4+ T cells 

>350/mm3

<100,000 

(by RT-PCR 

or bDNA)

Most experienced clinicians 

recommend deferring therapy 

and monitoring the CD4+ T cell 

count, recognizing that the 3-

year risk for untreated patients 

to experience AIDS is <15%.

Source: Adapted from DHHS, 2004.

* Clinical benefit has been demonstrated in controlled trials only for patients with CD4+ T cells <200/mm3, 

however, the majority of clinicians would offer therapy at a CD4+ T cell threshold <350/mm3.
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The strength of the recommendation for starting therapy in an 

asymptomatic patient must take into account prognosis for disease-free 

survival, potential benefits and risks of therapy, and the willingness of 

the patient to take, and adhere to, therapy (see Chapter V on Adherence 

to HIV Therapies). Prognosis for disease-free survival may be assessed by 

utilizing the data in Table 4-8. However, given the sex-based differences 

in viral load and CD4 count (See Chapter 1 Epidemiology and Natural 

History of HIV Infection in Women), these data, generated from a 

prospective cohort of men who have sex with men (MSM), should be 

extrapolated with caution to women.

Among the benefits of therapy are:

• prevention of progressive immunosuppression by control 

of viral load,

• delayed progression of clinical disease/progression to AIDS,

• prolongation of life, and

• possible decreased risk of transmission (Quinn, 2000).

The risks of starting therapy include:

• a decrease in quality of life associated with adverse drug 

effects and inconvenience of dosing,

• limitations of future options for therapy if resistance develops 

to current agents,

• potential long-term toxicity of therapy,

• unknown duration of effectiveness of therapy, and

• possible transmission of drug-resistant virus.
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Table 4-8: Risk for Progression to AIDS-Defining Illness Among a 

Cohort of Men Who Have Sex with Men, Predicted by 

Baseline CD4+ T Cell Count and Viral Load*

CD4 ≤ 200 cells/mm3

Plasma Viral Load (copies/mL)†

Percentage of AIDS-defining illness

bDNA RT-PCR n 3 years 6 years 9 years

 ≤ 500

501 – 3,000

3,001 – 10,000

10,001 – 30,000

 > 30,000

 ≤ 1,500

1,501 – 7,000

7,001 – 20,000

20,001 – 55,000

 > 55,000

0§

3

7

20

70

–

–

14.3

50.0

85.5

–

–

28.6

75.0

97.9

–

–

64.3

90.0

100.0

CD4 201 – 350∞ cells/mm3

Plasma Viral Load (copies/mL)†

Percentage of AIDS-defining illness

bDNA RT-PCR n 3 years 6 years 9 years

 ≤ 500

501 – 3,000

3,001 – 10,000

10,001 – 30,000

 > 30,000

 ≤ 1,500

1,501 – 7,000

7,001 – 20,000

20,001 – 55,000

 > 55,000

3

27

44

53

104

–

0

6.9

36.4

64.4

–

20.0

44.4

72.2

89.3

–

32.2

66.2

84.5

92.9

CD4 >350 cells/mm3

PlasmaViral Load (copies/mL)†

Percentage of AIDS-defining illness

bDNA RT-PCR n 3 years 6 years 9 years

 ≤ 500

501 – 3,000

3,001 – 10,000

10,001 – 30,000

 > 30,000

 ≤ 1,500

1,501 – 7,000

7,001 – 20,000

20,001 – 55,000

 > 55,000

119

227

342

323

262

1.7

2.2

6.8

14.8

39.6

5.5

16.4

30.1

51.2

71.8

12.7

30.0

53.5

73.5

85.0

* Adapted from data from the Multicenter AIDS Cohort Study (MACS). (Source: 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. Erratum: Science 1997; 275:14; adapted by Alvaro Muñoz, PhD, Johns Hopkins University, 

Baltimore, MD, 2001.)

† MACS numbers reflect plasma HIV RNA values obtained by version 2.0 bDNA testing. RT-PCR values are 

consistently 2–2.5-fold higher than first-generation bDNA values, as indicated. The version 3.0 bDNA 

assay provides similar HIV-1 RNA values as RT-PCR, except at the lower end of the linear range (<1,500 

copies/mL).

§ Too few subjects were in the category to provide a reliable estimate of AIDS risk.

∞ A recent evaluation of data from the MACS cohort of 231 persons with CD4+ T cell counts >200 and 

<350 cells/mm3 demonstrated that of 40 (17%) persons with plasma HIV RNA <10,000 copies/mL, none 

progressed to AIDS by 3 years (Phair, 2002). Of 28 individuals (12%) with plasma viremia of 10,000 

– 20,000 copies/mL, 4% and 11% progressed to AIDS at 2 and 3 years, respectively. Plasma HIV RNA was 

calculated as RT-PCR values from measured bDNA values.

Source: DHHS, 2004.
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RECOMMENDATIONS FOR INITIAL TREATMENT REGIMENS

Recommendations for antiretroviral treatment continue to evolve with the 

development of new medications and additional data from clinical trials. 

The most recent guidelines from the DHHS are shown in Table 4-9.

Although these guidelines illustrate generally recommended regimens, 

nonspecialists should consider expert consultation regarding initiation 

of a specific regimen whenever there is any question about patient 

management.

Although there are multiple possible effective regimens, individualized 

decisions about therapy should take into account considerations such 

as pill burden, dosing frequency, toxicities and side effects, drug-drug 

interactions, and specific patient variables (e.g., pregnancy, co-morbid 

conditions, plasma HIV-RNA level, lifestyle, etc).

Table 4-9a: Antiretroviral Regimens Recommended for Treatment of 

HIV-1 Infection in Antiretroviral-Naive Patients

This table is a guide to treatment regimens for patients who have no previous experience with HIV therapy. 

Preferred regimens are in bold type; these regimens have been selected by experts based on the totality of 

virologic, immunologic, and toxicity data. Clinicians initiating antiretroviral regimens in the HIV-1 infected pregnant 

patient should refer to Chapter VII HIV and Reproduction and to “Recommendations for Use of Antiretroviral 

Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 

Transmission in the United States” (http://www.aidsinfo.nih.gov/guidelines/).

NNRTI-Based Regimens # of pills 

per day

Preferred 

Regimens

Alternative 

Regimens

efavirenz + (lamivudine or emtricitabine) + (zidovudine or 

tenofovir DF) – except for pregnant women or women with 

pregnancy potential

efavirenz + (lamivudine or emtricitabine) + abacavir or 

(didanosine or stavudine*) – except for pregnant women or 

women with pregnancy potential**

nevirapine + (lamivudine or emtricitabine) + (zidovudine or 

stavudine or didanosine or abacavir or tenofovir)

2–3 pills/day

2–4 pills/day

3–6 pills/day

PI-Based Regimens

lopinavir/ritonavir (co-formulated as Kaletra®) + 

(lamivudine or emtricitabine) + (zidovudine)

atazanavir + (lamivudine or emtricitabine) + (zidovudine or 

stavudine* or abacavir or didanosine) or (tenofovir + ritonavir 

100mg/d)

indinavir/ritonavir† + (lamivudine or emtricitabine) + (zidovudine 

or stavudine* or abacavir or tenofovir or didanosine)

lopinavir/ritonavir (co-formulated as Kaletra® + (lamivudine or 

emtricitabine) + (stavudine* or abacavir or tenofovir or didanosine)

nelfinavir§ + (lamivudine or emtricitabine) + (zidovudine or 

stavudine* or abacavir or tenofovir or didanosine)

saquinavir (sgc or hcg)ø/ritonavir† + (lamivudine or emtricitabine) 

+ (zidovudine or stavudine* or abacavir or tenofovir or 

didanosine)

fosamprenavir + (lamivudine or emtricitabine) + (zidovudine or 

stavudine* or abacavir or tenofovir or didanosine)

fosamprenavir/ritonavir + (lamivudine or emtricitabine) + 

(zidovudine or stavudine* or abacavir or tenofovir or didanosine)

8–9 pills/day

3–6 pills/day

7–12 pills/day

7–10 pills/day

5–8 pills/day

13–16 pills/day

5–8 pills/day

5–8 pills/day
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Table 4-9a: Antiretroviral Regimens Recommended for Treatment of HIV-1 

Infection in Antiretroviral Naive Patients (continued)

Triple NRTI Regimen – Only when an NNRTI- or a PI-based 

regimen cannot or should not be used as first line therapy

# of pills 

per day

abacavir + lamivudine + zidovudine 2 pills /day

* Higher incidence of lipoatrophy, hyperlipidemia, and mitochondrial toxicities reported with stavudine 

than with other NRTIs

** Women with child bearing potential implies women who want to conceive or those who are not using 

effective contraception

† Low-dose (100–400 mg) ritonavir

§ Nelfinavir available in 250 mg or 625 mg tablet

ø sgc = soft gel capsule; hgc = hard gel capsule

Source: Adapted from DHHS, 2004.

Table 4-9b: Advantages and Disadvantages of Antiretroviral Components 

Recommended as Initial Antiretroviral Therapy

ARV Class Antiretroviral 

Agent(s)

Advantages Disadvantages

NNRTIs

NNRTI Class Advantages:

• Less fat maldistribution and 

dyslipidemia than PI-based 

regimens

• Save PI options for future 

use

NNRTI Class Disadvantages:

• Low genetic barrier to resistance

• Cross-resistance among NNRTIs

• Skin rash

• Potential for CYP450 drug interaction

Efavirenz • Potent antiretroviral activity

• Low pill burden and 

frequency ( 1-tablet per 

day)

• Neuropsychiatric side effects

• Teratogenic in nonhuman primates, 

contraindicated in pregnancy and avoid use in 

women with pregnant potential

Nevirapine • No food effect

• No evidence of increased 

adverse hepatic events 

with single-dose NVP for 

prevention of mother-tochild transmission

• Higher incidence of rash than with other 

NNRTIs, including rare serious hypersensitivity 

reaction

• Higher incidence of hepatotoxicity than with 

other NNRTIs; including serious cases of hepatic 

necrosis

• Women with CD4 > 250 cells/mm3 are at 

higher risk of symptomatic hepatic events
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Table 4-9b: Advantages and Disadvantages of Antiretroviral Components 

Recommended as Initial Antiretroviral Therapy (continued)

PIs

PI Class Advantages:

• NNRTI options saved for 

future use

• Longest prospective study 

data including data on 

survival benefit

PI Class Disadvantages:

• Metabolic complications – fat maldistribution, 

dyslipidemia, insulin resistance

• CYP3A4 inhibitors & substrates – potential for 

drug interactions (esp. with ritonavir-based 

regimens)

Lopinavir/

ritonavir

• Potent antiretroviral activity

• Co-formulated as Kaletra®

• Gastrointestinal intolerance

• Hyperlipidemia

• Little experience in pregnant women

• Food requirement

Atazanavir • Less adverse effect on lipids 

than other PIs

• Once-daily dosing

• Low pill burden

• Hyperbilirubinemia (indirect)

• PR interval prolongation – generally 

inconsequential unless combined with another 

drug with similar side effect

• Interaction with tenofovir and efavirenz – avoid 

concomitant use unless combined with RTV 

(ATV 300 mg qd + RTV 100 mg qd)

• Food requirement

Fosamprenavir • Lower pill burden than 

amprenavir (4 vs 16 

capsules/day)

• No food effect

• Lower pill burden than 

amprenavir/ritonavir

• Once daily regimen in 

patients with no history of 

PI failure

• No food effect

• Low-dose ritonavir/indinavir 

T1⁄2 & Cmin allows for 

twice-daily instead of 3-

times-daily dosing

• Eliminates food restriction 

of indinavir

• Possibly higher incidence of nephrolithiasis than 

with IDV alone

• High fluid intake required (1.5–2 liters of fluid 

per day) 

Nelfinavir • More favorable safety and 

pharmacokinetic profile in 

pregnant women than with 

other PIs

• Diarrhea

• Higher rate of virologic failure than with other 

PIs in comparative trials

• Food requirement

Saquinavir 

(hgc or sgc) + 

ritonavir

• Low-dose ritonavir reduces 

saquinavir daily dose and 

frequency - ↑ Cmax, Cmin, 

& T1⁄2

• Gastrointestinal intolerance (sgc worse than 

hgc)

NRTIs

• Established backbone of 

combination antiretroviral 

therapy

• Rare but serious cases of lactic acidosis with 

hepatic steatosis reported with most NRTIs

Triple NRTI 

regimen

Abacavir + 

zidovudine + 

lamivudine 

only

• Abacavir + zidovudine + 

lamivudine - Co-formulated 

as Trizivir®

• Minimal drug-drug 

interactions

• Low pill burden

• Saves PI & NNRTI for future 

option

• Inferior virologic response when compared to 

efavirenz-based and indinavir-based regimens

• Potential for abacavir hypersensitivity reaction
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Table 4-9b: Advantages and Disadvantages of Antiretroviral Components 

Recommended as Initial Antiretroviral Therapy (continued)

Dual NRTIs 

backbone 

of three or 

more drug 

combination 

therapy

Zidovudine + 

lamivudine

• Most extensive and 

favorable virological 

experience

• Co-formulated as 

Combivir® – ease of dosing

• No food effect

• Lamivudine – minimal side 

effects

• Bone marrow suppression with zidovudine

• Gastrointestinal intolerance

Stavudine + 

lamivudine

• No food effect

• Once-daily dosing (when 

extended release stavudine 

formulation becomes 

available)

Adverse effects associated with stavudine:

• Peripheral neuropathy, lipoatrophy, 

hyperlactatemia and lactic acidosis, reports 

of progressive ascending motor weakness, 

potential for hyperlipidemia

• Higher incidence of mitochondrial toxicity with 

stavudine than with other NRTIs

Abacavir + 

lamivudine

• No food effect

• Once-daily dosing 

• Co-formulation (Epzicom)

• Potential for abacavir hypersensitivity reaction

• Higher incidence of severe hypersensitivity 

reactions with once daily dosing reported in 

1 study

Tenofovir + 

lamivudine

• Good virologic response 

when used with efavirenz

• Well tolerated

• Once-daily dosing

• Data lacking for tenofovir use in patients with 

renal insufficiency

• Tenofovir – some reports of renal impairment

• Drug interactions with atazanavir and 

didanosine requiring dose adjustment

Didanosine + 

lamivudine

• Once-daily dosing • Peripheral neuropathy, pancreatitis – associated 

with didanosine

• Food effect – needs to be taken on an empty 

stomach

• Requires dosing separation from most PIs

• Potential increase in toxicities when used with 

ribavirin, tenofovir, hydroxyurea

NRTI + 

emtricitabine

• Long half-life of 

emtricitabine allows for 

once daily dosing (of 

emtricitabine)

• Co-formulation with 

tenofovir (Truvada)

Source: Adapted from DHHS, 2004.

RECOMMENDATIONS FOR ANTIRETROVIRAL THERAPY IN THE TREATMENT-EXPERIENCED PATIENT

The need for a change in antiretroviral therapy most commonly arises in two 

situations: medication toxicity and treatment failure.

• Medication toxicity: When the need to change therapy arises because of 

medication toxicity, it may be possible to simply change one component 

of a regimen. If the toxicity occurs in a regimen that has provided effective 

virologic control, the goal is to continue effective therapy by changing the 

component that causes toxicity. For example, in a patient taking an effective 

regimen of AZT/3TC/PI, the development of anemia could be attributed 

to AZT. A different NRTI that does not commonly cause bone marrow 

suppression (e.g., d4T) could be substituted. The similar toxicities of certain 

agents must be remembered when making such changes: for example, in a 

patient taking ddI, the development of peripheral neuropathy would not be 

expected to be alleviated by substituting d4T.

 There are other situations in which the toxicity is not as easily attributed to a 

single component of a regimen (e.g., rash, GI symptoms). In these instances, 
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a “drug holiday” (temporary discontinuation) of the entire regimen 

may be necessary to allow symptoms to resolve, and a new regimen 

initiated with some change in components. In most cases reinitiation of 

antiretroviral therapy would not be expected to be associated with any 

increase in side effects. However, in the case of certain serious or lifethreatening toxicities (see C. on page 115), such as abacavir–associated 

hypersensitivity or severe liver toxicity with nevirapine, the offending 

agent should never be resumed.

• Treatment failure: Changes in regimen for lack of efficacy may be 

triggered by evidence of clinical progression, progressive decline 

in CD4 count, and, most commonly, for incomplete virologic 

suppression or virologic rebound. Clinical failure is defined by the 

occurrence of HIV-related events after at least 3 months on an 

antiretroviral regimen, excluding immune reconstitution syndromes. 

Immunologic failure is the failure to increase 25–50 cells/mm3 above 

the baseline CD4 count in the first year of therapy or a decrease in 

the CD4 count below baseline while on therapy. Virologic failure is 

the failure to achieve HIV RNA <400 copies/mL by 24 weeks or <50 

copies/mL by 48 weeks on therapy or repeated detection of viremia 

after complete virologic suppression. When changes in therapy are 

contemplated, an increase in viral load or a downward trend in 

CD4 count should be confirmed with repeat determinations before 

changes are made. In general virologic failure occurs first, followed 

by immunologic failure, and then by clinical failure, although these 

events may be separated by months to years. 

 There are a number of possible reasons for treatment failure: patient 

factors (e.g., age (in some cohorts), pretreatment HIV-RNA level and 

CD4 count, active substance use, depression, baseline drug resistance 

or resistance related to prior treatment regimens); suboptimal 

adherence (including running out of medications); medication side 

effects or toxicity; pharmacokinetics (e.g., absorption, metabolism, 

penetration into body reservoirs, food or fasting requirements, 

drug-drug interactions); potency of the current regimen; and other 

unknown reasons. Sex, race, pregnancy and history of substance 

abuse have not been associated with treatment failure. It is important 

to try to distinguish among these different causes of treatment failure, 

since approaches to management will differ. 

 Failure increases the risk of disease progression and should be 

addressed aggressively. Assessing and managing a patient 

with extensive prior antiretroviral experience and treatment regimen 

failure is complex and expert advice is critical. 

Table 4-10 summarizes guidelines for patient assessment and 

management with suspected treatment failure. In general a 

distinction is made between patients with limited prior treatment 

and those with extensive prior treatment, since those with more 

limited antiretroviral experience have a greater likelihood of 

achieving maximal viral suppression with an appropriate change 

in regimen. In these patients changing therapy sooner rather than 

later is recommended to minimize continued selection of resistance 

mutations. 
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Table 4-10: Guidelines for Changing an Antiretroviral Regimen 

for Suspected Treatment Regimen Failure

Patient Assessment

• Review antiretroviral treatment history (drugs, doses, duration, adherence, tolerability, 

prior resistance testing).

• Perform physical exam to assess for signs of clinical progression.

• Assess adherence, tolerability, and pharmacokinetic issues.

• Distinguish between first or second, and multiple treatment regimen failures.

• Perform resistance testing while patient is taking therapy.

• Identify susceptible drugs and drug classes.

Patient Management: Specific Clinical Scenarios

• Limited prior treatment with low (but not suppressed) HIV RNA level (e.g., up to 

5000 copies/mL: The goal of treatment is to re-suppress viral replication. Consider 

intensifying with one drug (e.g., tenofovir) or pharmacokinetic enhancement (use 

of ritonavir boosting of a protease inhibitor) or most aggressively, change to a 

completely new regimen. If continuing the same treatment regimen, need to follow 

HIV RNA levels more closely, because ongoing viremia will lead to the accumulation 

of resistance mutations.

• Limited or intermediate prior treatment with single drug resistance: Consider 

changing one drug pharmacokinetic enhancement (few data available) or, most 

aggressively, change to a completely new regimen.

• Limited or intermediate prior treatment with more than 1 drug resistance: The goal of 

treatment is to suppress viremia to prevent further selection of resistance mutations. 

Consider optimizing regimen by changing classes (e.g., PI-based to NNRTI-based and 

vice versa) and/or adding new active drugs. 

• Prior treatment with no resistance identified: Consider the timing of obtaining the 

drug resistance test (e.g., was the patient off antiretroviral medications?) and/or 

nonadherence. Consider resuming the same regimen or starting a new regimen and 

then repeating genotypic testing early (e.g., 2–4 weeks) to see if a resistant strain has 

been selected.

• Extensive prior treatment and drug resistance: It is reasonable to continue the same 

antiretroviral regimen if there are few or no treatment options. In general, avoid 

adding a single active drug because of the risk of the development of resistance to 

that drug. In advanced disease with a high likelihood of clinical progression, adding a 

single drug may reduce the risk of immediate clinical progression. In this complicated 

scenario, expert advice should be sought.

Source: Adapted from DHHS, 2004

 Viral suppression may be difficult to achieve in patients with 

extensive prior drug exposure and the primary goals are to 

preserve immune function and prevent clinical progression. In a 

patient with extensive prior treatment and lower CD4 count (e.g., 

<200/mm3) a change in therapy is indicated to prevent clinical 

progression; with higher CD4 counts, risk of progression is less and 

a well-tolerated regimen may be continued, if it is impossible to 

construct a new regimen that is effective. Discontinuing therapy, 

even in the presence of ongoing viremia, leads to a rapid increase 

in viral load, a decrease in CD4 count, and increases the risk of 

clinical progression (Deeks, 2001; Lawrence, 2003) and is therefore 

not recommended (DHHS, 2004).
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 When a regimen is changed for lack of efficacy, the goal is to 

use medications that will minimize the likelihood of further viral 

resistance. Prior to the general availability of resistance testing, 

regimen changes to improve efficacy were made empirically. 

Some of the general principles from that empiric practice are 

still worth emphasizing, e.g. often an entire regimen (not just 

one medication) must be changed, and there is often significant 

cross-resistance among agents within a class. Now, however, when 

antiretroviral therapy is changed for lack of efficacy, information 

from resistance testing can be of pivotal importance in choosing a 

new regimen (see “Resistance Testing” below). Recommendations 

for regimen changes may also be found at 

http://www.aidsinfo.nih.gov.

 “Intensification” refers to the theory that some patients with a 

suboptimal decrease in viral load from an early regimen, may 

benefit from the early addition of a single new agent. This may 

also refer to the situation in which rebound occurs after complete 

viral suppression with limited prior treatment. In these patients, 

low levels of detectable virus (usually <1000 c/mL) are present, 

generally too low to obtain accurate resistance testing. This may 

be a unique situation in which it may be reasonable to add only a 

single medication, or to change only a portion of the combination, 

adding an agent to which the patient will likely be sensitive. 

RESISTANCE TESTING

There are two main techniques to assess the development of viral 

resistance to antiretroviral therapy. Phenotypic assays directly determine 

the amount of a medication required to inhibit HIV. Genotypic assays 

determine changes in the nucleotide sequences of the genes that code 

for the protease and reverse transcriptase enzymes. Interpretations 

of genotypic results require knowledge of which specific changes are 

associated with resistance. Results are reported as a string of three pieces 

of information for each mutation detected:

1. wild-type amino acid,

2. codon involved, and

3. amino acid coded for by mutated codon.

Table 4-11 shows the mutations known to be associated with 

resistance to specific agents (Bartlett, 2003). Updated listings of 

mutations and associated resistance can be found at: http://hivweb.lanl.gov or http://hivdb.stanford.edu.
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Table 4-11 Resistance Mutations Adapted from IAS-USA 

Drug Codon Mutations* Comment

Nucleosides and Nucleotides

AZT 41, 67, 70, 210, 215, 219 Mutations are “TAMs”** reduces 

susceptibility to AZT, d4T, ABC, ddl, 

ddC, TDF, 3TC.

3TC 184 (44, 118) 184 – high level 3TC resistance, 

increases activity of d4T, AZT, and TDF, 

reduces susceptibility to ddl, ddC, ABC.

ddC 65, 69, 74, 184

ddl 65, 74 Presence of 74 or 65 alone or combined 

with TAMs is associated with resistance 

to ddl. Multiple TAMs also decrease ddl 

susceptibility

d4T 41, 67, 70, 75, 210, 215, 

219

The d4T-specific mutation at 75 is 

seen mostly in vitro. In vitro resistance 

depends on number of TAMs, which 

reduce susceptibility to all NRTIs.

ABC 41, 65, 67, 70, 74, 115, 

184, 210, 215, 219

Resistance depends on number of TAMs 

± M184V; 184 alone does not confer 

resistance. Presence of M184V plus ≥3-4 

TAMs associated with ABC resistance. 

ABC selects for mutations that may 

confer cross-resistance to 3TC, ddl, and 

TDF.

TDF 65, 69 insertion, ≥ 3 TAMs 

including 41L or 210W 

Reduced activity with K65R and 

resistance with 69 insertion.

Multinucleoside 

resistance – A 

Q151M complex

151, 62, 75, 77, 116 Occurs with or without TAMs. Confers 

resistance to all NRTIs except tenofovir.

Multinucleoside 

resistance – B 

T69 insertion

69 (insertion), 41, 62, 67, 

70, 210, 215, 219

Requires TAMs. Confers resistance to all 

NRTIs and TDF but not to DAPD.

Multinucleoside 

resistance 

– Multiple TAMs

41, 67, 70, 210, 215, 219 Confers resistance to all NRTI including 

TDF.

NNRTIs

NVP 100, 103, 106, 108, 181, 

188C/L/H, 190

Y181C is favored mutation with NVP, 

unless combined with AZT, in which 

case K103N is favored.

DLV 103, 181, 236, 318

EFV 100, 103, 108, 181, 188L, 

190, 225

181C is not selected, but its presence 

contributes low-level cross resistance. 

Resistance with 188L but not 188C or 

188H.

Multi-NNRTI 

resistance

103, 188L Either mutation substantially reduces 

activity of all NNRTIs

Multi-NNRTI 

resistance 

accumulation

100, 106, 181, 190, 230 ≥2 of the mutations substantially 

reduces activity of all NNRTIs
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Table 4-11 Resistance Mutations Adapted from IAS-USA (continued)

Drug Major† Minor‡ Comment

Protease Inhibitors (PIs)

IDV 46, 82, 84 10, 20, 24, 

32, 36, 54, 

71, 73, 77, 

90

At least 3 mutations required for 

resistance (4x decreases in susceptibility).

NFV 30, 90 10, 36, 46, 

71, 77, 82, 

84, 88

D30N most common mutation: No PI 

cross-resistance. L90M occurs in some, 

leading to greater PI cross-resistance.

RTV 82, 84 10, 20, 32, 

33, 36, 46, 

54, 71, 77, 

90

Cross resistance with IDV common.

SQV 48, 90 10, 54, 71, 

73, 77, 82, 

84

90 develops 1st, then 48; Codon 48 

mutation unique, but L90M contributes 

to PI cross-resistance.

APV 50V, 84 10, 32, 46, 

47, 54, 73, 

90

I50V is associated with cross-resistance 

to LPV.

LPV/r 73 10, 20, 24, 

32, 33, 46, 

47, 50V, 53, 

54, 63, 71, 

73, 82, 84, 

90

≥6 mutations cause reduced response; 

the number may be as low as 4. 

I50V (selected by APV) decreases LPV 

susceptibility.

Atazanvir 50L 32, 46, 54, 

71, 82, 84, 

88, 90

Selects for 50L and 71 when initial PO; 

in PI experienced patients selects for 54 

and 84.

Multi-PI 

resistance

46, 82, 84, 

90

10, 54 ≥4 or 5 usually cause multiple PI 

resistance.

Fusion Inhibitors

Enfuvirtide (T20) Resistance in the gp41 envelope gene at 

positions 36-45.

Source: Adapted from D’Acquilla, 2002. Updated October, 2003 by the Drug Resistance Mutations Group, 

International AIDS Society–USA. Available at http://www.iasusa.org.(Accessed 3/04.)

* The distinction between primary and secondary mutations has been eliminated for NRTIs and NNRTIs by the 

International AIDS Society Expert Committee; this distinction has been retained for PIs, but with the terms “Major” 

or “Minor”.

**Thymidine-associated mutations

† Major Mutations develop first or are associated with decreased drug binding or reduced viral activity; these 

effect phenotype resistance.

‡ Minor Mutations appear later and, by themselves, do not significantly change phenotype resistance.

Both phenotypic and genotypic assays are difficult to perform if the viral 

copy number is less than 1000 c/mL. Their utility is also limited by an 

inability to detect resistant virus that makes up less than 20% of the total 

viral burden in a sample. It is also critical to recognize that these assays 

will only reliably detect mutations conferring resistance to medications 

the patient is taking at the time the assay is performed; samples from 

patients who are off therapy at the time of resistance testing are likely to 

show reversion to wild-type (sensitive) virus as the predominant circulating 
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viral strain. Thus, resistance testing is insensitive to mutations secondary 

to selective pressure that is no longer present after a change in regimen. 

Virions with these mutations likely still exist as a small percentage of 

circulating virus and may lead to clinical resistance if inactive drugs that 

test “sensitive” but are vulnerable to these resistance mutations are used; 

current assays will not detect their presence. A comparison of genotypic 

and phenotypic assays is shown in Table 4-12. 

Table 4-12: Comparison of Genotypic and Phenotypic Assays

Genotypic Assays

Advantages Disadvantages

• Less expensive ($300 to $480/test)

• Short turn-around of 1 to 2 weeks

• May detect presence of resistance mutations 

before they have resulted in phenotypic 

resistance

• Detect resistance only in dominant species 

(>20%)

• Interpretation requires knowledge of mutational 

changes, i.e., expertise

• Technician experience influences results

• May show discrepancy with phenotype

• Require viral load > 1000 c/mL

Phenotypic Assays

Advantages Disadvantages

• Interpretation more analogous to resistance 

testing of bacteria

• Assesses total effect, including mutations, 

mutational interactions

• Reproducibility is good

• Advantage over genotype when there are 

multiple mutations

• More expensive (usually $800 to $1000)

• Report takes 2 to 3 weeks

• Thresholds to define susceptibility are arbitrary 

and do not account for boosted PI levels

• Detects resistance only to single drug, not 

combinations

• Detect resistance only in dominant species 

(>20%)

• Require viral load >500-1000 c/mL

Source: Bartlett, 2003.

Many studies have shown that patients for whom resistance analysis is done 

before a change in antiretroviral therapy have a better virologic response 

to the new regimen than do patients in whom a change in therapy is based 

solely on antiretroviral history (Baxter, 1999; Durant, 1999, Zolopa 1999). 

Resistance testing may be useful in the following ways.

1. To determine the role of resistance in patients with virologic 

failure and maximize the number of active medications in a new 

regimen.

2. To determine the role of resistance in patients with suboptimal 

virologic control on a HAART regimen (and again maximize the 

number of active medications in a new regimen).

3. To determine whether there is drug resistance in a patient 

with acute HIV who is considering antiretroviral therapy (see 

“Treatment of Acute HIV Infection,” below).

Patients with pan-sensitive virus in the face of virologic failure should be 

questioned carefully, but nonjudgmentally, about their medication-taking 

behaviors. Therapeutic drug monitoring (TDM) can also be considered, 

although data are not yet available demonstrating that TDM improves 

clinical outcome. Current USPHS recommendations for the use of drug 

resistance assays are outline in Table 4-13.
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Table 4-13: Recommendations for Using Drug-Resistance Assays 

Clinical Setting/recommendations Rationale

Drug-Resistance assay recommended

Virologic failure during combination 

antiretroviral therapy (AI)*

Determine the role of resistance in drug 

failure and maximize the number of active 

drugs in the new regimen

Suboptimal suppression of viral load after 

antiretroviral therapy initiation (BIII)

Determine the role of resistance and 

maximize the number of active drugs in 

the new regimen, if indicated

Acute human immunodeficiency virus (HIV) 

infection, if decision is made to initiate 

therapy (AIII)

Determine if drug-resistant virus was 

transmitted and change regimen 

accordingly

Drug-resistance assay should be considered

Chronic HIV infection before therapy 

initiation (CIII)

Available assays might not detect minor 

drug-resistant species. However, should 

consider if significant probability that 

patient was infected with drug-resistant 

virus (i.e., if the patient is thought to 

have been infected by a person receiving 

antiretroviral drugs).

Drug-resistance assay not usually recommended

After discontinuation of drugs (DIII) Drug-resistance mutations might become 

minor species in the absence of selective 

drug pressure, and available assays might 

not detect minor drug-resistant species. 

If testing is performed in this setting, the 

detection of drug resistance may be of 

value, but its absence does not rule out the 

presence of minor drug-resistant species

Plasma viral load <1,000 HIV RNA copies/

mL (DIII)

Resistance assays cannot be consistently 

performed because of low copy number 

of HIV RNA; patients/providers may incur 

charges and not receive results

Source: DHHS, 2004.

* See Notes for Table 4-16 for explanation of evidence grading.

TREATMENT INTERRUPTIONS (DRUG HOLIDAY)

Interruption of antiretroviral therapy has been considered in a variety 

of different scenarios. Intermittent therapy was previously hypothesized 

by some to improve HIV-specific immunity. A clinical trial failed to 

show evidence for this. There do remain two situations where treatment 

interruptions are being assessed: 1) as a way to reduce total exposure to 

medication (which could provide a cost or toxicity benefit), and 2) prior to 

attempts at salvage therapy in patients with virologic failure and multiple 

resistance mutations. At the current time, however, treatment interruption 

should be considered experimental in both of these situations.
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D. TREATMENT OF ACUTE HIV INFECTION

To consider treatment of acute HIV infection, the clinician must first recognize 

its presence. In more than half of all patients who acquire HIV infection, there 

are clinical symptoms 1–6 wk after exposure. The symptoms vary in severity, 

but commonly include fever, lymphadenopathy, fatigue, rash, myalgias, 

and pharyngitis — a symptom complex that mimics mononucleosis. HIV 

antibodies will not yet be present at this point, but techniques that detect 

viral nucleic acids (see “Initial Diagnosis,” above) will confirm the diagnosis: 

a negative or indeterminate antibody test in conjunction with a positive HIV 

RNA or HIV DNA test is diagnostic of acute HIV infection. It is important 

to note, however, that a low level of HIV RNA (e.g., < 5000 c/mL) may 

be a false-positive result and should be repeated (Rich, 1999). In addition, 

an HIV DNA assay could be performed to clarify the diagnosis; this should 

almost always be positive in an infected person, regardless of RNA level. 

Relatively recent infection may also be diagnosed in a patient with negative 

HIV serologies in the previous 6–9 mo and a first positive result, even in the 

absence of a seroconversion syndrome.

The benefits of treating acute HIV infection are not completely defined. 

The rationale for early treatment is that there will be early suppression 

of viremia, which may preserve CD4 cell number and function including 

HIV-specific CD4 cells. There are also risks associated with early treatment 

that include the toxicities of the medications used and the possibility of 

early development of resistance. These unanswered questions about 

risks and benefits of early therapy should be addressed with the patient; 

enrollment in clinical trials and observational studies of acute HIV should 

be considered. In treating acute HIV, it is always important to use a threeor four-drug regimen that would be expected to provide complete viral 

suppression. In addition, after considering the source of exposure and 

local epidemiologic information, genotypic resistance testing may prove 

useful in this setting. In acute HIV infection, the patient’s predominant 

virus will be the strain that was transmitted, without reversion to the 

wild-type (pan-sensitive) virus seen in chronically infected patients who 

have stopped treatment. The potential risks and benefits of treating acute 

HIV are summarized in Table 4-14.

POSTEXPOSURE PROPHYLAXIS

See Chapter XIII on Occupational Exposure.

TREATMENT IN PREGNANCY

Antiretroviral treatment is indicated in pregnancy to reduce the risk 

of perinatal transmission whether or not therapy is yet needed to treat 

maternal disease. Specific guidelines for optimal therapy are addressed 

in Chapter VII (HIV and Reproduction). Information is also provided at 

http://www.aidsinfo.nih.gov.
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Table 4-14: Risks and Benefits of Early Initiation of 

Antiretroviral Therapy in Acute HIV Infection

Potential 

Benefits

• Control of viral replication and rate of mutation

• Prevention of progressive immunodeficiency; potential maintenance of 

a normal immune system

• Delayed progression to AIDS and prolongation of life

• Possible decreased risk of viral transmission

• Decreased severity of acute infection symptoms

• Possibly decreased viral setpoint (which may have a subsequent effect 

on rate of disease progression)

Potential 

Risks

• Reduction in quality of life from adverse drug effects and 

inconvenience of current maximally suppressive regimens

• Earlier development of drug resistance, if therapy fails to effectively 

suppress viral replication

- Transmission of drug resistant virus

- Limitation in future choices of antiretroviral agents due to 

development of resistance

• Drug-related short- or long-term serious toxicity

• Unknown duration of effectiveness of current antiretroviral therapies

Source: Adaoted from DHHS, 2004.

IMMUNE-BASED THERAPY

Therapy to augment the immune response to HIV may be possible 

through the use of HIV vaccines or cytokines, such as interleukin-2. 

Such strategies to enhance the control of HIV already provided by 

antiretroviral medications are being assessed in clinical trials, but are not 

part of current standard care.

ALTERNATIVE OR COMPLEMENTARY THERAPY

Some patients may present with knowledge or questions about alternative 

or complementary therapy or may indicate that they are already taking 

such therapy. All patients should be specifically asked about their use of 

such therapies, as they may not consider these to be medications and may 

not volunteer the information to their provider. Specific complementary 

therapies change rapidly, and their use varies widely with geography and 

patient demographics. For patients who do choose such therapies it is 

important to make sure that agents that have overlapping toxicities with a 

patient’s prescribed therapy are avoided and that discussions of alternative 

therapy are held in a way that does not alienate the patient from her 

involvement in medical care.
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V. COMPLICATIONS: OPPORTUNISTIC DISEASES

The risk for various opportunistic processes — so called because they take 

advantage of patients with a weakened immune system — is defined by 

the total CD4 lymphocyte count. They include opportunistic infections 

(OIs) and certain malignancies, and are similar to the diseases seen 

in other immunocompromised hosts such as recipients of solid organ 

transplants. In fact, AIDS was first recognized as a new entity by the 

characteristic pattern of opportunistic diseases — especially Pneumocystis

pneumonia and Kaposi’s sarcoma — that were being diagnosed in young, 

previously healthy gay men. The pattern and sequence of OIs that are 

seen as the total CD4 cell count decreases is so reliable that in most cases 

the total CD4 cell count limits the differential diagnosis (see Table 4-15).

Table 4-15: Correlation of Complications With CD4 Cell Counts

CD4 Cell Count* Infectious 

Complications 

Noninfectious†

Complications

>500/mm3 • Acute retroviral syndrome

• Candidal vaginitis

• Persistent generalized 

lymphadenopathy (PGL)

• Guillain-Barré syndrome

• Myopathy

• Aseptic meningitis

200-500/mm3 • Pneumococcal and other bacterial 

pneumonia

• Pulmonary tuberculosis

• Herpes zoster

• Oropharyngeal candidiasis (thrush)

• Cryptosporidiosis, self-limited

• Kaposi’s sarcoma

• Oral hairy leukoplakia

• Cervical intraepithelial neoplasia

• Cervical cancer

• B-cell lymphoma

• Anemia

• Mononeuritis multiplex

• Idiopathic thrombocytopenic 

purpura

• Hodgkin’s lymphoma

• Lymphocytic interstitial pneumonitis

<200/mm3 • Pneumocystis carinii pneumonia

• Disseminated histoplasmosis and 

coccidioidomycosis

• Miliary/extrapulmonary TB

• Progressive multifocal 

leukoencephalopathy (PML)

• Wasting

• Peripheral neuropathy

• HIV-associated dementia

• Cardiomyopathy

• Vacuolar myelopathy

• Progressive polyradiculopathy

• Non-Hodgkin’s lymphoma

<100/mm3 • Disseminated herpes simplex

• Toxoplasmosis

• Cryptococcosis

• Cryptosporidiosis, chronic

• Microsporidiosis

• Candidal esophagitis

<50/mm3 • Disseminated cytomegalovirus 

(CMV)

• Disseminated Mycobacterium avium

complex

Central nervous system (CNS) 

lymphoma

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

† Some conditions listed as “non-infectious” are probably associated with transmissible microbes. Examples 

include lymphoma (Epstein-Barr virus [EBV]) and cervical cancer (human papillomavirus [HPV]).

Source: Bartlett, 2003. Reprinted with permission.
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At total CD4 cell counts above 500, illnesses are rarely specifically 

associated with the patient’s HIV serostatus. Non-Hodgkin’s lymphoma 

and mucocutaneous KS are occasional exceptions; they can occur at 

varying CD4 cell counts, but are more frequently diagnosed at lower 

values. Infections that are virulent among HIV-seronegative individuals, 

such as tuberculosis and bacterial pneumonia, may, of course, occur at 

any CD4 cell count but are increasingly more common and more severe 

as the CD4 count declines. Between 200 and 500 cells, less serious 

HIV-associated problems begin to manifest themselves, such as oral 

hairy leukoplakia, various skin problems, shingles, and oral or vaginal 

candidiasis (thrush). Candida vaginitis, which is also common among 

women who do not have HIV, may be the first indication of HIV infection 

(Imam, 1990).

According to the 1993 version of the CDC case definition, AIDS may be 

defined by a number of serious opportunistic illnesses or by a decline in 

the total CD4 cell count below 200 (see Table 1-3 in Chapter I). This CD4 

cell count criterion acknowledges an important threshold for OI risk. 

Pneumocystis carinii pneumonia (PCP), the most common AIDS-defining 

OI and leading cause of death, is usually diagnosed as patients approach 

and drift below this critical number of total CD4 cells. Other OIs, such as 

toxoplasmosis, cryptococcal meningitis, and disseminated histoplasmosis, 

tend to occur as the CD4 cell count declines from less than 200 to below 

100 cells. Typically, end-stage illnesses such as CNS lymphoma, CMV endorgan disease, and disseminated MAC, tend to occur at very low CD4 cell 

counts, often less than 25 cells.

Antimicrobial therapy works in concert with the individual’s immune 

system to clear infection. Before the advent of potent combination 

antiretroviral therapy, HIV-associated opportunistic diseases could 

not be controlled without ongoing suppressive therapy, because the 

patients’ immune function was too weak to effect that control. Once an 

OI was diagnosed and treated acutely (“induction” therapy, borrowing 

from the language of oncology), treatment would be continued at lower 

“maintenance” levels or the OI would inevitably recur. “Cure” of OIs was 

not part of the vocabulary of HIV disease management. With potent 

combination antiretroviral therapy resulting in dramatic improvement 

in CD4 cell counts and immune function, both prophylactic and chronic 

suppressive therapies are being withdrawn successfully in responders. 

This has opened an entirely new era in the care of people with advanced 

HIV (see below).

A. OPPORTUNISTIC INFECTION PROPHYLAXIS

One of the early significant advances in the management of HIV/AIDS 

was the demonstration that chemoprophylaxis could prevent PCP and 

thereby improve survival. Before the development of potent combination 

antiretroviral therapy an important focus of the clinical research effort 

was to identify effective prophylactic agents for the other common OIs. 

The success of this research was in part responsible for the slowing of 

the death rate from AIDS that was first apparent near the end of 1995, 

just before the era of potent combination antiretroviral therapy began. 
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Recommendations for prophylaxis for specific OIs depend on a number 

of factors: the CD4 threshold that defines the greatest risk, the overall 

effectiveness of a given approach, the risk of resistance development, the 

presence of pregnancy, toxicity, and cost. The USPHS/IDSA guidelines 

for OI prophylaxis are updated periodically to reflect the most current 

understanding of disease risk and prevention. Current recommendations 

for initiating primary OI prophylaxis can be found at http://

www.aidsinfo.nih.gov, or in 2003 Medical Management of HIV Infection 

by John Bartlett, listed in the Resources appendix. (USPHS/IDSA, 2002) 

Table 4-16 summarizes recommendations for primary prophylaxis of the 

most common OIs.

Table 4-16: Prophylaxis to Prevent First Episode of Opportunistic 

Disease in Adults and Adolescents Infected with HIV

Pathogen Preventive Regimens

Indication First Choice Alternatives

I. Strongly Recommended as Standard of Care

Pneumocystis 

carinii1

CD4+ count 

<200/μL or 

oropharyngeal 

candidiasis

Trimethoprimsulfamethoxazole (TMPSMX), 1 DS po q.d. (AI) 

TMP-SMX, 1 SS po 

q.d. (AI)

Dapsone, 50 mg po 

b.i.d. or 100 mg po 

q.d. (BI); dapsone, 

50 mg po q.d. plus

pyrimethamine, 50 mg 

po q.w. plus leucovorin 

25 mg po q.w. (BI); 

dapsone 200 mg po plus

pyrimethamine, 75 mg po 

plus leucovorin, 25 mg 

po q.w. (BI); aerosolized 

pentamidine, 300 mg 

q.month via Respirgard 

II(TM) nebulizer (BI); 

atovaquone, 1500 mg po 

q.d. (BI); TMP-SMX, 1 DS 

po t.i.w. (BI)

Mycobacterium 

tuberculosis 

Isoniazidsensitive2

TST reaction ≥5 

mm 

or prior positive 

TST result without 

treatment 

or contact with 

case of active 

tuberculosis 

regardless of TST 

result (BIII)

Isoniazid, 300 mg po 

plus pyridoxine, 50 mg 

po q.d. x 9 mo (AII) 

or isoniazid, 900 mg 

po plus pyridoxine, 

100 mg po b.i.w. x 9 

mo (BII)

Rifampin, 600 mgpo q.d. 

(BIII) x 4 mo or rifabuin 

300 mg po q.d. (CIII) x 4 

mo Pyrazinamide, 15-20 

mg/kg po q.d. x 2 mo 

plus either rifampin, 600 

mg po q.d. (BI) x 2 mo or 

rifabutin, 300 mg po q.d. 

(CIII) x 2 mo 

Isoniazidresistant Same as above; 

high probability 

of exposure to 

isoniazid-resistant 

tuberculosis

Rifampin 600 mg po 

(AIII) or rifabutin, 300 

mg po (BIII) q.d. x 4 mo

Pyrazinamide 15-20 

mg/kg po q.d. plus either 

rifampin, 600 mg po (BI) 

or rifabutin, 300 mg po 

(CIII) q.d. x 2 mo

Multidrug-

(isoniazid 

and rifampin) 

resistant 

Same as above; 

high probability 

of exposure 

to multidrugresistant 

tuberculosis

Choice of drugs 

requires consultation 

with public health 

authorities. Depends on 

susceptibility of isolate 

from source patient

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Table 4-16: Prophylaxis to Prevent First Episode of Opportunistic Disease 

in Adults and Adolescents Infected with HIV (continued)

Pathogen Preventive Regimens

Indication First Choice Alternatives

Toxoplasma 

gondii3

IgG antibody 

to Toxoplasma 

and CD4+ count 

<100/μL

TMP-SMX, 1 DS po 

q.d. (AII)

TMP-SMX, 1 SS po q.d. 

(BIII): dapsone, 50 mg po 

q.d. plus pyrimethamine, 

50 mg po q.w. plus

leucovorin, 25 mg po q.w. 

(BI); dapsone, 200 mg po 

plus pyrimethamineˆ, 75 

mg po plus leucovorin, 

25 mg po q w (BI); 

atovaquone, 1500 mg 

po q.d. with or without 

pyrimethamine, 25 mg po 

q.d. plus leucovorin, 10 

mg po q.d. (CIII)

Mycobacterium 

avium complex4

CD4+ count 

<50/μL

Azithromycin, 1,200 

mg po q.w., (AI) q.d. 

or clarithromycin,4 500 

mg po b.i.d. (AI)

Rifabutin, 300 mg po 

(BI);azithromycin, 1,200 

mg po q.w. plus rifabutin, 

300 mg poq.d. (CI)

Varicella zoster 

virus

Significant 

exposure to 

chickenpox or 

shingles for 

patients who 

have no history of 

either condition 

or, if available, 

negative antibody 

to VZV

Varicella zoster (VZV) 

immune globulin 

(VZIG), 5 vials (1.25 mL 

each) im, administered 

≤96 h after exposure, 

ideally within 48 h (AIII)

II. Generally Recommended

Streptococcus 

pneumoniae5

 CD4+ count > 

200/μL

23 valent polysaccharide vaccine, 0.5 

mL im [BII]

None

Hepatitis B 

virus6,7 

All susceptible 

(anti-HBcnegative) patients 

Hepatitis B vaccine: 3 

doses (BII)

None

Influenza 

virus6,8

All patients 

(annually, before 

influenza season) 

Inactivated trivalent 

influenza virus vaccine: 

one annual dose (0.5 

mL) im (BIII)

Oseltamivir, 75 mg po 

q.d. (influenza A or B) 

(CIII); rimantadine, 100 

mg po b.i.d. (CIII), or 

amantadine, 100 mg po 

b.i.d. (CIII) (influenza A 

only)
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Table 4-16: Prophylaxis to Prevent First Episode of Opportunistic Disease 

in Adults and Adolescents Infected with HIV (continued)

Pathogen Preventive Regimens

Indication First Choice Alternatives

Hepatitis A 

virus6,7 

All susceptible 

(anti-HAVnegative) patients 

at increased 

risk for HAV 

infection (e.g., 

illicit drug users, 

men who have 

sex with men, 

hemophiliacs) or 

with chronic liver 

disease, including 

chronic hepatitis 

B or hepatitis C 

Hepatitis A vaccine: 

two doses (BIII)

None

III. Evidence for Efficacy but Not Routinely Indicated

Bacteria Neutropenia Granulocyte-colonystimulating factor (GCSF), 5-10 μg/kg sc q.d. 

x 2-4 w or granulocytemacrophage colonystimulating factor (GMCSF), 250 μg/m2 sc iv x 

2-4 w (CII)

None

Cryptococcus 

neoformans 

CD4+ count 

<50/μL 

Fluconazole, 100-200 

mg po q.d (CI)

Itraconazole capsule, 200 

mg po q.d. (CIII)

Histoplasma 

capsulatum9

CD4+ count 

<100/μL, endemic 

geographic area 

Itraconazole capsule, 

200 mg po q.d.(CI)

None

Cytomegalovirus 

(CMV)10 

CD4+ count 

<50/μL (and CMV 

antibody positivity 

Oral ganciclovir, 1g po 

t.i.d. (CI)

None

NOTES: Information included in these guidelines might not represent Food and Drug Administration (FDA) 

approval or approved labeling for the particular products or indications in question. Specifically, the terms 

“safe” and “effective” might not be synonymous with the FDA-defined legal standards for product approval. 

The Respirgard II nebulizer is manufactured by Marquest, Englewood, Colorado. 

Letters and roman numerals in parentheses after regimens indicate the strength of the recommendation 

and the quality of evidence supporting it. Categories reflecting the quality of evidence forming the basis for 

recommendations regarding the use of a product or measure for the prevention of opportunistic infection 

in HIV-infected persons: I — Evidence from at least one properly randomized, controlled trial; II — Evidence 

from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic 

studies (preferably from more than one center), or from multiple time-series studies or dramatic results from 

uncontrolled experiments; III — Evidence from opinions of respected authorities based on clinical experience, 

descriptive studies, or reports of expert committees. 

ABBREVIATIONS: Anti-HBc = antibody to hepatitis B core antigen; b.i.w.= twice a week; DS = double-strength 

tablet; HAART = highly active antiretroviral therapy; HAV = hepatitis A virus; HIV = human immunodeficiency 

virus; im = intramuscular; iv = intravenous; po = by mouth; q.d. = daily; q.m. = monthly; q.w. = weekly; 

SS= single-strength tablet; t.i.w. = three times a week; TMP-SMX = trimethoprim-sulfamethoxazole; sc = 

subcutaneous; and TST = tuberculin skin test.
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1Prophylaxis should also be considered for persons with a CD4+ percentage of <14%, for persons with a 

history of an AIDS-defining illness, and possibly for those with CD4+ counts >200 but <250 cells/μL. TMPSMX also reduces the frequency of toxoplasmosis and some bacterial infections. Patients receiving dapsone 

should be tested for glucose-6 phosphate dehydrogenase deficiency. A dosage of 50 mg q.d. is probably 

less effective than100 mg q.d. The efficacy of parenteral pentamidine (e.g., 4 mg/kg/month) is uncertain. 

Fansidar (sulfadoxine-pyrimethamine) is rarely used because of severe hypersensitivity reactions. Patients 

who are being administered therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected 

against Pneumocystis carinii pneumonia and do not need additional prophylaxis against PCP.

2Directly observed therapy is recommended for isoniazid, e.g., 900 mg b.i.w.; isoniazid regimens should 

include pyridoxine to prevent peripheral neuropathy. If rifampin or rifabutin are administered concurrently 

with protease inhibitors or non-nucleoside reverse transcriptase inhibitors, careful consideration should be 

given to potential pharmacokinetic interactions (54). See discussion of rifamycin interactions in paragraph 

11 in section on Tuberculosis. There have been reports of fatal and severe liver injury associated with the 

treatment of latent TB infection in HIV-uninfected persons treated with the 2 month regimen of daily 

rifampin and pyrazinamide; therefore it may be prudent to use regimens that do not contain pyrazinamide 

in HIV-infected persons whose completion of treatment can be assured (CDC. Update: Fatal and Severe 

Liver Injuries Associated with Rifampin and Pyrazinamide for Latent Tuberculosis Infection and Revisions in 

American Thoracic Society/CDC Recommendations, United States 2001 MMWR 50 (No. 34), Aug 31, 2001). 

Exposure to multidrug-resistant tuberculosis might require prophylaxis with two drugs; consult public health 

authorities. Possible regimens include pyrazinamide plus either ethambutol or a fluoroquinolone.

3Protection against toxoplasmosis is provided by TMP-SMX, dapsone plus pyrimethamine, and possibly by 

atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably 

provides little, if any, protection.

4See paragraph 9, in section on “Disseminated Infection with Mycobacterium avium complex” and 

references 53-54 for discussion of drug interactions. *During pregnancy, azithromycin is preferred over 

clarithromycin because of the teratogenicity in animals of clarithromycin.

5Vaccination may be offered to persons who have a CD4+ T-lymphocyte count <200 cells/μL, although 

the efficacy is likely to be diminished. Revaccination 5 years after the first dose or sooner if the initial 

immunization was given when the CD4+ count was <200 cells/μL and the CD4+ count has increased to 

>200 cells/μL on HAART is considered optional. Some authorities are concerned that immunizations might 

stimulate the replication of HIV. 

6Although data demonstrating clinical benefit of these vaccines in HIV-infected persons are not available, 

it is logical to assume that those patients who develop antibody responses will derive some protection. 

Some authorities are concerned that immunizations might stimulate HIV replication, although for influenza 

vaccination, a large observational study of HIV-infected persons in clinical care showed no adverse effect 

of this vaccine, including multiple doses, on patient survival (J. Ward, CDC, personal communication). Also, 

this concern may be less relevant in the setting of HAART. However, because of the theoretical concern that 

increases in HIV plasma RNA following vaccination during pregnancy might increase the risk of perinatal 

transmission of HIV, providers may wish to defer vaccination for such patients until after HAART is initiated.

7Hepatitis B vaccine has been recommended for all children and adolescents and for all adults with risk 

factors for hepatitis B virus (HBV). For persons requiring vaccination against both hepatitis A and hepatitis B, 

a combination vaccine is now available. For additional information regarding vaccination against hepatitis A 

and B, see CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States 

through universal childhood vaccination. Recommendations of the Advisory Committee on Immunization 

Practices (ACIP). MMWR 1991;40 (No RR13).

8Oseltamivir is appropriate during outbreaks of either influenza A or influenza B. Rimantadine or 

amantadine are appropriate during outbreaks of influenza A (although neither rimantadine nor amantadine 

is recommended during pregnancy). Dosage reduction for antiviral chemoprophylaxis against influenza 

might be indicated for decreased renal or hepatic function, and for persons with seizure disorders. 

Physicians should consult the drug package inserts and the annual CDC influenza guidelines for more 

specific information about adverse effects and dosage adjustments. For additional information about 

vaccination, antiviral chemoprophylaxis and therapy against influenza, see: CDC. Prevention and Control 

of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 

2001;50(No. RR-4).

9In a few unusual occupational or other circumstances, prophylaxis should be considered; consult a 

specialist.

10Acyclovir is not protective against CMV. Valacyclovir is not recommended because of an unexplained 

trend toward increased mortality observed in persons with AIDS who were being administered this drug for 

prevention of CMV disease.

Source: USPHS/IDSA, 2001. Available at http://www.aidsinfo.nih.gov.
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B. PRESENTATION AND MANAGEMENT OF THE MOST COMMON

COMPLICATIONS OF ADVANCED HIV DISEASE (AIDS)

Summaries are presented below. However, specific agents and dosing 

regimens for acute conditions and secondary opportunistic infection 

prophylaxis, respectively, can be found at http://www.aidsinfo.nih.gov, 

or in the 2003 Medical Management of HIV Infection by John Bartlett.

PNEUMOCYSTIS CARINII PNEUMONIA

The diagnosis of PCP can be challenging and requires a heightened 

index of suspicion. Although there are “classic” symptoms, findings on 

exam, and chest X-ray manifestations, the presentation of PCP can be 

subtle and nonspecific. The classic triad of fever, exertional dyspnea, and 

nonproductive cough occurs in only half of cases, although almost all have 

at least two of the following: fever, cough, dyspnea, lactate dehydrogenase 

greater than 460 U/L or an arterial partial pressure of oxygen (PaO2) less 

than 75 mm Hg. A careful history may reveal longstanding exertional 

dyspnea that has worsened incrementally over weeks to months. Physical 

exam findings are also nonspecific. Fine, dry “cellophane” rales may be 

heard or auscultation may be entirely normal. In 2–6% of patients, PCP 

may present as spontaneous pneumothorax. The classic X-ray findings 

are diffuse interstitial or perihilar infiltrates, but a wide range of X-ray 

abnormalities is possible and radiography is normal in over one third of 

cases. Extrapulmonary pneumocystosis is uncommon. PCP is suggested 

by oxygen desaturation with exercise, easily measured in the office or 

clinic with a pulse oximeter. This is particularly useful when symptoms 

are minimal, the patient does not appear acutely ill, and the chest X-ray is 

unimpressive. Severity of illness is indicated by hypoxemia or a widened 

alveolar to arterial oxygen difference (A-aDO2) on blood gas analysis.

Many diseases may have a similar presentation, including mycobacterial, 

fungal, viral, or bacterial pneumonias, heart failure, pulmonary KS, 

and pulmonary embolus. The definitive diagnostic test requires 

bronchoalveolar lavage of affected lung segments that is then 

concentrated and stained for P. carinii organisms. Experienced sites 

can make a histologic diagnosis from an induced sputum sample that 

is concentrated and stained, but this less invasive, cheaper diagnostic 

test should not be attempted where expertise in both obtaining and 

interpreting the smear is lacking.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the mainstay of treatment 

for PCP; intravenous or oral administration depends on the severity of 

the episode. There are a number of alternative regimens for patients who 

experience treatment-limiting toxicity or who fail to respond to TMP-SMX. 

PCP should be treated for 21 days. After completing acute therapy, the 

patient should begin routine daily PCP prophylaxis to prevent recurrence. 

Patients with PaO2 less than 70 mm Hg or with an A-aDO2 greater than 35 

on room air should receive adjunctive steroids, which have been shown 
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to decrease the incidence of ventilatory failure and death. A 21-day course 

of prednisone (40 mg twice daily for 5 days, then 20 mg twice daily for 5 

days, followed by 20 mg once daily for 11 days) is the most popular and 

cost-effective approach. No additional taper is required.

CANDIDIASIS

The appearance of mucosal candidiasis is often the first clinical indication 

of impaired T-cell immunity in HIV-infected individuals. Whereas oral 

and vaginal thrush are almost ubiquitous and Candida esophagitis is the 

second most common OI after PCP, candidemia and tissue-invasive disease 

are rare. Pharyngitis may be asymptomatic or may cause dysphagia. 

White plaques can be easily scraped from the pharynx or buccal mucosa; 

severe cases will involve the tongue, gums, and lips. Vaginitis causes a 

thick white discharge, pruritus, and sometimes dyspareunia, and has a 

similar appearance on speculum exam. Intense erythema may be the 

most prominent finding in some patients with either pharyngitis or 

vaginitis. Scrapings will be KOH-positive by microscopic exam and will 

grow readily in culture. These forms of candidiasis may be treated with 

topical or oral antifungals; topical agents are more cost-effective and 

avoid the risk of systemic side effects or drug interactions.

Candida esophagitis is a more serious infection that may result in 

significant weight loss because of odynophagia. Esophagitis should 

be considered when the patient describes midline substernal chest 

discomfort with swallowing instead of pain limited to the throat. It may 

occur in the absence of oropharyngeal thrush, and can be diagnosed 

by endoscopy or by barium swallow. Topical agents should not be used 

for esophagitis. Oral fluconazole, 200 mg once daily for 10 days, is the 

treatment of choice.

Prolonged usage of oral azoles such as fluconazole can result in resistant 

candidiasis, so it is important to avoid chronic use. Most experts try to 

use topical antifungals or intermittent courses of azole drugs whenever 

possible. Prophylaxis for vaginal candidiasis with topical antifungals 

should be considered when systemic antibiotics are given. Some patients 

with fluconazole-resistant esophagitis may respond to itraconazole, 

especially the cyclodextrin solution, oral voriconazole, or to oral 

amphotericin B solution. However, most patients with resistant infection 

will ultimately require intravenous (IV) amphotericin for relief.

CRYPTOCOCCAL MENINGITIS

Cryptococcal meningitis may present as nothing more than the worst 

headache of the patient’s life. Fever is common but meningismus may 

be minimal or absent. Altered mental status and elevated intracranial 

pressure above 180 mm of water portend a poorer prognosis. Therefore, it 

is important for patient management to obtain an opening pressure when 

performing the diagnostic lumbar puncture. Cranial nerve deficits and 
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seizures are only seen in patients who present very late in the course of 

their infection and are often antemortem events. The diagnosis is made by 

detection of cryptococcal capsular antigen in the cerebrospinal fluid (CSF); 

relying upon a positive India ink stain that demonstrates the organism’s 

thick capsule is too insensitive. Cryptococcus neoformans may also be 

cultured from blood and CSF. Computed tomography (CT) or magnetic 

resonance imaging (MRI) scans may reveal basilar inflammation, and in 

patients with intracranial hypertension, the ventricles may be enlarged. 

Very mild cases may be treated from the outset with oral fluconazole, 

400 mg once daily for 10 wk, followed by chronic suppressive therapy 

(200 mg once daily). Most experts prefer using intravenous amphotericin 

B at a dose of 0.7–1.0 mg/kg per day for the first 2 wk, with or without 

flucytosine, and then switching to fluconazole as described above if the 

patient is responding. Intracranial hypertension can be managed with 

frequent lumbar punctures to remove large volumes of CSF (20–30 mL at 

a time). Serum cryptococcal antigen may occasionally be positive before 

the onset of headache. It may also be detectable when extrameningeal 

infection occurs, and in the evaluation of a fever of unknown origin. In 

these situations, oral fluconazole is appropriate therapy.

TOXOPLASMOSIS

Toxoplasmosis manifests almost exclusively as an encephalitis in AIDS 

patients. The patient presents with a neurologic deficit, and classically 

one or more ring-enhancing space-occupying lesions can be seen on 

CT or MRI scan. However, the radiographic appearance of the lesions 

is not pathognomonic and may mimic other processes such as primary 

CNS lymphoma. Because serology may be negative and because it is 

often difficult to obtain a brain biopsy for a definitive diagnosis, the 

standard approach is a diagnostic trial of antitoxoplasma therapy with 

pyrimethamine and sulfadiazine for at least 2 wk. Both clinical and 

radiographic improvement should be evident in response to therapy 

if the patient has toxoplasmic encephalitis (TE). Clindamycin may be 

substituted for sulfidiazine if the latter is poorly tolerated. Although TE 

in AIDS patients results from reactivation of latent infection, a baseline 

negative IgG test for Toxoplasma gondii does not exclude the diagnosis, and 

seronegative patients will routinely receive a trial of therapy regardless 

of their serostatus. For this reason, and because PCP prophylaxis with 

TMP-SMX will also prevent TE, obtaining a Toxoplasma gondii IgG may 

not be very cost-effective. A situation where knowledge of Toxoplasma 

gondii serostatus is helpful is when a patient cannot tolerate TMP-SMX 

prophylaxis; in this case pyrimethamine should be added to second-line 

PCP prophylaxis with dapsone to provide protection from TE as well.

HERPES SIMPLEX VIRUS

HIV-infected individuals may have recurrent genital HSV that can be 

suppressed with oral antiviral drugs such as acyclovir, valacyclovir, and 

famciclovir. Both treatment and prophylaxis of HSV may require higher 
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doses and, in the case of treatment, longer administration than is required 

in the management of HIV-negative patients; this is particularly the case 

in women with more advanced immunosuppression (see Chapter VI on 

Gynecologic Problems). Definitive diagnosis is usually made by culturing 

HSV from the base of the lesion(s), although experienced clinicians will 

often rely on typical appearance, distribution, and symptoms. When 

patients develop severe mucocutaneous lesions or ulcers that persist 

for more than 4 wk, this unusually persistent form of HSV is considered 

an AIDS-defining illness. Similar to fluconazole-resistant candidiasis, 

injudicious chronic use of antiherpes drugs may result in drug-resistant 

infection, which then requires treatment with intravenous foscarnet. 

Varicella-zoster virus, a related member of the herpesvirus family, 

causes shingles, which responds to higher doses of antiherpes drugs 

than those needed for HSV. Shingles can be exquisitely painful and 

patients may have prolonged postherpetic neuralgia. Secondary bacterial 

infection may occur, so it is important to keep the lesions clean and to 

use topical or systemic antibiotics as needed. Control of pruritus and pain 

is essential for patient comfort. Drug-resistant varicella-zoster virus has 

been reported and is also treated with IV foscarnet.

CYTOMEGALOVIRUS

Cytomegalovirus (CMV) causes retinitis in 80–85% of AIDS patients 

with end-organ CMV disease. Gastrointestinal disease anywhere from 

the mouth to the anus is diagnosed in another 12–15%. Other diagnoses, 

such as encephalitis and pneumonitis, are uncommon (~1%). CMV 

retinitis can cause visual loss, and untreated, progresses inexorably 

to blindness. Because retinitis is a necrotizing process, with effective 

antiviral treatment the lesions become quiescent and atrophic, but the 

affected areas do not regain function. Retinitis near critical structures 

such as the macula or optic nerve may cause catastrophic visual loss 

even when the total infected area is small. Patients may be completely 

asymptomatic, or may complain of floaters (due to inflammatory debris), 

diminished acuity, or visual field defects when the lesion(s) is(are) in the 

periphery. Diagnosis is made by visual inspection of the entire retina by 

an experienced ophthalmologist using dilated indirect ophthalmoscopy. 

Extensive disease may lead to retinal detachment, which may require 

surgical repair. Treatment is usually begun with oral valganciclovir 

or with intravenous ganciclovir, foscarnet, or cidofovir for 2–3 wk, 

followed by chronic suppression with either less frequent IV doses 

or oral valganciclovir or ganciclovir. Chronic use of these intravenous 

agents requires the placement of an indwelling catheter for ease of 

administration, or IV therapy can be used briefly until an intraocular 

device can be inserted surgically that slowly releases small amounts 

of ganciclovir directly into the vitreous. Because CMV is a systemic 

infection with viremia, patients who receive the ganciclovir implant also 

need chronic suppressive therapy with oral valganciclovir to prevent the 

development of extraocular CMV disease. CMV can become resistant to 

antivirals. Refractory disease is often treated with intraocular injections, 
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which, like the ganciclovir implant, deliver high concentrations of drug 

to the site of active viral replication. End-organ disease at nonocular 

sites is treated with 2–3 wk of intravenous induction therapy; oral 

valganciclovir has not been studied for monocular disease but should be 

effective. There is no clear agreement that CMV disease at sites outside 

the eye requires chronic maintenance therapy, but with the availability 

of oral valganciclovir it seems reasonable to provide continued anti-CMV 

treatment in patients whose immune systems remain badly damaged 

(CD4 cells <100/mm3).

DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX (MAC)

Like CMV, disseminated MAC is one of the OIs that appears at end-stage 

disease, when the total CD4 cell count is extremely low. It presents 

nonspecifically with fever, weight loss, diarrhea, anemia, and sometimes 

abdominal discomfort due to organomegaly and impressive intraabdominal lymphadenopathy. Mycobacterial blood culture provides a 

definitive diagnosis; culture of sputum or other specimens is not helpful. 

Combination oral antimicrobial therapy is required and should include, at 

a minimum, an azalide (azithromycin or clarithromycin) and ethambutol, 

15–25 mg/kg per day. Other drugs, such as ciprofloxacin and amikacin, 

have been used but do not routinely provide much additional benefit; 

clofazimine has been shown to have an adverse effect on survival and 

should not be used.

TUBERCULOSIS

There is a bidirectional interaction between Mycobacterium tuberculosis 

and HIV; each facilitates acquisition of the other, so it is critical to assess 

all HIV-infected patients for active tuberculosis (TB), and to test all 

patients with active TB for HIV. Because TB is virulent enough to cause 

disease in patients with intact immune systems, it may occur in HIVinfected individuals who still have high CD4 cell counts. TB is especially 

virulent in HIV seropositive individuals. Aspects of this virulence include 

the high frequency of positive blood cultures and of disseminated 

(miliary) infection. However, standard combination antimicrobial therapy 

is effective as long as the patient is adherent and the acquired strain 

is not multidrug resistant. It is essential to provide directly observed 

therapy to ensure an adequate course of treatment and conversion of 

positive sputum cultures to negative. Until susceptibilities are known, 

all HIV-infected patients should be treated initially with at least four 

drugs expected to be active according to local susceptibility patterns; 

for susceptible TB, typically INH, rifampin or rifabutin, pyrazinamide 

and ethambutol or streptomycin are given for 2 months, followed by 

INH and rifampin or rifabutin for 4 months. Subsequently, when the 

results of susceptibility testing are available, therapy for drug-sensitive 

infection can usually be narrowed to two agents. Patients with advanced 

HIV disease or a delayed response to TB treatment (symptomatic and/
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or culture-positive after 2 months of treatment) should receive a total 

course of 9 months. Clinicians should work closely with their local health 

department to ensure that patients receive directly observed therapy, and 

to track and limit the spread of TB, especially resistant strains. All close 

contacts — especially young children — must be evaluated for TB so 

they may be treated promptly for active disease or given prophylaxis as 

indicated.

CRYPTOSPORIDIOSIS AND MICROSPORIDIOSIS

These enteric protozoa can cause debilitating diarrhea and weight loss in 

patients with advanced HIV disease. Diagnosis is made by special stool 

stains. Unfortunately there is no effective therapy (except for Septata 

intestinalis, which may respond to albendazole), so care is supportive. 

Every effort should be made to optimize the patient’s antiretroviral 

therapy because there are reported cases of clinical resolution (and even 

clearing of the organism from stool) with potent combination antiretroviral 

therapy. Patients may develop severe dehydration due to voluminous 

watery diarrhea. In addition to volume repletion, attempts at slowing 

the diarrhea should be made as follows by adding (not substituting) each 

additional agent in a stepwise manner: 1) diphenoxylate or loperamide, 

increased to their maximum dose, plus 2) tincture of opium or paregoric, 

with the dose titrated gradually until the desired effect is achieved, and, 

if additional control is needed, 3) parenteral somatostatin, which is very 

expensive.

PERIPHERAL NEUROPATHY

Distal, symmetrical polyneuropathy, typically affecting the feet more 

than the hands, may result from use of the neurotoxic dideoxy nucleoside 

analogues (didanosine, stavudine, zalcitabine) and much less commonly 

from dapsone, or may be a consequence of advanced HIV disease itself. 

Most patients present with paresthesias and/or numbness, but some 

experience pain that can be disabling. Examination reveals slow or absent 

ankle jerks, diminished vibratory and proprioceptive responses in both feet, 

and in patients whose primary complaint is pain, discomfort sometimes 

even with light touch. If drug toxicity is suspected, the offending agent(s) 

should be discontinued immediately and replaced. If this is accomplished 

quickly enough after the onset of symptoms, the syndrome may resolve 

entirely. When the nerve damage is not attributable to anti-HIV therapy 

or does not resolve after drug discontinuation, supportive care may be 

offered. Nonsteroidal antiinflammatory drugs; agents useful in chronic 

pain syndromes such as amitryptiline, phenytoin, or carbamazepine; the 

neurotransmitter inhibitor gabapentin; mexilitene, lamotrigine; and, in 

refractory cases, long-acting narcotics, all have a role in the management 

of dysesthesias and pain due to peripheral neuropathy.
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AIDS DEMENTIA COMPLEX (ADC)/HIV ENCEPHALOPATHY

In the pre-HAART era, frank dementia was the AIDS-defining illness 

in up to 10% of patients. The initial manifestations may be subtle, and 

can be uncovered by questioning the patient carefully about short-term 

memory loss and difficulty concentrating. Useful questions about the 

latter include the ability to balance a checkbook or to make change. In 

some patients, a depressed affect may be a prominent finding, and in 

others, unexplained seizures may bring the patient to medical attention. 

Psychomotor retardation — slowing of the impulses that match actions to 

thoughts and intentions — is another hallmark of AIDS dementia complex 

(ADC). CT and MRI scans show diffuse cortical loss with prominent 

sulci (“walnut sign”). A good sense of the patient’s level of intellectual 

functioning can often be obtained at the bedside. In subtle or difficult 

cases, especially when there is a prior history of depression or subnormal 

IQ, the patient can be referred for a battery of neuropsychologic tests 

that may clearly demonstrate the losses characteristic of ADC. There 

is no specific treatment for ADC other than effective antiretroviral 

therapy, although symptoms may respond in part to methylphenidate 

or selegiline. Patients may demonstrate a remarkable degree of recovery 

with antiretroviral therapy even when they present with advanced 

dementia, so it is valuable to attempt treatment of all patients, even those 

initially referred for nursing home care. It may be particularly useful to 

include agents that achieve good CSF levels.

WASTING SYNDROME (“SLIM DISEASE”)

Weight loss is common in HIV disease, especially in its advanced stages, but 

the CDC surveillance definition of wasting syndrome specifically refers 

to involuntary weight loss that exceeds 10% of the patient’s baseline 

weight in the presence of diarrhea (≥ 2 loose stools per day) or chronic 

weakness and documented fever (intermittent or constant) for at least 

30 days that is not attributable to a condition other than HIV itself. 

Typically wasting syndrome is accompanied by loss of muscle mass, for 

example in the temporal areas, and complaints of generalized fatigue 

and modest weakness. In severe cases the serum albumin level will be 

very low. Wasting can accompany any of the typical end-stage illnesses, 

such as disseminated MAC, or may occur by itself in the absence of 

any evident concomitant illness. Loss of weight, and, especially, of lean 

body mass, portends poorer survival. Appetite stimulants, such as the 

progestin megestrol acetate or the marijuana derivative dronabinol, 

may be used although weight gain with these agents typically consists 

of fat and water, rather than an increase in lean body mass. However, 

the psychologic benefit of an improved appetite and some weight gain 

cannot be underestimated, even if the gain is primarily fat. Recombinant 

human growth hormone has been used with some short-term success 

for improvement in lean body mass, but it is very expensive and must 
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be given parenterally. Other approaches include enteral and parenteral 

feedings, anabolic steroids such as nandrolone or oxandrolone, and 

thalidomide or pentoxifylline for cytokine suppression. Men with 

symptoms of hypogonadism often respond to testosterone replacement, 

but this approach has not been evaluated in women.

KAPOSI’S SARCOMA

Kaposi’s sarcoma (KS) is an endothelial cell tumor that, along with PCP, 

was the harbinger of the AIDS epidemic. It primarily affects gay and 

bisexual men, and is fairly uncommon among injecting drug users and 

women. It is caused by human herpesvirus-8. KS can occur at a range 

of total CD4 cell counts, but prognosis is poorer at lower values. Most 

commonly it is limited to mucocutaneous surfaces, where it is a cosmetic 

problem but not a significant threat to health. KS of the gastrointestinal 

mucosa is very vascular and may lead to slow, chronic blood loss. KS 

may also involve the lymphatic system, and may invade the viscera, 

especially lung parenchyma. Experienced clinicians can generally 

diagnose mucocutaneous KS by inspection, but a punch biopsy showing 

typical spindle-shaped cells is easy to obtain and is definitive. Visceral 

KS, which may occur in the absence of mucocutaneous disease, requires 

a tissue diagnosis.

Mucocutaneous KS may be treated with a number of local modalities 

including intralesional vincristine or vinblastine, radiation, and topical 

retinoids. Gastrointestinal lesions can be cauterized endoscopically. 

Visceral disease requires systemic chemotherapy. More recently, KS 

has regressed in patients begun on potent combination antiretroviral 

therapy alone.

SYSTEMIC LYMPHOMA

Several different types of lymphoma occur at increased frequency 

among HIV-infected individuals. These too may occur at any CD4 

cell count although once again prognosis is worse at lower absolute 

numbers of CD4 cells. HIV seropositive patients may develop Hodgkin’s 

disease, immunoblastic lymphoma, and Burkitt’s lymphoma as well as 

less common forms, but the most common type is an aggressive nonHodgkin’s B cell lymphoma. There is a marked tendency for extranodal 

presentations (Stage 1E), and AIDS patients have been described 

with non-Hodgkin’s lymphoma at a range of unusual sites. AIDSassociated lymphoma is diagnosed and staged in the same manner as in 

seronegative patients, and the same types of combination chemotherapy 

are used. However, HIV-infected patients typically require lower doses or 

aggressive support with granulocyte colony-stimulating factor because of 

their baseline bone marrow fragility.
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CENTRAL NERVOUS SYSTEM LYMPHOMA

Central nervous system lymphoma occurs at total CD4 cell counts 

well under 100 cells and is a typical end-stage complication. Definitive 

diagnosis is made by brain biopsy or CSF cytology in the presence of a 

space-occupying lesion(s) on CT or MRI scan. A presumptive diagnosis 

may sometimes be made by nuclear SPECT scan. Because brain 

biopsy may be difficult to obtain, patients who fail a trial of therapy 

for toxoplasmosis are often assumed to have CNS lymphoma. There is 

no effective cytotoxic chemotherapy for this disease, and irradiation is 

considered palliative. Survival after a diagnosis of CNS lymphoma is 

usually limited, on the order of a few months.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Progressive multifocal leukoencephalopathy is another end-stage 

complication of HIV disease, usually presenting as a focal neurologic 

deficit(s). It is caused by the JC virus, which can be detected by PCR 

performed on CSF. MRI scan of the brain demonstrates involvement of 

the white matter that can be focal or fairly diffuse, but is not usually 

associated with either mass effect or surrounding edema. Most commonly 

it affects areas adjacent to the cortex, but lesions can be located 

anywhere. Definitive diagnosis is made by brain biopsy or positive PCR, 

which is highly specific in the appropriate clinical context. Where these 

diagnostic modalities are unavailable, the typical MRI picture usually 

suffices. There is no specific proven therapy for this condition, although 

a number of case reports describe clinical remission in patients begun 

on potent combination antiretroviral therapy. In the pre-HAART era, 

survival was very limited, but now there are patients alive more than a 

few years after diagnosis.
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Figure 4-5: Guidelines for Use of Erythropoietin in the 

Anemic HIV Patient

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Source: John Bartlett, 2003. Reprinted with permission.
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CHRONIC HEPATITIS B AND C

Many of the same behaviors that put women at risk of acquiring HIV 

also result in hepatitis B and/or C infection. Up to 90% of HIV-infected 

individuals have evidence of prior exposure to hepatitis B (HBV) and up 

to 10% have chronic HBV infection (Homann, 1991; Bodsworth, 1991). 

Risk of developing chronic infection is increased in the presence of HIV 

co-infection (Bodsworth, 1991; Houssett,1992); limited data also suggest 

that HIV-HBV coinfection is associated with higher HBV DNA levels 

and worse prognosis in terms of liver-related morbiditiy and mortality 

(Thio, 2001; Colin,1999).Persistence of HbsAg for longer than 6 months is 

indicative of chronic infection; these patients should be tested for HbeAg 

and anti-Hbe and have periodic assessment (e.g., every 6 months) of 

transaminases, albumin, prothrombin time, bilirubin, complete blood 

count, and platelet count. Patients with chronic HBV infection are at 

increased risk of cirrhosis and end-stage liver disease and hepatocellular 

carcinoma. Periodic screening every 6–12 months with alfa fetoprotein 

(AFP) and/or liver ultrasound should be considered in patients with 

chronic HBV and other high risk characteristics (age >45 years, cirrhosis, 

family history of liver cancer). Indications for HBV treatment include: 

HbsAg positive > 6 months, evidence of active viral replication (HbeAg 

+ HBV DNA positive), and moderate or severe liver inflammation on 

biopsy. The goal of treatment is to prevent or delay the progression 

of liver disease; eradication of the virus is not possible with current 

therapies. Agents used to treat HBV include interferon, lamivudine (3TC), 

tenofovir, adefovir, and emtricitabine; 3TC, tenofovir, and emtricitabine 

should only be used as part of or in conjunction with a fully suppressive 

antiretroviral regimen.

A recent cross-sectional analysis of a large heterogeneous group of HIVinfected individuals found that 16% had HCV coinfection (Sherman, 

2002). Hepatitis C (HCV) becomes a chronic infection in about 85% of 

cases. Data from a recent meta-analysis indicate that HIV-HCV coinfected 

patients have a 2.9 times higher risk of progressive liver disease than 

those infected with HCV alone (Graham, 2001). There is some evidence 

that HCV may accelerate progression of HIV disease as well (Piroth, 

2000). Screening for HCV is recommended using a 2nd or 3rd generation 

HCV enzyme-linked immunosorbent assay with confirmation using HCV 

RNA testing. Hepatitis C viral loads do not correlate with severity of liver 

damage on biopsy. Serum transaminases should be monitored, especially 

ALT, which is more specific for hepatocellular injury. ALT levels may 

wax and wane, and may be normal or only modestly elevated. Screening 

for hepatocellular carcinoma with AFP and/or liver ultrasound should be 

considered, particularly in patients with cirrhosis. Indications for HCV 

treatment include: detectable HCV RNA, persistently elevated ALT levels, 

and liver biopsy with portal or bridging fibrosis and at least moderate 

inflammation and necrosis. The goals of treatment include eradication 

of HCV infection and prevention or delay of progressive liver disease. 

Recommended treatment for chronic HCV is pegylated interferon plus 

ribavirin; preliminary data suggest that HCV virologic response correlates 

with CD4 cell count in HIV-HCV coinfected patients (Soriano, 1996).
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Patients with either HBV or HCV infection should avoid alcohol 

consumption, which may increase risk of progressive liver disease. 

Transplantation of coinfected patients with end–stage liver disease has 

been successful and is being evaluated further.

ANEMIA

Modest anemia (≥ 9–10 g/dL) is a hallmark of chronic HIV infection and 

may be complicated by menstrual losses in women of childbearing age. 

Severe anemia (≤ 9 g/dL) may occur as part of certain opportunistic 

diseases, especially MAC, disseminated histoplasmosis, and lymphoma, 

and may also be the result of drug toxicity. Although severe anemia has 

been shown to be associated with a poorer prognosis for survival in a 

number of studies, diagnosis and treatment of the opportunistic process 

is often sufficient to improve anemia in these cases.

Patients who are symptomatic with exertional dyspnea and dizziness 

can be transfused acutely. Most HIV-infected patients become anemic 

gradually, and unconsciously limit their activities to control symptoms. 

These individuals can be managed with changes of antiretroviral or OI 

therapies known to be toxic to red blood cells, such as AZT (zidovudine) 

and TMP-SMX. In patients refractory to conservative management, 

red blood cell production can be stimulated by using recombinant 

erythropoietin along with sufficient iron replacement to stimulate 

production of new red cells (see Figure 4-5).

C. OPPORTUNISTIC DISEASE IN THE HAART ERA

The impact of highly active antiretroviral therapy on the natural history 

of opportunistic diseases has been profound, and the clinician must be 

familiar with at least the broad outline of these changes. There may be 

sufficient immune restoration that even patients with end-stage disease 

become capable of mounting an inflammatory response to opportunistic 

pathogens. This can result in worsening of the clinical manifestations of 

an OI that has been under treatment or atypical presentation of a new 

acute OI, generally within the first couple of months after initiating potent 

anitretroviral therapy, after CD4 cell counts have begun to improve. For 

example, in the case of MAC lymphadenitis, there may be the acute 

focal development of a tender, enlarged lymph node with negative blood 

cultures, whereas in the pre-HAART era the typical presentation would 

have been diffuse, with widespread nontender adenopathy and highgrade mycobacteremia. This seemingly paradoxical development of an 

OI with rising CD4 cell counts is likely due to an inflammatory response 

to an OI that was subclinical when HAART was begun. Similarly, immune 

reconstitution syndromes have been described for TB, PCP, toxoplasmosis, 

cryptococcal infection, and PML, when these infections have been under 

treatment. Management includes continuation of antiretroviral therapy 

while making sure there has been no recrudescence of the underlying 

OI, plus addition of NSAIDs or corticosteroids to alleviate the 

inflammatory reaction.
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Patients who recover pathogen-specific immunity in addition to the 

overall increase in CD4 cells may be able to discontinue chronic 

suppressive (maintenance) therapy, because the patient’s immune 

system is now capable of containing the infection. Thus far this has 

been best demonstrated for discontinuing chronic suppression for 

CMV retinitis. Similar phenomena have been described for other OIs, 

such as disseminated MAC, and there is no reason to think that other 

OIs will behave differently. Last, patients with previously untreatable 

opportunistic processes, such as PML or cryptosporidiosis, have had 

clinical remissions after initiating HAART.

A number of studies have shown that patients receiving primary 

prophylaxis for PCP and MAC are at very low risk of developing these 

OIs if prophylaxis is withdrawn after total CD4 cell counts have improved 

above the threshold levels for risk of each specific OI for at least 3–6 

mo. Most of these studies have been performed among patients with 

reasonably well controlled HIV viral loads, with the majority undetectable 

or at most, less than 10,000 copies. At this point, it is clear that specific 

prophylaxis can be safely stopped for any OI when CD4 cell counts have 

increased above the threshold of risk ≥ 3 months. The 2002 revision of 

the USPHS guidelines on OI prophylaxis describes the data and rationale 

for discontinuing suppressive therapy and prophylaxis in the appropriate 

patient. These guidelines are revised periodically just as the ones for 

treatment and HIV are, so it is wise to check www.aidsinfo.nih.gov.

VI. ALGORITHMS FOR DIAGNOSIS AND MANAGEMENT 

OF SYMPTOMS

Figure 4-6: Fever of Unknown Origin in Patients with AIDS

Figure 4-7: Acute Diarrhea in Patients with AIDS

Figure 4-8: Chronic Diarrhea (CD4 Count <300/mm3)

Figure 4-9: Cough, Fever, Dyspnea

Figure 4-10: Headache in Patients with AIDS

Figure 4-11: Advanced HIV Infection Plus Altered Status, New Seizures, 

Headache (Severe or Persistent), or Focal Neurologic 

Deficits

Figure 4-12: Sensory Neuropathies in Patients with AIDS

Figure 4-13: Odynophagia in Patients with AIDS
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Figure 4-6: Fever of Unknown Origin in Patients with AIDS

IV line or neutropenia (<500/mm3)

1. Consult appropriate algorithm • Headache, neuro sx - Neurologic algorithm • Cough, dypsnea - Pulmonary algorithm • Diarrhea - Diarrhea algorithm2. Other focal findings • Nasal sx - Evaluate for sinsusitis • IV line - Blood cultures antibiotics ± line removal with roll culture • Soft tissue inflammation-Aspirate/bx for  culture, CT scan • Adenopathy - Lymph node bx/aspirate • Abdominal pain - LFTs, amylase, CT scan

 Drugs Likely to Cause FeverCommon Less Common

SulfonamidesDapsoneAmphotericin BPhenytoinPenicillinsBarbituratesBleomycinCarbemazepineThalidomidePentamidineClindamycin

SalicylatesCephalosporins

INHRifampinStreptomycinPASCocaine productsAzathioprine

Localizing Findings

 Next Round of Tests• Evaluate for TB - culture sputum, urine• CT scan abdomen, chest ± head• Histoplasmosis - Antigen assay blood  and urine• Lumbar puncture - CSF analysis• Evaluate sinusitis and dental source• Lymphoma - Node bx, LDH, liver/  marrow bx• Biopsy liver (rarely pos with normal LFTs)• Gallium scan, indium WBC scan -  rarely useful• Biopsy marrow - yield lower than liver bx

Empiric antibiotics

Responds and/or blood culture pos treat

No response andcultures negative

Screening tests positive

Drug Holiday

Responds to D/C agent No response

M. aviumbacterium(most commoncause FUO)-treat

Crypt Agpositive LP 

and treat

Abnormalchest x-ray or hypoxemia

pulmonaryalgorithm

Cytopenia bone marrowaspirate/bx

Yes No

No Yes

Yes No

LFTs abnormalCholestasis changes: Ultrasound or CT ERCP or bxGranulomas: M. avium, TB, histoplasmosis

Cholangiopathy - CMV, cryptosporidia,  microsporidia, lymphoma KS idiopathic (30%)Hepatocellular: Hepatitis viruses, ETOH, 

 drug-induced, CMV

 No Drug Cause: Initial Evaluation

• CBC, differential, CD4 count• Chemistry panel, LDH• Urine culture and analysis• Blood culture• PPD and anergy screen• CD4 count <300/mm3 - mycobacterial  blood culture and serum  cryptococcal antigen• Chest x-ray ± blood gases/oximetry

Review meds and confirm fever

Source: Bartlett, 2001. Reprinted with permission.
154 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Figure 4-7: Acute Diarrhea in Patients with AIDS

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Source: Bartlett, 2001. Reprinted with permission.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 155

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IV

Figure 4-8: Chronic Diarrhea (CD4 Count < 300/mm3)

Continued on next page

Fever; bloodculture - bacteriaand mycobacteria

Review medications

No likelydrugs

Discontinue possible agents �

�������������toxin assay if

symptoms severe plus antibiotic

Afebrile or negativeblood culture No response Response

Response

Symptomsmodest: treatempirically*

No response or progression

1. Stool analysis: O & P x 1-2, modified AFB x 1-2, bacterial 

 culture x 1-2 �������������toxin assay x 1-2 stool microsporidia assay2. Fecal WBC exam3. Fever: blood culture - bacteria, ��������

Microsporidia Bacterial culture

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IsosporaCyclosporia��������������Giardia

Cryptosporidium ������������ �������

Treatempirically albendazole Antimicrobial

treatment

Metronidazoleoral vancomycinor observe

Treat

Antimicrobialtreatment

Treatempirically*� paromomycin

Metronidazole

Symptoms persist �

elimination of ���������� Symptoms persist or progress but pathogen eradicated

Negative stool studies ����������������������
156 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Figure 4-8: Chronic Diarrhea (CD4 Count < 300/mm3) (continued)

1. Endoscopy; Decision regarding initial procedure (upper vs lower) is based on clinical and laboratory findings2. Hydrogen breath test3. Stool microsporidia assay

Watery diarrhea, no cramps,no fecal WBC or blood

Cramps, fever, fecal WBC, or blood

Colonoscopy1. Histopath; H&E, Giemsa2. Stain for CMV; culture not indicated

No diagnosis

Upper endoscopy1. Routine histopathology; H&E, Giesma2. Small bowel aspirate for quantitative culture (if available)3. EM for microsporidia if studies for alternative agents negative4. Stain for CMV; culture not indicated No diagnosis

* Frequent small feedings, bland foods, avoid caffeine; low-lactose, low-fat, high-fiber diet. Supplement with polymeric formulas and antiperistaltic agents (loperamide or Lomotil progressing to 

tincture of opium octreotide) as necessary. 

Source: Bartlett, 2001. Reprinted with permission.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 157

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IV

Figure 4-9: Cough, Fever, Dyspnea

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158 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Figure 4-9: Cough, Fever, Dyspnea (continued)

Blood culture; sputumgram stain, culture �Quellung, LegionellaDFA and culture

Sputum stains: AFB,KOH, Gram and culturesfor bacteria, AFB, Nocardia,fungi; cytology

Effusion Focal infiltrate

Acute Chronic Sputum AFB x3 Thoracentesis: pleural fluid pH,

cell count, protein, gram stainand bacterial culture; AFB stainand culture, cytology �evaluation of associated parenchymal lesion

Diagnosis:Treat

No diagnosis(exudative effusion):pleural biopsy x3

Diagnosis:Treat

No diagnosis:Empiric treatment with 2nd/3rd generationcephalosporin, TMP-SMX, or betalactam -

betalactamase inhibitor or betalactam plus

macrolide

Nodular infiltrates orcavitary diseaseInjection drug use

Blood culture fortricuspid valveendocarditis

Neg. Pos.

Treat

Pos. Neg.

Treat Response: Treat until

afebrile x 5days

No response: Bronchoscopy

AFB smear pos: Treat for TB pending cultureNocardia or pathogenic fungus: TreatBacterial pathogen: Clinical correlationNo diagnosis: Bronchoscopy � transbronchial 

 biopsy

No Yes

Evaluation based onappearance of parenchymal lesion by x-ray or CT scan

Source: Bartlett, 2003. Reprinted with permission.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 159

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IV

Figure 4-10: Headache in Patients with AIDS

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Source: Bartlett, 2001. Reprinted with permission.
160 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Figure 4-11: Advanced HIV Infection Plus Altered Status, New 

Seizures, Headache (Severe or Persistent), or 

Focal Neurologic Deficits

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Source: Adapted from Bartlett, 2001. Reprinted with permission.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 161

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IV

Figure 4-12: Sensory Neuropathies in Patients with AIDS 

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Source: Bartlett, 2003. Reprinted with permission.
162 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

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Figure 4-13: Odynophagia in Patients with AIDS 

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Source: Bartlett, 2003. Reprinted with permission.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 163

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IV

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Raboud J, Montaner J, Conway B, et al. Suppression of plasma viral load 

below 20 copies/ml is required to achieve a long term response to therapy. AIDS. 1998;12:1619–1624. 

Rich JD, Merriman NA, Mylonakis SE, Greenough T, Flanigan T, Mady B, 

Carpenter CCJ. Misdiagnosis of HIV infection by HIV-1 plasma viral 

load testing: a case series. Ann Intern Med. 1999;130:37–39. 

Romeu J, Sirera G, Rego MJ et al. Cumulative risk for developing hyperlipidemia in HIV-infected patients treated with protease inhibitors. 39th 

Interscience Conference on Antimicrobial Agents and Chemotherapy; 

Sept 26–29, 1999; San Francisco, CA. Abstract 1293.

Scribner AN, Troia-Cancio PV, Cox BA, et al. Osteonecrosis in HIV: a casecontrol study. J Acquir Immune Defic Syndr Hum Retrovirol. 2000;25:

19–25. 

Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence 

among patients infected with human immunodeficiency virus: a crosssectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect 

Dis. 2002;34:831–837. 

Soriano V, Garcia-Samaniego J, Bravo R et al. Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodificiency virus. Hepatitis-HIV Spanish Study Group. Clin Infect Dis.

1996;23:585–591. 

Tebas P, Powderly WG, Claxton S et al. Accelerated bone mineral loss in HIVinfected patients receiving potent antiretroviral therapy. AIDS. 2000;14:

F63–67. 

Thiebaut R, Daucourt V, Mercie P et al. Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine 

Cohort, France, 1999. Group d’Epidemiologie Clinique du Syndrome 

d’Immunodeficience Acquise en Aquitaine. Clin Infect Dis. 2000;31:

1482–1487. 

Thio CL, Seaberg E, Skolasky RL, Kingsley LA, Phair J, Visscher B et al. HIV 

infection increases liver-related mortality in HBV-infected individuals. 

Hepatology. 2001;34:469. 
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Primary Medical Care

USPHS/ISDA. Guidelines for the prevention of opportunistic infections 

in persons infected with human immunodeficiency virus. 

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Accessed March 21, 2004.

Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B. HIV-1 genotypic resistance patients predict response 

to saquinavir–ritonavir therapy in patients in whom previous protease 

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U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 167

V

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I. INTRODUCTION

Adherence to HIV therapies is critical if patients are to achieve and 

maintain undetectable viral loads and avoid preventable opportunistic 

infections. Initial clinical trials of highly active antiretroviral therapy 

(HAART) demonstrated that 80–90% of patients receiving protease 

inhibitor therapy could achieve viral loads <400 copies/mL (Gulick, 

1997). However, currently in real-world clinical practice only 50% 

of patients achieve this goal (Lucas, 1999). The primary reason is 

nonadherence with therapy. Adherence with medications in any chronic 

disease is a challenge for most patients. As a general rule, only 50% of 

patients with chronic illnesses maintain “good adherence” (taking >80% 

of medication doses) over time. Patients with HIV infection have similar 

rates of adherence. Unfortunately in this infection, “good adherence” is 

not good enough, and the consequences of nonadherence are severe. 

Nonadherence with antiretroviral therapy is strongly associated with 

HIV disease progression and mortality (Hoggs, 2002).

This chapter addresses the important issues regarding adherence 

with HIV medications. Beyond this specific issue, there are other 

aspects of adherence with medical care, including adherence with 

recommendations for laboratory monitoring for toxicity and clinical 

response and adherence with appointment keeping, that are also critical 

factors in successful HIV treatment.

II. THE UNFORGIVING NATURE OF HIV AND THE 

MEDICATIONS TO TREAT IT

Adherence with medications is critical in HIV infections for several 

reasons involving both the nature of the virus and the drugs to combat 

it. First, the virus has a very high replication and mutation rate. If drug 

doses are intermittently missed, the virus quickly begins to replicate. 

In the presence of low levels of drug, viral mutations that confer drug 

resistance will thrive. Second, the most potent drugs, both protease 

inhibitors and nonnucleoside reverse transcriptase inhibitors, have 

broad class resistance. That is, when resistance to one drug in the class 

occurs, often resistance has developed to many other drugs in that class. 

Thus, nonadherence to one regimen can result in virus resistant to many 

antiretrovirals.

Finally, a patient needs to have near-perfect adherence, as shown in 

Figure 5-1, to achieve the undetectable viral load necessary to prevent the 

development of resistant virus (Paterson, 2000). For most chronic diseases, 

80% adherence is considered “good adherence.” However, only 49% of 

patients achieved undetectable viral load with this level of adherence.

V. ADHERENCE TO HIV THERAPIES

Laura W. Cheever, MD
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Figure 5-1: Adherence Rates Predict Viral Load Responses Viral Load <400 (% Patients)

Adherence with Protease Inhibitor Therapy

<70 70-79 80-89 90-94

0

20

40

60

80

100

>95

18

29 33

45

78

Adherence with Protease Inhibitor Therapy

Source: Adapted from Paterson, 2000. Modified with permission from American College of Physicians. 

Thus, in HIV infection, patients must have exceptionally high levels 

of adherence to therapy to prevent the emergence of resistant virus. 

Additionally, unlike other chronic diseases, such as hypertension, if HIVinfected patients are nonadherent, even for a few weeks, they may severely 

limit their future treatment options because of broad class resistance.

III. PREDICTORS OF ADHERENCE

Adherence is a complex behavior. In analyzing predictors of adherence, 

it is important to consider factors related to the patient, the treatment 

regimen, the doctor-patient relationship, and the system of medical care. 

Several patient-related factors are consistently predictive of adherence 

or nonadherence among HIV-infected individuals. Depression and active 

substance abuse (including alcohol, cocaine, or heroin) correlate with 

nonadherence, whereas the patient’s belief that they can both make HIV 

medication regimens fit into their life and be adherent with the regimen 

is predictive of adherence (Table 5-1, Cheever, 1999). In addition, one of 

the best predictors of adherence is adherence with previous therapy. 

In most chronic diseases, demographic characteristics, such as sex, race, 

income, education, and age, are not predictive of adherence (Haynes, 

1979). However, in the initial studies of these factors of HIV-infected 

patients, the data are inconclusive. In the HIV Cost and Services Utilization 

Study, a national probability sample survey, the investigators found that 

women, African Americans, Hispanics, younger adults, and patients with 

higher CD4 counts reported lower rates of adherence (Wenger, 1999). 

Other studies report conflicting results, and the relationship between 

these demographic variables and adherence needs further exploration.
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Table 5-1: Patient Factors Associated with Adherence

Strongly Associated

• Lack of depression

• Lack of active alcohol/substance abuse

• Self-efficacy (belief in one’s ability to take medication as instructed)

• Belief medications can be fit into their day

• Understanding the relationship of viral resistance and adherence

• Previous adherence

Inconsistently Associated

• Sex (males more adherent than females)

• Race (whites more adherent than blacks)

• Age (older patients more adherent than younger patients)

• Stage of disease (patients with lower CD4 counts more adherent than patients 

with higher CD4 counts)

Not Generally Associated

• Education, income, employment

• HIV risk factor

• Belief that medications will improve health 

In terms of the treatment regimen, side effects are a major cause of 

nonadherence (Heath, 2002). Adherence decreases as the number of 

doses per day, pills, or medications increase. Likewise, medications 

with food restrictions are harder to take as directed. Length of time on 

therapy also impacts medication adherence. Adherence tends to wane 

over time, which is a compelling reason to delay therapy until the risk of 

progression to AIDS is significant. Pharmacy and social work counseling 

of patients whenever HAART is initiated or the regimen is changed can 

be helpful in ensuring that patients understand dosing and side effects 

and can assist in developing strategies to avoid missing doses.

The doctor-patient relationship is also an important variable in adherence 

and should not be overlooked. Several studies have shown that patients 

who trust their doctor are more likely to adhere to therapy, including 

studies among HIV-infected patients (Altice, 2001). Most medical 

providers believe that they can predict which patient will be able to adhere 

to a medical regimen. However, studies have repeatedly shown that 

physicians, nurse practitioners, and nurses cannot predict with reliability 

which patients will adhere to therapy (Paterson, 2000). Table 5-2 lists the 

most common reason patients say they miss their medication (Chesney, 

1997; Eldred, 1998). These reasons vary significantly from the reasons that 

providers cite as reasons their patients miss doses (Gallant, 1998).
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Table 5-2: Reasons Patients Cite for Missing Medication

• Did not have medication at the time of the dose

• Simply “forgot” to take it

• Asleep at time of dose

• Too busy at the time

• Off usual daily schedule/routine

• Ran out of medication

• Using drugs/alcohol

• Pills too difficult to take (too many, too big, schedule too complicated)

• Didn’t want to be reminded of HIV/AIDS

• Didn’t want to take pills in front of others

The system of care can affect adherence to a medication regimen. 

Situations that facilitate patients’ access to medication, in terms of refill 

requests, reminders to refill medication, and mechanisms to obtain 

medications when gaps in medication insurance occur, can significantly 

affect a patient’s ability to adhere. Similarly, systems that help patients 

overcome barriers to seeking medical care, including problems with 

transportation, childcare, and paying for services, also assist in the 

patient’s adherence efforts. Finally, patient education is a critical part of 

improving adherence. Within the system of care, personnel and resources 

need to be dedicated to this important endeavor.

IV. ADHERENCE IN SPECIAL POPULATIONS

A. INCARCERATED PATIENTS

Incarcerated patients have unique challenges to medication adherence. 

Medical regulations vary significantly among correctional systems, and 

these regulations influence patients’ medication adherence. Correctional 

institutions may provide directly observed therapy of each dose of 

medication, which may result in excellent medication adherence. On 

the other hand, lockdowns and other security concerns supercede 

medical concerns and may result in missed doses. In correctional 

systems where HIV-infected inmates are identified and called by name 

to receive medications, many patients forego treatment rather than risk 

disclosure of their HIV infection. Additionally, the incarceration process 

itself provides many opportunities for potential disruption in access to 

medications. Most patients do not immediately access their antiretroviral 

medication on entry to the system or at times of transfer within the 

system. When patients are discharged from the penal system, they are 

provided with a limited supply of medication; often patients run out of 

medication before they can establish medical care in their communities, 

resulting in nonadherence with their regimen.
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B. HOMELESS PATIENTS

It is often assumed that homeless patients face insurmountable barriers 

to adherence with medications. Certainly, homelessness itself creates 

many challenges to adherence. Additionally, many homeless patients 

have mental illness or substance abuse that may further contribute to 

nonadherence. However, homeless patients can be successful in taking 

HAART. In a study of homeless and marginally housed patients from San 

Francisco, 38% of the 32 homeless patients taking protease inhibitors had 

high levels of adherence (Bangsberg, 2000). However, the group appears 

to be highly selected since only 34 of 153 patients in this marginally 

housed cohort were prescribed HAART.

C. CHILDREN AND ADOLESCENTS

Young children are dependent on the adults around them for their 

medication adherence. As with many HIV-infected adults, HIV-infected 

children may be in tenuous social situations due to poverty and unstable 

housing, in addition to illness among their parents. Many children are 

unable or unwilling to swallow unpalatable medication or pills, making 

dosing administration take hours each day. In one study, gastric tubes were 

placed in children who had extreme problems with taking medication. 

These children subsequently showed improvement in adherence, viral 

load, time necessary to administer doses, and interpersonal relationships 

with the persons administering the medication (Shingadia, 2000). 

Adolescents who have not disclosed their HIV status may miss doses 

because of lack of a private place to take their medication. Furthermore, 

adolescence is a time of testing limits and feelings of invulnerability, both 

of which may contribute to the likelihood of nonadherence.

V. MEASURING ADHERENCE

There are many methods to measure adherence including electronic devices, 

pill counts, and drug assays. However, in clinical practice, the most 

efficient method to measure adherence is simply to ask the patient 

(Icovicks, 1997). It is critical to ask over time as patients’ adherence will 

vary, for example, in response to re-initiation of substance abuse. 

When asked in a nonjudgmental way, most patients (80% in several 

studies) are truthful about their medication taking (Sackett, 1976). To 

get the most reliable information, patients should be given permission to 

have missed doses, asked in a nonjudgmental way, and given a specific 

time frame. For example, “Everyone misses doses some of the time. In the last 

2 weeks, how many doses have you missed?” 

Computer assisted self-interviewing (CASI) technology is increasingly 

used to assess adherence and improves the reliability of patient self 

report (Turner, 1998, Bangsberg, 2002). The technology is also used 

to simultaneously collect information on side effects and high risk 

behaviors that might be missed in a less structured format of a patientclinician interaction.
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Pharmacy records can also give important information regarding adherence 

when available to the clinical staff. Serum drug level tests are now commercially 

available. These are most useful when patients professing adherence are not 

responding well to therapy; however, low drug levels may also be due to poor 

absorption or drug-drug interactions as well as to nonadherence.

VI. IMPROVING ADHERENCE

Given the importance of adherence in HIV infection and the relatively low 

rates of adherence in any chronic disease, it is of utmost importance to support 

efforts to increase patient adherence. Many interventions have been shown 

to increase adherence with pill taking in chronic disease. However, most 

interventions only have a modest effect on adherence. Those that work best 

are multifaceted (working on more than one aspect of the pill taking behavior) 

and repetitive (having the intervention reapplied over time) (McDonald 

2002, Roter, 1998). With antiretroviral medication, it is critical to start the 

intervention before nonadherence, and viral resistance, have occurred.

In initiating a successful regimen, the most important thing to consider 

is whether the patient is ready to start antiretroviral therapy. The 

patient is usually the best judge of when to start therapy as long as she 

is well informed regarding the rigors of antiretroviral therapy and the 

consequences of nonadherence. Thus, the bulk of patient education efforts 

should be made before initiation of therapy. Given that the patient’s “first 

shot [of antiretrovirals] is the best shot,” most patients benefit in the long 

run by delaying therapy if they are not ready to start. The urgency of 

therapy increases as the CD4 count falls and the viral load increases. Many 

physicians feel pressured by practice guidelines for starting therapy. The 

best time to start therapy is when the patient is ready.

There are, however, a few “antiretroviral emergencies,” pregnancy being one 

of them. Clearly, for the pregnant woman, the cost benefit considerations 

are different, as outlined in Chapter VII on HIV and Reproduction. In the 

case of pregnant women, the time permitted for the patient to prepare to 

start therapy may be considerably compressed. Thus, even more intensive 

educational efforts are needed in this population.

Patient education is clearly important, with high returns on the investment 

made before starting therapy. Group education generally works better than 

one-on-one education, probably because of the support and practical peer 

advice that is shared (Roter, 1998). Many patients resist groups, but many 

find them beneficial if they can be convinced to go. Specific interventions 

to improve adherence are outlined in Table 5-3.

Many intervention trials in HIV infection are on-going or completed. The 

Health Resources and Services Administration funded the evaluation of 14 

U.S. based adherence programs. For antiretroviral naïve patients, programs 

that included readiness training, that is spending time with the patient before 

the initiation of therapy to prepare them to start, were most effective. For 

both naïve and experienced patients, programs that included peer support, 

whether in one-on-one or group sessions, were also highly effective. 
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Table 5-3: Interventions to Improve Adherence

Intervention Comments 

The Patient

Start when the patient is 

ready

• For pregnant women, the cost-benefit analysis of treatment is 

different.

Treat substance abuse and 

depression before initiating 

antiviral therapy

• If there is no antiretroviral emergency, patients with active substance 

abuse and depression should have these comorbidities addressed 

before initiation of antiretrovirals.

Engage the patient in 

medication tailoring

• Discuss with the patient in detail how the medications will fit into 

their daily routine, i.e., when (and if) meals are eaten, what the 

patient does on a daily basis that can be linked to dosing times.

Educate (group/individual) 

regarding:

 • The regimen

 • Side effects management

 • Consequences of 

nonadherence 

• Patient education is essential—both group and one-on-one 

education. 

• Involve caretakers and patient support network in educational efforts.

• Patients need to know exactly how to take their medication. A daily 

calendar with pills on it will help a patient to visualize the regimen.

• Before initiating therapy, patients should know which side effects to 

expect, what they can to do to manage them, and when to call the 

medical practice.

• Patients need to understand the serious consequences of nonadherence 

and what to do in the event of a late or missed dose.

Increase support • Patients should enlist the aid of family and friends to promote their 

adherence. The HIV health care team can provide support through 

office visits, home visits, and telephone calls, especially in the first 

days and weeks of antiretroviral therapy.

Use skill-building exercises 

as part of readiness training

• Have the patient use a trial of jellybeans in a pill box to accustom 

themselves to their pill-taking schedule before initiating therapy. 

Address barriers to 

adherence

• Have the patient consider when medications are likely to be missed 

and make plans to decrease these events.

• Some patients store a few doses in places where they spend a lot of 

time, such as at the houses of friends and relatives.

Use reminders • Alarm clocks, in the form of watch alarms or pill boxes, can decrease 

missed doses due to simply forgetting.

• Patients can place medications in locations they will notice them at 

dosing times, such on the breakfast table. 

Simplify as much as possible • Once or twice daily regimens are easiest for patients.

• Use as few pills and medications as possible.

• Try to use regimens that can be taken without regard to food intake.

Anticipate potential 

medications side effects

• Discuss potential side effects, their likely duration and ways to prevent 

or manage them.

The Regimen

Tailor the regimen to the 

patient’s lifestyle (and not 

the patient’s lifestyle to the 

regimen).

• Ask the patient about her daily routine, comfort in taking medications 

in front of others and at work.

• Construct a regimen that works for the patient.

Use pill boxes • Use of pill boxes allows the patient to carry her daily medication.

• Pill boxes allow for patients to easily recognize when they have 

missed a dose.

Make refills accessible • Develop policies to allow patients ready access to refills.
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Table 5-3: Interventions to Improve Adherence (continued)

The Doctor-patient Relationship

Develop a trusting 

relationship

• Rarely is initiation of antiretrovirals required at the first visit. Invest in 

the doctor-patient relationship before initiating therapy. 

Ask about adherence • Medical providers cannot predict adherence; you must ask the 

patient.

• Ask in a nonjudgmental way, with a specific time frame, to get good 

information.

• Give permission for missed doses before asking.

• Ask repetitively over time.

Use positive reinforcement • Share viral load and CD4 results and reinforce the relationship to 

adherence.

Listen to the patient • Individualize therapy based on patient preferences regarding fear of 

specific side effects or specific medication. Negotiate the regimen 

with the patient.

The System of Care

Maintain close follow-up at 

initiation

• Have telephone, office, or home contact with patient within first few 

days of therapy to assess for side of regimen effects and accurate 

understanding of regimen. 

Develop patient education 

program

• Consider use of nurses, case managers, pharmacists, and peers in 

patient education.

• Have written materials accessible. 

Incorporate the adherence 

message throughout the 

medical practice

• All staff members need to understand and promote the importance of 

adherence.

• Have pill boxes, alarms, and other adherence aids available to 

patients.

Source: Adapted from Cheever, 1999.

VII. CONCLUSION

Adherence with medications is critical in HIV infection. Whenever 

medications are prescribed, special emphasis must be placed on patient 

readiness and adherence. Many types of interventions can improve 

adherence, and it is vital that these are employed to give patients the 

best chance at an optimal response to HIV therapies.

REFERENCES

Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and 

adherence to antiretroviral therapy. J Acquir Immune Defic Syndr.

2001;28:47–58.

Bangsberg DR, Bronstone A, Hofmann R. A computer-based assessment 

detects regimen misunderstandings and nonadherence for patients on 

HIV antiretroviral therapy. AIDS Care. 2002;14:3–15.

Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease 

inhibitors, HIV-1 viral load, and development of drug resistance in an 

indigent population. AIDS. 2000;14:357–366.

Cheever LW, Wu AW. Medication adherence among HIV infected patients: 

understanding the complex behavior of taking this complex therapy. 

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Chesney MA. New antiretroviral therapies: adherence challenges and strategies. Abstracts of the 37th Interscience Conference on Antimicrobial 

Agents and Chemotherapy, Toronto, Canada. Evolving HIV Treatments: 

Advances and the Challenge of Adherence Symposium, 1997.

Eldred LJ, Wu AW, Chaisson RE, et al. Adherence to antiretroviral and pneumocystis prophylaxis in HIV disease. J Acquir Immune Defic Syndr Hum 

Retrovirol. 1998;18:117–125.

Gallant JE, Block DS. Adherence to antiretroviral regimens in HIV-infected 

patients: results of a survey among physicians and patients. J Int Assoc 

Physicians AIDS Care. 1998;4:32–35.

Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus 

infection and prior antiretroviral therapy. N Engl J Med. 1997;337:

734–739.

Haynes RB. Determinants of compliance: the disease and the mechanics of 

treatment. In: Haynes RB, Sackett DL, eds Compliance in Health Care. 

Baltimore: Johns Hopkins University Press; 1979:49–62.

Heath KV, Dinger J, O’Shaughnessy MV, Montaner JS, Hogg RS. Intentional 

nonadherence due to adverse symptoms associated with antiretroviral 

therapy. J Acquir Immune Defic Syndr. 2002;31:211–217.

Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of triple-combination 

therapy is predictive of mortality at baseline and after 1 year of followup. AIDS. 2002;16:1051–1059.

Icovicks J. Behavioral measures. Adherence to New HIV Therapies: a 

Research Conference. Washington, DC, NIH Office of AIDS Research, 

15–18, 1997.

Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in 

a large urban clinic: risk factors for virologic failure and adverse drug 

reactions Ann Intern Med. 1999;131:81–87.

McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA. 2002;288:

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Paterson DL, Swindels S, Mohr J, et al. Adherence to protease inhibitor 

therapy and outcomes in patients with HIV infection. Ann Intern Med. 

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Roter DL, Hall JA, Merisca R, et al. Effectiveness of interventions to improve 

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Sackett DL, Haynes RB, Gibson ES, et al. Randomized clinical trial of strategies for improving medication compliance in primary hypertension. 

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Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for 

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pediatric patients with human immunodeficiency virus. Pediatrics. 

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Turner CF, KU L, Rogers SM, Lindberg LD, Pleck JH, Sonenstein FL. Adolescent sexual behavior, drug use, and violence: increased reporting with 

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VI

A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

I. INTRODUCTION

Gynecologic problems are common among HIV-positive women and are 

frequently present at the time of initial presentation for evaluation and 

care. Minkoff et al. found that 46.9% of 262 HIV-infected women had a 

least one incident gynecologic condition with serial assessment (Minkoff, 

1999). In a study of women admitted to an inpatient AIDS service, 

although only 9% were admitted with a primary gynecologic problem, 

83% had coexisting gynecologic disease when evaluated (Frankel, 

1997). Some gynecologic issues are unrelated to the patients’ serologic 

status, whereas others are directly related to HIV disease and associated 

immunosuppression. Still others are associated epidemiologically 

with HIV because of common risk factors, such as sexual behavior or 

substance abuse.

In 2002, women accounted for 26% of the adult AIDS cases and 32% of the 

adult cases of HIV infection reported in the United States (CDC, 2002). 

Moreover, women have had the greatest increase in AIDS incidence in 

recent years when compared with other US population groups. With this 

background and the fact that HIV infection primarily affects women 

during their reproductive years, gynecologic and reproductive health 

care will play an increasingly important role in the overall care of 

the HIV-infected woman. With improved longevity and quality of life, 

gynecologic problems may be encountered more commonly or may be 

more prominent. With these issues in mind, the goal of this chapter 

is to use a problem-oriented approach in reviewing the most common 

gynecologic complaints together with their differential diagnosis, 

evaluation, management, and relationship to HIV.

II. ABNORMAL UTERINE BLEEDING/AMENORRHEA

A. WHAT IS CONSIDERED “ABNORMAL” BLEEDING?

A normal menstrual period should occur every 21 to 35 days and last 

between 2 and 6 days. The average blood loss during menses is 20 to 60 

mL, but up to 14% of healthy women have blood loss greater than 80 mL 

and are more likely to be anemic because of this (Mishell, 1997a).

Amenorrhea represents a sort of abnormal bleeding in that it is the 

lack of menstruation. Primary amenorrhea is defined as the absence of 

menses by age 16. Secondary amenorrhea is the absence of menses for a 

variable period of time, for at least 3 mo and usually 6 mo or longer, in a 

woman who has previously menstruated.

VI. GYNECOLOGIC PROBLEMS

Silvia Abularach, MD, MPH and Jean Anderson, MD
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B. RELATIONSHIP TO HIV DISEASE

Menstrual disorders are frequently reported by HIV-positive women. 

However, controlled studies have yielded conflicting evidence regarding 

whether HIV or HIV-related immunosuppression exerts a clinically 

significant direct effect on these reported disturbances (Chirgwin, 1996; 

Ellerbrock, 1996; Shah, 1994) and more definitive studies are needed. A 

recent large study of HIV-positive and high-risk HIV-negative women from 

the HERS and WIHS prospective cohorts found that HIV serostatus has 

little overall effect on amenorrhea or menstrual cycle length or variability. 

However, higher viral loads and lower CD4 counts were associated with 

increased cycle variability and polymenorrhea. (Harlow, 2000). Clark et al, 

using measurement of serum progesterone and follicle-stimulating hormone 

(FSH) levels, found higher than expected occurrence of anovulation and 

premature menopause in a small study of women 20-42 years old who 

participated in selected ACTG protocols.(Clark, 2001). Although numbers 

were too small to reach statistical significance, these menstrual disorders 

were more common among women with lower CD4 cell counts. 

In the setting of HIV infection, menstrual disorders may be related to 

confounding variables, such as weight loss, chronic disease, substance abuse, 

or use of psychotherapeutic medications (Harlow, 2003) and progestational 

agents used for appetite stimulation or contraception. The impact of 

antiretroviral therapy on menstruation has not been well studied but 

hypermenorrhea, or excessive menstrual blood loss, has been reported 

with ritonavir (Nielsen, 1999). The effect of HIV-RNA levels on menstrual 

function is unknown.

C. HISTORY

• Characteristics of bleeding: date of last normal menstrual period, 

duration and frequency of menses, amount of bleeding (number 

of pads/tampons used per day); presence of clots or associated 

pain/cramping; duration and pattern of menstrual irregularities or 

amenorrhea; presence of intermenstrual or postcoital bleeding.

• Other bleeding sources: gastrointestinal (GI) or bleeding from 

the urinary tract (vs. from a gynecologic source); history of easy 

bruising, nose or gum bleeds.

• History of gynecologic problems/other symptoms: abnormal 

Pap smears; uterine fibroids or polyps; prior ectopic pregnancy; 

abnormal vaginal discharge.

• Medical history: timing of diagnosis of HIV/AIDS and existing 

comorbid conditions; clinical symptoms of HIV; CD4 count and 

viral load; history of platelet disorders (thrombocytopenia is 

frequently diagnosed in HIV infection, particularly in individuals 

with more advanced stages of disease (Sloand, 1992); medications; 

history of substance abuse.

• Sexual history: last sexual intercourse and use of contraception 

and condoms.
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D. PHYSICAL EXAM

A careful and comprehensive abdominal and pelvic examination should 

be performed. The presence of abdominal tenderness or mass should 

be noted. The external genitalia, vagina, and cervix should be inspected 

for evidence of actively bleeding lesions (e.g., lacerations, condylomata, 

polyps) or inflammation. Bimanual and rectovaginal examinations assess 

the presence of pelvic tenderness, enlarged uterus, or other pelvic mass.

E. DIFFERENTIAL DIAGNOSIS

• Pregnancy. Pregnancy must be considered in any woman 

of reproductive age with irregular bleeding or amenorrhea. 

Pregnancy may be either intrauterine or ectopic (usually tubal); 

bleeding with an intrauterine pregnancy may indicate threatened 

or incomplete abortion or miscarriage or a serious obstetric 

complication in later pregnancy.

• Anovulation. Anovulation is the most common cause of abnormal 

uterine bleeding among reproductive-aged women. Typically, the 

woman has a history of menstrual irregularity and may go several 

months with no bleeding, followed by the onset of prolonged and 

heavy bleeding. Anovulatory bleeding is a diagnosis of exclusion, 

and organic, systemic, and iatrogenic causes of bleeding must 

be ruled out. Anovulation and oligoovulation are more common 

among perimenopausal women and adolescents soon after 

menarche.

• Perimenopause. In addition to anovulation/oligoovulation, women 

in perimenopause may have irregular menses because of declining 

estrogen levels.

• Uterine fibroids. Fibroids are common benign uterine tumors 

that are most often asymptomatic, but may cause heavy and/or 

prolonged periods.

• Cancer. Malignant processes in every part of the female genital 

tract (vulva, vagina, cervix, uterus, fallopian tubes, and ovaries) 

can potentially present with abnormal bleeding; most common in 

postmenopausal women.

• Genital tract infections. Cervicitis, endometritis, and even 

vaginitis and vulvitis may present with abnormal vaginal bleeding 

or spotting. Associated symptoms, including pain/tenderness, 

discharge, fever, and other signs and symptoms of infection, will 

aid in making the diagnosis. In very immunosuppressed patients, 

consider opportunistic processes, including tuberculous or 

cytomegalovirus (CMV) endometritis.

• Medical conditions. Thyroid disorders (hypothyroidism or 

hyperthyroidism), coagulopathy (including platelet disorders), 

cirrhosis, chronic illness/wasting.
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• Substance abuse. Drug use (including methadone) can lead to 

disturbances of the hypothalamic-pituitary axis, with resulting 

irregular bleeding or amenorrhea.

• Medications. Progestational agents, such as those used 

for contraception (e.g., Depo-Provera, Norplant) or for appetite 

stimulation (e.g., Megace) frequently cause irregular vaginal 

bleeding. Consider antiretroviral agents as a potential cause 

of abnormal bleeding. Medications that can affect prolactin 

concentrations and possibly result in amenorrhea include 

psychotropic drugs (tricyclic antidepressants, phenothiazines, 

opiates) and metoclopramide. Thalidomide has been also 

been associated with development of secondary amenorrhea 

(Frances, 2002).

F. EVALUATION

The basic evaluation includes the following:

• Pregnancy test (urine or serum): perform on all women with 

abnormal bleeding/amenorrhea within reproductive age range

• Laboratory tests:

- Complete blood count (CBC), platelet count

- Thyroid-stimulating hormone, prolactin levels — consider with 

any irregular bleeding/amenorrhea without apparent cause

- Follicle-stimulating hormone (FSH), estradiol — with 

oligomenorrhea/amenorrhea and/or signs/symptoms of 

decreased estrogen production (hot flashes, vaginal atrophic 

changes). These tests are particularly helpful in distinguishing 

ovarian failure (low estradiol, high FSH) and hypothalamic 

amenorrhea (e.g., with wasting) (low estradiol, low/normal FSH)

- Coagulation profile — if evidence of systemic bleeding, to rule 

out coagulopathy

• Cervical testing: for gonorrhea and chlamydia

• Pelvic ultrasound: with abnormal exam (uterine enlargement, 

adnexal mass, significant tenderness) or positive pregnancy test; 

ultrasound using the transvaginal approach is used commonly 

in the evaluation of abnormal bleeding to assess endometrial 

thickness, especially in peri- and postmenopausal women, or to 

look for other possible abnormalities (e.g., polyps, fibroids)

• Endometrial biopsy: indicated with postmenopausal bleeding, 

prolonged amenorrhea followed by onset of irregular or heavy 

bleeding, persistently irregular bleeding. Used liberally with 

any form of abnormal bleeding if no cause is found otherwise 

and bleeding does not respond to conservative (e.g., progestins, 

oral contraceptives) management. It is helpful in diagnosing 

endometritis, endometrial hyperplasia, and uterine cancer; 

endometrial tissue necessary to diagnose CMV or tuberculosis (TB) 

endometritis—alert your pathologist if these are considerations
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• Pap smear: do not perform with active bleeding; if cervical lesion 

seen, biopsy is required.

Further evaluation or referral is indicated based on results of these tests, 

severity of the problem, and response to basic management.

G. MANAGEMENT

Management depends on the diagnosis and results of testing. All women 

with a positive pregnancy test require referral to a specialist. If anovulatory 

bleeding is suspected, medical management may be attempted with 

oral contraceptive pills or cyclic progestins (medroxyprogesterone 

acetate 10 mg po qd for 10–14 days each month). These therapies help 

restore regular menstruation, reduce possible anemia, and protect the 

endometrium from prolonged estrogenic stimulation, which can cause 

hyperplasia or neoplasia. Oral contraceptive pills will also provide 

effective contraception, but are contraindicated in heavy smokers over 

the age of 35, with hypertension or other cardiovascular disease, and in 

diabetics and women with markedly abnormal liver function.

With severe bleeding and anemia, pelvic mass, findings suspicious for 

malignancy, or bleeding that is not resolved with conservative measures, 

referral is indicated.

III. ABNORMAL PAP SMEAR

In the setting of HIV infection 30–60% of Pap smears exhibit cytologic 

abnormalities and 15–40% have evidence of dysplasia; these rates are 

10–11 times greater than those observed among HIV-negative women 

(Maiman, 1998).

A. INTERRELATIONSHIP OF HIV AND HUMAN PAPILLOMAVIRUS

• Human papillomavirus (HPV) infection plays a causative role 

in lower genital intraepithelial and invasive neoplasia. The 

spectrum of HPV disease includes subclinical disease, classic 

genital warts and other HPV-related skin lesions, lower genital 

tract intraepithelial neoplasia, and invasive cancers of the lower 

genital tract. There are over 100 HPV subtypes, which are divided 

into low, intermediate, or high risk, based on oncogenic potential; 

nevertheless, these categories are not exclusive and “low-risk” HPV 

types have been described in cervical carcinomas.

• HPV is an extremely common infection; current evidence suggests 

that over 50% of sexually active adults have been infected with one 

or more genital HPV types, but most HPV infections are transient 

(Evander, 1995; Ho, 1998). Studies have shown that HIV-infected 

women have higher prevalence of HPV, higher incidence of HPV 

(Branca, 2003; Ahdieh, 2001), higher HPV viral load (Jamieson, 

2002), longer persistence of HPV (Ahdieh, 2000; Sun, 1997), higher 

likelihood of multiple HPV subtypes (Jamieson, 2002), and greater 
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prevalence of oncogenic subtypes (Minkoff, 1998; Uberti-Foppa, 

1998) than HIV-uninfected women. HPV viral load is independently 

associated with HPV persistence (Ahdieh, 2001).

• In HIV-positive women the prevalence and persistence of HPV 

infection increases with decreasing CD4 count and increasing HIV 

RNA levels (Palefsky, 1999) and some studies show that oncogenic 

HPV types may be more common with lower CD4 counts and/or 

higher viral loads. (Luque, 1999; Minkoff, 1998). Higher HPV viral 

loads are also associated with lower CD4 counts (Heard, 2000).

• Sun et al. (Sun, 1995) have suggested that the presence of 

immunosuppression shifts the ratio of latent:clinically expressed 

HPV infections from 8:1 in the general population to 3:1 in HIVpositive women with CD4 >500/mm3 to 1:1 in HIV-positive 

women with CD4 <200/mm3.

B. HIV AND CERVICAL DYSPLASIA

• Abnormal cervical cytology is more common among HIV-infected 

women and is associated with the presence of HPV infection 

and the degree of immunosuppression. Both frequency and 

severity of abnormal Pap smears and histologically documented 

dysplasia increase with declining CD4 counts and have also 

been associated with higher HIV-RNA levels (Garzetti, 1995; 

Shah, 1996; Davis, 2001). Incidence of abnormal Pap smears is 

increased in HIV-infected as compared to -uninfected women, and 

is associated with lower CD4 counts; progression and regression 

of Pap smear abnormalities have been associated with level 

of immunesuppression and plasma viremia, as reflected in 

CD4 count and HIV viral load (Massad, 2001; Schuman, 2003). 

Increased HPV viral load, seen in women with more advanced 

HIV, is also associated with increased frequency, severity, and 

incidence of cervical dysplasia (Heard, 2000; Weissenborn 2003; 

Cohn, 2001).

• In HIV-positive women dysplasia is associated with more extensive 

cervical involvement and is more likely to involve other sites in 

the lower genital tract, such as the vagina, vulva, and perianal 

region (Hillemanns, 1996; Korn, 1995; Maiman, 1990; Petry, 1996; 

Williams, 1994) as compared with HIV-negative women.

• Recent studies have shown increased incidence of oncogenic HPV 

types (Minkoff, 1998) and increased incidence of biopsy-proven 

cervical dysplasia (Ellerbrock, 2000) in HIV-positive women compared 

with HIV-negative controls. A French study found an increased 

likelihood of progression of cervical abnormalities in HIV-positive 

women, although analysis was based on Pap smear results only (Six, 

1998). A recent study also found an association between progression 

of abnormal Pap smears and high plasma HIV RNA levels (>100,000 

c/mL) (Sewell, 2000). Presently there is little evidence for increased 

rates of progression to invasive cancer, particularly if adequate 

screening and treatment programs are in place.
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C. HIV AND ANAL HPV/DYSPLASIA

• Anal HPV-DNA has been reported in up to 76% of HIV+ women 

and, when concurrent anal and cervical HPV data were available, 

anal HPV was more prevalent in both HIV-infected and highrisk HIV-uninfected women (Palefsky, 2001a). Anal HPV is more 

common with lower CD4 counts and with presence of cervical HPV. 

Multiple HPV types and oncogenic types are common (Lacey, 1999).

• Abnormal anal cytology or anal squamous intraepithelial lesions 

(ASIL) are reported in up to 26% of HIV-infected women; risk 

factors include lower CD4 count, increased HIV viral load, 

high HPV viral load, history of receptive anal intercourse, and 

concurrent abnormal cervical cytology (Holly, 2001; Kiviat, 1993).

• Sensitivity of anal Pap smears appears to be similar to cervical 

cytology, although grade of anal dysplasia may not correlate well 

with histology (Palefsky, 1997)

• Risk for invasive anal cancer is increased in patients with HIV/

AIDS (Grulich, 2000). 

D. INVASIVE CERVICAL CANCER IN HIV DISEASE

• In 1993, the CDC expanded the case definition of AIDS to include 

invasive cervical cancer.

• Oncogenic HPV types play a central role in the relationship 

between HIV and cervical cancer. Recent African data found that 

without high-risk HPV present, the risk ratio for cervical cancer 

between HIV-positive and HIV-negative women was approximately 

1 (Hawes, 2003).

• Although there is little evidence that HIV infection is having a 

large effect on cervical cancer rates, linking of US AIDS and cancer 

registries has found that observed cervical cancer cases in HIVinfected women are up to 9-fold higher than the expected number 

of cases ; however, the likelihood of cervical cancer was not related 

to CD4 count (Mbulaiteye, 2003). In an analysis of women in the 

HER study, the rate of invasive cervical cancer was 1.20/1000 

person-years in HIV-infected women as compared to 0/1000 personyears in high-risk HIV-negative women (Phelps, 2001). 

Mean CD4 cell count was 443 cells/mm3 at time of diagnosis of 

cervical cancer in women with HIV. Women with HIV and cervical 

cancer tend to be younger and less immunosuppressed compared 

with HIV-positive women with other AIDS-indicator conditions. 

Women with HIV and cervical cancer tend to be younger than 

HIV-negative women with cervical cancer (Lomalisa, 2000). A 

prospective cohort study from Italy found that the incidence 

of invasive cervical cancer as a first AIDS-defining condition 

continued to increase after the introduction of HAART, possibly 

due to the decrease seen in incidence of other AIDS-defining 

diseases after HAART (Dorrucci, 2001).
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• HIV-positive women with invasive cervical cancer appear to 

present at more advanced stages (especially with CD4 < 200/

mm3), may metastasize to unusual locations (e.g., psoas muscle, 

clitoris, meningeal involvement), have poorer responses to standard 

therapy, and have higher recurrences and death rates, as well 

as shorter intervals to recurrence or death, compared with HIVnegative women of similar stage (Klevens, 1996; Maiman, 1990).

E. SCREENING TESTS

• A single Pap smear is associated with false-negative rates of 

10–25%; accuracy is significantly improved with regular periodic 

screening. Controlled studies have not demonstrated a decrease 

in sensitivity or specificity with standard cervical cytology in HIVpositive women compared with HIV-negative controls (Adachi, 

1993; Spinillo, 1998).However, a prospective cohort study found 

that HIV-infected women were significantly more likely to have 

abnormal biopsy results with normal Pap smears as compared with 

high-risk HIV-uninfected women; predictors of discordant histology 

and cytology included presence of HPV by PCR and CD4 count 

<500/mm3. In this study 17 of 19 women with discordant results 

had abnormal Paps within one year of these results, using current 

guidelines for Pap smear screening (Anderson 2002). 

• Newer Pap smear screening techniques using liquid-based media 

appear to increase sensitivity, decrease inadequate smears, and 

reduce, but not eliminate, false-negative results; they also offer 

the possibility of direct HPV testing on collected specimens. 

They are more expensive than conventional Pap tests. A recent 

review of over 400 HIV-infected women who underwent both 

conventional and liquid-based cytologic screening found a 

significant decrease in the proportion of smears diagnosed as 

ASCUS/AGUS as well as the ASCUS/SIL ratio, with liquid-based 

preparations (Swierczynski, 2002).

• HPV testing can identify both oncogenic and nononcogenic 

viral types; HPV testing for cancer-associated types can play an 

important role in the evaluation of women with atypical squamous 

cells on Pap smear (Solomon, 2001).

• The role of HPV DNA testing as an alternative or addition to the 

Pap smear in HIV-positive women is unknown. One analysis 

suggested that adding HPV testing to standard Pap smear screening 

may be a cost-effective strategy if this allows modification of 

screening intervals (Goldie, 2001). A recent German study 

examining HPV DNA testing as a primary screening method for 

cervical dysplasia in 94 HIV-positive women found that HPV DNA 

testing identified high-grade cervical dysplasia more accurately 

than Pap smear (Petry, 1999).

• Pap smear results are reported according to the Bethesda System 

(Solomon, 2002) (Table 6-1).
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Table 6-1: Pap Smear Report for Bethesda System

Specimen 

adequacy

• Satisfactory for evaluation (note presence/absence of 

endocervical transformation zone component)

• Unsatisfactory for evaluation (specify reason)

General 

categorization

• Negative for intraepithelial lesion or malignancy

• Epithelial cell abnormality

• Other

Interpretation/result

• Negative for intraepithelial lesion or malignancy

- infections

- reactive changes (inflammation, radiation)

- atrophy

• Epithelial cell abnormalities

- atypical squamous cells (ASC)

- of undetermined significance (ASC-US)

- cannot exclude HSIL (ASC-H)

- low-grade squamous intraepithelial lesion, including HPV 

changes and mild dysplasia CIN1

- high-grade squamous intraepithelial lesion, including 

moderate and severe dysplasia, CIN2, CIN3

- squamous cell carcinoma

- glandular cell abnormalities

• Other

- endometrial cells in a woman ≥ 40 years of age

CIN, cervical intraepithelial neoplasia.

F. RECOMMENDATIONS FOR PAP SMEAR SCREENING AND COLPOSCOPY

• HIV-infected women should have a complete gynecologic 

evaluation, including a Pap smear and pelvic exam, as part of 

their initial evaluation (US Public Health Service (USPHS)/

Infectious Diseases Society of America (IDSA) 2001 accessed at 

http://www.aidsinfo.nih.gov).

• A Pap smear should be obtained twice in the first year after 

diagnosis of HIV infection. If these results are normal, annual 

examinations are then indicated.

• More frequent Pap smears should be considered:

- with previous abnormal Pap smear

- with HPV infection

- after treatment for cervical dysplasia

- in women with symptomatic HIV infection (including CD4 

counts <200/mm3)

• The American College of Obstetricians and Gynecologists 

recommends Pap smears every 3–4 mo for the first year after 

treatment of preinvasive cervical lesions, followed by Pap smears 

every 6 mo (ACOG, 1993). Vaginal Pap smears should be obtained 

after hysterectomy for persistent or recurrent cervical dysplasia.
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• Women receiving gynecologic and primary HIV care at the same 

location are more likely to have had Pap smear screening within 

the previous year (Stein, 2001).

• The role of anal cytology remains unclear and recommendations 

for routine anal Pap smear screening are not currently part of 

standard guidelines. However, the approach suggested by experts 

in this field is similar to recommendations for cervical Pap smear 

screening:

- perform anal Pap as part of initial evaluation and, if normal, 

repeat in 6 months

- if these results are normal, repeat annually

- more frequent anal Pap smears should be considered:

 with CD4<500/mm3

 presence of cervical dysplasia

 with previous abnormal anal Pap smear

 after treatment for anal dysplasia

- anal Pap smears with ASCUS or SIL should be evaluated with 

anoscopy and biopsy

• Anal Pap smears are performed by inserting a moistened Dacron 

swab 1–1.5 inches into the anal canal and rotating as it is slowly 

withdrawn over 15–20 seconds, maintaining contact with the 

mucosa; both rectal columnar and anal squamous cells must be 

obtained to have an adequate specimen. The swab should then be 

vigorously shaken in liquid–based cytology media.

• Indications for colposcopy are outlined in Table 6-2.

Table 6-2: Indications for Colposcopy

• Cytologic abnormality (atypia or greater, including ASC, AGC)

• History of untreated abnormal Pap smear 

• Consider periodic colposcopy after treatment of cervical dysplasia

• Consider with evidence of HPV infection

• Consider screening colposcopy with CD4 <200/mm3

 ASC, atypical squamous cells; 

AGC, atypical glandular cells.

• ASC (atypical squamous cells) represents the mildest cytologic 

abnormality in the Bethesda system; however, in the general 

population 5–17% of women with ASC have underlying CIN2-3 

and approximately 0.1% have invasive cancer (Solomon, 2001). 

The 2001 Bethesda system stratifies ASC into two categories: 

atypical squamous cells of undetermined significance (ASC US) 

and atypical squamous cells-cannot exclude HSIL (ASC-H), with 24-

92% of women with ASC-H having CIN2-3 confirmed with biopsy 

(Wright,2002). In a study of women with ASCUS, Wright (Wright, 

1996) found that HIV-positive women were approximately twice as 
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likely to have underlying dysplasia compared with HIV-negative 

women; a recent cross-sectional analysis of 761 Pap smears from 

HIV-positive women found that 27% were diagnosed as ASCUS; 

15% had underlying high-grade dysplasia (Holcomb, 1999a). 

Immunosuppression did not appear to increase the frequency 

of dysplasia associated with ASCUS on Pap smear. Incidence 

of ASCUS is increased in HIV-infected women (Massad, 2001). 

Referral for colposcopy is recommended for all HIV-infected 

women with ASC, irrespective of CD4 cell count, HIV viral load, or 

antiretroviral therapy (Wright, 2002).

Table 6-3: Suggested Frequency of Pap smears

Clinical Scenario Screening Frequency

Normal Pap 1 yr

Symptomatic infection / CD4 <200 6 mo

ASC/LSIL (evaluated and followed 

without treatment)

4–6 mo

Following treatment of preinvasive 

lesions

3–4 mo for first year, then 6 mo lesions

 ASCUS, atypical squamous cells of undetermined significance;

LSIL, low-grade squamous intraepithelial lesion.

• The risk of underlying pathology with a diagnosis of atypical 

glandular cells (AGC) is significant. The 2001 Bethesda system 

stratifies AGC into 3 categories: atypical glandular cells, either 

endocervical, endometrial, or “not otherwise specified” (NOS); 

atypical glandular cells, favor neoplastic; and endocervical 

adenocarcinoma-in-situ (AIS). Overall, various studies have found 

that 9–54% of women with AGC have CIN on biopsy, 0–8% have 

AIS on biopsy, and up to 9% have invasive cancer (Wright, 2002). 

The risk of a significant abnormality increases with the severity 

of the AGC reading. Colposcopy is indicated with any AGC on 

Pap, as well as endocervical sampling. Endometrial sampling is 

indicated with presence of atypical endometrial cells or AGC-NOS, 

in women older than 35 years, and in younger women with AGC 

who have unexplained vaginal bleeding (Wright, 2002). Because of 

the significant risk of invasive disease with AGC, favor neoplasia 

or endocervical AIS, women with these results should undergo 

diagnostic cervical conization if initial evaluation is negative for 

invasive cancer (Wright, 2002).

• Biopsies should be obtained at the time of colposcopy to confirm 

cytologic abnormalities and/or if abnormal areas are visualized.

• Because of the multicentric nature of lower genital tract 

intraepithelial neoplasia in the setting of immunosuppression, it 

is recommended that the entire lower genital tract (vagina, vulva, 

and perianal region) be examined at the time of colposcopy.
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G. MANAGEMENT OF CERVICAL AND OTHER LOWER GENITAL TRACT LESIONS

Management of abnormal Pap smears is outlined in Table 6-4. Documentation 

of a high-grade cervical lesion requires treatment. Standard excisional or 

ablative treatment is recommended, although HIV-positive women have an 

increased incidence of recurrence after treatment (over 50% recurrence 

rate), correlated with degree of immunosuppression (Fruchter, 1996; 

Holcomb, 1999b). Cryotherapy has had the highest rate of recurrences and 

should be avoided, if other treatment methods are available. Hysterectomy 

as treatment for recurrent or persistent cervical dysplasia has also been 

associated with significant recurrence rates in the vagina (Tate, 2002). 

Recurrences have been associated with detectable HIV RNA in plasma 

and higher mean HIV RNA levels (Keller, 2002) and may also be related 

to positive surgical margins with excisional treatment, which appear to 

be more common in HIV-positive women compared with HIV-negative 

women (Boardman, 1999). Abstinence should be emphasized until 

complete healing has occurred after treatment for cervical dysplasia, 

since the treatment has been shown to dramatically increase genital 

tract HIV shedding (Wright, 2001) and may increase risk of sexual 

transmission of HIV.

Table 6-4: Recommended Management for Abnormal Pap Smears*

Pap Smear Result Management

Unsatisfactory Repeat Pap smear

Partially obscuring 

 - inflammation

Evaluate for infection; consider repeat Pap

Epithelial cell abnormality

- atypical glandular cells - colposcopy, endocervical sampling; 

endometrial sampling if > 35 yrs. or with 

abnormal bleeding; cervical conization if 

initial evaluation negative and cytology 

favors neoplasia

- atypical squamous cells (ASCUS 

and ASC-H)

- colposcopy, biopsy if indicated; endocervical 

sampling if unsatisfactory colposcopy; follow 

with Pap every 6 months, consider repeat 

colposcopy annually if Pap unchanged

- low-grade squamous 

intraepithelial lesion (LSIL, CIN1)

- colposcopy, biopsy if indicated; endocervical 

sampling if unsatisfactory colposcopy; follow 

with Pap every 6 months, consider repeat 

colposcopy annually if Pap unchanged

- high-grade squamous 

intraepithelial lesion (HSIL, CIN2-

3, carcinoma-in-situ)

- colposcopy, biopsy, endocervical sampling; 

treat with loop excision or conization

- invasive carcinoma - colposcopy with biopsy or conization; treat 

confirmed invasive disease with surgery or 

radiation (referral to gynecologic oncologist 

needed)

*Management should be based on histologic findings when biopsy is performed.
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Topical vaginal 5-fluorouracil (5-FU) cream (2 g biweekly for 6 mo) was 

shown to reduce recurrence rates after standard treatment for high-grade 

cervical dysplasia in HIV-positive women in a recent clinical trial; over 

18 mo of follow-up, 31% of women who were only observed developed 

a recurrent high-grade lesion compared with 8% of women receiving 

5-FU. Disease recurred more slowly in women who had received 

antiretroviral therapy, compared with those who were antiretroviralnaïve (Maiman, 1999).

5-FU may play a role in secondary prophylaxis of preinvasive cervical 

lesions in some cases. However, clinical experience with this therapy 

is too limited to provide a recommendation for routine use. 5-FU may 

have significant mucosal toxicity and concerns have been raised about 

the potential for increased risk for transmission of HIV or other sexually 

transmitted infections (STIs) with this therapy.

Women with documented vaginal, vulvar, or anal dysplasia should be 

managed in consultation with a gynecologic specialist. Treatment options 

include observation, excisional biopsy, use of cavitational ultrasonic 

surgical aspiration, or laser vaporization; 5-FU has been used successfully 

for treatment of vulvar and vaginal lesions and recent small studies 

suggest a possible role for topical 1% cidofovir gel with lower genital tract 

HPV-related lesions (Koonsaeng, 2001; Snoeck, 2001a; Snoeck, 2001b). 

Regardless of type of treatment, recurrence rates are increased in HIVinfected women and close follow-up is needed (Chang, 2002).

The role of highly active antiretroviral therapy (HAART) and immune 

reconstitution in the management of lower genital tract precancerous 

lesions remains unclear. In one study use of HAART was associated 

with increased likelihood of regression of cervical dysplasia after 

treatment for 12 months (Heard, 2002). In the Women’s Interagency 

HIV Study (WIHS), after adjustment for CD4 count and Pap status, use 

of HAART was associated with increased regression and decreased risk 

of progression of cervical cytologic abnormalities (Minkoff, 2001). On the 

other hand, Palefsky found no effect of 6 months of HAART on anal HPV 

or ASIL (Palefsky, 2001b). With 15 months of follow-up, persistence of 

high-risk HPV and progression of SIL were comparable among women 

without antiretroviral treatment, those treated with nucleoside analogues 

only, and those treated with HAART (Lillo, 2001). Duerr and colleagues 

found no differences in regression of abnormalties on Pap smear, HPV 

acquisition or persistence after up to 24 mo on HAART compared with 

untreated women or women receiving non-HAART treatment. However, 

new abnormal Pap smear results were less likely in the HAART group 

(Duerr, 2000).

At the current time, HIV-positive women should continue to be followed 

closely for evidence of lower genital tract neoplasia, regardless of 

antiretroviral therapy or viral load.
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IV. GENITAL ULCERS

A. HISTORY

Duration and location of lesion(s); previous history of genital ulcers, 

syphilis, or genital herpes; associated symptoms (pain, pruritus, fever, 

etc.); medications and timing of ulcers relative to initiation of new 

medication; sexual history (including condom use); and CD4 counts and 

HIV RNA levels.

B. PHYSICAL EXAM

Dimensions and location of lesion(s); presence of pigmentation, edema, 

erythema, or induration; presence of associated exudate or tenderness; 

presence of oral lesions; associated lymphadenopathy or rash.

C. EVALUATION

• Syphilis serology or darkfield examination

• Culture or antigen test for herpes simplex virus (HSV)

• Biopsy: with unclear diagnosis, lack of response to treatment; 

consider special stains, if indicated (CMV, acid-fast bacillus)

• Culture for Haemophilus ducreyi: not widely available 

commercially; diagnosis of chancroid generally made with typical 

clinical presentation, after excluding syphilis and HSV

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

(See recent review Rosen, 2003)

INFECTIONS

HERPES SIMPLEX VIRUS

• most prevalent infectious cause of genital ulcers in the United States

• two distinct serotypes of HSV (HSV-1 and HSV-2), most cases of 

recurrent genital herpes (60–95%) are caused by HSV-2

• Since the late 1970s, the seroprevalence of HSV-2 infection has 

increased by 30%; infection is now detectable in 21.9% of people 

aged 12 or older nationwide (Fleming, 1997). Most people with 

HSV-2 do not know that they are infected, since they have 

mild or unrecognized symptoms; however, they may shed virus 

intermittently in the genital tract and transmit infection to their 

sexual partners. Age-adjusted HSV-2 prevalence is significantly 

higher among women than in men (Xu, 2002).

• typically lesions present as painful vesicles that ulcerate and 

heal without scarring

• primary infection often associated with systemic symptoms 

(fever, photophobia, headache); duration of lesions and viral 

shedding more prolonged with primary infection; after primary 

episode latency established in sacral dorsal root ganglia
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• nonprimary first episode herpes occurs in individuals with 

antibodies to HSV-2 or HSV-1 but no previous clinical symptoms 

of HSV; milder, shorter episode

• recurrent episodes occur at variable frequency; more localized 

lesions, shorter duration compared with first episodes (primary 

or nonprimary)

• viral shedding and sexual transmission can occur during 

asymptomatic periods

• HIV-positive patients:

- more frequent, prolonged, and/or severe episodes common with 

progressive immunesuppression; lesions may be atypical in 

appearance or location

- HSV viral shedding increases with declining CD4 counts 

(Augenbraun, 1995) and higher plasma HIV viral load (Wright, 

2003); may be more common in oral contraceptive or DepoProvera users and in women with severe vitamin A deficiency 

(Mostad, 2000); most viral shedding asymptomatic

- HSV is associated with increased risk for HIV transmission/

acquisition (Heng, 1994). Higher levels of cervical HSV have 

been associated with increased HIV shedding in the genital tract 

(McClelland, 2002) and plasma HIV viral load is increased during 

HSV reactivation (Schacker, 2002).

• Treatment: See Table 6-5.

- HIV-positive women often need higher doses and longer treatment 

courses, particularly with more advanced immunosuppression, 

and may benefit from suppressive therapy.

- Daily suppressive therapy reduces the frequency of recurrences 

by ≥ 75% among patients who suffer from frequent HSV episodes 

(i.e., six or more recurrences per year). Suppressive treatment 

reduces but does not eliminate viral shedding. Safety and efficacy 

with daily acyclovir for over 10 years.

Table 6-5: Recommended Management for HSV

Drug Dose

First clinical 

episode

Acyclovir

Acyclovir

Famciclovir

Valacyclovir

400 mg po three times a day for 7–10 days

200 mg po five times a day for 7–10 days

250 mg po three times a day for 7–10 days

1 g po twice a day for 7–10 days

Recurrent 

episodes

Acyclovir

Acyclovir

Famciclovir

Valacyclovir

400 mg po three times a day for 5–10 days

200 mg po five times a day for 5–10 days

500 mg po twice a day for 5–10 days

1 g po twice a day for 5–10 days

Daily 

suppressive 

therapy

Acyclovir

Famciclovir

Valacyclovir

400–800 mg po twice to three times a day

500 mg po twice a day

500 mg po twice a day

Severe disease Acyclovir 5–10 mg/kg body weight IV every 8 hr for 2–7 days or until 

clinical improvement is observed, followed by oral antiviral therapy 

to complete at least 10 days total therapy

Acyclovirresistant HSVFoscarnet

Topical Cidofovir 

gel 1%

40 mg/kg body weight IV every 8 hr or 60 mg/kg IV every 12 hr 

for 3 wk

applied to lesions once a day for 5 consecutive days

Source: CDC, 2002.
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- Acyclovir-resistant HSV: Usually cross-resistant to 

famciclovir, valacyclovir. The prevalence of resistant HSV 

in immunocompromised patients has remained stable at 

approximately 4–7% (Bacon, 2003). Most of these isolates are 

susceptable to foscarnet IV or topical cidofovir. Factors associated 

with acyclovir resistance are low CD4 counts and long-term 

exposure to acyclovir.

SYPHILIS

• systemic disease caused by Treponema pallidum

• definitive methods for diagnosing early syphilis are darkfield 

examination and direct fluorescent antibody test of lesion exudate 

or tissue

• presumptive diagnosis is possible using two types of serologic tests 

for syphilis: VDRL or RPR (nontreponemal) and a confirmatory 

FTA-ABS or MHA-TP (treponemal)

• nontreponemal test antibody titers usually correlate with 

disease activity and are used to assess treatment response; serial 

assessment during follow-up after treatment should use the same 

type of nontreponemal test

• HIV-infected patients may have abnormal serologic test 

results (e.g., unusually high titers, false negatives or delayed 

seroreactivity). However, generally serologic tests can be 

interpreted in the usual manner. If clinical findings suggest 

syphilis but serology is nonreactive, biopsy, darkfield examination, 

or direct fluorescent antibody staining of lesion material should 

be considered. The clinical presentation of syphilis is very 

variable at all stages; atypical manifestations may be seen in the 

setting of HIV disease. Neurosyphilis should be considered in the 

differential diagnosis of neurologic signs or symptoms in HIVinfected individuals (CDC, 2002).

• Treatment: See Table 6-6.

Table 6-6: Recommended Management For Syphilis

Stage Treatment

Primary and secondary syphilis 

and early latent syphilis

Benzathine penicillin G 2.4 million units IM (single dose); additional 

treatment recommended by some (i.e., three weekly doses of 

penicillin); some specialists recommend CSF examination before 

treatment and follow-up CSF examination after treatment in persons 

with initial abnormalities

If penicillin-allergic (nonpregnant 

patients only)

Doxycycline 100 mg po twice a day for 2 wk, OR tetracycline 500 

mg po 4 times a day for 2 wk

Late latent syphilis or syphilis 

of unknown duration (including 

tertiary syphilis)

Examination of the CSF must be performed before initiating 

treatment.

If the CSF examination is negative, patients should be treated with 

7.2 million units of benzathine penicillin G (three weekly doses of 

2.4 million units each) IM

Neurosyphilis Aqueous crystalline penicillin G 18–24 million units a day 

(administered as 3–4 million units IV every 4 hr) for 10–14 days 

(every 4 hr or continuous infusion)

Administration of benzathine penicillin 2.4 million units IM once 

per week for up to 3 weeks after completion of the IV regimen 

recommended by some 
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Table 6-6: Recommended Management For Syphilis (continued)

Recommended Follow-Up

Stage Treatment

Primary and secondary syphilis HIV-infected patients require clinical and serologic evaluation for 

treatment failure at 3, 6, 9, 12, and 24 mos after treatment.

Treatment failures necessitate a CSF examination and retreatment 

(three weekly doses of 2.4 million units of benzathine penicillin G if 

CSF examination is negative).

The latter regimen should also be considered for patients whose 

titers do not decrease fourfold within 6–12 mo.

Latent syphilis HIV-infected patients require clinical and serologic evaluation at 6, 

12, 18, and 24 mos after treatment.

The CSF examination should be repeated and appropriate treatment 

instituted if clinical symptoms develop, titers rise fourfold, or if titers 

fail to decline by >75% between the evaluations at 12 and 24 mo.

Neurosyphilis CSF examination should be repeated every 6 mo until the cell count 

is normal.

Retreatment should be considered if the cell count has not 

decreased after 6 mo or if the CSF is not entirely normal after 2 yr.

CSF, cerebrospinal fluid

Source: CDC, 2002

CHANCROID

• caused by H. ducreyi

• endemic in some areas of the United States; also occurs in 

discrete outbreaks

• 10% of patients with chancroid have coinfection with T. pallidum

or HSV

• initial presentation typically consists of a tender papule that 

becomes pustular and then ulcerative; the ulcer is usually well 

demarcated, with ragged undermined edges

• probable diagnosis can be made if the patient has one or more 

painful ulcers, there is no evidence of T. pallidum or HSV 

infection, and the clinical presentation appearance of ulcers and 

regional lymphadenopathy is typical for chancroid

• Response to treatment may be diminished in the HIV-infected 

patient; may require longer courses of therapy, increased risk for 

treatment failure

• Treatment:

- Azithromycin 1 g po (single dose), OR

- Ceftriaxone 250 mg IM (single dose), OR

- Ciprofloxacin 500 mg po twice a day for 3 days, OR

- Erythromycin base 500 mg po four times a day for 7 days.

- Note

♦ In HIV-positive patients use single-dose therapies only if follow-up 

can be ensured;

♦ Some experts recommend the 7-day erythromycin regimen in the setting of HIV infection.
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CYTOMEGALOVIRUS

• should be suspected in severely immunocompromised patients

• diagnosis requires biopsy of lesion with immunohistochemical 

stains

• cervical shedding of cytomegalovirus is associated with low CD4 

counts (Clark, 1997)

• Treatment:

- Ganciclovir 5 mg/kg IV twice a day for 2–3 wk, OR

- Foscarnet 60 mg/kg IV q 8 hr or 90 mg/kg q 12 hr for 2–3 wk.

OTHER INFECTIOUS CAUSES OF GENITAL ULCERS

• Lymphogranuloma venereum: rare in United States; 

associated with tender, usually unilateral inguinal or femoral 

lymphadenopathy, proctocolitis, rectal fistulas/strictures; 

diagnosis with serology and exclusion of other causes; treatment: 

doxycycline or erythromycin for 3 wk; HIV-positive individuals 

may require more prolonged treatment

• Granuloma inguinale (donovanosis): rare in United States; 

painless, progressive ulcers which bleed easily on contact, 

without regional lymphadenopathy; diagnosis with biopsy 

or tissue crush preparation; treatment trimethoprimsulfamethoxazole or doxycycline for 3 wk or until all lesions 

healed; CDC recommends adding aminoglycoside to regimen in 

HIV-positive patients

• Tuberculosis (Giannacopoulos, 1998): genital TB is generally a 

secondary manifestation of primary (usually pulmonary) disease. 

In the United States, the incidence of genital disease is <1% 

diagnosis is established by biopsy. Genital tuberculosis should 

be treated as is extrapulmonary disease; expert consultation is 

necessary.

INFLAMMATORY CONDITIONS

CROHN’S DISEASE

• This disease may be easily misdiagnosed because its principal 

clinical features (i.e., fever, abdominal pain, diarrhea, fatigability, 

weight loss) are often found in patients with HIV disease. 

Crohn’s disease may also present with genital ulcers, rectal 

fissures, perirectal abscesses, or intestinal fistulas. Sigmoidoscopy 

or barium enema is essential in making this diagnosis. Manage 

with expert consultation.

BEHÇET’S SYNDROME

• This is a multisystem disorder that presents with recurrent oral 

and genital ulcerations as well as uveitis, arthritis, and vasculitis. 

Vaginal ulcers are usually painless, whereas lesions on the 

external genitalia are generally painful. Ulcers range between 2 

and 10 mm in diameter, and they can be shallow or deep with 

a central yellowish necrotic base; either a single lesion or crops 

of lesions may be evident. Diagnosis is established based on the 

clinical presentation and biopsy. Treatment consists of topical or 

systemic corticosteroids.
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HIDRADENITIS SUPPURATIVA (DROEGEMUELLER, 1997)

• This is a chronic, refractory condition involving the skin, 

subcutaneous tissues, and apocrine glands. Lesions are painful 

and are associated with a foul-smelling discharge. Eventually, a 

deep-seated chronic infection of apocrine glands develops, with 

multiple draining abscesses and sinuses. A biopsy is necessary to 

establish the diagnosis. In the early stages of disease, treatment 

options include antibiotics, topical steroids, antiandrogens, and 

isotretinoin. Treatment of advanced disease requires surgical 

intervention.

NEOPLASTIC

• any nonhealing genital ulcer must be biopsied to rule out a 

neoplastic process

• squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, 

melanoma, lymphoma, Kaposi’s sarcoma

• refer to oncologist

DRUG REACTION

• has been described as rare side effect of treatment with zalcitibine 

and foscarnet

APHTHOUS GENITAL ULCERATIONS (ANDERSON, 1996)

• no specific etiology (typical or opportunistic organism) is 

identifiable

• similar to aphthous ulcers seen in the gastrointestinal tract

• most patients are significantly immunosuppressed (median CD4 

count 50/mm3)

• lesions can be painful, multiple, deep, and extensive (size 1–6 cm)

• associated morbidity includes immobility, bleeding, and 

superinfection

• most have been reported to be chronic and/or recurrent or relapsing

• oroesophageal ulcers coexist in about one third of cases and one 

fifth were associated with genital fistula formation

• Treatment:

- Consider empiric therapy for HSV.

- If empiric therapy fails, systemic steroids (prednisone 40–60 mg/

day for 1–2 wk, then taper) have been moderately successful.

- Thalidomide (200 mg/day for 2–4 wk) has been used in similar 

ulcers in the oropharynx or esophagus with complete healing in 

55–73% of these ulcers (Jacobson, 1997, 1999); there has been 

similar success anecdotally in genital apththous ulcers. (Warning: 

this drug is a powerful teratogen and should only be used in 

women of reproductive age after appropriate counseling and 

pregnancy testing and in the setting of reliable contraception 

or abstinence.)
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TRAUMA

• history of traumatic injury

• consider possibility of sexual violence

V. VAGINAL DISCHARGE

A. HISTORY

Duration and characteristics of discharge, associated symptoms (e.g., 

pruritus, malodor, burning, pelvic pain), sexual history (including condom 

and other contraceptive use), history of sexually transmitted diseases, 

history of douching, recent antibiotic use, CD4 counts and HIV-RNA 

levels, medications.

B. PHYSICAL EXAM

Complete genital inspection and bimanual pelvic examination; document 

the characteristics and amount of discharge as well as the presence of 

erythema, edema, and tenderness.

C. EVALUATION

• saline wet mount

• 10% potassium hydroxide (KOH) preparation

• vaginal pH determination

• testing for gonorrhea and chlamydia

• fungal culture, if indicated (signs/symptoms of yeast infection 

with negative findings on microscopy; chronic/recurrent yeast 

infections)

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

BACTERIAL VAGINOSIS (BV)

• most prevalent cause of vaginal discharge or malodor

• results from replacement of normal Lactobacillus dominant vaginal 

flora with increase in prevalence and concentration of mixed flora, 

including anaerobic bacteria, Gardnerella vaginalis, and Mycoplasma 

hominis

• 18–42% prevalence among HIV-infected women; BV is more 

prevalent and persistent as compared with HIV-negative controls 

and prevalence, persistence and severity increase with lower CD4 

counts (Cu-Uvin, 1999; Greenblatt, 1999; Jamieson, 2001). Use of 

antiretroviral drugs has been associated with lower prevalence of 

BV (Warren, 2001).
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• Some studies suggest that BV or BV-associated organisms (or lack 

of vaginal lactobacilli) may enhance HIV transmission (Martin, 

1999; Olinger, 1999). BV has been associated with increased HIV 

expression in the genital tract (Cu-Uvin, 2001).

• associated with increase in several obstetric and gynecologic 

complications, including pelvic inflammatory disease (PID), 

postabortion and posthysterectomy infections, preterm labor

• standard diagnosis by clinical criteria; requires three of the 

following: 1) a homogeneous grayish or yellowish discharge (may 

coat vaginal walls); 2) clue cells on microscopic examination; 

3) vaginal pH >4.5; 4) a positive whiff test (i.e., fishy odor of 

discharge before or after addition of 10% KOH)

• Treatment: See Table 6-7.

Table 6-7: Recommended Management For Bacterial Vaginosis

Metronidazole 500 mg po twice a day for 7 days

Clindamycin cream 2%, 5 g intravaginally at bedtime for 7 days

Metronidazole gel 0.75%, 5 g intravaginally once a day for 5 days

Note: Clindamycin cream is oil based and may weaken latex condoms and 

diaphragms. Alternative regimens: metronidazole 2 g po in single dose or 

clindamycin 300 mg po twice a day for 7 days or clindamycin ovules 100 

g intravaginally at bedtime for 3 days

Source: CDC, 2002

VULVOVAGINAL CANDIDIASIS

• Most commonly caused by Candida albicans; the prevalence of 

infections due to non-albicans species is increasing

• 75% of all women will have at least one episode of candidiasis, and 

40–45% will have two or more episodes; less than 5% of women 

experience recurrent episodes of candidiasis

• Typical symptoms: thick, white discharge and pruritus; other 

symptoms include vulvar burning, vaginal soreness, dyspareunia, 

and external dysuria

• Prevalence among HIV-infected women is 3–15%; most studies 

suggest no significant difference in prevalence of infection 

between relatively immunocompetent HIV-positive women and 

HIV-negative controls; recent longitudinal analysis from the HER 

Study found that vulvovaginal candidiasis occurred with higher 

incidence and greater persistence, but not greater severity, among 

HIV-infected as compared to high-risk HIV-uninfected women. 

Lower CD4 count and higher viral load were associated with 

vulvovaginal candidiasis (Cu-Uvin 1999;Duerr, 2003).
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• Possible confounding factor for HIV-positive women is more 

frequent use of antibiotics; pregnancy is also a predisposing factor 

for candidiasis irrespective of HIV status.

• Most studies show increased rates of vaginal (also rectal, oral) 

colonization in HIV-positive women, particularly with declining 

immune function. 

• In HIV-positive women 26–27% of vaginal isolates are non-albicans 

strains (Schuman, 1998); available studies are conflicting on 

the proportion of non-albicans strains in HIV-positive compared 

with HIV-negative women; most common is Candida glabrata. 

No association found to date between strain diversity and HIV 

progression. In general conventional antifungal therapies are not as 

effective against non-albicans species and 10–14 days of therapy with 

a non-fluconazole azole drug is recommended as first-line therapy.

• Diagnosis is made by identifying budding yeast or pseudohyphae 

on a wet mount or KOH preparation or Gram stain of vaginal 

discharge; positive identification can also be accomplished by 

means of culture

• Treatment: See Table 6-8.

- Special considerations in HIV-positive women:

♦ Topical therapies may be more effective when given for at least 

7 days; fluconazole may be more effective when given in two 

sequential 150 mg doses 3 days apart.

♦ Consider prophylactic use of topical antifungals when antibiotics 

are given

♦ Randomized, placebo-controlled trial of fluconazole 200 mg 

po weekly for prophylaxis of candidiasis in women with CD4 

<300/mm3 (median CD4 15/mm3): effective in preventing 

oropharyngeal candidiasis (relative risk .50, p<.001) and 

vaginal candidiasis (relative risk .64, p=.05), but not esophageal 

candidiasis (Schuman, 1997). Consider in selected cases with 

recurrent vaginal candidiasis.

♦ Recent study found that ritonavir and indinavir (and possibly 

other protease inhibitors) strongly inhibited secretory aspartyl 

proteinase (proteolytic enzyme produced by pathogenic Candida 

species, considered a virulence factor) activity and production in 

a dose-dependent fashion, and exerted a therapeutic effect in an 

experimental model of vaginal candidiasis, with efficacy similar to 

fluconazole (Cassone, 1999).

- Azole resistance:

Concerns have been raised about extensive use of oral azoles 

and promotion of azole resistance, possibly limiting use of these 

agents for other HIV-related indications. Current information 

about development of resistance is limited.

♦ ACTG 816: annual incidence of clinical failure to fluconazole 

(persistence of oral candidiasis after 200 mg/day or higher dose for 

14 days) 5.8% (median CD4 15/mm3); C. albicans primary etiology

♦ Community Programs for Clinical Research on AIDS—randomized, 

placebo-controlled trial of fluconazole 200 mg weekly for 

prophylaxis of candidiasis (described above) (median CD4 15/

mm3): after median 29 mo follow-up, fluconazole resistance <5% 

resistance in both fluconazole and placebo groups (Schuman, 1997a)
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Table 6-8: Recommended Management for Vulvovaginal Candidiasis

Topical Azoles

• Butoconazole 2% cream 5 g PV for 3 days*

• Butoconazole 2% cream 5 g (sustained release) PV application x 1

• Clotrimazole 1% cream 5 g PV for 7–14 days*

• Clotrimazole 100 mg vaginal tablet for 7 days

• Clotrimazole 100 mg vaginal tablet, 2 tablets for 3 days

• Clotrimazole 500 mg vaginal tablet x 1

• Miconazole 2% cream 5 g PV for 7 days*

• Miconazole 200 mg vaginal suppository for 3 days*

• Miconazole 100 mg vaginal suppository for 7 days*

• Tioconazole 6.5% ointment 5 g PV x 1*

• Terconazole 0.4% cream 5 g PV for 7 days

• Terconazole 0.8% cream 5 g PV for 3 days

• Terconazole 80 mg vaginal suppository for 3 days

* Available over the counter.

PV, vaginally. 

Note: These creams are oil-based and may weaken latex condoms and diaphragms.

Oral agent†

• Fluconazole 150 mg po x 1 

† Avoid concomitant use with terfenadine, astemizole, cisapride secondary to cardiotoxicity.

Others

• Nystatin 100,000 unit vaginal tablet, one tablet for 14 days (less effective)

• 1% Gentian violet applied to vagina 4 times at intervals of approximately 7 days‡

• Boric acid 600 mg intravaginal capsules bid for 2 wk‡

‡ May be useful in chronic/recurrent cases; gentian violet messy, causes mucosal exfoliation; encourage 

abstinence during treatment; reinforce condom use. 

Source: CDC, 2002.

♦ HIV Epidemiology Research Study (HERS): overall fluconazole 

resistance rare among C. albicans isolates with no evidence 

for progressive reduction in susceptibility over time; however, 

resistance frequent in non-albicans isolates from vagina and oral 

cavity; fluconazole resistance with non-albicans species more 

likely in HIV-positive women (Sobel, 2001). There was a trend 

towards more in vitro azole resistance in non-albicans species (all 

C. glabrata) in women with CD4 <300/mm3 who were receiving 

weekly fluconazole prophylaxis vs placebo. (Vazquez, 2001). 

♦ 139 isolates from vulvovaginal candidiasis in HIV-positive women: 

95–98% susceptibility of C. albicans to fluconazole, itraconazole, 

clotrimazole; C. glabrata: 44% resistance to fluconazole, 72% 

resistance to itraconazole and clotrimazole. Twenty percent of 90 

relapses/persistence were with same organism; emergence of 

drug resistance was not observed between sequential isolates. 

Twelve percent had recurrent infection with different strains or 

species (Li, 1997).
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There are no current data to suggest that intermittent therapy with a 

single dose of fluconazole increases development of azole resistance. 

Similarly, weekly prophylaxis with fluconazole was associated with 

infrequent development of resistance, which was not significantly 

different from placebo recipients. Nevertheless, long-term use of 

fluconazole may select for more resistant and difficult-to-treat nonalbicans species and should be used with caution. Further study 

is needed.

- Recurrent candidiasis (four or more symptomatic episodes 

per year):

♦ Evaluation:

 1. establish diagnosis — fungal culture may be needed

 2. identify/eliminate predisposing factors, if possible: uncontrolled 

diabetes, corticosteroid use, topical or systemic antibiotics, spermicides (conflicting data), tight-fitting synthetic underwear, douching, 

pregnancy, immunosuppression

 3. speciation/susceptibility testing

♦ Management options:

 1. longer duration of standard treatment regimen

 2. chronic intermittent therapy (e.g., with perimenstrual episodes)

 3. restriction of orogenital/anogenital sexual contact (anecdotal 

evidence only); double-blind, placebo-controlled trials of topical 

therapy for male sexual partners showed no benefit (Sobel, 1999)

 4.possible role for boric acid vaginal capsules, gentian violet

 5. maintenance therapy: initial intensive regimen (e.g., 7–14 days 

of topical therapy or a 150 mg oral dose of fluconazole repeated 3 

days later) followed by a maintenance regimen for at least 6 mo:

 a. fluconazole* 100–150 mg po every wk

 b. itraconazole* 400 mg po every month or 100 mg po every day

 c. clotrimazole 500 mg suppository per vagina every wk

 d. ketoconazole* 100 mg po every day (associated with rare 

but significant hepatotoxicity-monitor liver function; significant drug interactions with some antiretrovirals (see 

Chapter XIV on Pharmacologic Considerations in HIVinfected Pregnant Patients)

 6. immune reconstitution; potential benefit with protease inhibitors

* Note: avoid concomitant use with terfenadine, astemizole, cisapride 

secondary to cardiotoxicity.

TRICHOMONIASIS

• Caused by Trichomonas vaginalis

• HIV-positive women: 5–23% prevalence; incidence in HIV-positive 

women 10–17% (Minkoff, 1999; Sorvillo, 1998). Studies have not 

shown increased prevalence, incidence, persistence or recurrence 

compared with HIV-negative women or with lower CD4 counts 

(Cu-Uvin, 2002).

• Clinical features: profuse, malodorous, often frothy, yellow-green 

discharge and vulvar irritation; may have urinary symptoms 

or dyspareunia; signs of inflammation — vaginal erythema, 

“strawberry” vagina, cervix with punctate hemorrhages; may be 

asymptomatic in chronic cases
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• Diagnosis: saline wet mount (motile trichomonads seen in 50–70% 

culture-positive cases); Pap smear (60–70% sensitivity, false 

positives not uncommon); culture (95% sensitivity); DNA probes; 

monoclonal antibodies

• T. vaginalis cysteine proteases degrade and render nonfunctional 

secretory leukocyte protease inhibitor, a substance thought to 

protect mucosal surfaces from HIV transmission by inhibition of 

HIV protease activity necessary for infection of monocytes and 

macrophages (Draper, 1998)

• Treatment (CDC, 2002):

- Metronidazole 2 g po (single dose), OR

- Metronidazole 500 mg po twice a day for 7 days

- Note:

♦ No change in treatment based on HIV status

♦ Sex partners should be treated with the same regimen (>90% 

cure rates can be expected if partner is treated simultaneously); 

intercourse should be avoided until therapy is complete and 

patient and partner are asymptomatic

♦ Topical metronidazole less effective

♦ Metronidazole resistance is rare; organisms with decreased 

susceptibility usually respond to higher doses of metronidazole. 

If treatment failure occurs with either regimen, retreat with 

metronidazole 500 mg po twice a day for 7 days. If treatment 

failure occurs repeatedly, treat with metronidazole 2 g po once 

a day for 3–5 days. Patients with documented infection (with 

reinfection excluded) who have not responded to these measures 

should be managed in consultation with an expert.

GONORRHEA

• caused by Neisseria gonorrhoeae

• clinical presentation: commonly asymptomatic; vaginal discharge 

may be present; if untreated, 10–20% develop PID; urethra is 

primary site of colonization after hysterectomy and should be 

sampled with culture or DNA probe for testing in these patients; 

gonorrhea may also cause rectal infection, pharyngitis, and (rarely) 

disseminated infection

• diagnosis: culture, DNA probe, polymerase chain reaction (PCR) or 

ligase chain reaction (LCR). PCR/LCR can be used with cervical, 

urethral, or urine specimens; may detect gonorrhea and chlamydia 

simultaneously; sensitivity 93–98%, specificity >99%; able to 

detect 15–40% more infections than culture (Hook, 1999)

• prevalence/clinical presentation/diagnosis/treatment in HIVpositive patients: no difference compared with HIV-negative patients

• Treatment (CDC, 2002): Uncomplicated gonococcal infections of 

the cervix, urethra, and rectum

- Cefixime 400 mg po (single dose), OR

- Ceftriaxone 125 mg IM (single dose), OR

- Ciprofloxacin 500 mg po (single dose), OR
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- Ofloxacin 400 mg po (single dose)

- Levofloxacin 250 mg po (single dose), OR

- Alternative regimen:

♦ Spectinomycin 2 g IM (single dose)

- Note:

♦ It is recommended that women be presumptively treated for 

chlamydia, particularly in areas with high rates of coinfection, 

absence of chlamydial testing, and/or when patient may not 

return for results

♦ Sex partners should be treated for both gonorrhea and chlamydia 

if their last sexual contact was within 60 days before the diagnosis 

or onset of symptoms. If a patient’s most recent sexual contact 

occurred more than 60 days before the onset of symptoms, her 

most recent partner should be treated. Intercourse should be 

avoided until treatment is completed and symptoms have resolved.

♦ Culture and susceptibility testing recommended after apparent 

treatment failure with standard regimen

♦ Due to the increased prevalence of quinolone-resistant gonorrhea 

in Hawaii, California, or with infections acquired in Asia or 

the Pacific, the use of fluoroquinolones in these locations or 

circumstances is not advisable (CDC, 2002)

♦ Avoid use of quinolones and tetracyclines in pregnancy

CHLAMYDIA

• caused by Chlamydia trachomatis

• clinical presentation: asymptomatic infection common; abnormal 

discharge; symptoms of urethritis; if untreated, 10–40% develop 

PID

• diagnosis: culture (cell based), antigen detection, DNA probe, PCR/

LCR (90–100% sensitivity — see above) (Stamm, 1999)

• prevalence/clinical presentation/diagnosis/treatment in HIVpositive women: no differences compared with HIV-negative 

women

• Treatment (CDC, 2002):

- Azithromycin 1 g po (single dose), OR

- Doxycycline 100 mg po twice a day for 7 days

- Alternative regimens:

♦ Erythromycin base 500 mg po four times a day for 7 days, OR

♦ Erythromycin ethylsuccinate 800 mg po four times a day for 7 

days, OR

♦ Ofloxacin 300 mg po twice a day for 7 days, OR

♦ Levofloxacin 500 mg po for 7 days

- Note:

♦ Recommendations for the management of sex partners are the 

same as for gonorrhea (see above)

♦ Avoid use of doxycycline or quinolones in pregnancy

♦ Rescreening for chlamydia 3–4 months after treatment is 

recommended.
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OTHER

• Atrophic vaginitis: related to estrogen deficiency; irritative 

symptoms, vaginal dryness, and dyspareunia; the vaginal 

epithelium appears thin and a watery discharge may be present; 

treat with either topical or oral estrogen.

• Foreign body (retained tampon, toilet paper, etc.)

• Local irritants (spermicides, vaginal medications, toilet paper dye, 

hygeine sprays, soap, detergent, douches, etc.)

VI. PELVIC/ABDOMINAL PAIN

Abdominopelvic pain can be classified as acute, chronic, or cyclic. Acute 

pain is typically sudden in onset and short in duration, whereas chronic 

pain is of at least 6 mo duration. Cyclic pain is associated with the 

menstrual cycle.

A. HISTORY

Characteristics of pain: onset (rapid or gradual), character (crampy, 

colicky, sharp or dull), location (generalized or localized pain), and 

duration; associated symptoms: abnormal vaginal bleeding or discharge, 

gastrointestinal symptoms (e.g., nausea/vomiting, anorexia, constipation, 

diarrhea), and urinary (e.g., dysuria, frequency, urgency, hematuria) 

symptoms, fever or chills; history of other medical conditions; surgical 

history; gynecologic history: date of last menstrual period, use of 

contraception and condoms, history of STIs; medications; CD4 counts 

and HIV-RNA levels.

B. PHYSICAL EXAM

A complete set of vital signs should be obtained. The physical exam 

should focus on abdominal and pelvic findings. A complete abdominal 

exam should evaluate the presence and character of bowel sounds, 

distention, suprapubic or costovertebral angle tenderness, other 

abdominal tenderness (including rebound and guarding), and presence 

of masses. The pelvic exam should determine the presence of abnormal 

bleeding or discharge; reproducibility and location of tenderness (e.g., 

uterine, adnexal, or cervical motion tenderness); presence of a palpable 

abdominal or pelvic mass should be ruled out.

C. EVALUATION

• Pregnancy test

• Laboratory tests: CBC with differential, sedimentation rate, 

chemistry panel, others as indicated

• Wet mount/STI testing

• Urinalysis and urine culture
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• Stool studies (cultures, evaluation for ova and parasites, C. difficile 

toxin assay) — if indicated by GI symptomatology

• Pelvic ultrasound, computed tomography (CT) scans — if indicated

• Blood cultures — bacteria, Mycobacterium avium, if indicated

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

Includes but is not limited to:

• Pregnancy: refer; with pain and pregnancy ± bleeding, must 

suspect ectopic pregnancy, and urgent evaluation is indicated.

• Pelvic inflammatory disease: PID is an upper genital tract 

infection, usually polymicrobial in nature. Sexually transmitted 

organisms, including N. gonorrhea and C. trachomatis, are 

implicated in most cases of PID; bacterial vaginosis-associated 

organisms are also commonly present. Symptoms may be 

virtually absent or mild and nonspecific (e.g., abnormal bleeding, 

dyspareunia, vaginal discharge; less commonly right upper 

quadrant pleuritic pain secondary to perihepatitis). Current CDCrecommended criteria for diagnosis of PID are (CDC, 2002):

- Minimum criteria:

♦ uterine/adnexal tenderness

♦ cervical motion tenderness

 Because of difficulty in diagnosis and the potential for longterm complications, empiric therapy should be initiated if 

these criteria are present and no other cause for symptoms is 

identified.

- Additional criteria:

♦ oral temperature >101oF (>38.3oC)

♦ abnormal mucopurulent cervical or vaginal discharge

♦ elevated erythrocyte sedimentation rate

♦ elevated C-reactive protein

♦ documented cervical gonorrhea or chlamydia infection

♦ white blood cells on saline wet mount of vaginal secretions

 These criteria enhance specificity.

- Definitive criteria:

♦ endometritis on endometrial biopsy

♦ tuboovarian complex or thickened, fluid-filled tubes on 

transvaginal ultrasound or magnetic resonance imaging (MRI)

♦ laparoscopic abnormalities consistent with PID

 Warranted in patients who are severely ill and/or when diagnosis 

is uncertain.

- PID in the HIV-positive woman: Several studies have found 

increased seroprevalence of HIV in hospitalized PID patients 

(Hoegsberg, 1990; Sperling, 1991). A recent analysis of 

hysterctomy specimens from HIV-positive women and HIVnegative women, matched for surgical indication, found chronic 

endometritis twice as commonly in the HIV-positive specimens; 
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some degree of abnormal uterine bleeding had occurred in all 

cases (Kerr-Layton, 1998). Moreover, the clinical presentation 

among these women may be more severe or otherwise altered 

(e.g., lower white blood cell counts than HIV-negative women) 

(Barbosa, 1997; Cohen, 1998; Kamenga, 1995, Irwin, 2000); in 

African studies, more severe illness, including tuboovarian 

abscess, and longer hospital stays were found with significant 

immunosuppression. The microbiology of infection and response 

to standard antibiotic regimens are similar to HIV-uninfected 

women, although one study found mycoplasmas and streptococci 

were more likely to be isolated from HIV-positive women (Irwin, 

2000). Some studies have reported a greater need for surgical 

intervention (Korn, 1993). CMV and tuberculosis may cause upper 

genital tract infection in rare cases and should be considered in 

appropriate clinical situations. A recent study from Kenya found 

similar efficacy of oral ambulatory therapy in HIV-positive and 

HIV-negative women with PID (Bukusi, 1999). Decisions about 

oral vs. parenteral therapy should be individualized.

Table 6-9: Indications for Hospitalization in Patients with PID

• Inadequate response to outpatient therapy

• Uncertain diagnosis; surgical emergency cannot be excluded

• Pregnancy

• Inability to tolerate or follow outpatient regimen

• Immunosuppression (low CD4 counts, clinical AIDS, on immunosuppressive 

drugs, other significant comorbidity)

• Tuboovarian abscess or other evidence of severe illness, nausea and 

vomiting, or high fever

- Treatment (CDC,2002):

♦ Parenteral regimens:

 Cefotetan 2 g IV every 12 hr, PLUS 

doxycycline 100 mg PO or IV, OR

 Cefoxitin 2 g IV every 6 hr, PLUS

doxycycline 100 mg PO or IV, OR

 Clindamycin 900 mg IV every 8 hr, PLUS

gentamicin loading dose IV or IM (2 mg/kg of body weight), followed 

by a maintenance dose (1.5 mg/kg) every 8 hr. Single daily dosing of 

gentamicin may be substituted.

♦ Oral regimens:

 Ofloxacin 400 mg po twice a day for 14 days OR levofloxacin 500 mg 

po once daily for 14 days WITH or WITHOUT metronidazole 500 

mg po twice a day for 14 days.

 Ceftriaxone 250 mg IM, OR cefoxitin 2 gm IM once and probenecid 

1 g po in a single dose concurrently, OR other parenteral third-generation cephalosporin (ceftizoxime or cefotaxime) PLUS doxycycline 100 

mg po twice a day for 14 days WITH or WITHOUT metronidazole 

500 mg po twice a day for 14 days.
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 For alternative oral and parenteral regimens, please see the CDC 

2002 Guidelines for Treatment of Sexually Transmitted Diseases.

 Parenteral therapy may be discontinued 24 hr after there is 

evidence of clinical improvement. Oral therapy with doxycycline 

100 mg every 12 hr (consider the addition of metronidazole 500 mg 

every 12 hr, particularly with presence of tuboovarian abscess) or 

clindamycin 450 mg four times a day should then be instituted to 

complete a 14-day treatment course. Sexual partners of women 

diagnosed with PID should be evaluated and treated presumptively 

for gonorrhea and chlamydia if they have had sexual contact 

within the 60 days preceding the onset of symptoms.

• Ruptured/hemorrhagic ovarian cyst: can cause acute abdominal 

pain; bleeding associated with rupture is usually self-limited but 

may require surgical intervention.

• Ovarian torsion: acute, severe, unilateral lower abdominal/pelvic 

pain, often with history of previous similar episodes; palpable 

adnexal mass often present. Surgical intervention required.

• Uterine leiomyomas (fibroids): may cause pain with rapid 

enlargement, degeneration, or torsion; referral indicated

• Endometriosis: cause of acute or chronic pain, usually includes 

secondary dysmenorrhea and/or dyspareunia; referral to 

gynecologic specialist indicated if endometriosis suspected

• Dysmenorrhea: affects about half of all menstruating women; 

cyclic pain with menses. Primary dysmenorrhea is menstrual 

pain in the absence of pelvic pathology; secondary dysmenorrhea 

is associated with underlying pathology (such as endometriosis). 

Treatment of primary dysmenorrhea consists of nonsteroidal antiinflammatory drugs (NSAIDs) (80% effective) or oral contraceptive 

pills (90% effective). Treatment of secondary dysmenorrhea is 

directed at the specific underlying problem.

• Mittelschmerz: pain with ovulation, generally self-limited; manage 

with NSAIDs

• Gastrointestinal pathology: includes appendicitis; diverticulitis 

(pain generally localizes to the left lower quadrant; usually seen at 

older ages); irritable bowel syndrome (pain is usually intermittent, 

cramp-like, and more common in the left lower quadrant; 

exacerbated by certain foods); inflammatory bowel disease; 

infectious enterocolitis (pain, cramping, diarrhea); obstruction 

(colicky pain, distention, vomiting, obstipation). Opportunistic 

infections, including cryptosporidia, CMV, and M. avium may be 

causes of chronic diarrhea in patients with AIDS, and clinical 

features usually include abdominal pain.

• Urinary tract pathology: renal/ureteral stones, cystitis, and 

pyelonephritis

• Medication-related: indinavir (renal stones); didanosine 

(pancreatitis)
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VII. PELVIC MASS

A. HISTORY

Presence and duration of associated symptoms: pain, abnormal 

vaginal bleeding or discharge, urinary symptoms (e.g., frequency, 

urinary retention), gastrointestinal symptoms (e.g., nausea, vomiting, 

constipation, diarrhea), or constitutional symptoms (e.g., fever, chills, 

weight loss or gain).

B. PHYSICAL EXAM

A complete abdominal and pelvic examination should be performed, 

with particular attention given to the size, location, mobility, and 

characteristics of the mass (if palpable) as well as to signs of ascites; 

lymph node survey. With functional ovarian cysts, a normal ovary may 

be up to 5–6 cm in size for a woman in the reproductive age range. 

A palpable ovary in a postmenopausal woman may be abnormal and 

requires further evaluation.

C. EVALUATION

• Pregnancy test: if premenopausal

• Laboratory tests: CBC with differential; chemistry panel; tumor 

markers, if indicated (e.g., CEA, Ca-125; frequent false positives 

and false negatives, should only be used in conjunction with other 

diagnostic procedures)

• Radiologic studies: pelvic ultrasound (transabdominal/

transvaginal), CT, and magnetic resonance imaging (MRI), as 

indicated. Ultrasound is generally the first diagnostic modality 

employed in evaluating pelvic anatomy; concerning characteristics 

include complex or solid mass, presence of ascites. CT/MRI are 

better at imaging GI tract, retroperitoneal lymphadenopathy, liver

 Additional evaluation involving procedures such as laparoscopy, 

colonoscopy, etc., require referral to appropriate specialists.

D. DIFFERENTIAL DIAGNOSIS

• Ectopic pregnancy: the primary consideration in the setting of 

an adnexal mass and a positive pregnancy test, urgent evaluation 

indicated.

• Ovarian functional cyst: Functional cysts are the most common 

ovarian masses found among women of reproductive age; 

resolution occurs spontaneously in 1–3 mo.

• Uterine leiomyomas (fibroids): often asymptomatic, but may 

be associated with heavy and/or prolonged menses, urinary 

frequency.

• Endometrioma: consider in women with a documented or 

suspected history of endometriosis.
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• Hydrosalpinx/pyosalpinx and tuboovarian abscess: consider 

with history suggestive of PID; initial management with broadspectrum antibiotics, even if patient asymptomatic.

• Benign or malignant ovarian neoplasm: Surgical intervention 

is required. No evidence of increased prevalence in HIV-positive 

women; anecdotal reports suggest ovarian cancer may present 

at more advanced stage, with poorer response to cytoreductive 

surgery and chemotherapy (Rojansky, 1996). Non-Hodgkins 

lymphoma of ovary described in an HIV-positive woman (Neary, 

1996).

• Retroperitoneal lymphadenopathy: may present as pelvic mass; 

possible causes include tuberculosis, lymphoma

• Gastrointestinal masses: includes diverticular abscess, bowel 

malignancy

In general, the presence of a pelvic or abdominal mass requires expert 

consultation and referral to an appropriate specialist.

VIII. URINARY SYMPTOMS

A. HISTORY

Duration and severity of urinary symptoms; specific symptoms: dysuria, 

frequency, urgency, hematuria, nocturia, incontinence; associated 

symptoms, including pain (suprapubic or flank), fever, chills, and weight 

loss; other medical conditions (e.g., diabetes, sickle cell disease); surgical 

history; medications; CD4 count and HIV-RNA level

B. PHYSICAL EXAM

Vital signs; document presence of suprapubic tenderness or flank or 

costovertebral angle tenderness

C. EVALUATION

• Microscopic exam of urine

• Urine culture and sensitivity

• Gonorrhea/chlamydia testing, if indicated

• Urine cytology: consider in woman over age 50 who presents with 

irritative symptoms or hematuria and negative culture

• Urine for acid-fast bacillus (AFB) culture, purified protein 

derivative (PPD): if indicated, urinary TB suspected

• Intravenous pyelogram (IVP): if indicated; consider if stones, 

urinary tract anomalies, or urinary TB suspected

• Other tests: cystoscopy, urodynamics — refer to appropriate 

specialist
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D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

• Bacterial urinary tract infection: lower tract (cystitis) or upper 

tract (pyelonephritis); may be asymptomatic and clinical signs 

and symptoms cannot reliably distinguish between upper and 

lower tract infection. Classically cystitis characterized by the 

presence of dull, suprapubic pain; typical associated symptoms 

include dysuria, urinary frequency and urgency, and occasionally 

hematuria. Pyelonephritis associated with flank or costovertebral 

pain and tenderness to percussion, as well as systemic signs/

symptoms, including fever, chills, nausea, vomiting, tachycardia. 

Treat with appropriate antibiotics; severe pyelonephritis requires 

hospitalization for IV antibiotics and hydration.

• Urethral syndrome: dysuria, frequency with negative urine 

culture; rule out urethritis due to gonorrheal or chlamydial 

infection

• Renal/ureteral stones: severe, colicky pain; usually associated 

with urinary stasis or chronic infection, although may be related 

to metabolic abnormalities, such as gout or problems with calcium 

homeostasis; a significant side effect associated with indinavir 

therapy.

• Interstitial cystitis: symptoms include severe urinary frequency 

and urgency (urinating as often as every 15 minutes daytime and 

nighttime) as well as suprapubic or perineal discomfort before, 

during, and after urination; refer for definitive evaluation

• Urinary tuberculosis: one of the most common sites of 

extrapulmonary TB; gross or microscopic hematuria and pyuria 

with negative bacterial culture should lead to consideration; 

manage with expert consultation

• Tumors: most common presenting complaint is gross or 

microscopic hematuria; hematuria without identifiable etiology 

(e.g., infection) requires referral to urologist

• Urinary incontinence: can be caused by many factors, including 

anatomic displacements related to aging and childbearing; bladder 

muscle (detrusor) instability; neurologic disease; infection; 

fistulas secondary to surgical injury, radiation, or cancer; and 

some medications. Rule out infection with culture and “overflow” 

incontinence (secondary to overdistended bladder) with postvoid 

catheterization for residual urine determination. Further 

evaluation requires referral to urogynecologist or urologist

• Urinary retention: may be caused by obstruction, neurologic 

disorders, or certain medications (e.g., antihistamines, 

antidepressants, antipsychotics, opiates, antispasmodics, 

terbutaline, over-the-counter cold remedies)
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IX. GENITAL WARTS

Genital warts are a common manifestation of HPV infection. HPV types 6 

and 11 are usually the cause of visible genital warts. Oncogenic types (i.e., 

16, 18, 31, 33, and 35) are occasionally found in visible warts and have 

been associated with squamous intraepithelial neoplasia of the external 

genitalia (see section on abnormal Pap smear, above).

A. HISTORY

Location of warts, duration, and the presence of associated symptoms 

(itching, irritation, pain, bleeding); history of prior occurrences of similar 

lesions and their treatment; history of abnormal Pap smear results

B. PHYSICAL EXAM

Complete examination of the external genitalia as well as of the cervix, 

vagina, and perianal region should be performed; location and size of 

warts should be documented. Genital warts can present as cauliflowershaped growths (condyloma acuminata); smooth, dome-shaped, skincolored papules; keratotic warts with a thick horny layer; or flat or 

slightly raised flat-topped papules.

C. RELATION TO HIV

HIV-infected women are more likely to have HPV coinfection and both 

prevalence and incidence of genital warts are increased compared with 

HIV-negative women (Silverberg, 2002; Conley, 2002). Both prevalence 

and clinical expression of HPV increase with progressive clinical disease 

and immunologic decline. Immunosuppressed women may not respond 

as well to treatment and have more frequent recurrences after therapy. 

Squamous cell carcinomas that arise in or resemble genital warts may 

occur more commonly in the setting of immunosuppression, making 

confirmation of diagnosis with biopsy more frequently necessary.

D. EVALUATION

• Biopsy: Typical condyloma accuminata are diagnosed by 

inspection and do not require biopsy, although current 

CDC guidelines suggest biopsy when the patient is 

immunocompromised. A biopsy of the lesion and histopathologic 

confirmation of the diagnosis are always indicated in the following 

situations:

- diagnosis is uncertain

- warts do not respond to therapy

- lesions worsen during therapy

- warts are pigmented, indurated, fixed, or ulcerated

• Colposcopy: Colposcopy and directed biopsies of the entire lower 

genital tract should be considered in HIV-positive women with 

evidence of HPV infection. Colposcopy should be performed to 

rule out the presence of high-grade squamous intraepithelial 

lesions before initiating treatment of cervical warts.
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• Treatment: The primary goal of treatment is the removal of 

symptomatic lesions. When left untreated, visible warts may resolve 

spontaneously, may remain unchanged, or may increase in number 

or size. There is no evidence that currently available therapies 

eradicate HPV, have an effect on the natural history of infection, or 

affect the subsequent development of cervical cancer. Infectivity 

may or may not be decreased by the removal of visible warts.

The treatment modality depends on the number, size, and location of 

the warts. When there are a small number of lesions and they are fairly 

small, a topical agent may be employed. Table 6-10 displays providerapplied and patient-administered regimens recommended by the CDC 

(CDC, 2002).

Most treatment modalities are associated with mild to moderate 

discomfort and local irritation. Persistent hypo- or hyperpigmentation 

is common after ablative therapies and scarring or chronic pain at 

the treatment site can occur but is rare. Intralesional interferon is an 

additional alternative treatment but is expensive and associated with a 

high frequency of systemic side effects. Treatment method should be 

changed if there is not substantial improvement after three provideradministered treatments or if there is not complete clearance after six 

treatments. Combining modalities does not appear to increase efficacy 

but may increase complications. Recurrence rates are significant with all 

modalities; frequent follow-up will allow retreatment when new warts 

are small and few in number. When the number of warts is large or 

the lesions are very extensive, referral for possible laser surgery should 

be considered. In one study relapse rates of treated genital warts in 

HIV-positive patients was lower in those on combination antiretroviral 

therapy and was correlated with HIV-RNA levels (Giovanna, 1998).

Table 6-10: Recommended Management for Genital Warts

Provider-applied Patient-applied

80–90% trichloroacetic or 

bichloroacetic acid (weekly if necessary) 

Cryotherapy with liquid nitrogen 

or cryoprobe–repeat every 1–2 wk. 

Remove excess acid with talc powder, 

baking soda, or liquid soap.

Podofilox .5% solution or gel applied 

twice a day for 3 days followed by 

4 days of no therapy. May repeat 

application for up to 4 cycles; 

application should be limited to .5 mL 

per day and <10 cm2 area of warts

10–25% podophyllin resin (weekly 

if necessary). Application should be 

limited to <.5 mL of podophyllin or 

<10 cm2 of warts per session and 

preparation should be thoroughly 

washed off 1–4 hr after application 

to reduce local irritation. Because 

of concern about potential systemic 

absorption and toxicity, avoid use on 

mucosal surfaces.

Imiquimod 5% cream applied three 

times per wk for as long as 16 wk. The 

treated area should be washed with 

mild soap and water 6–10 hr after 

application.

Surgical removal (laser or excision)

Note: Avoid use of podophyllin, podofilox, and imiquimod during pregnancy.

Source: CDC, 2002.
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X. GENITAL MASSES/NODULES

A. HISTORY

Duration; changes in size or appearance; associated symptoms (e.g., 

pain/tenderness, itching, edema); history of similar nodules and their 

treatment; sexual history (including presence of similar lesions on 

genitals of partner); medications; CD4 count and HIV-RNA level

B. PHYSICAL EXAM

Document anatomic location, number, and size of the nodules; presence 

of associated edema, erythema, induration, fluctuance, tenderness, 

discharge, or bleeding

C. EVALUATION

Biopsy indicated if etiology is unclear; culture of abscess contents

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT (ROSEN, 2003)

• Bartholin’s abscess: Bartholin’s glands are normally nonpalpable 

and located deep in the perineum at the 5 and 7 o’clock positions 

in the entrance to the vagina. Obstruction of a Bartholin’s duct by 

nonspecific inflammation, infection (e.g., gonorrhea or chlamydia) 

or trauma can lead to the formation of an abscess; exquisitely 

tender. Treatment consists of incision and drainage.

• Molluscum contagiosum: an asymptomatic viral disease that 

primarily affects skin of the vulva, although it can present as a 

generalized skin disease in immunosuppressed individuals; spread 

by close contact, both sexual and nonsexual. Clinical features: 

small nodules or domed papules, usually 1–5 mm in diameter; 

the more mature nodules appear to have an umbilicated center. 

This disease tends to be self-limited; however, disease course may 

be complicated by repeat infection and autoinoculation of the 

virus. Treatment consists of serial applications of liquid nitrogen 

or of removal of the nodules with a dermal curet and chemical 

cauterization of base with 85% trichloroacetic acid or ferric 

subsulfate. Molluscum contagiosum affects 5–10% of HIV-positive 

patients; extensive, severe lesions that show poor response to 

therapy are common; such unresponsive lesions, however, have 

been found to regress with HAART (Calista, 1999).

• Tumors, other masses: biopsy required; expert consultation indicated.
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XI. GENITAL ITCHING/IRRITATION

A. HISTORY

Duration, location, and severity of pruritis/irritation; associated 

symptoms (erythema, edema, vulvar burning, dysuria, dyspareunia); 

prior episodes of similar symptoms and treatment; exposure to particular 

agents (e.g., soaps, sprays, vaginal contraceptives, douches, colored toilet 

tissue, etc.) coincident with the beginning of symptoms; presence of 

similar symptoms in close contacts; medications, including antibiotics; 

CD4 count and HIV-RNA level

B. PHYSICAL EXAM

Physical appearance and distribution of the irritated area (e.g., diffuse 

rash, papular or vesicular lesions, skin burrows, etc.); associated findings, 

including erythema, edema, and tenderness, vaginal discharge; if a more 

generalized process is suspected (e.g., allergic reaction to detergent, 

scabies, etc.) more thorough inspection of the skin throughout the body 

may be indicated.

C. EVALUATION

• Fungal culture/KOH preparation: indicated if a fungal infection 

is suspected.

• HSV culture: herpes may appear atypically and should be ruled 

out in the presence of vesicular lesions, unexplained abrasions, 

or fissuring, or if warranted by history.

• Skin scrapings: scraping of skin papule is with a needle, and 

the crust is placed under a drop of mineral oil on a slide; eggs, 

parasites, or fecal pellets microscopically visualized by this 

technique are diagnostic of scabies or pubic lice.

D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT (ROSEN, 2003)

• Fungal infection: Although the primary symptom associated 

with fungal infections is itching, women also complain of vulvar 

burning, dysuria, and dyspareunia, particularly with involvement 

of vulvar skin. Examination often reveals edema, erythema, and 

excoriation; pustular lesions may be found to extend beyond the 

line of erythema when extensive skin involvement is present. 

Diagnosis is established by means of a KOH preparation or 

fungal culture. Treatment is topical application of an antifungal 

preparation. (See vulvovaginal candidiasis in the Vaginal Discharge 

section above.)

• Allergic/irritative reaction: Contact dermatitis frequently 

affects the vulvar skin, particularly the intertriginous areas; 

etiologic agents include urine or feces, latex, semen, cosmetic or 

therapeutic agents (including vaginal contraceptives, lubricants, 

sprays, perfumes, douches, fabric dyes, fabric softeners, synthetic 
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fibers, bleaches, soaps, chlorine, dyes in toilet tissues, and local 

anesthetic creams); severe cases of dermatitis may be due to 

poison ivy or poison oak. Typical symptoms are itching, vulvar 

burning, and tenderness. Examination of the skin reveals 

erythema, edema, and inflammation; the skin may be weeping 

and eczematoid. Secondary infection may occur.

 Treatment involves removing the offending agent. Severe lesions 

may be treated with wet compresses of Burow’s solution diluted 

1:20 for 30 min several times a day. If possible, the vulva should 

be dried with cool air from a hair dryer following the compresses. 

Lubricating agents such as Eucerin cream or petroleum jelly can 

help reduce the itching. Nonmedicated baby powders can be used 

to facilitate vulvar dryness. Symptomatic relief can be achieved 

with hydrocortisone (0.5% to 1%) or fluorinated corticosteroid 

(Valisone 0.1% or Synalar 0.01%) lotions or creams into the 

skin two to three times a day for a few days. Dermatitis due to 

poison ivy or poison oak may require treatment with systemic 

corticosteroids. The use of white cotton undergarments is 

advisable, and tight-fitting clothing should be avoided.

• Scabies/lice:

- Scabies is a parasitic infection produced by the itch mite, 

Sarcoptes scabiei. The main symptom reported is severe, 

intermittent itching that tends to be more intense at night. 

Lesions can present as vesicles, papules, or burrows; any area 

of skin may be affected: the hands, wrists, breasts, vulva, 

and buttocks are most often affected. HIV-infected and other 

immunosuppressed patients are at increased risk for Norwegian 

scabies, a disseminated dermatologic infection; this can appear 

classically as hyperkeratotic, nonpruritic lesions; as crusting with 

pruritis; a pruritic, papular dermatitis; or lesions resembling 

psoriasis (Schlesinger, 1994).

♦ CDC-recommended treatment for scabies (CDC, 2002):

 Permethrin cream (5%) applied to all areas of the body from the neck 

down and washed off after 8–14 hr.

♦ Alternative regimens:

 Lindane (1%) 1 oz of lotion or 30 g of cream applied to all areas of 

the body from the neck down and washed off thoroughly after 8 hr 

OR ivermectin 200 ug/kg po, repeated in 2 weeks.

 Lindane should not be used by pregnant or lactating women or after 

a bath.

 Itching may persist for days following treatment; antihistamine 

therapy should be considered for symptomatic relief. Bedding and 

clothing should be decontaminated (machine washed or dry-cleaned) 

or removed from body contact for at least 72 hours. Norwegian 

scabies should be managed in consultation with an expert.

- Pediculosis pubis is due to infestation by the crab louse, Phthirus 

pubis, or pubic louse. Transmission is by close contact, but the 

louse can also be acquired from bedding or towels. This infection 

is usually confined to the hairy areas of the vulva (eyelids are 

occasionally infested). The presenting symptom is constant 

itching in the pubic area. Eggs, adult lice, and fecal material 
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can be seen upon close examination (without magnification). 

The diagnosis can be definitively established by microscopic 

visualization, as described above.

♦ The CDC-recommended treatment (CDC, 2002) is permethrin 

1% cream rinse applied to affected areas and washed off after 10 

min or, lindane 1% shampoo (applied for 4 min and thoroughly 

washed off; lindane not recommended for pregnant or lactating 

women) OR pyrethrins with piperonyl butoxide (applied to the 

affected area and washed off after 10 min). If symptoms do not 

resolve, patients should be reexamined in 1 wk; if lice or eggs are 

seen at the hair-skin junction, the patient should be retreated. All 

clothing and bedding must be decontaminated. Close household 

contacts and sexual contacts (within the previous month) should 

be treated.

XII. BREAST LUMP

A. HISTORY

If palpable by the patient, duration of the lump; any associated 

symptoms (e.g., tenderness, nipple discharge, cyclic pain); changes in 

the characteristics of the lump (e.g., increase in size); history of previous 

breast lumps; family history of breast disease or cancer or history of 

genetic screening showing BRCA-1 or BRCA-2 mutation.

B. PHYSICAL EXAM

Symmetry, contour, and appearance of the skin; presence of edema, 

erythema, skin dimpling, or nipple retraction; presence and size of 

dominant masses, nodularity, tenderness; nipple discharge (including 

color); and lymphadenopathy (axillary and supraclavicular).

C. EVALUATION

• Mammogram: should be performed with any persistent palpable 

mass or other suspicious changes in the breast (e.g., bloody nipple 

discharge, skin retraction). A negative mammogram alone is not 

sufficient to rule out malignant pathology in a patient with a 

palpable breast mass or bloody nipple discharge; further evaluation 

and possible biopsy are indicated.

• Ultrasound: most helpful to distinguish cystic and solid masses; 

useful initial test in younger women when simple cyst suspected.

• Needle aspiration: for cystic lesion; fluid can be discarded if clear 

and if mass disappears; otherwise send fluid for cytology, and 

biopsy may be needed.

• Biopsy: indicated in cases of dominant mass (even with 

normal mammographic findings) or suspicious nonpalpable 

mammographic findings.
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D. DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

• Fibrocystic change: Typically found among women who are 30–50 

yr old. Fibrocystic changes usually present as breast nodularity 

associated with cyclic bilateral pain or tenderness, which is worse 

premenstrually. Breast engorgement, increased density, and cyst 

formation are common and vary with menstrual cycle phase. The 

pain/discomfort associated with this condition can be relieved 

wearing a brassiere that gives adequate support. Analgesics can aid 

in symptomatic relief; some women have reported improvement of 

symptoms with vitamin E (400 IU a day) and decrease in caffeine 

consumption. Oral contraceptives are known to decrease benign 

breast disease. The appearance of a persistent dominant mass 

requires biopsy.

• Fat maldistribution syndrome: HIV or antiretroviral treatment 

may affect breast tissue, resulting in gynecomastia or increased 

fatty deposition (Pantanowitz, 2002)

• Breast abscess/mastitis: Usually presents with tender breasts with 

evidence of inflammation (redness, swelling); if abscess present, 

may palpate fluctulent mass; fever may be present. Generally 

bacterial etiology, but consider tuberculous mastitis/abscess in 

appropriate circumstances. Treatment includes antibiotics, incision 

and drainage of abscess. Consider biopsy and/or other diagnostic 

tests with non-response.

• Benign breast tumor: Most frequently diagnosed benign tumors of 

the breast are fibroadenomas, usually found in women aged 20–35. 

Typically, most masses are about 2–3 cm in diameter, although 

they can become much larger. Examination reveals a firm, smooth, 

rubbery mass that is freely mobile. Inflammation, skin dimpling, 

and nipple retraction are absent. On mammographic examination, 

the mass appears smooth with well-defined margins. Definitive 

diagnosis is established by means of biopsy. A fibroadenoma 

may simply be observed; however, a large, growing, or otherwise 

suspicious mass should be surgically excised.

• Breast cancer: Incidence of breast cancer increases with age; 

risk factors include positive family history, early menarche, late 

menopause, and nulliparity or late childbearing. If a palpable 

mass is present, it is usually firm and nontender with irregular 

margins; it may be fixed to skin or underlying tissue. Definitive 

diagnosis is established by means of biopsy, and referral to a 

surgeon is indicated. Although there is no apparent increase in 

incidence of breast cancer among HIV-positive women and most 

cases occur with CD4 counts above 200/mm3, breast cancer in the 

setting of HIV infection tends to occur at a relatively early age, is 

more likely to be bilateral and to have unusual histology, and is 

more aggressive, with early metastatic spread and poor outcome. 

Kaposi’s sarcoma and non-Hodgkins lymphoma may also be 

localized to the breast in women with AIDS. (Pantanowitz, 2002; 

Voutsadakis, 2002).
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XIII. MENOPAUSE

As HIV-positive women live longer and more women nearing menopause 

or postmenopausal become infected, menopausal issues become more 

important to consider and address. The association between HIV/AIDS 

and premature ovarian failure remains unclear.

Menopause is defined as the permanent cessation of menstruation 

caused by the loss of ovarian function. The mean age at which women 

undergo menopause is genetically predetermined and in the United 

States averages between 51 and 52 yr of age. Certain medical conditions, 

such as osteoporosis and cardiovascular disease, have been linked to 

estrogen deficiency and women with HIV may be at increased risk for 

these conditions, particularly if they are on potent antiretroviral therapy 

(see Chapter IV Primary Medical Care); associations have also been 

proposed between menopause and Alzheimer’s disease and colon cancer 

(Hurd, 1996; Mishell, 1997b).

A. HISTORY

Last menstrual period and recent menstrual pattern (cycle length, 

duration, and amount of flow); any irregular or intermenstrual bleeding 

or spotting; hot flashes; genitourinary dryness/atrophy; decreased libido; 

anxiety, irritability, sleep disturbances, and depression; difficulty with 

memory; urinary symptoms

B. PHYSICAL EXAM

Vagina appears smoother in contour, “drier”; may be more easily 

traumatized and more vulnerable to infection.

C. EVALUATION

If indicated, confirmation of menopause can be provided by an elevated 

serum follicle-stimulating hormone level and a low estradiol level.

D. MANAGEMENT

• Hormone Replacement Therapy (HRT) (combined estrogen– 

progestin replacement therapy)

 The benefits and risks associated with HRT have been extensively 

studied among women who are HIV-negative. HRT is known to 

ameliorate symptoms of vasomotor instability (e.g., hot flashes, 

sleep disturbances, irritability, etc.) and urogenital atrophy (e.g., 

vaginal dryness, dyspareunia, etc.). HRT also is associated with 

decreased risk of osteoporosis and osteoporosis-related fractures 

and colon cancer (Women’s Health Initiative, 2002). However, 

results of a recent large randomized, placebo-controlled study of 

combined estrogen-progestin therapy found a small but statistically 

significant increase in incidence of breast cancer, dementia, stroke, 

pulmonary embolism, and cardiovascular disease (Rousouw, 
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2002; Shumaker, 2003; Chlebowski, 2003). HRT should no longer 

be given for primary or secondary prevention of cardiovascular 

disease. A recent prospective cohort study found increased breast 

cancer risk from even brief exposures to both estrogen only and 

estrogen–progestin combination hormone replacement (Beral, 

2003), although risk was substantially greater for combination 

HRT. Given current data, the primary indication for HRT is for the 

short-term management of menopausal symptoms. It is unclear 

whether lower doses of combined estrogen-progestin therapy or 

estrogen alone are associated with similar spectrum or magnitude 

of risks, although there is an increased risk of endometrial cancer 

in women treated with estrogen only. Because of the higher 

prevalence of active liver disease in hepatitis B or C coinfected 

patients and the potential increase in risk for cardiovascular 

disease associated with metabolic changes of long-term 

antiretroviral therapies, HRT may be associated with increased risk 

in the setting of HIV infection. 

• Alternatives to HRT

- Progestin-only regimens (medroxyprogesterone acetate 10–30 mg 

or norethindrone 1–5 mg daily) may help relieve hot flashes 

in women; effect of long-term therapy on breast cancer risk 

unknown.

- Nonhormonal lubricants and/or moisturizers or Estring (vaginal 

ring with estradiol reservoir that is changed every 90 days — 

minimal systemic absorption) for the management of urogenital 

atrophy.

- Bisphosphonates (e.g., Fosamax) for the prevention or treatment 

of osteoporosis.

- Selective estrogen receptor modulators (raloxifene 60 mg 

po every day) offer bone and cardiovascular benefit without 

evidence of breast or endometrial stimulation; no effect on hot 

flashes, small increase in risk of venous thromboembolism.

XIV. HEALTH MAINTENANCE ISSUES (HILLIARD, 1996)

• Gynecologic evaluation: annually and as indicated by presence 

of symptoms, follow-up of ongoing problems, exposure to STIs, 

development of abnormal Pap smear, or other need for referral 

based on primary care evaluation

• Pap smears: twice within the first year of diagnosis and then 

annually; more frequent screening indicated with history of 

abnormal Pap, HPV infection, after treatment for cervical 

dysplasia, and with symptomatic HIV disease

• STI screening:

- annual syphilis screening or with development of neurologic 

signs/symptoms
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- gonorrhea/chlamydia screening: offer annually at time of 

routine gynecologic visit, if sexually active; perform as indicated 

by the presence of relevant symptoms or findings on exam, with 

recent change in sexual partners, history of STI in sexual partner, 

periodically as indicated by sexual practices (commercial sex 

workers, multiple partners, inconsistent use of condoms), or with 

patient request

• Mammography: The American Cancer Society recommends 

annual mammography beginning at age 40 (Smith, 2003a); women 

at increased risk (e.g., first-degree relative(s) with breast cancer, 

BRCA 1 or BRCA 2 mutation) may benefit from earlier initiation 

of screening or the addition of screening modalities other than 

mammography, such as ultrasound or MRI. Mammogram should 

be performed with presence of persistent palpable mass or other 

suspicious findings on exam

• Screening for colorectal cancer: begin screening at age 50 with 

annual fecal occult blood testing OR flexible sigmoidoscopy 

every 5 years OR double contrast barium enema every 5 years 

OR colonoscopy every 10 years; women with colorectal cancer 

or adenomatous polyp in any first-degree relative before age 60 

or in two or more first-degree relatives at any age should have 

colonscopy every 5-10 years beginning at age 40 or 10 years 

before youngest case in immediate family. Women with certain 

conditions (familial polyposis, personal history of inflammatory 

bowel disease, adenomatous polyps, or colon cancer ) have altered 

recommendations for screening. Please refer to American Cancer 

Society Guidelines for the Early Detection of Cancer, 2003 (Smith, 

2003b).

• Osteoporosis prevention: 1000–1200 mg/day calcium in 

premenopausal women; 1200–1500 mg/day in postmenopausal 

women; regular performance of weight-bearing exercise. Periodic 

bone density screening should be considered in postmenopausal 

women, in particular those with risk factors for osteoporosis (e.g., 

Caucasian or Asian race/ethnicity; alcohol abuse; smoking; low 

body mass index; chronic steroid use). Women are at increased 

risk for osteoporosis as compared to men, and risk increases after 

menopause. Recent studies suggest an association between HIV 

infection and possibly antiretroviral therapy and loss of bone 

density (Thomas, 2003); therefore, women with HIV may be at 

additional risk for osteopenia and osteoporosis. 

• Lipid screening: Assess risk factors for hyperlipidemia at initial visit 

and periodically: history of cardiovascular, peripheral vascular, or 

cerebrovascular disease; age >55; family history; smoking; diabetes; 

hypertension; obesity; physical inactivity. Periodic lipid profile 

screening based on risk factors, baseline results, and antiretroviral 

regimen and/or ongoing treatment for hyperlipidemia.
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XV. GUIDELINES FOR GYNECOLOGIC REFERRAL

In general, referral to an obstetric-gynecologic specialist should be 

considered under the following circumstances:

• Uncertain diagnosis with gynecologic condition part of differential 

diagnosis

• Diagnosis of pregnancy

• Inadequate response to standard treatment regimens for 

gynecologic conditions

• Possible need for surgical intervention

• A premalignant or malignant condition is suspected

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U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 231

COLOR

PLATES

PLATE 1 

Trichomonads in a saline wet mount (high power) (Monif, 1982; Fig. 22-

2; reprinted with permission from Harper & Row.)

PLATE 2. 

Clue cells of G. vaginalis vaginitis on a saline wet mount (high power) 

(Monif, 1982; Fig. 22-3; reprinted with permission from Harper & Row.) 

COLOR PLATES
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PLATE 3. 

Candida in a saline wet mount (high power) (Monif, 1982; Fig. 22-4B; 

reprinted with permission from Harper & Row.)

COLOR PLATE 4. 

Vaginal candidiasis: thrush patches on the vaginal wall of a patient with 

candidiasis (courtesy J. Anderson, MD).
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Color Plates

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COLOR

PLATES

COLOR PLATE 5. 

Severe vulvar intraepithelial neoplasia (VIN3) (Wilkinson and Stone, 

1995; Fig 6.27; reprinted with permission from Williams & Wilkins.)

COLOR PLATE 6. 

Nontender chancres (kissing lesions) in a woman with primary syphilis 

(Wilkinson and Stone, 1995; Fig 8.46; reprinted with permission from 

Williams & Wilkins.)
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COLOR PLATE 7. 

Extensive vulvar condylomata acuminata (human papillomavirus) 

(Wilkinson and Stone, 1995; Fig 9.3; reprinted with permission from 

Williams & Wilkins.)

COLOR PLATE 8. 

Cervical intraepithelial neoplasia (CIN3) demonstrating coarse 

mosaicism and punctuation on posterior lip (Burghardt, 1991; 

Fig. 11.37; reprinted with permission from Thieme Medical Publishers.)
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Color Plates

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COLOR

PLATES

COLOR PLATE 9. 

Mucopurulent cervicitis caused by C. trachomatis (Holmes, 1999; Plate 

16; reprinted with permission from McGraw Hill.)

COLOR PLATE 10. 

Profuse purulent frothy vaginal discharge due to trichomonas (Holmes, 

1999; Plate 21; reprinted with permission from McGraw Hill.)
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COLOR PLATE 11. 

Pelvic inflammatory disease, proven chlamydial pyosalpinx. Right tube 

is swollen and tortuous (arrow) (Holmes, 1999; Plate 17; reprinted with 

permission from McGraw Hill.)

COLOR PLATE 12. 

Chancroid (Holmes, 1999; Plate 32; reprinted with permission from 

McGraw Hill.)

uterus
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COLOR

PLATES

COLOR PLATE 13. 

Condyloma latum in secondary syphilis (Holmes, 1999; Plate 47; 

reprinted with permission from McGraw Hill.)

COLOR PLATE 14. 

Lesion of herpes simplex (courtesy J. Anderson, MD).
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COLOR PLATE 15. 

Herpes simplex in woman with AIDS, CD4<50 

(courtesy J. Anderson, MD).

COLOR PLATE 16. 

Apthous genital ulceration (courtesy J. Anderson, MD).
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COLOR

PLATES

COLOR PLATE 17. 

Apthous oral ulceration (courtesy J. Anderson, MD).
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240 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

REFERENCES

Burghardt E. Colposcopy – Cervical Pathology – Textbook and Atlas, 2nd revised 

and enlarged edition. New York: Thieme Medical Publishers, 1991.

Holmes KK, Sparling PF, Mardh, P-A, et al, eds. Sexually Transmitted Diseases, 

3rd Ed. New York: McGraw Hill, 1999.

Monif GRG. Infectious Diseases in Obstetrics and Gynecology. Philadelphia: 

Harper & Row, 1982.

Wilkinson EJ, Stone IK. Atlas of Vulvar Disease. Baltimore: Williams & 

Wilkins, 1995.
U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 241

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VII

I. INTRODUCTION 

The ability to become pregnant and to bear children is uniquely female. 

With increasing numbers of HIV-infected women, 80% of whom are of 

childbearing age, and concerns about perinatal transmission of HIV, 

pregnancy in the setting of HIV infection has been a focus of much 

interest, research, and often discrimination. From 1989 to 1994 it was 

estimated that 1.5 to 1.7/1000 U.S. childbearing women were HIVpositive (Davis, 1998); however, this number may grow as more women 

become infected through sexual exposure, often unaware of their risk, 

and as more women who know they are infected choose to become 

pregnant because of therapeutic advances in care and prevention of 

vertical transmission. Almost one-third of HIV-infected men and women 

receiving medical care in the US desire children in the future (Chen, 

2001). Furthermore, 20% of serodiscordant couples would practice 

unsafe sex in order to conceive (Klein, 2003). 

This chapter will review issues related to contraception and pregnancy 

and will discuss guidelines for care during pregnancy to optimize the 

health of both the mother and the fetus and infant. 

II. COUNSELING 

The American College of Obstetricians and Gynecologists (ACOG) 

advocates reproductive counseling for all women of child bearing age as 

a part of primary care. For women known to be HIV-infected, education 

and counseling about pregnancy and HIV should be done early in the 

course of HIV care, not delayed until the woman is pregnant, so that 

decisions about contraception and if or when to get pregnant can be most 

informed and carefully considered. Discussions about pregnancy should 

be repeated at intervals throughout care, especially when personal 

circumstances change (e.g. new sexual partner, postpartum); when there 

is nonuse of effective contraception; where therapies are considered 

which may have adverse effects in pregnancy; or when the woman 

expresses a desire to become pregnant. Over one half of pregnancies in 

U.S. women are unplanned, and many of the risk factors for unintended 

pregnancy also place women at increased risk for HIV. These include: 

• substance abuse (patient or partner) 

• mental illness 

• domestic violence 

VII. HIV AND REPRODUCTION

Jean Anderson, MD
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HIV and Reproduction

242 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

Adolescents are at an increased risk of unintended pregnancy and 

may also be at increased risk for HIV because of frequent unstable 

sexual relationships and unsafe sexual practices. Women with 

advanced HIV disease and HIV dementia may be at increased risk 

for unintended pregnancy if they are dependent on a contraceptive 

method (such as condom use or oral contraceptives) that requires 

negotiation with a sexual partner or other ongoing patient action 

(i.e., remembering to take pills). Issues to discuss when counseling 

about reproductive issues are listed in Table 7-1. 

Table 7-1: HIV and Pregnancy Counseling Issues 

• Impact of HIV on pregnancy course/outcome

• Impact of pregnancy on HIV progression

• Other reproductive issues based on maternal factors 

- coexisting drug/alcohol use 

- advanced maternal age 

- hypertension, diabetes, etc. 

• General preconception issues 

- nutritional counseling (e.g. folic acid) 

- importance of early and intense prenatal care

• Long term health of mother and care for children (guardianship issues) 

• Perinatal transmission

• Use of antiretrovirals and other medications in pregnancy 

• Safe conception if partner HIV-negative 

III. CONTRACEPTION 

The majority of HIV-infected U.S. women use some form of contraception, 

most commonly condoms (Wilson, 1999; Watts, 1999). Women using no 

form of contraception do not necessarily intend to become pregnant 

but may lack significant power in their sexual relationship, be under 

pressure from partner or family to have children, may not have 

disclosed their HIV status to their partner, be unaware of their options 

concerning contraception or believe they cannot become pregnant, have 

a disorganized lifestyle that precludes consistent use of contraception, 

or simply have decided to take their chances. Unplanned also does not 

necessarily mean unwanted; several studies show low rates of elective 

pregnancy termination in HIV-positive women (Smits, 1999; Greco, 1999) 

and no significant difference in repeat pregnancy rates in HIV-positive 

compared with HIV-negative women from an inner-city population 

(Lindsay, 1995). Table 7-2 outlines currently available methods of 

contraception, their effectiveness, side effects and contraindications, and 

noncontraceptive benefits. 
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Table 7-2: Contraceptive Methods

Method Failure Rates 

(% Pregnancies) in 

First Year of Typical 

and Perfect Use 

Contraindications Benefits Potential Side 

Effects

Convenience Disadvantages

Typical Perfect

HormonalCombined oral contraceptive pill (OC)

3 0.1 History of CVD, DVT, 

stroke; Hypertension; High LDL/HDL ratio; >35 and heavy smoker; Markedly impaired liver function; Hepatocellular adenoma; Headache with focal neurologic symptoms; Diabetes with nephropathy, retinopathy, neuropathy, or vascular disease; Breast cancer; Major surgery with immobilization 

Decreased menstrual pain, PMS, and blood loss; May reduce acne; Decreased benign breast disease; Decreased functional ovarian cysts; Decreased ovarian and endometrial cancers; Decreased PID

Nausea; Headache; Weight gain; Dizziness; Breast tenderness; Vaginal spotting; Chloasma; Depression

Use independent from sexual intercourse

No STI protection; May increase susceptibility to some STIs; Must remember to take pill daily

Combined estrogenprogestin injection (Lunelle)

0.03-0.1 0.03-0.1 Same as for OCs Same as for OCs Similar to OCs; more 

spotting/irregular bleeding than with OCs

Use independent from sexual intercourse; Daily action not required

No STI protection; May increase susceptibility for some STIs; Must have IM injection monthly in medical office (5 day “grace” period)

Combined estrogenprogestin vaginal ring (Nuva Ring)

N/A 0.6 Same as for OCs Same as for OCs Similar to OCs; possible 

increased vaginal discharge

Use independent from sexual intercourse; Vaginal ring inserted for 3 wks out of every mo – precise placement not required

No STI protection; May increase susceptibility for some STIs
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Table 7-2: Contraceptive Methods (continued)

Method Failure Rates 

(% Pregnancies) in 

First Year of Typical 

and Perfect Use 

Contraindications Benefits Potential Side Effects Convenience Disadvantages

Typical Perfect

Hormonal (continued)Combined estrogenprogestin patch (Ortho Evra)

0.6–0.8 (may be higher with wt > 90kg)

0.6 Same as for OCs Same as for OCs; improved 

user compliance

Similar to OCs; Skin irritation

Use independent from sexual intercourse; Patch applied weekly 3 of 4 weeks

No STI protection; May increase susceptibility for some STIs

Depomedroxyprogesterone acetate (DMPA)

0.3 0.3 Unexplained vaginal 

bleeding; Breast cancer 

Decreased risk of seizures; May have protective effects against PID, ovarian and endometrial cancer; Decreased blood loss, anemia Amenorrhea

Menstrual changes (spotting, irregular bleeding, amenorrhea); Weight gain Breast tenderness; Headache; Adverse effect on lipids; Depression

Often causes amenorrhea; Requires only 4 injections/yr; Requires no ongoing action by user; Use independent from sexual intercourse

No STI protection

Norplant 0.9 0.9 Same as above Same as above Tenderness or infection at 

site; Menstrual changes; Hair loss; Weight gain; Breast tenderness; Depression 

Provides 5 yr of contraception; Requires no ongoing action by user; Use independent from sexual intercourse

No STI protection

Progestin-only pill 1.1–13.8 0.5 Same as above Same as above Menstrual changes 

(spotting, irregular bleeding, amenorrhea); Breast tenderness; Depression; Weight gain

Use independent from sexual intercourse

No STI protection; Ectopic pregnancy more likely among progestin-only pills than other forms of hormonal contraception; Must remember to take pill daily
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Barrier MethodsCondom, male (latex, polyurethane, natural membrane)

12 3 Allergy to condom material Protects against STIs, 

including HIV (except for natural memberane). Delays premature ejaculation

Allergy or sensitivity to condom material; Decreased sensitivity

Inexpensive and readily available; Does not require a prescription

Requires partner possible cooperation; Possible loss of spontaneity during sex

Condom, female 21 5 Polyurethane allergy Protects against STIs, 

including HIV

Allergy or sensitivity to polyurethane; Possible decreased sensitivity

Woman controlled; Less likelihood of breakage; Can be inserted up to 8 hr before intercourse; Does not require a prescription 

May be awkward to use; Aesthetically unappealing to some limited data

Cervical cap — parous/nonparous 

36/18 26/9 Latex allergy; Abnormal 

cervical/ vaginal anatomy; History of TSS or recurrent UTIs; Known or suspected cervical/uterine malignancy; Abnormal Pap; Vaginal or cervical infection; Recent delivery or spontaneous/induced abortion

Limited STI protection Pelvic pressure; Vaginal 

irritation; Allergy or sensitivity to latex; Vaginal or urinary tract infections

Woman controlled; Can be inserted ahead of time 

Efficacy based on high motivation; Spermicide reapplication required with each act of coitus; Should not be used during menses

Diaphragm 18 6 Latex allergy; Abnormal 

vaginal anatomy; History of TSS or recurrent UTIs

Limited STI protection; Reduces risk of PID

Same as above Woman controlled; Can be 

inserted up to 6 hr before intercourse

Same as above, except may be used during menses

Spermicides 21 6 Allergy to nonoxynol-9 Protection against some 

STIs, significant against gonorrhea/chlamydia;In vitro activity against HIV

Vaginal irritation; Allergy; Vaginal and urinary tract infection

Woman controlled; Does not require a prescription; Easily available and inexpensive

Efficacy reduced when used without a barrier method; May increase susceptibility to HIV with frequent sexual activity; No protection against HIV

IUD (CopperParagard) 0.8 0.6 Recent (within 3 mo) or recurrent pelvic infection; 

Postpartum, postabortion endometritis; Active STI; Women at increased risk for STIs; Severely distorted uterine cavity

None Menstrual cramping; 

Increased bleeding; Risk of PID and uterine perforation following insertion; Anemia

Provides contraception for 10 yrs; Requires no ongoing user action

No STI protection; Increased risk of PID 
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Table 7-2: Contraceptive Methods (continued)

Method Failure Rates 

(% Pregnancies) in 

First Year of Typical 

and Perfect Use 

Contraindications Benefits Potential Side Effects Convenience Disadvantages

Typical Perfect

Levonorgestrel intrauterine system (Mirena)

0.1–0.3 0.1 Same as for Copper IUD Overall reduction in 

menstrual blood loss (20% amenorrhea after 1 yr); Possible decreased rates of anemia, PID

Increased incidence of irregular bleeding in 1st 6 mo (compared to Copper IUD); Risk of PID and uterine perforation following insertion

Provides contraception for 5 yr; Requires no ongoing user action

No STI protection

Female surgical sterilization

0.4 0.4 Desire for future fertility; 

Active pelvic infection

Possible decreased risk of ovarian cancer; Decreased risk of salpingitis

Pain at surgical site; Subsequent regret; Increased risk of ectopic pregnancy if failure

Provides permanent contraception; Requires no ongoing user action

Permanent; No STI protection

Nonsurgical female sterilization (Essure)

0.2–0.4 0.2–0.4 Desire for future fertility; 

Active pelvic infection

Probably similar to surgical sterilization (experience limited)

Subsequent regret; Increased risk of ectopic pregnancy if failure; Cramping, nausea/vomiting with placement; Expulsion or uterine perforation (<3%)

Provides permanent contraception; Requires no ongoing user action; Lower cost, does not require surgery or general anesthesia as compared to surgical sterilization

Permanent; No STI protection; Requires office procedure for insertion, use of alternate contraception for 3 mo, and hysterosalpingographic confirmation of tubal occlusion

Male sterilization 0.15 0.10 Desire for future fertility None Pain at surgical site; 

Subsequent regret

Provides permanent sterilization for the man

Same as above, except sterility not immediate

Pregnancy Rate

Emergency contraception -Levonorgestrel 0.25mg/ Ethinylestradiol 50μg (Preven) - Levonorgestrel 0.75mg (Plan B)

3.2% (57% expected 

pregnancies prevented) 1.1% (85% expected pregnancies prevented)

Established pregnancy None Nausea and vomiting (less 

with Plan B); Changes in next menses (generally minor)

Can be used after unprotected intercourse or with other contraceptive “failure” (e.g. condom breakage)

Should be used within 72 hrs of intercourse; No STI protection; Failure rate higher if intercourse during fertile phase of cycle

CVD, cardiovascular disease; DVT, deep vein thrombosis; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PID, pelvic inflammatory disease; PMS, premenstrual syndrome; IUD, intrauterine device; STI, sexually transmitted infection; TSS, toxic shock syndrome; UTI, urinary tract infection Source: Hatcher, 1998; Johannson, 2004.
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Hormonal methods of contraception, particularly combined estrogenprogestin oral contraceptives (OCs), can have significant drug interactions, 

resulting in either decreased contraceptive effectiveness or increased or 

decreased concentrations of the coadministered drug. Use of nelfinavir, 

ritonavir, lopinavir, and nevirapine are associated with decreases in 

ethinyl estradiol (estrogen component of OCs) with possible decrease 

in effectiveness (and possible increase in breakthrough bleeding); an 

alternative or additional method should be used. Indinavir, atazanavir and 

efavirenz are associated with increases in ethinyl estradiol and indinavir 

and atazanavir are associated with increases in norethindrone (progestin 

component in many OCs). Norethindrone levels are increased over 100% 

with atazanavir. The clinical significance of these increases in hormonal 

blood levels is unclear, but they raise concerns about potential increase 

in estrogen- or progestin-related side effects. Alternative methods of 

contraception should be considered; if OCs are used, lowest effective doses 

of affected hormonal components should be prescribed and an additional 

method is recommended. Amprenavir (and probably fos-amprenavir) not 

only increases blood levels of ethinyl estradiol and norethindrone, but 

OCs decrease amprenavir levels as well; these drugs should not be coadministered and an alternative contraceptive method should be used. 

Other medications known to interact with oral contraceptives (and in 

some cases with progestin-only contraceptives) include tetracyclines, 

penicillin, oral hypoglycemic agents, rifampin, tricyclic antidepressants, 

oral anticoagulants, ß-blockers, methyldopa, vitamin C, benzodiazepines, 

and seizure medications. Clinicians treating women who are at risk for drug 

interactions should review the need for possible use of alternative methods 

of contraception or dose adjustment for the interacting agent. There is 

minimal information about drug interactions with use of newer hormonal 

contraceptive methods (patch, vaginal ring, estrogen-progestin injection). 

Concerns have been raised about possible increased risk of HIV 

transmission or acquisition in hormonal contraceptive users. There is 

evidence that both combined oral contraceptives and progestin-only 

contraceptives may increase genital tract HIV shedding; furthermore, 

oral contraceptives have been associated with increased cervical ectopy, 

which has also been linked with genital tract HIV shedding. Similarly, 

ectopy or other epithelial changes secondary to hormonal contraception 

or associated effects on immune response may increase susceptibility 

to HIV, and animal studies have suggested a link between progesterone 

implants and vulnerability to simian immunodeficiency virus (Mostad, 

1998; Plummer, 1998). Data from epidemiologic studies are conflicting 

and inconclusive regarding the relationship of these methods of 

contraception and HIV transmission (Martin, 1998; Stephenson, 1998; 

Kiddugavu, 2003; Wang, 1999; Kapiga, 1998). At the current time, given 

their effectiveness, overall safety, and ease of use, hormonal methods of 

contraception remain an appropriate option for HIV-infected or at-risk 

women. These women should be advised that these contraceptives do 

not protect against HIV transmission and consistent condom use should 

be emphasized. 
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Use of the intrauterine device (IUD) has been accompanied by concerns 

about a potential increased risk for HIV susceptibility. However, a recent 

large prospective cohort study of almost 2500 HIV-uninfected women 

found no association between IUD use and HIV transmission; there was 

also no increased risk associated with increasing duration of use (Kapiga, 

1998). Furthermore, another study from Kenya found no increase in 

overall complications or infection-related complications in HIV-positive 

IUD users as compared to HIV-negative IUD users and complications 

did not differ by CD4 count (Morrison, 2001). Use of the IUD was not 

associated with increased rate of cervical HIV shedding 4 months after 

insertion over baseline pre-insertion shedding rates (Richardson, 1999). 

However, risk of pelvic inflammatory disease is increased in IUD users 

who are at increased risk for acquiring other sexually transmitted 

infections (STIs) and a recent study found an association between IUD 

use and bacterial vaginosis, also a risk factor for PID (Joesoef, 2001). 

Furthermore, copper IUDs are associated with increased menstrual flow 

and duration, possibly contributing to transmission risk and anemia in 

HIV-positive women. The IUD should be used cautiously in the setting 

of HIV infection. 

Spermicides have in vitro activity against HIV; however, standard 

spermicidal doses of nonoxynol-9 (N-9) have been associated with an 

increase in irritation, colposcopic and histologic evidence of inflammation, 

and decreased numbers of vaginal lactobacilli in N-9 users, compared with 

placebo recipients (Stafford, 1998). In a randomized placebo-controlled 

clinical trial of N-9 conducted among commercial sex workers with high 

rates of sexual activity, N-9 did not protect against HIV infection, resulted 

in increased vaginal lesions, and possibly caused increased transmission 

(Richardson, 2002). Although these adverse effects might not occur with 

less frequent use, given current evidence, spermicides containing N-9 

should not be recommended as an effective means of HIV prevention. 

A meta-analysis of randomized controlled trials using N-9 also found no 

evidence of protection against HIV acquisition (Wilkinson, 2002) and N9 appears to offer no protection against sexually transmitted infections 

such as gonorrhea or chlamydia (WHO, 2002). 

Condoms — used consistently — reduce HIV transmission risk by 80% 

and provide the best known protection against sexual transmission of 

HIV. They should be emphasized for all HIV-infected and at-risk women 

to decrease risk of HIV transmission/acquisition and transmission/

acquisition of other STIs. Other barrier contraceptive methods provide 

limited STI protection and have not been shown to offer significant 

protection against HIV transmission. 

Because male and female condoms are used for both prevention of 

infection and prevention of pregnancy, these two separate issues should 

be distinguished when counseling patients. There is some evidence that 

condom use is less likely in HIV-infected women using other methods of 

contraception. Condom use should be reinforced for HIV-positive or at-risk 

women when prevention of pregnancy is not a concern: postmenopausal 
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women, during pregnancy, despite infertility, and with the use of other 

methods of contraception. As with use of contraception in general, use of 

condoms for HIV prevention is related to education, relationship to sexual 

partner, and chaos in life. There is some indication that use of HAART 

and decrease in viral load may lead to drop-off in condom use. 

IV. PREGNANCY TESTING 

Indications for pregnancy testing in currently or recently sexually active 

women: 

• missed menses (unless on Norplant or Depo-Provera) 

• irregular bleeding (unless on Norplant or Depo-Provera) 

• new onset of irregular bleeding after prolonged amenorrhea on 

Norplant/Depo-Provera 

• new onset pelvic pain 

• enlarged uterus or adnexal mass on exam 

• consider before instituting new therapies 

Pregnancy tests are performed on blood or urine and may be qualitative 

(positive/negative) or quantitative. Quantitative tests are useful in early 

pregnancy when ectopic pregnancy or abnormal intrauterine pregnancy 

(e.g., missed abortion) is suspected. Several qualitative urine pregnancy 

tests are available over the counter. Most pregnancy tests in current use are 

positive before the first missed menses with normal intrauterine pregnancy. 

Table 7-3 lists types of available pregnancy tests and their sensitivity.

Table 7-3: Pregnancy Tests

Sensitivity Comments

Radioimmunoassay - 

blood 

Positive within 7 days of 

fertilization

Quantitative or qualitative 

Used to follow women with 

possible ectopic pregnancy

Enzyme immunoassay 

- blood 

- urine

Positive approximately 

10 days after fertilization

Available for home urine 

testing — positive results 

require confirmation

Antibody agglutination 

inhibition 

- urine

Positive approximately 

18–21 days after 

fertilization 

False positives may occur with 

hypothyroidism, renal failure, 

immunologic disorders, 

increased luteinizing hormone

V. HIV AND FERTILITY 

Recent studies in Africa, as well as in developed countries, have suggested 

that HIV may have an adverse effect on fertility in both symptomatic and 

asymptomatic women (Desgrees, 1999; L.M. Lee, 2000; Zaba, 1998). A 

cross-sectional study from Uganda found likelihood of pregnancy lower 

in HIV-positive women compared with HIV-negative women and lowest 
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in women who were symptomatic from HIV or were coinfected with 

syphilis. A prospective study in the same population found that pregnancy 

rates were lower and pregnancy loss was more common in HIV-infected 

women (Gray, 1998). There are longer intervals between births for HIVpositive women compared to HIV-negative women (Glynn, 2000) and 

higher HIV viral loads have been associated with longer times to achieve 

pregnancy in women trying to conceive (Nguyen, 2003). In addition, both 

advanced disease stage and HIV-related therapies may be associated with 

abnormal sperm counts in HIV-infected men and menstrual dysfunction 

in HIV-infected women. 

VI. EFFECTS OF PREGNANCY ON HIV INFECTION 

A. CD4 COUNT AND HIV RNA LEVELS IN PREGNANCY

In both HIV-positive and HIV-negative women the response of CD4 cell 

counts to pregnancy is variable (Tuomala, 1997). Many studies have 

suggested that there is a decline in absolute CD4 cell counts in pregnancy, 

which return to baseline at the end of pregnancy or during the postpartum 

period. The decline in CD4 count is thought secondary to hemodilution; 

on the other hand, percentage of CD4 cells remains relatively stable. 

Therefore, percentage, rather than absolute number, may be a more 

accurate measure of immune function for HIV-infected pregnant 

women (Brettle, 1995; European Collaborative Study and the Swiss HIV 

Pregnancy Cohort, 1997; Miotti, 1992). When comparing changes in CD4 

count/percentage over time, there is no difference between HIV-positive 

pregnant and nonpregnant women (O’Sullivan, 1995), suggesting that 

pregnancy does not accelerate decline in CD4 cells. HIV RNA levels 

(viral load) remain relatively stable throughout pregnancy in the absence 

of treatment (Burns, 1998). However, recent data suggest that HIV-RNA 

levels increase during the postpartum period regardless of ARV treatment 

(although use of HAART appears to blunt the effect), possibly due to 

immune activation associated with hormonal changes or to unmasking 

of a pregnancy-related viral load suppression. The implications for risk 

of transmission and treatment recommendations in the early postpartum 

period are unclear (Cao, 1997; Truong, 2003; Watts, 2003). The increase 

in viral load postpartum does not appear to reflect a long-lasting effect of 

pregnancy on viral load (Minkoff, 2003). 

B. CLINICAL COURSE OF HIV IN PREGNANCY

Most studies to date examining the impact of pregnancy on HIV disease 

have been small but have not shown significant differences in HIV 

progression or survival between pregnant women and nonpregnant 

women with HIV infection. A recent meta-analysis of seven prospective 

cohort studies found no overall significant differences in death, HIV 

disease progression, progression to an AIDS-defining illness, or fall in 

CD4 count to below 200/mm3 between cases and controls (French, 
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1998). A subsequently reported prospective study of 331 women with 

known dates of seroconversion were followed for a median of 5.5 years; 

during this time 69 women were pregnant. There were no differences 

in progression between those who were and were not pregnant during 

follow-up (Alliegro, 1997). In addition, a long-term observational study 

showed no difference in viral load, CD4, or clinical disease progression 

in women with repeat pregnancy, compared to those with only one 

pregnancy (Minkoff, 2003). 

VII. EFFECT OF HIV ON PREGNANCY COURSE AND OUTCOME 

Adverse pregnancy outcomes may occur secondary to underlying 

disease processes (or their treatment), as well as for unknown reasons. 

Approximately 10% of U.S. pregnancies end prematurely, and preterm 

birth is the leading cause of perinatal morbidity and mortality. Data 

have accumulated that HIV, especially when more advanced, may result 

in increases in certain pregnancy complications. However, results of 

studies are conflicting. Some studies suggest that HIV-infected women 

have an increase in other risk factors for adverse pregnancy outcome 

(such as smoking, drug use, poor prenatal care) and if these risk factors 

are controlled for, there is no independent effect of HIV on adverse 

outcomes (Lambert, 2000). Furthermore, concerns have been raised that 

antiretroviral treatment itself may increase some adverse outcomes in 

pregnancy (see discussion under Antiretroviral Treatment). A recent 

study of 497 HIV-infected pregnant women enrolled in a perinatal 

clinical trial found that risk factors for adverse pregnancy outcomes 

(preterm birth, low birth weight, and intrauterine growth retardation) in 

antiretroviral-treated women are similar to those reported for uninfected 

women (Lambert, 2000). Table 7-4 summarizes the relationship between 

common pregnancy-related complications and HIV (Brocklehurst, 1998a; 

D’Ubaldo, 1998; van Bentham, 2000; Ngweshemi, 2003; Dreyfuss, 2003; 

Coley, 2001; Ladner, 1998). 

Both HIV and pregnancy may affect the natural history, presentation, 

treatment, or significance of certain infections, and these, in turn, may be 

associated with pregnancy complications or perinatal infection. 

A. VULVOVAGINAL CANDIDIASIS

Pregnancy is associated with both increased rates of colonization and an 

increase in symptomatic infections with species of Candida. HIV infection 

is also associated with an increase in colonization and possible increased 

infection rates, especially with declining immune function (Burns, 1997; 

Cu-Uvin, 1999; Duerr, 1997; Schuman, 1998; Spinillo, 1994). Therefore, 

pregnant women with HIV infection may be particularly susceptible 

to yeast infections. Only topical azole agents should be used during 

pregnancy and should be given for at least 7 days. Prophylactic topical 

therapy should be considered during courses of systemic, especially 

broad-spectrum, antibiotics.
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Table 7-4: Adverse Pregnancy Outcomes and Relationship to 

Untreated HIV Infection

Adverse Pregnancy 

Outcome 

Relationship to HIV Infection 

Spontaneous abortion evidence of possible increased risk

Stillbirth evidence of increased risk in developing countries

Perinatal/infant mortality evidence of increased risk in developing countries

Intrauterine growth 

restriction 

evidence of possible increased risk

Low birth weight (<2500 g) evidence of possible increased risk, especially with 

more advanced disease

Preterm delivery evidence of possible increased risk, especially with 

more advanced disease

Preeclampsia no data

Gestational diabetes no data

Placental abruption no data

Placenta previa no data

Chorioamnionitis most recent studies do not suggest an increased 

risk in clinical or histologic chorioamnionitis; 

however, evidence of possible increased risk in 

developing countries

Oligohydramnios no data

Group B strep infection no data

Fetal malformation no evidence of increased risk

B. BACTERIAL VAGINOSIS

Bacterial vaginosis (BV) has been associated with several adverse pregnancy 

outcomes, including preterm labor and birth, premature rupture of 

membranes, low-birth-weight infants, chorioamnionitis and amniotic fluid 

infection, postpartum and postabortal endometritis, and perinatal HIV 

transmission. HIV infection has been associated with increased prevalence 

and persistence of BV, and prevalence, persistence, and severity increase with 

lower CD4 cell counts (Jamieson, 2001). If BV is diagnosed during pregnancy, 

preferred therapies are metronidazole 250 mg po tid x 7 days or clindamycin 

300 mg po bid x 7 days, since only oral agents have been shown to reduce 

preterm births in women with BV (Hauth, 1995; McGregor, 1995; Morales, 

1994). Because BV is more common in the setting of HIV, and because both 

BV and HIV have been linked to increased risk of preterm birth, pregnant 

women with HIV should be regularly asked about signs or symptoms of 

vaginal infection and, if present, evaluated for possible BV. Infection should 

be treated if identified. Currently, there are insufficient data to suggest that 

screening for and treating BV during pregnancy in the general population 

reduces the overall rate of preterm birth (Berg, 2001). A recent meta-analysis 

(Caro-Paton, 1997) found no relationship between metronidazole exposure 

during the first trimester of pregnancy and birth defects. 
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C. GENITAL HERPES SIMPLEX

Primary herpes simplex virus (HSV) infection during pregnancy has 

been associated with spontaneous abortion and prematurity. Congenital 

or intrauterine infection is uncommon but maternal HSV shedding at 

delivery is associated with neonatal HSV infection, which is almost 

always symptomatic (including skin, eye, and central nervous system 

involvement, or disseminated infection involving multiple organ 

systems) and frequently lethal. The risk of neonatal herpes is greatest 

with primary HSV, especially when acquired close to delivery (30–50%), 

whereas only 0–3% of neonates become infected with recurrent maternal 

disease at delivery; however, because recurrent HSV is more common 

than primary disease, most neonatal infections are associated with 

recurrent HSV. Two thirds or more of mothers with infected infants are 

asymptomatic during pregnancy; only one third have a history of HSV 

in themselves or their sexual partner. Because most neonatal infection 

occurs during vaginal delivery, if genital lesions or prodromal symptoms 

are present at the time of labor or membrane rupture, cesarean section 

should be performed. Cesarean section is not indicated for recurrent HSV 

distant from the genital tract (e.g., thigh, buttocks) (ACOG, 1999b). 

HIV infection, particularly with evolving immune compromise and higher 

plasma HIV viral load (Wright, 2003), is associated with increased HSV 

shedding and more frequent, severe, and prolonged episodes of genital or 

perianal herpes (Augenbraun, 1995). Higher doses and/or longer courses 

of antiviral agents may be required and suppressive therapy is often 

beneficial in nonpregnant individuals. Infection with HSV-2 is common 

among pregnant HIV-infected women and reactivation of herpes in labor 

occurs more frequently in the setting of HIV infection (Hitti, 1997). 

Treatment of symptomatic HSV infections and suppressive therapy for 

frequent recurrences should be offered during pregnancy to HIV-infected 

women (USPHS/IDSA, 2003). The risk for herpes is high in infants of 

women who acquire genital HSV in late pregnancy and such women 

should be managed in consultation with an expert. The use of oral acyclovir 

prophylactically in late pregnancy has been shown to suppress genital 

HSV outbreaks and HSV shedding in HIV- women and may reduce the 

need for cesarean section for recurrent HSV (Brocklehurst, 1998a; Watts, 

2001; Scott, 2001); however, this strategy has not been evaluated in HIV+ 

women, who are more likely to have HSV-2 antibodies and to have both 

symptomatic and asymptomatic reactivation of genital HSV. Therefore, use 

of acyclovir for the purpose of reducing the need for cesarean section in all 

HIV+ women is not recommended (USPHS/IDSA, 2003). 

Acyclovir is the drug of choice for HSV therapy during pregnancy and 

there is no current evidence for increased risk for major birth defects 

or other adverse pregnancy outcomes (Reiff-Eldridge, 2000). While 

experience with valacyclovir is more limited, its safety profile is expected 

to be similar to acyclovir, since it is the prodrug of acyclovir. Experience 

with use of famciclovir in pregnancy is limited and exposures to this 
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drug should be reported to the Famciclovir Registry at 1-888-669-6682. 

Documented HSV infections during pregnancy which do not respond to 

these agents should be managed with expert consultation. 

Prevention of neonatal herpes should also emphasize prevention of 

acquisition of herpes in susceptible women in pregnancy. If her sexual 

partner has a history of oral or genital HSV infection, serologic evidence 

of HSV infection, or infection status is unknown, the pregnant woman 

should be counseled to avoid unprotected genital and oral sexual contact 

during pregnancy. Type-specific HSV serology may be useful to identify 

the pregnant woman at risk for HSV and to guide counseling, especially 

if her sexual partner has HSV infection. At the onset of labor, all 

women should be questioned carefully about HSV symptoms, including 

prodromal symptoms, and all women should be examined carefully for 

herpetic lesions, in order to make judicious decisions about the use of 

cesarean section. 

D. HUMAN PAPILLOMAVIRUS

Genital warts may be more frequently seen and often enlarge and 

become friable during pregnancy and in some cases may mechanically 

obstruct the vaginal canal in labor; perinatal exposure can result in 

laryngeal papillomatosis in infants and children, although a recent 

prospective study suggests that the risk of perinatal transmission of 

human papillomavirus (HPV) is low (Watts, 1998). Both HPV infection in 

general and genital warts are more common in HIV-infected individuals, 

correlated with level of immunosuppression. Imiquimod, podophyllin, 

and podofilox should not be used in pregnancy. In women with large 

volume or bulk of genital warts treatment in late pregnancy with laser, 

excision, or cavitronic ultrasonic aspiration may be considered. Cesarean 

section is not currently recommended to prevent neonatal exposure to 

HPV, although in rare instances cesarean section may be indicated when 

extensive lesions obstruct the vagina. Pregnant women with abnormal 

Pap smears should undergo colposcopy and cervical biopsy, if indicated; 

increased bleeding may occur with biopsy during pregnancy. Endocervical 

currettage should not be performed during pregnancy. Pap smear should 

be repeated with or without colposcopy at 34–36 weeks gestation in 

women with initial abnormal Pap smear to rule out progression of 

dysplasia. Women with preinvasive cervical lesions can deliver vaginally, 

if otherwise appropriate; women with suspected invasive cervical cancer 

should be referred to a gynecologic oncologist. 

E. SYPHILIS

Syphilis is more prevalent in HIV-infected populations and HIV may 

affect clinical manifestations, serologic response, or response to treatment 

for syphilis. Pregnancy does not alter the clinical manifestations of 

syphilis but untreated primary or secondary syphilis during pregnancy 

affects essentially all fetuses, with 50% rate of prematurity, stillbirth, or 

neonatal death (Radolf, 1999). Even with later stages of syphilis, there 
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is a significant increase in adverse pregnancy outcomes, although the 

frequency and severity of fetal disease decrease with longer duration 

of untreated maternal infection. Manifestations of congenital syphilis 

in the newborn include mucocutaneous lesions, hepatosplenomegaly, 

osteochondritis/periostitis, jaundice, petechiae/purpura, and meningitis. 

Congenital syphilis can generally be prevented by identification and 

appropriate treatment of syphilis during pregnancy. All pregnant women 

should have serologic testing for syphilis at the beginning of prenatal 

care and testing should be repeated at 28 wk gestation and at delivery, 

particularly in women who remain at risk for infection. Any woman with 

stillbirth after 20 wk gestation should be tested for syphilis. Development 

of neurologic symptoms mandates evaluation for possible neurosyphilis. 

Treatment of syphilis during pregnancy should be the penicillin regimen 

appropriate for the stage of syphilis, although a second injection one 

week after the first in cases of primary, secondary, or early latent syphilis 

should be considered, because of concerns about effectiveness of standard 

therapy in pregnant women and in the setting of HIV infection (USPHS/

IDSA, 2003). HIV-positive women with late latent syphilis or syphilis of 

unknown duration should have cerebrospinal fluid examination before 

treatment. If there is concern for neurosyphilis, treatment should be with 

7–10 days of IV penicillin (CDC, 2002). 

Ultrasound evidence of hydrops or hepatosplenomegaly suggesting fetal 

syphilis increases risk for treatment failure and should be managed 

with expert consultation. Treatment in the second half of pregnancy is 

associated with the Jarisch-Herxheimer reaction in up to 40% of cases, 

with resulting premature labor and/or fetal distress (Myles, 1998); fetal and 

contraction monitoring for 24 hrs should be considered, especially in the 

setting of abnormal ultrasound findings, or, alternatively, patients should 

be advised to seek immediate attention after treatment if contractions 

or decrease in fetal movements occur (USPHS/IDSA, 2003). Pregnant 

women with a history of penicillin allergy should be skin tested and, if 

necessary, desensitized and treated with penicillin, because there are no 

proven effective alternatives to penicillin for treatment and prevention 

of congenital syphilis. Even with appropriate treatment of the pregnant 

woman with syphilis, fetal infection may still occur and neonates should 

be carefully evaluated for evidence of congenital infection. 

Clinical and serologic follow-up should be performed in the third trimester 

and at delivery and at 3, 6, 9, 12, and 24 mo after treatment. Treatment 

failure should be managed with cerebrospinal fluid examination and 

retreatment. Some experts recommend monthly serologic testing after 

treatment after pregnancy with retreatment if there is a rise in titer. 

F. CYTOMEGALOVIRUS

Cytomegalovirus (CMV) is the most common cause of congenital viral 

infection in the United States: .2–2.2% of liveborn infants acquire this 

infection perinatally (ACOG, 1993a). Most maternal CMV infections are 

asymptomatic but may cause a mononucleosis-like illness. Transmission 
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can occur sexually or with injection drug use, because CMV has been 

recovered from virtually all body fluids. Transmission can also occur with 

oral contact with infected secretions (i.e. from children). Transmission of 

CMV from mother to infant may occur in utero (1–2% of infants born to 

women with CMV prior to pregnancy and up to 50% of infants born to 

women with primary infection during pregnancy), intrapartum (25–50% 

of exposed infants), and through breastfeeding (40–60% of exposed 

infants) (USPHS/IDSA, 2003). In general, it is in utero infection that 

results in significant neonatal/infant effects. Ninety percent of infected 

infants are asymptomatic at birth, but symptomatic infection is more 

likely with maternal infection acquired early in pregnancy. Even if 

asymptomatic, many infected infants subsequently develop deafness, 

mental retardation, or delayed psychomotor development. More 

severe clinical manifestations include symmetric growth restriction, 

hepatosplenomegaly, chorioretinitis, microphthalmia, hydrocephaly, 

microcephaly, and cerebral calcifications. 

In the setting of HIV infection, in utero infection was detected in 4.5% 

of infants, compared to 1–2% transmission noted in previous studies of 

CMV-seropositive HIV-negative women. By six months of age, 40% of 

HIV-infected infants were CMV-seropositive compared to 15% of HIVuninfected infants born to HIV-infected mothers (Kovacs, 1999). Because 

symptomatic infection in the newborn is usually associated with primary 

CMV infection of the mother during pregnancy, and because >90% of 

HIV-infected pregnant women are CMV seropositive in most studies, the 

risk of symptomatic infection in the newborn is low (Kovacs, 1999; MussiPinhata,1998; Quinn, 1987), and treatment of asymptomatic maternal 

CMV infection in order to prevent infant infection is not indicated 

(USPHS/IDSA, 2003). There have been some reports that cotransmission 

of HIV and CMV may be related to more rapid HIV progression (Kovacs, 

1999; Mussi-Pinhata, 1998). 

Testing for antibody to CMV should be considered in pregnancy, especially 

if the CD4 count is <100/mm3 for reasons of maternal health evaluation; 

however, seropositivity is common and does not preclude viral shedding 

during pregnancy and perinatal transmission. Methods to reduce risk of 

exposure to CMV include safer sexual practices, careful handwashing, 

and transmission of only CMV antibody-negative blood products. Primary 

prophylaxis is not routinely recommended; however, after CMV disease 

(retinal or invasive CMV disease), chronic suppression is indicated in 

pregnancy and should be continued with expert consultation concerning 

choice of agents. (See Opportunistic Infection Prophylaxis below.) 

G. TOXOPLASMOSIS

Approximately one third of U.S. women have toxoplasma antibodies, 

reflecting prior infection. Primary infection occurs in approximately .1–.5% 

of pregnancies and places the fetus at risk for congenital toxoplasmosis. 

Congenital infection is more common when infection in the mother occurs 

during the third trimester (59% in third trimester vs. 9% in first trimester) 
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but is generally more severe when occurring in the first trimester. Although 

the majority of infected infants are asymptomatic at birth, most will develop 

some sequelae of congenital toxoplasmosis; two thirds of infants infected 

after maternal first trimester infection have severe manifestations and 5% 

are stillborn or die in the perinatal period (ACOG, 1993a). 

Congenital toxoplasmosis may affect all systems, but the most common 

findings are chorioretinitis, microcephaly, hydrocephaly, and cerebral 

calcifications. 

Transmission of toxoplasmosis from a mother with antibody evidence of 

prior infection can occur in the setting of HIV infection (as opposed to 

in HIV-uninfected women), but does not seem to be common (0–3.7% in 

two studies), although there are limited data in more immunosuppressed 

mothers (European Collaborative Study and Research Network in 

Congenital Toxoplasmosis, 1996; Minkoff, 1997b). 

Testing for IgG antibodies to toxoplasma is recommended for all HIVinfected individuals soon after the diagnosis of HIV is made and should 

be considered as part of prenatal testing in HIV-positive pregnant women. 

Primary prophylaxis and prophylaxis against recurrent disease in pregnancy 

are discussed below (See Opportunistic Infection Prophylaxis). Pregnant 

women with symptoms including fever, chills, malaise, lymphadenopathy, 

myalgias, and headache should be evaluated serologically for possible 

primary toxoplasmic infection. Evidence of primary infection or active 

toxoplasmosis should be evaluated and managed with expert consultation. 

Detailed ultrasound examination of the fetus should be performed in this 

situation to look for evidence of congenital toxoplasmosis. Infants born to 

women infected with HIV and seropositive for toxoplasma should also be 

evaluated for evidence of congenital toxoplasmosis if suspected by clinical 

presentation of the infant. 

To prevent exposure to toxoplasmosis, pregnant women should be 

counseled to avoid raw or undercooked meat, wash hands after contact 

with raw meat or with soil, and wash fruits and vegetables well before 

eating them raw. Cats should preferably be kept inside and fed only 

canned or dried commercial food; litter boxes should be changed daily, 

preferably by someone who is not HIV-positive or pregnant. 

H. HEPATITIS B 

Approximately 300,000 new cases of hepatitis B virus (HBV) infection 

occur each year and more than 1 million Americans are chronic 

carriers. Most patients who become infected have complete resolution 

of infection and develop protective levels of antibody (anti-HBs). 

Chronic HBV infection develops in 1–6% of persons who are infected 

as adults; they are chronically HBsAg+ and are at risk of chronic liver 

disease, including cirrhosis and hepatocellular carcinoma (CDC, 1991). 

The presence of HBeAg indicates active viral replication and increased 

infectivity. HBV is transmitted parenterally, sexually, perinatally, and 

through household or institutional contact. Approximately one quarter of 
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regular sexual contacts of infected individuals will become seropositive 

and sexual transmission accounts for 30–60% of new infections. Perinatal 

transmission, usually with intrapartum contact with maternal blood and 

genital secretions, occurs in 10–20% of women who are HBsAg+, but 

increases to approximately 90% if the mother is also HBeAg+. Chronic 

HBV infection develops in about 90% of infected newborns, who are at 

high risk of chronic liver disease (ACOG, 1998). 

All pregnant women should be screened for HBsAg. Symptomatic acute 

HBV infection should be treated supportively, with special attention to 

maintaining blood glucose levels and clotting function. Risk of preterm 

labor and birth may be increased with acute HBV infection in pregnancy. 

Treatment of chronic HBV infection is generally not indicated in 

pregnancy. Antiretroviral therapy containing lamivudine (3TC) may 

potentially decrease risk of perinatal HBV transmission in women with 

high HBV DNA levels, although this has not been examined in the setting 

of HIV infection. 

Infants born to women who are HBsAg+ should receive hepatitis B 

immune globulin and initiate HBV vaccination within 12 hr after birth. 

HBV vaccine can be safely administered during pregnancy and should be 

considered in women who are high risk (injection drug use, STIs, multiple 

sexual partners, household or sexual contact of HBV carrier) and are antiHBs- or anti-HBc-negative, indicating susceptibility. Some experts argue 

for more liberal use of vaccination in HIV-infected individuals, because 

HBV infection in the setting of HIV infection increases risk for chronic 

HBV infection. HIV can impair response to HBV vaccine; therefore, 

testing for hepatitis B surface antibody is recommended 1–2 mo after the 

third vaccine dose. Full revaccination should be considered for those who 

are nonresponders (ACOG, 1998; Bartlett, 1999).

I. HEPATITIS C 

Hepatitis C virus (HCV) infection is primarily transmitted by injection 

drug use, but may also be transmitted sexually. Approximately 50% 

of those with acute HCV infection develop biochemical evidence of 

chronic liver disease, and 20% or more ultimately have chronic active 

hepatitis or cirrhosis and are at risk for hepatocellular carcinoma (CDC, 

1998). Coinfection with HIV increases the risk and speeds the rate of 

development of progressive liver disease (Graham, 2001; Soto, 1997). 

Cofactors influencing disease progression include age, low CD4 cell 

count, and history of alcoholism. There is evidence that HCV infection 

may also hasten progression of HIV infection (Piroth, 2000). 

Women newly diagnosed with HIV in pregnancy should have testing 

for antibody to HCV by enzyme immunoassay; positive results should 

be confirmed with HCV polymerase chain reaction (PCR) and liver 

function abnormalities should be documented. Negative serologic 

screening associated with history of risk factors for HCV transmission or 

unexplained liver function abnormalities is an indication for performance 

of HCV viral RNA testing, especially with low CD4 cell counts. Studies 
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have shown that serum transaminases tend to decrease during pregnancy 

in HCV-infected women, but may rise transiently postpartum, while 

HCV-RNA levels tend to increase during pregnancy (Gervais, 2000; 

Conte, 2000). Treatment of HCV infection aims to eradicate infection 

and prevent the long-term complications of progressive liver disease and 

generally includes combination therapy with interferon plus ribavirin. 

However, treatment is generally not recommended during pregnancy 

(USPHS/IDSA, 2003) and evaluation for treatment, including liver 

biopsy, can be delayed until three months or more after delivery to allow 

pregnancy-related changes in disease activity to resolve. Ribavirin is 

teratogenic at low doses in multiple animal species and both women and 

men of childbearing potential receiving ribavirin should be counseled 

regarding the need for effective contraception during and for six months 

after completion of therapy. 

Women coinfected with HIV and HCV should avoid alcohol, both during 

and after pregnancy, because alcohol use increases risk of cirrhosis. 

Vaccination against hepatitis A, if the woman is anti-HAV-negative, is 

recommended because the risk for fulminant hepatitis associated with 

hepatitis A is increased in HCV-infected individuals; this vaccination may 

be given safely during pregnancy (ACOG, 1998; Bartlett, 1999). 

The risk of perinatal transmission of HCV is significantly higher among HIVinfected compared to HIV-uninfected women and has been reported to be 

approximately 22% or an increase in relative risk of 1.7–7.5-fold (European 

Paediatric Hepatitis C Virus Network, 2001). This may be related to higher 

HCV RNA levels seen in the setting of HIV infection, since perinatal 

transmission in both HIV-infected and –uninfected women is related to 

higher plasma HCV RNA levels (Yeung, 2001), although HCV transmission 

is highest with higher HCV RNA levels in the setting of HIV (Thomas, 1998). 

Furthermore, maternal coinfection with HIV and HCV may also increase 

risk for perinatal HIV transmission (Hershow, 1997). Scheduled cesarean 

section may reduce the risk of HCV transmission among HIV-coinfected 

women; in one large study scheduled C-section was associated with a 

reduction in transmission of almost two-thirds compared to other modes 

of delivery, although concomitant mother-to-child transmission of HIV was 

not controlled for (European Paediatric Hepatitis C Virus Network, 2001). 

Perinatal HCV transmission may be more likely in HIV-infected infants 

born to dually infected mothers (Papaevangelou, 1998). 

VIII. PERINATAL TRANSMISSION 

The baseline rate of perinatal HIV transmission without prophylactic 

therapy is approximately 25%. The timing of transmission is a critical 

factor impacting on development of preventive interventions. There is 

evidence that transmission can occur during the course of pregnancy, 

around the time of labor and delivery, or postpartum through breastfeeding; however, two thirds to three quarters of transmission appears 

to occur during or close to the intrapartum period, particularly in nonbreast-feeding populations (Mofenson, 1997). 
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POTENTIAL VARIABLES IN TRANSMISSION

A. HIV-RELATED FACTORS

• Plasma HIV RNA level: HIV RNA levels correlate with risk of 

transmission in both antiretroviral-treated and untreated women. 

The risk of perinatal transmission appears to be extremely low 

in women with undetectable plasma viral loads, but transmission 

has been reported at all levels of maternal HIV RNA. There is no 

upper limit of HIV RNA above which perinatal transmission always 

occurs (Garcia, 1999; Mofenson, 1999; Shaffer, 1999; Cooper, 2002). 

• Strain variation (genotype): Each HIV-infected individual’s 

viral pool is composed of a variety of HIV quasispecies. One 

recent study found that in utero transmission was associated with 

transmission of major maternal viral variants, whereas intrapartum 

transmission was associated with transmission of minor maternal 

viral variants, suggesting that different selective pressures may be 

involved in determining the pattern of viral strain transmission 

depending on timing of transmission (Dickover, 2000). HIV in 

vaginal secretions can be derived from local expression and may 

have significant genotypic differences from plasma virus, with 

possible implications for perinatal transmission (Subbarao, 1998). 

• Biologic growth characteristics (phenotype): Fetal blood 

mononuclear cells may be more susceptible to macrophage-tropic, 

non-syncytium-inducing HIV phenotypes and this may influence 

mother-to-infant HIV transmission (Palasanthiran, 1994; Reinhardt, 

1995). 

• Genital tract viral load: There is general correlation between 

plasma and genital tract viral load but discordance has been 

reported and may help explain some cases of transmission 

with undetectable plasma HIV RNA. In the Thai short-course 

zidovudine (ZDV) clinical trial, both plasma and cervicovaginal 

HIV RNA levels were suppressed by ZDV treatment and both 

were independently correlated with transmission (Chuachoowong, 

2000). The female genital tract can also be a reservoir for virus 

with a different drug-resistance pattern than that observed in 

plasma (Fang, 1998). The use of HAART has been associated 

with undetectable HIV RNA levels in the genital tract and viral 

suppression in the genital tract may occur rapidly after initiating 

therapy (Cu-Uvin, 2000). It is possible that intra-cellular HIV in 

the genital tract can lead to transmission, even in the presence of 

antiretroviral treatment (Tuomala, 2003). 

• Antiretroviral resistance: Special concerns have been 

raised about a possible increased risk for mother-to-child 

transmission associated with the potential development of 

antiretroviral resistance related to the use of single agents (i.e., 

ZDV or nevirapine) or dual nucleosides during pregnancy for 

perinatal prophylaxis. These regimens do not totally suppress 

viral replication, a common denominator in the development 
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of antiretroviral drug resistance, since the process of reverse 

transcription necessary for viral replication is mutation prone. 

In addition, the increasing prevalence of resistance in both ARV 

treatment-experienced and newly-infected and treatment-naïve 

individuals (implying transmission of resistant strains) makes the 

relationship between drug resistance and perinatal transmission 

even more critical to understand. 

 The presence of resistance mutations has been described in 

pregnant women and mother-to-child transmission of resistant 

virus has been reported, although it appears to be rare (Frenkel 

1995; Johnson 2001). Studies to date of resistance mutations 

in the setting of ZDV monotherapy during pregnancy have 

shown increasing prevalence of ZDV mutations over time and 

an association with length of drug exposure and more advanced 

disease (Eastman, 1998; Welles, 2000; Sitnitskaya, 2001; Palumbo, 

1999). Most studies, including PACTG 076, PACTG 185, Swiss 

cohort, or the PACTS, have not shown an increased risk of 

perinatal transmission associated with the detection of ZDV or 

other resistance mutations (Eastman, 1998; Kully, 1999; Palumbo 

1999; Mofenson, 2002). However, in a recent Women and Infants 

Transmission Study (WITS) substudy, 25% of 142 maternal isolates 

from women receiving ZDV in pregnancy had at least one ZDVassociated resistance mutation and, on multivariate analysis, the 

presence of resistance mutations was independently associated 

with perinatal transmission (Welles, 2000). It has been pointed out 

that the characteristics of women in this cohort (mean CD4 count 

at delivery 315 cells/mL, usually did not receive ZDV in labor or 

for the neonate) and the factors associated with development of 

resistance (use of ZDV prior to pregnancy, higher HIV-RNA level, 

and lower CD4 count) illustrate the importance of current USPHS 

guidelines (discussed under Antiretroviral Therapy below) which 

advise the use of HAART in these circumstances, both for the 

woman’s health and for prophylaxis against perinatal transmission. 

There is also some evidence that ARV-resistant virus may have 

decreased fitness for transmission; in the WITS substudy, when a 

transmitting mother had a mixed viral population of wild-type and 

low-level resistant virus, only the wild-type virus was found in the 

infant, suggesting that virus with low-level ZDV resistance may be 

less transmissable (Colgrove, 1998). 

 Selection of nevirapine-resistant virus has also been detected in 

women who received a single dose of nevirapine for prevention of 

perinatal transmission. In the HIVNET 012 clinical trial, ARV-naïve 

Ugandan women received one dose of nevirapine during labor 

and in 111 women who had detectable viral replication, 21 (19%) 

had genotypic mutations associated with nevirapine resistance at 

6 weeks (Eshleman, 2001). However, maternal drug resistance was 

not associated with increased risk of perinatal transmission: rates 

of resistance were similar among mothers whose children were or 

were not infected. 
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• CD4 cell count: Lower CD4 count or decreased CD4:CD8 

ratio have been consistently associated with increased risk of 

transmission. 

• Maternal immune response: Studies have been inconsistent 

when evaluating the role of maternal antibodies, including antigp120, anti-gp41, anti-p24, and autologous neutralizing antibody 

titers. ß-chemokine and cytokine responses may affect risk of 

transmission (Pitt, 2000; Rich, 1998). 

B. MATERNAL/OBSTETRIC FACTORS

• Clinical stage: Maternal symptomatic disease or AIDS-defining 

illness are consistently associated with higher risk for transmission. 

Women with primary HIV infection in pregnancy, at which time 

plasma viremia is high, are also at increased risk for transmission 

(Nesheim, 1996). 

• STIs/other coinfections: STIs have been shown to increase 

genital tract HIV shedding and also increase plasma viremia 

(Plummer, 1998), both of which may increase risk for perinatal 

transmission. STIs (Mandelbrot, 1996), syphilis (M.J. Lee, 1998), 

bacterial vaginosis (Taha, 1998), and placental malaria have been 

associated with increased risk for vertical transmission, as have 

increased levels of genital tract inflammatory cells (Panther, 2000; 

Chandramohan, 1998). 

• Vitamin A deficiency: Vitamin A deficiency has been associated 

with increased risk of perinatal HIV transmission and increased 

genital tract HIV shedding (Nimmagadda, 1998). However, a recent 

randomized trial of vitamin A supplementation in South Africa 

found no overall reduction in mother-to-child transmission of HIV, 

although vitamin A recipients were less likely to have a preterm 

delivery, and in preterm deliveries, those infants assigned to the 

vitamin A group were less likely to be infected (Coutsoudis, 1999). 

A controlled clinical trial in Malawi of vitamin A supplementation 

combined with iron and folate vs iron and folate alone also 

found no effect on HIV perinatal transmission (Kumwenda 

2002), although vitamin A did improve pregnancy outcome 

(increased birth weight and decreased infant anemia). In another 

randomized trial of vitamin A or multivitamins (B, C, E) from 20 

weeks gestation through completion of lactation, vitamin A was 

actually associated with increased risk of HIV MTCT. Multivitamin 

supplementation was associated with reduced child mortality and 

MTCT through breastfeeding among women with immunologic or 

nutritional compromise (Fawzi, 2002) 

• Substance abuse: Illicit drug use during pregnancy has 

been associated with increased risk for perinatal transmission 

(Landesman, 1996; Lyman, 1993; Rodriguez, 1996). 
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• Cigarette smoking: Cigarette smoking has been associated with an 

increased risk of perinatal transmission (Burns, 1994; Turner, 1997). 

• Antiretroviral therapy: Monotherapy with ZDV or with nevirapine, 

as well as dual nucleoside agents, have demonstrated effectiveness 

in reducing perinatal transmission in randomized clinical trials (see 

page 284 Table 7-8). In the PACTG 076 study (ZDV given antepartum/

intrapartum/neonatal), reduction in plasma viral load accounted 

for only 17% of ZDV’s effectiveness, suggesting pre- and/or postexposure prophylaxis as other possible mechanisms of action 

(Sperling, 1996). Although there are no completed clinical trials 

examining effectiveness of HAART regimens in reducing perinatal 

transmission, prospective cohort data from the WITS found that 

the protective effect of antiretroviral therapy increased with the 

complexity and duration of the regimen, and the use of HAART was 

associated with the lowest rates of transmission, 1.2% of 250 women 

(Cooper, 2002). Preliminary results from the PACTG 367 study, a 

combined retrospective and prospective chart analysis of over 2000 

HIV-infected pregnant women at 67 U.S. clinical sites, found that 

in all subgroups of viral load, lowest transmission rates were seen 

with multiagent ARV therapy (Shapiro, 2004), both dual therapy and 

HAART. 

• Sexual behavior: Unprotected sex with multiple partners has 

been associated with increased risk for perinatal transmission 

(Bulterys, 1997). 

• Preterm delivery: Delivery at preterm gestational age has been 

associated with increased risk for perinatal transmission (Kuhn, 

1997, 1999). 

• Duration of membrane rupture: A recent metaanalysis from 

15 prospective cohort studies, including almost 5000 deliveries, 

examined the role of duration of ruptured membranes in perinatal 

transmission (International Perinatal HIV Group, 2001). The 

likelihood of transmission increased linearly with increasing 

duration of ruptured membranes, with a 2% increase in risk for 

each hour increment. Women with clinical AIDS had the most 

pronounced increase in risk, with a 31% probability of vertical 

transmission after 24 hr of ruptured membranes. This study did 

not include women receiving HAART and did not control for viral 

load. The effect of duration of membrane rupture with very low 

viral loads is not clear. 

• Placental disruption-abruption, chorioamnionitis: Clinical and 

histologic chorioamnionitis (Goldenberg, 1998; Mwanyumba, 2002) 

has been associated with increased risk of transmission. Placental 

abruption causing disruption of fetal-placental barrier and possible 

increased exposure of the fetus to maternal blood has also been 

suggested as a risk factor for transmission. 
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• Invasive fetal monitoring: Use of fetal scalp electrodes or 

fetal scalp sampling increases exposure of the fetus to maternal 

blood and genital secretions and may increase risk of vertical 

transmission (Maiques, 1999). Amnioscopy and amniocentesis 

increased risk in the French Perinatal Cohort (Mandelbrot, 1996). 

• Episiotomy, forceps: Use of episiotomy or vacuum extraction or 

forceps may potentially increase risk of transmission by increasing 

exposure to maternal blood/genital secretions with trauma to 

maternal or neonatal tissue. On the other hand, judicious use 

of these techniques to shorten duration of labor or ruptured 

membranes with vaginal delivery may decrease likelihood of 

transmission. 

• Vaginal vs. cesarean delivery: Several studies (done before 

routine use of viral load testing and use of combination 

antiretroviral therapy in pregnancy) indicate that cesarean delivery 

performed before the onset of labor and rupture of membranes 

significantly reduces the risk of perinatal HIV transmission 

by 55–80% (European Mode of Delivery Collaboration, 1999; 

International Perinatal HIV Group, 1999; Kind, 1998; Mandelbrot, 

1998). Whether cesarean delivery offers any benefit when the 

mother is receiving HAART and/or if she has low or undetectable 

viral load is unknown, and cesarean section is not recommended 

in those circumstances (ACOG, 2000). 

C. FETAL/NEONATAL FACTORS

Fetal/neonatal factors, including an immature immune system 

(particularly in the premature infant) and genetic susceptibility, as 

expressed by human lymphocyte antigen (HLA) genotype (Just, 1995) 

or CCR-5 receptor (a coreceptor for macrophage-tropic strains of HIV; 

a homozygous deletion in this gene confers a high degree of natural 

resistance to HIV sexual transmission) mutations may play a role 

in perinatal transmission (Kostrikis, 1999; Mangano, 2000; Philpott, 

1999). A recent study from South Africa (Kuhn, 2000) found that early 

acquired cellular immune responses to HIV, presumably from in utero 

exposure, were present in over one third of 86 uninfected infants born 

to HIV-infected mothers. These detectable immune responses appeared 

to provide complete protection against subsequent HIV transmission at 

delivery and through breast-feeding. 

D. BREAST-FEEDING

Overall breastfeeding appears to increase the risk of perinatal transmission 

by 5–20% (DeCock, 2000). In 1998 breastfeeding is estimated to have 

accounted for up to 50% of newly infected children globally (Fowler, 

1999). Factors that have been associated with an increased risk of breast 

milk transmission include the following: 
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• Maternal factors: 

- acute HIV infection or recent seroconversion (Dunn, 1992), most 

likely related to high HIV viral loads 

- advanced HIV infection clinically or with low CD4 counts 

- high plasma or breast milk viral load 

- inflammatory breast conditions, such as mastitis or breast abscess 

- cracked nipples 

- vitamin A deficiency 

- colostrum 

• Newborn factors: 

- Oral thrush 

- Other mucosal lesions due to trauma or infection 

- Preterm birth or low birthweight 

- Nutritional deficiencies 

• Breastfeeding characteristics: 

- Timing –highest in first months, increases with longer duration of 

breastfeeding (Miotti, 1999) 

- Pattern of breastfeeding-mixed feeding (addition of other solids or 

liquids to breastmilk) associated with increased risk over exclusive 

breastfeeding (Coutsoudis, 2000) 

A recent randomized clinical trial of breastfeeding vs. formula feeding in 

Kenya (Nduati, 2000) found that formula feeding prevented 44% of infant 

infections and was associated with a significantly improved survival. 

STRATEGIES FOR PREVENTION OF PERINATAL TRANSMISSION

Based on the potential factors impacting perinatal HIV transmission 

discussed above, several basic approaches to prevention have been 

suggested. These include: 

• Identification and treatment of modifiable risk factors 

• Decreasing viral load 

• Decreasing viral exposure 

• Stimulation of the immune system (passive or active 

immunization) 

Currently, most major efforts at prevention are aimed at decreasing 

viral load. 
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IX. GUIDELINES FOR CARE 

A. ANTEPARTUM

HISTORY/PHYSICAL EXAMINATION

(See also Chapter IV on Primary Medical Care.) 

• HIV history: date of diagnosis; history of HIV-related symptoms 

or opportunistic infections or malignancies; lowest CD4 cell 

count; highest and current viral load; complete antiretroviral 

history, including specific drugs, side effects or toxicity, length of 

treatment, adherence, results of resistance testing (if performed), 

and response to treatment 

• Pregnancy history: previous pregnancies and outcomes, 

complications, mode of delivery, use of antiretroviral prophylaxis, 

and HIV status of other children 

• Signs or symptoms of HIV/AIDS: (initial and follow-up 

evaluations) assess signs or symptoms that suggest symptomatic 

HIV infection or AIDS (e.g., generalized lymphadenopathy, thrush, 

constitutional symptoms such as fever [38.5°C] or diarrhea >1 mo, 

herpes zoster involving two episodes or >1 dermatome, peripheral 

neuropathy, wasting, dysphagia, shortness of breath, persistent 

mucocutaneous herpetic ulcerations, cognitive dysfunction, etc.). 

• Signs or symptoms of pregnancy-related complications:

(the initial and follow-up evaluations) elevated blood pressure, 

significant edema, severe headache, vaginal bleeding or leakage of 

fluid, intractable nausea and vomiting, dysuria, abnormal vaginal 

discharge, persistent abdominal or back pain or cramping, decrease 

in fetal movement, etc. Gingival disease has recently been 

identified as a risk factor for preterm labor (Hill, 1998). 

• Signs or symptoms of ARV toxicity: (initial and follow-up 

evaluations) nausea/vomiting, abdominal pain, jaundice, extreme 

fatigue, skin rash. 

 Certain symptoms of HIV disease, antiretroviral toxicity, and 

normal or abnormal pregnancy may overlap, resulting in possible 

delay in appropriate diagnosis and management. 

• Relevant family history of possible heritable diseases.

LABORATORY EXAMINATION BY TRIMESTER SEE TABLE 7-5.
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VII

Table 7-5: Laboratory Evaluation in the HIV-Infected 

Pregnant Woman

Test Comment

Entry into Prenatal Care and Ongoing

HIV serology Unconfirmed HIV infection; + test with 

other techniques; always repeat in the 

case of a new diagnosis to rule out 

false+

CD4 cell count/% HIV RNA Repeat every 3–4 mo or as indicated to 

monitor changes with ARV therapy; at 

milestones for therapeutic decisions, re: 

ARV therapy/OI prophylaxis

Viral resistance testing (genotyping) Acute HIV infection, virologic failure, 

sub-optimal viral suppression after 

initiation of ARV therapy, or high 

likelihood of exposure to resistant virus 

based on community prevalence or 

source characteristics

CBC Repeat at minimum of every trimester 

in women on stable ARV therapy; for 

changes in regimen, repeat q 2–4 wk 

until stable; in general, consider more 

frequent testing if low or receiving 

marrow-toxic drugs (e.g., ZDV)

Serum chemistry panel (liver enzymes, 

electrolytes, +/- amylase)

Repeat at minimum of every trimester 

in women on stable ARV therapy; for 

changes in regimen, repeat q 2–4 wk 

until stable. Repeat as indicated with 

abnormal results or use of hepatotoxic/

nephrotoxic drugs 

Syphilis serology

Hepatitis serology: HBsAg, anti-HCV, 

anti-HAV 

Order anti-HBs or anti-HBc and antiHAV to screen for hepatitis B and A 

vaccine candidates. If anti-HCV+, order 

HCV-RNA

Rubella, Blood type and Rh, Antibody 

screen, Urine culture, GC/chlamydia 

testing, Pap smear

Cytobrush can be used

PPD + skin test = ≥5 mm induration; anergy 

testing not indicated; obtain CXR if at 

high risk for TB exposure

Hemoglobin electrophoresis, red blood 

cell indices

Perform in women at increased risk for 

hemoglobinopathies 

G6PD Optional — may consider screening 

black women or those receiving 

oxidant drugs (e.g., dapsone, 

sulfonamides) 
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Table 7-5: Laboratory Evaluation in the HIV-Infected Pregnant Woman 

(continued)

Test Comment

CMV IgG Consider especially with CD4 <100 

mm3 or in patients at low risk for CMV 

(non-IDU)*

Toxoplasmosis IgG Screen all patients with initial HIV 

diagnosis; repeat with CD4 <100/

mm3 and not on TMP-SMZ, or with 

symptoms suggestive of toxoplasmic 

encephalitis 

Urine toxicology screen As indicated 

Serum screening for Tay-Sachs disease Consider screening both partners if at 

increased risk (Ashkenazi Jews, FrenchCanadian, or Cajun descent)

Bacterial vaginosis screening Consider in women at high risk for 

preterm labor (previous preterm birth); 

women with signs/symptoms of vaginitis

16–20 wk

Ultrasound Gestational dating, anomaly screen; 

repeat as indicated to monitor fetal 

growth 

Maternal serum ∂-fetoprotein** Voluntary; requires counseling; 

screening test for neural tube and 

abdominal wall defects; abnormal 

result (usually >2.5 multiple of the 

median) requires further evaluation 

Triple screen (HCG, unconjugated 

estriol, ∂-fetoprotein)**

Voluntary; requires counseling; 

noninvasive test to determine risk of 

neural tube & abdominal wall defects, 

Down syndrome, and trisomy 18 

24–28 wk

CBC, Syphilis serology, Antibody screen

Diabetes screen Glucose 1 hr after 50 g glucola — 3 

hr oral GTT if abnormal; may need 

additional glucose monitoring in 

women on protease inhibitors (consider 

20 wk screening and repeat at 24–28 

wk if on PIs)

32–36 WK

GC/chlamydia testing

Group B streptococcus culture (35–37 

wk) (vaginal and rectal)

Recommend intrapartum chemoprophylaxis 

with IV PCN G (2.5 million units q 4 hr) if 

positive (or if GBS bacteriuria during current 

pregnancy or with previous infant with 

invasive GBS disease; if unknown GBS status, 

IP prophylaxis with delivery <37 wk gestation, 

membrane rupture ≥ 18 hr or IP temperature 

≥ 100.4oF/38.0oC (Schrag, 2002).
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Table 7-5: Laboratory Evaluation in the HIV-Infected Pregnant Woman 

(continued)

Test Comment

CD4, HIV-RNA Results may influence decisions about 

mode of delivery

Syphilis serology Consider in high-risk patients or 

populations 

Other Considerations

Test Indication

Liver enzymes, electrolytes Assess more frequently in third 

trimester in setting of NRTI therapy, 

nevirapine, recent changes in ARV 

therapy

Serum lactate, electrolytes, liver 

enzymes; consider anion gap, CPK, 

amylase, lipase

Signs or symptoms suggest possible 

lactic acidosis in setting of NRTI 

therapy, especially if long-term

Fasting lipid profile Consider at baseline and at 3–6 mo 

after starting PI- or NNRTI-based 

therapy; subsequent measurements 

based on initial results and risks

Liver enzymes (ALT, AST) every 2 wks in 

the first 6 wks of treatment, then every 

mo for first 12 wks; then every 1-3 

mo.; more frequently in patients with 

pre-existing liver disease

Initiation of nevirapine therapy (does 

not apply to single dose prophylactic 

therapy in labor)

* Seroprevalence CMV IgG in US adults is 50–60%; IDU patients ≥90% 

** Accurate gestational age is essential for interpretation of both tests. 

** Though not yet considered standard of care, 1st trimester screening for genetic abnormalities can be 

done with nuchal lucency assessment on ultrasound and with biochemical markers.

 ARV, antiretroviral; OI, opportunistic infections; CBC, complete blood count; PPD, purified 

protein derivative; G6PD, glucose 6-phosphate dehydrogenase; CMV, cytomegalvirus; TMP-SMZ, 

trimethoprim-sulfamethoxazole; HCG, human chorionic gonadotropin; GTT glucose tolerance test; 

PCN G, penicillin G; IDU injection drug use. PI, protease inhibitor; CXR, chest x-ray; R/o, rule out; 

GBS, Group B streptococci; IP, intrapartum CPK, creatine phosphokinase; NRTI, nucleoside reverse 

transcriptase inhibitor; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PI, protease 

inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor

ANTEPARTUM FETAL SURVEILLANCE/TESTING

The general purpose of antepartum fetal testing and surveillance 

is to identify fetal abnormalities or compromise so that appropriate 

interventions can be undertaken to optimize fetal health and prevent 

fetal damage or death; or, in some instances, to aid in decisions regarding 

continuation of pregnancy (ACOG, 1999). 

• Fetal surveillance: Indications include: 

- maternal conditions in which risk of fetal death is increased. This 

includes (but is not limited to) hemoglobinopathies, chronic renal 

disease, systemic lupus erythematosus, hypertension, and diabetes. 

- pregnancy-related conditions in which risk of fetal death is increased. 

This includes pregnancy-induced hypertension, decreased fetal 
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movement, oligohydramnios, polyhydramnios, intrauterine growth 

retardation, postterm pregnancy, mild to moderate isoimmunization, 

previous fetal death, and multiple gestation. 

 - HIV considerations: There are no data specifically on the need 

for and use of fetal surveillance techniques in the HIV-infected 

woman during pregnancy, and HIV per se is not an indication for 

fetal testing. However, HIV-infected women who have coexisting 

medical conditions placing the fetus at increased risk should have 

fetal surveillance; furthermore, HIV infection, especially when more 

advanced or associated with substance abuse, may be associated 

with increased risk for poor fetal growth, which places the fetus 

at increased risk. May consider in pregnant women on HAART 

particularly when containing newer agents with little experience 

of use in pregnancy. Need for fetal surveillance in the HIV-positive 

pregnancy should be determined on an individual basis. 

 Fetal surveillance techniques include: 

- Fetal movement assessment: “kick-counts” – perception of 10 distinct 

movements in a period of up to 2 hr is reassuring. 

- Nonstress test (NST): reactive or reassuring test is defined as two or 

more fetal heart rate accelerations (at least 15 beats/min above baseline 

and lasting at least 15 sec on fetal monitor) within a 20-min period. 

- Contraction stress test (CST): negative or reassuring test is absence of 

late or significant variable fetal heart rate decelerations with at least 

three contractions (lasting at least 40 sec) within 10 min. 

- Biophysical profile: consists of an NST combined with observations of 

fetal breathing, fetal movements, fetal tone, and amniotic fluid volume 

by real-time ultrasonography. Each component is given a score of 2 

(normal or present) or 0 (abnormal or absent); a composite score of 8 

or 10 is normal. 

- Modified biophysical profile: combines NST and amniotic fluid index 

(AFI), which is the sum of measurements of the deepest amniotic 

fluid pocket in each abdominal quadrant; normal AFI is >5 cm. This 

test combines a short-term indicator of fetal acid-base status (NST) 

and an indicator of long-term placental function (AFI); placental 

dysfunction often leads to poor fetal growth and oligohydramnios. 

- Umbilical artery Doppler velocimetry: evaluation of flow velocity 

wave forms in the umbilical artery; in the normally growing fetus, 

characterized by high-velocity diastolic flow; of benefit only in 

pregnancies complicated by intrauterine growth restriction. 

 Although there is no data from randomized clinical trials, 

antepartum fetal surveillance has been consistently associated 

with lower rates of fetal death than in untested pregnancies 

from the same institution or than historic controls with similar 

complicating factors. Testing should be initiated at 32–34 wk 

gestation, but may be started as early as 26–28 wk in pregnancies 

at very high risk. When the condition prompting testing persists, 

testing should be repeated periodically (weekly or, in some 

cases, biweekly) until delivery. Fetal reevaluation should also 

be repeated with significant deterioration in maternal medical 

condition or acute decrease in fetal movement, regardless of the 

time elapsed since the previous test. 
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 NST, CST, biophysical profile, and modified biophysical profile are 

the most commonly used forms of testing and have a negative 

predictive value >99%. However, they are not predictive of acute 

events, such as placental abruption or umbilical cord accidents. On 

the other hand, the positive predictive value of an abnormal test 

can be quite low and the response to an abnormal result should 

be dictated by the individual clinical situation. Any abnormal test 

result requires further evaluation or action. Maternal perception 

of decreased fetal movements should be evaluated by NST, CST, 

biophysical profile, or modified biophysical profile. If normal, 

the mother can be reassured that the fetus is in no immediate 

danger. A nonreactive NST or abnormal modified biophysical 

profile is usually followed by additional testing with a CST or full 

biophysical profile. Management will be based on results of these 

tests, gestational age, degree of oligohydramnios (if assessed), and 

maternal condition. Oligohydramnios should prompt evaluation for 

membrane rupture. Depending on the degree of oligohydramnios, 

the gestational age, and the maternal medical condition, 

oligohydramnios warrants either delivery or close maternal/fetal 

surveillance. 

• Ultrasound. Indications for obstetric ultrasound are many. Some 

of the more common include (ACOG, 1993b): 

- pregnancy dating 

- evaluation of fetal growth 

- evaluation of vaginal bleeding during pregnancy 

- determination of fetal presentation 

- suspected multiple gestation 

- significant uterine size/clinical dates discrepancy 

- pelvic mass 

- suspected ectopic pregnancy 

- document fetal viability/rule out fetal death 

- biophysical profile for antepartum fetal surveillance 

- suspected polyhydramnios/oligohydramnios 

- placental localization 

- abnormal serum ∂-fetoprotein or triple screen 

- evaluation for fetal anomalies 

- evaluation of fetal condition in late registrants for prenatal care 

 With transvaginal ultrasound, an intrauterine gestational sac can 

be seen by 5 wk after the last menstrual period and fetal heart 

activity can be detected by 6 wk. First-trimester bleeding is the 

most common indication for early ultrasound, when the major 

differential diagnoses are threatened abortion (miscarriage) 

and ectopic pregnancy. Accurate pregnancy dating is best 

accomplished in the late first and second trimesters. 
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 In the setting of HIV infection, an ultrasound should be considered 

in the second trimester for accurate dating, which is important 

later in gestation if scheduled cesarean section is planned to avoid 

premature delivery (see below). This will also allow survey of 

fetal anatomy and screening for anomalies. A third trimester (or 

other follow-up) ultrasound(s) should be considered, particularly in 

women with more advanced disease, those on HAART, and/or with 

other maternal pregnancy-related factors possibly impacting on 

fetal growth, in order to monitor growth. 

• Amniocentesis/chorionic villus sampling/percutaneous 

umbilical blood sampling: Because of concerns about increasing 

risk of perinatal transmission with these invasive techniques, they 

should be performed only for obstetric indications, with careful 

counseling; attempts to minimize viral load prior to the procedure 

should be considered. 

ANTIRETROVIRAL TREATMENT

(See Table 7-6.) Although there are special considerations in using 

antiretroviral drugs during pregnancy, the basic principle is that 

therapies of known or possible benefit to the woman should not be 

withheld during pregnancy unless there are known adverse effects 

for mother, fetus, or infant that outweigh the potential benefits 

(Minkoff, 1997a). The goals in the use of antiretroviral drugs during 

pregnancy are two-fold: (1) treatment of maternal infection and (2) 

reduction in the risk of perinatal transmission. Pregnant women 

meeting the criteria outlined for other adults and adolescents should 

be offered standard combination antiretroviral therapy, generally 

including two nucleoside reverse transcriptase inhibitors (NRTIs) and 

a protease inhibitor (PI) or a non-nucleoside reverse transcriptase 

inhibitor (NNRTI) (excluding efavirenz). (See Chapter IV on Primary 

Medical Care.) If such criteria are not met, ARV therapy appropriate 

for prevention of perinatal transmission, including combination 

treatment, should be offered. 
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Table 7-6 Preclinical and Clinical Data Relevant to the Use of Antiretovirals During Pregnancy (See Safety and Toxicity of Individual Antiretroviral Drugs in pregnancy for more detail on drugs)

Antiretroviral drug FDA 

pregnancy 

category†

Placental passage 

[newborn: mother 

drug ratio]

Long-term animal 

carcinogenicity studies

Animal 

teratogen studies

Nucleoside and nucleotide analogue reverse transcriptase inhibitorsAbacavir (Ziagen, ABC)

C Yes (rats) Positive (malignant and non-malignant 

tumors of liver, thyroid in female rats, and preputial and clitoral gland of mice and rats)

Positive (rodent anasarca and skeletal malformations at 1000 mg/kg (35x human exposure) during organogenesis; not seen in rabbits)

Didanosine (Videx, ddI) 

B Yes (human) [0.5] Negative (no tumors, lifetime rodent 

study) 

Negative

Emtricitabine (Emtriva, FTC) 

B Unknown Not completed Negative

Lamivudine (Epivir, 3TC) 

C Yes (human) [~1.0] Negative (no tumors, lifetime rodent 

study) 

Negative

Stavudine (Zerit, d4T) 

C Yes (rhesus monkey) 

[0.76]

Positive (mice and rats, at very high dose exposure, liver and bladder tumors)

Negative (but sternal bone calcium decreases in rodents)

Tenofovir DF (Viread) B Yes (rat and 

monkey)

Not completed Negative (osteomalacia when given to 

juvenile animals at high doses)

Zalcitabine (HIVID, ddC) 

C Yes (rhesus monkey) 

[0.30–0.50]

Positive (rodent, thymic lymphomas) Positive (rodent hydrocephalus at high 

dose)

Zidovudine (Retrovir, AZT, ZDV)

C Yes (human) [0.85] Positive (rodent, noninvasive vaginal 

epithelial tumors)

Positive (rodent near-lethal dose)
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Table 7-6 Preclinical and Clinical Data Relevant to the Use of Antiretovirals During Pregnancy (continued)

Antiretroviral drug FDA 

pregnancy 

category†

Placental passage 

[newborn: mother 

drug ratio]

Long-term animal 

carcinogenicity studies

Animal 

teratogen studies

Non-nucleoside reverse transcriptase inhibitorsDelavirdine (Rescriptor) 

C Unknown Positive (hepatocellular adenomas and 

carcinomas in male and female mice but not rats, bladder tumors in male mice)

Positive (rodentventricular septal defect)

Efavirenz (Sustiva) D Yes (cynomologus 

monkey, rat, rabbit) [~1.0]

Positive (increased hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas in female but not male mice)

Positive (cynomologus monkeyanencephaly, anophthalmia, micro-ophthalmia)

Nevirapine (Viramune) 

C Yes (human) [~1.0] Positive (hepatocellular adenomas and 

carcinomas in mice and rats) 

Negative

Protease inhibitorsAmprenavir (Agenerase) 

C Unknown Positive (hepatocellular adenomas and 

carcinomas in male mice and rats) 

Negative (but deficient ossification and thymic elongation in rats and rabbits)

Atazanavir B Unknown Not completed NegativeFosamprenavir (Lexiva) 

C Unknown Positive (increased benign and malignant 

liver tumors in male rodents) 

Negative (deficient ossification with amprenavir but not fosamprenavir)

Indinavir (Crixivan) C Minimal (humans) Positive (thyroid adenomas in male rats 

at highest dose) 

Negative (but extra ribs in rodents) 

Lopinavir/Ritonavir (Kaletra)

C Unknown Not completed Negative (but delayed skeletal ossification 

and increase in skeletal variations in rats at maternally toxic doses)
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Nelfinavir (Viracept) B Minimal (humans) Positive (thyroid follicular adenomas and 

carcinomas in rats)

Negative

Ritonavir (Norvir) B Minimal (humans) Positive (rodent, liver adenomas and 

carcinomas in male mice)

Negative (but cryptorchidism in rodents)

Saquinavir (Fortovase) 

B Minimal (humans) Not completed Negative 

Fusion inhibitorsEnfuvirtide (Fuzeon) B Unknown Not done Negative† Food and Drug Administration Pregnancy Categories: A - Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later 

trimesters). 

B - Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate but well-controlled studies of pregnant women have not been conducted. C - Safety in human pregnancy has not been determined; animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential 

benefit outweighs the potential risk to the fetus. 

D - Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women 

may be acceptable despite its potential risks. 

X - Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.Source: Perinatal HIV Guidelines Working Group, 2005. 
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Nevertheless, there are additional issues to consider with treatment 

in pregnancy: 

• Pharmacokinetics: (See Table 7-7.) There are potential changes 

in dosing secondary to the physiologic changes during pregnancy; 

at the current time, pharmacokinetic information on existing 

antiretroviral agents during pregnancy is limited, and has not been 

correlated with clinical efficacy. PK data on the NRTI and NNRTI 

drugs studied are similar to that in nonpregnant adults and these 

drugs cross the placenta to a variable extent. In general protease 

inhibitors have different PK levels during pregnancy and do not 

cross the placenta. Adequate drug levels are achieved in pregnant 

women with nelfinavir 1250 mg bid (Bryson, 2002), but levels 

were low and more variable with dosing 750 mg tid. Small PK 

studies conducted with non-boosted indinavir and saquinavir, as 

well as lopinavir/ritonavir, found inadequate drug concentrations 

in pregnancy using standard dosing; adequate drug levels were 

achieved with saquinavir 800 mg/ritonavir 100 mg (Acosta, 2004) 

and a boosted indinavir PK study is underway, as well as a trial of 

altered dosing of lopinavir/ritonavir. PK parameters of nevirapine 

are not significantly altered in pregnancy (Aweeka, 2004), but 

several recent studies show prolonged postnatal drug levels for 

over 3 weeks in a significant proportion of women after a singledose of nevirapine given in labor (Jourdain, 2004). 

• Perinatal transmission: The effect of different drugs and drug 

combinations on vertical transmission. Current information 

from clinical trials on the use of antiretroviral agents during the 

antepartum period and perinatal transmission are summarized in 

Table 7-8. 

 Although there are no clinical trial data regarding effectiveness of 

HAART in reducing perinatal transmission, there is prospective 

cohort data which suggests that the lowest rates of transmission 

occur with effective combination ARV therapy and with reductions 

in viral load to undetectable levels. Both choice of ARV therapy 

and suppression of viral load to <1000 copies/mL are important 

and probably additive. An analysis of the WITS (Cooper, 2002) 

cohort found the transmission rate was 1.2% in women receiving 

HAART and was 1% when HIV-RNA levels were suppressed below 

400 c/mL. Preliminary results of a retrospective/prospective 

combined analysis (PACTG 367) of over 4000 women found that in 

all subgroups of viral load, multiagent ARV—both dual nucleoside 

and HAART—was associated with the lowest rates of perinatal 

transmission and when viral load was <1000 c/mL in these 

women, transmission rate was <1% (Shapiro, 2004). 
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Table 7-7: Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human 

Pregnancy and Recommendations for Use in Pregnancy 

Antiretroviral drug Pharmacokinetics in 

Pregnancy

Concerns in Pregnancy Rationale for Recommended Use in Pregnancy

NRTI/NtRTIs See text for discussion of potential maternal and 

infant mitochondrial toxicity.

NRTIs are recommended for use as part of combination regimens, usually including two NRTIs with either an NNRTI or one or more PIs. Use of single or dual NRTIs alone is not recommended for treatment of HIV infection (AZT alone may be considered for prophylaxis of perinatal transmission in pregnant women with HIV RNA <1,000 copies/mL)

Recommended agents (NRTI/NtRTIs)Zidovudine* Pharmacokinetics 

not significantly altered in pregnancy; no change in dose indicated

No evidence of human teratogenicity. Welltolerated, short-term safety demonstrated for mother and infant

Preferred NRTI for use in combination antiretroviral regimens in pregnancy based on efficacy studies and extensive experience; should be included in regimen unless significant toxicity or stavudine use.

Lamivudine* Pharmacokinetics 

not significantly altered in pregnancy; no change in dose indicated

No evidence of human teratogenicity. Welltolerated, short-term safety demonstrated for mother and infant

Because of extensive experience with lamivudine in pregnancy in combination with zidovudine, lamivudine plus zidovudine is the recommended dual NRTI backbone for pregnant women.
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Table 7-7: Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and 

Recommendations for Use in Pregnancy (continued)

Antiretroviral drug Pharmacokinetics in 

Pregnancy

Concerns in Pregnancy Rationale for Recommended Use in Pregnancy

Alternate agents (NRTI/NtRTIs)Didanosine Pharmacokinetics 

not significantly altered in pregnancy; no change in dose indicated

Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together

Alternate NRTI for dual nucleoside backbone of combination regimens. Didanosine should be used with stavudine only if no other alternatives are available.

Emtricitabine No studies in human 

pregnancy

No studies in human pregnancy Alternate NRTI for dual nucleoside backbone of 

combination regimens. 

Stavudine Pharmacokinetics 

not significantly altered in pregnancy; no change in dose indicated

No evidence of human teratogenicity. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together

Alternate NRTI for dual nucleoside backbone of combination regimens. Stavudine should be used with didanosine only if no other alternatives are available. Do not use with zidovudine due to potential for antagonism.

Abacavir* Phase I/II study in 

progress.

Hypersensitivity reactions occur in ~ 5–8% of nonpregnant persons, a much smaller percentage are fatal and usually associated with rechallenge; rate in pregnancy unknown. Patient should be educated regarding symptoms of hypersensitivity reaction

Alternate NRTI for dual nucleoside backbone of combination regimens. See footnote regarding use in triple NRTI regimen.#

Insufficient data to recommend use (NRTI/NtRTIs)Tenofovir No studies in 

human pregnancy. Phase I study in late pregnancy in progress.

Studies in monkeys show decreased fetal growth and reduction in fetal bone porosity within two months of starting maternal therapy. Clinical studies in humans (particularly children) show bone demineralization with chronic use; clinical significance unknown.

Because of lack of data on use in human pregnancy and concern regarding potential fetal bone effects, tenofovir should be used as a component of a maternal combination regimen only after careful consideration of alternatives.
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Not recommended (NRTI/NtRTIs)Zalcitabine No studies in human 

pregnancy

Rodent studies indicate potential for teratogenicity and developmental toxicity

Given lack of data and concerns regarding teratogenicity in animals, not recommended for use in human pregnancy unless alternatives not available

NNRTIsRecommended agents (NNRTIs)Nevirapine Pharmacokinetics 

not significantly altered in pregnancy; no change in dose indicated

No evidence human teratogenicity. Increased risk of symptomatic, often rash-associated and potentially fatal, liver toxicity among women with CD4+ lymphocyte counts > 250/mm3 when first initiating therapy, unclear if pregnancy increases risk.

Nevirapine should be initiated in pregnant women with CD4+ lymphocyte counts > 250/mm3 only if benefit outweighs risk; if used, monitor closely for liver toxicity in first 18 weeks of therapy. Women who enter pregnancy on nevirapine regimens and are tolerating well may continue therapy, regardless of CD4+ lymphocyte count.

Not recommended (NNRTIs)Efavirenz No studies in human 

pregnancy

Significant malformations (anencephaly, anophthalmia, cleft palate) were observed in 3 (15%) of 20 infants born to cynomologus monkeys receiving efavirenz during the first trimester at a dose giving plasma levels comparable to systemic human therapeutic exposure; there are three case reports of neural tube defects in humans after first trimester exposure; relative risk unclear.

Use of efavirenz should be avoided in the first trimester, and women of childbearing potential must be counseled regarding risks and avoidance of pregnancy. Alternative effective regimens should be considered, if available. Use after the second trimester of pregnancy can be considered if other alternatives not available and if adequate contraception can be assured postpartum.
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Table 7-7: Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and 

Recommendations for Use in Pregnancy (continued)

Antiretroviral drug Pharmacokinetics in 

Pregnancy

Concerns in Pregnancy Rationale for Recommended Use in Pregnancy

Delavirdine No studies in human 

pregnancy

Rodent studies indicated potential for carcinogenicity and teratogenicity

Given lack of data and concerns regarding teratogenicity in animals, not recommended for use in human pregnancy unless alternatives not available

Protease Inhibitors Hyperglycemia, new onset or exacerbation of 

diabetes mellitus, and diabetic ketoacidosis reported with PI use; unclear if pregnancy increases risk. Conflicting data regarding preterm delivery in women receiving PIs

Recommended agents (Protease Inhibitors)Nelfinavir Adequate drug 

levels are achieved in pregnant women with nelfinavir, 1250 mg, given twice daily

No evidence of human teratogenicity. Welltolerated, short-term safety demonstrated for mother and infant. Nelfinavir dosing at 750 mg three times daily produced variable and generally low levels in pregnant women

Given pharmacokinetics data and extensive experience with use in pregnancy compared to other PIs, preferred PI for combination regimens in pregnant women, particularly if HAART is being given solely for perinatal prophylaxis. In clinical trials of initial therapy in non-pregnant adults, nelfinavir-based regimens had a lower rate of viral response compared to lopinavir/ritonavir or efavirenz-based regimens, but similar viral response compared with atazanavir or nevirapine-based regimens.
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Saquinavir-soft gel capsule [SGC] (Fortavase)/ritonavir

Adequate drug levels are achieved in pregnant women with saquinavir-SGC 800 mg boosted with ritonavir 100 mg given twice daily.Recommended adult dosing of saquinavirSGC 1000 mg plus ritonavir 100 mg may be used.No pharmacokinetic data on saquinavirhard gel capsule [HGC]/ritonavir in pregnancy, but better GI tolerance in non-pregnant adults.

Well-tolerated, short-term safety demonstrated for mother and infant. Inadequate drug levels observed in pregnant women when saquinavirSGC given alone at 1200 mg three times daily.

Given pharmacokinetics data and extensive experience with use in pregnancy, ritonavirboosted saquinavir-SGC can be considered a preferred PI for combination regimens in pregnant women.

Alternative agents (Protease Inhibitors)Indinavir Study underway 

to evaluate pharmacokinetics of indinavir 800 mg with ritonavir 100 mg, given twice daily

Theoretical concern re: increased indirect bilirubin levels, which may exacerbate physiologic hyperbilirubinemia in the neonate, but minimal placental passage. Two studies including six women receiving indinavir 800 mg three times daily showed marked lower levels during pregnancy compared to postpartum, although suppression of HIV RNA was seen

Alternate PI to consider if unable to use nelfinavir or saquinavir-SGC/ritonavir. Use of unboosted indinavir during pregnancy is not recommended. Optimal dosing for the combination of ritonavir/indinavir in pregnancy unknown.
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Table 7-7: Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and 

Recommendations for Use in Pregnancy (continued)

Antiretroviral drug Pharmacokinetics in 

Pregnancy

Concerns in Pregnancy Rationale for Recommended Use in Pregnancy

Lopinavir/ritonavir Phase I/II safety and 

pharmacokinetic study in progress using twice daily lopinavir 400 mg and ritonavir 100 mg

Limited experience in human pregnancy Preliminary studies suggest increased dose may 

be required during pregnancy, though specific dosing recommendations not established. If used during pregnancy, monitor response to therapy closely. If expected virologic result not observed, consider increasing dose in consultation with a specialist with expertise in HIV in pregnancy.

Ritonavir Phase I/II study in 

pregnancy showed lower levels during pregnancy compared to postpartum

Minimal experience in human pregnancy Given low levels in pregnant women when used 

alone, recommended for use in combination with second PI as low dose ritonavir “boost” to increase levels of second PI

Insufficient data to recommend use (Protease Inhibitors)Amprenavir No studies in human 

pregnancy

Oral solution contraindicated in pregnant women because of high levels of propylene glycol, which may not be adequately metabolized during pregnancy. 

Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use of capsules during pregnancy. Oral solution contraindicated

Fos-amprenavir No studies in human 

pregnancy

No experience in human pregnancy Data are insufficient regarding safety and 

pharmacokinetics in pregnancy to recommend use during pregnancy. 

Atazanavir No studies in human 

pregnancy

Theoretical concern re: increased indirect bilirubin levels, which may exacerbate physiologic hperbilirubinemia in the neonate, although transplacental passage of other PIs has been low

Data are insufficient regarding safety and pharmacokinetics in pregnancy to recommend use during pregnancy. 
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Fusion InhibitorsInsufficient data to recommend use (Fusion Inhibitors)Enfuvirtide No studies in human 

pregnancy

No experience in human pregnancy Data are insufficient regarding safety and 

pharmacokinetics in pregnancy to recommend use during pregnancy. 

NRTI=nucleoside reverse transcriptase inhibitor; NtRTI=nucleotide reverse transcriptase inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; PI= Protease inhibitor; SGC=soft gel capsule; HGC=hard gel capsule* Zidovudine and lamivudine are included as a fixed-dose combination in Combivir®, and zidovudine, lamivudine, and abacavir are included as fixed-dose combination in Trizivir®.# Triple NRTI regimens including abacavir have been less potent virologically compared to PI-based HAART regimens. These regimens should be used only when an NNRTI or PI-based HAART regimen cannot be used (eg, due to significant drug interactions). A study evaluating use of zidovudine/lamivudine/abacavir among pregnant women with HIV RNA < 55,000 copies/mL as a class-sparing regimen is in development. Source: Perinatal HIV Guidelines Working Group, 2005.
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Table 7-8: Overview of Antiretroviral Intervention Trials to Prevent Mother-to-child Transmission of HIV

Site/sponsor Antepartum Intrapartum Post-partum Mother Post-partum Infant Results

US (PACTG 076)•Randomized, placebocontrolled•Formula feeding•N=477

Starting at 14-34 wksArm 1: ZDV 100 mg 5x/dArm 2: Placebo

Arm 1: ZDV intravenous infusionArm 2: Placebo

No ARV Arm 1: ZDV 2 mg/kg qid 

x 6 wkArm 2: Placebo

•At 18 mo, tx 7.6% ZDV vs 22.6% placebo, 68% efficacy(Connor, 1994)

THAILAND (CDC)•Randomized, placebocontrolled•Formula feeding•N=392

Starting at 36 wks Arm 1: ZDV 300 mg bidArm 2: Placebo

Arm 1: ZDV 300 mg q 3 hr Arm 2: Placebo

No ARV No ARV

•At 6 mos, tx 9.4% ZDV vs 18.9% placebo, 50% efficacy (Shaffer, 1999)

IVORY COAST (CDC)•Randomized, placebocontrolled•Breastfeeding•N=280

Starting at 36 wks Arm 1: ZDV 300 mg bidArm 2: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg q 3 hrArm 2: Placebo (stopped 2/98)

No ARV No ARV

•At 3 mos, tx 16.5% ZDV vs 26.1% placebo, 37% efficacy(Wiktor, 1999)
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IVORY COAST/BURKINA FASO (DITRAME; ANRS 049a)•Randomized, placebocontrolled•After trial completion, continued to enroll into an open-label ZDV regimen cohort•Breastfeeding•N=400

Starting at 36-38 wksArm 1: ZDV 300 mg bidArm 2: Placebo(stopped 2/98)

Arm 1: ZDV 600 mg x1Arm 2: Placebo(stopped 2/98)

Arm 1: ZDV 300 mg bid x 1 wkArm 2: Placebo(stopped 2/28)

No ARV

•At 6 mos, tx 18.0% ZDV vs 27.5% placebo, 38% efficacy•At 15 mos, tx 21.5% ZDV vs 30.6% placebo, 30% efficacy •At 24 mos (pooled analysis with CDC), tx 22.5% ZDV vs 30.2% placebo, 26% efficacy•18 mo mortality: 17.6% ZDV vs 22.1% placebo•Open-label ZDV cohort (N=209), 15 mo tx with ZDV regimen, 19.6%(Dabis, 1999; DITRAME ANRS 049 Study Group, 1999; Leroy, 2002)

THAILAND/PHPT (Harvard)•Randomized, comparative, factorial•No placebo (076-like control)•Formula feeding•N=1,437

ZDV 300 mg bidArm 1 (Long-Long, LL): 28 wksArm 2 (Long-Short, LS): 28 wksArm 3 (Short-Long, SL): 36 wksArm 4 (Short-short, SS): 36 wks

ZDV 300 mg q 3 hrArm 1: OralArm 2: OralArm 3: OralArm 4: Oral

No ARV

ZDV 2 mg/kg qidArm 1: 6 wksArm 2: 3 dArm 3: 6 wksArm 4: 3 d

•Interim analysis 3/99 (N=449 enrolled), stopped SS arm due to sig higher tx than LL, — At 6 mos, tx 10.5% SS vs 4.1% LL•Final analysis 7/00, no sig differences; — At 6 mos, tx 6.5% LL vs 4.7% LS vs 8.6% SL•In utero tx sig different: — 1.6% [LL+LS] vs 5.1% [SL+SS](Lallemant, 2000)
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Table 7-8: Overview of Antiretroviral Intervention Trials to Prevent Mother-to-child Transmission of HIV (continued)

Site/sponsor Antepartum Intrapartum Post-partum Mother Post-partum Infant Results

SOUTH AFRICA, UGANDA, TANZANIA (PETRA)•Randomized, placebocontrolled•Breastfeeding•N=1,797

Starting at 36 wksArm 1: ZDV 300 mg bid plus 3TC 150 mg bidArm 2: PlaceboArm 3: PlaceboArm 4: Placebo (stopped 2/98)

Arm 1: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hrArm 2: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hrArm 3: ZDV 300 mg q 3 hr plus 3TC 150 mg q 12 hrArm 4: Placebo(stopped 2/98)

Arm 1: ZDV 300 mg bid plus 3TC 150 mg bid x 7 dArm 2: ZDV 300 mg bid plus 3TC 150 mg bid x 7 dArm 3: PlaceboArm 4: Placebo(stopped 2/98)

Arm 1: ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 7 dArm 2: ZDV 4 mg/kg bid plus 3TC 2 mg/kg bid x 7 dArm 3: PlaceboArm 4: Placebo(stopped 2/98)Petra Study Team

•At 6 wks, tx:— 5.7% AP/IP/PP (63% efficacy)— 8.9% IP/PP (42% efficacy) — 14.2% IP — 15.3% placebo•At 18 mos, tx: — 14.9% AP/IP/PP— 18.1% IP/PP — 20.0% IP— 22.2% placebo(Petra Study Team, 2002)

FRANCE (ANRS 075)•Non-randomized, open-label •Formula feeding•N=445

Standard ZDV after 14 wks 3TC 150 mg bid added at 32 wks

Standard intravenous ZDV Non-study ARV Standard ZDV x 6 wks 

3TC 2 mg/kg bid x 6 wks

•Tx 1.6% ZDV/3TC vs 6.8% 1994-97 historical, ZDV-alone control(Mandelbrot, 2001)

THAILAND (Ministry of University Affairs, Bangkok)•Non-randomized, open-label •Formula feeding•N=106

Starting at 34 wksZDV 300 mg bid plus 3TC 150 mg bid

ZDV 300 mg q 3 hr plus 3TC 150 mg q 3 hr 

No ARV ZDV 2 mg/kg qid x 4 wks

•At 18 mos, tx 2.8% vs 11.7% historical, ZDV-alone control (N=60: 36 wk start, oral IP, 4 wk infant)(Chaisilwattana, 2002)
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UGANDA (HIVNET 012)•Randomized; originally had 3rd placebo arm, stopped 2/98 •Breastfeeding•N=626

Arm 1: No ARVArm 2: No ARVArm 3: No ARV

Arm 1: NVP 200 mg x1Arm 2: ZDV 300 mg q3 hrArm 3: Placebo (stopped 2/98)

No ARV Arm 1: NVP 2 mg/kg x 1 at 

48-72 hrArm 2: ZDV 4 mg/kg bid x 7 dArm 3: Placebo (stopped 2/98)

•At 14-16 wks, tx 13.1% NVP vs 25.1% ZDV, 47% efficacy•At 18 mos, tx 15.7% NVP vs 25.8% ZDV, 41% efficacy(Guay, 1999)

US/EUROPE/BRAZIL/BAHAMAS (PACTG 316)•Randomized, [NVP] placebocontrol •Women and infants received non-study standard ARV •Formula feeding•N=1,248

Non-study ARV (23% ZDV alone, 36% combo without PI, 41% combo with PI)

Standard intravenous ZDV Arm 1: NVP 200 mg x 1 Arm 2: Placebo

Non-study ARV Standard ZDV 

(with or without other ARV) x 6 wksArm 1: NVP 2 mg/kg x 1 at 48-72 hrArm 2: Placebo

•Stopped early due to low 1.5% overall tx (53% in utero)•At 6 mos, tx 1.4% NVP vs 1.6% placebo(Dorenbaum, 2002)

SOUTH AFRICA (SAINT) •Randomized, comparative •Breastfeeding (42%) and formula feeding•N=1,331

Arm 1: No ARVArm 2: No ARV

Arm 1: NVP 200 mg x1Arm 2: ZDV 600 mg then 300 mg q 3 hr plus 3TC 150 mg q 12 hr

Arm 1: NVP 200 mg x 1 at 24-48 hrArm 2: ZDV 300 mg bid plus 3TC 150 mg bid x 7 d

Arm 1: NVP 6 mg x 1 at 24-48 hr (>2kg)Arm 2: ZDV 12 mg bid plus 3TC 6 mg bid x 7 d (>2 kg)

•At 8 wks, tx 12.3% NVP vs 9.3% ZDV/3TC (p=0.11)(Moodley, 2003)

THAILAND (CDC)•Non-randomized, open-label •Formula feeding•N=195 

Starting at 34-36 wksZDV 300 mg bid ZDV 300 mg q3 hrs plus NVP 

200 mg x1

No ARV ZDV 2 mg/kg qid x 4 wks plus 

NVP 6 mg x 1 at 48-72 hr

•Tx 4.6%(Chalermchokcharoenkit, 2004)
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Table 7-8: Overview of Antiretroviral Intervention Trials to Prevent Mother-to-child Transmission of HIV (continued)

Site/sponsor Antepartum Intrapartum Post-partum Mother Post-partum Infant Results

THAILAND/PHPT (Harvard)•Randomized, comparative •All women/infant get shortcourse ZDV•Formula feeding•N=1,844

Starting at 28 wksArm 1: ZDV 300 mg bid Arm 2: ZDV 300 mg bidArm 3: ZDV 300 mg bid

Arm 1: ZDV 300 mg q 3 hr Arm 2: ZDV 300 mg q 3 hr plus NVP 200 mg x 1Arm 3: ZDV 300 mg q 3 hr plus NVP 200 mg x 1

No ARV Arm 1: ZDV 2 mg/kg qid 

x 7 dArm 2: ZDV 2 mg/kg qid x 7 dArm 3: ZDV 2 mg/kg qid x 7 d plus NVP 6 mg x 1 at 48-72 hr

•Interim analysis 6/02: --ZDV alone Arm 1 stopped due to higher tx than in ZDV/NVP Arm 3 •Analysis through 3/03: --ZDV alone 6.3%--Arms 2 & 3 combined 1.7%--NVP/placebo 2.8%--NVP/NVP 1.9%(Lallemant, 2004)

MALAWI (Fogarty)•Randomized, comparative •Designed for infants of women 1st identified as HIV+ in labor/PP •Breastfeeding•N=1,119

No ARV No ARV No ARV Arm 1: NVP 2 mg/kg x 1 at 

48-72 hrArm 2: NVP 2 mg/kg x 1 at 48-72 hr plus ZDV 4 mg/kg bid x 7 d 

At 6-8 wks, tx rate:NVP 20.9%NVP/ZDV 15.3% (26.8% efficacy); when limited to infants uninfected at birth:NVP 12.% vs NVP/ZDV 7.7% (36.4% efficacy)(Taha, 2003)

MALAWI (Fogarty)•Randomized, open label•Breastfeeding•N=894

No ARV NVP 200 mg x 1 No ARV Arm 1: NVP 2 mg/kg x 1 at 

48-72 hrArm 2: NVP 2 mg/kg x 1 at 48-72 hr plus ZDV 4 mg/kg bid x 7 d 

At 6-8 wks, tx rate:NVP 14.1%NVP/ZDV 16.3% (p=.36)When limited to infants uninfected at birth:NVP 6.5% vs NVP/ZDV 6.9% (p=.88)(Taha, 2004)

Courtesy: Lynne Mofenson, M.D.
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 •Fetal/infant adverse effects: Potential teratogenicity, 

carcinogenicity, mutagenicity, or fetal/neonatal side effects/

toxicity from transplacentally transferred drugs. The potential for 

adverse effects may be related to several factors: the drug itself, 

dose, gestational age at exposure, duration of exposure, interactions 

with other drugs or agents to which the fetus is exposed, and 

the genetic make-up of mother and fetus. Potential toxicity of 

antiretroviral drugs with perinatal exposure applies both to the 

infected and uninfected fetus and/or infant. 

 Information about the safety of drugs in pregnancy comes from 

animal toxicity studies, anecdotal experience, cohort studies, 

registry data, and clinical trials. Preclinical data do not necessarily 

correlate with adverse effects in humans. There are approximately 

1200 known animal teratogens, but only about 30 are known 

human teratogens. Of currently available drugs, ZDV is the 

agent for which there is the most information, and information 

about other antiretrovirals agents, particularly when used in 

combination, is more limited. Issues related to specific drugs 

and their possible impact on fetal safety are addressed below; all 

antiretroviral drugs are discussed in more detail in Chapter XIV 

on Pharmacology and the U.S. Public Health Service Task Force 

Recommendations for the Use of Antiretroviral Drugs in Pregnant 

Women Infected with HIV-1 for Maternal Health and for Reducing 

Perinatal HIV-1 Transmission in the United States, which is 

updated regularly online at http://www.aidsinfo.nih.gov. 

- Zidovudine (ZDV): In the PACTG 076 study the only side effect 

significantly different between ZDV and placebo recipients was the 

presence of anemia in ZDV-exposed infants; however, the anemia 

was mild and resolved spontaneously without need for transfusion 

(Connor, 1994). There has been no evidence of increase in congenital 

abnormalities in infants exposed to ZDV in utero, compared with 

the general population. Uninfected children who were participants 

in the PACTG 076 study have now been followed for nearly 6 years 

with no evidence of impact of ZDV on growth, neurodevelopment, or 

immunologic status (Culnane, 1999). 

 Two transplacental carcinogenicity studies in mice showed 

different results: in one study (Olivero, 1997), two very high doses 

(approximately 25x and 50x daily human therapeutic exposure) 

were associated with an increase in lung, liver, and female genital 

tract tumors; in the second study (Ayers, 1997), a much lower dose 

(approximately 3x human therapeutic exposure) was not associated 

with an increase in tumors. A consensus conference reviewed all 

available information and concluded that the known benefits of 

zidovudine far outweighed the theoretical risks, but recommended 

long-term follow-up of infants exposed in utero to zidovudine or 

other antiretrovirals. In a follow-up of over 700 infants with in utero 

exposure to ZDV, no malignancies were observed in up to 6 yr of age 

(Hanson, 1999). 

- Efavirenz: In primate studies efavirenz was associated with 

anencephaly, anophthalmia, microophthalmia, and cleft palate at doses 

comparable to human exposure. There have been four reports of central 

nervous system defects in human infants with early in utero exposure. 

Efavirenz should be avoided during pregnancy, particularly early 
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pregnancy, and in women at risk for pregnancy (trying to get pregnant 

or unsafe sexual practices). Pregnant women who have conceived 

while on efavirenz should be counseled about possible fetal risks and 

ultrasound screening should be considered to look for fetal anomalies. 

- Amprenavir: Amprenavir oral solution contains high levels of 

propylene glycol (the capsule form does not contain propylene 

glycol). Pregnant women and infants and children under the age 

of 4 are unable to adequately metabolize and eliminate propylene 

glycol, leading to accumulation and potential serious adverse events, 

including hyperosmolarity, lactic acidosis, seizures, and respiratory 

depression. Amprenavir oral solution is contraindicated in pregnancy 

and in children under the age of 4 yr. 

- Indinavir: Indinavir has been associated with indirect 

hyperbilirubinemia and increased risk for renal stones. There are 

theoretical concerns from in utero exposure to indinavir about risk for 

renal stones in neonates who cannot voluntarily hydrate themselves 

adequately and possible complications associated with exacerbation of 

physiologic hyperbilirubinemia (especially in premature infants, who 

are at greater risk for neonatal jaundice and kernicterus); however, 

placental passage of indinavir in humans appears to be minimal, 

which should minimize risk. Third trimester in utero exposure to 

indinavir in Rhesus monkeys found fetal plasma drug levels only 

1–2% of maternal drug levels and no exacerbation of physiologic 

hyperbilirubinemia in neonates. Nevertheless, neonates exposed 

to indinavir late in gestation should be closely monitored. Because 

of its short half-life, these concerns probably do not apply to use of 

indinavir earlier in pregnancy. 

- Atazanavir: The most common laboratory abnormality observed 

with use of atazanavir is hyperbilirubinemia, with 15–24% of 

subjects receiving atazanavir developing jaundice or scleral icterus. 

This abnormality was reversible with drug discontinuation and did 

not appear to be associated with increased risk of liver injury. The 

degree of placental passage and the potential risk of exacerbation of 

physiologic hyperbilirubinemia in neonates is unknown. 

- Tenofovir: Recent studies in animal models suggest potential risks 

for bone abnormalties with infant (and possibly fetal) exposure to 

relatively low doses of tenofovir (Castillo, 2002; Tarantal, 2002). No 

human studies in pregnancy are available. 

- Hydroxyurea: Although hydroxyurea is not a true antiretroviral drug, 

it has been used in some antiretroviral regimens in the past; this 

agent is no longer recommended as part of any antiretroviral regimen. 

Hydroxyurea has been referred to as a “universal teratogen” with 

evidence of teratogenicity in every animal species studied and defects 

involving multiple organ systems. This agent should be avoided during 

pregnancy and in women at risk for pregnancy. 

- Mitochondrial toxicity: A large prospective cohort of almost 4400 

HIV uninfected or HIV-indeterminant children (2644 with perinatal 

antiretroviral exposure) born to women with HIV identified 12 cases 

of mitochondrial dysfunction over 18 months of follow-up (0.26%), 

all with antiretroviral exposure (Barret, 2003); risk was higher with 

exposure to combination ARV therapy (primarily ZDV/3TC) than to 

ZDV alone. All children presented with neurologic symptoms, often 

with abnormal magnetic resonance imaging and/or hyperlactatemia, 

and all had deficit in one of the mitochondrial respiratory chain 

complexes and/or abnormal muscle biopsy. The same group has 

reported an increase in febrile seizures during the first 18 months 
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of life among uninfected infants with antiretroviral exposure 

(French Perinatal Cohort Study Group, 2002). Other studies have 

found associations between antiretroviral exposure and markers 

of mitochondrial dysfunction, including lower mitochondrial DNA 

quantity (Poirier, 2003) and transient hyperlactatemia (Giaquinto, 2001). 

 However, a retrospective review of deaths occurring among over 

16,000 HIV-exposed but uninfected children (with and without 

antiretroviral exposure) followed 1986-1999 in five large prospective 

US cohorts found no deaths felt consistent with mitochondrial 

dysfunction. In this study most ARV exposure was to ZDV alone 

(Perinatal Safety Review Working Group, 2000). Neurologic adverse 

events were reviewed in 1,798 infants exposed to ZDV/3TC or 

placebo in the PETRA study, an African perinatal prophylaxis 

trial; no increased risk of neurologic events was observed among 

children treated with ZDV/3TC compared with placebo, regardless 

of intensity of treatment (Petra Study Team, 2002). In a review of 

clinical symptoms in 2414 uninfected children, 1008 with perinatal 

antiretroviral exposure, and with median follow-up of over 2 years, 

there was no association between antiretroviral exposure and clinical 

manifestations (European Collaborative Study, 2003). Mitochondrial 

toxicity can also manifest as cardiomyopathy and in a study of 382 

uninfected infants, serial echocardiograms for the first 5 years of life 

found no significant differences in ventricular function stratified by 

ZDV exposure (Lipshultz, 2000). 

 Although there is conflicting data regarding ARV exposure and 

mitochondrial dysfunction, the likelihood of severe or fatal 

manifestations appears to be extremely small. However, mitochondrial 

dysfunction should be considered in ARV-exposed but uninfected 

children who present with severe clinical findings of unknown 

etiology, particularly neurologic findings. Appropriate monitoring 

should be considered for all exposed infants. 

 Given the limited and relatively short-term experience with all 

antiretroviral agents in pregnancy, long-term follow-up of infants 

exposed to these medications in utero is important. 

• Adverse pregnancy outcomes: Concerns about possible increased 

risk for preterm delivery were raised by a small retrospective series 

of pregnant women receiving combination antiretroviral therapy 

(Lorenzi, 1998). Subsequently a large European cohort of almost 

4000 mother-child pairs (only 323 on combination therapy) found 

a 2.6-fold (95% CI 1.4-4.8) increase in preterm delivery associated 

with exposure to combination therapy with or without protease 

inhibitors compared with no treatment, after adjusting for CD4 

count and injection drug use; risk was doubled in women who were 

on therapy before pregnancy as compared with those initiating 

therapy in the third trimester (The European Collaborative Study 

and the Swiss Mother+Child HIV Cohort Study, 2000). 

 In contrast, a preliminary report from an observational study of 

pregnant HIV-infected US women found no association between 

combination ARV therapy and preterm birth in over 3000 women, 

82% of whom received combination therapy (Read, 2003). The 

highest rates of preterm delivery was among women on no ARV 

therapy. A large meta-analysis of 7 clinical studies including 2,123 

pregnant women receiving antenatal ARV therapy and 1,143 

women on no therapy found no increased rates of preterm labor, 
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low birth weight, low Apgar scores, or still birth with exposure 

to multiple ARV drugs as compared to one drug alone or to no 

therapy (Tuomala, 2002). 

 Given this conflicting data, no changes in antiretroviral 

management are indicated in pregnancy. Several studies have 

found increased preterm birth rates in women on no ARV therapy, 

especially with more advanced disease (Brocklehurst, 1998b; Leroy, 

1998; Martin, 1997) 

• Maternal adverse effects: 

- Hepatotoxicity/Skin rash: Women, particularly those with CD4 

counts >250/mm3, have an increased risk of developing symptomatic, 

often rash-associated, nevirapine-related hepatotoxicity (Stern, 2002) 

and deaths from hepatic failure have been reported in pregnant 

women receiving HAART regimens including nevirapine (Lyons, 2003; 

Langlet, 2000). It is not known whether pregnancy increases risk for 

hepatotoxicity in women receiving nevirapine; however, because some 

of the early symptoms of hepatotoxicity are relatively nonspecific 

and can be confused with common symptoms during pregnancy, 

health care providers for pregnant women receiving nevirapine 

should be aware of this potential complication and should regularly 

and frequently monitor clinical symptoms and hepatic transaminases 

(i.e., ALT and AST), particularly during the first 18 weeks of therapy, 

when this toxicity is most likely. When suggestive clinical symptoms 

develop, accompanied by elevation in ALT and/or AST, or when 

transaminases are significantly elevated in the absence of symptoms, 

nevirapine should be stopped and should not be restarted in the 

future. (USPHS Guidelines). When antiretroviral therapy is being 

started in pregnancy and CD4 counts are greater than 250/mm3, 

nevirapine should be used as part of the regimen only if benefit 

clearly outweighs the risk. These toxicities have not been reported 

in women receiving single dose nevirapine for prevention of perinatal 

transmission. 

- Lactic acidosis/steatosis: Lactic acidosis and hepatic steatosis, 

clinical disorders linked to mitochondrial toxicity in long-term 

nucleoside analogue users, may have a female preponderance, and 

a possible genetic susceptibility has been suggested. Bristol-Myers 

Squibb has reported several maternal deaths due to lactic acidosis/

hepatic steatosis, all in women receiving a combination of d4T/ddI 

as part of their antiretroviral regimen at the time of conception and 

for the duration of pregnancy, and other non-fatal cases of lactic 

acidosis have been reported in pregnant women receiving this 

combination (Mandelbrot, 2003). All nucleoside analogue drugs can 

induce mitochondrial dysfunction, but use of ddI and/or d4T carries 

greater risk than use of ZDV, 3TC, abacavir, or tenofovir because of 

their greater potential for interfering with mitochondrial replication. 

Typical initial symptoms are relatively nonspecific and include 

nausea, vomiting, abdominal pain, dyspnea, and weakness. Metabolic 

acidosis with elevated serum lactate and liver enzymes is common. It 

is not known if pregnancy increases the incidence of this syndrome; 

however, pregnancy itself can mimic some of the early symptoms of 

lactic acidosis/hepatic steatosis and is also associated with some rare 

but life-threatening disorders of liver metabolism (acute fatty liver of 

pregnancy; hemolysis, elevated liver enzymes and low platelets—the 

HELLP syndrome). Therefore, pregnant women receiving nucleoside 

analogue drugs should have liver enzymes and electrolytes evaluated 
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more frequently during the last trimester of pregnancy and any new 

symptoms should be evaluated promptly and thoroughly. Signs and 

symptoms of lactic acidosis/hepatic steatosis tend to improve with 

drug discontinuation; therefore, if this condition is suspected drugs 

should be stopped promptly. Because of the maternal deaths noted 

above, clinicians should prescribe the combination of d4T/ddI 

during pregnancy with caution and generally only when other 

nucleoside analogue combinations have failed or been associated 

with unacceptable toxicity or side effects. 

- Interaction of drugs with pregnancy-related side effects/

physiologic changes:

- Drugs that cause gastrointestinal upset may not be well tolerated 

in early pregnancy when morning sickness is common and may 

increase risk for nonadherence or inadequate blood levels from 

vomiting. In this situation, all ARVs should be discontinued and 

restarted when the nausea and vomiting is gone or has been 

effectively treated. 

- Protease inhibitors and hyperglycemia: Protease inhibitors (PIs) 

have been associated with the development or worsening of 

existing hyperglycemia or diabetes and pregnancy also increases 

risk for glucose intolerance. It is unknown whether the use of PIs 

in pregnancy will exacerbate risk for development of gestational 

diabetes. Women receiving PIs in pregnancy should have their 

glucose levels monitored closely and be questioned regularly about 

symptoms of hyperglycemia. 

- Anemia: Several antiretroviral agents, in particular ZDV, may cause 

bone marrow suppression and result in anemia. Pregnant women 

are at increased risk for anemia because of increased demands on 

nutritional stores, including iron and folic acid, and the addition 

of ARV regimens including ZDV may exacerbate anemia. Iron 

and folate supplementation should generally be given, as well as 

nutritional counseling to maintain adequate intake of other nutrients. 

Administration of ZDV is usually associated with macrocytosis; this 

should be kept in mind when evaluating anemia and should not 

exclude consideration of causes of microcytic or normocytic anemia, 

nor should it result in an assumption of causes of macrocytic anemia, 

such as folate or B12 deficiency. Treatment of anemia, including use 

of erythropoietin, may be considered in such women, as opposed to 

discontinuation of drug. 

ANTIRETROVIRAL DRUG RESISTANCE ISSUES

The development of antiretroviral drug resistance is one of the major 

factors leading to therapy failure in HIV-infected individuals and there are 

concerns that resistance may also limit the effectiveness of antiretroviral 

drugs in providing prophylaxis against perinatal transmission (see IX A 

above). Resistance emerges under selective pressure, especially when 

viral replication is not completely suppressed. Women who have been 

treated in the past with incompletely suppressive regimens (e.g., single or 

dual nucleosides); have documented clinical, immunologic, or virologic 

failure with previous regimens (with or without a history of resistance on 

genotypic or phenotypic testing); or have a history of nonadherence or 

problems with intolerance are at increased risk for having resistance to 

one or more antiretroviral agents. These factors should be considered in 

decisions about choice of ARV regimen during pregnancy. 
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There is also an increasing prevalence of antiretroviral drug resistance in 

newly infected and treatment naïve individuals, implying transmission 

of drug-resistant strains. The prevalence of antiretroviral drug resistance 

in surveys of U.S. and European newly infected individuals who had 

never been exposed to therapy has been >10% for primary resistance 

mutations in the reverse transcriptase gene in the majority of studies 

and ranged as high as 23%; primary resistance mutations in the protease 

gene ranged from 1–16% (Wainbert, 1998; Weinstock, 2000; Little, 1999; 

Boden, 1999). Drug resistance testing is recommended if a woman has 

acute HIV infection during pregnancy and should be considered in 

pregnant women who are ARV naïve but have significant probability of 

having been infected with drug-resistant virus (Perinatal HIV Guidelines 

Working Group, 2004). 

GENERAL PRINCIPLES FOR ANTIRETROVIRAL TREATMENT IN PREGNANCY

(Perinatal HIV Guidelines Working Group, 2004) 

• Decisions regarding choice of antiretroviral regimens for maternal 

treatment should be the same in pregnant and nonpregnant 

women, with the additional considerations outlined above. 

• Monitor CD4 count/viral load according to guidelines for 

nonpregnant adults: in pregnancy, this should be done 

approximately each trimester, but may be needed more frequently 

with failing or altered therapy. CD4 percentage may be a more 

accurate reflection of immune status during pregnancy than 

absolute CD4 cell count, because of possible variation in absolute 

CD4 count secondary to dilutional effects associated with 

hemodynamic changes in pregnancy. 

• The three-part ZDV chemoprophylaxis regimen (Table 7-9) should 

be recommended as a minimum for all HIV-infected pregnant 

women to reduce the risk of perinatal HIV transmission. Current 

clinical trial and epidemiologic data confirm the effectiveness of 

this regimen; no other regimen studied to date in randomized 

clinical trials has shown superior results. However, cohort 

studies have suggested additional benefit to decreasing perinatal 

transmission with use of combination ARV regimens.

 In women already receiving antiretroviral therapy when they 

become pregnant and this regimen does not include zidovudine, 

ZDV should be included as part of the regimen after 14 wk 

gestation, if feasible. There is evidence that duration of prior ZDV 

therapy in women with more advanced disease may not reduce 

effectiveness of ZDV in decreasing perinatal transmission (Stiehm, 

1999). However, ZDV should not be substituted for another 

antiretroviral agent when this is likely to reduce the efficacy of 

this regimen in treatment of maternal disease, i.e., with previous 

clinical failure of ZDV or history of documented ZDV resistance. 

The decision to add ZDV to an effective regimen must take into 

account the possible effect on adherence. 
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Table 7-9: Zidovudine Perinatal Transmission Prophylaxis 

Regimen

Antepartum Initiation at 14–34 wk gestation and continued throughout 

pregnancy 

A. PACTG 076 Regimen: ZDV 100 mg 5 times daily 

B. Acceptable Alternative Regimen: 

• ZDV 200 mg 3 times daily or 

• ZDV 300 mg 2 times daily

Intrapartum During labor, ZDV 2 mg/kg intravenously over 1 hr, followed by a 

continuous infusion of 1 mg/kg/hr intravenously until delivery.

Postpartum Oral administration of ZDV to the newborn (ZDV syrup, 2 mg/kg 

every 6 hr) for the first 6 wk of life, beginning at 8–12 hr after birth.

 In some circumstances ZDV cannot be used during the antepartum 

period (e.g., intolerance to ZDV). Stavudine (d4T) and ZDV are 

pharmacologically antagonistic and should not be used together; 

therefore, women on d4T-containing regimens with prior ZDV 

failure should be continued on the most effective regimen for their 

disease and ZDV should be excluded if d4T is maintained. 

 ZDV administration is recommended during the intrapartum 

period and for the newborn regardless of the antepartum 

antiretroviral regimen. 

• Effective combination antiretroviral therapy is recommended 

(including ZDV if feasible) for women with clinical, immunologic, or 

virologic indications for treatment and for maximum prevention of 

perinatal transmission (regardless of clinical or immunologic status). 

 Women who present in labor with no prior antepartum 

antiretroviral therapy should be treated with one of several effective 

regimens, described below (Intrapartum) and in Table 7-10. 

• Women with high CD4 counts and low or undetectable HIV-RNA 

levels, for whom initiation of antiretroviral therapy for the treatment 

of maternal infection would be considered optional, should be 

counseled about the potential benefits and risks of combination 

therapy and offered this therapy, along with the three-part ZDV 

perinatal prophylaxis regimen. Combination therapy should be 

selected based on efficacy data (in studies generally conducted 

among non-pregnant individuals); safety data for both mother and 

fetus/infant; and general experience with use in pregnancy. When 

several potential effective regimens are available and no specific 

safety concerns have been identified, in general drugs with wider 

experience in pregnancy should be selected. 

 Using ZDV alone is an option in this situation (with current 

USPHS guidelines when viral load <1000 copies/mL). This has the 

advantage of limiting exposure to other drugs during pregnancy but 

there are concerns about potential selection of ZDV-resistant viral 

variants and limitation of future maternal therapeutic options, as well 
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Table 7-10: Comparison of Intrapartum/Postpartum Regimens for HIV-1-infected Women in Labor Who Have Had No 

Prior Antiretroviral Therapy (Scenario #3)

Drug 

Regimen 

Source of 

Evidence 

Maternal 

Intrapartum 

Infant 

Postpartum 

Data on 

Transmission 

Advantages Disadvantages

ZDV Epidemiologic 

data, U.S.; compared to no ZDV treatment 

2 mg/kg intravenous bolus, followed by continuous infusion of 1 mg/kg/hr until delivery 

2 mg/kg orally every six hours for six weeks* 

Transmission 10% with ZDV compared to 27% with no ZDV treatment, a 62% reduction (95% CI, 19–82%) 

Has been standard recommendation 

Requires intravenous administration and availability of ZDV intravenous formulationAdherence to six week infant regimen Reversible, mild anemia with 6 week infant ZDV regimen

ZDV/3TC Clinical trial, 

Africa; compared to placebo 

ZDV 600 mg orally at onset of labor, followed by 300 mg orally every three hours until delivery AND 3TC 150 mg orally at onset of labor, followed by 150 mg orally every 12 hours until delivery 

ZDV 4 mg/kg orally every 12 hours AND 3TC 2 mg/kg orally every 12 hours for seven days 

Transmission at six weeks 9% with ZDV-3TC vs. 15% with placebo, a 42% reduction 

Oral regimen Adherence easier than six weeks of ZDV 

Requires administration of two drugs
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Nevirapine Clinical trial, 

Africa; compared to oral ZDV given intrapartum and for one week to the infant 

Single 200 mg oral dose at onset of labor 

Single 2 mg/kg oral dose at age 48–72 hours** 

Transmission at six weeks 12% with nevirapine compared to 21% with ZDV, a 47% reduction (95% CI*, 20– 64%) 

Inexpensive Oral regimen Simple, easy to administer Can give directly observed treatment 

Unknown efficacy if mother has nevirapine-resistant virus Transient nevirapine resistance mutations detected at 6 weeks postpartum in 19% of women receiving single-dose intrapartum nevirapine, and 46% of infants who became infected despite receiving nevirapine

ZDVNevirapine Theoretical ZDV 2 mg/kg intravenous 

bolus, followed by continuous infusion of 1 mg/kg/hr until delivery AND Nevirapine single 200 mg oral dose at onset of labor 

ZDV 2 mg/kg orally every six hours for six weeks AND Nevirapine single 2 mg/kg oral dose at age 48–72 hours** 

No data Potential benefit 

if maternal virus is resistant to either nevirapine or ZDV Synergistic inhibition of HIV replication with combination in vitro 

Requires intravenous administration and availability of ZDV intravenous formulation Adherence to six week infant ZDV regimen Unknown if additive efficacy with combination Transient nevirapine resistance mutations detected at 6 weeks postpartum in 15% of women receiving single-dose intrapartum nevirapine with ZDV or other antiretroviral drugs

ZDV, zidovudine; CI, confidence interval; 3TC, lamivudine* ZDV dosing for infants <35 weeks gestation at birth is 1.5 mg/kg/dose intravenously, or 2.0 mg/kg/dose orally, every 12 hours, advancing to every 8 hours at 2 weeks of age if >30 weeks 

gestation at birth or at 4 weeks of age if <30 weeks gestation at birth [121].

** If the mother received nevirapine less than one hour prior to delivery, the infant should be given 2 mg/kg oral nevirapine as soon as possible after birth and again at 48-72 hours.
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 as possibly increasing the risk for transmission. The development of 

resistance should be minimized by the relatively short duration of 

therapy and the more limited viral replication present in individuals 

with low HIV RNA level and high CD4 count. Follow-up of women 

enrolled in the PACTG 076 study has shown no significant differences 

in immunologic status or progression of disease (median followup 4.2 yr) in women who received ZDV compared with placebo 

recipients. (Bardeguez, 1998). However, recent data from PACTG 367 

suggests that there is increased efficacy for prevention of perinatal 

transmission with combination ARV therapy, even when HIV-RNA is 

<1000 copies/mL (Shapiro, 2004). 

• In antiretroviral-naive patients clinicians may consider delaying 

initiation of ARV therapy until after 10–12 wk of gestation, based 

on considerations of the woman’s health status, the potential (but 

generally low) risk of delaying therapy for several weeks, and the 

potential benefits of avoiding first trimester drug exposure for 

the fetus and the primary time period of nausea and vomiting in 

pregnancy. 

• In antiretroviral-experienced patients, who become pregnant or are 

referred into prenatal care while receiving ARV therapy, therapy 

should be continued or modified, subject to the considerations 

outlined above. If pregnancy is recognized in the first trimester, 

some women and their clinicians may consider temporary 

discontinuation of therapy until after completion of the first 

trimester because of concerns about potential teratogenicity, or 

because of significant nausea and vomiting in early pregnancy 

leading to concerns about inadequate absorption of medications. 

 Current data are insufficient to either support or refute fetal risk 

with early exposure to antiretroviral agents with the exception of 

efavirenz. Discontinuation of therapy may lead to viral rebound, 

which could theoretically increase risk of intrauterine HIV 

transmission or have an adverse effect on maternal disease. The 

woman’s clinical, immunologic, and virologic status should also be 

considered in decisions regarding continuation of therapy in the 

first trimester. 

 If the decision is made to stop therapy temporarily, all agents 

should be stopped simultaneously and restarted simultaneously in 

the second trimester to avoid development of drug resistance. 

• Decisions regarding use of ARV therapy during pregnancy should 

be made by the woman after detailed discussion of benefits and 

potential risks of therapy. This includes discussion of: 

- treatment recommendations for health of the HIV-infected woman, 

- current information regarding effectiveness of antiretroviral therapy in 

reducing perinatal transmission, 

- known or potential effects of antiretroviral drug exposure on the 

pregnant woman, 

- known or potential effects of antiretroviral drug exposure on the 

fetus/newborn, and 

- the importance of adherence to any prescribed antiretroviral regimen. 
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 There continue to be missed opportunities in prevention of 

transmission of HIV from mother to child. HIV has to first 

be identified in the woman; situations where counseling and 

testing have not been available or not utilized because of lack of 

perception of risk on the part of the woman or her health care 

provider have been associated with perinatal transmission in 

some cases. Women who become infected or seroconvert during 

pregnancy may be missed unless HIV testing is repeated later 

in pregnancy. Lack of prenatal care and active substance abuse, 

which frequently coexist, have also been linked to potentially 

avoidable increased risk for transmission (Bardeguez, 2000). 

ANTIRETROVIRAL PREGNANCY REGISTRY

The Antiretroviral Pregnancy Registry is a collaborative effort between 

pharmaceutical companies, the Centers for Disease Control and 

Prevention (CDC), the National Institutes of Health (NIH), and obstetric 

and pediatric practitioners to collect observational information on 

antiretroviral exposure during pregnancy in order to assess potential 

fetal/infant anomalies after exposure to these agents. Patient names are 

not used and information is confidential. Health care providers who are 

treating HIV-infected pregnant women are strongly encouraged to report 

cases of prenatal exposure to antiretroviral drugs to the Registry: 1011 

Ashes Drive, Wilmington, NC 28405; telephone (800) 258-4263; fax (800) 

800-1052, Internet access www.APRegistry.com. 

OPPORTUNISTIC INFECTIONS

Prophylaxis indications and recommendations for primary prophylaxis 

of opportunistic infections in pregnancy are noted in Table 7-11. Once 

an individual has had the following infections, prophylaxis to prevent 

recurrence is recommended as standard of care. (See Chapter IV on 

Primary Medical Care.) First-choice regimens are outlined. 

• Pneumocystis carinii pneumonia: same regimen as for primary 

prophylaxis. Criteria for discontinuation: CD4 > 200/mm3 for ≥ 3 

mo. 

• Toxoplasmic encephalitis: sulfadiazine 500–1000 mg po qid 

plus pyrimethamine 25–50 mg po qd plus leucovorin 10–25 mg 

po qd; counsel regarding concerns about potential teratogenicity 

of pyrimethamine. Criteria for discontinuation: CD4 >200/mm3

for ≥ 6 mo and completed initial therapy and asymptomatic for 

toxoplasmosis. 

• Disseminated Mycobacterium avium complex: azithromycin 

500 mg po qd plus ethambutol 15 mg/kg po qd. Criteria for 

discontinuation: CD4 >100/mm3 for ≥ 6 mo and completed 12 mo 

of MAC therapy and asymptomatic for MAC. 

• CMV: choice of agents should be individualized in pregnancy after 

consultation with experts. Criteria for discontinuation: CD4 >100–

150/mm3 for ≥ 6 mo and no evidence of active disease and regular 

ophthalmic examinations. 
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Table 7-11: Opportunistic Infections and Primary Prophylaxis in Pregnant WomenStrongly Recommended

Pathogen Indication Regimen Alternatives Comments

Pneumocystis carinii

CD4< 200/mm3 or oral thrush

TMP-SMZ DS 1 po qd TMP-SMZ SS 1 po qd

Dapsone 50 mg po bidDapsone 100 mg po qdAerosolized pentamidine (AP) 300 mg q mo (via Respirgard II nebulizer)TMP-SMZ DS 1 po tiw

Some providers may prefer to use AP in first trimester because of lack of systemic absorption and fetal exposure, secondary to theoretical concerns about possible teratogenicity with systemic medications.Criteria for stopping primary prophylaxis: CD4 > 200/mm3 for ≥ 3 mo.

Mycobacterium tuberculosisINH-sensitiveINH-resistant multidrug (INH and rifampin) resistant

TST reaction ≥ 5mm orprior positive TST without treatment or contact with active TBSame; high probability of exposure to INH-resistant M. tuberculosisSame; high probability of exposure to multidrug M. tuberculosis

INH 300 mg po qd plus pyridoxine 50 mg po qd x 9 moINH 900 mg po biw plus pyridoxine 100 mg po biw x 9 moRifampin 600mg po qd x 4 mo.

Rifampin 600 mg po qd x 4 mo

Some providers may choose to initiate phrophylaxis after the first trimester, because of concerns about possible teratogenicity. Anecdotal experience with rifampin has not been associated with adverse pregnancy outcomes. Pyrazinamide should generally be avoided, particularly in the first trimester, because of lack of information concerning fetal effects. INH use during pregnancy has been associated with elevated risk for hepatotoxicity and LFTs should be monitored.Choice of drugs requires consultation with obstetric experts and public health authorities.Consult with obstetric experts and public health authorities if alternative regimen required

Toxoplasma gondii 

IgG antibody to Toxoplasmaand CD4 < 100/mm3

TMP-SMZ DS 1 po qd

TMP-SMZ SS 1 po qd If patient cannot tolerate TMP-SMZ, the recommended alternative 

is dapsone-pyrimethamine-leucovorin; however, because of the low incidence of TE during pregnancy and possible fetal risk with pyrimethamine, chemoprophylaxis may reasonably be deferred until after pregnancy Criteria for stopping primary prophylaxis: CD4 > 200/mm3 for ≥ 3 mo.

Mycobacterium avium complex 

CD4 < 50 mm3 Azithromycin 1200 

mg po qw 

Rifabutin 300 mg po qd Some providers may prefer to defer prophylaxis until after the first 

trimester, because of general concerns about administering drugs in early pregnancy. Experience with rifabutin in pregnancy is limited.Criteria for stopping primary prophylaxis: CD4 > 100/mm3 for ≥ 3 mo.

TMP-SMZ, trimethoprim-sulfamethoxazole; INH, isoniazid; TST, tuberculin skin test; TE, toxoplasmic encephalitis; LFT, liver function tests.Source: Adapted from USPHS/IDSA, 2001.
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• Histoplasmosis: amphotericin B 1.0 mg/kg iv qw; may be 

preferred, particularly during the first trimester, because 

of embryotoxicity and teratogenicity in animals exposed to 

itraconazole. 

• Cryptococcosis: amphotericin B 0.6–1.0 mg/kg iv qw-tiw; may 

be preferred, particularly during the first trimester, because of 

craniofacial and skeletal abnormalities in infants after prolonged 

in utero exposure to fluconazole. Criteria for discontinuation: CD4 

>100–200/mm3 for ≥ 6 mo and completed initial therapy and 

asymptomatic for cryptococcosis. 

• Coccidiomycosis: amphotericin B 1.0 mg/kg iv qw; may be 

preferred, particularly during the first trimester, because of 

craniofacial and skeletal abnormalities in infants after prolonged in 

utero exposure to fluconazole.

IMMUNIZATIONS (ACOG, 1991; CDC, 1993; USPHS/IDSA, 2001) 

Immunization should be considered in pregnancy when the risk for 

exposure is high, risk of infection for mother or fetus is high, and the 

vaccine is thought unlikely to cause harm. HIV-infected individuals with 

immune suppression should avoid live virus or live bacteria vaccines. 

HIV-positive persons who are symptomatic or have low CD4 cell 

counts may have suboptimal responses to vaccination. Some, but not 

all, studies have shown a transient (<4 wk) increase in viral load after 

immunization. This is of some theoretical concern, given the association 

between viral load and perinatal transmission. This increase in viremia 

may be prevented with appropriate antiretroviral therapy (Bartlett, 2003). 

For this reason, clinicians may consider deferring routine vaccination 

until after the patient is on an effective antiretroviral regimen and 

avoiding administration late in pregnancy, close to delivery, when most 

transmission is thought to occur. 

Current immunization recommendations for HIV-positive pregnant 

women are: 

• pneumococcal vaccine — “generally recommended” if not 

received during previous 5 years; consider revaccination if initially 

immunized with CD4 < 200/mm3 with increase to CD4 > 200/

mm3 in response to ARV treatment. 

• influenza vaccine — “generally recommended”; administer before 

flu season annually.

• tetanus-diphtheria (Td) vaccine — booster dose every 10 yr 

after completion of primary series.

• hepatitis B vaccine — “generally recommended” for all 

susceptible (anti-HBc-negative) patients; three doses at 0, 1, 6 mo.
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• hepatitis A vaccine — “generally recommended” for all susceptible 

(anti-HAV-negative) patients with chronic hepatitis C or hepatitis 

B; also indicated before travel to endemic areas, in injection drug 

users, and with community outbreaks; two doses at 0, 6 mo.

• enhanced potency inactivated polio vaccine — use if not 

previously immunized and traveling to areas where risk for 

exposure is high; oral polio vaccine is a live virus vaccine and is 

contraindicated in HIV-positive persons.

• immune globulins

- immune globulin recommended for measles exposure in 

symptomatic HIV-positive persons and hepatitis A with exposure 

to HAV in close contact/sex partner or travel to underdeveloped 

country (especially in patients with advanced HIV, who may have 

poor antibody response to vaccine)

- hyperimmune globulins recommended: 

• varicella-zoster virus (VZV) immune globulin-susceptible adult 

(undetectable antibodies to VZV or no history of either chickenpox 

or shingles) after significant exposure (household, hospital room, 

close indoor contact >1 hr, prolonged face-to-face contact) to 

chickenpox or VZV; give within 96 hr of exposure.

• hepatitis B immune globulin (HBIG)-needlestick or sexual contact 

with HBsAg+ person in susceptible individual (anti-HBc-negative); 

HBIG should be given and HBV vaccine series should be started 

within 14 days of exposure. 

REDUCTION OF SECONDARY RISK FACTORS

Treatment of STIs or other coinfections; encouragement of safer sexual 

practices during pregnancy; discouragement of smoking and drug use; 

and substance abuse treatment should be employed as measures that 

may decrease risk of perinatal transmission. 

FREQUENCY OF VISITS

Determined on an individual basis, based on gestational age, health of 

the mother, presence of pregnancy-related complications, antiretroviral 

regimen and response, and psychosocial needs. In uncomplicated 

pregnancies visits generally are scheduled monthly in early pregnancy 

and every 1–2 wk from 28–30 wk of gestation until delivery. Coordinate 

with other health care visits when possible. 

CONSULTATIONS TO CONSIDER DURING PREGNANCY

Certain consultations may be needed during pregnancy in the HIVinfected woman. Ideally, many of these can be handled within the same 

clinic or center where the patient is seen for obstetrical care or for primary 

medical care. When possible, referral of the pregnant woman with HIV to 

an obstetrician with HIV expertise and experience is advised. In this case 

many of the HIV-specific treatment issues may also be managed by this 

individual. In general, possible consultative needs include: 
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• Perinatology: to address special obstetrical concerns, including 

use of HIV-related or other medications in pregnancy, discussions 

about fetal monitoring/evaluation, other appropriate antepartum/

intrapartum evaluation and management. When indicated, 

consultation should ideally be with a perinatologist who has HIV 

experience/expertise 

• Infectious disease/HIV specialist (particularly important 

if newly diagnosed in pregnancy): to address HIV-related 

treatment issues, including choice of ARV regimen, need for OI 

prophylaxis or treatment 

• Pediatrics: to address care of the infant after birth, including 

testing for HIV, use of zidovudine and PCP prophylaxis in exposed 

infants 

• Nutrition: to address proper diet, need for nutritional or vitamin/

mineral supplementation; food safety issues, when needed 

• Substance abuse management: when indicated 

• Psychiatry/psychology: to address signs/symptoms of 

depression, other psychiatric disorders and their management, 

if needed 

• Social services: to address needs related to housing, 

transportation, domestic violence, access to medications and to 

medical care, etc. 

COUNSELING AND SUPPORT

• Support systems: At the initial visit the health care provider 

should assess the patient’s support system — who knows her 

HIV status, problems encountered with disclosure, family and/

or friends to whom she turns for ongoing support, barriers to 

disclosure to sexual or needle-sharing partners. These issues 

should be readdressed at intervals throughout pregnancy as 

needed. The use of peer counselors may be especially helpful. 

• Contraception use postpartum: Discussion about postpartum 

contraceptive plans should be initiated in early to midpregnancy 

to allow comprehensive education and counseling about available 

options and adequate time for informed decision making. 

• Condom use during pregnancy: Sexual activity should be 

reviewed at each visit and condom use reinforced. 

• Drug use/treatment: History of and/or ongoing substance abuse, 

including tobacco and alcohol, as well as illicit drugs, should 

be assessed at the initial visit and at intervals during prenatal 

care, if indicated. Type of substance(s), amount of use, route of 

administration, and prior drug or alcohol treatment should be 

documented. The patient should be counseled about specific risks 

associated with substance abuse in pregnancy (see Chapter X on 

Substance Abuse) and drug or alcohol treatment during pregnancy 

should be encouraged and facilitated for active problems. 
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• Adherence: Each patient should be educated and counseled 

about the importance of adherence to prescribed medications, 

particularly antiretroviral drugs, before they are initiated and 

medication adherence should be assessed and reinforced at each 

visit. (See Chapter V on Adherence.) 

• Clinical trials: Pregnant HIV-positive women should be informed 

about the availability of and offered participation in clinical trials 

for which they are eligible. 

• Advance directives: The issue of advance directives for care in 

the event of sudden deterioration in the woman’s health, as well 

as guardianship plans for children in the event of the mother’s 

incapacitation or death, should be discussed; legal assistance 

should be facilitated, if needed.

X. INTRAPARTUM 

The goals of intrapartum management are to further reduce the risk of 

perinatal transmission and to minimize the risk of maternal and neonatal 

complications. 

A. UNIVERSAL PRECAUTIONS

Gowns, gloves, and eye protection should be used in all deliveries and 

in examinations or procedures likely to generate splashing blood or 

amniotic fluid. (See Chapter XIII on Occupational Exposure.) When used, 

this should provide adequate protection for healthcare workers. Medical 

care should not be altered due to considerations of potential occupational 

exposure. 

B. FETAL/MATERNAL MONITORING

External fetal monitoring should be employed but avoid use of fetal scalp 

electrodes or fetal scalp sampling unless necessary to ensure fetal wellbeing. Avoid artificial rupture of membranes unless obstetrically indicated. 

C. MODE OF DELIVERY

Cesarean section, when performed before the onset of labor and/or 

membrane rupture (scheduled or elective), has been associated with 

decreases in mother-to-child transmission ranging from 55–80% in the 

absence of ARV prophylaxis and with ZDV alone (International Perinatal 

HIV Group, 1999; European Mode of Delivery Collaboration, 1999). Studies 

included a meta-analysis of 15 prospective cohort studies including over 

7800 mother-infant pairs and an international randomized mode of 

delivery clinical trial. Both studies were done before viral load testing 

and use of optimal combination ARV regimens became standard of care 

in the US. Neither study found a benefit with cesarean section performed 

after onset of labor or membrane rupture. Recent data from PACTG 367 
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(Shapiro, 2004) in almost 2900 pregnancies found that in all subgroups 

of viral load, combination ARV therapy was associated with the lowest 

rates of transmission and with viral load <1000 c/mL, MTCT rates were 

significantly lower with multiagent vs single-agent ARV therapy (0.6% 

vs 2.2%, adjusted OR 0.2, 95% CI 0.04, 0.8) but did not differ by mode 

of delivery. Recent observational data from over 4500 women in the 

European Collaborative Study found that among women with undetectable 

viral load and after adjusting for ARV therapy during pregnancy, scheduled 

cesarean section was not associated with additional benefit in reduction of 

transmission (Thorne, 2004).

When making decisions about mode of delivery, potential maternal 

risks with cesarean section should be considered. Maternal morbidity 

and mortality are increased with cesarean section over vaginal delivery 

(Hebert, 1999). Although this risk is most marked with urgent or 

emergency cesarean section or after labor or membrane rupture, 

complications after scheduled cesarean section still exceed those seen 

with vaginal delivery (Roman, 1998; Gregory, 1998; Van Ham, 1997; 

McMahon, 1996). Most complications relate to postpartum infections 

(e.g., endometritis, wound infection, urinary tract infection, pneumonia) 

but also include complications related to hemorrhage, since blood loss is 

generally greater with cesarean section. Factors which increase the risk 

of complications include low socioeconomic status, genital infections, 

malnutrition, and smoking, and prolonged labor or membrane rupture, 

some of which may be more common in the setting of HIV infection. 

Current data suggest that cesarean section is associated with a slightly 

increased risk of complications among HIV-infected women than among 

uninfected women, with the greatest differences seen among women with 

more advanced disease (European Mode of Delivery Collaboration, 1999; 

Watts, 2000; Read, 2001; Marcollet, 2002; Semprini, 1995; Grubert, 1999; 

Maiques-Montesinos, 1999; Vimercati, 2000; Grubert, 2002; Rodriguez, 

2001; Urbani, 2001; European HIV in Obstetrics Group, 2004). However, 

complication rates in most studies of HIV-infected women were generally 

within the range reported among HIV-uninfected women and were not 

of sufficient frequency or severity to outweigh the potential benefit in 

selected cases where scheduled cesarean section may further decrease 

risk of MTCT (Perinatal HIV Guidelines Working Group, 2004). HIVinfected women, particularly when more immunosuppressed, may be 

at increased risk of postpartum endometritis, even with vaginal delivery 

(Temmerman, 1994). 

Current recommendations (Perinatal HIV Guidelines Working Group, 

2004; ACOG, 2000): 

• Counsel all HIV-infected pregnant women about the possible 

benefit vs risk of scheduled cesarean section, as well as the 

limitations of current data. The woman’s autonomy to make an 

informed decision regarding route of delivery should be respected 

and honored.
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• Scheduled cesarean section should be recommended in the 

following situations: 

- HIV-RNA >1000 c/mL (regardless of ARV therapy). 

- Women with unknown HIV-RNA level, not on ARV therapy or 

receiving ZDV alone.

• Cesarean section is unlikely to add additional benefit in reduction 

of MTCT with HIV-RNA <1000 c/mL in ARV-treated mothers.

• The most recently determined HIV-RNA level should be used 

when counseling about mode of delivery. 

• Scheduled cesarean section should be performed at 38 weeks 

gestation, based on clinical and ultrasonographic estimates of 

gestational age, to minimize risk of labor or membrane rupture 

prior to procedure. This is associated with a small increased risk 

of iatrogenic preterm delivery and infant respiratory distress 

syndrome, as compared to standard recommendations for 

scheduled cesarean section at 39 weeks when indicated in HIVuninfected women. 

• When scheduled cesarean section is performed, ZDV infusion 

should begin three hours before surgery to achieve adequate blood 

levels. 

• Other ARV medications taken during pregnancy should be given 

on schedule. 

• Prophylactic antibiotics are generally recommended at the time of 

scheduled cesarean section, although no controlled studies have 

evaluated their efficacy in this situation. 

• Women who have planned scheduled cesarean section but present 

in early labor or shortly after membrane rupture should be 

counseled and managed on an individual basis, based on most 

recent HIV-RNA level, ARV therapy, and projected length of labor 

(based on cervical dilatation at admission, rate of cervical change, 

and status of membranes/length of rupture). Cesarean section 

after 4 or more hours of membrane rupture is less likely to reduce 

MTCT and risks of perioperative infection after cesarean section 

are increased with increasing duration of membrane rupture. 

D. INTRAPARTUM ARV MANAGEMENT

ARV medications taken during pregnancy should be continued 

on schedule during the intrapartum period, regardless of route of 

delivery. If one or more ARV agents are not tolerated during labor 

because of nausea or vomiting, the entire regimen should be stopped 

simultaneously and restarted simultaneously after delivery. Women 

who are taking combination ARV regimens for the purpose of reducing 

risk of MTCT and who do not yet meet criteria for starting ARV therapy 

for treatment of maternal disease may discontinue treatment after 

delivery. Recent pharmacokinetics data has shown prolonged levels 

of nevirapine postnatally with levels persisting for over 3 weeks in a 
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significant proportion of women who received a single-dose of NVP in 

labor (Muro, 2004; Jourdain, 2004); this has raised concerns that stopping 

all drugs in an NVP-containing regimen at the same time will result in a 

variable period of time during which the woman is exposed to functional 

monotherapy and may be at increased risk for developing resistance. 

The role of staggered stopping of components of an ARV regimen in this 

situation is unclear and the duration of continued therapy needed with 

a “tail” is unknown. A recent report of women receiving NVP/ZDV/3TC 

during pregnancy found that stopping the NVP at delivery and continuing 

ZDV/3TC for 5–7 additional days made no difference in development of 

resistance (Lyons, 2005). 

Regardless of ARV regimen used during pregnancy, women with HIV 

infection should receive ZDV in labor: 2 mg/kg ZDV in a 1 hr IV loading 

dose, followed by 1 mg/kg/hr by IV infusion. In women on a d4Tcontaining regimen during pregnancy, intrapartum ARV management 

should involve IV ZDV OR continuation of the oral combination ARV 

regimen, but not both, because of the pharmacologic antagonism between 

ZDV and d4T. As noted above, if scheduled cesarean section is planned, 

ZDV infusion should begin 3 hr preoperatively. 

For women who present in labor with no prior antiretroviral therapy, several 

effective regimens are available. (Guay, 1999; Perinatal HIV Guidelines 

Working Group, 2004; Wade, 1998) These are outlined in Table 7-10. 

There has been increasing concern with use of single-dose NVP either 

alone or in addition to other antiretrovirals because of data showing rates 

of NVP resistance after delivery ranging from 15%–40% (Eshleman, 2001; 

Cunningham, 2002; Jourdain, 2004; Martinson, 2004) in women with 

detectable viremia. Variables associated with development of maternal 

NVP resistance include longer half-life of nevirapine in individual women 

(Jackson, 2000), high baseline HIV-RNA level or low baseline CD4 count 

(Eschleman, 2001), viral subtype (subtype D.A) (Eshleman, 2004), body 

compartment (breast milk vs plasma) (Lee, 2003), and timing of sampling 

post NVP administration (Martinson, 2004; Eshleman, 2001). In the SAINT 

trial in South Africa, in which women received both an intrapartum and 

a postpartum NVP dose, NVP resistance was detected in 67% of women 

and 53% of infected infants, with no further benefit in terms of reducing 

transmission (Sullivan, 2002). The potential implications for future 

maternal treatment options from resistance to one dose of nevirapine are 

unclear. However, in a recent report of women who were started on NVPcontaining HAART regimens after delivery, exposure to single-dose NVP 

in labor was associated with inferior virologic response (HIV-RNA <50 c/

mL) after 6 months of treatment; those with documented NVP-resistance 

were least likely to have optimal viral suppression (Jourdain, 2004). 

NVP-resistance has also been detected in 17%–46% of infected infants 

after exposure to single-dose NVP (Eshleman, 2001) or single-dose NVP in 

addition to short-course ZDV (Chaix, 2004). Specific resistance mutations 

differed between mother and infant (Eshleman, 2001) and there was no 

evidence that the development of NVP-resistance increased risk of MTCT 

(Eshleman, 2001; Chaix, 2004). 
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Women of unknown HIV status who present in labor with no prenatal 

care may be offered rapid HIV testing, after careful counseling and with 

informed consent. Positive results should be confirmed by standard 

serologic testing but enable the initiation of an appropriate antiretroviral 

regimen to reduce the risk of perinatal transmission. 

E. VAGINAL CLEANSING

A promising potential intervention to reduce transmission at the time 

of vaginal delivery is vaginal cleansing to decrease neonatal exposure 

to maternal blood and genital secretions. A clinical trial of 0.25% 

chlorhexidine manual vaginal cleansing on admission and every 4 hr 

until delivery in over 3300 women compared to some 3600 controls found 

no significant impact on HIV transmission, except when membranes had 

been ruptured for more than 4 hr before delivery (Biggar, 1996). However, 

this intervention reduced early neonatal and maternal postpartum 

infectious morbidity and neonatal mortality (Taha, 1997). A prospective 

trial of vaginal lavage using 0.2% or 0.4% chlorhexidine or no intervention 

also found no overall reduction in transmission with lavage, although data 

suggested that lavage before membrane rupture with chlorhexidine 0.4% 

may reduce MTCT (Gaillard, 2001). A more recent small (n=107) vaginal 

cleansing study using benzalkonium chloride found no effect on perinatal 

HIV transmission or perinatal/infant mortality (Mandelbrot, 2002). 

Currently, vaginal cleansing cannot be recommended for prevention of 

mother-to-child transmission. 

XI. POSTPARTUM 

A. INFANT FEEDING

When replacement feeding is acceptable, feasible, affordable, sustainable, 

and safe, breastfeeding should be discouraged in women known to be 

HIV-infected, because of the well-documented increased risk for MTCT 

of HIV with breastfeeding. In low-resource settings, where there may 

be no good alternatives to breastfeeding, HIV-infected women should be 

counseled and assisted to exclusively breastfeed (breastmilk only without 

any additional solids or liquids) for up to 6 months, followed by rapid 

weaning (WHO, 2001). Breastfeeding mothers should be taught proper 

breastfeeding technique, including prevention, recognition, and prompt 

management of breast problems (e.g., mastitis, abscess, cracked nipples) 

or oral thrush or other oral lesions in the infant. 
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B. ASSESS HEALING

Assess healing of wound sites, uterine involution, and appropriate 

cessation of postpartum bleeding. Because of the potential for an increase 

in post-cesarean section wound infection, assessment of wound healing 

should be done between the time of hospital discharge and the routine 

postpartum visit. 

C. CARE FOR MOTHER AND INFANT

HIV-infected mothers may neglect their own care while trying to provide 

appropriate care for their infant and other children or family members. 

It is essential that she be linked with comprehensive medical and 

supportive care services, including HIV specialty care; primary medical 

and gynecologic care; family planning; mental health or substance abuse 

treatment services; and assistance with food, housing, transportation, and 

legal/advocacy services, if needed. Although there are few data available, 

HIV-infected women may be at increased risk for postpartum depression. 

Women who have received ZDV monotherapy during pregnancy should 

be reevaluated in the postpartum period with clinical assessment, CD4 

count, and HIV RNA level to determine need for ongoing antiretroviral 

therapy. It is essential that access to and continuity of antiretroviral 

treatment as needed for maternal health be ensured. 

Because of the physical recovery from giving birth, the stresses and 

demands of caring for a new baby, and possible postpartum depression, 

the new mother may be particularly vulnerable to problems with 

adherence to ARV treatment. Additional support and attention to this 

issue is warranted. 

Similarly, the HIV-exposed infant should be linked into ongoing pediatric 

care, with HIV diagnostic tests as described below and appropriate HIV 

specialty care if HIV-infected. 

D. CONTRACEPTION/CONDOM USE

Discussions about contraception and condom use should be continuous 

throughout pregnancy and reviewed and reinforced at the time of the 

postpartum visit. 

E. LONG-TERM FOLLOW-UP OF MOTHER AND INFANT

All HIV-positive mothers and infants exposed to ZDV and/or other 

antiretroviral drugs or combinations during pregnancy should have 

long-term follow-up to assess possible late effects of these therapies on 

HIV progression in the mother or neoplasia or organ-system toxicity in 

exposed children. 
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XII. CARE OF THE HIV-EXPOSED INFANT (Working Group on 

Antiretroviral Therapy and Medical Management of HIV-Infected 

Children, 2004)

A. DIAGNOSIS OF HIV 

The standard for diagnosis of HIV infection in exposed infants is the 

use of viral assays (HIV DNA PCR (preferred), HIV RNA PCR, or viral 

culture) obtained within 48 hr of birth, at 1–2 mo, and 3–6 mo. HIV can 

be excluded in non-breastfed infants with two or more negative tests 

performed at age ≥ 1 mo, with one of these performed at age ≥ 4 mo. 

HIV IgG antibody tests will generally be positive in exposed infants for 

up to 18 mo of age because of transplacental passage; two negative tests 

performed at > 6 mo and at least 1 mo apart will also exclude infection 

in infants without clinical evidence of infection. P24 antigen testing is 

less sensitive than other virologic tests and has a high frequency of falsepositive results in infants <1 mo of age. 

HIV DNA PCR is the preferred virologic assay for diagnosis with 93% 

(90% CI=76–97%) sensitivity by age 14 days (Dunn, 1995). Data 

on use of HIV RNA PCR are more limited but sensitivity appears to 

be comparable to HIV-DNA PCR for early diagnosis of HIV infants. 

HIV culture is sensitive for early diagnosis but is more complex and 

expensive, and has a longer turnaround time for results. Using these tests 

approximately 40% of infected infants can be identified by age 48 hr and 

are considered to have early or intrauterine infection; infants with initial 

negative testing during the first week after birth and subsequent positive 

tests are considered to have intrapartum infection. Almost all infected 

infants can now be diagnosed by the age of 4–6 mo. ZDV monotherapy 

for perinatal prophylaxis has not been shown to delay detection of HIV or 

decrease sensitivity or predictive value of virologic assays (Connor, 1994; 

Kovacs, 1995), although performance of these tests when the mother has 

received more intensive combination antiretroviral therapies has not 

been studied. 

B. ARV TREATMENT

All HIV-exposed infants should receive ZDV prophylaxis (2 mg/kg every 

6 hr) for the first 6 wk of life as part of the three-part zidovudine regimen 

to prevent perinatal HIV transmission. If the mother has received 

no antepartum or intrapartum ZDV, the newborn regimen should be 

started as soon as possible after delivery, preferably with 6–12 hr of 

birth. For preterm infants (<35 wks), ZDV 1.5 mg/kg IV or 2.0 mg/kg 

po q 12 hr, then increased to q 8 hr at 2 wk (if >30 wks at birth) or 4 

wk (if <30 wks at birth) is recommended (Capparelli, 2003). Initiation 

of ZDV prophylaxis for the neonate within 48 hr (most infants initiated 
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ZDV within 24 hr) of birth resulted in an approximately 50% decrease 

in infection compared with no therapy (Wade, 1998). A recent clinical 

trial of infant post-exposure prophylaxis (no maternal antepartum or 

intrapartum ARV exposure) in breastfeeding infants in Malawi found that 

single-dose infant nevirapine plus one week of ZDV had 36.4% efficacy 

as compared to single-dose infant nevirapine alone when evaluation was 

limited to infants uninfected at birth (Taha, 2003). This study does not 

address whether this regimen is superior to 6 wks of ZDV alone, which 

remains the standard recommendation from the USPHS. The use of 

single-dose nevirapine in mothers and newborns has been associated 

with the development of nevirapine resistance in a certain proportion of 

infants infected despite prophylaxis, as noted above. The implications of 

this resistance for progression of infection or response to future NNRTIcontaining ARV regimens is unknown. The efficacy of other ARV agents 

or combinations in HIV-exposed infants, particularly in cases where 

the mother is known or suspected to have ZDV or NVP resistance, is 

unknown and appropriate dosing regimens in neonates are not welldefined for many drugs. 

Once infection is documented, more intensive combination antiretroviral 

therapy is recommended with clinical symptoms of HIV infection or 

evidence of immunesuppression (immune categories 2 or 3 — Table 7-12) 

regardless of age or viral load. Some experts recommend initiating 

potent ART as soon as the diagnosis is confirmed, regardless of clinical 

or immunologic status or viral load, because HIV-infected infants under 

the age of 12 mo are considered to be at high risk for disease progression 

and the prognostic value of standard virologic or immunologic parameters 

is less than that for older children. Once HIV infection is confirmed, 

decisions about antiretroviral therapy should be made in consultation with 

a specialist in the treatment of pediatric HIV infection. 
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Table 7-12: 1994 Revised Human Immunodeficiency Virus Pediatric Classification System

<12 Mo 5 Yr 6–12 Yr

Immune Category CD4/mm3 % CD4/mm3 % CD4/mm3 %

Category 1: no suppression ≥ 1500 ≥ 25% ≥ 1000 ≥ 25% ≥ 500 ≥ 25%Category 2: moderate suppression

750–1499 15%–24% 500–999 15%–24% 200–499 15%–24%

Category 3: severe suppression

<750 <15% <500 <15% <200 <15%

Clinical Category Children < 13 Yr

Category N: not symptomatic

Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A.

Category A: mildly symptomatic

Children with 2 or more of the following conditions but none of the conditions listed in categories B and C:• Lymphadenopathy (≥0.5 cm at more than two sites; bilateral = one site • Dermatitis• Hepatomegaly • Parotitis• Splenomegaly • Recurrent or persistent upper respiratory infection, sinusitis, or otitis media

Category B: moderately symptomatic

Children who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIV infection. Examples of conditions in clinical category B include, but are not limited to, the following:• Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or • Herpes zoster (ie, shingles) involving at least two distinct episodes or 

thrombocytopenia (<100,000/mm3) persisting for ≥ 30 days more than one dermatome

• Bacterial meningitis, pneumonia, or sepsis (single episode) • Leiomyosarcoma• Candidiasis, oropharyngeal (ie, thrush) persisting for > 2 months • Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia 

in children aged > 6 months complex

• Cardiomyopathy • Nephropathy• Cytomegalovirus infection with onset before age 1 month • Nocardiosis• Diarrhea, recurrent or chronic • Fever lasting > 1 month• Hepatitis • Toxoplasmosis with onset before age 1 month• Herpes simplex virus (HSV) stomatitis, recurrent (ie, more than • Varicella, disseminated (ie, complicated chickenpox)

two episodes within 1 year)

• HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month

Category C: severely symptomatic

Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of LIP (which is a category B condition)

Source: Adapted from CDC, 1994.
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C. PNEUMOCYSTIS CARINII PNEUMONIA PROPHYLAXIS

All HIV-exposed infants should receive P. carinii pneumonia prophylaxis 

with trimethoprim-sulfamethoxazole (150/750 mg/m2/day in two divided 

doses po tiw on consecutive days) beginning at 4–6 wk and extending 

for the first year of life or until HIV infection is excluded. Dapsone or 

atovaquone are alternatives. 

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VIII

I. INTRODUCTION

Over the past five years, medical and public health researchers and 

policy makers have noted the growing role of behavioral, social, and 

cultural matters in outcomes in health and disease. A consistent 

theme among the recommendations and findings in their reports is the 

interdependent role of cultural issues in health care and quality of care. 

Cultural issues in health care were identified as important in medical 

education (Cuff, 2004), in the health care work force (Smedley, 2004; 

Gebbie, 2003), in health care disparities (Smedley, 2003), and in health 

communications (Nielsen-Bohlman, 2004). These inquiries suggest the 

need for core competencies, as reflected in curricular changes as well as 

new directions in research and policy. Women and the cultural factors 

related to gender are among the issues emphasized by policy makers, 

researchers, and clinicians alike

Culture is defined as learned and shared behaviors, beliefs, and values 

that provide meaning to an individual’s life and that serve as a lens and 

guiding framework through which individuals, families, and communities 

understand and respond to their experiences (Hahn, 1995). Culture is 

affected by home, religion, ethnic group, language, neighborhood, school, 

and age-group (Cruickshank, 1989; Helman, 2000). Culture, social and 

economic status, and gender roles significantly influence the decisions 

women make when seeking health care and can be both a positive and 

a negative factor in facilitating use of health services. Providers who can 

effectively identify and address cultural factors associated with illness 

and its management are in a better position to improve diagnosis, 

treatment strategy, and patient outcomes. 

This chapter will discuss the cultural and social considerations, including 

gender roles, for women living with HIV infection and help identify the 

benefit that provider-based assessment tools can offer in improving 

women’s access to and utilization of HIV primary health care.

II. ECONOMIC ISSUES

Poverty remains a basic underlying context for most women living with 

HIV infection. In the US women with HIV are often poor and un- or 

under-insured. Their ability to improve their economic status is often 

impaired by lack of education or work skills and their role as mothers or 

caretakers for other family members, who may also have HIV infection. 

They may depend on the economic support (including insurance benefits) 

VIII. ADDRESSING CULTURAL ISSUES TO

IMPROVE QUALITY OF CARE

Barbara Aranda-Naranjo, PhD, RN, FAAN,

Magda Barini-Garcia, MD, MPH, 

Moses B Pounds, PhD, and Rachel Davis, RN, ACRN
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of their husband or boyfriend, making them particularly vulnerable if 

abandoned. Women also generally have lower-paying jobs and often 

earn less for comparable work than men. Ultimately food, housing, and, 

when substance abuse is present, the need for drugs or alcohol may take 

priority over health care. Lack of insurance, transportation, or flexible 

working hours can also affect access to appropriate care (Bunting, 1999).

The economic situation is most extreme in sub-Saharan Africa, where 

national economies and social institutions in the hardest-hit countries have 

been devastated because so many individuals in their most-productive 

years have become sick or have died from HIV/AIDS. Husbands, who are 

often the primary wage earners, may leave their wives when they learn 

the woman is HIV-infected. Besides caring for themselves, the women left 

behind become the sole supporters and care givers for their children and 

other family members. Lack of food, housing, and employment as well as 

lack of clean water, electricity, and other basic resources may be deficient 

or lacking and impact the health care professional’s ability to provide 

basic primary care in addition to antiretroviral treatment (ART).

Many women with HIV have had to rely on the government public 

health and social service system for help and health care and may 

have experienced difficult moments in asking for help or have suffered 

humiliation on behalf of their families in trying to get what they need 

(Sowell, 1999). Because of stigma and poverty, women are vulnerable 

to a decreased ability to meet their needs, including housing, food, 

and work, as well as decreased access to health care services and/or 

delayed health-care seeking for themselves (Amaro, 1995; Mays, 1987). 

Women with dependent children and those who are pregnant may be 

even more reluctant to seek care, partly because they fear having their 

children taken from them, particularly when issues of substance abuse 

are involved (Pivnick, 1991).

III. GENDER ROLES AND SOCIAL EXPECTATIONS

While women have central responsibilities within their families, gender 

roles often constrain their authority and influence their ability to make 

decisions about their own health and medical care. Women’s social 

responsibilities clearly affect their health seeking behaviors, potentially 

delaying their own treatment and resulting in the placement of others’ 

priorities above their own (Anderson, 1993). Women often defer their 

needs to those of their children and significant others. In a study of innercity HIV-positive women and their infants, most women studied secured 

medical care for their infants, but only 46% reported ever seeking HIVrelated health care for themselves (Butz, 1993). Women may experience 

more stigma and discrimination related to HIV than men because of 

its connotations with promiscuity and prostitution and sexuality in 

general. Because of past experiences of stigma and discrimination, many 

minority women tend not to trust the entire health and human service 

infrastructure. These factors combine to make health care less accessible 
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VIII

and less of a priority in the lives of many HIV-infected women. Women 

who are at risk fear getting tested for HIV based on the stigma of testing 

positive (Gupta, 2002). Therefore, they may delay seeking care until they 

are quite ill.

Along with the stigma and discrimination of an HIV diagnosis, women 

living with HIV experience alterations in their personal relationships. The 

core of many women’s identify is mediated through their relationships 

to their children and significant others, and to their roles in the family 

structure. A diagnosis of HIV may result in abandonment or violence 

by partners. When multiple family members are also infected with HIV, 

the woman is generally the caretaker when they are ill, resulting in 

significant social, psychological, and economic burdens (Gupta, 2002). 

The well-being and the return of normalcy for a family depend on the 

care-seeking ability of the woman and the sensitivity of health care 

providers in facilitating the process of seeking care (Anderson, 1999). 

Each of the woman’s relationships—including her relationships with 

members of the health care team—may affect the others and each can 

have a profound impact on how the woman makes choices about her HIV 

infection and comorbidities.

The social position and imbalances of gender/power in many societies 

contribute to low self-esteem and difficulties negotiating safe sexual 

practices with their partners. The implementation of an empowerment 

program for Latina immigrant women demonstrated that targeting 

broader sociocultural issues may increase the skills necessary for these 

women to avoid transmission of HIV infection by their sexual partners 

(Gomez, 1999). The women in this study showed significant increases 

in comfort with sexual communication, were less likely to maintain 

traditional sexual gender norms, and reported changes in decision 

making power.

Providers need to understand the choices that women have made and 

the social support structures that best serve them, based on their roles 

and cultural beliefs. Significant relationships may include informal 

relationships and non-family members who can help the woman 

throughout her HIV disease course. These important non-family 

relationships may replace a family system that has not provided the 

support needed since the woman was diagnosed with HIV. Within the 

African American population, one can find various arrangements that 

constitute a family and that provide great support for women in times of 

crisis (Asante,1995). Many Hispanic women have madrinas (godmothers) 

and comadres (friends related by marriage or baptism) who are great 

sources of support for them during times of crisis. Providers need to 

understand the family dynamics in order to facilitate trust, understanding, 

and empowerment of these women so that they can choose the options 

that fit their culture and their life’s reality. Before giving the initial HIV 

test results and discussing disclosure issues, it is essential to have an 

understanding of the communication dynamics in the family, especially 

with the significant other of the woman.
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IV. PSYCHOLOGICAL ISSUES 

Women face an array of psychological issues, related not only to possible 

coexisting substance abuse, mental illness, domestic violence, and poverty, 

but also to the stresses of living with HIV disease and often being the primary 

care provider for the family. Most HIV/AIDS-infected minority women are 

stigmatized even before becoming HIV infected because of drug use, race, or 

poverty (Wofsy, 1987). Many of these women are single heads of households 

with young, dependent children, and, in general, lack a community of 

support such as that seen among gay men (Weiner, 1991). This situation 

affects the actual and perceived availability of supportive resources over 

the course of HIV disease. Limited emotional resources affect HIV-infected 

women’s access to both psychological and medical services. Low self-esteem 

is the rule rather than the exception and plays a major role in ability to access 

and adhere to care.

Women experience a variety of emotions related to their HIV infection. 

They may feel anger at a partner who infected them sexually or guilt with 

a partner to whom they have been unable to disclose their status or guilt if 

they have transmitted HIV to any of their children. 

At the initial visit with the health care provider the woman may feel 

overwhelmed and experience shock, disbelief, guilt, anger, sadness, and even 

suicidal ideation. At intermediate visits, many of the same emotions are still 

present, although some may be more attenuated while others may have 

greater prominence. Emotional assessments should be continued in order to 

provide appropriate interventions and help establish trust. Crisis visits may 

occur frequently until the woman and her family stabilize their lives, as well 

as the medical conditions of all infected family members. Reasons for crisis 

may range from HIV issues to domestic violence to medical deterioration 

of one or more family members. These scenarios call for all team members 

to work together and devise a plan or procedure that will address the issues 

and problems that arise. A debriefing session by the care coordinator/social 

worker with the woman after the crisis has been resolved is important to 

prevent potential future crises.

Despite this complex picture and against all odds, many of these women 

have strong coping abilities and profound survival instincts. Some studies 

have suggested that interventions to support use of active coping strategies 

as physical symptoms increase may be effective in promoting positive 

adaptation to HIV disease (Moneyham, 1998).

V. PROVIDER-PATIENT COMMUNICATION

The recent Institute of Medicine study Unequal Treatment called particular 

attention to the role of culture in undermining effective communication 

between members of racial/ethnic minorities and their providers (Smedley, 

2003). Clinical decision making (Eisenberg, 1979), patient satisfaction, adherence 

to treatment, and poor health outcomes are related to the communication 

between patients and their providers. While the IOM study focused on US racial 

and ethnic minorities, many of the issues are relevant internationally.
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Providers working with HIV-infected women face the challenges of 

understanding how culture influences the access and use of health services, 

the place of HIV in the priorities of women’s everyday lives and the 

constraints of social and cultural traditions on women’s decision making 

around health and disease. When providers don’t understand the cultural 

beliefs of their patients, they increase the likelihood that these beliefs will be 

barriers to providing care. Providers should assess their own cultural beliefs 

and consider how they affect their behavior towards patients.

Most of us understand some of the basic differences in culture, such as 

food, dress, music and language. But it is more difficult to understand 

that people may view the world from different perspectives. When we 

are aware of differences, we may change our behavior out of respect for 

restrictions between males and females or customs about greetings or 

otherwise adjust our behavior. Even when we are not fluent in another 

culture’s traditions, making accommodations may be easier with people 

we know and with groups we frequently interact with. Cross-cultural 

misunderstandings and confusion are more likely to arise when both 

provider and patient lack experience with each other’s culture. 

Because of the cultural diversity of communication styles and the 

potential for missed communication and misunderstanding between 

patients and providers, it is vital that health care professionals understand 

that different cultures communicate differently. Factors impacting crosscultural communication include the meaning of specific words, the pacing 

of language, the volume and tone of the spoken words, and whether or 

not gestures are utilized as part of the communication process.

Effective communication makes use of context, as well as words, gestures, 

and symbols.

“Individuals from low-context cultures prefer a direct, literal 

style of interaction, and people are expected to say more or 

less exactly what they mean. Examples of low-context cultures 

are: United States, Canada, Europe, Israel, and Australia. Lowcontext cultures value self-expression skills such as clarity, 

fluency, and brevity. Speakers often seek to convince and 

persuade their listeners.” 

“The Orient, the Arab world, and much of Africa are examples 

of high-context cultures. The preferred style of interaction is 

an indirect one in which meaning is carried less by the literal 

meaning of the words and more by contextual clues such as 

the place, time, and situation and the relationships between 

speakers. High-context cultures value harmony, subtlety, 

sensitivity, and tact more than clarity. Speakers often seek to 

connect with their listeners.” (McKay, 1995)

Understanding the differences between low-context and high-context 

cultures can enhance the interaction between the client and the 

provider. Culture is not the enemy or adversary of clinicians. Like any 

other information in the clinical encounter, culture is information that a 

provider can understand and learn to manage. 
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The questions in Table 8-1 can be used as a tool that providers can apply 

to understanding clients from a different culture. This approach creates 

an atmosphere in which patients can become partners in the provision of 

their care (Weeks, 1979).

Table 8-1: Questions to Enhance Provider Understanding of 

Clients from a Different Culture

Assumptions– Provider’s and Patient’s

• What are the patient’s assumptions? What are my assumptions?

• What assumptions about health do I bring to the interaction?

• What assumptions about illness do I bring to the interaction?

• Do I assume the patient knows why she is there?

• Do I assume that I know what she wants to get out of the interaction or the 

visit? Am I clear about what I want to get out of the interaction?

• Do I assume the patient wants to get better? Get better in what regard?

• Am I assuming that she wants what I would want if our roles were reversed? 

Did I ask to assure that this in fact the case?

• Am I assuming that she will tell me if she cannot adhere to the treatment plan? 

Did I confirm that she could tell me if she would not be able?

Health Literacy and Complementary Therapies

• Is what I am saying understandable by the patient? Can she read?

• Is the patient clear that this is a partnership and that we are engaging in joint 

care planning?

• Am I presenting the information in a non-judgmental and non-coercive way?

• Are there others from whom the patient has sought care? What did they 

tell her?

• Is there someone else the patient would like to include in her care?

• Has the patient used any other therapies, medications, herbs, elixirs, ointments, 

teas to help her with this problem? 

Patient Priorities

• What questions can I ask to initiate a dialog and partnership for joint care 

planning? What is important to her?

• Does she want to get better? What does “better” mean to her?

• What does she need to get better?

• What can we do to help her get better? Address non-medical and medical issues.

• What can we do first? Look for tasks/ activities that will be a small start and 

yield early successes.

Holistic Approach

• How have I attended to the non-medical health, wellness, and quality of life needs?

• There are things that we may not be able to help with. Are there others we can 

find to help with these issues?
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Additional considerations

Provider Level: 

• Therapeutic alliance is important. Partnering in care will improve health 

outcomes.

• Don’t have to do it all at once. Small successes are great motivators for next steps. 

• Need for on going assessment since situations change constantly.

• Need to ask questions in a simple and non judgmental way.

• Need to demonstrate respect for the patient and her differences.

• Understand that we as health care providers bring both positive and negative 

issues to the therapeutic relationship. Strive to increase the positive and 

decrease the negative.

• Improved insights into patient motivations and what they are ready to tackle 

and when are critical.

• Understand that we have the power to improve as we assume our patients do.

• Improved quality of life and clinical outcomes matter.

System Level Interventions 

Senior leadership should make these expectations clear and model them for staff

• Communication styles and strategies that demonstrate respect for diversity – 

diversity of signs, posters, pamphlets (also sensitive to limited English proficiency) 

are important.

• Consents, legal documents and releases should be written in easy-tounderstand English. Translations should also be in plain language.

• Physical environment should be warm and welcoming.

• Team effort and team approach are key.

VI. CULTURAL ISSUES

Because most women living with HIV infection in the United States 

come from two primary groups, African and Hispanic Americans, this 

section will focus on cultural beliefs associated with these two groups. 

A comprehensive care program that broadly addresses the sociocultural 

aspects of a woman’s life in a collaborative and multidisciplinary fashion 

will facilitate the treatment and care of women from diverse cultural 

backgrounds. These examples will illustrate strategies and approaches 

that local providers can adapt to their patients and the local circumstances 

in which women struggle to negotiate their care.

A. HISPANIC CULTURE

In Hispanic populations, one complex facet of cultural sensitivity and 

competency lies in the diversity of the subgroups that make up this 

population in the United States. The subgroups and their representation 

are: Mexican American, 58.5%; Central and South American, 10.8%; 

Puerto Rican, 9.6%; Cuban, 3.5%; all other Hispanic (including Spaniards), 
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17.8% (U.S. Census Bureau, 2001). Each of these subgroups has its distinct 

culture, as well as various levels of assimilation into the general population. 

Providers need to address these distinctions in developing intervention 

and prevention programs for HIV/AIDS and other health issues. 

Amidst the diversity among Hispanic Americans, social scientists have 

identified cultural values that most Hispanics share regardless of their 

country of origin. The identified core values are (Marin, 1989):

• Familismo - the importance of the family to the individual

• Colectivismo - the importance of friends and extended family 

members, such as godmothers (madrinas) and godfathers (padrinos)

• Simpatia - the act of being polite; respectful not confrontational

• Personalismo - the preference to be with other persons of the same 

ethnic group

• Respeto - the act of upholding one’s own integrity without damaging 

another person

For Hispanics, HIV/AIDS is not an individual issue, but one that affects 

the family structure and the unity within the community. In many 

Hispanic families the husband makes the decisions for all members 

of the family, including his wife. The extended family in the Hispanic 

culture may also play a major role in making decisions. Clinicians need 

to assess the role of the woman within her family and her culture and her 

adherence to strict cultural beliefs.

VIII

CASE STUDY: HISPANIC

NAME: DE

AGE: 35 YEARS

ETHNICITY: MEXICAN AMERICAN

DE came into our program on 11/4/93. Her first visit with the physician was the 

day she learned of her HIV status, when she was 27 weeks pregnant with her 

second child. She had a 14-month-old daughter who was followed for urological 

problems. Her HIV risk factors included two heterosexual partners and history of 

a blood transfusion after her first pregnancy in 1992 because of hemorrhage. 

She stated she was tested because of the blood transfusion. We performed HIV 

testing on her daughter, and explained the risk to her unborn child; the plan of 

care for the child after birth was reviewed.

At the time of diagnosis DE had a CD4 count of 178. She maintained her health 

during her pregnancy, continued to care for her daughter, and began getting 

care for her HIV disease. With psychological evaluation, she tested in the lower 

ranges for verbal intelligence and conceptual processing.

DE’s support system included her mother (who initially did not know DE’s status), 

and her common-law husband, who was not the father of her oldest child, but 

was the father of the child she was carrying. The HIV test results for her daughter 

and husband were negative. DE experienced a variety of emotions, including fear, 

anxiety, and depression, and needed much support from the entire staff to assist 

her not only in understanding what HIV was and how it affected her and her 

family, but also in obtaining financial support. As with most new clients, DE was 
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Case Study: Hispanic (continued)

distrustful of staff initially, but with care, concern, and perseverance, our entire 

team (physicians, nurses, social workers, psychologist, foster granny volunteers, 

etc.) developed a trusting relationship with her. 

Her second child was a boy, and within 1-2 months of life it was obvious he 

was infected and he had a very low CD4 count. DE never missed a clinical 

appointment for him and, in fact, was always there even before clinic began. She 

provided excellent care to her son, learned to give him his medications, and had 

good relationships with the medical staff.

By 1996 her own health had deteriorated significantly and her care was 

transferred to another physician, but she continued to bring her son to our 

program for care. She was linked with hospice services and almost died several 

times, but each time improved to the point where she was ultimately taken off 

the hospice list. Her determination to personally care for her son was a strong 

motivating factor in her ability not only to stay alive, but to actually improve her 

health status.

DE was able to make the choice as to how and where her son would spend 

his last days, and was at his bedside when his short life ended. She let balloons 

loose into the sky at his burial to signify that her son had gone to heaven.

DE continues to live, and both she and her husband have dropped in to the clinic 

occasionally to visit and to show us photos of the family trip to Disney World, 

pictures of her son in his last hours, etc. DE has also become involved with the 

Pediatric AIDS quilt project, started by one of our program nurses.

B. AFRICAN AMERICAN CULTURE

As with other minorities, African Americans experience high rates of 

unemployment and overall poverty. Any discussion of core values must 

be evaluated in the context of these concerns. Even though family conflict 

is reported in all races and socioeconomic groups, minorities have a 

higher rate of conflict because they are more vulnerable to arrest by 

the police and referral to public agencies (Gibbs, 1990). These problems 

may be more appropriately viewed as community problems rather than 

problems of the black family (Gilbert, 2002). Amidst the complexity of life 

for African American individuals and their families, they are sustained by 

their core values, which have historical roots in Africa.

The core values that most African Americans embrace have been 

described by Sudarkasa (1996). The seven core values are respect, 

responsibility, reciprocity, restraint, reverence, reason, and reconciliation. 

They are defined as follows:

• Respect - the respect for others, from parents and relatives to 

elders or leaders in the community.

• Responsibility - being accountable for self and for those less 

fortunate in one’s own extended family and in one’s community.

• Reciprocity - giving back to family and community in return for 

what has been given (mutual assistance).
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• Restraint - giving due consideration to the family or

 community/group when making decisions.

• Reverence - deep awe and respect towards God, towards the 

ancestors and towards many things in nature.

• Reason - taking a reasoned approach to settling disputes within the 

family or the community.

• Reconciliation - the art of settling differences; that is, putting a 

matter to rest between two parties.

Respect and responsibility were major guiding principles for behaviors 

within families in Africa that have been carried over to African American 

families today. Restraint is related to the notion of “sacrifice.” Parents 

exercise restraint over their own destinies in order to provide for their 

children, who in turn repay the “sacrifice” by, in many instances, putting 

their parent’s needs before their own (Sudarkasa, 1988).

Spirituality is a strong cultural value among both African American 

and Hispanic American women. Historically, the church in the African 

American community has been the single most important organization 

advocating for public policies to influence improvements in health, 

education, and financial quality of life (Poole, 1990). From this perspective 

there is a continuum between religion and one’s quality of life. As the 

guiding center for the extended family, reinforcing the sense of self and 

self-esteem within the culture, the church offers opportunities for the 

whole family’s development (Butler, 1992).

Churches in the African American community have created and 

mobilized leaders and increased hope (Neeleman, 1998; USDHHS, 1998). 

In order to provide comprehensive health care to African American and 

Hispanic women, programs should include the spiritual dimension in all 

aspects of care.

Many African Americans share a distrust of the health care system related 

to historical experiences such as the Tuskegee experiment. Airhihenbuwa 

(1990) suggests that African Americans operate in a society where rules 

and social systems appear to be adversarial. The degree to which they 

perceive the odds against them as manageable or overwhelming will 

depend to a significant degree on the transactional competency and 

success of their parents, the competence of the role models in their 

primary community, and the availability and accessibility of resources 

and support to help them in their coping efforts (Myers, 1983).
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CASE STUDY: AFRICAN AMERICAN

NAME: BA

AGE: 43 YEARS

ETHNICITY: AFRICAN AMERICAN

BA was referred to the program after delivering a baby boy 71⁄2 weeks 

prematurely; he was born withdrawing from drugs and was subsequently found 

to be HIV infected. After the referral was made at 5 p.m. on a Friday, two nurse 

case managers went to the hospital to meet with BA and to initiate the process 

of caring for her child. While there, local law enforcement officers came into the 

patient’s room and informed her that they were removing her newborn son from 

her custody because of her drug use during pregnancy.

BA was 43 years old and had a history of injection drug use since the age of 15 

when she ran away from home. She was homeless at the time of delivery and 

was attempting to reunite with her family. She had had no prenatal care.

On initial assessment she was happy but nervous and apprehensive about the 

possibility that her child could be infected with HIV. Doctors had told her that 

her uterus was so badly scarred from sexually transmitted diseases that she was 

unlikely to get pregnant. This pregnancy was a pleasant surprise for her and she 

saw this baby as a gift, a miracle from God.

She was admitted to an outpatient drug rehabilitation program and her baby 

was placed in foster care. With the help of her caseworker she reunited with her 

mother and sisters after revealing her HIV status. She also met with her spiritual 

counselor on a regular basis to discuss life and death issues.

BA completed her 6-month drug rehabilitation program successfully and was 

able to petition the courts and get her son back. She tended not to keep her 

own medical appointments and deferred most of her energy to her child’s care. 

She was in the hospital when her son became very ill and was also hospitalized. 

She was able to talk with the pediatrician and sign advance directives for her 

child. He died in his mother’s arms during that hospitalization. When the nurses 

and caseworker came to be with her at the hospital, she shared the following: 

“I have done a lot of things wrong in my life and I didn’t think I had a chance to 

get in the pearly gates. But you know I have loved my son and he knew that. I 

tried to be the best mother I could be for the short time I had him. So when I die 

and I go up and see St. Peter at the pearly gates he is just going to nod his head 

no. As I am just about to leave I hear someone running and I turn around to hear 

a little boy screaming “St. Peter, that’s my mom and she loved me and I love her. 

You have to let her in!” 

BA remained clean for the entire year that her infant was alive, but relapsed 

back into drug dependence upon his death. She lived two years, during 

which time she was back and forth between drug rehabilitation programs and 

hospitalizations for her HIV infection. A key factor in her care was the assignment 

of a case manager and the coordination with her drug rehabilitation team. She 

had constant contact with her spiritual counselor, with whom she had had a 

long-lasting relationship since childhood. BA died surrounded by her family, the 

staff, and her spiritual counselor.
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C. COMMUNITY

In addition to the major core values of a culture, other considerations 

include the “vital signs” of the community in which the woman lives. 

These vital signs include, but are not limited to, prevailing cultural 

beliefs, pressing issues for the community, employment rate, the level 

of poverty, the definition of health espoused by most people in the 

community, access to health care, characteristics of the community 

leaders and their followers, support structures, and the level of trust in 

the health care system. These factors can be described as a community’s 

ecological system (Meyer, 1988). 

Health care providers should be encouraged to view the people 

of the community in the context of their social environment. The 

interrelatedness of individuals to their environment leads one to view 

people not as solitary subjects, but as integral parts of a whole. With 

both Hispanics and African Americans the community is vital to a 

good and healthy life. However, both of these populations experience 

a disproportionate level of displacement due to the requirements for 

economic survival. Health and human service providers who want to 

serve these populations with sensitivity and quality must understand the 

complexity of living with HIV disease in the midst of poverty. According 

to Fullilove (1996), psychological well-being depends on strong, nurturing 

places.

VII. INTERVENTIONS

The following interventions are suggested to help health care providers 

give more effective and culturally-appropriate care:

• Strategies that utilize a holistic approach towards women’s care 

should include the social, economic, and psychological well-being 

of the individual.

• Assign a case manager/case coordinator to help the woman 

negotiate multiple parts of the health care/social services system; 

help decrease anxiety and establish trust; and serve as a broker 

and advocate for her and her family’s needs. 

• Teach the woman about the structure of the health and human 

services system in her community.

• Establish peer interventions so that women are able to talk with 

other infected women about negotiating day-to-day responsibilities 

and dealing with stigma/discrimination issues.

• The initial visit is often filled with many different emotions and 

reactions. Take time to deal with these reactions, begin the process 

of developing trust, assess possible suicidal thoughts, and give 

information in small bites over several closely spaced visits. 

• Give simple straightforward explanations.

• Identify the woman’s ethnic subgroup of origin, when appropriate.
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• Include a bilingual provider on the health care team (do not 

use the children or the custodian to translate; this demonstrates 

a lack of respect and may result in miscommunication or 

misunderstanding).

• Diagram the family structure and discuss the role of each member; 

review the role of women within the family; family dynamics need 

to be understood before recommending disclosure actions.

• Develop or link with empowerment programs targeting sexual 

communication, negotiation, and self-esteem.

• Recognize extended family members as key supports for the 

patient.

• Explore the cultural values and beliefs of the woman, both at the 

initial assessment and over time.

• Show respect for spiritual beliefs and how they affect advance

directives and other decisions women make

• Initial assessment by the case manager or peer outreach worker 

in the home may give additional insights into the family structure 

and the roles the woman fulfills within her family.

• Understand each woman’s priorities and develop strategies to meet 

those needs she considers most important.

• During intermediate visits, work on establishing trust between 

the woman and her provider/health care team. Trust is an 

essential continuous, dynamic process requiring open and ongoing 

communication between women and their health care providers/

team.

• During regular visits, inquire about the health status of all 

members of the family, especially the children; continue to assess 

the emotional status of the woman.

• Identify and have a working knowledge of the core values of the

community you are serving.

• Develop an alliance with key community based organizations.

• Teach staff about the effect of community and culture on the 

woman’s decision-making and belief/value system.

• Identify women who have to leave their community for long 

periods of time for employment (e.g., migrant workers), and assist 

them in making connections for health care while away and in 

ensuring access to needed medications.

VIII. SUMMARY 

Women living with HIV infection are living with a multitude of medical 

and social problems. They live not in isolation but as integral members 

of their communities and primary caregivers for their families. Although 

HIV infection is often not their primary concern, this does not mean they 
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do not want help. To understand and assist women living with HIV, it is 

important to take a systems approach, to look at the whole to understand 

the parts, to think in loops rather than in straight lines (O’Connor, 1997). 

High quality care for women living with HIV disease is best given by 

addressing not only her medical needs, but also her economic needs, her 

relationships, her emotional responses, her culture, and her community: 

all of the faces of a multi-faceted life.

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IX

I. INTRODUCTION

While healthcare providers for women living with HIV focus primarily on 

the physical manifestations related to HIV, understanding the emotional 

experience of the woman and the potential psychiatric problems associated 

with HIV is important to optimize care. 

The health care provider can provide significant comfort during normal 

adjustment phases and common emotional transitions through skilled 

emotional support, assessment of coping skills, patient education, and 

empathy. When normal adjustment issues give way to formal psychiatric 

or neuropsychiatric disorders, accurate diagnosis and appropriate 

treatment are required.

Further care may require referral for substance abuse treatment or 

psychiatric evaluation, or referral to programs of social support, housing, 

case management, and other services, depending on the needs of the 

individual. Care providers who develop a comprehensive treatment 

plan for the HIV-positive woman that includes emotional support and 

psychiatric treatment for comorbid psychiatric conditions help her to feel 

that the entirety of her pain and suffering is being addressed.

For a more detailed discussion of the neurological manifestations of 

HIV, see chapter IV; and for more discussion about substance abuse and 

treatment, see chapter X.

This chapter will address a range of psychiatric issues relating to HIV 

disease in women, from normal adjustment issues to psychiatric disorders, 

and will make specific recommendations for provider and program 

response, evaluation, and management.

II. PERSPECTIVES ON BEING A WOMAN WITH HIV 

Three different perspectives are important to develop a more comprehensive 

view of the woman experiencing HIV: 1) the individual perspective as the 

woman journeys through the common emotional milestones of HIV; 2) the 

perspective of women as a group, because women, in contrast to men, tend 

to cope with HIV within the context of their most important relationships; 

and 3) the contemporary context of the majority of HIV-infected U.S. 

women who are members of racial or ethnic minorities, living in poverty, 

affected directly or indirectly by substance abuse, and often with personal 

experiences of adult victimization and/or childhood abuse. The experience 

of the woman infected with HIV at any given time may be more influenced 

by one or another of these dimensions.

IX. PSYCHIATRIC ISSUES

Joyce Seiko Kobayashi, MD
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For example, the initial shock of an HIV diagnosis may be experienced 

with personal fears of stigma and suffering; or with common concerns 

about rejection and abandonment by a partner; or simply experienced 

as further victimization in the context of a traumatic history and 

daily struggles to survive. The way women face the challenges of HIV 

personally, as women, and in the context of their past histories is a strong 

predictor of psychiatric co-morbidity (Sherbourne, 2003). The goal of 

skilled support is to facilitate positive transformation of this experience.

A. EMOTIONAL MILESTONES: THE EXPERIENCE OF THE INDIVIDUAL

HIV-POSITIVE WOMAN

The emotional adjustment after learning that one is HIV-positive, 

including coping as an individual on a daily basis with the demands of 

having HIV and becoming an HIV patient, commonly follows a natural 

course of progression through stages (See Table 9-1). For every “shock” 

-- a new diagnosis, a new symptom, the need to take more pills, more 

intrusions on daily routines -- there is often the “aftershock” of anger 

and avoidance, fear and denial. While emotional adjustment may vary 

by culture, race, and ethnicity, by level of social support and caretaking 

responsibilities, and by age and severity of physical and psychiatric 

symptoms, these emotional milestones are broadly applicable. With 

knowledgeable support and timely clinical intervention, these reactions 

can be transformed into acceptance, with important opportunities 

for prevention of HIV transmission to others and safer behaviors for 

oneself. 

B. COPING WITH HIV: THE EXPERIENCE OF HIV-POSITIVE WOMEN IN THE

CONTEXT OF RELATIONSHIPS

Women experience HIV infection within the context of their various 

relationships. When examining HIV-infected adults in medical care in 

the U.S., over one-quarter have children; women are more than three 

times as likely to have children compared to men and are more than 

twice as likely to live with their children (Schuster, 2000). In a prospective 

observational cohort of 871 HIV-positive women, 35% had a family 

member with HIV infection, including one-half of Latina women, onethird of black women, and one-fifth of white women; in 38% this was a 

sibling, 24% a husband, and 27% had more than one family member with 

HIV (Fiore, 2001). In a clinic-based sample in Connecticut (N=68), nearly 

three out of four of the HIV-positive women knew at least one person who 

had died of AIDS (Ickovics, 1998).
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Table 9-1: Providing HIV Care at Emotional Milestones

Patient Milestones

Health Care Provider Skills Required

Be Able To Educate Patient About Show Empathy For

HIV prevention Discuss high-risk behaviors with ease

Discuss prevention measures (e.g, condoms, safe sex, clean needles) with ease

HIV, HIV diseaseHIV transmissionNegotiating safe behaviors

DenialLack of interestHigh-risk behaviors

Deciding to get tested for HIV

Discuss details of sexual histories with easeIdentify high-risk behaviorsHelp patient prepare for resultsHelp patient anticipate emotional impact

HIV antibody testing Denial

AmbivalenceFear

Accepting, understanding HIVpositive serostatus

Tell bad news with empathyAnticipate common concernsEncourage discussionAssess emotional impact

HIV antibody testingHIV disease, prognosisHIV transmission behaviorsCD4, viral load

Denial, angerFears of rejection, stigmaFears of deathContinuing high-risk behaviors

Disclosure of HIV serostatus

Discuss decisions about whom to tellDiscuss decisions about when to tell

Anticipating reactionsNegotiating safe sex

Conflicts about disclosureRejection, fears of rejection

Accepting the “patient role”

Establish rapport, trust, mutual respectEncourage partnership, foster autonomyElicit concerns, encourage questionsCommunicate patient tasks clearly 

Patient tasksPatient responsibilities

Ambivalence, distrustAnger, rejectionOppositional behaviorTesting limits

Initiating positive health behaviors

Identify harmful behaviorsRefer for substance, psychiatric treatmentEstablish alliance for good health

Health promotionHarm reductionLifestyle, behavior change

Anger, griefDifficulty changing behaviorsResistance to treatment
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Table 9-1: Providing HIV Care at Emotional Milestones (continued)

Patient Milestones

Health Care Provider Skills Required

Be Able To Educate Patient About Show Empathy For

Appointments, adherence

Forge and maintain treatment allianceUnderstand barriers to treatmentDiscuss risk/benefit decision makingAnticipate side effects

Importance of follow-upMedications, side effectsAdherence skillsViral resistance

Anger, defiance, hostilityBurden of adherence demandsFear of failure, self-blameMissed appointments, doses

Coping with physical symptoms

Identify symptoms, provide reliefEncourage accurate description of symptomsProvide emotional support, compassion for distress

Etiology of symptomsLimitations of treatmentRisks/benefits of treatment

Discomfort, distress, painBreakthrough of denialAnger, impatienceFear of progression of illness

Confronting serious illness

Diagnose, treat, diminish sufferingTell bad news with empathyRecognize emotional impact, show compassionListen

Illness, treatment specificsPrognosisOpportunities for change in behaviors; “lessons”

Anger, blaming self, providerFear of dyingSufferingDependency needs

Improvement in health status

Consolidate lessons learned from illnessEncourage health promotion behaviors

Realistic expectationsReassessing work limitations

Unrealistic expectationsReturn of denial

Transition to disability Initiate discussion about disability

Assess legal disabilityProvide emotional support

Realistic goals, expectationsAdvance care directivesDisability entitlementsPermanency planning

Grief, demoralizationAnger, denialLoss of self esteem

Confronting death Balance hope, discuss common fears

Provide accurate prognosis, allow time to prepareSupport appropriate denial for daily functionDiscuss palliative care, communication with “family”

Prognosis, likely coursePalliative measures

Denial, anger, blameFear, grief
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Developmental psychologists have characterized fundamental differences 

in the way women and men think about themselves (Gilligan, 1993), with 

significant implications for clinical practice. Although any generalization 

about gender may be wrong in the individual case, two overarching 

observations derived from this research are important to understand 

the ways women and men tend to differ in their reaction to being HIVpositive. First, women more frequently define themselves in the context 

of their relationships to others; and second, while men more frequently 

fear intimacy, women more often fear separation (Surrey, 1982). Whether 

these differences are more evolutionary and transcultural, or derive from 

socialization and economic forces, an understanding of these differences 

is important to increase providers’ sensitivity and to enhance their 

effectiveness in working with women living with HIV.

Although there are universal fears about dying alone and being abandoned 

when ill, it is not uncommon to hear HIV-positive men express fears 

about becoming dependent on others, whereas HIV-positive women tend 

to worry more about those who are dependent on them as their illness 

progresses. Men often lose self esteem if they are not able to continue 

working, or feel anger and may wish to distance themselves from others 

whom they feel obligated to support; women more frequently lose self 

esteem if they are unable to continue taking care of others. Many women 

with HIV are single mothers and feel shame or guilt if they are unable to 

take care of their children as they feel they should. 

These reactions may lead women to accept being the target of anger or 

abuse, or to suppress their own anger, in order to avoid finding themselves 

alone; they may continue to use drugs for fear of losing a substanceusing partner; or they may feel guilty about taking time away from 

responsibilities for others in order to address their own needs. It may be 

difficult to self-motivate and establish good self-care independently when 

“no one” will benefit from these efforts except for the woman herself. In 

a study of delays in seeking care among HIV-positive individuals, women 

were 1.6 times more likely to delay medical care than men; having a child 

in the household increased the likelihood of delay (Stein, 2000). Women 

who have been abused, are poor, or have in other ways experienced 

powerlessness in their lives may be even less convinced that they are 

“worth it.” 

On the other hand, the motivation to take care of others may encourage 

some HIV-positive women to undertake major changes in their own 

behavior, such as giving up longstanding drug dependencies during 

pregnancy, or engaging in discussions that frighten them, such as about 

permanency planning or advance directives. Other women with HIV 

may take on the responsibility of bringing their children or partners into 

medical care despite significant barriers, including their own fatigue or ill 

health, and may demonstrate remarkable resourcefulness in seeking out 

additional avenues of support. 
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The clinician should show respect for the degree of caring the woman 

demonstrates, and acknowledge the impact HIV has on the people 

she cares about. These are clinical opportunities to build trust and 

strengthen an alliance around common concerns. Giving permission 

for the HIV-positive woman to attend to her own needs, and in other 

ways “empowering” her, may over time be as important as instructions 

about what specific health behaviors to follow. The health care provider 

who first acknowledges her priorities in taking care of others, and then 

reminds her that she will not be able to continue that care unless she 

first takes care of her own health, is likely to be more successful in terms 

of her health outcomes. When the woman feels her values have been 

respected, and when sufficient trust has been established, the provider’s 

concerns will be experienced as caring and supportive, rather than as 

rejection or criticism.

In certain circumstances, such as in negotiating safe sex with an unreceptive 

partner, the provider may even be more directive, and encourage a woman 

to develop the necessary skills to be more assertive about her own health 

concerns. Developing these skills may also be helpful within the healthcare 

setting. In the HIV Cost and Services Utilization Study (HCSUS) of HIVinfected U.S. adults in medical care, women with CD4 counts below 200 

cells/mm3 were less likely to receive effective combination antiretroviral 

therapy than men (Shapiro, 1999). 

C: SURVIVING WITH HIV: HIV-POSITIVE WOMEN IN THE CONTEXT OF

POVERTY, SEXUAL ABUSE, AND SUBSTANCE ABUSE

POVERTY

The majority of women with AIDS in the United States are unemployed, 

and 83% live in households with incomes less than $10,000 per year. 

Only 14%, aged 15-44 years, are currently married, compared to 50% 

of all women in the United States. Twenty-three (23%) of HIV-positive 

women live alone, 2% live in various facilities, and 1% are homeless. 

Approximately 50% have at least one child less than the age of 15 years. 

The majority of women with AIDS in the U.S. are from minority racial 

and ethnic groups, with African Americans and Latinas comprising over 

three-quarters of cases. (Bozzette, 1998; Shapiro, 1999; Barkan, 1998) (See 

Table 9-2 for a comparison of women and men in HCSUS.) They are 

frequently without easy access to medical care. Poverty and the related 

experiences of racism, sexism, and stigmatization are the dominant 

themes in their lives. 

Poverty and homelessness can be as devastating to the person and 

personality as the physical sequelae of HIV. For many women who are 

living on the street or in transient residences, are feeling overwhelmed by 

the needs of their children, or are battered within their relationships, illicit 

drugs may seem to be the best antidote. In the book Women, Poverty and 

AIDS (Farmer, 1996), which contains a comprehensive discussion of these 
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issues, Shayne and Kaplan state that “safe sex is an economic compromise 

for many poor women who rely on sex as a source of employment, as a 

means to establish ownership or proprietary rights in relationships, or as 

a means of getting tangible supports, generally short in supply.” 

Table 9-2: A Demographic Comparison of HIV-positive 

Women and Men*

Women Men Level of 

Significance

African American 54% 27% < .001

Unemployed 76% 59% NA

Incomes < $5000/yr 30% 17% < .001

Without medical 

insurance

85% 63% < .001

< 35 yr old 44% 31% < .001

* Analysis based on 1996 figures of men vs. women living with HIV/AIDS; women were 26% of

231,4000 reported cases 

NA, not applicable. 

Source: Bozzette, 1998.

It is hard to make the medical treatment needs for HIV relevant unless 

the woman feels her provider recognizes and has some understanding 

of her daily struggles for survival. Women may feel that their medical 

providers are simply adding to their burdens by asking them to prevent 

transmission to others (especially when they may have little choice in 

safer sex practices) or to adhere to complicated medical regimens. 

In one study investigating ways to improve health care utilization, a 

sample of HIV-positive women from a needle exchange program and from 

a correctional facility indicated that “shelter and food/clothing ranked 

first among unmet needs for services” (Thompson, 1995). Poverty and 

unemployment were also viewed as more serious problems than HIV/

AIDS by a group of women in treatment at a state psychiatric facility 

(Weinhardt, 1998).

More than one-third of a nationally representative sample of HIV-positive 

individuals in care went without or postponed care at least once in a sixmonth period for one of four competing subsistence needs: needing the 

money for food, clothing or housing; not having transportation; not being 

able to get out of work; and being too sick. Having at least one competing 

subsistence need was associated with never having received antiretroviral 

therapy (Cunningham, 1999).

There are many concrete services such as transportation, child care, 

food programs, income and employment support, and housing that can 

increase the ability of HIV-positive women to participate in health care. 

Many women who have substance abuse disorders with psychiatric 
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comorbidity may qualify for entitlement programs that they have not 

explored. Vocational rehabilitation programs are often facilitated by 

medical or psychiatric referrals. Community-based programs for people 

with HIV often include food banks and vans, and sometimes offer childcare 

or emergency shelter. Lack of housing is a major factor in medical illness 

and should be considered in developing an individual treatment plan. 

For example, residential programs that engage clients in substance abuse 

treatment contracts can provide both housing and incentives to abstinence 

from substance abuse.

CHILDHOOD SEXUAL ABUSE AND ADULT VICTIMIZATION

Sexual abuse and domestic violence are experienced within the lifetimes 

of a significant portion of American women, regardless of their economic 

status, ethnicity, or HIV status. When childhood sexual abuse is defined 

as physical contact of a sexual nature with children less than 14 years of 

age, prevalence estimates range from 28% to 36% (Wyatt, 1986). Although 

childhood abuse research is limited by the methodology of self-report, 

sampling, and definitional issues, it shows remarkably consistent high 

lifetime prevalence rates of childhood sexual abuse and adult physical or 

sexual assault for women who are HIV-positive or at risk for HIV.

A history of childhood sexual abuse is also associated with multiple HIV 

transmission and risk behaviors. In a study of 3,346 women, those who 

had a history of childhood sexual abuse were more likely than those who 

had not to report problems with alcohol, use of drugs, receiving money or 

drugs in exchange for sex, unwanted sex, a greater number of unprotected 

sex acts, a greater number of partners, and a greater proportion of sex acts 

accompanied by drugs or alcohol in the past 90 days. Analyses suggested 

that for these women with a history of childhood sexual abuse, participation 

in non-sexual risky behaviors “may be a bridge to participation in sexual 

behaviors that increase the risk of HIV infection” (NIMH Multisite HIV 

Prevention Trial Group, 2001). In a study of street-recruited women from 

three different major urban sites, with demographics similar to a large 

portion of the population of women with HIV, 12% of 918 women reported 

that they had been sexually assaulted in the previous 12 months (Wong, 

1993). In comparison with those who were not sexually assaulted, rape was 

associated with higher rates of sex for drug exchange, reporting more than 

100 lifetime sex partners, smoking crack, and twice the likelihood of being 

infected with HIV and syphilis. 

Sexual assault in adult women is estimated to be two to four times as likely 

for women who are survivors of childhood sexual abuse. A study of 327 

women with or at risk for HIV (Zierler, 1991) found that 35% of women 

with HIV were sexually assaulted as adults. Forty-five percent of women 

who reported rape as adults had been sexually abused during childhood or 

as teenagers. Among women with HIV, adult sexual assault was associated 

with more sexual partners, unprotected sex involving drugs, earlier age of 

injection drug use, teen pregnancy, sexually transmitted infections, and 

need for gynecologic surgery. 
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In a study of 230 HIV-positive women in New York City, 50% experienced 

abuse in childhood, 68% as adults, and 7% reported physical assault or 

rape in the previous 90 days. History of childhood abuse was significantly 

correlated with adult and recent trauma (Simoni, 2000). In the HCSUS 

study, 20.5% of women with HIV in care reported domestic violence 

or physical harm since diagnosis (Zierler, 2000), and in the prospective 

HIV Epidemiology Research Study (HERS) cohort, the incidence of abuse 

among HIV-positive women with CD4 count >350 cells/mm3 was 6.92 

per 100 person-years (Gruskin, 2002). Among 357 men and women living 

with HIV/AIDS, 68% of women (and 35% of men) reported a history of 

sexual assault since age 15 (Kalichman, 2002). A recent study of 1645 

subjects enrolled in the Women’s Interagency HIV Study (Cohen, 2000) 

found that among both HIV-positive and seronegative, at-risk women, two 

out of every three women (67% and 66%, respectively) had experienced 

domestic violence during their lifetimes, and almost one out of three (31% 

and 27%, respectively) had been sexually abused as children. There was 

no significant difference in prevalence associated with race, ethnicity, 

education level, or marital status, although domestic violence was more 

frequently reported among older, unmarried, unemployed women.

Multiple studies have also established a relationship between childhood sexual 

abuse in women and adult-onset depression (Weiss, 1999). In a study of 236 

women ages 36-45, increasing severity of abuse was associated with increasing 

risk for depression (Wise, 2001). Both HIV-positive and at-risk women have 

higher rates of depression than the general population, and depression 

increases with physical symptoms (See below). HIV-positive men and women 

who are survivors of sexual assault report greater anxiety, depression, and 

evidence of borderline personality disorder (Kalichman, 2002). 

There are major implications from these findings for medical care, 

psychiatric and substance abuse treatment, and HIV prevention efforts. 

HIV-infected and at-risk women who have experienced childhood and/or 

adult sexual and/or physical abuse or other domestic violence see HIV 

and their relationship to the health care system through the prism of 

those experiences. These experiences also influence their likelihood of 

continuing risky sexual or substance using behaviors.

Women with a history of childhood sexual abuse may be susceptible to 

a variety of misperceptions. A directive style of recommending medical 

treatment, for example, may be perceived as coercive. A treatment with major 

side effects or a surgical procedure may be experienced as abusive intrusions 

in their lives or bodies. A friendly relationship with a health care provider may 

take on unwarranted sexual overtones. Efforts at health education may not be 

heard when the individual is suddenly lost in thought or actually dissociating 

because of sudden memories of abuse. Pain may be amplified because of 

experiences of physical abuse and risk being dismissed as drug-seeking. 

Clinicians, in turn, may have particular responses to women who have 

been abused and should understand their vulnerability to unproductive 

“countertransference” reactions, such as being provoked into becoming 

the anticipated abusive figure or feeling compelled to rescue the 
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individual. The clinician must ask in order to know. A simple and direct 

question should be used: e.g., “Would you mind if I ask if you have ever 

been the victim of physical or sexual abuse?” or “Has anyone ever hurt 

you physically or abused you sexually?” “Is there anyone in your life right 

now who makes you feel unsafe?” These questions should routinely be 

asked as part of the medical history. If there is a positive response, the 

details of current abuse must be explored. If there is a negative response, 

the possibility of an abuse history should nevertheless be kept in mind. 

Medical care, treatment, and prevention efforts should be conceptualized 

with attention to the impact of violence and trauma in their lives 

(Fullilove, 1992). Lack of trust, low self esteem, and feelings of 

powerlessness are frequently experienced. Supportive measures, such 

as having a female provider, participation in support groups, receiving 

supportive psychotherapy or treatment with psychiatric medications, 

assistance with social resources, or receiving vocational rehabilitation 

can increase trust and self esteem and ultimately empower these women. 

Education about prevention should be a part of comprehensive care when 

there is high risk for continuing transmission behaviors. 

ILLICIT DRUG USE

As many as one-third of HIV-positive women exposed to HIV through 

heterosexual contact use noninjection drugs, and the use of these drugs 

increases the likelihood of high-risk sexual behaviors (Klein, 1997). Women 

who use drugs by injection may be more likely to follow as a second user 

of shared needles, increasing their risk of HIV acquisition, as well as 

acquisition of hepatitis B and C (Bennett, 2000).

There is a high rate of psychiatric comorbidity among women with HIV 

who use drugs and/or alcohol (see Chapter X on Substance Abuse). 

Each factor can exacerbate the other and relapses, in turn, are often 

associated with increased medical morbidity. In the HCSUS database, 

co-occurring psychiatric symptoms and drug dependence and/or heavy 

alcohol consumption were found in an estimated 13% of persons with 

HIV. Sixty-nine percent of those with substance-related problems also 

had psychiatric symptoms, and 27% of those with psychiatric symptoms 

had a substance-related problem (Galvan, 2003). A three-year longitudinal 

study of HIV-positive intravenous drug users (IDUs) found that 47% had 

experienced at least four episodes of major depressive disorder, while 

less than 40% of IDUs with current major depression received treatment 

(Johnson, 1999).

Investigators using a National Survey of Veterans found that the 

combination of substance abuse and post-traumatic stress disorder 

(PTSD) increased the rate of HIV infection almost 12-fold, compared to 

those without either disorder (Hoff, 1997). Because of the association 

between a history of sexual violence, substance abuse and PTSD, a 

similarly increased rate of HIV may be expected among women with this 

constellation of conditions. 
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Active substance abuse has been associated with nonadherence with 

antiretroviral therapy and general medical care. Medical providers caring 

for substance-using women with HIV should consider both psychiatric 

assessment and substance abuse treatment in the plan of care. The 

combination of psychiatric and substance abuse treatment when there is 

comorbidity has been shown to be effective (Lyketsos, 1997); if treatment 

for both problems is not offered at the same time, a relapse in one 

condition may destabilize the other. 

III. NEED FOR MULTISERVICE CLINICAL PROGRAMS 

Women with HIV who have multiple diagnoses and require a variety of 

services to be adequately supported through their illness. The varied 

needs of these women require specific multiservice program components 

(Morrow, 1997) and care provider training (Table 9-3) for effective 

comprehensive care. The clinical issues in these diverse subpopulations 

of HIV-positive women with complex histories and comorbidities can be 

managed best through such programs, which are responsive to both their 

clinical and concrete needs. Some of these services may be available 

through community-based AIDS service organizations and require close 

coordination with medical care. 

Table 9-3: Multiservice Clinical Program Components 

Common Clinical Issues 

for HIV-positive Women

Clinical Program Response

Lack of trust; fears of 

abandonment

Continuity of care; nonjudgmental attitude; 

patience; female providers

Chronic low self esteem Respect, acceptance, listening, time

Complex personal situations Multiservice coordination: housing; 

transportation; vocational rehabilitation and 

education; linkage to entitlement programs

Responsibility for children and 

others in household

Child care, respite programs; integrated 

pediatric and women’s care; permanency 

planning and advance directives assistance

Stigmatization Awareness of care provider reactions; social 

support groups

Continuing high-risk behaviors Prevention education via the primary health 

care provider

Feelings of powerlessness; lack of 

assertiveness and skills

Case management; outreach support; patient 

education; new skills training

Domestic violence; exploitive 

relationships

Women’s shelters; domestic violence 

counseling; legal aid; psychotherapy

Substance use and psychiatric 

comorbidities

Psychiatric and substance abuse treatment 

programs integrated with medical care

Optimally, treatment for formal psychiatric and substance use disorders 

can be available on site (Kobayashi, 2000) and integrated with primary 

medical care. Savings from unnecessary emergency room visits and 
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preventable hospitalizations may help offset the labor-intensive costs of 

these multiservice programs. If a broad array of services is not provided for 

these populations with such a complex layering of needs, routine medical 

care is likely to be complicated by intermittent follow-up, medication 

nonadherence, frequent presentations in crisis in emergency room 

settings, and suboptimal medical outcomes.

IV. PSYCHIATRIC DISORDERS 

Psychiatric disorders among women with HIV infection require diagnosis 

and treatment. According to the HCSUS, a national probability sample 

of HIV-positive adults receiving medical care, the prevalence of anxiety 

and mood disorders, illicit drug use, significant alcohol use, and use of 

psychotropic medications among individuals with HIV is significantly 

higher than in the general population (Bing, 2001; Orlando, 2002; Galvan, 

2002; Vitiello, 2003). A detailed diagnostic interview of the 57% in this 

sample who initially screened positive for a psychiatric disorder or illicit 

drug use in the previous six months estimated that 29.1% of all HIV-positive 

patients had a major psychiatric disorder: anxiety disorders (20.3%); mood 

disorders (17.2%); major depression (15.3%), panic disorder (12.3%), 

and PTSD (10.4%) (Vitiello, 2003). An analysis of data from 847 women 

in the HCSUS reported that younger age, having HIV-related symptoms, 

using avoidant coping strategies, reporting increased conflict with others, 

experiencing prior physical abuse, needing income assistance, and putting 

off going to the doctor because of caring for someone else increased risk for 

psychiatric morbidity (Sherbourne, 2003).

If women with these disorders do not receive appropriate treatment, their 

participation in medical follow-up or their ability to adhere to complicated 

medication regimens can be compromised. HIV-positive women with 

untreated psychiatric disorders may also engage in high-risk behaviors, 

potentially increasing risk of transmission to others or personal risk of 

being exposed to other STIs. 

A. DEPRESSIVE SYMPTOMS AND MOOD DISORDERS

Women across cultures and around the world have lifetime incidence rates 

of major depressive disorders twice that of men. In the U.S., the incidence 

of major depression in the general populations is approximately 10-15% 

(American Psychiatric Association, 2000). Two large scale longitudinal 

natural history cohort studies of HIV-positive women (WIHS, HERS) used 

the Center for Epidemiologic Studies Depression Scale (CES-D) score 

of 16 or higher to reflect “probable cases of depression.” These studies 

suggest rates of depressive symptoms or disorders in HIV-positive women 

(42-51%) that are more than twice the rate found with HIV-positive men 

or the general population (Cook, 2002; Ickovics, 2001). In the WIHS 

cohort, HIV-positive women also reported poorer mental health quality of 

life than either physically well or chronically ill members of the general 

population or than HIV-positive men across all participating sites.
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A longitudinal cohort study of 93 HIV-positive women and 62 HIVnegative women without current substance abuse found that HIV-positive 

women were four times more likely (19.4%) to meet clinical criteria for 

current major depressive disorder than HIV-negative women (4.8%), 

with significantly more anxiety symptoms (Morrison, 2002). The HCSUS 

study (N=2,864) found that HIV-positive individuals with probable mood 

disorders had significantly lower scores on health-related quality of life 

measures (Sherbourne, 2000). Among a sample of 234 African American 

men who have sex with men (159 HIV+) and 135 African American 

women (100 HIV+), there was a high prevalence of anxiety spectrum 

disorders (38%) and mood disorders (23%) in both groups, and significant 

rates of PTSD (50%) among the women (Myers, 1999). 

Table 9-4: Common Clinical Misperceptions Regarding 

Psychiatric Issues

Psychiatric 

Issue/ Disorder

Clinical Misperceptions Remember to 

Ask About

Major depression “Anyone with HIV would 

be depressed or grieving,” 

forgetting biologic 

depression

Vegetative symptoms (early 

morning awakening, diurnal 

mood variation, appetite 

disturbance); anhedonia more 

than sadness

Bipolar mood 

disorder

“Depressed mood must 

mean depression,” 

forgetting bipolar symptoms

Hypomanic/manic symptoms 

(history of racing thoughts, 

hyperactivity, no need for sleep, 

grandiose plans, irritability)

Psychosis “The patient seems 

normal,” forgetting 

hallucinations and paranoia

Psychotic symptoms: “Do you 

ever hear your name called, turn 

around and no one is there?” 

“Ever feel that strangers are 

talking about you as you walk 

down the street?”

Delirium “The patient is clearly 

schizophrenic or psychotic” 

forgetting acute medical 

etiologies

Distractibility, disorientation, 

dysarthric speech; inability 

to sustain, focus attention; 

misperceptions; mumbling or 

muttering

Sexual abuse/ 

assault history 

“Too personal; may 

embarrass or offend”

“Were you ever sexually, 

physically abused in childhood? 

Assaulted as an adult?” Do not 

ask details.

Anxiety, panic, 

agoraphobia

“Must be drug-seeking”; 

“Anyone would be 

anxious”

Panic symptoms, sense of doom, 

tachycardia (repeated episodes), 

impairment of function; avoids 

crowded places

Domestic 

violence

“Seems like a nice person” “Is there anyone in your life now 

or in the past who makes you 

feel unsafe?”

Suicidal ideation “May plant the thought in 

their mind, provoke it”

“Have you ever felt like hurting or 

killing yourself? Have a plan?” Have 

the means?
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A meta-analysis of 10 published studies found that the frequency of major 

depressive disorder was nearly two times higher among HIV-positive 

individuals than HIV-negative controls (Ciesla, 2001).

Depressive symptoms may result from a myriad of depressive disorders, 

including bereavement, adjustment issues/disorders, post-traumatic stress 

disorders, borderline personality disorders, major depressive disorder or 

bipolar depression, and can present with numerous comorbid conditions, 

such as substance use disorders that can cause secondary organic mood 

disorders. From a clinical perspective, depressive symptoms require 

careful differential diagnostic assessment because of different treatment 

requirements (See Tables 9-4 and 9-5). 

Isolating and characterizing the extent to which some depressive 

symptoms may derive from an organic mood disorder directly related to 

HIV infection of the central nervous system is a difficult task. A specific 

role for an HIV-related central nervous system effect on psychiatric 

symptoms, however, is implied in the HCSUS study, which found that 

patients who initiated or maintained ARV therapy had fewer psychiatric 

symptoms 8 months later, and this was significantly related to higher 

CD4 cell counts, fewer opportunistic infections, and fewer HIV-related 

symptoms (Chan, 2003). Similarly, in a Canadian study of 234 HIVpositive participants who were depressed at baseline (52% of the total), 

an analysis of change in the CES-D before and after initiating protease 

inhibitor–containing HAART regimens found a significant improvement 

in depressive symptoms, after controlling for CD4 count, employment 

status, income, and age (Low-Beer, 2000).

B. IMPACT OF DEPRESSION AND MENTAL HEALTH SERVICES ON

ANTIRETROVIRAL THERAPY, ADHERENCE, OUTCOME, AND COST

According to a number of recent studies, women with HIV who do not have 

access to mental health services and/or whose depressive symptoms and 

disorders are not treated are less likely to be on antiretroviral medication, 

less likely to be adherent to antiretroviral medication, and more likely to 

have a poor medical outcome at more cost.

ACCESS TO MENTAL HEALTH SERVICES:

In the HERS study, 38% of HIV-positive women and 35% of high risk HIVnegative women reported needing mental health services in the prior six 

months and, of those, only 67% of HIV-positive and 65% of HIV-negative 

women actually received services (Schuman, 2001). In the WIHS cohort, 

50% of HIV-positive women reported contact with a counselor or other 

mental health professional at one or more study visits, but at baseline, 

there was less likelihood of use of mental health services among women 

with no college education and who were African American (Cook, 2002). 

An estimated 27.2% of HIV-positive men and women in the HCSUS took 
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psychotropic medications, including antidepressants (20.9%), anxiolytics 

(16.7%), antipsychotics (4.7%), and psychostimulants (3.0%). Of 

patients with major depression or dysthymia, 43.2% reported receiving 

antidepressants and 34.3% reported receiving anxiolytics (Vitiello, 2003). 

In the HCSUS study, 61.4% of adults in HIV care used mental health 

or substance abuse services. Although the HIV population sampled 

had high mental health utilization compared to the general population, 

socioeconomic factors associated with poorer access to health services 

predicted lower likelihood of using mental health outpatient services, 

raising concerns that these are the same subpopulations with limited 

rates of antiretroviral usage (Burnam, 2001). 

ACCESS TO AND ADHERENCE WITH ANTIRETROVIRAL THERAPY: 

Women have significantly lower rates of HAART utilization than men 

(Shapiro, 1999). Among 273 HIV-positive women in the HERS study, 80 

women had CD4 counts below 200/mm3, and of these only 23% were 

on HAART (Gardner, 2002). In the WIHS study, women with significant 

depressive symptoms were much less likely to be on HAART regimens, as 

were women with poor mental health quality of life. However, if women 

had recently received mental health services, they were significantly 

more likely to be on HAART (Cook, 2002). In an analysis of merged 

Medicaid and surveillance data from New Jersey for HIV-positive women 

and men, patients with depression who received antidepressant treatment 

were more likely to receive antiretroviral treatment than those with 

untreated depression (Sambamoorthi, 2000). HIV-positive women who 

were depressed and were treated with antidepressants were almost twice 

as likely to be on ARV therapy compared to those who were depressed 

and not yet treated with antidepressant medication (Turner, 2001).

The presence of depression or other mood disorders may also affect 

adherence to antiretroviral therapy, when this is prescribed. Patients in 

the HCSUS with depression (Odds Ratio, OR=1.7), generalized anxiety 

disorder (OR=2.4), or panic disorder (OR=2.0) were more likely to be 

nonadherent than those without a psychiatric disorder (Tucker, 2003).

MEDICAL OUTCOME: 

After controlling for potential confounding variables, women with 

chronic depressive symptoms also had a more rapid decline in CD4 

counts compared with women with limited or no depressive symptoms 

(Ickovics, 2001). Depressed women with HIV were found to have increased 

mortality. Participants in the HERS study with depressive symptoms 

were nearly twice as likely to die as those without, after controlling 

for clinical evidence of declining health over time. Among respondents 

with no reported HIV-related symptoms at baseline, those with chronic 

depressive symptoms were 3.6 times more likely to die than those with 
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limited or no depressive symptoms, although unmeasured mediators of 

this effect could include adherence, healthcare utilization, and psychiatric 

treatment. For women whose CD4 count was less than 200, HIV-related 

mortality for those with chronic or intermittent depressive symptoms was 

54% and 48% compared with 21% for those with limited or no depressive 

symptoms. Evans et al. suggest that depression may decrease natural 

killer cell activity and lead to an increase in viral load (Evans, 2002).

COST: 

After controlling for socioeconomic and clinical characteristics, HIVpositive New Jersey Medicaid recipients diagnosed with depression 

and treated with antidepressant medications had a 24% reduction in 

total monthly health care costs compared to those with depression who 

remained untreated (Sambamoorthi, 2000). 

C. NEUROPSYCHIATRIC DISORDERS

HIV-associated dementia (HAD) is characterized by significant 

changes in cognitive, motor, and behavioral function consistent with a 

subcortical dementia. HIV-associated minor cognitive-motor disorder 

(MCMD), seen at earlier stages of illness, is associated with at least two 

of the following: impaired attention or concentration, mental slowing, 

impaired memory, slowed movements, lack of coordination, personality 

change, and acquired cognitive-motor abnormality on neurological or 

neuropsychological testing.

Antiretroviral therapy has had a dramatic effect on the neuropsychiatric 

disorders associated with HIV/AIDS. Median survival following the 

diagnosis of AIDS dementia complex (HAD) increased to a greater extent 

than that for all other AIDS illnesses, from 11.9 months in 1993-1995 to 

48.2 in 1996-2000, in a study in Australia (Dore, 2003). A study based on 

the semiannual administration of a neuropsychological battery to women 

in the HERS study with CD4 counts less than 100 /mm3 demonstrated 

that antiretroviral therapy, particularly when taken for more than 18 

months, had a significant impact on neurocognitive function compared 

to those women not treated with HAART, with improved verbal fluency, 

psychomotor, and executive functions (Cohen, 2001).

However, there have been reports of increased incidence of HIV 

encephalopathy over time with increasing antiretroviral use and increased 

prevalence of HIV encephalopathy at the time of death. This may indicate 

that, although there is longer survival after initial HIV infection in the HAART 

era and effective combination therapy decreases overall prevalence of central 

nervous system opportunistic infections, these therapies may be less active in 

preventing direct HIV-1 effects on the brain (Neuenburg, 2002).
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It is important to remember that symptoms of neuropsychiatric disorders 

can be confused with depression. If a patient has a low CD4 count without 

prior antiretroviral therapy, it may be appropriate to assess the response 

of these symptoms to a standard antiretroviral regimen before initiating 

antidepressant medication (See Chapter IV). Finally, both psychotropic 

and antiretroviral medication can cause neuropsychiatric symptoms as side 

effects. See Treisman (2002) for a thorough discussion of these issues.

V. DIAGNOSIS OF MAJOR DEPRESSIVE DISORDER 

Major depressive disorders are frequently undiagnosed (Asch, 2003) and 

once diagnosed, are often under-treated. Care providers may project their 

own feelings and think “I’d be depressed too, under the circumstances,” 

and not think about intervening with medication. Substance disorders are 

sometimes missed as contributors to the depression, and bipolar disorder 

is often not recognized when depression is the presenting symptom.

Normal grief or sadness does not require treatment with medication. The 

central feature of a major depressive disorder is the loss of pleasure in 

all activities or “anhedonia,” rather than sadness alone. Waves of grief 

are usually accompanied by lighter moments or even laughter as the 

most acute grief subsides. Sadness for other reasons, such as a major 

disappointment, is also responsive to environmental change such as an 

enjoyable activity, and the mood will be quickly reversed if the source of 

the disappointment changes. 

This is not the case in a major depressive episode, where the world has 

no joy regardless of the activity or turn of events, and where the outlook 

is gloom and doom regardless of the likelihood of a positive change. 

There may be obsessive rumination on past wrongs, or preoccupation 

with guilt or regrets that are impossible to balance with any feelings of 

accomplishment or hope. In addition to depressed mood, anhedonia, and 

hopelessness, major depressive disorders are usually accompanied by 

vegetative or biologic symptoms: low energy and psychomotor retardation; 

sleep disturbance (hypersomnia or insomnia), early morning awakening 

(around 2:00 AM to 4:00 AM); appetite disturbance (hyperphagia or 

hypophagia); decreased libido and, constipation. Finally, there may be 

cognitive changes such as decreased attention and concentration, social 

withdrawal and tendency toward isolative behavior, diminished range of 

affect, uncharacteristic irritability, and increased use of drugs or alcohol. 

In the most severe cases, psychotic symptoms such as delusions and 

hallucinations may be present.

The mood of a major depressive disorder is often worse in the morning, 

whereas the sadness of adjusting to difficult events tends to worsen 

over the course of the day, followed by a new day which is filled with 

more hope. A family history of mood disorders is often present. The 
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constellation of depressive symptoms develop together over a course 

of weeks or months and can help to differentiate major depressive 

disorders from similar disturbances related to medical illnesses. 

Hopelessness indicates severe depression and is the most consistent 

predictor of completed suicides. The suicidal ideation associated with 

bipolar depression can be particularly dangerous. A combination of 

psychotherapy and antidepressant medication has been shown to be 

therapeutic for HIV-positive patients with major depressive disorders 

(Markowitz, 1998).

Some of the clinical misperceptions that get in the way of evaluating 

major depression and other psychiatric disorders are listed in 

Table 9-4 (page 359), along with reminders for complete assessment. For 

the complete diagnostic criteria of each disorder, see the DSM-IV-TR of 

the American Psychiatric Association (2000).

Table 9-5: Differential Diagnosis of Major Depressive Disorder (MDD) 

Condition Differentiated from MDD by:

Bipolar disorder Racing thoughts, increased energy, decreased need for sleep, 

irritability or angry outbursts, hypersexuality (these may 

coexist with depressed mood in a mixed bipolar state)

Grief Onset associated with the loss; responsive to positive 

changes in the environment with enjoyment or less sadness; 

decreasing severity over time; preoccupation with deceased; 

“psychotic” symptoms related to deceased such as seeing, 

being visited by the deceased; rare suicidal intent although 

reunion fantasies may exist

Adjustment 

disorder with 

depressed mood

Sadness is rarely as profound; little anhedonia; no 

vegetative symptoms; identifiable precipitant; responsive to 

environmental change; suicidal ideation and intent may still 

occur; severe cases may respond to antidepressants

Organic mood 

disorder

Identifiable etiology linked by time; may be associated with 

cognitive deficits; test for specific medical conditions such as 

TSH, B12, VDRL or RPR, CNS evaluation; no family history

Dementia Less concern with cognitive decline; more gradual changes; 

may respond with laughter; worse at night; specific 

neurological deficits; CT or MRI scan often abnormal

Delirium Fluctuating mental status with altered level of consciousness; 

distractibility; inability to focus or sustain attention; dysarthric 

speech; agitation; medical etiology; usually acute onset

Medication- or 

substance-induced 

mood disorders

Onset with use of: steroids, anticholinergics, sedativehypnotics, anticonvulsants, antiparkinsonians, beta-blockers, 

anti-TB meds; sympathomimetics; azidothymidine, stavudine; 

all illicit drugs (urine toxicology screen, medication history)

TSH, thyroid-stimulating hormone; VDRL/RPR, nontreponemal serologic tests for syphilis.
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VI. PSYCHOPHARMACOLOGY FOR THE HIV-POSITIVE 

WOMAN: GENERAL GUIDELINES 

Numerous studies have indicated that psychotropic medications are safe and 

effective for HIV-positive individuals and do not adversely affect the immune 

system (Ferrando, 1999; Rabkin 1999; Repetto, 2003; Robinson, 2002). Standard 

antidepressant medications are generally well tolerated. While specific 

medications and common clinical dosing ranges are listed in Table 9-6 and are 

discussed below, the following general guidelines should be kept in mind when 

approaching psychotropic medications with the woman with HIV: 

• Start low, go slow: There is evidence that for antipsychotic 

medication, women in general require lower doses than men. 

Use slow upward titration as with geriatric patients. (ADA, 2004; 

Seeman, 2004). 

• Expect the unexpected: HIV-positive patients often experience 

unusual side effects, or common side effects at low doses, or 

complicated drug-drug interactions. 

• Dynamic monitoring: Changes in weight, metabolism, other 

medications, or medical illness episodes require frequent updating 

and reevaluation of dosing or choice of medications; this is 

particularly important with increased weight or abdominal girth, 

new onset of hyperlipidemia, or hyperglycemia. (see below and 

chapter XIV Pharmacology). 

• Interdisciplinary coordination: Psychiatrists and primary health 

care providers should be in regular communication with each other 

about clinical updates, dosing changes, and major medical events. 

• Suspect substances: Depression may be complicated by alcohol, 

anxiety by withdrawal syndromes, mania by psychostimulants; 

patients often forget that when their consumption has decreased, their 

CNS sensitivity to the effects of these substances increases over time. 

• Address medication adherence: Use medication boxes, simple 

regimens, written instructions, coordination with antiretroviral 

therapies, and patient education. Non-adherence or discontinuation 

may diminish the overall treatment effect if not specifically 

targeted (Ferrando, 1999). 

• Potential drug-drug interactions are a concern in prescribing 

psychotropic and antiretroviral medications. The primary 

cytochrome P450 systems at issue for psychiatric medications are 

CyP2D6 and CyP3A4: The major CYP450 drug-drug interactions to 

keep in mind are included in Table 9-7.

Common potential side effects of all of the antidepressant medications include 

agitation, irritability, sedation, sexual dysfunction, weight gain, headache, 

gastrointestinal distress, dry mouth, and activation of mania. There may be 

discontinuation syndromes with paroxetine and venlafaxine so these drugs 

should be tapered when increasing or decreasing the dose. Venlafaxine may 
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also cause hypertension. “Second generation antipsychotics”, as listed in Table 

9-6, are routinely recommended over traditional antipsychotic medications 

such as haloperidol, except for acute or short-term use, because of potential 

improvement of “negative” (affect, social interaction) as well as “positive” 

(hallucinations, delusions) psychotic symptoms, and lower associated 

incidence of extrapyramidal side effects such as dystonia, akathisia and the 

long-term risk of dyskinesia. However, recent concern about the association of 

olanzapine, clozapine (not recommended for first-line use) and, to some extent, 

quetiapine and risperidone, with weight gain and possible increased risk for 

diabetes and dyslipidemias, necessitates extreme caution in using these agents 

in conjunction with antiretroviral medications which may also be associated 

with hyperlipidemia and lipodystrophy, hyperglycemia and weight gain. 

Hyperprolactinemia may occur with quetiapine or olanzapine, with associated 

sexual side effects or galactorrhea.

Tolerance, dependence and withdrawal syndromes, including rebound anxiety, 

can complicate the use of benzodiazepines, especially alprazolam, and patients 

should be warned about sedation, cognitive effects and slowed reflexes, 

especially with regard to driving when using these agents.

Adverse effects with mood stabilizing drugs include potential significant weight 

gain with both valproic acid and lithium, still considered first line agents for 

mood stabilization. Depression may increase with valproic acid when some 

patients experience more “antimanic” than true mood stabilizing effect. Valproic 

acid may also be associated with more serious adverse effects, including hepatic 

dysfunction, thrombocytopenia or pancreatitis. Lithium may be superior for 

patients with clinical history dominated by clear cycles of mania. Because 

lithium is excreted through the kidneys, patients are at risk of toxic lithium 

levels if they become dehydrated due to vomiting or diarrhea, excess sweating 

or use of diuretics. Carbamazepine and oxcarbazepine are related compounds 

which may be helpful in primary or adjunctive mood stabilization, although 

both may be sedating. Oxcarbazepine may be associated with hyponatremia, 

but has the advantage of fewer drug-drug interactions and does not require 

monitoring with blood levels. Carbamazepine has been associated with rare 

instances of severe hematologic and dermatologic complications, but has been 

safely used in the setting of HIV infection with careful clinical monitoring. 

Lamotrigine interacts with both valproic acid, which doubles lamotrigine levels, 

and with carbamazepine, which cuts lamotrigine levels in half; lamotrigine has 

also been associated with severe rash upon occasion.

Finally, patients who experience severe or unusual side effects, have multiple 

diagnoses or require multiple medications, or are not responding at routine 

doses with initial medications should be referred for psychiatric consultation.
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Table 9-6: Common Psychiatric Medications

Disorder Medications and common dosing ranges*

Major depressive disorder 

(with or without anxiety)

Citalopram (Celexa) or Escitalopram (Lexapro) 10–40 mg (SSRI)

Fluoxetine (Prozac) 10–60 mg (SSRI)

Paroxetine (Paxil) 10–40 mg (SSRI)

Sertraline (Zoloft) 25–200 mg (SSRI)

Bupropion (Wellbutrin-SR) 100–1000 mg; usually AM and midday

Mirtazipine (Remeron) 15-30 mg

Venlafaxine (Effexor-XR) 37.5–225 mg

HIV-related depression/

fatigue (with or without minor 

cognitive motor disorder)

Methylphenidate (Ritalin) 10–60 mg in divided doses, AM and midday

Bipolar mood disorder Carbamazepine (Tegretol) 400–1200 mg in divided doses, titrated 

slowly by blood levels (4–12 mcg/ml)

Gabapentin (Neurontin) 600-1800 mg in divided doses

Lamotrigine (Lamictal) 25 mg, then 50 mg daily for two weeks each; 

then 100 mg daily for one week, followed by 200 mg daily

Lithium carbonate 600–1800 mg or Lithium CR 450mg – 1350mg in 

divided doses titrated by blood levels (0.6–1.0 mEq/L)

Oxcarbazepine (Trileptal) starting at 150–300 mg bid for one week, 

titrated very slowly 300–1200 mg in divided doses

Valproate/valproic acid (Depakote) 500–2000 mg in divided doses, 

titrated by blood levels (50–100 mg/mL)

Psychotic symptoms (also 

severe PTSD, Bipolar disorder)

Ziprasidone (Geodon) 40–240 mg (with food) twice daily

Aripiprazole (Abilify) 10–30mg

Risperidone (Risperdal) 0.5–6 mg once to twice daily

Quetiapine (Seroquel) 25–600 mg twice daily

Olanzapine (Zyprexa) 2.5–20 mg

Anxiety disorders (also PTSD) 

and Panic attacks

Paroxetine (Paxil) 10–40 mg

Sertraline (Zoloft) 25–200 mg

Buspirone (Buspar) 15–30 mg in divided doses

Lorazepam (Ativan) 1–6 mg in divided doses

Alprazolam (Xanax)0.75–4 mg in divided doses

Clonazepam (Klonopin) 1–4 mg in divided doses

Insomnia Trazadone (Desyrel) 25–100 mg

Benadryl 25–100mg

Lorazepam/Clonazepam at night dose

Temazepam (Restoril) 15–60 mg

Zolpidem (Ambien) 5–10 mg

Alcohol dependence Disulfiram (Antabuse) 250–500 mg daily to three times/week

Alcohol withdrawal Tranxene 15–30 mg q 2–6 hr

Opiate dependence Methadone 60–120 mg

Opiate withdrawal Methadone 5–40 mg in divided doses, tapered by 5 mg/day

Clonidine 0.3–0.6 mg in three divided doses

SSRI=selective serotonin reuptake inhibitor; PTSD=Post Traumatic Stress Disorder

* Many psychiatric medications are now available in extended release and rapidly 

dissolving, as well as liquid and parenteral forms.

Source: Modified from Schatzberg, 1998
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Table 9-7: Pharmacokinetic Drug Interactions between Psychotropic 

Drugs and ARVs

Drug CYP 

Substrate

CYP 

Inhibitor

Pharmacokinetic 

data/comments

Amitriptyline (Elavil) 

Nortriptyline (Pamelor) 

Desipramine (Norpramin)

Imipramine (Tofranil) 

Clomipramine (Anafranil) 

Doxepin (Sinequan)

2D6 RTV decreased desipramine clearance by 

59% in vitro.

RTV increased amitriptyline levels*. 

NFV increased desipramine levels*. 

Mirtazapine (Remeron) 2D6 Increases in serum level of mirtazapine may 

be seen with RTV co-administration.

Paroxetine (Paxil) 2D6 2D6 Increases in serum level of paroxetine may 

be seen with RTV coadministration.

Venlafaxine (Effexor) 2D6 2D6 (weak) Increases in serum level of venlafaxine may 

be seen with RTV co-administration.

Fluoxetine (Prozac) 2D6 2C19, 2D6, 

3A4 (weak)

DLV Cmin increased by 50%, RTV AUC 

increased by 19%*.

Citalopram (Celexa) 2C19 Drug interactions unlikely w/ antiretrovirals.

Sertraline (Zoloft) 2C19 2D6 (weak) Drug interactions unlikely w/ antiretrovirals.

Bupropion (Wellbutrin, Zyban) 2B6>

3A4

Clinically important drug interactions w/ 

PIs unlikely (preliminary in vitro data show 

weak inhibition by RTV).

Trazodone (Desyrel) 3A4 Increases in serum level of trazodone may 

be seen with PI coadministration. Decreases 

in serum level of trazodone may be seen 

with EFV or NVP co-administration.

Nefazodone (Serzone) 3A4 +3A4 Increases in serum level of nefazodone 

may be seen with PI co-administration. 

Decreases in serum level of nefazodone 

may be seen with EFV and NVP coadministration. Nefazodone may increase 

serum level of PIs and NNRTIs.

Fluvoxamine (Luvox) 2D6 +3A4 Increases in serum level of fluvoxamine 

may be seen with RTV co-administration. 

Fluvoxamine may increase serum level of 

PIs and NNRTIs.

Haloperidol (Haldol) 3A4>2D6, 

1A2

Increases in serum level of haloperidol may 

be seen with PIs.

Decreases in serum level of haloperidol may 

be seen with EFV and NVP.

Perphenazine (Trilafon) and 

thioridazine (Mellaril)

2D6 (2D6 

inhibitor)

Increases in serum level of perphenazine 

and thioridazine may be seen with NFV 

and RTV.

Olanzapine (Zyprexa) 1A2>2D6 RTV decreased olanzapine AUC by 50%*

Escitalopram (Lexapro) 2D6 No drug interaction with RTV 

Interaction with other PI and NNRTI unlikely
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Table 9-7: Pharmacokinetic Drug Interactions between Psychotropic Drugs 

amd ARVs (continued)

Drug CYP 

Substrate

CYP 

Inhibitor

Pharmacokinetic 

data/comments

Quetiapine (Seroquel)

Ziprasidone (Geodon)

3A4 Increases in serum level of quetiapine 

and ziprasidone may be seen with PI coadministration.

Decreases in serum level of quetiapine and 

ziprasidone may be seen with EFV and NVP 

co-administration.

Aripiprazole (Abilify) 3A4, 2D6 Increases in serum level of aripiprazole may 

be seen with PI co-administration.

Decreases in serum level of aripiprazole 

may be seen with EFV and NVP coadministration.

Risperidone (Risperdal) 2D6>3A4 Increases in serum level of risperidone may 

be seen with RTV co-administration.

Alprazolam (Xanax) 3A4 Alprazolam AUC decreased by 12%*.

Alprazolam clearance decreased by 59% 

and t1/2 increased by 200%*. 

Triazolam (Halcion)

Midazolam (Versed)

3A4 RTV increased triazolam AUC 20% 

and increased t1/2 by 12-fold*. Coadministration with PIs and EFV is 

contraindicated.

Zolpidem (Ambien) 3A4 RTV increased zolpidem AUC by 27%*

Chlordiazepoxide (Librium)

Clorazepate (Tranxene) 

Estazolam (ProSom)

Flurazepam (Dalmane)

Clonazepam (Klonopin)

3A4 Increases in serum level of 

chlordiazepoxide, clorazepate, estazolam, 

clonazepam, and flurazepam may be seen 

with PI co-administration.

Lorazepam (Ativan)

Temazepam (Restoril) 

Oxazepam (Serax)

Glucuronidation Interaction unlikely

Lorazepam was not affected by EFV*

Diazepam (Valium) 1A2 and 2C9> 

3A4 and 2C19

RTV may decrease serum level of diazepam

Carbamazepine 3A4 +3A4 May decrease serum level of PIs and 

NNRTIs. Consider TDM** .

Oxcarbazepine -34A May decrease serum level of PIs and 

NNRTIs. Consider TDM** (especially at high 

dose oxcarbazepine).

Lamotrigine Phase II 

Glucuronidation

RTV, NFV, LPV/r may decrease lamotrigine 

serum concentration.

* Interactions based on pharmacokinetic (PK) data. If no clinical PK data available, drug-drug interaction 

predictions are based on pharmacology principles.

** TDM = Therapeutic Drug Monitoring

Source: Paul Pham, The John Hopkins University School of Medicine, Baltimore, MD, 2003.
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VII. EVALUATION OF SUICIDE RISK 

Women are significantly more likely to attempt suicide than men, but 

men are significantly more likely to complete the suicide (male:female 

ratio of at least 4:1). Caucasians commit suicide at twice the rate of 

African Americans and Hispanics. It is estimated that 90% of individuals 

have a psychiatric disorder at the time of suicide and 45–79% of those 

have major depression. Fifteen percent of individuals with a mood 

disorder commit suicide (Buzan, 1996). 

Women more commonly attempt suicide by overdose, whereas men use 

more violent means, such as firearms or hanging. Women who have few 

social supports, have been widowed or divorced, or who have a history 

of sexual abuse are at increased risk for suicide. Women with children 

attempt suicide less frequently. Any risk factor is increased by the 

presence of alcohol, psychosis, or an organic mental syndrome. 

It is likely that suicide rates are decreasing among individuals with HIV 

(Marzuk, 1997). This may be due to a global or specific treatment effect 

of antiretroviral therapies (Chan, 2003), which can improve organic 

mood disorders and cognitive function (Ferrando, 1998), in addition to 

increasing longevity and hope. 

To assess suicide risk, the clinician must inquire about it (see Table 9-

8). Knowing that this does not increase the likelihood an individual will 

attempt suicide. The clinician should practice a standard way of asking, 

such as “Have you ever had thoughts of hurting yourself?” or “. . . of 

ending your life?” or “Do you ever feel that life is not worth living?” 

Table 9-8: Risk Factors in the Evaluation of Suicide Risk 

• Significant suicidal ideation

• Specific intent or plan; available means 

• Hopelessness

• Previous suicide attempts

• Depressed mood, mood disorders

• Family history of suicide or mood disorders

• Schizophrenia, psychosis (not necessarily command hallucinations) 

• Organic mental syndromes

• Intoxication with alcohol, other substances 

• Recent major loss, particularly through suicide 

• Preoccupation with death 

• Fantasies of reunion through death 

• Homicidal rage 

• Caucasian race
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VIII. CARE PROVIDER ISSUES 

One of the most important relationships the woman living with HIV 

has is the relationship with her health care provider. The dynamics of 

this relationship can have significant impact on the experience of the 

HIV-positive woman, and she will be affected not only by what the 

clinician communicates about HIV disease and treatment, but by how 

the information is communicated and how the provider relates to her. 

The practitioner who is able to establish a trusting relationship with the 

patient may find that the strength of their relationship can motivate the 

HIV-positive woman as much as lectures about viral load. Care providers, 

in turn, may experience, and should be aware of, a variety of potential 

reactions to their patients.

Women who use/abuse drugs or alcohol may provoke strong reactions 

in care providers, commonly frustration and disapproval, particularly 

when the woman is pregnant or has children. Providers may feel anger 

when the woman’s learned helplessness, particularly in sexual situations, 

results in her submitting repeatedly to unsafe sex, or provide inadequate 

pain control in response to provocative and insistent behavior on the 

part of the patient, in order to try to assert control. As is the case with 

other medical conditions, providers may personalize nonadherence with 

medications or medical follow-up as an affront to their good intentions or 

perceive it as a lack of commitment to treatment, rather than adherence 

to different priorities. Appointments missed to take care of children or 

because of problems with transportation may be misinterpreted as poor 

motivation for treatment. Providers who may then convey frustration or 

disappointment to a patient (e.g., with her nonadherence to medication) 

may find that she does not return because she has personalized this as 

a rejection.

On the other hand, providers may also collude with the HIV-positive 

woman’s feelings of powerlessness and try to take control over things she 

can actually handle herself with sufficient support. Protective concerns 

and anger at an abusing partner may tempt the provider to cross 

professional boundaries and try to rescue the patient. Frank disregard 

or avoidance of medical treatment may be mistakenly excused without 

exploring the real meaning of the behaviors. Care providers might assume 

that a woman is missing visits because she is overwhelmed with the care 

of her children when she is actually angry at a particular provider, or so 

frightened about the illness that she avoids treatment. Initiating multiple 

medications may be the point at which she is forced to break through the 

denial and confront her illness. 

For the female health care provider, the experience of taking care of 

women with HIV can be both more rewarding and more depleting than 

general medical care. Personal identification with the patient may work 

positively to increase empathy, or negatively to increase projection of 

one’s own values and expectations on the individual. Female providers 

may also experience amplified grief because of the death of a patient with 

whom they have developed a genuine connection. 
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Providers who are either prone to experience patient deaths as their 

own clinical failures, or who have deep compassion for the suffering of 

their patients, may be vulnerable to experiencing professional burnout, 

particularly if subjected to multiple, sequential losses. The practitioner 

who can cope with these challenges, however, may find personal and 

professional satisfaction in providing a combination of important services 

to a subpopulation of women who remain profoundly underserved. 

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X

I. SUBSTANCE USE AND ABUSE

Substance use is more prevalent in the United States than is generally 

appreciated. Statistics described in the 2002 National Survey on Drug Use 

and Health (NSDUH) give the following picture on drug use in American 

men and women (SAMHSA, 2002). Approximately 46% of the American 

population will use an illegal drug in their lifetime. It is estimated from 

the NSDUH data that in the general population, 10.3% of men and 6.4% 

of women have used illegal drugs in the last month. Over the past year, 

35 million Americans will have used an illegal drug. Only a fraction of 

drug-using persons are truly drug-dependent (also called drug-addicted). 

It is estimated that 7.1 million people meet the definition of illicit drug 

dependence, defined as compulsively continuing drug-seeking and drugusing behavior even in the face of negative consequences, including 

health, social, family, legal or work problems.

The general rates of legal drug dependence dwarf the amount of illegal 

drug addiction. In 2002, 120 million persons reported consuming alcohol 

in the last 30 days and 71.5 million persons used a tobacco product. At 

least 54 million of the alcohol consumers are dependent on alcohol 

through binge or very heavy drinking. The alcohol-dependent individuals 

are almost three times as numerous as the number of illegal drug users. 

In contrast to illegal drug use rates where almost twice as many men 

as women use illegal drugs, alcohol consumption rates are nearly equal 

for men and women in the general population. However, women were 

much less likely to be binge drinkers. It is important to note that rates of 

drug and alcohol use are equal in adolescent males and females (12–17 

yr. old), suggesting a trend toward comparable substance use patterns for 

men and women. Regular use of cigarettes (nicotine dependence), was 

nearly equal for men and women.

Unfortunately, the majority of alcohol and/or drug dependent women 

and men, who could benefit from substance abuse–related emotional/

psychologic and health treatment, never receive any form of therapeutic 

intervention. In 2002, only 7.5% of women who needed treatment for 

an alcohol problem and 20.4% of women who needed treatment for an 

illegal drug problem actually received care at a specialty facility for these 

problems.

This chapter will focus on drug and alcohol dependence as a disease, 

discuss associations with a variety of comorbid conditions, review the 

epidemiology of substance abuse in the United States, and outline ways 

to identify and treat substance abuse in women.

X. SUBSTANCE ABUSE

Henry Francis, MD and Victoria A. Cargill, MD, MSCE
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II. EPIDEMIOLOGY OF SUBSTANCE ABUSE

The frequency and danger of drug and alcohol dependence and behaviors 

of drug and alcohol use are greatly underestimated by the American 

public and health care professionals. The two commonly used legal drugs, 

alcohol and tobacco, are more frequently consumed than all the illegal 

drugs combined (Table 10-1). Marijuana and cocaine (including crack 

cocaine) are the most frequently used illegal drugs. Inhalants are used 

predominately by adolescents. A more recent trend in adolescents is to use 

club drugs like g-hydroxybutyrate, ecstasy (MDMA), Rohypnol, ketamine, 

methamphetamine, and LSD at all-night parties called “raves” or “trances.” 

Surprisingly, heroin, which is viewed as a highly prevalent drug, is actually 

one of the least favored drugs of preference in the U.S. population.

Table 10-1: Prevalance of Drug use

Drug Alcohol

Alcohol 155,476,000

Tobacco 84,731,000

Marijuana 25,755,000

Cocaine 5,902,000

Hallucinogens 4,749,000

Inhalants 2,084,000

Stimulants 3,181,000

Heroin 404,000

Source: Adapted from the 2002 National 

Survey on Drug Use and Health (SAMHSA, 

2002); past year use

The rates of illicit drugs used vary 

slightly by ethnicity (Table 10–2) and 

in a major way by gender. Estimates 

for gender-specific drug use indicate 

that women are almost 50% less 

likely to use illicit drugs compared 

with men. The male-to-female 

illicit drug use rate relationship is 

consistent throughout all ethnic 

groups. Ethnic comparisons of drugs 

used demonstrated that the highest 

rates of drug use occur in young 

adults aged 18–25.

White American men and women 

have higher rates of alcohol

use than African Americans or 

Hispanic Americans (Table 10-3). For 

all alcohol-using groups, alcohol 

consumption is highest in young 

adults (18–25 yr). 

Table 10-2: Illicit Drug use 

Estimates by Age and Ethnicity 

in the US

Percent US Population

Age (yr) White Hispanic

African 

American

12–17 24.0 20.8 18.5

18–25 39.6 27.0 30.9

26 or 

older

10.2 10.5 13.5

Source: Adapted from the 2002 Survey on 

Drug Use and Health (SAMHSA, 2002); past 

year use

Table 10-3: Alcohol use 

Estimates by Age and Ethnicity 

in the US

Percent US Population

Age (yr) White Hispanic

African 

American

12–17 20.1 10.9 16.6

18–25 66.8 49.8 48.3

26 or 

older

57.5 46.1 43.6

Source: Adapted from the 2002 Survey on 

Drug Use and Health (SAMHSA, 2002); past 

month use
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III. SUBSTANCE ABUSE AND HIV

Substance abuse is a major risk behavior for acquisition of HIV infection. 

The most recent HIV/AIDS statistics in the US show that 26% of women 

living with HIV/AIDS at the end of 2002 were infected through injection 

drug use (IDU). Non-injection drug use (NIDU) is also associated with 

increased risk of HIV infection, most likely related to high risk sexual 

behaviors. Use of illicit drugs and alcohol abuse are generally associated 

with larger numbers of sexual partners, increased rates of STIs, decreased 

rates of condom use, increased likelihood of sex with an injection drug 

user and, for illicit drugs, increased risk of exchange of sex for money 

or drugs (Woods, 2000; Molitor, 1998; Word, 1997; Sanchez, 2002). Crack 

cocaine use has been associated with increased likelihood of engaging in 

anal sex (Gross, 2000). Although IDU-related HIV transmission is most 

closely related to sharing injection equipment, a significant portion of 

transmission is related to sexual behaviors. Even after controlling for 

other potential risk factors, HIV infection rates tend to be higher among 

individuals who abuse alcohol (Petry, 1999). Individuals who abuse 

one drug or alcohol are more likely to use/abuse other substances as 

well. Over half of cocaine-dependent and 17–50% of heroin-dependent 

individuals abuse alcohol and alcohol use is associated with needle 

sharing in both heroin- and cocaine-abusing persons (Petry, 1999).

While under the effects of these substances, individuals have impaired 

decision-making ability or a reduced ability to understand or evaluate 

their actions. Disinhibition with drug use is known to decrease 

compliance with safer sex precautions or drug paraphernalia hygeine. Sex 

and drug-related HIV risk behaviors are strongly associated in women. 

Women acquire HIV, hepatitis B and C, and STIs often through sexual 

partnerships with injection drug users. 

Among HIV-infected women, substance abuse is common. Although 

learning that she is HIV-infected may provide a woman incentive for 

stopping drug or alcohol use in order to better care for herself, it may 

also be more difficult to curtail substance abuse because of feelings of 

despair and hopelessness about the diagnosis of HIV. HIV status did not 

affect use of heroin or cocaine in a large cohort of HIV-infected and highrisk HIV-uninfected women followed for over 6 years (Macalino, 2003). 

In HIV cohort studies, 40–80% of individuals consume alcohol and rates 

of alcohol dependence are increased (Kresina, 2002). 

The coexistence of substance abuse and HIV has a number of implications. 

The stigma and discrimination associated with drug and alcohol abuse, 

as well as the disorganization often seen in the lifestyle of those with 

active substance abuse, can lead to denial, delay in diagnosis of HIV, and 

reluctance to seek care. The signs and symptoms of drug and alcohol 

dependence, as the comorbidities associated with these conditions, may 

overlap with the signs and symptoms of HIV, further complicating and 

delaying early diagnosis and care. Such delays have been associated 

with increased morbidity and mortality in drug-using populations. The 
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comorbidity associated with substance abuse, such as alcohol-induced 

liver cirrhosis or IDU-related hepatitis C, may accelerate HIV progression 

and/or significantly complicate HIV management. Active substance 

abuse is consistently associated with poor adherence to medical care and 

to antiretroviral medications. Individuals who are heavy alcohol users 

are one-fourth as likely to achieve virologic suppression on HAART as 

non-drinkers (Miguez, 2001). Both alcohol and methadone have potential 

drug-drug interactions with some antiretroviral agents, possibly increasing 

toxicity or decreasing effectiveness of ARV drugs. 

Primary care providers are uniquely positioned to identify early 

indications of drug use-related HIV risks and signs of other comorbidities 

and to engage drug users in treatment at earlier stages of drug dependence. 

New and younger initiates to injection drug use engage in particularly 

high-risk behaviors for acquisition and transmission of infectious diseases 

and HIV (Carneiro, 1999). In primary care settings, interventions can be 

put in place to prevent further transmission (Anderson, 1996) of HIV 

or other infections. Misconceptions about the legal, social, and health 

implications of testing positive for HIV reduce early detection efforts, 

particularly among patients at high risk (Harvey, 1999).

IV. COMORBIDITY RELATED TO SUBSTANCE ABUSE

Substance abuse is associated with a number of medical consequences 

and comorbid conditions, some of which are listed in Table 10-4. These 

conditions represent only a few of the many disease states either directly 

associated with substance abuse or exacerbated by substance abuse. 

Excessive alcohol use places women at risk for cirrhosis, epilepsy and 

dementia, psychiatric disorders, cardiomyopathy, peptic ulcer disease, 

pancreatitis, malnutrition, and malignancies. Intravenous drug use 

continues to be implicated in a number of infectious diseases, such as 

hepatitis and endocarditis, and smoking tobacco is the most common 

cause of lung cancer and airway diseases, and has been implicated in 

other malignancies such as cervical carcinoma (Waggoner, 1994).

Table 10-4: Medical Conditions and Sequelae Associated with 

Drug and Alcohol Abuse

• HIV

• STIs

• Tuberculosis

• Hepatitis (A, B, C, D 

and GBV-C)

• Bacteremia

• Endocarditis

• Cirrhosis

• Cancer

• Cellulitis

• Thrombophlebitis

• Poor nutrition

• Pneumonia

• Cutaneous abscesses

• Cognitive dysfunction

• Septic emboli

• Trauma

The comorbid conditions related to substance abuse may delay diagnosis 

of HIV and complicate management of both HIV and substance abuse. 

Hepatitis C is a marker of poorer outcomes for HIV and has been 

associated with decreased survival and increased HIV progression. Some 
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have postulated that HCV, rather than being the primary cause of poor 

outcomes, may be a marker of later access to care and injection drug 

use, based upon a cohort of 823 HIV infected patients with and without 

HCV co-infection. (Greub, 2000; Tedaldi, 2003; Sulkowski, 2002). Both HIV 

infection and alcohol abuse have been reported to accelerate hepatitis Cinduced liver disease and when all three are present together, this effect 

may be magnified. End-stage liver disease has become the leading cause of 

death in specific patient populations with HIV infection, and coinfection 

with viral hepatitis and alcohol abuse appear to be the major risk factors 

for progression of liver disease and death (Kresina, 2002). 

Treatment with highly active antiretroviral therapy (HAART) is associated 

with improved outcomes in patients with substance abuse and comorbidities 

such as hepatitis coinfection (Benhamou, 2001). This underscores the 

importance of timely identification and treatment of substance abuse and 

its sequelae, as well as HIV. In both substance abuse treatment programs 

and primary care clinics, strategies are needed to identify HIV and manage 

HIV and comorbid conditions associated with HIV and/or substance abuse 

or have established linkages into appropriate care. 

V. SUBSTANCE ABUSE IN WOMEN

Women who use drugs and alcohol have different risk factors for initiating 

use, have accelerated progression to dependence (Zilberman, 2003), and have 

an increased vulnerability to the medical and psychosocial consequences of 

substance use as compared to men, and as such require different approaches 

for the diagnosis and management of drug use and its sequelae. Women need 

treatment plans and care sites that address their personal, social, and familial 

needs, but most addiction diagnosis and treatment paradigms have been 

based upon the experiences in treating male users. Family circumstances, 

stigma, community environment, social status, and the nature of her primary 

relationships all affect the treatment of substance abuse in women. Several 

studies suggest that women drug users are more socially isolated, depressed, 

and dependent upon partners than their male counterparts (SandersPhillips, 2002). Women who have experienced violence, whether sexual or 

physical, are more likely to use alcohol, as well as marijuana or crack cocaine 

(Fullilove, 1992; Miller, 2000). These women, often due to imbalances in the 

power of their relationships, as well as a past history of abuse, are less likely 

to insist upon condom use, placing themselves at risk for HIV and other STIs 

(Fenaughty, 2003; Amaro, 2000). 

Underlying psychiatric conditions, such as depression or other psychiatric 

disorders, may influence initiation or continuation of substance use (“selfmedicating” depression). The prolonged use of drugs or alcohol in this 

setting can exacerbate, rather than improve, these problems. Female drug 

and alcohol users as a group are more likely to suffer from depression and 

anxiety disorders than the general population or other medical groups. 

The strong association between drug use and alcohol abuse and mental 

health disorders is evident in environmental and genetic predisposition to 
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addictive, impulsive, and compulsive behaviors and personality disorders. 

A conservative estimate is that over 50% of drug or alcohol-dependent 

women have one or more comorbid mental health conditions. Successful 

treatment of the drug or alcohol dependence is unlikely until their mental 

illness is treated.

Prevention intervention strategies for women with substance abuse 

must include both contextual relevance (eg, dealing with an IDU 

sexual partner) and real-world appropriate planning, such as condom 

use strategies in the setting of drug/alcohol intoxication. In addition 

to treatment of the underlying substance abuse and HIV, if present, 

treatment and prevention of comorbid conditions (eg, STIs, hepatitis C) 

are important, as these may facilitate sexual and perinatal transmission of 

HIV. Although they are growing in number, still relatively few treatment 

facilities accommodate women who are pregnant or have small children. 

Those sites that can address the medical, drug and alcohol use, and living 

circumstance challenges simultaneously will have the greatest appeal and 

utility for drug and alcohol-abusing women.

VI. IMPACT OF SOCIETAL PERCEPTIONS AND BELIEFS

Numerous social, moral, personal, and situational beliefs adversely affect 

a substance-abusing woman’s health. Historically, U.S. society’s response 

to drug addiction is punitive, stigmatizing, and prejudiced against drug 

users and their families. The negative public sentiment surrounding illicit 

drug use is especially evident in criminal justice sentencing practices. 

Health providers often share these views of drug users as unreliable and 

noncompliant. Value-laden judgments may affect provider willingness 

to treat this population and influence the care provided and therapeutic 

regimens prescribed. Providers may also be reluctant to raise the subject 

of substance abuse treatment with patients because of misconceptions 

about the effectiveness of treatment.

Women with drug and alcohol abuse are more likely to experience poor 

health and are less likely to access services, receive treatment, or seek 

health care, partially because of the stigma of substance abuse. Suspicion, 

fear, and distrust of the health care system result in reluctance among drug 

users to disclose medically necessary information. Negative sanctions, 

such as mandatory HIV testing during pregnancy and incarceration of 

drug-using pregnant women for child abuse, have intensified fears about 

contact with the health system. For economically disadvantaged women 

with HIV and drug abuse problems, the fear of discrimination, retribution, 

loss of housing, or loss of children may become more important than 

seeking or engaging in health services (Sly, 1997) and may keep them 

from receiving personally tailored prevention messages.

Individuals who are drug or alcohol dependent, even though they 

may exhibit dysfunctional behavior, retain the right to be evaluated as 

individuals and to be treated with respect and equality, regardless of 

conflicts in values or beliefs between patient and care provider.
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VII. IDENTIFICATION OF SUBSTANCE USE/ABUSE

A. DIAGNOSIS BY HISTORY

Identification of substance use can be a challenge, given the myriad of 

illnesses it can mimic. However, the biggest barrier to identification is 

denial. Given the stigma associated with substance use, as well as the 

stereotypes associated with substance use, health care providers must 

entertain the diagnosis in all patients. Substance use must be a diagnosis 

to be excluded in the differential diagnoses of many medical conditions. 

Table 10-5 lists clues to a possible alcohol and drug abuse diagnosis. These 

clues include erratic behavior, agitation, disorientation, doctor “hopping,” 

child custody loss, and frequent unexplained accidents.

Table 10-5: Clues to Drug and Alcohol Abuse

Medical History Behavioral Clues Social History Clues

• HIV infection

• Endocarditis

• Hepatitis B or C 

infection

• Septic emboli

• Septic thrombophlebitis

• Pancreatitis

• Cirrhosis

• Agitation

• Somnolence

• Disorientation

• Erratic behavior

• Doctor “hopping”

• Frequent unexplained 

accidents

• Inability to retain 

employment

• Child custody loss

• Seemingly unexplainable 

financial difficulties

• Relationship distress

The diagnosis of drug and alcohol dependence is made by taking a 

careful history of drug and alcohol use, as well as a directed medical and 

psychosocial history; performing a complete physical evaluation; and 

laboratory testing for the presence of drugs and/or alcohol, or for the 

complications of drug and alcohol abuse.

The most commonly used instruments to detect and assess drug and 

alcohol abuse are the CAGE survey, the Diagnostic and Statistical Manual 

of Mental Disorders, Fourth Edition (DSM-IV) alcohol/drug abuse/

dependence diagnostic criteria, and the Addiction Severity Index.

If the provider cannot get a sense of the patient’s substance use from 

unstructured questions, the CAGE survey offers a nonthreatening 

alternative approach. The CAGE survey is a four-question format 

intended to be used in primary care and other non-substance abuserelated health care facilities.

1. Have you felt that you ought to Cut down on your drinking or drug use?

2. Have people Annoyed you by criticizing your drinking or drug use?

3. Have you ever felt bad or Guilty about your drinking or drug use?

4. Have you ever had a drink or used drugs first thing in the morning 

(Eye opener) to steady your nerves, get rid of a hangover, or to get 

the day started?
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There are several other simple alcohol-screening instruments, including 

TWEAK, T-ACE, Michigan Alcoholism Screening Test (MAST), Alcohol 

Use Disorders Identification Test (AUDIT), and Rapid Alcohol Problems 

Screen (RAPS). TWEAK (an acronym for Tolerance, Worry about drinking, 

Eye-opener, Amnesia, and Cut down on drinking) and AUDIT perform 

better than CAGE in women (Bradley, 1998). Both TWEAK and T-ACE 

have been validated for alcohol screening in pregnancy (Russell, 1994).

Screening tests like these can be very useful for getting substance-addicted 

patients into a trajectory for substance abuse care. Otherwise, these 

patients may be seen in different parts of the health care system for other 

problems, while the substance abuse is not identified or addressed.

Some patients will come to medical attention because of substance 

intoxication or withdrawal. As with substance abuse in general, 

entertaining the diagnosis and recognizing the constellation of signs 

and symptoms is critical to recognition of intoxication and withdrawal 

syndromes. Alcohol intoxication may be characterized by inebriation, 

sedation, ataxia, and slurred speech. However, this extreme of behavior 

is witnessed in only a subset of patients. Of the 113 million Americans age 

12 and older who reported alcohol use, 33 million reported binge drinking 

(meaning they drank 5 or more drinks on one occasion 5 or more days 

during the past 30 days) (SAMHSA, 1999). Alcohol withdrawal can vary 

from agitation to the more florid syndromes associated with delirium 

tremens. This includes labile blood pressure, autonomic instability, visual 

hallucinations, and death. It should be noted that delirium tremens may 

be fatal if untreated. The mortality may be as high as 35%, but with early 

recognition and treatment, that risk decreases to 5% (Grossman, 2001).

Opiate intoxication is associated with sedation, including somnolence 

or “nodding.” There has been a resurgence in heroin popularity, with 

an estimated 81,000 new heroin users in 1997 (SAMHSA, 1999). Opiate 

withdrawal is characterized by the loss of central nervous system 

depression. These signs include piloerection, vomiting, diarrhea, agitation, 

irritability, and sweating. Cocaine, and its alkaline cheaper form, crack, 

are highly addictive. Intoxication with cocaine is associated with euphoria, 

as well as profound hypertension (secondary to vasoconstrictive effects). 

Increased pulse rate and dilated pupils are also associated with cocaine 

intoxication. Cocaine/crack withdrawal is associated with irritability, 

agitation, and mood lability.

The DSM-IV criteria for drug dependence are developed for the 11 classes 

of commonly abused drugs (including alcohol) and include 7 major 

criteria (Table 10-6). DSM-IV criteria determine dependence by finding 

evidence of physical or psychologic dependence on a drug or tolerance 

to it, disruption of social life patterns, and disregard of the negative 

medical consequences of using drugs. A person is considered to be drug 

dependent if they fulfill 3 of the 7 criteria within a 12 month period.
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Table 10-6: DSM-IV Drug Dependence Criteria

• Presence of drug withdrawal symptoms/syndrome

• Escalation of drug doses or reduced effect of the same dose

• Persistent inability to reduce or control drug use

• Increased time obtaining and using the drug

• Personal and business activities reduced by drug use

• Substance taken in larger amounts or for longer than intended

• Knowledge of drug use’s negative health and personal effects, 

yet continuing to use drugs

Source: Adapted from DSM-IV, 4th edition, 1994.

The Addiction Severity Index (ASI) (NIH, 1995) is most commonly used 

to help health care givers assess the severity of the drug and/or alcohol 

addiction in persons who are already determined to have a drug use 

problem and for whom a treatment plan must be developed. The ASI is 

a detailed, 1-hr assessment of environmental, historical, physiologic, and 

drug-related factors contributing to that individual’s drug use. The specific 

areas of evaluation include drug and alcohol use, psychiatric problems, 

legal problems, family/social issues, and employment/ support concerns. 

Physical and psychologic signs of drug use and changes in medical and 

mental health status are also assessed. The data accumulated by ASI 

information is useful for developing treatment plans that include lifestyle 

change goals. The ASI is also a useful instrument for assessing progress at 

different follow-up points because it is time-based and yields quantitative 

composite scores for each problem area.

B. DIAGNOSIS BY LABORATORY AND CLINICAL EXAMINATION

Substance abuse disorders are erratically diagnosed on physical 

examination for a number of reasons including: 1.) caregivers’ lack of 

interest 2.) lack of awareness of drug use signs or 3.) the signs may be 

subtle. Most drug and alcohol-dependent persons have jobs and lead a 

“normal” life, without the stereotypic dysfunction of severe alcoholism or 

injection and noninjection drug use. Cocaine snorting can be suspected 

by seeing a damaged nasal mucosa; hypodermic marks or “tracks” suggest 

injection drug abuse, although the absence of visible marks does not rule 

this out. The single most useful examination is of the eyes. Nystagmus 

is often seen in abusers of sedatives/hypnotics or cannabis. Mydriasis is 

often seen in persons under the influence of stimulants or hallucinogens 

or in withdrawal from opiates. Miosis is a classic hallmark of opioid effect. 

Evidence of multiple minor (or past major) injuries can also be a clue to 

possible substance abuse.
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Drugs may be detected in almost any fluid or tissue in the body. The 

most common samples for drug tests are urine, blood, saliva, hair, 

sweat, and breath (Wolff, 1999). Urine testing is the most available and 

useful testing format. There are test kits that can be used in offices 

and at home and require simple collection of a urine sample. Urine 

test limitations, however, are numerous. These limitations include the 

ability to detect only recent drug or alcohol use, as seen in Table 10-7. 

Adulterated urine samples and changes in the acidity of the urine may 

prevent quantification of illegal drugs in urine. Blood testing is available 

to many caregivers but is more expensive and more cumbersome than 

urine analysis. Blood testing is more accurate at quantitative detection of 

drugs in the user. Saliva may also be useful and correlates well with drug 

levels in the blood. Hair analysis is a more recent technology and may 

be a future tool for drug detection. It has the advantage of detecting drug 

use over a 1–3-mo period, depending on a person’s hair growth rate. The 

reasons that the test is not used widely are that cosmetic hair treatments, 

i.e., hair bleaching, may change drug level results, in addition to other 

factors such as hair pigmentation and hair growth rate. Sweat testing is 

another noninvasive test that is more useful for monitoring drug relapse 

during drug treatment. It is designed to continuously monitor a person’s 

drug use over a period of time by placing a special absorbant pad on the 

skin. The pad collects microscopic amounts of sweat produced by the 

body over time and is analyzed later for presence of drugs. Breath testing 

is commonly used to estimate the concentration of alcohol in an alcohol 

user and is a reliable reflection of blood alcohol.

Table 10-7: Duration of 

Drug Detection

Drug Duration of 

Detection

Alcohol 6–10 hours

Amphetamines 12 hours

Barbiturates 2–30 days

Valium 4–5 days

Cocaine 24–72 hours

Heroin 24–72 hours

Marijuana 3–30 days

Methaqualone 4–24 days

Phencyclidine 

(PCP)

3–10 days

Methadone 3–5 days

Sex, food, 

gambling

N/A

Overall, the urine tests are the 

most reliable tests for clinicians 

to use. However, test results may 

be difficult to interpret for the 

inexperienced care giver because 

the results may be confounded by 

secondary drug exposures, chemical 

characteristics of the drugs to be 

detected, drug level variations in 

different body tissues and fluids, 

and test method variations. Drug 

testing properly used is a useful 

adjunct to clinical and behavioral 

drug use assessment and a useful 

but limited drug use screening tool. 

Drug tests should not be used as the 

sole criteria for detecting substance 

use but, properly used, they are 

helpful during drug therapy, and 

follow-up.
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VIII. TREATMENT READINESS AND HARM REDUCTION

Substance abusers vary in their readiness to change their behaviors. 

Providers who are attuned to the patient’s stage of readiness 

(precontemplative to action-oriented) will have the greatest success in 

facilitating behavior change (Prochaska, 1992). Motivating factors for 

treatment readiness in women are most commonly associated with 

difficulty in raising their children or in response to interventions by social 

services departments (Brady, 1999). Unlike men, women are more likely to 

express their treatment readiness in nonsubstance use settings, especially 

in mental health care sites (Lex, 1991). For that reason, drug and alcohol 

treatment readiness should be evaluated in all health care settings.

For persons who are not ready for addiction treatment, caregivers can 

provide harm reduction interventions, aimed at reducing the damaging 

effects or harm resulting from risk behaviors and practices such as the 

sharing of syringes and other drug injection equipment and/or unsafe sex 

practices resulting from the use of drugs and alcohol (Des Jarlais, 1995). 

Comprehensive strategies that can effectively target high-risk populations 

consist of a hierarchy of risk reduction approaches that, depending on the 

composition and needs of the populations being served, may include needle 

exchange programs or community outlets providing condoms (Sumartojo, 

1996). Sexually transmitted infection prevention programs, education 

programs, social and work skills building programs, and health and drug/

alcohol use treatment programs should be provided through community 

resources. Programs targeting drug- and alcohol-using populations and 

subpopulations are all useful in preventing diseases such as HIV, STIs, 

hepatitis, and tuberculosis and should eventually lead to encouraging the 

substance user to seek help in stopping drug or alcohol use (Needle, 1997).

A patient’s history and behavior may be more predictive of treatment 

readiness, potential for engaging in care and adhering to therapeutic 

regimens than provider judgments based on gender, race, or ethnic 

background. There is a direct relationship between patient adherence 

with substance abuse treatment and the quality of the patient-provider 

relationship; however, the lack of physician training in the care of injection 

and other drug or alcohol abusers and the negative attitudes about drug use 

pose significant barriers (Laine, 1998).

IX. TREATMENT OF SUBSTANCE ABUSE

A. TREATMENT PROGRAMS

The most effective treatment programs are comprehensive, multidimensional, 

and can be effectively delivered in outpatient, inpatient, and residential 

settings. In addition to behavioral (counseling, cognitive therapy, or 

psychotherapy) and/or pharmacologic therapies, the patient may 

need other medical services, family therapy, family planning, violence 

prevention, parenting instruction, vocational rehabilitation, and social and 

legal services (Table 10-8).
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Table 10-8: Components of Drug and Alcohol Abuse Treatment

Personal Needs Treatment Needs

• Family services

• Housing and transport

• Financial services

• Legal services

• HIV/AIDS services

• Educational services

• Medical services

• Vocational services

• Child care services

• Mental health services

• Family planning services

• Behavioral therapy

• Clinical and case management

• Intake and processing

• Treatment plans

• Pharmacotherapy

• Continuity of care

• Substance use monitoring

• Self-help/peer support groups

• Substance education

Treatment programs should also provide repeated assessments for HIV, 

hepatitis B and C, tuberculosis, and other infectious diseases, as well as 

noninfectious diseases like diabetes and hypertension, and counseling 

and referral for relevant mental health treatment.

The most successful treatment occurs when the environmental, social, 

behavioral, medical, and addiction problems are found early and treated 

over a long period of time (more than a year). Though it would be desirable 

to detect and treat drug use and alcohol abuse early after onset, when 

patterns of use are more easily treated or modified (Coates, 1998), most 

drug treatment modalities target more advanced stages of dependence, 

when medical or legal interventions are needed. Most patients do not 

seek treatment until symptoms and associated consequences are severe. 

Women’s drug use problems tend to occur at an older age of onset and 

develop more rapidly than in men. Women also often learn of their 

HIV infection and other comorbid conditions much later than men. 

The late diagnosis of drug use and other diseases may result in shorter 

survival. The confluence of factors that complicate health care for female 

substance abusers underscores the importance of early engagement and 

retention of women in care.

Effective treatment of drug dependence produces reductions in drug use 

by 40–60%, significant decreases in criminal activity during and after 

treatment, and increases in full-time employment. Effective treatment 

also reduces risk of HIV transmission (as well as other infectious diseases) 

by a reduction in risky behavior. Methadone treatment programs have 

consistently been linked to lower rates of HIV infection (Metzger, 1993). 

Similarly harm reduction interventions also play an important role in 

decreasing risky behavior. In a prospective study of 259 untreated injection 

drug users, syringe exchange programs demonstrated a two to six-fold 

decreased odds of HIV risk behavior. These findings were most pronounced 

for those individuals without other sources of syringes (Gibson, 2002). 

Establishing accessible care in primary care settings offers countless 

opportunities to initiate prevention and treatment interventions targeted to 
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adults, adolescents, and other population groups at risk for drug and alcohol 

abuse and associated problems. Easy health access for women is particularly 

important because their motivation for drug use/alcohol abuse is most often 

to cope with negative mood or anxiety (McCaul, 1999). Providers should be 

accessible and should monitor individual triggers for stress and levels of 

stress sufficient to produce drug use complications or relapse.

B. PHARMACOLOGIC INTERVENTIONS

Today even the most severe physical withdrawal symptoms can be 

managed with appropriate pharmacologic treatments, reducing the 

complications of physiologic dependence in the treatment of drug 

dependence. Drugs for alcohol and sedative-hypnotic dependent persons 

are important for controlling and preventing serious medical consequences 

of drug withdrawal while other medications like methadone can help 

stabilize a patient and facilitate a return to productive functioning. 

Other important pharmacologic interventions include the treatment of 

comorbid conditions common in drug and alcohol abusing populations. 

Use of antidepressants in psychiatrically impaired substance abusers is as 

important as therapies directed to the effects of the drugs of abuse.

The pharmacologic treatments for drug use are well known but not well 

understood by many health caregivers. Several classes of medications 

may be used to treat, modulate, or prevent drug use.

OPIATE ADDICTION

Opiate agonist drugs like methadone, 1-a-acetyl-methadol (LAAM) and 

buprenorphine are used as opiate substitutes for opiate-dependent 

persons. These three drugs, used to treat addiction, block the ability 

of the illicit drugs to attach to opiate receptors, therefore decreasing 

a person’s craving for the drug without causing euphoria. This is the 

most misunderstood medical approach to addiction treatment. Although 

methadone, LAAM, and buprenorphine are addictive, they are successful 

in helping addicts to stop their negative and harmful behaviors associated 

with drug use and begin to concentrate on developing the skills to 

discontinue drug use entirely. It is the drug craving that is associated 

with drug use relapse and criminal behavior and it is its prevention 

that makes substitution medications work successfully as part of a 

drug treatment program. Methadone suppresses withdrawal for 24 hr 

(four to six times the duration of the effects of heroin) and decreases or 

eliminates drug craving; it is not sedating, can be dosed once a day, and 

can be administered orally. Furthermore, it is medically safe even when 

used continuously for 10 years or more.

LAAM is a newer synthetic opiate resembling methadone. LAAM can 

block the effects of heroin for up to 72 hr with minimal side effects when 

taken orally. Its long duration of action permits dosing just three times 

per week, thereby eliminating the need for daily dosing and take-home 

doses for weekends.
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Buprenorphine is a partial opioid agonist which has recently been 

approved by FDA for office-based and program-based treatment of 

opiate addiction. Some of the advantages of using buprenorphine are 

milder withdrawal symptoms, lower risk of overdose, and availability to 

patients in the offices of physicians trained and certified in the use of the 

medication. If used in the proper dosage, buprenorphine is as effective as 

methadone or LAAM.

These substitution medications are not a cure for drug dependence but 

important adjuncts to care. It has been shown that while an opiate user is 

on methadone, she is much less likely to commit a crime and more likely 

to succeed in completing a drug treatment program. When combined 

with behavioral therapies or counseling and other supportive services, 

these pharmacologic approaches are highly effective for treating heroin 

addiction, particularly in those with long-term dependence and repeated 

prior treatment failures.

Antagonist medications like naloxone and naltrexone block the effects of 

morphine, heroin, and other opiates. As antagonists, they are especially 

useful as antidotes. Naltrexone, with a duration of action ranging from 1 

to 3 days depending on the dose, blocks the pleasurable effects of heroin 

and is useful in treating some highly motivated individuals, such as 

professionals who do not want to lose their jobs. It is also successful in 

preventing relapse by former opiate dependent individuals released from 

prison on probation.

ALCOHOL ADDICTION

Antabuse (disulfiram) is used in the context of alcohol abuse treatment 

to cause negative effects when the patient consumes alcohol. The 

drug interferes with alcohol metabolism, causing the production of 

acetaldehyde, a noxious chemical that causes severe flushing, nausea, and 

vomiting. The effectiveness of therapy is dependent on patient adherence 

to a daily medication dose. Acamprosate (Putzke, 1996) is a newer drug 

currently used in Europe that increases alcohol abstinence and decreases 

craving by affecting g-aminobutyric acid and glutamate brain receptors. 

Naltrexone also has been found to decrease alcohol craving and relapse. It 

was approved in 1994 by the FDA for the treatment of alcohol dependence 

(Volpicelli, 1992; Anton, 1999).

COCAINE ADDICTION

There are no effective medications for treating cocaine addiction but 

in some cases treating comorbid mental health problems may improve 

chances of stopping cocaine use in the cocaine or crack-dependent 

person. Pharmacologic therapies have been specifically targeted at 

decreasing the dysphoric effects of cocaine withdrawal. Unfortunately, 

studies examining antidepressant medications targeting numerous 

neuron targets and multiple generations of antidepressant medications 

such as fluoxetine, sertraline, maprotilene, phenelzine, trazodone, and 
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lithium have not proven successful in assisting a person to permanently 

stop cocaine or crack use (McCance, 1997). Dopaminergic agents such as 

bromocriptine, amantadine, haloperidol, bupropion, and others have also 

not been proven to be effective. However, in studies using desipramine, 

carbamazine, and bupropion, the mental health effect of these drugs 

was clinically helpful for a patient’s successful drug cessation in drug 

treatment programs (Kranzler, 1999).

DETOXIFICATION

Detoxification is used either to prevent serious medical or psychologic 

complications of drug withdrawal from alcohol or sedative hypnotics or to 

ease the symptoms of withdrawal from the other drugs that do not have 

withdrawal syndromes with any significant morbidity or mortality (all other 

drugs of abuse) (Prater, 1999). In either case, detoxification protocols are 

not treatments for drug use but are part of a drug use treatment strategy.

Detoxification of alcoholics and sedative hypnotic users will prevent severe 

and sometimes fatal complications of drug withdrawal. For alcoholics, 

chlordiazepoxide (Librium) sedation is an important part of patient therapy. In 

most persons with alcohol dependence detoxification with a benzodiazepine 

can be completed on an outpatient basis with supportive care. However, about 

10% of alcohol-dependent persons will have sufficiently severe withdrawal 

symptoms, histories of withdrawal complications, or other comorbid illnesses 

that require in-patient management. If a woman is pregnant, Librium should 

not be used. Alternative medications, especially for persons with severe liver 

disease are lorazepam (Ativan) and oxazepam (Serax). In conjunction with the 

sedatives, thiamine to prevent Wernicke-Korsakoff syndrome and clonidine 

or β-blockers to control noradrenergic symptoms may be helpful. Withdrawal 

from sedative hypnotics is characterized by severe, chronic anxiety, which 

may need long-term controlled, tapering doses of sedatives. Carbamazine 

(Tegretol) and valproic acid have also been used to control anxiety in sedativehypnotic patients (Eickelberg, 1998).

Detoxification for other types of drug abuse is useful for diminishing the 

symptoms of drug withdrawal but does not have any long-lasting beneficial 

effect on the drug user. For example, clonidine (Gold, 1979) and lofexidine 

(Bearn, 1996) are used in this way because they decrease the adrenergic 

symptoms of opiate withdrawal. These measures are short term and do 

not address the true underlying problems of drug use. Even though the 

effects of detoxification are only short term, it is one of the few drug use 

interventions reimbursable in most health systems (O’Brien, 1997).

NEW PHARMACOLOGIC APPROACHES

The combined use of antagonist-agonist medications has been evaluated for 

drug treatment, with the biologic objective of preventing activation of opiate 

receptors and other drug use–related cell receptors. Research has found that 

treating nicotine-addicted persons with mecamylamine prevents smoking 

relapse (Rose, 1994). This may be a useful adjunct therapy for persons in 

tobacco cessation programs.
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Anticraving medications are used to prevent a person from wanting to take 

the drug. The biology and psychology of craving and its prevention are not 

well understood but it has been proven to be effective in treating addiction 

to nicotine. Bupropion (Wellbutrin, Zyban), an antidepressant medication, 

has been successfully used to treat cigarette craving (Ferry, 1999).

Vaccines against addictive drugs are intended to block the binding of 

illicit drugs to their cellular receptors. Although no vaccines are currently 

available for human use, there is evidence that a vaccine against cocaine 

may be possible to develop. Much future research is planned in this area.

C. COGNITIVE/BEHAVIORAL INTERVENTIONS

Behavioral and cognitive interventions are a vital part of drug and alcohol 

addiction treatment and prevention. Cognitive-behavioral therapies are based 

on the assumption that learning processes play an important role in the 

development of drug use and dependence and therefore are important in 

efforts to reduce use and dependence. Behavioral methods are employed to 

identify high-risk relapse situations, extinguish triggers to drug use, develop 

self-monitoring of use behavior, and establish competing coping responses. 

By learning to recognize situations conducive to substance use, patients can 

develop individual coping strategies to avoid circumstances that place them at 

risk for relapse. Perhaps the single most important factor for short- and longterm relapse prevention is the learning and application of individual coping 

skills. Avoidance of other drug users and drug use environments are key tools 

for maintaining abstinence. Brief interventions with as little as 5 minutes of 

education and counseling about safe drinking guidelines, the consequences 

of alcohol on health, the patient’s medical status, and the improvements 

that may occur if alcohol use is stopped or reduced, have been shown to 

be effective in reducing alcohol consumption and its medical and social 

consequences in general medical settings and may be of use in HIV clinics as 

well (Petry, 1999). Five to 15 minute interventions have also been shown to be 

effective in increasing smoking cessation rates (Dolan-Mullen, 1999).

There are at least 11 research-validated therapies using a variety of 

behavioral, social, and incentive-based systems to treat drug use (NIH, 

1999). The objectives of the different programs include removing patients 

from stressful environments to get care (short-term and long-term 

residential homes), providing alternatives to pharmacologic treatment 

(outpatient drug-free programs), and providing community-specific 

interventions (community-based programs for drug users and recently 

released criminals). There are several psychotherapy programs, based on 

the patient’s willingness to recognize drug use as a problem and to stay off 

drugs, with or without incentives.

The 12-step self-help groups/meetings are important nonmedical, 

behavioral drug use intervention and prevention activities used by 10–15 

million Americans in 500,000 or more groups (Goldsmith, 1989). These 
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meetings emphasize fellowship and provide support for maintaining 

abstinence from alcohol, other drugs, or addictive behaviors like overeating. 

These programs are not intended to replace medical and behavioral drug 

use treatments but are meant to add to their effectiveness. The largest 

12-step groups are Alcoholics Anonymous; Narcotics Anonymous, for all 

drug users including alcoholics; Al Anon, to support family and friends of 

alcoholics and drug users; and Overeaters Anonymous (Chappel, 1999). 

In 1976, Women for Sobriety was established as a 12-step program to 

help women, when it was recognized that Alcoholics Anonymous did 

not address adequately the specific needs of alcohol-dependent women 

(Katkulas, 1996). Rational Recovery, a self-help group based on cognitive/

behavioral principles, is also available in many large cities.

X. PREDICTORS OF DRUG TREATMENT RETENTION AND THE 

DURABILITY OF TREATMENT GAINS

Predictors of treatment retention include high motivation, legal pressure, 

receiving psychologic counseling while in treatment, no prior violations 

of the law, and an absence of other psychologic problems (NIDA, 1998). 

Specific characteristics, such as injection drug use, age, race, socioeconomic 

status, level of education, and occupation do not predict adherence to 

drug treatment programs. The most accurate predictors of drug program 

retention and medication adherence are health care beliefs, health care 

access, familiarity of the treatment setting, availability of case management 

social support, and perceived support from the clinical staff.

Provider and patient recognition of the chronic nature of drug addiction 

and the need for long-term treatment is essential to successful and durable 

addiction care. It has also been shown that lasting reductions in drug use 

are greater for patients who remain in treatment for a minimum of 3 mo 

or longer (Simpson, 1997) and are treated with a combination of medical, 

behavioral and cognitive treatments.

Available treatment options continue to expand, providing therapeutic 

combinations that, when appropriately matched to patients’ specific 

treatment needs, can increase the patient’s chances of staying drug-free 

(McLellan, 1997). Treatments taking care of a patient’s specific social and 

personal needs increase an individual’s chances of successfully completing 

the treatment program and have improved posttreatment outcomes. 

Treatment for women that is woman-focused and targets the unique needs 

of women, including their children; interpersonal, cultural, and contextual 

issues; and employment and housing considerations are also known to 

increase effectiveness (Metsch, 1995). Participation in these programs 

enables women with children to develop stronger life and social skills to 

ensure stable independent living practices (Hughes, 1995).
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XI. RELAPSE

Drug addiction is a chronic disease characterized by periodic drug use 

relapses. Although many treated persons relapse, it is wrong to conclude 

that treatment has failed or that the individual is hopeless. Like diabetes, 

hypertension, or other chronic diseases, the individual with a substance 

abuse problem will need frequent and long-term follow-up to maintain a 

drug-free state. Not surprisingly, simultaneous treatment for concurrent 

medical, mental health, and drug use problems offers significantly higher 

rates of success. The interventions that successfully address comorbidity 

maximize linkages between school, community, clinic, and other health 

service delivery systems. Woman-focused HIV prevention interventions 

include overcoming gender, cultural, and power barriers that increase 

risks, such as learning negotiation strategies for gaining partner 

acceptance for condom use, dealing with parenting responsibilities, and 

resolving interpersonal conflicts. The relative success and durability of 

approaches that have multiple and mutually reinforcing outcomes depend 

on coordination among professional and material resources in a rational, 

systematic, and cost-effective manner.

Treatment should be judged by the same criteria used for other chronic 

disease interventions: Will it help lengthen the time between relapses, 

ensure the individual can function in society, and minimize long-term 

physical damage?

XII. SUBSTANCE ABUSE IN PREGNANCY

It is difficult to determine the true prevalence of substance abuse by 

pregnant women. Stigma, criminal laws regarding child endangerment, 

and denial all contribute to the epidemiologic conundrum. Crosssectional studies at large urban centers, given the high-risk populations 

served, may overestimate community drug use health problems. In 1990, 

a Centers for Disease Control and Prevention study in Rhode Island 

revealed a statewide prevalence of illicit drug use of 7.5% (CDC, 1990). A 

cross-sectional study in Florida revealed that 15% of unselected women 

had evidence of recent drug or alcohol use on urine toxicologic screening 

(Chasnoff, 1990). Punitive approaches to the problem of substance abuse 

during pregnancy risk threatening privacy rights. These approaches 

further serve as deterrents to health-seeking behavior, and may further 

threaten the health of women and children.

The sequelae of substance use in pregnancy is beyond the scope of this 

chapter, however, a few specific drugs will be highlighted.

Smoking tobacco during pregnancy is associated with increased perinatal 

mortality, bleeding complications in pregnancy, low birth weight infants 

and preterm delivery and a possible increase in behavioral and learning 

problems among school-aged children whose mothers smoked during 

pregnancy (ACOG, 1997; Milberger, 1996). It is estimated that there could 

be as much as a 10% reduction in fetal and infant deaths if all pregnant 

women stopped smoking (Kleinman, 1988).
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Alcohol use in pregnancy is associated with risk of fetal alcohol 

syndrome. This congenital syndrome is characterized by three findings: 

growth retardation, facial abnormalities, and central nervous system 

dysfunctions. Skeletal abnormalities and structural cardiac defects 

are also seen in the fetal alcohol syndrome, but it is the performance 

deficits that are most obvious. Decreased IQ, fine motor dysfunction, and 

hyperactivity are all common findings (ACOG, 1994).

Cocaine use in pregnancy poses maternal as well as fetal hazards. Some 

of these stem from the intense vasoconstriction associated with cocaine 

(malignant hypertension, cardiac arrhythmias, and cerebral infarction). 

Cocaine has been associated with premature rupture of membranes, 

preterm labor and delivery, growth retardation, cognitive development 

delays, and placental abruption. There are also documented cases of in 

utero fetal cerebral infarction (MacGregor, 1987).

Opiate addiction during pregnancy also poses serious risk to the mother 

as well as the fetus. Newborn infants of narcotic-addicted mothers are 

at risk for several complications, including the potentially fatal narcotic 

withdrawal syndrome. Withdrawal syndromes may appear 24 hr after 

birth, but may be delayed as long as 10 days after birth (Levy, 1993).

Beyond the medical ramifications for the mother and the fetus, substance 

abuse in pregnancy raises the specter of the legal system. There have 

been at least 200 women, in 30 states, criminally prosecuted for using 

illicit drugs or alcohol during pregnancy (Jos, 1995). Actions such as these 

have the potential to turn the provider into a law enforcement officer, and 

ultimately to drive away from prenatal care the very women who most 

need it. The conundrum of substance abuse in pregnant women and how 

society can best approach the problem continues. Providers should focus 

on screening and assessment of substance abuse and referral of pregnant 

women with drug and/or alcohol abuse into care and treatment.

XIII. ANTIRETROVIRAL THERAPY IN SUBSTANCE ABUSERS

There is often a lack of compassion toward people who have contracted 

HIV through stigmatized behavior, such as drug use (Hajela, 1998). Such 

sentiments are compounded by perceptions about adherence among 

drug users and the threat to public health associated with nonadherence 

leading to multidrug-resistant strains of HIV or other infectious diseases 

(Gourevitch, 1996). These assumptions may lead to blanket denial of 

appropriate antiretroviral therapy to individuals with a past or current 

history of substance abuse.

Although active substance abuse (including alcohol, cocaine, and heroin) 

is associated with nonadherence, patient readiness for antiretroviral 

therapy must be carefully assessed on an individual basis, and those who 

have been treated for drug dependence may be even more adherent than 

the general population or other medical groups. However, drug users are 

less likely to receive care, and injection drug users are among those least 

likely to receive antiretroviral therapies even when these treatments 
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are available and free (Shapiro, 1999). Demographic characteristics of 

patients, including race/ethnicity, sex, age, and socioeconomic status are 

generally not predictive of medication adherence, although depression 

and low literacy have been associated with poorer adherence to HAART 

(Stone, 2001). Another challenge in the management of HIV infection 

in a substance-abusing woman is to recognize the potential for drug 

interaction between methadone, as well as street drugs, and antiretroviral 

therapies. The clinical experience in this area is limited; however, there 

are well-recognized drug interactions between certain antiretroviral 

therapies and methadone. Of the nucleoside reverse transcriptase 

inhibitors, only abacavir has been associated with an increase in 

methadone clearance. Both nevirapine and efavirenz are associated with 

significant decreases in the methadone level with opiate withdrawal a 

common consequence. As this increases the potential for heroin relapse, 

it is essential that this potential outcome be discussed with patients in 

advance of the prescribing of these therapies, with a clear plan to address 

this possibility with the patient’s drug treatment provider (ie, increasing 

methadone dose). Alterations in methadone levels have been seen with 

the protease inhibitors; however lopinavir/ritonavir has been associated 

with decreases in methadone levels and subsequent opiate withdrawal 

(see Table 10-9). 

With newer ARV agents and dosing schedules allowing once-a-day 

antiretroviral regimens, the possibility of directly observed therapy 

(DOT), particularly in the setting of methadone clinics, offers a practical 

solution to concerns about adherence for patients in these settings.

Table 10-9: Drug Interactions Between Antiretroviral Drugs 

and Methadone

Drug Effect Recommendation

Nucleoside Reverse Transcriptase Inhibitors

Zidovudine (ZDV) No data Unchanged

Lamivudine (3TC) No change in drug 

concentrations

Unchanged

Didanosine (ddI) EC ddI level unchanged; 

buffered ddI AUC decreased 

63%

No change EC ddI; may 

consider increase in buffered 

ddI dose or maintain standard 

dosing

Stavudine (d4T) D4T level decreased 27% No dose adjustment

Zalcitabine (ddC) No data Unchanged

Abacavir (ABC) Increase in methadone clearance Close clinical monitoring; may 

require increase in methadone 

dose
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Table 10-9: Drug Interactions Between Antiretroviral Drugs and 

Methadone (continued)

Drug Effect Recommendation

Nucleotide Reverse Transcriptase Inhibitors

Tenofovir (TDF) No data Unchanged

Non-nucleoside Reverse Transcriptase Inhibitors

Nevirapine (NVP) NVP level unchanged; 

methadone level significantly 

decreased

Close clinical monitoring; may 

require increase in methadone 

dose

Efavirenz (EFV) Methadone level significantly 

decreased

Close clinical monitoring; may 

require increase in methadone 

dose

Delavirdine (DLV) No data Unchanged

Protease Inhibitors

Indinavir (IDV) No change in methadone levels Unchanged

Ritonavir (RTV) Methadone level decreased 

37%

Close clinical monitoring; may 

require increase in methadone 

dose

Saquinavir (SQV) Methadone AUC decreased 

20%, when co-administered as 

SQV 400 mg bid

No dose adjustment for 

this regimen, but monitor 

and titrate to methadone 

response, if necessary

Nelfinavir (NFV) NFV may decrease methadone 

levels, but minimal effect on 

maintenance dose

Close clinical monitoring; may 

require increase in methadone 

dose

Amprenavir (APV) Methadone level decreased 

13%; APV Cmin decreased 25%

Monitor and titrate 

methadone if needed

Fos-Amprenavir 

(fAPV)

Presumably similar interaction 

to APV

Monitor and titrate 

methadone if needed

Lopinavir (LPV) Methadone AUC decreased 

53%

Close clinical monitoring; may 

require increase in methadone 

dose

Atazanavir (ATV) No data Unchanged

AUC area under the curve concentration

Cmin trough level

EC enteric-coated

Source: Adapted from Table 21, DHHS, 2004.

XIV. CRIMINAL JUSTICE SETTINGS

Women are the fastest growing segment of the prison population, and their 

drug-related crimes are increasingly more serious (FBI, 1997). Criminal 

justice reports show that substance use is implicated in the incarceration 

of 80% of men and women in state, federal, and local prisons. Persons 

either violated drug laws, stole property to buy drugs, have a history of 

substance abuse or addiction, or engaged in some combination of these 

(Maruschak, 1997). The more prior convictions an individual has, the 

more likely s(he) is to be drug dependent.
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The most serious offense for 40% of women in state and federal prisons 

is the violation of drug laws. The enactment of mandatory sentencing 

policies has been associated with a 10-fold increase in the number of 

women incarcerated for drug crimes between 1986 and 1996.

Statistics show alcohol present in 31% of crimes, a combination of alcohol 

and other drugs in 16%, and other drugs alone 9%. A recent study 

confirms that alcohol has a high association with violent crime: twentyone percent of violent felons in state prisons committed their crimes 

while under the influence of alcohol alone.

State officials have estimated that 70–85% of inmates need some level 

of substance abuse treatment; however, only about 13% actually receive 

treatment (Harlow, 1997). Those individuals with substance abuse 

histories are also more likely to have a history of physical and sexual 

abuse (National Minority AIDS Council, 1997). Criminal justice reports 

attribute the overwhelming majority of AIDS cases among inmates to 

injection drug use, with an incidence of new AIDS cases among inmates 

17 times higher than that in the general population.

Inmates who have received appropriate treatment in prison are 50–60% 

less likely to be arrested again during the first 18 mo after release. For 

each offender who successfully completes treatment and returns to the 

community as a sober citizen with a job, it is estimated that reduced crime 

and arrest, prosecution, and incarceration costs, health care savings, and 

potential earnings accrue in the first year after release (Califano, 1998). 

One study found that total savings can exceed costs by a ratio of 12 to 

1; another found that for every $1 invested in drug treatment, there is a 

return of up to $7. Levels of criminal activity have also been shown to 

decline by two thirds from the period before treatment to a comparable 

period after treatment.

XV. CONCLUSION

Drug and alcohol abuse have strong associations with HIV and other 

comorbid medical and psychiatric problems. Substance abuse may 

increase risk for HIV and other STI acquisition/transmission; may delay 

identification of HIV and entry into care; and may complicate management 

of HIV and other disorders. Women with substance abuse problems have 

special needs and require unique approaches to management. Health care 

providers should screen all women (including pregnant women) for drug 

and alcohol use/dependence and be knowledgeable about appropriate 

referrals and linkages. HIV prevention and treatment interventions 

should be part of comprehensive substance abuse treatment services and 

all HIV-infected women with drug and/or alcohol abuse problems should 

have access to substance abuse treatment.
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Adolescence is a time of significant cognitive, emotional, and 

physical development and is often characterized by exploration and 

experimentation. As adolescents explore intimacy and sexuality 

and develop autonomy, it is also a time of heightened vulnerability, 

including risk for HIV infection. This chapter focuses on young 

women as it reviews the epidemiology of HIV/AIDS in adolescents 

and provides guidelines for HIV counseling and testing, medical 

|and psychosocial care, and strategies for linking HIV-infected and 

at-risk youth to care.

I. EPIDEMIOLOGY

Adolescents are at high risk for HIV infection. Worldwide, one out of 

every two new cases of HIV—half of 5 million new infections 

in 2001—occurred in youth ages 15–24. In developing countries, 

women are becoming infected at significantly younger ages 

than men, with a higher percentage of young women in 

their teens and early twenties having HIV than women in 

any other age groups (UNAIDS, 2002). In the United States, 

(CDC, 2001) more than half (53%) of adolescents newly infected 

with HIV are female, and 50% of all new infections, or some 

20,000 new cases per year, are estimated to occur in youth 

ages 13 to 24. In addition, 19% of U.S. AIDS cases are reported in young 

adults in their twenties. Given a 10-yr period, on average, from initial 

infection to clinical manifestations of AIDS, most of these young people 

were likely infected during their teens.

Compared with adults, female adolescents represent a much higher 

proportion of HIV/AIDS cases. In 2001, adolescent girls ages 13–19 yr 

accounted for 48% of incident adolescent AIDS cases, whereas female 

adults made up 26% of incident adult AIDS cases. At highest risk are 

African American youth, who made up 66% of cumulative teen HIV 

cases through 2001, while representing only 15% of the U.S. adolescent 

population (CDC, 2001).

A. SEXUAL RISK

The majority of adolescent females (51%) with AIDS were infected 

through heterosexual intercourse. Moreover, an additional 30%, who 

are classified as having “no identified risk” because they were unable 

to identify their partners’ risk, are also assumed to have been infected 

through heterosexual encounters (CDC. 2001). This is consistent with 

XI. ADOLESCENTS1

Donna Futterman, MD

1 This article was adapted with permission from a 2-part series that appeared in the AIDS Clinical Care February and 

March 1999 issues: Chabon B, Futterman D. Adolescents and HIV. AIDS Clin Care 11:9–16; Hoffman ND, Futterman D, 

Myerson A. Treatment issues for HIV+ adolescents. AIDS Clin Care 11:17–24.
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widespread lack of awareness of their potential risk for HIV infection 

among sexually active adolescents and adult women. For example, of 

adolescents known to be HIV positive, 75% of young women are unable 

to identify their partners’ risk factors (Futterman, 1993). Furthermore, for 

many adolescents “having sex” means heterosexual vaginal intercourse 

and some adolescent females may engage in receptive anal intercourse in 

the belief that this preserves their virginity and is safer (Haglund, 2003). 

A much smaller proportion of female youth (13% of 13–19-yr-olds and 

25% of 20–24-yr-olds) were infected through injection drug use, compared 

with 39% of adult women with AIDS. Adolescents who were infected 

perinatally account for a small but growing number of adolescents with 

HIV/AIDS, and some are not diagnosed until adolescence.

Clinicians working with adolescents have noted additional risk factors for 

youth. A significant proportion of adolescents with HIV have experienced 

childhood sexual abuse; of adolescents screened at the Adolescent AIDS 

Program at Montefiore Medical Center, 25–40% report having been 

sexually abused (Futterman, 1993). Childhood sexual abuse has been 

associated with subsequent feelings of powerlessness in sexual situations 

and increased risk for unsafe sexual activity.

Moreover, 20% of sexually infected HIV-positive youth seen in an 

adolescent program reported having a parent who is also HIV-infected 

(Chabon, 2001). Further research is needed to assess parental influence 

on their children’s HIV status. Nevertheless, children of parents with 

HIV generally live in the same high-prevalence neighborhoods as their 

parents and may also face increased risk as a sequela of parental illness 

or substance abuse. Clinicians should ascertain a history of sexual abuse 

or forced sex as well as parental HIV history when taking a history with 

adolescents.

B. SEXUALLY TRANSMITTED INFECTIONS AND PREGNANCY

Sexually active teens are also at risk for pregnancy and other sexually 

transmitted infections (STIs). According to the 2001 Youth Risk Behavior 

Survey, nearly half (43%) of all U.S. female high school students are 

sexually active (including 60% of 12th-graders), and 9% report having been 

pregnant (CDC, 2002). Approximately 1 million teens become pregnant 

each year, 74–85% of them unintentionally. Both STIs and pregnancy are 

markers for unsafe sexual activity and, in addition, STIs (both ulcerative 

and inflammatory) increase susceptibility for HIV infection. Two thirds of 

the 12 million cases of STIs reported in the United States each year occur 

in youth under age 25, and 1 out of 4 are reported in adolescents. Younger 

teens, particularly females, are least likely to be considered at risk or to be 

screened, particularly if they are asymptomatic, which is the case with the 

majority of STIs in women. For example, chlamydia is asymptomatic in 

three fourths of infected women, whereas approximately half of gonorrhea 

infections in women have no symptoms. This is especially salient because 

adolescent women have the highest age-specific incidence rates for both 

gonorrhea and chlamydia; 79% of reported cases of chlamydia occur in 

young women (46% in 15–19-yr-olds and 33% in 20–24-yr-olds).
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C. HEIGHTENED VULNERABILITY FOR INFECTION

Adolescents are at risk for HIV and STIs as a result of the interplay 

between behavioral, biological, and socioeconomic factors (Institute of 

Medicine, 1997).

BEHAVIORAL RISK

During adolescence, sexual activity is often initiated, risk-taking and 

experimentation are normative, and many sexually active adolescents 

fail to take appropriate prevention precautions, despite basic knowledge 

of HIV transmission and prevention. During their last sexual encounter, 

nearly half of 9th-through 12th-grade girls did not use condoms, whereas 

11% reported having more than 3 sexual partners. Many teens follow a 

pattern of sexual “serial monogamy” and may not consider themselves 

as having multiple partners. More than 1 in 5 (20–24%) of female high 

school students report episodic heavy drinking or current marijuana 

use, which can impair judgment and increase potential for high-risk 

behaviors. Most high school seniors have used alcohol, and 1 out of 4 

students report having 5 or more drinks at least once during the past 30 

days. About 25% smoke marijuana, 15% report using inhalants, and more 

than 1 in 50 have injected illegal drugs (CDC, 2002).

Specific populations of teens are at especially high risk, including 

adolescents who are lesbian, bisexual and transgender, homeless or 

runaway, injection drug users, mentally ill, and youth who have been 

sexually or physically abused, incarcerated, or in foster care. These 

youth experience increased vulnerability and multiple health and social 

problems as a result of abuse and neglect and lack of services and care. 

Lesbian and bisexual females may view themselves at lower risk but 

those who are sexually active with gay male peers are at risk for infection 

because of higher HIV prevalence among gay males (Ryan, 1998).

BIOLOGICAL RISK

Several biological factors also contribute to heightened risk in adolescent 

females. During puberty, the cervix undergoes physical maturation 

that makes the cellular lining less susceptible to infection as the 

single-layer columnar epithelium of the cervix is replaced with thicker 

multilayered squamous cells. Until this occurs, the cervix is much more 

vulnerable to STIs, particularly chlamydia and gonococcus, which have 

an affinity for columnar cells and have also been shown to facilitate STI 

transmission. At the same time, male-to-female transmission of STIs is 

much more efficient than female-to-male transmission given the larger 

surface area of the lower female genital tract and mechanics of sexual 

intercourse, which can result in mucosal trauma to women. In addition, 

STIs which facilitate HIV transmission are more likely to remain 

asymptomatic in women, and thus unrecognized and untreated, for a 

longer period of time.
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SOCIOECONOMIC RISK

Adolescents are the most uninsured and underinsured group in the 

United States and are the least likely to receive office-based medical 

care or to use primary care services. Twenty-five percent of youth ages 

15–29 have no health insurance and approximately 1 in 5 suffers from 

at least one serious health problem. Poverty, poor access to care, and 

lack of education and prevention skills further increase vulnerability 

to HIV. Additional barriers include mistrust of the health care system, 

fear of inappropriate disclosure, and providers’ lack of understanding of 

adolescent rights to confidentiality and care without parental consent for 

sensitive health issues.

Moreover, many adolescents use emergency and walk-in facilities for 

acute care needs. As a result, they lack a primary care provider who can 

ensure ongoing care and address prevention and health promotion needs. 

Because adolescence is a time when help-seeking behaviors and attitudes 

about health and self-care are formed, the experiences adolescents have 

with health care providers are especially important. They form the basis 

for future provider-client interaction, communication patterns, and 

relationships.

II. HIV CARE FOR ADOLESCENTS

Cornerstones of adolescent care include consent policies, confidentiality, 

accessibility, outreach, and linkage to care and prevention. Even though 

youth prefer health care settings that are geared to their needs, most teens 

will not receive care in adolescent programs. Although most facilities are 

unable to offer the ideal “one-stop shopping” for teens, quality care can be 

provided by identifying a staff member and/or provider team who wants 

to work with adolescents and by adapting adult and family programs to 

meet an adolescent’s needs. This can be done by accommodating walkins because youth do not often plan ahead, addressing payment barriers, 

and providing flexible appointments that will not conflict with school or 

work.

A. CONFIDENTIALITY AND LEGAL ISSUES

All states have laws that allow minors to consent to treatment without 

parental consent for specific health services including emergency care, 

STIs, or reproductive health and substance abuse treatment services. 

In many, but not all, states, this includes the right to consent for HIV 

counseling and testing. However, not all providers are aware of these 

rights or understand their significance for adolescents, and these rights 

vary by state and the medical service provided. Most importantly, lack 

of confidentiality may cause adolescents to avoid or delay needed care. 

Even though parental consent may not be needed to provide an HIV test 

or HIV-related care, providers should carefully assess an adolescent’s 

cognitive capacity to understand the implications of having HIV disease 

and should encourage them to involve a supportive adult in their care.
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B. COUNSELING AND TESTING

Although most youth do not think they are at risk for HIV infection, 

they prefer providers to initiate discussion concerning HIV prevention 

and risk assessment. All adolescents should receive HIV prevention 

education, and sexually active adolescents should routinely receive HIV 

counseling and be offered HIV testing with informed consent (Committee 

on Pediatric- AIDS, 2001). This enables providers to identify HIV-positive 

youth and provide ongoing medical care and support services, while 

relieving anxiety and reinforcing preventive behaviors for youth who are 

HIV negative. For adolescents who are not sexually active, counseling 

provides an opportunity to talk about sexual readiness, delaying 

intercourse, and low-risk ways to explore intimacy. New protocols for 

rapid, simple HIV counseling and testing are being developed for use in 

health care settings (www.adolescentaids.org; CDC, 2003). 

New testing options such as those that test for antibodies in oral fluids 

or urine are helpful with youth who are afraid of needles and allow 

providers to offer testing in a variety of settings including mobile vans, 

school-based clinics, and drug treatment programs. Same-day testing is 

now FDA approved and is useful by eliminating the need for a return 

visit for results, but will require careful planning for the delivery of HIVpositive results. Meeting adolescent needs for flexibility, accessibility, 

and low- or no-fee HIV testing is important in overcoming primary 

barriers to accessing care and can serve as an entry point to care. Like 

other underserved populations, adolescents are generally diagnosed with 

HIV/AIDS late in the course of illness, relatively few receive care for HIV 

disease, and most do not know they are infected. Thus, ensuring access to 

HIV counseling and testing is essential in enabling adolescents to receive 

ongoing treatment and care.

Although counseling and testing for adults has generally been based 

on one initial pretest counseling session with providers, a “one-shot” 

approach to counseling is not effective with all at-risk youth. Two short 

counseling sessions before testing, using personalized risk reduction 

plans, can increase condom use and prevent new HIV and other sexually 

transmitted infections. Pre- and posttest counseling provide an opportunity 

to promote preventive health behaviors and to assess substance use 

and family planning needs, while providing basic information on HIV, 

obtaining consent, and conducting a comprehensive risk assessment 

(Table 11-1). More extensive guidelines are also available for adolescent 

HIV counseling and testing in all health settings (Chabon, 1998). Because 

adolescents may have misconceptions about aspects of HIV transmission 

and prevention, providers should assess their capacity to understand 

basic concepts of HIV disease and viral transmission. Effective HIV 

counseling for adolescents should be culturally sensitive and tailored to 

an adolescent’s developmental needs. In addition, providers should take 

special precautions to ensure confidentiality in institutional settings such 

as foster care, residential treatment, or detention.
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Table 11-1: Teen AIDER (Assess, Inquire, Discuss, Educate, 

Readiness) Interview for HIV Counseling, Testing, 

and Risk Reduction

Assess and Inquire

Create a confidential atmosphere

• Assure youth about confidentiality of visit and ability to consent for testing per local 

laws

• Assure youth that testing is their choice

• Acknowledge that it can be embarrassing to discuss sexual behaviors

• Help youth to identify supportive adult who is aware that youth is being tested

HIV/AIDS Knowledge

• Allow adolescent to verbalize understanding of HIV, clarify misconceptions, and fill in 

gaps in knowledge

• Assess feelings about testing and previous HIV testing experiences

• Inquire if youth knows anyone with HIV/AIDS (e.g., sexual partner, family member)

Sexual Risk Assessment

• Assess sexual behaviors without making assumptions about sexual orientation; not 

all youth are heterosexual and not all youth who have engaged in same-sex behavior 

self-identify as lesbian or gay

• Assess number of partners, age differential, and partner’s known risks

• Assess frequency of substance use in the context of sexual behavior

• Assess consistency of condom use and obstacles to use such as unassertiveness, 

desire to become pregnant, fear of violence, and religiosity

• Assess for history of sexual abuse or rape

Substance Use and Other Risk Assessment

• Assess level of drug and alcohol use and reasons and context in which use occurs

• Review risk of impaired judgment that may lead to unsafe sex

• Assess potential need for drug treatment

• Assess violence and substance use in home and community

Discuss and Educate

• Discuss abstinence

• Discuss sexual activities that don’t involve exchange of body fluids (outercourse)

• Demonstrate proper male condom, female condom, and dental dam use on 

anatomical model and provide opportunity for practice

• Rehearse effective ways to communicate risk reduction with sexual partner(s)

• Discuss harm-reduction strategies for youth using drugs

• Develop a personalized risk-reduction plan

• Discuss postponing sex for youth who are not sexually active

• Determine referral needs (e.g., medical, psychosocial, school/vocational, substance 

abuse, reproductive health, legal, housing, psychiatric)

Readiness For HIV Testing and Referral

• Adolescent should be informed about both anonymous and confidential testing

• Provide education about partner notification programs and other options for 

disclosure to partners

• Assess understanding of meaning of a positive and negative test result

• Assess understanding of benefits of early intervention

• Determine with youth if testing should occur at this time and obtain 

informed consent

• Strategies for coping (how to relieve stress and anxiety during the testing process)

• Arrange follow-up appointment and method for confidentially contacting youth, 

if needed

Source: Adapted with permission from: Chabon B, Futterman D. Adolescents and HIV. AIDS Clin Care 

11: 9–16, 1999.
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Knowledge of appropriate condom use and widespread availability of 

condoms are especially important in promoting risk-reduction behaviors 

among youth. All facilities that provide health care for adolescents should 

make condoms available and providers should demonstrate condom use 

with anatomical models. Adolescents have difficulty using condoms 

during intercourse for several reasons, including: 1) lack of knowledge 

about effective use; 2) lack of communication and social skills; 3) lack of 

availability of condoms at the time of sexual activity; and 4) impulsive 

behavior exacerbated by drug or alcohol use. Gender and power 

imbalances in relationships make condom use especially difficult for 

adolescent women whose partners are older and who are just beginning 

to develop communication and negotiation skills. Helping youth identify 

their personal values may increase self-esteem and help them resist 

pressures to engage in sexual risk behaviors (Table 11-2).

Table 11-2: Factors Associated with Condom Use

Encourages Use Discourages Use

• Knowledge about condoms

• Belief in effectiveness

• Discussion with health care provider

• Self-esteem/self-efficacy

• Communication/negotiation skills 

• Availability/accessibility 

• Drug/alcohol use

• Relationship power imbalances

• Peer pressure

• Lack of effective sex education

• Lack of media/cultural support

C. PREVENTION

Promoting abstinence and risk reduction among adolescents is especially 

challenging because developmental characteristics encourage concrete, 

short-term thinking and experimentation and increased reliance on 

peers. Thus, successful primary and secondary programs for adolescents 

are those that provide interventions to increase self-esteem and selfefficacy, build social skills, and provide basic information geared to 

the adolescent’s developmental level, using a peer support model. For 

high-risk youth, the AIDS Risk Reduction Model (Catania, 1990) has been 

widely used to foster primary and secondary prevention, based on the 

premise that behavior must first be acknowledged as risky before youth 

will initiate change.

School-based programs that provide comprehensive health education 

in conjunction with school health clinics offer optimal opportunities 

to reinforce positive health behaviors and ensure routine screening for 

a range of health and mental health concerns. But they are especially 

important in reducing risk and identifying sexually active youth who 

are at risk for STIs and pregnancy. A comprehensive review of schoolbased programs designed to reduce risky behavior in teens found that 

adolescents who received AIDS education were less likely to engage 

in sexual activity and more likely to practice safer sex than peers who 

lacked AIDS education in school (Kirby, 1994). In particular, successful 
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programs include skills building, reinforcement of values and norms to 

prevent unprotected sex that are based on age and experience levels, 

and discussion of social influence and pressure. School clinics also offer 

an important venue for access to condoms and appropriate instruction 

on condom use. Although not widely available, school clinics provide an 

important site for HIV counseling and testing for in-school youth, given 

new rapid testing options. Ultimately, successful prevention must also 

involve society and the media—until youth see abstinence, condom use, 

and safer sex discussions incorporated into sex scenes in music videos 

and movies, they will not believe that this is a social norm. 

Adolescents who are HIV-infected are also in need of risk reduction 

counseling to prevent transmission of HIV to uninfected sexual partners 

and to prevent acquisition of other STIs or reinfection with other 

HIV strains.

D. LINKING YOUTH TO CARE

Linking at-risk youth to care is essential in meeting their needs for 

risk-reduction education and appropriate ongoing HIV medical and 

psychosocial care. Barriers to care include stigma associated with HIV, 

lack of independent transportation, dependence on parents for health 

insurance or other financing for care, and feelings of vulnerability. Most 

HIV-infected youth do not know they are infected, and many providers 

are not aware of available community service agencies that can address 

their multiple mental health and social service needs. Community 

outreach is a primary component in ensuring access to care for youth 

with HIV disease. Peer-based outreach services are frequently employed, 

as adolescents are more likely to listen to their peers. Unlike adult 

women who have more opportunities to obtain HIV testing and to access 

care related to their reproductive health needs, adolescents who are not 

pregnant require proactive outreach efforts to promote HIV testing and 

engage them in care. This includes city-wide campaigns to encourage 

testing and to make it more widely available, with direct linkages to 

adolescent health care facilities. One such initiative — a social marketing 

campaign spanning the continuum from HIV prevention through testing 

to care — was developed by the Adolescent AIDS Program at Montefiore 

Medical Center in New York City in 1996. “HIV. Live with it. Get Tested” 

was designed with marketing experts, health providers, and most 

importantly youth themselves, to combine media advertisements such as 

posters and radio and TV ads with community outreach in settings where 

at-risk youth access information and are likely to congregate. Using teen 

language for sexual activity (e.g., “Knockin’ Boots” or “Gettin Busy”) to 

promote testing and care services through a coalition of adolescent HIV 

programs and community-based youth agencies, the initiative is intended 

to help adolescents link the concept of having sex with HIV risk and the 

importance of HIV testing. The initiative focuses annual activity around 

a “Get Tested! Week” launched with a youth-led Town Hall meeting and 

peer outreach (Futterman, 2001; www.adolescentaids.org).
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E. HIV CLINICAL AND PSYCHOSOCIAL CARE

Although the natural history of HIV infection in adolescence is still being 

defined, the course of disease appears to follow that of adults. A national 

prospective study with sites in 13 cities—AMHARN—was funded by NIH 

and HRSA to identify the course of disease in adolescents, including its 

spectrum, manifestations, effects of puberty, and developmental and 

psychosocial interactions (Rogers, 1998; Rudy, 2001). Initial findings 

suggest that adolescents may have greater potential for immune 

reconstitution than adults as a result of residual thymic function, which 

underscores the need for aggressive outreach efforts and access to early 

effective treatment and has also identified a high prevalence of sexually 

transmitted infection in this population.

PHYSICAL EXAM, LABORATORY TESTS AND IMMUNIZATIONS

Physical examinations for adolescents should follow guidelines used 

for adults; however, providers should use Tanner staging of puberty 

(characterizing breasts, genitalia, and pubic hair) to interpret blood values 

and prescribe medications (Schneider, 1998). Because sexually active 

adolescents are at very high risk for STIs, providers should routinely 

screen with cervical cytology, and for chlamydia, gonorrhea, syphilis, 

and hepatitis B and C, and follow tuberculosis screening guidelines for 

adults with HIV infection. Pregnancy testing should be performed when 

indicated by history or exam findings, but should always be considered 

with missed menses, abnormal bleeding, or development of pelvic 

pain. Adolescents require more immunizations than adults (Table 11-

3). Because immunizations may briefly boost viral load, they should 

be scheduled on the same day as or after viral load measurements. At 

present, CD4 counts and viral load measurements are interpreted as for 

adults and used to guide treatment.

Table 11-3: Immunizations for Adolescents

• Measles, mumps and rubella (MMR) booster

• Diphtheria-tetanus toxoid (dT) booster

• Hepatitis B vaccine (3 in series)

• Hepatitis A vaccine (2 in series) (not routine; recommended for males who have sex 

with males)

• Influenza (yearly)

• Pneumococcal vaccine

• HIB (optional)

• Varicella zoster vaccine for contacts (not currently approved for HIV+ persons)

Source: Reprinted with permission from: Hoffman ND, Futterman D, Myerson A. Treatment issues for HIV+ 

adolescents. AIDS Clin Care 11:17–24, 1999.
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HIV TREATMENT

Information from clinical trials is limited because few adolescents 

have participated in existing clinical trials. While adolescent trials are 

under development, HIV and opportunistic infection treatment and 

prophylaxis recommendations for postpubertal adolescents currently 

follow clinical guidelines for adults. Because pubertal changes may affect 

pharmacokinetics, dosage is based on Tanner staging rather than age. 

For example, pediatric dosing should be used for adolescents who have 

entered/are in early puberty (Tanner stage I/II), wherease dosing for 

adolescents in midpuberty (Tanner III/IV) should be based on whether 

or not they have completed the growth spurt. Adolescents who have 

completed puberty (Tanner V) should receive adult dosages.

Treatment adherence, which is challenging for adults, can be especially 

challenging for adolescents, who struggle with a range of developmental 

tasks that require them to balance dependence with increasing autonomy. 

As with any successful work with adolescents, the first step in promoting 

adherence is establishing a solid therapeutic alliance. Providers must 

develop a systematic approach that facilitates adherence by addressing 

four areas of interaction, including building trust, assessing and facilitating 

readiness, helping teens initiate and practice the new treatment regimen, 

and providing ongoing support for adherence (Table 11-4). This approach 

addresses barriers to maintaining a complex medication schedule for 

adolescents, such as lack of privacy in school, home, or residential 

settings, the need to develop a reminder system, and the incongruity of 

having a serious illness while exhibiting few visible indicators of disease. 

For example, the most common reasons for missing medication by youth 

in a Los Angeles adolescent HIV/AIDS program include forgetfulness, 

side effects, the inconvenience of having to take so many pills, and the 

fact that taking the medication is a continual reminder of being HIV 

infected (Belzer, 1998).

AMHARN has designed a multilevel adherence initiative, Project TREAT 

(Treatment Regimens Enhancing Adherence in Teens), to address 

medication adherence in adolescents. A monograph describing the model 

has been developed for providers and is available from HRSA (Schietinger, 

1999; Rogers, 2001). Based on Prochaska and DiClemente’s Transtheoretical 

Model of Change, Project TREAT acknowledges the uniqueness of each 

adolescent’s readiness for treatment. The model has developed specific 

interventions and materials (video and audio tapes and booklets) for each 

stage of readiness to facilitate successful adherence. (The Stages of Change 

are: Precontemplation, Contemplation, Preparation, Action, Maintenance, 

and Relapse.) Practice regimens with vitamins help youth rehearse their 

medication regimen, while enabling them to problem-solve potential 

barriers without risking underdosing. Medications must be integrated into 

the adolescent’s daily routine. Ideally, adolescents should be prescribed 

a daily or twice-daily medication regimen. Many providers also initiate 

treatment without using protease inhibitors; these are incorporated into 

later regimens after the adolescent has demonstrated effective adherence, 

to avoid risking potential cross-resistance to protease inhibitors.
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Table 11-4: Adherence: Using your EARS

Engage

• Establish therapeutic alliance and build trust; goal is active participation by adolescent 

in all aspects of treatment

• Address immediate needs (health, housing, insurance, family, and partners)

• Educate about HIV infection: transmission, disease course, and benefits of 

medications

Assess

• Stage HIV infection

• Assess mental health and cognitive abilities

• Assess physical ability to take medicines

• Assess support systems and disclosure issues: family and friends

• Assess readiness to begin medications

Readiness

• Decide with adolescent on regimen that integrates clinical needs with lifestyle—show 

different pills/combinations

• Solidify support systems: family and/or treatment buddy

• Practice chosen regimen with surrogate vitamins; distribute medications into a weekly 

medication planner, program one-day pill timer with the adolescent

• Address adherence barriers discovered in practice run

Support

• Provide ongoing support with frequent clinic visits and phone contact 

• Acknowledge and address side effects

• Develop strategies to ensure tolerability and regularity

• Facilitate interactions with other youth taking medications

Source: Reprinted with permission from: Hoffman ND, Futterman D, Myerson A. Treatment issues for HIV+ 

adolescents. AIDS Clin Care 11:17–24, 1999.

PSYCHOSOCIAL ISSUES

The Adolescent AIDS Program has identified five key issues that 

adolescents with HIV/AIDS must address in coping with their changing 

health status: 1) receiving an HIV diagnosis; 2) disclosing an HIV status 

to parents, partners, and others; 3) coping with HIV disease; 4) becoming 

symptomatic; and 5) preparing for death (Kunins, 1993).

1.Receiving an HIV diagnosis: Providers should instill a sense 

of hope and encouragement when giving adolescents an HIV 

diagnosis. Asymptomatic youth must learn to balance healthy 

denial and preoccupation with HIV infection. Concrete thinking 

makes it difficult for some youth to integrate the concept of 

disease latency and asymptomatic infection. Support is essential in 

helping youth integrate this life-changing information. Individual 

and peer group interventions with psychologists and social workers 

can help facilitate adjustment. Psychotropic medication may be 

needed to manage preexisting psychiatric problems and for anxiety 

and depression that may accompany the diagnosis.

2.Disclosure of HIV status: After learning their diagnosis, 

adolescents must decide who to inform and when to disclose their 

HIV status. Telling their parents is difficult for many adolescents 

who fear losing their love and support. Fear of rejection and loss 
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of confidentiality is also a concern in disclosing to sexual partners. 

Providers should offer to help with disclosure and offer guidance 

in determining when it is safe and appropriate for the youth 

to disclose her HIV status. Role-playing and working through 

scenarios ahead of time can help the adolescent manage potential 

fears and concerns.

3.Coping with HIV: Adolescents also need guidance in learning 

how to interpret changes in their viral load and CD4 counts. Since 

fluctuation in results may cause some youth to panic, providers 

can help by explaining that variation is common and significant 

changes will not prevent them from leading satisfying and 

productive lives.

4.Becoming symptomatic: The appearance of HIV-related 

symptoms can be especially disturbing for adolescents who may 

have only superficially acknowledged their HIV status. For some 

youth, becoming symptomatic may encourage them to fight HIV 

and may enhance treatment adherence and self-care. Others, 

however, may feel overwhelmed and may lose their motivation 

to live. When symptoms occur, providers should explore their 

meaning, correct misconceptions about their significance, and 

ensure that adequate services and support are available.

5.Preparing for death: Many adolescents have limited experience 

with death and have naive perceptions about what to expect. 

Introducing the topic by talking about living wills and health 

care proxies before HIV becomes too advanced is a practical way 

to help youth begin to deal with issues related to death. When 

clinically appropriate, providers can help adolescents explore 

their feelings about dying by discussing options for dying in the 

hospital or at home, talking about funeral or memorial services, 

and exploring child custody or permanency planning with 

adolescent parents.

MENTAL ILLNESS AND SUBSTANCE USE

Mental illness and substance abuse are important comorbidities for HIVpositive adolescents. Accurate screening and diagnosis are essential in 

helping adolescents cope with their disease and successfully maintain 

their treatment regimen. Case studies of adolescents and young adults 

with HIV indicate a high prevalence of depression, bipolar disorder, and 

anxiety, often predating their HIV diagnosis. Similarly, many adolescents 

with HIV report alcohol and drug abuse. Of adolescents in the REACH 

study, 14% percent of females and more than 25% of males report weekly 

use of alcohol during the past 3 mo. During the same period, 7% of females 

and 20% of males reported using hard drugs (Rogers, 1998; Murphy 

2001). In addition, as already noted, a high proportion of HIV-positive 

male and female youth report childhood sexual abuse (see Chapter I on 

Epidemiology and Natural History), which has many psychological and 

behavioral sequelae, including depression, posttraumatic stress disorder, 

substance abuse, suicidality, and risk for HIV infection.
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III. SUMMARY

The high risk of adolescent females for HIV infection makes the 

development of realistic prevention programs a vital necessity. This 

includes wider availability of prevention skills building and the routine 

offering of HIV counseling and testing to sexually active teens in all 

programs that provide adolescent care. Although most youth will not 

receive services in adolescent programs, services can be readily adapted 

to provide a “youth-centered” approach, by such basic accommodations 

as offering flexible hours and low or no payment for services and care 

as well as providers who are knowledgeable about adolescents. Relevant 

clinical trials should be made available to adolescents, and there should 

be wide dissemination of information to health care providers about 

providing adolescent-related HIV care, such as use of Tanner staging for 

determining appropriate dosage. Youth at high risk for HIV should be 

identified and engaged in primary care as soon as possible, and outreach 

programs are an important component for programs that seek to link HIVpositive youth to care. Adolescents with HIV need intensive individual 

and group support to maintain health and reduce transmission to others. 

Health care providers in all settings that serve adolescents need to assist 

in making services visible, flexible, affordable, confidential, culturally 

appropriate, and available for all adolescents.

REFERENCES

Belzer M, Slonimsky G, Tucker D. Antiretroviral adherence issues among 

HIV+ youth. Presented at the Annual Meeting of the Society for Adolescent Medicine 1998. J Adol Health. 1998;22:160.

Catania JA, Kegeles SM, Coates TJ. Toward an understanding of risk behavior: An AIDS risk reduction model. Health Education Q. 1990;17:53–72.

Centers for Disease Control and Prevention. HIV/AIDS Surveillance Rep. 

2001;13:1–44.

Centers for Disease Control and Prevention. Youth risk behavior surveillance—United States 2001. MMWR. 51:1-62, 2002.

Centers for Disease Control and Prevention. Advancing HIV Prevention: 

New Strategies for a Changing Epidemic—United States 2003. MMWR. 

2003;52:329–332.

Chabon B, Futterman D, Jones C. Adolescent HIV counseling and testing 

protocol. In: Ryan C, Futterman D. Lesbian and Gay Youth: Care and 

Counseling. New York: Columbia University Press; 1998:152–161.

Chabon B, Futterman D, Hoffman N. HIV infection in parents of youth with 

behaviorally acquired HIV. Am J Public Health. 2001;1:649–650.

Committee on Pediatric AIDS, American Academy of Pediatrics. Adolescents 

and HIV infection: the role of the pediatrician in prevention and intervention. Pediatrics. 2001;107:188–190.

Futterman D, Hein K, Reuben N, et al. Human immunodeficiency virusinfected adolescents: the first 50 patients in a New York City program. 

Pediatrics. 1993;91:730–735.
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Futterman D, Peralta L, Rudy B, Wolfson S, Guttmacher S, Rogers A. HIV. 

Live with it. Get tested: Social marketing to promote HIV testing to adolescents. J Adolesce Health Supplement: The adolescent medicine HIV/

AIDS research network: selected clinical research. 2001;29(3S):19–29.

Haglund K. Sexually abstinent African-American adolescent females’ 

descriptions of abstinence. J Nurs Scholarsh. 2003;35:231–236.

Institute of Medicine. The Hidden Epidemic: Confronting Sexually Transmitted 

Infections. Washington, DC: National Academy Press; 1997.

Kirby D, Short L, Collins J, et al: School based programs to reduce sexual 

risk behaviors: a review of effectiveness. Public Health Rep. 1994;109:

339–360.

Kunins H, Hein K, Futterman D, et al. A guide to adolescent HIV/AIDS program development. J Adolesc Health. 1993;14(Supp):S1–S168.

Murphy D, Durako S, Moscicki AB, et al. No change in health risk behaviors 

over time among HIV-infected adolescents in care: role of psychological 

distress. J Adolesce Health. Supplement: The adolescent medicine HIV/

AIDS research network: selected clinical research, 2001;29(3S):57–63

Rogers AS, Futterman DC, Moscicki AB, et al. The REACH project of the 

Adolescent Medicine HIV/AIDS Research Network: Design, methods, 

and selected characteristics of participants. J Adol Health. 1998;22:

300–311.

Rogers AS, Miller S, Murphy D, Tanney M, Fortune T. The TREAT (Therapeutic Regimens Enhancing Adherence in Teens) program: theory 

and preliminary results. J Adolesce Health. Supplement: The adolescent 

medicine HIV/AIDS research network: selected clinical research. 

2001;29(3S):30–38.

Rudy B. Crowley-Nowick P, Douglas S. Immunology and the REACH Study: 

HIV immunology and preliminary findings. J Adolesce Health. Supplement: The adolescent medicine HIV/AIDS research network: selected 

clinical research. 2001;29(3S):39–48.

Ryan C, Futterman D. Lesbian and Gay Youth: Care and Counseling. New 

York: Columbia University Press; 1998.

Schietinger H, Sawyer M, Futterman D, et al. Helping adolescents with HIV 

adhere to HAART. TREAT Monograph: HRSA/HAB; 1999.

Schneider M. Physical examination of adolescents. In: Friedman S, et al, eds. 

Comprehensive Adolescent Health Care. St. Louis: Mosby-Year Book; 1998.

UNAIDS. AIDS Epidemic Update, 2002. Available at: www.unaids.org/html/

pub/publications/irc-pub03/epiupdate2002_en_pdf.pdf. Accessed 

January 12, 2004.
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I. INTRODUCTION

This chapter is meant to provide ideas for coping with symptoms that impact 

quality of life throughout HIV disease and to prepare for issues faced near 

the end of life. Aggressive palliative care anticipates, prevents, and relieves 

suffering on emotional and spiritual levels as well as the physical. Because of 

gaps in traditional medical education related to end-of-life issues (Weissman, 

1998), information in this chapter focuses on care near the end of life which 

is consistent with the new definition of palliative care (Hanson, 1997). Much 

documentation needs to be done in palliative care because the practice comes 

from an oral tradition. The challenge to readers is to share successes and failures 

in order to expand the literature especially for those living in countries with 

fewer resources.

Hospice, an early form of palliative care, developed in London during the late 

1960’s when Dame Cicely Saunders proposed using an interdisciplinary team 

to focus on the “relief of suffering” rather than simply on long-term survival 

for persons living with advanced cancer. This care was ideally delivered in the 

home and focused on relieving physical symptoms that might impede successful 

psychosocial and spiritual life closure prior to death (Saunders, 1966). In 1980, 

the World Health Organization defined palliative care as:

“The active total care of patients whose disease is not responsive 

to curative treatment. [It] . . .affirms life and regards dying as a 

normal process, . . . neither hastens nor postpones death, . . . 

integrates the psychological and the spiritual aspects of care, . . . 

offers a support system to help patients live as actively as possible 

until death, . . . and offers a support system to help the family 

cope during the patient’s illness and in their own bereavement.” 

(Doyle, 1998)

There are many differences between patients with cancer, who eventually learn 

that their disease is no longer being contained by treatment, and patients with 

HIV/AIDS, who suffer from a more episodic illness with very difficult to predict 

endpoints. In HIV disease palliative care is best woven into the general fabric of 

care from the time of diagnosis (Bloomer, 1998; Dudgeon, 1995). A small group 

of HIV providers, invited by the Health Resources and Services Administration 

(HRSA) of the Department of Health and Human Services, which oversees the 

Ryan White CARE Act, have attempted to define what this care should be in HIV 

disease:

“. . . that care which is patient- and family-centered and optimizes 

quality of life by active anticipation, prevention, and treatment 

of suffering through respectful and trusting relationships formed 

with an interdisciplinary team throughout the continuum of 

illness: addressing physical, intellectual, emotional, social, and 

spiritual needs and facilitating patient autonomy, access to 

information, and choice.” (Unpublished meeting report, HIV/AIDS 

Bureau, HRSA, 1999.)

XII: PALLIATIVE AND END-OF-LIFE CARE

Carla S. Alexander, MD
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420 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

As HIV disease becomes a chronic rather than terminal illness, management must 

be accomplished in the overall context of life (Breitbart, 1996). Good supportive 

care means “to be safe and not to be hurt, to be given refuge or sanctuary, to be 

comforted and accepted, to belong, and to give and receive love” (National Hospice 

Organization, 1997). Adjusting goals may be challenging for health care workers 

who use only a “cheerleading” approach to support. Involving the patient and her 

support system in decisionmaking affords her a sense of control over her disease 

that ultimately extends to the end of life (Fogel, 1993; Newshan, 1998). All staff 

must learn to value the impact of symptoms on the woman’s daily life as much as 

they do viral load and the CD4 cell count.

HIV disease has been associated with shame and a negative stigma (Chung, 1992; 

Abercrombie, 1996; Sowell, 1999) resulting in the isolation of many who are 

infected, especially women. Those who suffer from the disease are frequently 

without social support or the financial means, including health insurance, 

necessary for coping with their disease (Chung, 1992; Cohen, 1998; Nannis, 1997; 

Pergami, 1993; Sowell, 1997). As the traditional care giver, a woman may not have 

anyone else to care for her. She may have also suffered many personal losses 

leaving her emotionally drained and unable to provide care for someone else 

(Sarna, 1999). She must cope with knowing that she will one day be dying herself 

and that she must make provisions for her children and other dependents who 

will be left behind.

II. QUALITY OF LIFE

The overarching goal of palliative care is to relieve or reduce suffering and 

promote quality of life. With HIV disease, the unpredictable and episodic course of 

illness makes it difficult to estimate an individual’s prognosis. Use of combination 

therapy has decreased mortality rates by 23–90% depending on the population 

examined (Pezzotti, 1999; Sendi, 1999). Quality of life (QoL) alone has become 

an important outcome measure and providers now need to pay more attention to 

pain, fatigue, anorexia, and other symptoms that can be present even when the 

disease markers are improving (Barroso, 1999; van Servellen, 1998). Each provider 

must become adept at anticipating symptoms related to therapies and offering the 

woman a mechanism for preventing or controlling these side effects.

Despite prolonged survival, physical and spiritual distress, psychological pain, and 

grief remain a part of the illness (O’Neill, 1997). There does come a point in illness 

when quality of life becomes more important than quantity of life. The transition 

away from aggressive, curative care can be as difficult for members of the health 

care team as it is for patients and families (Finucane, 1999).

Several studies have specifically considered quality of life in women with HIV 

disease (Farsides, 1995; Rosenfeld, 1996; Sowell, 1997). Sowell found that social, 

and particularly psychological, symptoms have a major impact. Quality of life has 

been affected by “HIV treatment, physical symptoms, psychological well-being 

and [change in] role functioning.” Sarna (1999) found that problems arise in four 

domains: physical, psychological, social, and sexual. Another study, however, noted 

that financial concerns were the number one disrupter. This is followed by “worry 

about family,” “distress at losing others,” and “worry about progression of disease.”
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Routinely measuring quality of life throughout the disease alerts health 

care providers to changes and stresses that may not always be obvious 

during a busy clinic visit. (See example of a quality of life form at www.tmgweb.com/modules.htm; Module 22.) Completing questionnaires every 

3–4 mo or at the time of a clinical change may help the woman communicate 

with her providers. These answers can assist providers by monitoring 

problems and targeting interventions more specifically (Sarna, 1999). Quality 

of life scales have traditionally reflected functional status; for example, the 

Karnofsky Performance Status assigns a global ranking that reflects activity during 

any given day. The Medical Outcomes Study (Wu, 1997) is frequently used in 

the HIV population and has been shortened for easier use in the clinical setting. 

However, many of these scales, because they are function based, may not be as 

useful as the woman becomes more debilitated and approaches end of life.

In advanced disease one’s focus is often directed to psychosocial and spiritual 

concerns that can be addressed even while bedridden. When we are healthy, not 

being able to leave the bed might seem unbearable. Approaching death, priorities 

shift; relationships and momentary pleasures become more important. In fact, it 

is not unusual for people to feel that their quality of life is better during this period 

because they are unable to perform mundane tasks and thus more inclined to 

focus on personal goals. The Missoula-Vitas Quality of Life Instrument (available 

through Vitas Healthcare Corporation, phone (305) 350-6033) has recently been 

developed specifically for those with deteriorating functionality. With this form 

the patient notes the importance of each domain and scoring reflects how the 

change in each characteristic, such as symptom control and sense of well-being, 

affects the individual woman. It is always useful simply to ask the woman how 

she would rank her own quality of life and what things are most important to her 

at the present time.

III. SYMPTOMS THROUGHOUT DISEASE

Three symptom surveys of outpatients with HIV/AIDS (Carr, 1994; Ferris, 1995; 

Sims, 1995) are summarized in Table 12-1. As disease advances it may not be 

possible to eliminate the cause of a symptom, but the woman and her family 

should be educated about symptom management and thus be empowered to 

master these symptoms.

Fatigue, pain, and difficulty with sleep are three symptoms that occur throughout 

the course of HIV disease (van Servellen, 1998; Whalen, 1994) and are often 

overlooked by providers. Patients believe they “must put up with” these problems 

and may avoid acknowledging them to providers. Women do not want to appear 

less courageous in coping with their disease or to distract the provider. Women 

who have a history of past or current substance abuse may fear being labeled as 

“drug-seeking” or may fear relapse if given pain medication. On the other hand, 

providers often do not inquire about these symptoms because they may not know 

how to manage them or feel inadequate to address them.

Dame Cicely Saunders, the founder of modern-day hospice, introduced the term 

“total pain” (Saunders, 1966) which is a model for how to approach all symptoms. She 

recognized that each complaint has a physical, emotional, and even spiritual component. 

If pain, or another symptom, is difficult to relieve with usual measures, it may be that 
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the woman has assigned special meaning to the symptom. She may be afraid her disease 

is getting worse or that “it is God’s punishment.” Both of these beliefs can exacerbate 

any symptom. Particularly when a symptom seems difficult to control, it is useful to 

ask the patient: “What does the pain (or nausea or shortness of breath) mean to you?” 

or “Why do you think you have this symptom?”

Table 12-1: Common Symptoms in HIV Disease

Symptom # 1 # 2 #3

Anorexia/weight 

loss

91% 31% 61%

Fatigue/weakness 77% 50%

Pain 63% 52% Total 84%

Shortness of 

breath

48% 22% 

(Respiratory 

problem)

11% 

(Dyspnea)

Nausea/GI upset 35% 28% 21%

Cough 34% 27% 19%

Anxiety/depression 32% 24% (Depression) 

40% (Anxiety)

20% 

(Depression)

Skin breakdown 24% 24% 

(Skin problem)

42% 

(Skin problem)

Diarrhea 24% 18%

Confusion/

dementia

43% 29%

Constipation 24% 18%

Fever 13% 27%

#1 Ferris, 1995. #2 Carr, 1994. #3 Sims,1995. 

A. IDENTIFYING AND DEFINING THE PROBLEM

Instead of a “review of systems,” it may be useful to think of a “review of 

symptoms” moving from the head down to the feet. All symptoms can be 

approached similarly (MacDonald, 1998) by asking about the character (what 

does it feel like); the location (including radiation to other parts of the body); 

what makes it worse, what makes it better; and are there any other symptoms 

associated. It is also useful to ask how symptoms limit or affect daily activity. 

Asking these questions lets the woman know that you are interested in the 

particulars of how this affects her life, that her perception of her daily comfort is 

as important to you as is her viral load.

In cancer patients with symptoms such as fatigue, it has been shown that just 

the act of asking and being aware of the importance of this symptom to the 

patient provides some relief from it. A problem often worsens when the patient 

tries to deal with it alone and her fear of what is causing it grows. Routinely 

using a checklist of symptoms such as the Memorial Symptom Assessment Scale 
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(Portenoy, 1994b) will alert the practitioner to issues facing the patient. A review 

of symptoms will also alert the provider to the appearance of new symptoms that 

might herald progression of disease.

B. QUANTIFYING SYMPTOMS

Two simple methods can be used to quantify symptom severity: 1) on a scale 

of zero to 10, where zero means the absence of any symptom and 10 is the 

very worst it can be, how would the patient score her pain or fatigue? and 

2) the visual analog scale is a straight, 10-cm line upon which the patient can make 

a mark representing how severe the symptom feels with the left end of the line 

representing “not at all” and the right being “the worst” (see Table 12-2). Distance 

along the line can be measured in centimeters, resulting in a numeric figure to 

record in the medical record for comparison purposes. Actual numbers are unique 

to the individual reflecting her perception and should not be used to compare her 

with other patients. Quantification is a mechanism for judging effectiveness of 

therapy and may alert the provider to a change in disease status.

Table 12-2: Pain Intensity Scales

0 – 10 Numeric Pain Intensity Scale*

0 1 2 3 4 5 6 7 8 9 10

 No Moderate Worst

 Pain Pain Pain 

 Possible

Visual Analog Scale (VAS)†

 No Pain As Bad

 Pain As It Could

 Possibly Be

* If used as a graphic rating scale, a 10-cm baseline is recommended.

† A 10-cm baseline is recommended for VAS scales.

Source: Adapted from Acute Pain Management Guideline Panel, 1992 (AHCPR, 1994).

C. MANAGEMENT OF INDIVIDUAL SYMPTOMS

Effective symptom management is based on a thorough understanding of the 

symptom and education of the patient and family, allowing them to anticipate 

crisis episodes with appropriate planning. It requires a multidisciplinary approach. 

The goal is to help the patient “move from a feeling of helplessness to a feeling 

of supremacy over the symptom” and develop and retain as much control over 

her life and illness as possible through the use of practical advice and emotional 

support (WHO, 1998). Symptoms can be managed with medications and/or 

nonpharmacologic interventions. In general, the oral route for medications is 

preferred to the parenteral; treatment regimens are tailored to the individual.
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FATIGUE

Scope of the Problem

This is the most frequent complaint of persons with HIV disease in a number 

of different series (Laschinger, 1999; van Servellen, 1998). Seventeen to 60% of 

persons, even before they are diagnosed with AIDS, have this complaint (Breitbart, 

1998). “Chronic fatigue” is present when symptoms of disproportionate tiredness, 

unrelated to activity or exertion, last for 1 mo or more. Patients complain of 

“lack of energy, stamina, or endurance.” Women with fatigue have complained of 

decreased stamina at work, lowered quality of work, and frequent absenteeism 

possibly putting their jobs at risk (Semple, 1993).

Once the problem and its meaning to the woman are well delineated, it is important 

to rule out and treat correctable etiologies (Table 12-3). Anemia, depression, fear 

of the unknown, hypothyroidism, adrenal or testosterone insufficiency (even in 

women), occult infection (particularly abscess or Mycobacterium avium complex 

[MAC]), end-stage renal, pulmonary, or cardiac disease, malnutrition, lack of 

exercise, and disease progression itself all cause asthenia and fatigue (O’Dell, 

1996). In HIV disease, it is often a combination of these factors.

In a study of 438 ambulatory patients in New York City (52% of these had 

intravenous drug use as an exposure factor), Breitbart showed a significant 

correlation between fatigue and the presence of pain (p<.0001), higher 

psychologic distress and poorer QoL (p<.0001), more depressive symptoms on 

the Beck Depression Inventory (p<.0001), and greater hopelessness on the Beck 

Hopelessness Scale (p<.0001) (Breitbart, 1998).

Table 12-3: Treatable Causes of Fatigue

• Adrenal/hormonal insufficiency • Insomnia

• Anemia • Lack of exercise

• Depression • Malignancy

• Disease progression • Malnutrition

• End-stage organ disease • Medications

• Fear of the unknown • Metabolic (low K/Mg)

• Hypothyroidism • Occult infection (abscess/MAC)

APPROACH TO MANAGEMENT

It is important to work with the woman on ways to manage her fatigue even while 

the work-up is being pursued:

1. Showing interest in alleviating this symptom offers her emotional 

support, which in itself helps relieve the fatigue.

2. Referring her for a physical therapy assessment and prescription 

of simple strengthening exercises not only physically attacks the 

problem but allows her to begin to rebuild her own self-esteem.
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3. Keeping a diary of what helps minimize her fatigue and what 

she can accomplish in a day as well as a daily numeric score 

(see quantifying symptoms, page 423) involves her in her own 

improvement and provides a better picture of how this symptom 

affects her daily life.

4. As each possible etiology is addressed, remind the woman 

to have realistic expectations in order to avoid becoming 

discouraged by false hopes.

5. Using a positive, encouraging tone and setting small goals are 

helpful.

6. Nurses are adept at helping women find ways to eliminate or 

modify energy-consuming activities.

7. For many people, addressing spiritual issues or supportive 

counseling at this time may also provide comfort and 

encouragement.

8. Making use of other health care practitioners not only helps 

the woman to cope with this exhaustion but also releases the 

provider to concentrate more on those physical aspects of 

management that need to be addressed.

Pharmacologic treatments include methylphenidate 2.5–5.0 mg in the morning 

and repeated in early afternoon or high-dose prednisone followed by a rapid 

taper. The latter therapy is usually needed only with very advanced disease when 

the concern for further long-term immunosuppression is not the most important 

aspect of management.

PAIN

Scope of the Problem

Breitbart (1996) has reported that pain in women with HIV disease is 

“prevalent, often severe, and highly distressing.” Laschinger (1999), in reporting 

a phenomenologic study, states that the “pain experience embodies more 

than physical pain” (not unlike the “total pain” of Saunders). For this reason, 

understanding and controlling pain in women with HIV disease can be quite 

difficult because the practitioner must tease out the myriad components in order 

to optimally manage this symptom.

Surveys of ambulatory populations with HIV disease have documented that 

the prevalence of pain is 40–60% (Breitbart, 1996; Lebovits, 1989; O’Neill, 1993; 

Singer, 1993). For those who have more advanced disease and may be bedridden, 

these figures increase to as much as 83%. However, of those who do have pain, 

only about 40% are actually treated and of those treated only about 40% ever 

have adequate pain relief and can still rate their pain as a “seven out of ten” in 

severity (Anand, 1994). These findings are universal and not limited to those with 

a history of substance abuse.

In HIV disease, pain can be caused by the disease itself, by therapies used to 

treat the disease, or by unrelated problems. The most frequent types of pain are 

abdominal pain and peripheral neuropathy (Anand, 1994; Newshan, 1998) or 

those caused by infections such as oral, esophageal, or genital/perineal herpes or 

fungus. Medications for treatment are based on location and type of pain.
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As in cancer patients, up to 80% of persons with HIV disease having pain will 

experience more than one pain simultaneously (Singer,1993). It is not unusual for 

a patient who has obtained relief from one pain to notice another type of pain that 

has been masked by the now-relieved pain. It is important to listen to and believe 

the patient. Carefully document all pain components and their characteristics 

to avoid a picture of “pseudoaddiction” or a label of “drug-seeking,” in which an 

individual who is only partially treated continues to ask for pain medication 

(Weissman, 1989).

One approach to pain management often neglected in the literature is the 

“phenomenologic,” which means understanding the human experience of 

pain from the perspective of the patient. Before the use of protease inhibitors, 

Laschinger (1999) conducted a qualitative study of 22 Canadian patients, 

predominately gay men but with the one woman who had parallel experiences. 

They identified four substantive themes as components of pain: physical pain, 

painful losses, pain of not knowing, and social pain. The one additional factor 

found in the woman was that she also had concerns related to her children.

“Physical pain” included joint pain, headache, neuropathic and abdominal 

pain, and skin and mouth lesions. “Losses” referred to loss of energy, time, 

independence, and relationships. “Not knowing” meant the added anxiety of 

fearing that the pain might be life-threatening. And “social pain” reflected inability 

to continue to participate in usual activities. The woman’s fears had to do with 

how the knowledge of her disease might impact her children’s schooling and how 

her death would impact their futures. This is a small but important study because 

it records the actual feelings of patients as opposed to asking for a provider’s 

perception of what pain means to the patient. Although only one woman was 

represented, the findings are in keeping with our clinical experience.

Neuropathic Pain

The HIV virus invades both central and peripheral nervous systems where it 

may be dormant for years or cause acute symptoms. The most common pain 

syndromes are headache and peripheral neuropathy. The etiology may be 

immune-modulated, infectious, or drug-related. Treatment should be based on 

the etiology and location of pain and often requires an adjuvant medication in 

addition to opioids.

Adjuvants for neuropathic pain are usually an anticonvulsant (e.g., carbamazepine 

or gabapentin), an antidepressant (e.g., nortriptyline), or an NSAID. One of these 

medications is started at the same time as the opioid; use of the former may 

allow use of lower doses of opioid and consequently fewer side effects, although 

constipation cannot be avoided. In the past, it was believed that opioids were 

ineffective for neuropathic pain but it is now known that this type of pain simply 

requires higher doses of opioids. Table 12-4 describes frequent etiologies of 

neuropathic pain.
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Table 12-4: Neuropathies in Patients with HIV/AIDS

PREDOMINANTLY SENSORY NEUROPATHY (PSN) OF AIDS

Immune-mediated:

• Inflammatory demyelinating polyneuropathies (IDPs)

• Acute (Guillain-Barré syndrome)

• Chronic (CIDP)

Infectious:

• Cytomegalovirus polyradiculopathy

• Cytomegalovirus multiple mononeuropathy

• Herpes zoster

• Mycobacterial (MAI) 

Toxic/nutritional:

• Alcohol, Vitamin deficiencies (B6, B12)

• Anti-retrovirals: ddI (didanosine), ddC (zalcitabine), d4T (stavudine)

• Anti-virals: foscarnet

• PCP prophylaxis: dapsone

• Anti-bacterial: metronidazole

• Anti-mycobacterials: INH (isoniazid), rifampin, ethionamide

• Anti-neoplastics: vincristine, vinblastine

Other Medical 

Conditions:

• Diabetic neuropathy

• Post-herpetic neuralgia

Barriers to Pain Relief

There are many reasons offered by providers throughout the world for not 

prescribing adequate pain relief (American Pain Society, 1999). Many societies 

fear “addiction” or diversion of medications. Health care workers often approach 

pain management with inadequate training in pain management skills (Field, 

1997; Portenoy, 1994a). Without appropriate knowledge of the pathophysiology 

either of pain or of its relief, providers may have the same fears as the public, 

believing that treating pain can “cause” addiction or that they must “save” powerful 

pain killers for a time when they might be “more needed.” Also there may be the 

conviction that one should “bear the pain” to show strength or religious faith. All 

of these notions, while widely believed, have no basis in fact. See Table 12-5.

Principles of Pain Management

Pain, as with any symptom, should be described, quantitated, treated, and 

promptly reevaluated with appropriate dose modification of therapy. The AHCPR 

Guidelines for Management of Cancer Pain recognize that pain experienced by those 

with HIV disease is comparable with the chronic pain experienced by persons 

with cancer, which often requires management with opioids. Unlike blood 

pressure, which might be regulated over weeks, pain should be controlled within 

the shortest time possible to prevent the development of long-term symptoms 

such as depression and anhedonia.

It is useful to start with the WHO ladder approach, which uses non-opioids 

initially and progresses through combinations of therapies and next to stronger 

opioids depending on the patient’s response. (See Table 12-6.) However, in HIV 
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pain, opioids are frequently needed because of the severity of the pain, and there 

is growing literature that the use of the “second step, or weak opioids” might best 

be bypassed in HIV-related pain. This second step includes “combination” pain 

medications, those containing an opioid plus aspirin or acetaminophen, which 

may increase the risk of hepatotoxicity or bleeding in women receiving highly 

active antiretroviral therapy. Becoming familiar with one or two agents for pain 

relief makes pain management easier.

Table 12-5: Barriers to Pain Management

Problems Related to Health Care Professionals

• Inadequate knowledge of pain management

• Poor assessment of pain

• Concern about regulation of controlled substances

• Fear of patient addiction

• Concern about side effects of analgesics

• Concern about patients becoming tolerant to analgesics

Problems Related to Patients

• Reluctance to report pain

- Concern about distracting physicians from treatment of underlying disease

- Fear that pain means disease is worse

- Concern about not being a “good” patient

- Reluctance to take pain medications

- Fear of addiction or of being thought of as an addict

- Worries about unmanageable side effects

- Concern about becoming tolerant to pain medications

Problems Related to the Health Care System

• Low priority given to cancer and AIDS pain treatment

• Inadequate reimbursement

- The most appropriate treatment may not be reimbursed or may be too costly for patients and families

• Restrictive regulation of controlled substances

• Problems of availability of treatment or access to it

Source: Adapted from AHCPR, 1994.
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Table 12-6: Pharmacologic Approaches to Pain Management: 

WHO Three-step Ladder 

WHO Three-step Ladder

Step 3: Severe Pain

Morphine

Hydromorphone

Methadone

Levorphanol

Fentanyl

Oxycodone

±Nonopioid analgesics

±Adjuvants

Step 2: Moderate Pain

APAP or ASA +

Codeine

Hydrocodone

Oxycodone

Dihydrocodeine

Tramadol (not available with 

ASA or APAP)

±Adjuvants

Step 1: Mild Pain

Aspirin (ASA)

Acetaminophen (APAP)

Nonsteroidal anti-inflammatory 

drugs (NSAIDs)

±Adjuvants

 “ 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. 

Source: Adapted from WHO, 1986.

The following guidelines (including Table 12-7) are helpful in prescribing pain 

medication (American Pain Society, 1999):

1. Use a grading system (such as the scale of 0–10) to document pain 

severity and relief from pain for monitoring the effectiveness of 

therapy.

2. Start with a dose that will acutely relieve the pain. This may be 

given intravenously or subcutaneously to achieve a rapid response. 

Care should be taken to observe for any signs of respiratory 

depression in opiate-naive patients.

3. Next, begin a low dose every 3–4 hr (based on the half-life of the 

drug) “around-the-clock” and not on an as-needed basis. The initial 

dose should be chosen based on the age, size, and renal/hepatic 

function of the patient. (Suggestions are given in any standard 

pain-management text such as Principles of Analgesic Use in the 

Treatment of Acute and Cancer Pain, 5th ed., available from the 

American Pain Society at http://www.ampainsoc.org).
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4. In addition to the every 3-4 hr. “around-the-clock” dose, include 

provision for a supplemental, or “breakthrough,” dose of about 

one sixth of the total daily opioid dose to be given every 1–2 hr 

between the scheduled doses should the pain not be controlled. 

This allows for development of a steady state drug level and 

avoids alternation of great pain intensity with somnolence. This is 

the same approach used to control hyperglycemia with a sliding 

scale of regular insulin based on glucometer readings; these doses 

are based on pain scores.

5. When pain is fairly well controlled, it is appropriate to change the 

patient to a long-acting pain medication for ease of administration. 

The dose is calculated by adding together the total dose taken 

in 24 hr and dividing by the half-life of the new preparation. For 

example, for a medication meant to be given every 12 hr: divide 

the total dose by two and this number will be your dose every 

12 hr. Don’t forget the breakthrough dose. This is a short-acting 

opioid, preferably of the same type as the long-acting one for use 

at times that the pain is not adequately controlled (equals 1/6 

daily total dose).

6. Liquid formulations are useful for those with difficulty swallowing, 

as are rectal suppositories; “sprinkles,” which can be mixed with 

soft food; or patches, which can be absorbed through the skin if 

adequate subcutaneous fat is present.

Table 12-7: Mnemonic for Assessment of Pain

A — Ask about pain regularly; Access systematically

B — Believe the patient and family

C — Choose treatment options appropriate to patient and setting

D — Deliver medications on an “around-the-clock” basis with adequate 

“breakthrough” doses

E — Evaluate results frequently; Empower patients and families to control 

Source: Adapted from AHCPR, 1994.

Side Effects

Table 12-8 outlines several common side effects of opioids. Opioids usually cause 

drowsiness in the first 24–36 hr and patients should be advised that this will 

resolve. Use a low dose to initiate therapy but be prepared to increase the dose 

over the next 48 hr based on the patient’s pain scores. Nausea is another common 

side effect in those first few days and can be treated with an antiemetic such 

as prochlorperazine or lorazepam. All opioids slow bowel motility and patients 

should be given a stool softener when pain medication is prescribed.

Many prescribers will use an antiemetic or methylphenidate to counteract these 

symptoms over a few days. Prolonged sleeping after the initial dosing may simply 

reflect the woman’s need for rest, which has not been possible because of the 

pain. If side effects are pronounced over a longer period, it is best to talk with the 

woman about what else is going on and it may be useful to discuss analgesic use 

with a pain specialist and involve other team members.
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Table 12-8: Common Side Effects of Opioid Analgesics

Constipation Requires prescription of stool softener at the time of 

prescribing opioid; tolerance does NOT develop

Drowsiness

 Resolves after 24–36 hr; extended sleeping can be 

from exhaustion; may need psychostimulant, e.g., 

methylphenidate

Nausea Prescribe antiemetic with first prescription; resolves in 

several days; may need around-the-clock dosing

Urinary retention Uncommon side effect; change opioids or adjuvants

Itching/twitching May indicate toxic levels due to decreased elimination; 

lengthen interval; rotate opioids

Although many providers fear respiratory depression, this is unusual unless an 

opiate-naive patient is given a large, parenteral dose initially. Most pain (85–90%) 

can be controlled with oral medications. If the patient is having severe pain 

in a controlled situation such as a hospital or hospice, an initial subcutaneous 

injection of morphine or hydromorphone may control the pain more rapidly. 

Once a patient is on an appropriate dose, side effects (except for the slowed bowel 

motility) generally resolve and patients return to their usual level of functioning, 

or even improved activity, because the pain is relieved.

With very high doses, twitching or myoclonus may occur and in this case, it is 

possible to alternate two different opioids (referred to as “rotating”) or to change 

to another drug entirely (Galer, 1992). If twitching develops, the patient may have 

decreased renal or hepatic clearance. In this case the dosing interval should be 

lengthened or different opioids can be used in an alternating fashion.

Opioid Conversions

Many opioid preparations are available. These drugs are not equivalent on a 

milligram-to-milligram basis and it is possible to see what appears to be “drugseeking behavior” if the conversion dose chosen is too low. When changing 

from one medication to another, use a conversion chart to find the total dose 

in morphine-equivalent units and convert according to the table (see Table 12-

9). There is no “ceiling effect” with opioids as there is with other medications 

such as acetaminophen, aspirin, or tricyclics; i.e., there is no toxic dose and the 

patient should be given whatever dose relieves her pain. Just as pain scores 

are individual, so are ultimate doses. It may be useful to seek the guidance of 

someone knowledgeable in pain management if you as the provider are not 

experienced with these medications.
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Table 12-9: Dose Equivalents for Opioid Analgesics in Opioidnaive Adults and Children ≥50kg Body Weight

Drug Approximate 

Equianalgesic Dose

Usual Starting Dose for 

Moderate to Severe Pain

Opioid 

Agonist

Oral Parenteral Oral Parenteral

Morphine 30 mg q 3–4 hr 

(repeat around 

the clock 

dosing)

60 mg q 3–4 

hr (single dose 

or intermittent 

dosing)

10 mg q 3–4 hr 30 mg q 3–4 hr 10 mg q 3–4 hr

Morphine, 

controlled-release 

(MS Contin, 

Oramorph)

90–120 mg q 

12 hr

N/A 90–120 mg 

q 12 hr

N/A

Hydromorphone 

(Dilaudid)

7.5 mg q 3–4 hr 1.5 mg q 3–4 hr 6 mg q 3–4 hr 1.5 mg q 3–4 hr

Levorphanol 

(Levo-Dromoran)

4 mg q 6–8 hr 2 mg q 6–8 hr 4 mg q 6–8 hr 2 mg q 6–8 hr

Methadone 

(Dolophine, other)

20 mg q 6–8 hr 10 mg q 6–8 hr 20 mg q 6–8 hr 10 mg q 6–8 hr

Oxymorphone 

(Numorphan)

N/A 1 mg q 3–4 hr N/A 1 mg q 3–4 hr

Combination Opioid/NSAID Preparations

Codeine (with 

aspirin or 

acetaminophen)

180–200 mg 

q 3–4 hr

130 mg q 

3–4 hr

60 mg q 3–4 hr 60 mg q 2 hr 

(IM/SC)

Hydrocodone (in 

Lorcet, Lortab, 

Vicodin, others)

30 mg q 3–4 hr N/A 10 mg q 3–4 hr N/A

Oxycodone 

(Roxicodone, 

also in Percocet, 

Percodan, Tylox, 

others)

30 mg q 3–4 hr N/A 10 mg q 3–4 hr N/A

Source: Adapted from AHCPR, 1994.

Pain Management with a History of Substance Abuse

Those who have used opioids in the past may have a higher tolerance and 

thus require higher than usual doses. “Addiction” is a psychological craving and the 

use of drugs “to get high” or despite personal harm should not be confused with 

tolerance. When treating someone who has previously abused drugs (or is doing 

so currently), it is useful to discuss the full plan ahead of time. The patient should 

understand that this is a two-way interaction, that she must be truthful about her 

pain and its severity/relief as the provider will endeavor to control the pain. Most 

people with an addiction history who have legitimate pain are thankful to have it 

dealt with in an adult manner and understand that this is not a time to engage in 

manipulative behavior. In fact, many are afraid to take narcotics for fear of relapse.
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Seeking a higher dose of drug does not necessarily mean that the patient is “drugseeking.” “Losing” or forging prescriptions, stealing from or having them “stolen” 

by others, visiting multiple providers for duplicate prescriptions and injecting oral 

formulations (Portenoy, 1994a) are signs that the patient may not be using the 

medication appropriately. She must understand that she will be given adequate 

drug to last for a clearly described interval, she cannot obtain refills on weekends, 

and there is only one provider who can write her prescriptions. Situations 

involving tampering with prescriptions or selling medication should be turned 

over to legal authorities and will sever the patient-provider supply of medication. 

Written contracts are used in some clinics but a well-documented discussion in 

the medical record is adequate.

Women with a history of substance abuse are often poorly emotionally defended 

and may have inadequate coping skills for even minor frustrations. Low selfesteem and little self-confidence can impact pain and make it worse. Breitbart 

noted that pain in women is more intense and that those with a history of 

opportunistic infections or intravenous drug use are “more likely to experience 

pain” (Breitbart 1996).

Management of pain is not easy and requires a great degree of trust on both sides. 

Being consistent, open, and fair are important attributes for the provider to model. 

Providing positive feedback, reducing harm through education, and attempting to 

understand individual circumstances are most helpful to the patient. Clearly, as a 

patient approaches the end of life, old habits and fears often resurface and, at this 

time, the patient may need more support than usual.

Gender Differences

There is a growing amount of literature suggesting that pain in women is 

undertreated. Breitbart reported that women with HIV disease appear to have 

“higher levels of pain intensity . . . [and are] more likely than men with AIDS to 

have their pain under-medicated” (Breitbart 1996).

SLEEP DISTURBANCE/INSOMNIA

Scope of the Problem

Insomnia and excessive daytime sleepiness are primary complaints in persons 

with HIV disease regardless of stage. Cohen et al. (1996) reported that fully two 

thirds of patients with AIDS have difficulty falling asleep without correlation with 

CD4 count. Insomnia includes difficulty falling asleep, difficulty staying asleep, 

and early morning awakening.

For women fatigue is not necessarily related to sleep patterns although it is 

important to document what the sleeping pattern is. Using questions similar 

to those in Table 12-10, try to determine the pattern of sleep problems, the 

frequency, associated events, and other factors listed below. Treatment should be 

tailored to the etiology. If you see patients in a busy setting, it is useful to have 

them fill out a card recalling specific characteristics of the symptom. A nurse can 

help the patient complete this card, leaving the provider to focus on therapy and 

documentation.
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Table 12-10: Sleep Problems (Sample Questionnaire for Office Use)

Do you have trouble  falling asleep? Or  staying asleep?

Do you take naps during the day?  Yes  No How many hours ________?

Do any of the following wake you up? 

 headache  fever/night sweats 

 bad or vivid dreams  leg cramps 

 problems breathing  fear 

 chest pain/heartburn  another person in the house 

 abdominal pains  other ______________________ 

 need to pass urine ______________________

 need to move bowels ______________________

What have you tried for sleep?

 Drug store product  Counting sheep or other meditation

 Sleeping pill from friend  Warm bath

 Hot milk  other ______________________

 Reading ______________________

 Music ______________________

Assessment

Having the patient keep a sleep diary; bringing a family member to appointments 

to comment on sleep patterns; and clearly documenting bedtime, how long it 

takes her to go to sleep, and how long she can stay asleep provide the best picture 

of this problem. Include a full history of caffeine and alcohol intake and describe 

the environment and other factors that might affect sleep. Review current 

medications to eliminate these as a possible etiology that may cause insomnia, 

particularly NNRTIs and selective serotonin reuptake inhibitors taken at bedtime. 

Remember that injection drug users may have night sweats and abdominal pains 

as signs of withdrawal. Simple sleep-wake reversal may herald liver damage. Sleep 

disorder, classically early morning wakening, may be a symptom of depression 

(Nokes, 1999).

Management of Insomnia

Treat the underlying problem whenever possible starting with simple 

environmental modifications, e.g., fresh air; quiet (may need white noise emitter); 

avoiding exercise, heavy meals, large amounts of alcohol, or arguing just before 

bed. Plain acetaminophen or aspirin in low doses if not contraindicated may be 

helpful, as are short-acting hypnotics or sedating antidepressants, e.g., trazedone 

50 mg qhs. When underlying depression is identified, appropriate treatment with 

an SSRI or a tricyclic antidepressant is indicated. (See Chapter IX on Psychiatric 

Issues.) Short-acting benzodiazepines are useful acutely but should be avoided 

long-term or in patients with dementia because they may increase confusion 

(Phillips, 1999). Physical interventions such as massage, relaxation exercises, and 

deep breathing are also beneficial.
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PRURITUS

Generalized pruritus without a rash may be secondary to dry skin, 

hepatic dysfunction, or an allergic reaction. The rash with scabies in an 

immunocompromised host may be diffuse and might require biopsy if symptoms 

do not respond to empiric therapy.

Along with specific therapy for scabies, the patient should be given an 

antihistamine to break the cycle of itching. Low doses of an opioid are not 

uncommonly required to conquer this symptom. If the symptoms have been 

present for weeks, it may be necessary to follow the nighttime scabies treatment 

with 1% hydrocortisone lotion each morning.

If the itching is thought to be secondary to hepatic dysfunction, holding 

hepatotoxic agents and using an H2 blocker such as around-the-clock cimetidine 

for several days is helpful. As the hepatic enzymes return to normal, medications 

can be resumed at lower doses and/or with longer dosing intervals. This is true if 

the underlying pathology is not related to the lactic acidosis associated with some 

antiretroviral therapies. In this case consult a liver specialist before reintroducing 

medications. These patients are partially relieved with a 1% hydrocortisone lotion 

containing menthol.

HICCUPS

When intractable, this symptom can lead to poor oral intake and weight loss as 

well as to depression because of an interruption of all normal activity. Simple 

mechanical measures such as drinking out of the “wrong” side of the glass and 

swallowing up-hill against gravity may transiently interrupt these symptoms. 

The usual medical treatment is low-dose (12.5–25 mg) chlorpromazine orally. 

Metochlopramide, baclofen, amantadine, benzodiazepines, and haloperidol (Kaye, 

1989; Woodruff, 1999) have also been described as useful although there is little 

evidence base for these recommendations. One treatable cause for this symptom 

is persistent and severe esophageal candidiasis, which requires aggressive therapy 

of this infection for relief. Malignancy impinging on the phrenic nerve can also 

cause hiccup and a chest X-ray is recommended to rule out a mass.

XEROSTOMIA (DRY MOUTH)

This condition can be secondary to medications such as antidepressants, 

anticholinergics, or HIV medications such as didanosine or zalcitibine. It is 

generally reversible if noticed soon enough and the drug is stopped. However, 

if this condition persists without detection and treatment, it may become 

permanent. Direct invasion of the salivary gland with HIV can also cause dry 

mouth. Treatment should be directed at the etiology.

Artificial saliva, drinking extra fluids with meals, and fluoride treatments administered 

by a dentist may be necessary to reverse this symptom. If it is not noticed in a timely 

manner, tooth decay and gingival disease may occur, resulting in caries and “sore” 

teeth. Left untreated, the patient may withdraw from society and become quite 

depressed because of the inability to be comfortable during a meal with others. 

Pilocarpine drops taken orally 4 times per day have been useful in this syndrome 

(LeVeque, 1993). However, the onus is on the provider to ask about the presence of 

this symptom on a regular basis to detect, treat, and reverse the problem.
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DYSPNEA

In the original hospice studies in this country, dyspnea was one of the five 

symptoms correlated with a shortened life expectancy even when patients had no 

demonstrable disease in the cardiovascular or pulmonary systems. Dyspnea is an 

uncomfortable feeling of not being able to breathe although the oxygen saturation 

may be normal. Treatment should be directed at the presumed etiology using 

bronchodilators, diuretics, and steroids as necessary. In the hospice literature 

morphine has been used anecdotally as an aerosol with significant relief although 

this has not been formally proven to be useful; subcutaneous or oral morphine 

can also be used (start with 5 mg every 3–4 hr). Clinical trials are needed to 

compare aerosolized morphine with saline nebulizers, which some authors have 

found equally useful.

Benzodiazepines are desirable to interrupt the cycle of dyspnea and panic that 

sets in when an individual is having difficulty breathing. A long-acting drug such 

as lorazepam 0.5 mg can be given around the clock every 6–8 hr to minimize the 

anxiety in this setting.

IV. PROGNOSIS

The use of combination or highly active antiretroviral therapy and the ability to 

measure the existing human immunodeficiency viral burden have significantly 

impacted the course of HIV disease. With improved antiretroviral therapy, use 

of prophylaxis for opportunistic infections, and treatment by providers who are 

knowledgeable about HIV disease, patients can look forward to living longer and 

healthier lives. However, particularly in resource-poor nations, most will die of 

this disease. To set realistic goals, the provider must have some sense of the 

individual’s expected survival time.

Being able to give the patient and family a realistic appraisal of life expectancy, 

particularly near the end of life, is an important adjunct to disease management. 

For example, if the woman has several months to live, this may be the best time to 

review and clarify who will help with decisionmaking as she becomes acutely or 

seriously ill. It is also a time to investigate and make decisions about guardianship 

as well as to make a will and determine general advance directives. Deciding 

which medications to discontinue and when depends upon the provider’s 

projection of how long the patient has to live.

Although overall prognosis may be difficult to estimate, there are general signs 

that reflect advanced disease or failure of the immune system (National Hospice 

Organization, 1996). For example, repeated episodes of opportunistic infections, 

uncontrollable weight loss, or frequent hospitalizations all suggest that the 

woman is no longer “doing well.” Once this decline begins and all antiretrovirals 

have been exhausted or the woman opts for no further aggressive therapy, it 

is reasonable to focus on issues related to life closure. As the woman becomes 

weaker, certain therapies may be withdrawn and attention should be directed 

toward psychosocial and spiritual tasks.
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In 1996, before widespread use of combination therapies, the National Hospice 

Organization published Medical Guidelines for Determining Prognosis in Selected NonCancer Diseases, 2nd ed. (N.H.O., 1996) (Table 12-11), which described indicators 

for a shortened life expectancy in several chronic diseases including HIV/AIDS. 

When several of these indicators are present, one should consider the prognosis to 

be limited unless the use of new or unapproved therapies is possible.

Wasting syndrome based on loss of lean body mass (Kotler, 1989) and anemia 

are both independent risk factors for decreased survival (Moore, 1999). Median 

time to death can be related to the severity of each. Persistent oral thrush is 

also an independent predictor of progression of AIDS. Concurrent unresponsive 

malignancy or end-stage organ failure shortens the prognosis. Worldwide, 

hepatitis C is rapidly becoming a leading cause of death.

Although it is not well documented, the woman’s personal goals may significantly 

affect life expectancy. The experience in hospice care is that people must have 

completed psychosocial and spiritual goals before being able to peacefully “let 

go.” For women with children this may mean making reasonable guardianship 

arrangements called permanency planning. For others it may mean resolving a 

relationship or coming to terms with her life events or accomplishments. Saying 

goodbye to loved ones and to care providers is a last necessary step before death.

Table 12-11: Factors Associated with Shortened Life Expectancy

• CD4 persistently low • Advanced disease: <50 cells/cc

• Viral burden remains 100,000 copies/mL despite 

combination therapy

• Functional status <50 (Karnofsky Performance 

Status) • Spending >50% of day in bed

• Failure of optimized therapy • Multi-drug resistance or failure

• Desire to forego more therapy

Often occurs after multiple hospitalizations

• Anemia (hemoglobin <12) • Persistent oral thrush

• Significant wasting • Loss of >30% lean body mass

• Progressive hepatitis C • Hepatic failure; drug intolerance

• Progressive multifocal 

leukoencephalopathy • Progressive dependencies; dementia 

• Unresponsive Kaposi’s sarcoma involving an 

organ • Progression despite therapy 

• End-stage organ disease • Renal, hepatic, or cardiac failure

• Persistent diarrhea >1 mo • No response to treatment

• Unresponsive lymphoma/ other malignancy • Acknowledgment by patient and family of poor 

prognosis

• Desire of patient for death

Source: Adapted from Moore, 1999; N.H.O., 1996.
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V. TELLING THE TRUTH AND BREAKING BAD NEWS

Communication skills are particularly important as the woman’s health begins 

to decline. Being a good listener is paramount and there are concrete skills that 

can be learned. 

Baile and Buckman discuss how to talk about difficult topics described in 

Table 12-12 (Baile, 1998). They note the importance of paying attention to 

the physical environment when having serious discussions with patients and 

families. It is important to have privacy, quiet, and lack of interruptions as 

much as possible. The provider should sit down to talk with whatever “family” 

the patient wishes to include. The use of touch may be comforting although it 

is important to gain permission first. Body language and eye contact are a part 

of the setting.

Table 12-12: Mnemonic for Breaking Bad News

S — Setting and listening Skills

P — Patient & family; Perception of condition

I — Invitation to patient to determine how much Information he/she 

wants to know

K — Knowledge; reviewing the facts

E — Explore Emotions & Empathize

S — Summary & Strategy

Source: Adapted from Baile, 1998.

When discussing emotionally laden issues or breaking bad news, it is best to 

ask what the perceptions are of those present, whether you are addressing the 

woman alone or her friends and family. “Before I talk, tell me how you think 

you are [she is] doing?” “What are your concerns at this time?” Not only does this 

help the provider to know where to begin but it provides a vocabulary to use in 

this discussion. Words used by them will suggest vocabulary as well as degree of 

comprehension. Avoiding jargon or strictly medical terms is helpful. In the case 

of bad news, it is useful to provide a warning statement such as “I have some bad 

news for you” or “This is a very difficult time and I want you to be prepared.” 

Once the facts have been communicated, it is important to determine what the 

reaction is to this news. Providing a period of silence may help those involved to 

gather their thoughts before speaking (Weissman, 1998).

Listening skills include asking open-ended questions and repeating the last 

comment made by the patient or family member to clarify what has been 

said. Acknowledge emotions by using empathic responses even if the feelings 

themselves are unimaginable to you. After a period of discussion, develop a 

strategic plan with the patient or family by discussing expectations and goals. Use 

this time to reassure that there will be future conversations. Summarize what has 

been discussed and ask for any remaining questions.
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VI. REALISTIC GOAL SETTING AND ADVANCE CARE 

PLANNING

We must all learn to think ahead to a time when we may not be healthy and able 

to care for ourselves. Women, in particular, need to make provisions for others 

they care for such as children or an elderly parent. Thinking ahead prevents 

confusion and also assures that no one person will be burdened with matters 

near the time of death. Each woman needs to select someone who will be able 

to manage her legal affairs and also someone to make medical decisions for 

her should she not be able to do so. This may be two different people but it is 

important for the woman to discuss her own wishes with that person early in her 

illness. By doing it at a time when she feels well, she can remain in control and 

make her own choices (see Table 12-13).

Table 12-13: Making Plans Ahead of Time

1. Appointment of Power of Attorney for health 

matters and for financial matters 

These are two different issues; the healthcare POA 

does not last beyond the death; therefore, all plans 

must be made and executed ahead of time.

2. Appointment of guardian for children Be certain that children & guardian are both aware 

of these plans.

3. If there are children left behind Many people make a scrap book, write a letter, or 

even make a video to remind younger children who 

their mother was.

4. Make a will if there is anything you own that 

you would like to leave to a particular person

This includes money, a home, dishes from your 

grandmother, or jewelry that has a special meaning 

to you.

5. Discuss with family or friends how and where 

you would like to die

You can be involved in planning a funeral or 

memorial service; can pick out your clothes and 

pallbearers.

6. Discuss desires regarding care before death:

• For nutrition and hydration

• For cardiopulmonary resuscitation 

• For being kept alive on machines

It may be helpful to think about what you might 

want in different situations. For example, if you 

would be bed-bound; if you were no longer able 

to care for yourself; if you would not be able to 

recognize people or carry on normal conversations.

A. IMPORTANCE OF MAINTAINING HOPE

To provide the most supportive and sensitive care throughout illness, the provider 

must understand the overall goals of the patient. As the woman moves through 

her disease it is necessary to intermittently discuss these, preferably while the 

patient is feeling well and able to feel more in control of her disease. Just as 

quality of life evolves, so do desired outcomes. Many medical providers seem to 

fear that having these discussions might “take away hope.”

Hope is not false expectation. It can be redefined in an acceptable way for the 

individual. Whereas hope for a long life may no longer be possible, hope for being 

able to leave good memories behind for children may be fulfilled by making a 

scrapbook, audio tape, or even a video. One can simply hope for days that are 

meaningful (Bennett, 1995). Multiple studies document that having a sense of 

spiritual (not necessarily religious) well-being has a positive effect on health 

(Colman, 1999).
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Hope “. . . is the emotion upon which all the other emotions of elation are grounded. 

. . shaped by a glimpse of something not yet clearly within sight. . . always looks 

toward creative changes. . . an expression of the will to live. . . of an individual’s trust 

in life. . . even terminally ill persons express the feeling that things will somehow 

get better. . . that as long as we live, we live for a better future” (Kast, 1991). It 

is not a commodity that one person gives to another but is within the individual 

and can be modified accordingly. Ernst Bloch in The Principle of Hope wrote:

“What matters is learning to hope. Hope does not abandon its post. It is 

in love with success rather than failure. Hope, superior to fear. . . reaches 

out; it broadens rather than narrows” (Bloch, as cited in Kast, 1991).

He apparently “saw hope in daydreaming, fantasy, and imagination.” Albert 

Schweitzer also believed that imagination was what allows the human to tolerate 

the present.

B. PERSONAL GOALS

In discussing goals, it is useful to ask the woman, “What aspects of your life are 

most important to you? What have you accomplished in your life that makes you 

feel proud?” This is also a time to determine which other persons she cares about 

and who provides her support. Frequently, it is a family anniversary or event, 

such as the birth of a grandchild, that comprise the woman’s true goals.

Each of us has dreams. It is up to the provider or other members of the team 

to discover those and help the woman to see how they might be achieved. With 

HIV disease the young woman may not have had time to realize her dreams. In 

this case, the team must help her value the life she has had and to discover and 

acknowledge what it is that she wishes remembered about her life. She can also 

be assisted in grieving the loss of future. Sharing a funny story or memory of a 

special event helps the young woman know that she has left her mark.

C. ADVANCE CARE PLANNING

Once the provider understands what is important to the woman, it is much easier to 

talk about the kind of care she would like to receive near the end of life. Being able 

to hold her granddaughter may be more important than living another year. Once 

broad goals cans be identified, the team needs to shift from a tactical approach to 

care to a more strategic one. Bennett (1995) refers to this as changing from a “curebased approach to a psychosocial model.” It means to target an overall goal rather 

than to get bogged down in correcting the electrolytes. Being at home may be more 

pertinent than having the last potassium adjusted or receiving the final days of a 

course of intravenous antibiotics. Being free of pain and in a dry bed with loved ones 

present may be the ultimate goal.

Although the term “advance directive” makes sense to those in the health care 

environment, these words may be essentially meaningless to the woman and those 

who make up her support system. In trying to determine what the patient wants it is 

necessary to use concrete and explicit terms when discussing this topic. It is important 

to develop a “psychosocial success” register where psychosocial desires and resolutions 

can be formally recognized; this might be done during a case conference with staff.
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VII. END-OF-LIFE ISSUES

A. PHYSICAL COMFORT NEAR THE END OF LIFE

When the patient is bedridden, it is comforting to be surrounded by photos or 

objects that remind her of events and people she would like to remember or 

that make her happy. Being in a home-like environment is the desired resting 

place for many (American Health Decisions, 1997). Attention to reducing noise, 

providing a fan or some means of air movement, serving small portions of food 

several times throughout the day rather than three large meals, and playing music 

or reading stories may all provide comfort. If the patient has a favorite pet or 

small children she might enjoy short visits with them.

Complementary therapies such as massage, guided imagery, or acupuncture are 

widely used and can provide comfort to those for whom they are familiar. Others 

may not appreciate being touched by strangers and it is always important to 

discuss these methods before introducing them. Likewise, incense or peppermint 

oil may be used to mask unpleasant odors; activated charcoal on a gauze pad or 

chlorophyll tablets can accomplish the same result.

Cultural beliefs and rituals become very important at this time. Use the rest of 

your team to discover what practices must be respected, because ignorance of 

these might inhibit a peaceful transition and leave bad memories for families 

and friends. For example, some cultures or religions require that the patient 

receive fluids or that the health care workers give the appearance of performing 

resuscitation attempts or efforts to prevent the actual death. Knowing these 

beliefs ahead of time will allow for the staff to prepare and conversations to be 

held that might preclude misunderstanding.

Once the patient and family have made the final decision for “No cardiopulmonary 

resuscitation (CPR),” many health care workers are at a loss for exactly what to do. 

Although fluids and antibiotics may be withheld, there are still many techniques 

that staff can employ to support the patient and family as a unit. It has been 

suggested that “Orders to Intervene” should be written.

Alexander, Perrone, and Reiss (Alexander, 1999) have developed a mnemonic 

for remembering simple medical orders that might be implemented as an example 

of these interventions (see Table 12-14). The care provider should recognize 

that despite the end of curative interventions, there is always something that 

can be done to comfort both patient and family. By reversing “No CPR” and 

writing orders for “RPC” the team can continue to offer support. Reassurance 

of continued involvement by the health care team, presence at the bedside on 

a predictable basis, and an attitude of caring that respects individual goals and 

comfort are the least that can be done. The Oxford Textbook of Palliative Medicine, 

2nd ed. (Doyle, 1998) contains a wealth of knowledge for those who want to give 

good supportive care.
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Table 12-14: Physician’s Card

Side One

Comfort Measures at LIFE’S END

L — LIPS, mouth & eyes moistened; ice chips; artificial saliva /tears

I — INCONTINENCE of bowel & bladder expected–use catheter; bed pad

F — FEVERS expected: around the clock antipyretics (oral or suppository)

E — ELIMINATE all but essential meds

S — SYMPTOM management–be aggressive

E — EATING less is expected; diet as desired

N — NURSING call orders–revise

D — DECUBITUS/skin care/turning q 2 hr

Side Two

Making the decision to write “Do Not Resuscitate” orders is often difficult but 

it does not mean that there is “nothing else to be done.” Once the order “No 

CPR” is written reverse your thinking and write orders for RPC: 

R — Reassurance 

• you will continue to care for the patient and family

• symptoms which interfere with good quality of life will be controlled 

• there are effective ways for coping with stresses and for grieving 

• patient and family concerns will direct how and where care is provided 

P — Presence 

• be there to hold conversations

• visit on a regular basis 

• sit down and hold a hand 

• listen respectfully 

C — Caring 

• provide comfort measures 

• honor the individual 

• share laughter and touch 

Facilitate “life review” and these important conversations: 

• Thank you 

• Please forgive me 

• I forgive you

• I love you 

• Goodbye 

Source: Alexander, 1999, © University of Maryland, Baltimore, 1999 Palliative Care Program, Permission to 

reproduce for educational purposes granted.

B. CLINICAL TREATMENT

Treatments that have been used throughout active disease may need to be 

modified as the woman comes closer to dying. Using complex diagnostic 

procedures and prolonged courses of therapy may not be necessary at the end 
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of life and may be a significant burden to the patient. Short bursts of antibiotics 

may be all that is needed to arrest a symptom. Such judgments must be based 

on realistic prognosis as discussed earlier in this chapter. For example, a woman 

resistant to oral antifungal agents may need a brief course of intravenous therapy 

if this offers the quickest relief of her symptoms.

If there are high fevers and sweats presumed secondary to MAC she may 

no longer tolerate the usual combination of drugs, and single-agent or 

short-burst doses may be adequate to control symptoms at a time when a reduced 

pill count is the overriding goal. One of the difficult aspects of managing the 

end stages of illness is knowing when it is appropriate to discontinue certain 

therapies. Much of this decisionmaking is based on the provider’s ability to 

provide realistic prognostic information to the patient and family. For example, 

prophylactic therapies might be discontinued in the last 3–4 weeks of life; they 

can easily be resumed should the woman become symptomatic.

C. CONVERSATIONS FOR THE END OF LIFE

Families often fear that discussing death might “scare” the dying person. However, 

most people know when they are dying and are relieved at being able to discuss 

their fears or beliefs. Women in particular often feel a need to “protect” those 

around them and may be more comfortable talking about their impending death 

with someone who is not a family member. Although most people feel awkward 

around someone who is very ill or dying because they “don’t know what to say,” 

there are a number of things to talk about.

Most people near the end of life want to know that their time on earth has been 

worthwhile. They want to know that they have been loved, that they will be 

remembered, and that they are forgiven for things they may have done wrong. 

One simple method for achieving these goals is to “do life review” which means 

to ask to hear stories of the person’s life: what she is most proud of, what is the 

funniest thing that ever happened to her, what she is ashamed of or wishes she 

hadn’t done. By asking these questions, the listener can reassure the person that 

those positive memories will stay alive. By talking about negative events, they can 

be minimized or forgiven.

An anonymous hospice nurse once said that there are five important conversations 

for the dying person to have to assure a peaceful death (Byock, 1997). These are 

“Thank you,” “Forgive me,” “I forgive you,” “I love you,” and “Goodbye” (Table 12-

15). The last of these is the most difficult both for the dying woman and for those 

who will be left behind. But this is the most important conversation because the 

dying need to feel reassured that those left behind will be able to take care of 

themselves. This is especially true of women regarding spouses and children; it 

is accentuated when the woman is young and there are young children involved. 

Those being left behind must also say goodbye by giving the dying woman 

“permission to go,” which represents their acceptance of the finality of the death. 

This permission must also be verbally granted by health care providers who may 

have become like family members near the end of a long illness.
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Table 12-15: Five Important Conversations to 

Complete for a “Peaceful” Death

• Thank you.

• Please forgive me. 

• I forgive you.

• I love you.

• Goodbye.

Forgiveness and reconciliation are spiritual as well as personal issues (Hall, 

1998). Depending on the woman’s belief system, it may be important to have a 

priest, a pastor, a rabbi, or other spiritual representative present throughout the 

last month of life. In societies where large numbers of women are dying, there 

may be insufficient care givers because this is a role often assumed by women. 

It is important to find someone to sit with the dying woman to provide comfort 

and security in her last hours. Simple presence without conversation represents 

real support and caring.

Puchalski defines spirituality as “whomever or whatever gives one a transcendent 

meaning in life.” She suggests doing a spiritual assessment of the woman at the 

same time that other historical information is gathered. The mnemonic FICA is 

useful for remembering what questions to ask (Table 12-16).

Table 12-16: Spiritual Assessment — FICA

F — Faith or beliefs Do you consider yourself spiritual or religious?

What things do you believe in that give meaning to your life?

I — Importance and 

Influence

What influence does it have on how you take care of yourself? 

What role do your beliefs play in regaining your health?

C — Community Is there a person or group who are really important to you? 

Are you part of a religious community?

A — Address How would you like your health care providers to address these 

issues?

Adapted from Puchalski, 2000.

D. TIME OF DEATH

At the time of death it is important to be familiar with the woman’s customs. 

Friends and family present may want to hold hands or stand in a circle around the 

bed. A prayer or song may be said or sung together. In many cultures, the women 

(or men, depending upon the belief system) will want to wash the body, perhaps 

apply oils, and to wrap the body in appropriate garments. Staff should be aware of 

these practices and allow the family as much time as is needed to complete these 

rituals. It may be necessary to wait for other friends or family members to arrive 

to say their own goodbyes. Children should not be kept from participating and will 

understand the death within their own age-related construct.
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E. GRIEF AND BEREAVEMENT

Grief is the process and work of adjusting to the irrevocable loss of persons, 

objects, relationships, and dreams. The grieving period often begins before death 

(anticipatory grieving) but may appropriately extend for two years or more after 

death depending upon the nature of the relationship. Grief is a normal response 

to loss and includes such symptoms as sadness, crying, withdrawal from other 

friends and family, loss of drive or ability to concentrate, and fears of “losing one’s 

mind” or experiencing physical symptoms similar those of the person who died. 

The grieving person requires significant support such as brief visits, phone calls, 

or invitations to simple social events. Many community hospice programs can 

provide this type of support.

One role of the palliative care team is to assure that care is given to those left 

behind, the bereaved. Because of the concentration of activity near the time of 

death, the bereaved may not feel the full impact of the death for at least two weeks 

after the actual event. Contact at this time is helpful as is remembering the person 

on important anniversaries such as one month after the death, holidays, and days 

particular to the individual who died such as a birthday or wedding anniversary. 

The first and tenth year anniversaries of the death are a often a difficult time 

for families and friends. Many cultures have rituals related to the date of death 

that continue to comfort those surviving. Coping strategies that have been useful 

throughout the disease can also be applied after the death of a loved one.

MULTIPLE LOSS

Having to mourn a second or third person soon after the death of the first is 

generally more than any individual is able to cope with alone. Dean (1995) found 

a direct relationship between the number of bereavement episodes suffered by 

one person and the development of “stress response” symptoms or, as Rando says, 

“psychic numbing” (Rando, 1993). Although the phenomenon of “multiple loss” 

has been acknowledged in association with natural disasters and concentration 

camp survivors, there has been little published about how to cope with and 

resolve the issues raised by multiple loss.

Many survivors of multiple loss are afraid to openly grieve for fear of losing 

control of their emotions. Holding onto this grief produces a syndrome 

similar to that seen with “burn-out” (Bennett, 1995; Price, 1984). Emotional 

numbing, withdrawal from others, misdirected anger, a lack of pleasure in 

anything, and resorting to use of drugs or alcohol are all common elements 

of this syndrome. Kastenbaum (1969) called this series of consecutive losses 

“bereavement overload.” More recently Nord (1996) has delineated four stages 

of response to multiple AIDS-related loss. These are not mutually exclusive 

stages and may occur at random rather than in a linear fashion. These stages 

are: 1) shock and denial, 2) overload and confusion, 3) facing reality, and 

4) reinvestment and recovery.

The traditional bereavement model is inadequate for grieving the multiple 

losses experienced by survivors of AIDS-related loss. Care of persons with AIDS 

is complicated by the fact that the care giver may himself or herself be infected 

and facing death. It is important to be able to refer the care giver for appropriate 
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medical care and counseling. Depression is not unusual and, particularly in those 

who are also infected, should be treated appropriately and aggressively, even at 

the time of death of the loved one.

Not only members of the gay and hemophiliac communities (which have been hit 

particularly hard by the epidemic), but mothers of inner city minority youth who 

may have experienced the death of more than one child and are often alone in 

trying to resolve their grief are at risk for complicated mourning. “When multiple 

deaths occur, the people to whom the mourner would ordinarily go for support 

are gone” (Rando, 1993). Therefore, new models for dealing with these losses 

need to be developed. Survivors of multiple loss might be helped by a referral for 

professional counseling.

A time-honored hospice technique has been to attempt to make the sufferer aware 

of the many manifestations of grief by verbalizing that thoughts of “going crazy” 

are not unusual and by reassuring those grieving that they, as survivors, are and 

will be OK (Table 12-17). According to Nord (1996), “social support, community 

involvement, and fostering a sense of purpose are useful” toward achieving the 

goal of empowerment, which helps reduce the role of victim. Achieving a sense 

of balance in life and pursuing a “life outside of AIDS” give survivors a necessary 

source of detachment. Physical exercise, meditation, and trips away from the 

usual environment are acceptable methods used to care for the care provider 

(Table 12-18). An active sense of humor is also helpful.

Table 12-17: Methods for Coping with Multiple Loss

• Acknowledge the loss

• Normalize feeling of “going crazy”

• Physical exercise; adequate sleep

• Community service; foster “sense of purpose”

• Keep the memory alive

• Perform rituals, e.g., quilt panel, memorial service

“Bearing witness” means keeping the memory alive; the AIDS quilt is a good 

example. The quilt is also an example of the power and importance of ritual. 

Making a quilt panel is a shared experience that provides support for the makers 

and for the viewers. Memorial services on a regular basis can be comforting and 

assist the survivor in bringing closure for an individual death.

GUIDELINES FOR AFTER THE DEATH

Mallinson (1997) has outlined guidelines for addressing grief that might be useful 

in working with those who are surviving loss from HIV disease. Simply rehearsing 

words or phrases ahead of time makes it easier for the health care team to interact 

with survivors during a time many find awkward.

• Acknowledge the death: “I understand that your [partner; spouse] 

died last week. How is this going for you?”
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• Validate the importance to the survivor: “You knew her for a long 

time, and the two of you were very close. What was she like?”

• Speak of the deceased when appropriate: “I remember when 

Tommy was first born. This would have been his second birthday 

this week. How are you feeling?”

• Note the existence of multiple losses: “Since you have been 

coming to clinic, you have lost your partner, your best friend, 

and now, your daughter. I can’t imagine what it is like. How do 

you handle the grief?”

• Learn about grief and loss: Take courses, attend workshops, read 

research, and acquire therapeutic communication skills.

Table 12-18: Facilitating the Grieving Process

1. Share your thoughts

2. Make time for enjoyable activities

3. Exercise regularly

4. Treat yourself to little extras

5. Work through your grief gradually

Source: Leash, 1994.

VIII. CARE OF THE CARE PROVIDER

Palliative care is difficult work because it requires that team members suspend 

personal needs or beliefs in deference to the desires of the patient and family. It 

requires a degree of emotional maturity and insight regarding personal feelings 

or beliefs that might interfere with the work. One must develop coping skills for 

both external and internal stressors (Bennett, 1995). “Debriefing” is important and 

must be a recognized part of this care.

Although “support groups” often seem like a useful mechanism, they can be 

burdensome themselves and are not helpful for everyone. Staff must have a 

recognized way to “take a time-out” and be flexible enough to “cover” for a colleague 

who needs a bit of time to “regroup” (Puckett, 1996). Many who do hospice work 

have learned to take breaks or minivacations, to develop outside interests, or to do 

community service of another type. Without conscious support of all members of 

the team the burn-out rate would undoubtedly be high (Price, 1984).
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XIII

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I. INTRODUCTION

The risk of HIV transmission to medical personnel has been recognized since 

1984, with the first reported case of HIV transmitted to a health care worker 

(HCW) following needlestick injury (Anonymous, 1984). Since that time, 

information regarding occupational exposure and outcomes has been collected. 

As of December 2001, there were 57 confirmed cases and 138 possible cases of 

occupationally-acquired HIV infection among U.S. health care workers reported 

to the Centers for Disease Control and Prevention (CDC) (Gerberding, 2003). 

Among the confirmed cases, the most common occupations were nurses (23), 

laboratory technicians (20), and physicians (6). A HCW is defined as any person 

whose activities involve contact with patients or with blood and/or body fluid 

from patients in a health care, laboratory, or public safety setting. An exposure is 

defined as a percutaneous injury (needlestick or other cut with a sharp object), 

mucous membrane or nonintact skin (e.g., chapped or abraded skin, dermatitis), 

or prolonged contact and/or contact involving an extensive area with blood, 

tissue, or certain other body fluids. Table 13-1 lists types of exposure that yield a 

significant health care risk for HIV transmission. Table 13-2 lists body fluids with 

their relative relationship to risk to exposure. When possible, biomolecular assays, 

including nucleic acid sequencing, have been used to determine the similarity 

in viral strain between the infected HCW and the possible source (Diaz, 1999).

Table 13-1: Types of Exposure Associated with Transmission

Percutaneous • Needlestick

• Cut with sharp object

• Human bite

Mucocutaneous • Nonintact skin

- Abraded 

- Chapped 

- Dermatitis

• Mucous membrane

• Other‡

‡Any contact without barrier protection to concentrated virus in a research laboratory or production 

facility requires clinical evaluation. There is a theoretical but undocumented risk to HCW from exposures 

to intact skin.

XIII: OCCUPATIONAL EXPOSURE

Rani Lewis, MD
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Table 13-2: Body Fluids and Risk of Exposure

High Risk of 

Transmission

Poorly Defined Risk 

of Transmission

Low Risk*

• Blood, serum

• Semen

• Vaginal secretions

• Other body fluids visibly 

contaminated with blood

• Amniotic fluid

• Cerebrospinal fluid

• Pleural fluid

• Peritoneal fluid

• Pericardial fluid

• Synovial fluid

• Cervical mucus

• Emesis

• Feces

• Saliva

• Sweat

• Tears

• Urine

• Sputum

• Nasal secretions

* Unless visibly contaminated with blood.

Source: CDC, 2001.

Table 13-3: Recommendations for HIV Postexposure Prophylaxis 

after Percutaneous Injury

Infection Status of Sources

Exposure 

Type

HIVPositive 

(Asx or HIVRNA <1500 

c/mL)

HIVPositive 

(Sx HIV/AIDS, 

acute HIV, 

or HIV-RNA 

>1500 c/mL)

Source of 

unknown 

HIV status

Unknown 

sourceØ

HIVNegative

Lower Risk¶ Basic 2-

drug PEP 

recommended 

Expanded 

3-drug PEP 

recommended

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** 

for source 

with HIV risk 

factors§

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** in 

settings where 

exposure to HIVinfected persons 

is likely

No PEP 

warranted

Higher Risk† Expanded 

3-drug PEP 

recommended

Expanded 

3-drug PEP 

recommended

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** 

for source 

with HIV risk 

factors§

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** in 

settings where 

exposure to HIVinfected persons 

is likely

No PEP 

warranted

¶ Less severe (e.g., solid needle and superficial injury).

** The designation , “consider PEP,” indicates that PEP is optional and should be based on an 

individualized decision between the exposed person and the treating clinician.

§ If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be 

discontinued.

† More severe (e.g, large-bore hollow needle, deep puncture, visible blood on device, or needle used 

in patient’s artery or vein).

Ø Unknown source (e.g., a needle from a sharps disposal container)

Adapted CDC, 2001.
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XIII

In 1995, the Centers for Disease Control and Prevention (CDC) published a report 

of known cases of occupational exposure in France, the United Kingdom, and the 

United States (CDC, 1995). An important finding from this retrospective casecontrol study was that postexposure prophylaxis (PEP) with zidovudine (ZDV) 

was associated with a significant reduction in seroconversion. This prompted the 

formation of a U.S. Public Health Service interagency working group, composed 

of members from the CDC, the Food and Drug Administration, the Health 

Resources and Services Administration, the National Institutes of Health, and 

other expert consultants, who developed guidelines for the use of PEP for HCWs 

after occupational HIV exposure; these recommendations were updated in 2001 

and expanded to include recommendations for management of occupational 

exposure to hepatitis B and hepatitis C viruses (CDC, 2001) (Table 13-3, 13-4).

This chapter will review risk factors for transmission and the magnitude of risk 

for HIV transmission from an occupational exposure, prevention of exposures, 

and postexposure management, including PEP with antiretroviral medications.

Table 13-4: Recommendations for HIV Postexposure Prophylaxis 

after Mucous Membrane and Nonintact Skin∞ Exposures

Infection Status of Sources

Exposure 

Type

HIVPositive 

(Asx or HIVRNA <1500 

c/mL)

HIVPositive 

(Sx HIV/AIDS, 

acute HIV, 

or HIV-RNA 

>1500 c/mL)

Source of 

unknown 

HIV status

Unknown 

sourceØ

HIVNegative

Small 

Volume¶

Consider basic 

2-drug PEP

Basic 2-

drug PEP 

recommended 

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** 

for source 

with HIV risk 

factors§

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** in 

settings where 

exposure to HIVinfected persons 

is likely

No PEP 

warranted

Large 

Volume†

Basic 2-

drug PEP 

recommended 

Expanded 

3-drug PEP 

recommended 

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** 

for source 

with HIV risk 

factors§

Generally, no 

PEP warranted; 

however, 

consider basic 

2-drug PEP** in 

settings where 

exposure to HIVinfected persons 

is likely

No PEP 

warranted

∞ For skin exposures, follow-up is indicated only if there is evidence of compromised skin integrity 

(e.g., dermatitis, abrasion, or open wound).

Ø Unknown source (e.g. splash from inappropriately disposed blood).

¶ Small volume (i.e., a few drops).

** The designation , “consider PEP,” indicates that PEP is optional and should be based on an 

individualized decision between the exposed person and the treating clinician.

§ If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should 

be discontinued.

† Large volume (i.e., major blood splash).
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456 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

II. MAGNITUDE OF RISK

Correct estimation of the likelihood of transmission following occupational 

exposure is limited by the relative infrequency with which HIV transmission 

to HCWs is reported. In addition, the retrospective nature of this reporting 

leads to an increased potential for invalid analysis of the risks. There have 

been prospective and retrospective reviews of all published cases that implicate 

occupational exposure. The most complete prospective study performed on data 

from the United States estimates that the risk of HIV transmission following 

occupational exposure via single needlestick injury is 0.3% (Bell, 1997). This 

is compared to a risk of 1–6% for clinical hepatitis (serologic evidence of HBV 

23–27%) after percutaneous exposure to HBsAg-positive blood; 22–31% for 

clinical hepatitis (serologic evidence of HBV 37–62%) (Werner, 1982) after 

similar exposure to HBeAg-positive blood in unvaccinated health-care workers; 

and an average incidence of 1.8% infection with hepatitis C virus (HCV) after 

accidental percutaneous exposure to an HCV-positive source (Alter, 1994; Mitsui, 

1992; Puro, 1995). Ippolito and coworkers reviewed the world literature on 

occupational exposure from an HIV-seropositive source and determined risk to 

be approximately 0.09% following a mucocutaneous exposure (Ippolito, 1993). As 

noted in Table 13-2, the risk from skin exposure or exposure to body fluids/tissues 

other than blood has not been clearly defined. Risk of HIV transmission increases 

with multiple exposures and with presence of risk factors listed below.

III. RISK FACTORS FOR OCCUPATIONAL HIV TRANSMISSION

The likelihood of HIV infection following exposure is affected by the presence of 

certain risk factors. Cardo and coworkers (1997) performed a case-control study of 

internationally gathered cases of percutaneous exposure of HCWs to HIV-infected 

blood in an attempt to determine factors that increased or decreased the risk of 

transmission (see Table 13-5). Their data indicate that HCWs who took ZDV after 

potential exposure had an 81% lower risk of becoming infected (95% confidence 

interval, 48–94%) than those who did not take this medication.

In general, risk factors include:

• Type of contact or exposure. Exposure has been classified into 

several risk categories (Table 13-1), including percutaneous, 

mucocutaneous, and intact skin contact, with different risks of 

transmission.

• Type of body fluid. The risk for transmission after exposure 

to fluids or tissues other than HIV-infected blood has not been 

quantified but is thought to be significantly lower than for blood 

exposure (Table 13-2) (Henderson, 1990).

• Quantity of blood. Exposure to larger quantities of blood from 

an HIV source, as indicated by a deep needlestick, exposure 

to a needle placed directly into a vessel, or visible blood on 

the injuring device is associated with an increased risk of 

transmission. Hollow-bore needles transfer more blood than solid 

needles and account for most exposures resulting in occupational 

transmission of HIV (Gerberding, 2003; Mast, 1993).
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• Disease status of source patient. Exposure to blood from patients 

with terminal illness increases risk. This likely reflects risk 

associated with exposure to higher levels of virus in blood (higher 

viral loads). HIV-RNA level has been shown to be a significant 

factor in the risk of perinatal transmission. Individuals with acute 

HIV infection also have very high HIV-RNA levels and probably 

represent an increased risk of transmission if occupational 

exposure occurs. HCW seroconversion has been reported after 

exposure to an HIV-infected patient with undetectable viral load 

(CDC, 1998b). Other factors often present in late-stage disease, 

such as more virulent syncytia-inducing HIV strains, may also 

increase risk.

• Host defenses. There is some limited evidence that the immune 

response of the HCW may affect the risk of transmission (Pinto, 

1997). Pinto et al. demonstrated an HIV-specific cytotoxic Tlymphocyte response among HIV-exposed but uninfected HCWs 

when the peripheral blood mononuclear cells were stimulated 

in vitro by HIV mitogens. Along with similar responses seen 

in other groups with repeated exposure without infection, this 

suggests the possibility that the host immune response may 

prevent HIV infection after exposure.

• Postexposure prophylaxis. The data of Cardo et al. (1997) confirm 

the efficacy of PEP in limiting the risk of HIV transmission to 

HCWs. Several case reports of transmission in the setting of 

prompt initiation of PEP, however, indicate that this therapy is 

not 100% effective. There are at least 21 cases worldwide of PEP 

failure, including prophylaxis with 2 or more antiretroviral drugs 

in some cases, following HCW exposure (Gerberding, 2003). HIV 

resistance to the antiretroviral drugs used or delay in initiation 

of medication has been hypothesized to play a role in these (and 

other, non-HCW) prophylaxis failures.

Table 13-5: Logistic-Regression Analysis of Risk Factors for 

HIV Transmission after Percutaneous Exposure 

to HIV-infected Blood

Risk Factor

U.S. Cases* All Cases+

Adjusted Odds Ratio (95% CI)*

Deep injury 13.0 (4.4–42) 15.0 (6.0–41)

Visible blood on device 4.5 (1.4–16) 6.2 (2.2–21)

Procedure involving needle in artery or vein 3.6 (1.3–11) 4.3 (1.7–12)

Terminal illness in source patient§ 8.5 (2.8–28) 5.6 (2.0–16)

Postexposure use of zidovudine 0.14 (0.03–0.47) 0.19 (0.06–0.52)

* All risk factors were significant (p<.02)

* All risk factors were significant (p<.01)

‡ CI denotes confidence interval. Odds ratios are for the odds of seroconversion after exposure in 

workers with the risk factor as compared with those without it.

§ Terminal illness was defined as disease leading to death of the source patient from AIDS within 2 

months after the health care worker’s exposure.

Source: Cardo, 1997.
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IV. PREVENTING OCCUPATIONAL EXPOSURE

Limiting HCWs’ exposure to potentially infectious materials is the key to reducing 

the risks of occupational exposure. Universal precautions, as recommended by 

the Occupational Safety and Health Administration (OSHA), reflect the concept 

that all blood and body fluids are potentially infectious and must be handled 

accordingly. Personal protective equipment (Table 13-6) should be used to prevent 

blood and other potentially infectious material from reaching a HCW’s clothing, 

skin, eyes, mouth, or mucous membranes (CDC, 1987).

Table 13-6: Personal Protective Equipment

• Gloves

• Gowns

• Laboratory coats

• Face shields

• Eye protection

• Mouthpieces

• Resuscitation bags

Handwashing should be done after touching blood, body fluids or secretions, 

or contaminated items, whether or not gloves are worn. Hands should also 

be washed after removing gloves and between patient contacts. Gloves should 

be worn when in contact with blood or body fluids (including blood drawing), 

mucous membranes or nonintact skin, or items contaminated with possibly 

infectious material; it is strongly recommended that gloves be worn when 

performing any invasive procedure. Clinicians performing surgery, deliveries, or 

other invasive procedures likely to generate splashes of blood or other body fluids 

should wear a mask and eye protection or face shield. The use of double-gloving 

in surgical procedures has been shown to reduce the risk of direct blood contact 

for operating room personnel (Greco, 1995; Konig, 1992). Needles and other sharp 

instruments should be handled with great care and disposed of in approved sharps 

containers. As a rule, do not recap, bend, or break used needles. During surgery 

hand-to-hand passage of sharp instruments (e.g., needles, scalpels) should be 

minimized—consider passing these instruments first onto a surgical tray or pan.

Risk of occupational exposure and need for universal precautions applies not 

only to physicians, nurses, and laboratory workers, but also to medical, nursing, 

or dental students, and to dentists. Since reports of patient-to-dentist and dentistto-patient HIV transmission seen in the late 1980s (CDC, 1991a), both the CDC 

and the American Dental Association have included recommendations regarding 

the use of barrier precautions in dental settings and sterile technique in the 

preparation of dental equipment (American Dental Association, 1988).

Another group at increased but less well defined risk are emergency medical 

technicians, paramedics, and law enforcement agents. These individuals are 

frequently in contact with patients of unknown or noncommunicated HIV 

status, in emergency situations. OSHA regulations requiring the availability of 
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face masks, mouth shields, and ventilation masks are designed to reduce the 

risk to emergency technicians and other public safety workers. Given the highly 

unpredictable nature of their risk for exposure, general infection control measures 

are recommended, even when the risk appears low (International Association 

of Fire Fighters, 1988). Given the prevalence of HIV infection within prison 

populations, correctional officers are also at increased risk for occupational 

exposure and should use universal precautions (Hammett, 1991). Intentional 

human bites are more common in correctional facilities and may present a risk 

of infection transmission and should be evaluated appropriately. 

V. HIV INFECTION FOLLOWING OCCUPATIONAL EXPOSURE

There is limited information regarding the symptomatology seen in HCWs 

experiencing seroconversion from occupational exposure. Approximately four 

fifths of cases were associated with symptoms consistent with primary HIV 

infection, usually 2–6 weeks after exposure (CDC, 1998b). The mean time to 

seroconversion is 65 days, and of infected HCWs who seroconvert, 95% have done 

so within 6 mo after exposure (Busch, 1997). There are rare reported cases of 

HCWs who remain negative for HIV antibody at 6 mo, but seroconvert by 12 mo 

after exposure (Ciesielski, 1997; Konig, 1992). Delayed seroconversion has been 

associated with simultaneous exposure to hepatitis C in two cases, one of which 

resulted in fulminant and fatal HCV (Ridzon, 1997). Further information regarding 

the effect of coinfection with other viral illnesses remains to be determined.

HCWs presenting for HIV exposure PEP need to be counseled regarding risks of 

other viral illnesses to which they may have been exposed, especially hepatitis 

B and hepatitis C viruses. HCWs at risk for occupational exposure to hepatitis B 

should have appropriate vaccination.

Hepatitis C virus is the most common chronic blood-borne infection in the United 

States. The Third National Health and Nutrition Examination Survey (NHANES 

III) data estimate 3.9 million Americans have been infected with HCV, with 

36,000 new infections reported per year (CDC, 1998c). HCV seroconversion most 

often occurs after percutaneous exposure in the health care setting. Infection via 

mucous membrane exposure, although extremely rare, has been reported (Sartori, 

1993). There is no vaccine or immunoglobulin available for HCV PEP.

VI. POSTEXPOSURE MANAGEMENT

Health care organizations are required to have exposure-control plans, including 

postexposure management and follow-up for employees at risk. OSHA mandates 

reporting of exposure incidents.

A. EXPOSURE SITE MANAGEMENT

Wounds and puncture sites should be washed with soap and water; mucous 

membranes exposed should be flushed with water. The application of bleach to 

skin or mucosal surfaces is not recommended.
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B. EXPOSURE EVALUATION

The type of body fluid involved, type of exposure (percutaneous, mucosal, 

nonintact skin, etc.), and the severity of the exposure (quantity of blood, duration 

of contact, etc.) should be evaluated and will affect decisions about PEP (see 

Tables 13-1, 13-2).

C. SOURCE PATIENT EVALUATION

The source individual of the exposure should be evaluated for possible HIV 

infection and, if status is unknown, should be tested, after appropriate consent 

(see Table 13-7). In the absence of risk factors and clinical findings consistent 

with acute HIV infection, a negative result with use of a sensitive enzyme 

immunoassay for HIV screening implies a transmission risk of zero. (Gerberding 

2003). Medical information such as previous HIV test results; HBV, HCV testing; 

clinical signs, symptoms, or diagnoses; and history of risk exposures (e.g., injection 

drug use) may be relevant in making initial decisions regarding PEP. Rapid HIV 

testing, if available, may be particularly useful in the setting of occupational 

exposure and can decrease unnecessary antiretroviral exposure, save money, and 

decrease anxiety. Confirmation of reactive results with screening assay or rapid 

test is not necessary to start PEP, but should be done before the source patient 

is informed. If the source patient has signs/symptoms consistent with possible 

acute HIV infection, testing should include plasma HIV-RNA levels. Initiation of 

PEP, if indicated, should not be delayed while awaiting test results. If the source 

is known to be HIV-infected, information about clinical stage of infection, recent 

CD4 counts, viral load testing, antiretroviral treatment history, and antiretroviral 

resistance testing, if available, are important in choosing an appropriate PEP 

regimen; however, initiation of PEP should not be delayed if this information is 

not immediately available.

Table 13-7: Evaluation of Occupational Exposure Sources

Known Sources

• Test known sources for HBsAg, anti-HCV, and HIV antibody

- Direct virus assays for routine screening of source patients are not recommended

- Consider using a rapid HIV-antibody test

- If the source person is not infected with a bloodborne pathogen, baseline testing or further follow-up 

of the exposed person is not necessary

• For sources whose infection status remains unknown (e.g., the source person refuses testing), consider 

medical diagnoses, clinical symptoms, and history of risk behaviors

• Do not test discarded needles for bloodborne pathogens

Unknown Sources

• For unknown sources, evaluate the likelihood of exposure to a source at high risk for infection

- Consider likelihood of bloodborne pathogen infection among patients in the exposure setting

CDC, 2001.

The source patient should also be tested for anti-HCV and HBsAg to assess the 

HCW’s risk for hepatitis B and C. Confidentiality of the source patient should be 

maintained at all times.
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D. BASELINE AND FOLLOW-UP TESTING

Baseline testing for HIV antibody should be performed to establish serostatus 

at the time of exposure and should be repeated at 6 wk, 12 wk, and 6 mo 

postexposure, regardless of the use of PEP. An extended duration of follow-up 

may be considered with simultaneous exposure to HCV or use of highly active 

antiretroviral therapy regimens for PEP because of theoretical concerns about 

delay in HIV seroconversion in these situations. Pregnancy testing should be 

offered to HCWs of reproductive age if pregnancy status is unknown.

In addition to HIV, hepatitis B and C are significant concerns. For the HCW exposed to 

an HCV-positive source, baseline and follow-up testing (at 4–6 mo) for anti-HCV and 

serum alanine aminotransferase is recommended. Confirmation by a supplemental 

assay (such as recombinant immunoblot assay or HCV PCR) is recommended for all 

positive anti-HCV results by enzyme immunoassay (CDC, 2001).

If the HCW has previously received the hepatitis B virus (HBV) vaccine and antiHBsAg level, which reflects vaccine-induced protection, is unknown, this should 

be tested; if inadequate, hepatitis B immune globulin is recommended, as well as 

a booster dose of vaccine. Recommendations for PEP for hepatitis B exposures are 

outlined in Table 13-8.

Table 13-8: Recommendations for Postexposure Prophylaxis After 

Exposure to Hepatitis B Virus

Vaccination and 

antibody response 

status of exposed 

person****

Source HBsAg* positive Source 

HBsAg* 

negative

Source unknown or 

not available for 

testing

Unvaccinated HBIG# x 1 and initiate 

HB vaccine series##

Initiate HB 

vaccine 

series

Initiate HB vaccine 

series

Previously vaccinated

- known 

responder**

No treatment No 

treatment

No treatment

- known 

nonresponder@@

HBIG x 1 and initiate 

revaccination or HBIG 

x 2***

No 

treatment

If known high risk 

source, treat as if 

source were HBsAg 

positive

- antibody response 

unknown

Test exposed person for 

anti-HBs###

1. If adequate**, no treatment 

necessary

2. If inadequate@@, administer 

HBIG x 1 and vaccine booster

No 

treatment

Test exposed person 

for anti-HBs

1. If adequate**, no 

treatment necessary

2. If inadequate@@, 

administer vaccine booster and 

recheck titer in 1-2 months

Adapted CDC 2001

**** persons who have previously been infected with HBV are immune to reinfection and do not require 

postexposure prophylaxis

* Hepatitis B surface antigen

# Hepatitis B immune globulin (dose: 0.06 mL/kg intramuscularly)

## Hepatitis B vaccine

** A responder is a person with adequate levels of serum antibody to HBsAg (> or = 10 mIU/mL)

@@ A nonresponder is a person with inadequate levels of serum antibody to HBsAg (<10 mIU/mL)

*** The option of giving one dose of HBIG and reinitiating the vaccine series is preferred for 

nonresponders who have not completed a second 3-dose vaccine series. Two doses of HBIG are 

preferred for persons who have previously completed a second vaccine series but failed to respond

### Antibody to HBsAg
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E. COUNSELING THE HCW

• Decisions regarding appropriate postexposure management 

should be individualized; the HCW should be counseled about 

their personal risk based on considerations outlined above, and 

recommendations made about initiating PEP.

• The HCW should be informed that knowledge about the 

effectiveness and the toxicity of the antiretroviral drugs used for 

PEP is limited and failures of PEP have occurred. The addition 

of antiretroviral drugs other than ZDV to a PEP regimen is based 

on the superiority of combination antiretroviral regimens over 

monotherapy in the treatment of HIV-infected individuals and 

the theoretical considerations regarding possible resistance 

concerns and the utility of using drugs having activity at 

different stages in the viral replication cycle.

• The medical history of the HCW, including medications, presence 

or possibility of pregnancy, or other medical conditions, should 

be obtained and may influence decisions or recommendations 

about PEP, including choice of regimen.

• A specific PEP regimen should be recommended, when 

indicated, and the rationale for its selection should be discussed. 

Information should be given about how to take the medications, 

potential side effects and measures to minimize these, possible 

drug-drug interactions with recommended regimen and any 

medications that should not be taken while taking PEP, clinical 

monitoring for toxicity, and symptoms that should prompt 

immediate evaluation. Emphasize the importance of adherence.

• PEP may be declined by the HCW.

• The HCW should be urged to seek medical evaluation with the 

development of any acute illness during the follow-up period. 

The differential diagnosis in this situation must include acute 

HIV infection, drug reaction, toxicity from the PEP regimen, or 

other medical illness.

• Measures to reduce the risk of possible secondary transmission 

during follow-up (especially in the 6–12 wk after exposure) 

should be discussed and recommended. These include use 

of condoms or abstinence to prevent sexual transmission and 

pregnancy; not donating blood, plasma, tissue, or organs; and, 

in lactating mothers, discontinuing breastfeeding or pumping 

breasts and discarding breastmilk during this period.

• There is no need to modify clinical responsibilities based on 

HIV exposure.

• Each HCW should be given a contact name and/or number to 

call for concerns or questions.

F. POSTEXPOSURE PROPHYLAXIS FOR HIV

The decision regarding which and how many antiretroviral agents to use is largely 

empiric and should try to balance the risk for infection against the potential toxicity of 

the PEP regimen. Current recommendations are to use a two- or three-drug regimen 

based on level of HIV transmission risk and possibility of drug resistance (see Table 

13-4). PEP should be initiated as soon as possible following exposure, preferably within 

1–2 hours, and continued for 4 wk. Specific drug recommendations are outlined in 
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Table 13-9. Standard dosing should be used. The FDA has reports of 22 HCW receiving 

nevirapine-containing PEP regimens with serious reactions, including 12 cases of 

hepatotoxicity and 14 with skin reactions (including Stevens Johnson syndrome). 

Nevirapine should be avoided in PEP regimens (Johnson, 2000; CDC 2001).

Table 13-9: Potential Antiretroviral Regimens For 

Post-exposure Prophylaxis

Regimen Comment

Basic

zidovudine (ZDV) + 

lamivudine (3TC)

ZDV only drug with established efficacy; has high rates of 

GI intolerance, fatigue, headache-monitor CBC

3TC well tolerated and can be given qd; ZDV/3TC 

available as co-formulation

stavudine (d4T) + 

lamivudine (3TC)

d4T with good short-term tolerance; 3TC as above

didanosine (ddI) + 

lamivudine (3TC)

Both can be given with qd dosing; ddI must be taken on 

empty stomach; peripheral neuropathy with ddI in 5-12%, 

pancreatitis in 1-9% (fatal in 6% of those who develop 

pancreatitis)

tenofovir (TDF) + 

lamivudine (3TC)

TDF well tolerated, effective for PEP in primate model, can 

be given with qd dosing; 3TC as above

Expanded 

(Basic regimen plus one of the following)

lopinavir/

ritonavir (LPV/r)

Potent; should be taken with food; monitor liver enzymes

atazanavir (ATV) +/-

ritonavir (RTV)

Potent, well tolerated, can be given with qd dosing; 

boosted well with RTV; should be taken with food; 

monitor liver enzymes

nelfinavir (NFV) Well tolerated except for diarrhea; should be taken with 

dose; monitor liver enzymes

fosamprenavir/

ritonavir (fAPV/r)

Low pill burden, can be given qd; no food effect; monitor 

liver enzymes

indinavir (IDV) Risk of renal stones; requires tid dosing; must be taken on 

empty stomach

efavirenz (EFV) Potent, concern for short-term central nervous system side 

effects in health care workers; qd dosing

abacavir (ABC) 

(should not be 

combined with 

TDF/3TC because 

of high rate of 

early virologic 

nonresponse)

Rare but potentially fatal hypersensitivity reaction; less 

potent in combination with basic regimens; available as 

coformulation with ZDV/3TC

Adapted: Bartlett 2004 

These regimens include those recommended in USPHS 2001 guidelines except for d4T/ddI, which is no longer 

recommended as part of antiretroviral treatment regimens because of high incidence of toxicity. Additional 

possible regimens are included with agents not available at the time the 2001 guidelines were developed.
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Of the HCWs receiving PEP (ZDV or a combination of agents), almost 50% 

report subjective side effects and these have led to discontinuation of therapy 

in approximately one third of cases (CDC, 2001). Gastrointestinal side effects are 

common but are not serious and can generally be managed, as is the case with 

most adverse effects seen with PEP. Serious side effects, including renal stones and 

pancytopenia, have been reported but are rare. For more details about side effects 

with different antiretroviral agents, see Chapter XIV on Pharmacology. Laboratory 

monitoring should include a complete blood count and renal and hepatic function 

tests at baseline and 2 wk after initiation of PEP; more in-depth testing may be 

indicated based on underlying medical conditions or specific toxicity associated 

with drugs in the PEP regimen (e.g., glucose testing if on a protease inhibitor). Table 

13-10 outlines situations for which expert consultation is advised (see Chapter 15 for 

resources on PEP consultation).

Table 13-10: Situations for which expert consultation regarding 

PEP is advised

• Delayed (i.e., later than 24–36 hours) exposure report

- the interval after which there is no benefit from postexposure prophylaxis (PEP) is undefined

• Unknown source (e.g., needle in sharps disposal container or laundry)

• Known or suspected pregnancy in the exposed person

• Resistance of the source virus to antiretroviral agents known or suspected

• Toxicity of the initial PEP regimen

- adverse symptoms, such as nausea and diarrhea are common with PEP

- symptoms often can be managed without changing the PEP regimen by prescribing antimotility and/

or antiemetic agents

- modification of dose intervals (i.e., administering a lower dose of drug more frequently throughout 

the day, as recommended by the manufacturer), in other situations, might help alleviate symptoms

Adapted CDC, 2001.

VII. SPECIAL CONSIDERATIONS

A. ANTIRETROVIRAL RESISTANCE

It is unclear how antiretroviral resistance influences risk of HIV transmission. 

Occupational transmission of drug-resistant strains has been reported despite 

use of PEP with combination drug regimens (Perdue, 1999; Beltrami, 2000a). 

In a study of occupational exposures 39% of 41 source patients had resistance 

mutations to reverse transcriptase inhibitors and 10% to protease inhibitors 

(Beltrami, 2000b). If resistance of the source patient’s virus to one or more of the 

drugs in the PEP regimen is known or suspected (based on drug history, virologic 

response to treatment, or prior resistance testing), drugs should be selected to 

include agents to which the virus is likely to be sensitive. Clinical consultation 

with an expert in HIV treatment should be obtained for guidance in this situation. 

However, it is important not to delay starting PEP because of resistance concerns; 

if resistance is known or suspected, a third or fourth drug may be included in the 

regimen until consultation is obtained.
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B. THE PREGNANT HCW

In addition to the counseling issues noted above, the pregnant HCW should be 

informed about what is known and not known about potential risks, benefits, and 

side effects for the fetus and herself related to the antiretroviral agents used in 

PEP. (Issues relating to the use of antiretroviral drugs in pregnancy are discussed 

in Chapter VII: HIV and Reproduction and in Chapter XIV: Pharmacology.) PEP 

should not be denied on the basis of pregnancy and pregnancy should not prevent 

the use of an optimal PEP regimen. However, regimens containing efavirenz or 

a combination of ddI and d4T should generally be avoided. For breastfeeding 

HCWs, temporary discontinuation of breastfeeding should be considered while 

on PEP to avoid infant exposure to these drugs.

VIII. THE HIV-SEROPOSITIVE HCW

There has been great controversy about HCWs who are infected with HIV and 

continue to work. The infection of several patients by an HIV-seropositive dentist 

is well known although poorly understood. In a retrospective evaluation of over 

22,000 patients treated by 51 health care workers infected with HIV (over three 

quarters in surgical or dental disciplines) no cases of transmission of HIV from 

HCW to patient were documented (Laurie, 1995). Health care workers with 

HIV may also themselves be at risk for contracting a communicable disease; 

appropriate precautions should be taken and appropriate immunizations given.

All clinicians with exudative or transudative skin lesions should refrain from direct 

patient care until these lesions have healed. It is believed that HIV-positive HCWs 

who follow universal precautions and do not perform invasive procedures pose no 

risk to their patients. Furthermore, there are no current data suggesting that HIVpositive HCWs performing nonexposure-prone invasive procedures should have 

their practice restricted, assuming they use universal precautions, appropriate 

technique, and adequate sterilization and disinfection of instruments. 

“Exposure-prone” procedures require more consideration. Exposure-prone 

characteristics include digital palpation of a needle point in a body cavity or the 

simultaneous presence of the HCW’s fingers and a needle or sharp instrument 

in a poorly visualized or highly confined anatomic space. These procedures 

are associated with increased risk for percutaneous injury to the HCW and 

potential increased risk to the patient. It is recommended that all HCWs who 

perform these procedures know their HIV status. HIV-positive HCWs performing 

exposure-prone procedures should seek counsel from an expert review panel on 

a case-by-case basis. Mandatory testing of HCWs is not recommended. The ethics 

of patient notification of exposure to an HIV-infected HCW continues to be argued 

(Blatchford, 2000; Donnelly, 1999). 

It is imperative that institutions have a standard policy on the management of 

HIV-infected HCWs, as well as policies on the management of a HCW potentially 

infected by a patient (CDC, 1991c).
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Henderson DK, Fahey BJ, Willy M et al. Risk for occupational transmission of human immunodeficiency virus type 1 (HIV-1) associated with 

clinical exposures: a prospective evaluation. Ann Intern Med. 1990;113:

740–746.

International Association of Fire Fighters. Guidelines to prevent transmission of communicable disease during emergency care for fire fighters, 

paramedics, and emergency medical technicians. New York: International Association of Fire Fighters; 1988.

Ippolito G, Puro V, De Carli G. The Italian study group on occupational risk 

of HIV infection. The risk of occupational human immunodeficiency 

virus infection in health care workers: Italian multicenter study. Arch 

Intern Med. 1993;153:1451–1458.

Johnson S, Baraboutis JG, Sha BE, Proia LA, Kessler HA. Adverse effects 

associated with use of nevirapine in HIV postexposure prophylaxis for 2 

healthcare workers (letter). JAMA. 2000;284:2722–2723.

Konig M, Bruha M, Hirsch HA. Perforation of surgical gloves in gynecologic 

operations and abdominal Cesarean section. Geburtshilfe Frauenheilkd. 

1992;52:109–112.

Laurie RM, Chamberland ME, Cleveland JL, et al. Investigations of patients 

of health care workers infected with HIV. Ann Intern Med. 1995;122:

653–657.

Mast ST, Woolwine JD, Gerberding JL. Efficacy of gloves in reducing blood 

volumes transferred during simulated needlestick injury. J Infect Dis. 

1993;168:1589–1592.

Mitsui T, Iwano K, Masuko K, et al. Hepatitis C virus infection in medical 

personnel after needlestick accident. Hepatology. 1992;16:1109–1114.

Perdue B, Wolderufael D, Mellons J, Quinn T, Margolick J. HIV-1 transmission by a needlestick injury despite rapid initiation of four-drug postexposure prophylaxis. (Abstract 210). In: Program and Abstracts of the 

6th Conference on Retroviruses and Opportunistic Infections. 1999: 

Chicago, Ill; 107.
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Occupational Exposure

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Pinto LA, Landay AL, Berzofsky JA, Kessler HA, Shearer GM. Immune 

response to human immunodeficiency virus (HIV) in healthcare workers occupationally exposed to HIV-contaminated blood. Am J Med. 

1997;102(Suppl 5B):21–24.

Puro V, Petrosillo N, Ippolito G. Italian study group on occupational risk of 

HIV and other bloodborne infections. Risk of hepatitis C seroconversion 

after occupational exposures in health care workers. Am J Infect Control. 

1995;23:273–277.

Ridzon R, Gallager K, Ciesielski C, et al. Simultaneous transmission of 

human immunodeficiency virus and hepatitis C virus from a needlestick injury. N Engl J Med. 1997;336:919–922.

Sartori M, La Terra G, Aglietta M, Manzin A, Navino C, Verzetti G. Transmission of hepatitis C via blood splash into conjunctiva [letter]. JAMA. 

1993;25:270–271.

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inoculations: use of e antigen to estimate infectivity. Ann Intern Med. 

1982;97:367–369.
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XIV

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I. LIST OF TABLES

Table 14-1: Abbreviations................................................................................................471

Table 14-2: FDA Pregnancy Categories ................................................................. 472

Table 14-3: Antiretrovirals ............................................................................................. 473

Table 14-4: Commonly Used Antimicrobials for the................................... 482

Treatment and Prevention of Opportunistic 

Infections in HIV-Infected Patients

Table 14-5: Safety of Commonly Used Antimicrobials.............................. 496

Table 14-6: Drug Interactions of Antiretrovirals ............................................. 498

Table 14-7: Clinically Pertinent Food-Drug Interactions ........................... 534

Table 14-8: Drugs of Special Consideration in Women............................... 534

Table 14-9: Alternative/Complimentary Medication to ............................ 535

Avoid in Pregnancy

Table 14-10: Dosing of Antiretroviral Agents in Renal ................................. 537

Insufficiency and/or Hepatic Insufficiency 

II. INTRODUCTION

The decision to administer drugs to a pregnant woman is largely based on 

the therapeutic benefit to the mother and/or fetus vs. the potential risk 

to the mother and the developing fetus. Clinicians are often advised to 

avoid prescribing drugs for pregnant patients because human safety data 

in pregnancy are lacking for many, if not most medications. However, in 

some clinical situations the benefits of treatment far outweigh the risks. 

These are important considerations when selecting agents to treat patients 

with human immunodeficiency virus (HIV), to prevent mother-to-child 

HIV transmission, and to prevent or treat opportunistic infections.

There is limited information concerning the safety of many antiretrovirals 

in pregnancy. Mutagenicity, carcinogenicity, and teratogenicity studies in 

animals are the basis for most data on safety in pregnancy. However, generally 

animals are administered doses 5 to 20 times higher than those given to 

humans; clinical applicability to human treatment is not always clear.

It is now standard care to treat HIV-infected patients with an “antiretroviral 

cocktail” or a combination of antiretroviral agents, making it difficult 

to assess the safety of a single antiretroviral agent. More prospective 

XIV: PHARMACOLOGIC CONSIDERATIONS IN

HIV-INFECTED PREGNANT PATIENTS

Paul Pham, PharmD, and Patricia Barditch-Crovo, MD
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clinical data are needed. Clinicians are encouraged to report all in utero 

exposures to the Antiretroviral Pregnancy Registry (telephone 1-800-

258-4263; Fax 1-800-800-1052; Internet access www.APRegistry.com), a 

collaborative effort of pharmaceutical manufacturers with an advisory 

committee of obstetric and pediatric practitioners. Observational data on 

antiretroviral exposure during pregnancy are collected and are used to 

assess potential teratogenicity of these drugs.

The tables contained in this chapter include detailed information about 

pharmacologic agents commonly used in the treatment of HIV-infected 

women and drugs often used in pregnancy or as complementary therapies, 

with particular emphasis on issues related to their use in pregnancy.

III. PHARMACOKINETICS OF DRUGS IN PREGNANCY

Although many physiologic changes occur during pregnancy, few trials 

have been conducted to evaluate their clinical significance on the 

pharmacokinetics of commonly used drugs. Physiologic changes that 

may affect drug pharmacokinetics include delayed gastric emptying, 

decreased intestinal motility, increased volume of distribution (an 

average increase of 8L), increased renal blood flow (by 25–50%), and 

increased glomerular filtration rate (by 50%) (Davidson, 1974; Dunnihoo, 

1992; Parry, 1970). Pharmacokinetics parameters of nevirapine given as a 

single dose of 200 mg at the onset of labor were similar but more variable 

than in nonpregnant adults, possibly due to incomplete absorption 

associated with altered gastrointestinal function during labor (Mirochnick, 

1998). Recent data suggests that NVP levels may be detectable as long 

as 3 weeks after a single dose given at onset of labor (Jourdain, 2004). 

Pregnancy does not change the pharmacokinetics of ZDV, 3TC, d4T, and 

ddI (Moodley, 1998; Schuman, 1990; Wang, 1999). Serum concentrations 

of the PIs that have been studied in pregnancy (indinavir [IDV], ritonavir 

[RTV], and saquinavir [SQV]) appear to be lower in pregnancy when 

given as single PIs (without boosting) (Perinatal Guidelines Working 

Group, 2004). SQV achieves adequate drug levels when boosted with 

RTV (Acosta, 2001) and nelfinavir (NFV) achieves adequate levels when 

given as 1250 mg twice daily (Bryson, 2002). A recent pharmacokinetic 

study including 4 women on an IDV-containing regimen with or without 

ritonavir (RTV) found a decrease in plasma concentrations of IDV during 

pregnancy with spontaneous increase postpartum in two women on IDV 

alone, consistent with metabolic induction of cytochrome P450 activity 

in pregnancy; this induction was offset by the concomitant use of RTV 

(Kosel, 2003). The clinical significance of these differences in pregnancy 

is unclear.
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Table 14-1: Abbreviations 

Drug Abbreviations

ABC: Abacavir (Ziagen) INV: Invirase (saquinavir, HGC)

APV: Amprenavir (Agenerase) IVIG: Intravenous immune globulin

ATV: Atazanavir (Reyataz) LPV/r: Lopinavir/Ritonavir (Kaletra)

AZT: Zidovudine (Retrovir) NFV: Nelfinavir (Viracept)

CBV: Combivir (AZT+3TC) NNRTI: Non-nucleoside Reverse 

Transcriptase Inhibitor

ddI: Didanosine (Videx) NRTI: Nucleoside Reverse Transcriptase 

Inhibitor

d4T: Stavudine (Zerit) NVP: Nevirapine (Viramune)

ddC: Zalcitabine (Hivid) PI: Protease Inhibitor

DLV: Delavirdine (Rescriptor) RBT: Rifabutin (Mycobutin)

EFV: Efavirenz (Sustiva) RTV: Ritonavir (Norvir)

FTC: Emtricitabine (Emtriva) SQV: Saquinavir (Invirase, Fortovase)

ENF: Enfuvirtide (Fuzeon, T-20) 3TC: Lamivudine (Epivir)

FTV: Fortovase (saquinavir, SGC) TDF: Tenofovir (Viread)

fAPV: Fosamprenavir (Lexiva) TMP-SMX: Trimethoprim 

sulfamethoxazole (Bactrim, etc.)

HU: Hydroxyurea TZV: Trizivir (ABC+AZT+3TC)

IDV: Indinavir (Crixivan) VZIG: Varicella zoster immune globulin

INH: Isoniazid ZDV: Zidovudine (Retrovir)

Miscellaneous Abbreviations

ART: Antiretroviral Therapy pk: pharmacokinetcs

ARV: antiretroviral po: by mouth

AUC: area under the concentration time 

curve (i.e. total drug exposure)

qd: daily

Cmax: peak serum concentration qid: four times per day

Cmin: trough serum concentration qm: monthly

EC: Enteric Coated qod: every other day

HAART: Highly Active Antiretroviral 

Therapy

qw: every week

IV: Intravenous soln: solution

IM: Intramuscular tid: three times per day

VL: Viral Load tiw: three times per week

bid: twice per day TAM: thymidine analogue mutation

biw: twice per week TDM: Therapeutic drug monitoring

hs: bedtime (hour of sleep) ULN: upper limit of normal

mo: month
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Table 14-2: FDA Pregnancy Categories

A Adequate and well-controlled studies of pregnant women fail to 

demonstrate a risk to the fetus during the first trimester of pregnancy 

(and there is no evidence of risk during later trimesters).

B Animal reproduction studies fail to demonstrate a risk to the fetus and 

adequate and well-controlled studies of pregnant women have not been 

conducted.

C Safety in human pregnancy has not been determined, animal studies are 

either positive for fetal risk or have not been conducted, and the drug 

should not be used unless the potential benefit outweighs the potential 

risk to the fetus.

D Positive evidence of human fetal risk based on adverse reaction data 

from investigational or marketing experiences, but the potential benefits 

from the use of the drug in pregnant women may be acceptable despite 

its potential risks.

X Studies in animals or reports of adverse reactions have indicated that 

the risk associated with the use of the drug for pregnant women clearly 

outweighs any possible benefit.
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Table 14-3: Antiretrovirals

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience 

in Pregnancy

Comments

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Abacavir (Ziagen®, ABC)

300 mg bid or 600 mg qdAvailable as 300 mg tablets; 10 mg/ml oral solution; Trizivir: ZDV 300 mg/ 3TC 150 mg/ ABC 300 mg Epzicom: 3TC 300 mgABC 600 mg

Hypersensitivity reaction—fever, rash, fatigue, malaise, GI symptoms, and arthralgias (noted in 2–3% of patients). Mandatory and permanent discontinuation with hypersensitivity reaction. Deaths reported upon rechallenge; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

C Rodent studies demonstrated 

placental passage, anasarca, skeletal malformation at 1000 mg/kg dose (35 times human therapeutic levels) during organogenesis. However rabbits receiving 8.5 times human therapeutic levels did not have fetal malformation.

Based on ex vivo data, placental transfer was 32–66% (Bawdon, 1998).

No data on use for prevention of perinatal transmission.

Zidovudine (Retrovir®, AZT, ZDV) 

300 mg po bid, PACTG protocol dosing: Prenatal: 100 mg 5x per day (alternatively 300 mg bid) beginning at weeks 14–34; Intrapartum 2 mg/kg IV for first hour then 1 mg/kg IV until birth. Infant received 2 mg/kg po q 6 h for the first 6 wk of life beginning 8–12 hr after birthAvailable as 100 mg capsules; 300 mg tablets; 10 mg/ml IV solutions; 10 mg/mL oral solution; 300 mg Combivir (ZDV 300 mg/3TC 150 mg), Trizivir (ZDV 300 mg/3TC 150 mg/ABC 200 mg)

GI intolerance, malaise; headache (in 5–10%); bone marrow suppression (anemia and neutropenia seen more commonly with late stage AIDS); myalgia; myopathy; transaminase elevation; fingernail discoloration; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

C Prolonged high dose ZDV exposure 

associated with nonmetastasizing vaginal squamous tumors in 13% of adult rodents, possibly due to concentration of unmetabolized ZDV in rodent urine (but not in humans). Transplacental carcinogenicity studies in mice with differing results: (1) doses 25-50 times human dose given in late gestation resulted in increase in lung, liver, female reproductive tract tumors in offspring exposed to highest dose level; (2) doses approximately 3 times human therapeutic exposure in pregnancy associated with no increase in tumor incidence in offspring. No evidence of fetal malformations or developmental toxicity with doses up to 500-600 mg/kg/day in pregnant rats, mice, rabbits

Human studies demonstrated 85% placental passage. No excess maternal toxicities or fetal defects noted with AZT during pregnancy. Long-term toxicity data (up to 6 yrs.) for infants exposed to AZT in utero and postpartum did not show an increased risk of tumors or abnormal developmental parameters.

The nucleoside analogue with the most extensive clinical data on safety and efficacy during pregnancy. When feasible all antiretroviral regimens for the prevention of perinatal transmission should include AZT.
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Table 14-3: Antiretrovirals (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience 

in Pregnancy

Comments

Stavudine (Zerit®, d4T) Wt >60 kg dose: 40 mg po bid. Wt <60 kg dose: 30 mg 

po bidXR: wt >60kg 100 mg po qd. Wt <60 kg 75 mg po qd.Available as 15, 20, 30, 40 mg capsules; 1mg/mL for oral solution. New 100 mg extended release capsule (Zerit XR) Released early 2003.

Peripheral neuropathy (in 5–15% of patients); transaminase elevation (in 8% of patients); rare cases of lactic acidosis and severe hepatomegaly with steatosis, lipodystrophy; pancreatitis; rare cases of rapidly progressive ascending neuromuscular weakness

C Studies in rhesus monkeys 

demonstrated 76% placental passage. Not teratogenic in rodents, but decreased sternal bone calcium. Carcinogenic studies not completed.

Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving combination of d4T and ddI as component of ARV therapy.No increase in birth defects noted in Antiretroviral Pregnancy Registry

Combination of d4T and ddI should be prescribed in pregnancy with caution, generally only when other NRTI drug combinations have failed or caused unacceptable toxicity/side effects. Due to the antagonism between AZT and d4T, they should never be used together as a part of a HAART regimen.
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Didanosine (Videx®, ddI) Wt >60 kg dose: 200 mg po bid or 400 mg po qd (tabs); 

400 mg po qd (EC); 250 mg po bid or 500 mg po qd (powder). Wt <60 kg dose: 125 mg po bid or 250 mg po qd (tabs); 250 mg po qd (EC); or 167 mg po bid or 334 mg po qd (powder).Available as 25, 50, 100, 150 200 mg chewable buffered tablets; 100, 167, 250 mg buffered powder for oral solution; 125, 200, 250, or 400 mg enteric coated capsulesTake 1/2 hr. before or 2 hr. after meals.

GI intolerance (diarrhea, mouth sores), peripheral neuropathy in (5–12% of patients); pancreatitis (in 1–9% of patients with 6% of cases fatal); transaminase elevation; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

B Not teratogenic or carcinogenic in 

rodent studies.

Placental passage approximately 50% PACTG 249 Phase I study showed that ddI was well tolerated by mother and fetus when started at weeks 26–36. (Wang, 1999).

GI side effects may limit use. The pediatric powder and EC tablet formulations are better tolerated (for every 4 g of ddI, mix with 200 cc of Maalox®).

Lamivudine, (Epivir®, 3TC) 150 mg po bid or 300 mg po qd Available as 150 mg, 300 

mg tablets; 10 mg/mL oral solution; Combovir (ZDV 300 mg/3TC 150 mg); Trizivir (ZDV 300 mg/3TC 150 mg/ABC 300 mg); Epzicom: 3TC 300 mg/ABC 600 mg

Generally very well tolerated; occasional headache; nausea; diarrhea; abdominal pain; and insomnia; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

C Not teratogenic or carcinogenic in 

rodent studies.

Human studies demonstrated 100% placental passage. No increase in birth defects noted in Antiretroviral Pregnancy Registry.

Associated with reduction in perinatal transmission when combined with ZDV (PETRA clinical trial) in later pregnancy or labor plus 1 wk post partum to mother and newborn (see chapter VII Reproduction).

Emtricitabine (Emtriva®, FTC) 

200 mg po qd Available as 200 mg capsulesTruvada: FTC 200 mg/ TDF 300 mg 

Occasional headache, diarrhea, nausea, rash, generally of mild to moderate severity; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

B No increase in fetal malformations 

in mice and rabbits. Unknown if placental passage.

No dataPlacental passage unkown

Similar to 3TC, FTC is active against hepatitis B. Resistance profile is identical to 3TC. Little experience in pregnancy.Not indicated for treatment of chronic HBV infection and safety and efficacy not established in patients with HBV/HIV coinfection.
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Table 14-3: Antiretrovirals (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience 

in Pregnancy

Comments

Zalcitabine, (Hivid®, Dideoxycytidine, ddC)

0.75 mg po tid Available as 0.375, 0.75 mg tablets.

High incidence of peripheral neuropathy (17–31% of patients); stomatitis, aphthous ulcers; hepatitis; rare cases of pancreatitis reported; rare cases of lactic acidosis and severe hepatomegaly with steatosis.

C Studies in rhesus monkey 

demonstrated 30–50% placental passage. Carcinogenic in rodent studies resulting in thymic lymphoma. Teratogenic in rodent studies resulting in hydrocephalus at high dose (see Table 14-6 Drug-Drug Interactions)..

Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses.

ddC is not a component in currently recommended ARV regimens; should not be used with ddI or d4T due to additive peripheral neuropathy and other toxicity.

Nucleotide Reverse Transcriptase Inhibitors (N+RTIs)Tenofovir DF (Viread®, TDF)

300 mg po qdAvailable as 300 mg capsules.Tuvada: TDF 300 mg/FTC 200 mg

Generally well tolerated. Most common side effects: Headache, diarrhea, nausea and vomiting. Asymptomatic elevation of CPK and transaminase levels in 10%. Neutropenia in 7% and increased amylase in 6%. Rare reports of renal insufficiency. Rare lactic acidosis with hepatic steatosis

B Gravid Rhesus monkeys study 

showed no fetal malformations, however reduction in body weight, insulin-like growth factor, and fetal bone porosiity was observed (25 times AUC with human therapeutic dosing) (Tarantal, 2004).Placental passage demonstrated in rats and monkeys.

No dataPlacental passage unknown

Should be taken with food. Data from monkeys support the use of tenofovir DF for post-exposure prophylaxis.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)Efavirenz (Sustiva®, EFV)

600 mg po q hs Available as 50, 100, 200 mg capsules or 600 mg tabletsTake on empty stomach.

Morbilliform rash in 15–27% of patients with 1–2% requiring discontinuation; one case of StevensJohnson syndrome reported; CNS effects (confusion, depersonalization, abnormal dreams) usually seen in up to 52% of patients and resolve in 2–4 wk; transaminase elevation in 2–3% of patients, hyperlipidemia.

D Placental passage of 100% 

seen in cynomolgus monkeys, rats, and rabbits. Teratogenicity demonstrated in cynomolgus monkeys resulting in anencephaly, anophthalmia, microphthalmia. Increase in hepatocellular adenomas and carcinomas and pulmonary alveolar bronchiolar adenomas in female mice at exposures 1.7 times human therapeutic doses.

4 cases of central nervous system defects with 1st trimester exposure; birth defects observed in 3 of 88 live births with 1st trimester exposure and 0 of 11 births with exposure later in pregnancy (Antiretroviral Pregnancy Registry) 

Efavirenz should be avoided during pregnancy (particularly early pregnancy) and in women trying to conceive or not using effective contraception.
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Nevirapine (Viramune®, NVP)

200 mg po qd for 14 days then 200 mg po bidAvailable as 200 mg tablets or 50 mg/5mL oral suspension.

Rash in 17% of patients (7% discontinued due to rash, many patients require hospitalization) StevensJohnson syndrome reported; transaminase elevation; severe hepatitis; fever; nausea; headache.Women may be at increased risk of rash and liver toxicity, especially with CD4 >250 cells/mm3 (Mazhude, 2002; Bersoff-Matdra, 2001; Stern, 2002)

C Not teratogenic in rodent studies. 

No data on carcinogenicity.

Nevirapine-associated skin rash and hepatotoxicity (including hepatic failure) reported in pregnancy (Knudtson, 2003; Lyons, 2003; Langlet, 2000). These toxicities have not been reported in women or infants receiving HIVNET 012 two-dose regimen for prevention of perinatal transmission.

In HIVNET 012 administration of single-dose nevirapine given to mother during labor and to infants within 72 hr of delivery was compared with administration of AZT during labor and AZT for 7 days to infants. The 18 mo data showed that 26% of infants in the AZT and 16% of infants in the nevirapine arm were infected, a 41% reduction with nevirapine (Jackson, 2003). Monitor LFTs q 2wk x 1st 4 wk, then q mo x 4 mo; then q 1-3 mo. Use with caution as part of combination regimen in pregnant women for purpose of prevention of perinatal transmission. Contraindicated in women with CD4 counts > 250/mm3.

Delavirdine (Rescriptor®, DLV)

400 mg po tid Available as 100 mg or 200 mg tablets

Rash in 18% of patients (4.3% discontinued due to rash, usually does not require discontinuation unless mucous membrane involvement); rare erythema multiforme or Stevens Johnson syndrome; headache; increased transaminase levels (see Table 14-6 Drug-Drug Interactions)

C Placental passage of 4–15% 

in late-term rodent studies. Teratogenic in rodent studies resulting in ventricular septal defects. Maternal toxicity, embryotoxicity and decreased pup survival seen with doses five times the human dose. No data on carcinogenicity.

Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses.

Due to the availability of more potent NNRTIs (e.g., nevirapine) use of delavirdine is generally not recommended. 
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Table 14-3: Antiretrovirals (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience 

in Pregnancy

Comments

Protease Inhibitors (PIs)Lopinavir/Ritonavir (LPV/r) (Kaletra®)

Lopinavir 400 mg/ritonavir 100 mg (3 capsules or 5 mL) twice daily with foodAvailable as 133.33 mg lopinavir/33.3 mg ritonavir capsules; 80 mg lopinavir/20 mg ritonavir per mL oral solution.

Diarrhea in 13.8–23.8% of patients; nausea, vomiting, abdominal pain, asthenia, headache and rash reported. Class adverse events such as hyperlipidemia, fat redistribution and hyperglycemia are possible.

C No treatment-related 

malformations in animal studies. No embryonic or fetal development toxicities seen in rabbits. Delayed skeletal ossification and increase in skeletal variations in rats at maternally toxic doses.

No human data available.Preliminary data indicate minimal placental passage of ritonavir; unknown for lopinavir

Ritonavir (Norvir®, RTV)

600 mg po bid (when used as sole PI), butRitonavir now used at lower doses with other PIs as pharmacologic enhancer or booster. (See Table 14-6)Available as 100 mg capsules; 600 mg/7.5 mL oral solution. Take with food, if possible (may improve tolerability)

Severe GI intolerance (nausea, vomiting, diarrhea; abdominal pain, common with 600 mg bid dosing); taste perversion; asthenia; circumoral and peripheral paresthesias; pancreatitis; lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation (increased incidence seen with hepatitis B and C coinfection); elevated CPK and uric acid. 

B Not teratogenic but slight increase 

in cryptorchidism reported in rodent studies. Increase in liver adenomas and carcinomas in male mice (4 times human therapeutic dose). No carcinogenic effects in rats.

Minimal transplacental passage.

Use may be limited by GI intolerance at full dose. Better tolerated when used as booster with another PI (RTV 100 mg bid and 2nd PI).

Saquinavir, SQV (Invirase®, INV, hard gel capsules; Fortovase®, FTV soft gel capsules)

INV or FTV 400 mg po bid with ritonavir 400 mg po bid. Invirase not recommended as sole PI; Fortovase 1200 mg po tid when used alone (see Table 14-6)Available as: Invirase 200 mg capsules; Invirase 500 mg tablets; Fortovase 200 mg capsules; take Fortovase with large meal. 

GI intolerance (nausea, diarrhea, abdominal pain); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation.

B Placental passage in rat 

and rabbit is minimal. No teratogenicity reported in rodent studies. No data on carcinogenicity.

Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses.Minimal transplacental passage.

Invirase 1,000 mg RTV/ 100 mg bid is the preferred dosing regimen due to better pharmacokinetics and tolerance.
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Indinavir, IDV(Crixivan®) 800 mg po tid (see Table 14-6) 400/400 mg 

or 800/100 mg or 800/200 mg IDV/RTV bid + EFV 600 mgAvailable as 200, 333, 400 mg capsules. Take 1 hr before or 2 hr after meals; may take with low fat meals

Nephrolithiasis +/- hematuria in 5–15% of patients (48 oz of fluid recommended to decrease incidence); indirect hyperbilirubinemia (≥2.5 mg/dL in 10–15% of patients); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation.

C Placental passage is significant 

in rats, but low in rabbits. Not teratogenic in rodent studies (but extra ribs have been reported). Incidence of hyperbilirubinemia in neonatal Rhesus monkeys increased with neonatal but not in utero exposure. No data on carcinogenicity.

Insufficient information to provide reliable and definitive conclusions regarding the risk to pregnant women and their developing fetuses. Minimal transplacental passage.

Due to theoretical concerns of hyperbilirubinemia and nephrolithiasis in newborns, indinavir should be avoided during late pregnancy.

Nelfinavir, NFV(Viracept®) 750 mg po tid or 1250 mg po bid

Available as 250 mg tablets; 625 mg tablets; FDAapproved 50 mg/g oral powder. Take with increased fat meal

Diarrhea (treatable with Imodium or pancrealipase); lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation.

B Not teratogenic in rodent studies. 

No data on carcinogenicity.

No increase in birth defects noted in Antiretroviral Pregnancy Registry. Minimal transplacental passage.

The combination of AZT, 3TC, and nelfinavir is widely used and has been well tolerated during pregnancy.

Fosamprenavir, fos APV (Lexiva®) (prodrug of amprenavir)

1400 mg po bid with RTV: 1400 mg Lexiva/200 mg RTV po qd (not recommended for PI-experienced patients) or 700 mg Lexiva/100 mg RTV po bidAvailable as 700 mg tablets

GI intolerance most common (nausea, vomiting, diarrhea); headache; rash (in 19% of patients), usually mild-moderate but Stevens Johnson syndrome reported; lipodystrophy syndrome; hyperglycemia; increased triglycerides and/or cholesterol; transaminase elevation.

C Increased abortions in rabbits, 

reduction in pup survival and body weight in rats. Placental passage unknown

No data Use with caution in patient 

with sulfa allergy
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Table 14-3: Antiretrovirals (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience 

in Pregnancy

Comments

Amprenavir, APV (Agenerase®)

1400 mg bid (oral solution); <50 kg: APV 20 mg/kg bid (max 2800 mg/day oral solution). APV and RTV oral solutions should not be co-administered due to competition of metabolic pathway of the two vehicles. Available as 15 mg/mL oral solution; also as 50 mg capsules, but capsules and solution NOT interchangeable on mg-per-mg basis. Capsules rarely used because of high pill burden—APV largely replaced by fAPV.

GI intolerance most common (nausea, vomiting, diarrhea); rash (in 20–27% of patients), Stevens Johnson syndrome (in approximately 1%); paresthesias; headache; lipodystrophy syndrome; hyperlipidemia; transaminase elevation

C Increased incidence benign and 

malignant liver tumors in male rodents at exposures 2- to 4-fold higher than human dosing. Increased abortions in rabbits and increased incidence of deficient bone ossification in rabbits and rats at exposures lower than recommended human dosing. Reduced body weight in rodent offspring at exposures 2-fold higher than human dosing.

Placental passage unknown. No data in use of APV in pregnant women

Use of oral solution contraindicated in pregnant women, patients with renal or hepatic failure, or those treated with disulfiram or metronidazole because of inability to adequately metabolize propylene glycol base. Use with caution in patients with sulfa allergy.

Atazanavir, ATV(Reyataz®) 400 mg qd with food. With RTV: 300 mg qd/RTV 

100 mg qdAvailable as 100 mg, 150 mg, 200 mg capsules.

Common: Reversible benign hyperbilirubinemia (grade 3-4 occurring in 35–47% of patients), jaundice, and scleral icterus.Occ: nausea, vomiting, abdominal pain, lipodystrophy, rash, headache, and mild transaminase elevation minimal impact on serum lipids.

B No teratogenic effects in rats or 

rabbits

No dataPlacental passage unknown

Avoid near term due to the potential exacerbation of physiologic hyperbilirubinemia in the neonate.
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Fusion InhibitorsEnfuvirtide (Fuzeon®, T-20)

90 mg (1ml) SQ q12h into upper arm, anterior thigh or abdomen with each injection given at a site different from the preceding injection siteEach single-use vial contains 108 mg of enfuvirtide to be reconstituted with 1.1 mL of sterile water for injection with delivery of approx. 90 mg/1mL

Common ADR: local site reaction (grade 3 or 4) including pain (9%), erythema (32%), pruritus (4%), induration (57%), and nodules or cysts (26%) (with 3% requiring d/c). Occ: Bacterial pneumonia (reported in 4.68 events vs. 0.61 events per 100 pts-years.Hypersensitivity reaction (<1%): symptoms may include rash, fever, nausea, vomiting, chills, hypotension, elevated transaminases – may recur on rechallenge.

B Not teratogenic in animal studies No data

Placental passage unknown

A clear advantage of enfuvirtide is the lack of cross-resistance with currently available antiretrovirals, however, as with other antiretrovirals and as seen in clinical trials, salvage therapy with enfuvirtide is only as good as the background regimen with which it is combined.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Trimethoprimsulfamethoxazole, TMP-SMX (Bactrim®, Septra®, Cotrim®, Sulfatrim®)

PCP prophylaxis: 1 DS po qd, 1 SS po qd, 1 DS po tiw PCP treatment: 5 mg/kg (based on the trimethoprim component) po or IV q 8 h

Fever; leukopenia; rash and/or GI intolerance (in 25–50% of HIV-infected persons, most patients tolerate readministration of lower dose after 2 wk of discontinuation); megaloblastic anemia; neutropenia; thrombocytopenia. Hematologic toxicity increased with folate depletion and high dosestreat with leucovorin 3–15 mg qd x 3 days. Reversible hyperkalemia (with high doses); photosensitivity; renal failure; hemolytic anemia with G6PD deficiency; hepatitis including cholestatic jaundice; thrush; erythema multiforme; Stevens Johnson syndrome.

C Cleft palate has been 

observed in some animals.

In a surveillance study of Michigan Medicaid recipients, 2296 exposures to trimethoprim/sulfamethoxazole in the first trimester resulted in a 5.5% incidence of birth defects. This incidence suggests an association between the drug and congenital defects (cardiovascular); however, other factors such as mother’s disease, concurrent drug use, and chance may be involved (Briggs, 1998).

Most authorities consider sulfonamides safe in pregnancy. Theoretical risk of kernicterus in the neonate if administered near term.

Azithromycin (Zithromax®) MAC prophylaxis: 1200 mg po q week; 

MAC treatment: 500 mg or 600 mg po qd (in combination with ethambutol +/- rifabutin)

GI intolerance (4%); diarrhea; nausea; abdominal pain; vaginitis; reversible hearing loss (more common with 500 mg x 30–90 days); increased transaminases

B Animal studies show 

no harm to the fetus. 

Azithromycin and erythromycin were compared for the treatment of chlamydia in pregnancy. The authors recommended using azithromycin due to efficacy and better tolerability. Effect on the fetus was not evaluated (Adair, 1998).

The benefit of azithromycin administration for MAC prophylaxis or treatment outweighs potential risk of congenital malformations.
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Clarithromycin (Biaxin®) MAC prophylaxis: 500 mg po bid 

MAC treatment: 500 mg po bid (in combination with ethambutol and/or rifabutin.)

GI intolerance (4%); diarrhea; headache; reversible doserelated hearing loss; taste disturbances

C Studies in monkeys 

show growth retardation, cleft palate, and embryonic loss

The Teratogen Information Service in Philadelphia reported that the outcome of 34 first or second trimester exposures were similar to those expected in the nonexposed population. The 122 pregnancies exposed to clarithromycin in the 1st trimester did not have increased major or minor malformations when compared with matched controls. Incidence of spontaneous abortion was higher in clarithromycinexposed group compared with controls (14% vs 7%) (p=.04) (Schick, 1996). 

Should be used with caution during pregnancy because of teratogenicity in animals.

Pyrazinamide 15 mg/kg/day for latent TB (2.0 

g max); 20o–25 mg/kg/day for active TB (2.0 g max); 30–50 mg/kg 2–3 times/wk (3.0–4.0 g max) for intermittent therapy

Nongouty polyarthralgia; asymptomatic hyperuricemia; hepatitis (dose related, frequency not increased when given with INH or rifampin, rarely serious); GI intolerance; gout 

C No animal data 

available.

No human data available. Due to insufficient data 

pyrazinamide should generally be avoided in pregnancy. INH, rifampin, and ethambutol are recommended as first-line agents for treatment of drug-sensitive TB during pregnancy.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Isoniazid (INH, Tubizid®, Nydrazid®)

300 mg po qd Age-related hepatitis: <20 

yr old-nil/35 yr old-6%/45 yr old-11%/ 55 yr old-18%; drug should be discontinued if transaminase levels are >3–5 x normal limits; allergic reactions; fever; peripheral neuropathy (especially with preexisting alcoholism, diabetes, pregnancy, malnutrition); glossitis

C Animal studies show 

embryocidal effect, but not teratogenic. 

Retrospective analysis of more than 4900 exposures to INH did not show increased fetal malformations. (Snider, 1980).

The American Academy of Pediatrics and the American Thoracic Society recommend that pregnant women with a positive PPD should receive INH if HIV-positive, have had recent TB contact, or have an X-ray showing old TB; start after 1st trimester if possible.

Rifampin (Rifadin) 10 mg/kg/day (600 mg/day 

max) for TB prophylaxis or active TB; 600 mg 2–3x/wk with DOT

Orange discoloration of urine, tears, sweat; hepatitis—usually cholestatic changes during first month (frequency not increased when given with INH); jaundice (usually reversible with dose reduction and/or continued use); GI intolerance; hypersensitivity reactions; flu-like syndrome with intermittent use characterized by dyspnea, wheezing

C Animal data 

show congenital malformations—cleft palate, spina bifida, and embryotoxicity.

Several reviews have evaluated treatment of TB in pregnancy. All concluded that rifampin was not teratogenic and recommended use of the drug with INH and ethambutol if necessary (American Thoracic Society, 1986).

The American Thoracic Society recommends rifampin in combination with INH and ethambutol if treatment for drugsensitive TB is needed during pregnancy. Many drug interactions. Because of potential increased risk of hemorrhagic disease in neonates, prophylactic vitamin K 10 mg should be administered to the neonate.

Rifabutin (Mycobutin®) 300 mg po qd (dose is decreased to 150 mg qd or 

300 mg 3x/wk when used with indinavir, nelfinavir, amprenavir; 150 qod with RTV or LPV/r; 450 mg qd or 600 mg 3x/wk with EFV; 300 mg 3x/wk with NVP; 150 mg 3x/wk with SQV/RTV. Not recommended with DLV or SQV alone (Fortovase). 

Orange discoloration of urine, tears, sweat; uveitis with eye pain, photophobia, redness and blurred vision—usually seen with high doses (600 mg/day or concurrent use of fluconazole or clarithromycin); hepatitis; GI intolerance; allergic reactions

B Animal data showed 

skeletal abnormalities. 

No human data available. Experience with rifabutin 

in pregnancy is limited. Many drug interactions with dose modifications recommended. (See Drug Interactions Table 14-6)
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Ethambutol (Myambutol®) 15-25 mg/kg po qd (1.6 g max); 35-50 mg/kg 2x/wk (4.0 g max); 

25-30 mg/kg 3x/wk (2.4 g max)

Optic neuritis (decreased acuity, reduced color discrimination, constricted fields, scotomata—dose related and infrequent with 15 mg/kg); GI intolerance; confusion; precipitation of acute gout.

C Teratogenic in animal 

studies.

No congenital defects have been reported. In 38 patients exposed to ethambutol during pregnancy, no increased risk of birth defects observed (including embryonic optic nerve toxicity). (Brobowitz, 1974).

The CDC considers ethambutol safe in pregnancy.

Atovaquone (Mepron®) 750 mg po bid for PCP treatment or prophylaxis; 

1500 mg po qd for PCP prophylaxis; 1500 mg po bid for toxoplasmosis treatment (with pyrimethamine or sulfadiazine)

GI intolerance (nausea, vomiting, diarrhea); headache; rash. 7–9% required discontinuation due to side effects

C Not teratogenic in 

rat studies. Maternal and fetal toxicities (decreased fetal weight, early fetal resorption and postimplantation fetal loss) reported in rabbits.

No human data available. Alternative regimen for PCP 

prophylaxis and treatment due to high cost, poor GI tolerance, and lack of safety data in pregnancy. Preferred regimens for PCP prophylaxis and treatment include trimethoprim/sulfamethoxazole and dapsone. Third-line treatment and prophylaxis for toxoplasmosis

Hydroxyurea (Hydrea®, Droxia®) 500 mg po bid Dose-dependent leukopenia, anemia and thrombocytopenia; 

GI intolerance (N/V/D, constipation), stomatitis; rash; alopecia

D Hydroxyurea is 

teratogenic in several animal studies; anomalies include nervous system, palate, skeleton, neural tube and cardiac defects.

Eight case reports of hydroxyurea exposure during pregnancy did not demonstrate teratogenicity, however, the data are too limited to draw any conclusions (Briggs, 1998).

Contraindicated due to high incidence of teratogenicity in animal studies and limited human experience. No longer recommended as part of HAART.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Amphotericin B (Fungizone®) 0.5–1.2 mg/kg IV qd depending on specific condition. 0.7 mg/

kg for cryptococcal meningitis

40–50% incidence of fever and chills; 30–40% incidence of renal tubular acidosis—dose dependent and reversible in absence of prior renal damage and dose <3 g (reduced with hydration and sodium loading); 20% incidence of hypokalemia; hypomagnesemia; anemia; phlebitis and pain at infusion site; hypotension; nausea; vomiting; metallic taste; headache

B Animal studies 

demonstrated amphotericin to be harmless in pregnancy.

The Collaborative Perinatal Project identified 9 1st trimester exposures to amphotericin and found no adverse fetal effect (Briggs, 1998).

Can be used in pregnancy for the treatment of serious fungal infections.

Flucytosine (Ancobon®) 25 mg/kg q 6 h (monitor levels – goal 50–100 mcg/mL at 

steady state)

GI intolerance (N/V/D); marrow suppression with leukopenia or thrombocytopenia (dose related with renal failure, serum concentration >100 mg/mL or concurrent amphotericin); confusion; rash; hepatitis (dose related); enterocolitis; headache; photosensitivity reaction; peripheral neuropathy

C Teratogenicity 

reported in animal studies. 

Three case reports of second and third trimester exposure resulted in no defects in the newborns, however, no conclusion can be drawn (Briggs, 1998).

4% of administered dose converts to 5FU in the fungal organism. 5FU has been associated with congenital malformations. Use with amphotericin for the treatment of cryptococcal meningitis may reduce relapse rates but does not reduce mortality or speed recovery (van der Horst, 1997). Use in pregnancy only if benefits outweigh potential risks.

Nystatin 500,000 units 5x/day (oral 

thrush)

GI intolerance (N/V/D) B No animal data 489 first trimester exposures 

to nystatin were observed in a Michigan Medicaid recipients surveillance study. No association between nystatin and congenital defects was observed (Briggs, 1998).

Due to low systemic absorption nystatin may be used in the management of thrush during pregnancy.
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Clotrimazole 10 mg troches 5x/day (oral 

thrush) 100 mg intravaginal tablets bid x 3 day or qd x 7 day. 1 applicator (5g) vaginal cream q hs x 7–14 day (Candida vaginitis)

GI intolerance (N/V); transaminase elevation. Topical treatment (rare): burning, erythema, pruritus

C Embryotoxic in 

rats and mice. Not teratogenic in mice, rabbits, and rats.

2624 exposures to clotrimazole (vaginal use) were observed in the first trimester in a Michigan Medicaid recipients surveillance study. No association between clotrimazole and congenital defects were observed (Briggs,1998)

Due to minimal systemic absorption nystatin is preferred over clotrimazole in the management of thrush during pregnancy. Vaginal use in 1st trimester should be on risk/benefit basis

Fluconazole (Diflucan®) C. esophagitis: 200–800 mg/day. 150 mg po x 1 for 

Candida vaginitis; 150 mg po q wk for multiple recurrencesCryptococcal infection: 200–400 mg/day.

Dose-related GI intolerance including bloating, nausea, vomiting, pain, anorexia, weight loss (8–11% with dose <400 mg/day, 30% with dose >400 mg/day); reversible alopecia in 10–20% of patients receiving 400 mg/day for 3 months; transaminase elevation to >8 x normal; rare cases of fatal hepatitis and Stevens Johnson syndrome

C Teratogenic in animal 

studies. 

Craniofacial, limb and cardiac defects have been reported in 4 infants with 1st trimester exposure to high-dose fluconazole (Pursley, 1996; Aleck, 1997). Anomalies do not appear to be increased among infants born after exposure to single dose fluconazole in the 1st trimester (Mastroiacovo, 1996; Sorenson, 1999). 

Contraindicated in the 1st trimester due to potential for teratogenicity. Use topical agents in treatment of C. vaginitis in pregnancy.

Itraconazole (Sporanox®) 100–400 mg po qd, depending on specific condition Headache; GI intolerance— nausea (10%) and vomiting; 

rash (8%); hypokalemia reported with high doses (600 mg per day); adrenal insufficiency; impotence; gynecomastia; leg edema; transaminase elevation, rare cases of fatal hepatitis

C Teratogenic in 

rats and mice (encephaloceles, macroglossia, and skeletal malformation).

FDA has received 14 case reports of malformations following use of itraconazole, 4 were limb defects. However in another report of 80 exposures to single-dose itraconazole or fluconazole no malformations were reported (Rosa, 1996).

Contraindicated in the 1st trimester due to potential for teratogenicity.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Voriconazole (Vfend®) IV: 6 mg/kg IV q12h x 2 doses (load), then 3-4 mg/kg IV q12h 

infused over 1-2 hours. PO: (>40 kg) 200 mg po tid x 1 da (load), then 200-300 mg po bid; (<40 kg) 100 mg po q12h, may be increased to 150 mg po q12h (administer on an empty stomach, avoid high fat food!)

Common: Visual disturbances (“abnormal vision” described as blurriness, color changes, and enhanced vision) seen in 20.6% of pts but less than <1% required discontinuation. Occ: Inc.LFTs (13%) and alk phos required d/c in 4–8%. hallucination (4.3%), rash (6%), nausea/vomiting.

D Teratogenic in animal 

studies

No data Avoid in pregnancy.

Do not use with EFV or RTV (400 mg bid)

Pyrimethamine (Daraprim®) 

Acute treatment of toxoplasmosis: Pyrimethamine 100–200 mg loading dose, then 50–75 mg po qd, in combination with sulfadiazine 4–6 g po per day in four divided doses for at least 6 wk, plus leucovorin 10–20 mg po qd; Toxoplasmosis maintenance dose: After acute treatment, pyrimethamine 25–50 mg po qd, plus sulfadiazine 2–4 g po per day in four divided doses, plus leucovorin 10–25 mg po qd Toxoplasmosis prophylaxis: Pyrimethamine 50–75 mg po q wk, in combination with dapsone, plus leucovorin 25 mg po q wk

Folic acid deficiency with megaloblastic anemia and pancytopenia (dose-related and reversed with leucovorin); allergic reactions; GI intolerance (nausea, anorexia, vomiting)

C Teratogenic in animal 

studies. 

No adverse fetal effects were reported in two reviews of treatment of toxoplasmosis in pregnancy (Matsui, 1994; Wong, 1994). 

If pyrimethamine is used during pregnancy, concomitant leucovorin (folinic acid) supplementation (25 mg/day) is recommended, especially during the 1st trimester, to prevent hematologic toxicity.
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Sulfadiazine Acute treatment of 

toxoplasmosis: Sulfadiazine 4–6 g po per day in four divided doses, in combination with pyrimethamine 50–75 mg po qd for at least 6 wk, plus leucovorin 10–20 mg po qd Toxoplasmosis maintenance dose: After acute treatment, sulfadiazine 2–4 g po qd in four divided doses, pluspyrimethamine 25–50 mg po qd, plus leucovorin 10–25 mg po qd

Allergic reactions—rash, pruritus; crystalluria with renal damage, urolithiasis and oliguria; GI intolerance; photosensitivity; hepatitis; fever; periarteritis nodosum, Stevens Johnson syndrome; serum sickness

C At high doses, 

animals developed cleft palate and bone abnormalities. 

Extensive use in humans without complication except one case of agranulocytosis that was possibly associated (Briggs, 1998).

Theoretical risk of kernicterus in the neonate if administered near term.

Aerosolized pentamidine 

PCP prophylaxis—300 mg nebulized q mo

Asthma reaction reported in 2–5% of patients; cough seen in 30% of patients 

C Systemic pentamidine 

is embryotoxic but not teratogenic in rats and rabbits

Aerosolized pentamidine given to 15 women during the 2nd and 3rd trimesters did not alter pregnancy outcome or cause fetal harm (Nanda, 1992).

CDC and manufacturer advise against the use of pentamidine during pregnancy due to the lack of data; however, aerosolized pentamidine may be considered safe due to minimal systemic absorption (Kaplan, 1995). Concerns have been raised about adequate drug distribution during pregnancy due to restrictive changes with an enlarged uterus.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Intravenous pentamidine

PCP treatment—3–4 mg/kg IV qd

Nephrotoxicity—seen in 25% (usually reversible with discontinuation); hypotension (administer IV over 60 min to decrease risk); hypoglycemia—seen in 5–10% (usually occurs after 5 days of treatment including past treatment, may last days or weeks) may lead to insulin—dependent diabetes; marrow suppression (leukopenia; thrombocytopenia); GI intolerance with nausea, vomiting, abdominal pain, anorexia, and bad taste; transaminase elevation; pancreatitis; toxic epidermal necrolysis; fever

C Not teratogenic 

in rat and rabbit studies, however, has been shown to be embryocidal.

Spontaneous abortion reported, but causal relationship has not been established. 

Use in pregnancy only if benefits outweigh potential risks. Due to the toxicity profile Bactrim or clindamycin/primaquine is preferred

Primaquine 15–30 mg (base) po qd (in 

combination with clindamycin for the treatment of PCP)

Hemolytic anemia (G6PD deficiency); methemoglobinemia; GI intolerance; neutropenia 

C No animal studies 

available. 

No human data available. Theoretical concern is 

hemolytic anemia in G6PD-deficient fetus. Should screen for G6PD deficiency in mother before use.

Albendazole (Albenza®) 400 mg po bid x 3 weeks for microsporidiosis Diarrhea; abdominal pain; transaminase elevation; 

hepatotoxicity; reversible pancytopenia and neutropenia

C Teratogenic and 

embryotoxic in rodent and rabbit studies.

No human data available. Contraindicated in 

pregnancy.
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Dapsone 100 mg po qd (PCP 

prophylaxis). 100 mg po qd plus trimethoprim x 3 wk (PCP treatment). 50 mg po qd or 200 mg q wk plus leucovorin and pyrimethamine (PCP + toxoplasmosis prophylaxis).

Rash; blood dyscrasias including methemoglobinemia and sulfhemoglobinemia and hemolytic anemia (with or without G6PD deficiency); nephrotic syndrome; fever, nausea, anorexia; blurred vision; photosensitivity; tinnitis; insomnia; irritability; headache (transient); rare “sulfone syndrome”—fever, exfoliative dermatitis, jaundice, adenopathy; methemoglobinemia and anemia 

C No animal 

teratogenicity studies conducted. Carcinogenic risk in rats.

No adverse effects reported. (Luzzi, 1993).

Dapsone has been used extensively in the treatment of malaria and for chemoprophylaxis of leprosy without producing major fetotoxicity or causing birth defects. Recommend screening for G6PD deficiency in mother before use.

Acyclovir (Zovirax®) 5–10 mg/kg IV q 8 h; 200–800 

mg po x 3–5 times per day

GI intolerance (nausea and vomiting; diarrhea); renal toxicity (especially with rapid IV infusion); dizziness; transaminase elevation; itching, headache. Toxicities are infrequent.

C Not teratogenic but 

potential to cause chromosomal damage at high doses. 

Birth defects reported in 23 of 1002 exposures; however, this was not statistically different from the expected rate. (Glaxo Wellcome, 1996)

Acyclovir is 1st choice for therapy of HSV infections in pregnancy and should be used for VZV if parenteral therapy indicated.

Valacyclovir (Valtrex®) 1000 mg po tid (for zoster); 500 mg po bid (for recurrent 

HSV); 500–1000 mg po qd (for HSV suppression)

GI intolerance—nausea, vomiting, diarrhea; headache; constipation

B Not teratogenic in 

animal studies.

No human data available but likely to be similar to acyclovir.

Recommendation similar to acyclovir since valacyclovir is converted to acyclovir. Valacyclovir is preferred treatment for chicken pox in pregnancy.

Famciclovir (Famvir®) 500 mg po q 8 h (for zoster); 125–250 mg q 12 h (recurrent 

HSV and HSV suppression)

Headache; nausea; fatigue B Carcinogenic, but 

not embryotoxic or teratogenic in animal studies. 

No human data. Until more data are 

available, acyclovir is 1st choice in pregnancy.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Ganciclovir (Cytovene®)

CMV retinitis Induction: 5 mg/kg IV q12h x 2 wk then Maintenance: 5 mg/kg IV qd

Neutropenia (ANC <500 in 15–20%; usually early in treatment and responds within 3–7 days to drug holiday or to G-CSF); thrombocytopenia (platelet count <20,000 in 10%, reversible). Monitor CBC 2–3 times/wk and discontinue if ANC <500-750 or platelet count <25,000; anemia; fever; rash; CNS—headache, seizures, confusion, changes in mental status; abnormal liver function tests (2–3%)

C Teratogenic (in 

concentrations comparable to those achieved in humans) and embryotoxic: cleft palate, anophthalmia, hydrocephalus, aplastic kidney and pancreas (rabbits); growth retardation.

No human data. Based on limited data and 

weighing toxicity of the various drugs, ganciclovir is 1st choice for treatment during pregnancy; for retinal disease intraocular implants or intravitreous injections should be considered to limit fetal exposure to systemically administered drugs. Monitor fetus with fetal movement counts in 3rd trimester and periodic ultrasound after 20 wk gestation for evidence of significant anemia, manifest as hydrops fetalis. Evaluate newborn for bone marrow suppression.

Valganciclovir (Valcyte®) Induction: 900 mg po bid w/ food x 3 weeks; Maintenance: 

900 mg po qd.

Diarrhea; nausea; fever; bone marrow suppression; LFT elevation.

C Teratogenic (in 

concentrations comparable to those achieved in humans) and embryotoxic: cleft palate, anophthalmia, hydrocephalus, aplastic kidney and pancreas (rabbits); growth retardation.

No data Concerns expected to be 

same as with ganciclovir. Monitor fetus with fetal movement counts in 3rd trimester and periodic ultrasounds after 20 wk gestation for evidence of significant anemia, manifest as hydrop fetalis. Evaluate newborn for bone marrow suppression.
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Cidofovir (Vistide®) CMV retinitis Induction: 5 

mg/kg q week x 2 weeks then q2 weeks (give concurrently with probenecid and hydration). Probenecid Regimen: 2 g given 3 hours prior to cidofovir and 1 g given at 2 and 8 hours after infusion (total 4 g); >1L normal saline 1 or 2 hrs immediately before cidofovir infusion.

Nephropathy—dose dependent, reduced with hydration and probenecid. (Side effect of probenecid includes chills, fever, headache, rash and nausea in 30–50% of patients); uveitis; GI intolerance; neutropenia; metabolic acidosis 

C Embryotoxic 

and teratogenic (meningomyelocele, skeletal abnormalties) in rats and rabbits,

No human data available. Ganciclovir is 1st choice 

for treatment during pregnancy. Use only if benefits appear to outweigh potential risks.

Foscarnet (Foscavir®) CMV retinitis Induction: 60 

mg/kg IV q 8 hr or 90 mg/kg IV q12hr x 14 day. Maintenance: 90–120 mg/kg IV qd. Acyclovir-resistant HSV or VZV: 40 mg/kg IV q 8 h or 60 mg/kg IV q 12 h x 3 wk

Renal failure (usually reversible; 30% get serum creatine (Cr) >2 mg/dL; (monitor Cr 1–3 times/wk and discontinue if Cr >2.9 mg/dL); mineral and electrolyte changes—reduced magnesium, phosphorus, ionized calcium, potassium (monitor serum electrolytes 1–2 times/wk and monitor for symptoms of paresthesias); seizures (10%); fever; GI intolerance; anemia; genital ulceration; neuropathy

C Skeletal malformation 

or variation in animal studies.

No human data available. Due to high incidence of 

nephrotoxicity, monitoring of aminiotic fluid volume by ultrasound weekly after 20 wk gestation to detect oligohydramnios is recommended. Electrolyte and renal function should be evaluated in neonate if therapy given near delivery.

Ribavirin (Rebetrol®) Treatment of hepatitis C (in 

combination with interferon): <75 kg—400 mg q am and 600 mg q pm. >75 kg—600 mg bid 

Hemolytic anemia (mean hgb decrease is 3 g/dL); leukopenia; hyperbilirubinemia; increased uric acid.

X Ribavirin has been 

demonstrated teratogenic in low doses in multiple animal species (limb abnormalties, craniofacial defects, exencephaly, anophthalmia) in rodents (and in all animals tested), but not in primates when given during the first trimester.

No data available. Use of ribavirin 

contraindicated during pregnancy and in male partners of pregnant women.
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Table 14-4: Commonly Used Antimicrobials for the Treatment and Prevention of Opportunistic Infections in HIV-Infected Patients (continued)

Drug Name Dosing Adverse Effects FDA 

Class

Animal Data Human Experience in 

Pregnancy

Comments

Interferon (Roferon®, Intron®) Treatment of hepatitis C (in combination with ribavirin): 3 

million units 3 x/week. IM or SQ. Also used at higher doses for treatment of hepatitis B and Kaposi’s sarcoma

Flu-like syndrome; GI intolerance (N/V/D, anorexia); CNS toxicity (delirium; obtundation and depression); neutropenia, anemia, thrombocytopenia, increased transaminase; rash; alopecia; proteinuria

C Abortifacient in rhesus 

monkeys when given 20–500 times the human dose.

Limited case reports of interferon exposure during pregnancy do not suggest an association with birth defects; however, data are too limited to draw a conclusion.

Since goal of treatment of HCV is to prevent longterm sequelae, treatment in pregnancy rarely indicated and generally not recommended.

Peg-interferon (Peg-Intron® [alfa2B]/ Pegasys®[alfa-2A])

Peg-Intron: 1mcg/kg SC q week (with ribavirin). [Dose reduction to 0.5 mcg/kg recommended for ANC<750 or plt<50k and D/C if ANC<500 or plt <25K]. Pegasys: 180mcg SC qweek (with ribavirin)[dose reduce with heme toxicity].Peg-inteferon alfa-2A or alfa-2B and ribavirin is treatment of choice for HCV.

Common: Flu-like symptoms, headache, dizziness, fatigue, fever, rigor, injection site inflammation, depression (29%), insomnia, alopecia, GI (abd. pain, anorexia, N/V/D.) Occasional: Thrombocytopenia, neutropenia, hypo and hyperthyroidism, LFTs elevation.

C Abortifacient in rhesus 

monkeys.

No data Since goal of treatment of 

HCV is to prevent longterm sequelae, treatment in pregnancy rarely indicated and generally not recommended.

Caspofungin 70 mg IV load on day 1, then 

50 mg IV qd (infuse over 1 hour)

Generally well tolerated. Histamine-mediated symptoms including rash, facial swelling, pruritus and sensation of warmth have been reported. Rare: Fever, phlebitis, nausea, vomiting, headache, eosinophilia, proteinuria, increased alk phos and hypokalemia

C Animal data with 

exposure similar to a 70 mg dose in human resulted in incomplete ossification of skull, torso, cervical ribs and talus/calcaneous.

No data Avoid in pregnancy until 

more data becomes available. 
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Thalidomide (Thalomid®) 50–200 mg/da po—used for treatment of aphthous ulcers, 

wasting

Sedations, rash, neuropathy, constipation, neutropenia found in up to 50%

X – High potential for birth 

defects, including absent or abnormal limbs; cleft lip; absent ears; heart, renal or genital abnormalties. Single dose can be associated with teratogenic effects.

Contraindicated in pregnancy and in women at risk for pregnancy (not using effective contraception or trying to conceive).

ANC, absolute neutrophil count: CBC, complete blood count; CMV, cytomegalovirus; CNS, central nervous system; G-CSF, granulocyte-colony stimulating factor; G6PD, glucose-6-phosphate dehydrogenase; GI, gastronintestinal; INH, isoniazid; MAC, Mycobacterium avium complex; N/V/D, nausea/vomiting, diarrhea; PCP, Pneumocystis carinii pneumonia.
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Table 14-5: Safety of Commonly Used Antimicrobials

Drug Name FDA 

Class

Animal Data Human Experience in Pregnancy Comments

Metronidazole B Animal (rodents) data show risk of 

carcinogenicity. 

2 meta-analyses, a population-based case-control study, and a prospective controlled cohort study have not found increased risk in birth defects (Diav-Citrin, 2001; Czeizel, 1998, CaroPaton, 1997; Burtin 1995)

Most authorities feel metronidazole is safe in the 2nd and 3rd trimester. Use with caution in 1st trimester.

Clindamycin B No fetal harm demonstrated in rat 

studies. Cleft palate observed in one mouse strain.

In a surveillance study of Michigan Medicaid recipients, 647 exposures to clindamycin during the first trimester resulted in a 4.8% incidence of birth defects. Patterns of anomalies do not support an association between clindamycin and congenital effects (Briggs, 1998).

Clindamycin is usually considered safe to use during pregnancy.

Penicillins B Carcinogenicity demonstrated in 

rats after prolonged subcutaneous administration of penicillin in peanut oil. 

Several collaborative perinatal project reports involving over 12,000 exposures to penicillin derivatives during the 1st trimester indicated no association between penicillin derivative drugs and birth defects (Briggs,1998).

Penicillins are usually considered safe to use during pregnancy.

Cephalosporins B Not teratogenic or fetotoxic. Extensive pregnancy exposure was not associated with birth 

defects.

Cephalosporins are usually considered safe to use during pregnancy.

Erythromycin B No teratogenic effect in rat studies. In a surveillance study of Michigan Medicaid recipients, 6972 

patients exposed to erythromycin during the first trimester resulted in a 4.6% incidence of birth defects. Patterns of anomalies do not support an association between erythromycin and congenital malformations.

Avoid estolate salt (due to hepatotoxicity in 10% of patients). Other forms are usually considered safe to use during pregnancy. 

Tetracyclines D Teratogenic in animal studies 

resulting in retardation of skeletal development and embryotoxicity.

Tetracyclines are contraindicated in pregnancy due to retardation of skeletal development and bone growth, enamel hypoplasia, and discoloration of teeth of fetus. Maternal liver toxicity has also been reported.

Contraindicated.
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Fluoroquinolones C Animal data demonstrated 

arthropathy in immature animals resulting in erosions in joint cartilage.

In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), 666 cases of fluoroquinolone exposure (the majority during the 1st trimester) showed a congenital malformation rate of 4.8%. From previous epidemiologic data, this rate did not exceed the background rate (Schaefer, 1996).

Based on animal data and the availability of alternative antimicrobial agents, the use of fluoroquinolones during pregnancy is contraindicated.

Aminoglycosides D Fetotoxicity reported in rodent 

studies.

Eighth cranial nerve toxicity in the fetus is well documented with exposure to kanamycin and streptomycin and can potentially occur with other aminoglycosides.

Gentamicin is classified by the FDA as “C” (although it has the same potential adverse effects).Use as preferred aminoglycoside if treatment indicated.

Imipenem C Animal studies (monkeys) show 

increased embryogenic loss.

No data in humans. Due to the lack of human data, use only 

in life-threatening infections.

Meropenem B No risk. No data in humans. Due to the lack of human data, use only 

in life-threatening infections.

Chloramphenicol C No animal data. A collaborative perinatal project monitored 98 exposures 

during the first trimester and 348 exposures anytime during pregnancy. No relationship between chloramphenicol and malformations were found (Briggs, 1998). 

Although apparently nontoxic to the fetus, chloramphenicol should not be used near term due to the potential of cardiovascular collapse (gray baby syndrome).

Aztreonam B Animal studies show no harm to 

the fetus. 

No human data available. Likely to be safe in pregnancy, but due 

to the lack of data, use only if absolutely needed.

Methenamine C No animal data. In a surveillance study of Michigan Medicaid recipients, 209 

exposures to methenamine during the first trimester resulted in a 3.8% incidence of birth defects. This data did not support an association between methenamine and congenital defects.

The benefit of methenamine therapy is not likely to be worth the potential risk of use during pregnancy.

Nitrofurantoin B Not teratogenic or fetotoxic in rat 

and rabbit studies.

In a surveillance study of Michigan Medicaid recipients, 1292 exposures to nitrofurantoin resulted in a 4.0% incidence of birth defects. These data did not support an association between nitrofurantoin and congenital defects (Briggs, 1998).

Most authorities feel that use of nitrofurantoin is safe during pregnancy.

Vancomycin C No animal data. The manufacturer has received reports of vancomycin use 

during pregnancy without adverse fetal effects.

Consider use only when the benefit outweighs the risk of drug administration.
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Table 14-6 Drug Interactions of Antiretrovirals

Primary drug Interacting drug Mechanism of 

interaction

Effect Time 

course

Severity Comments/ management 

recommendation

Drug Interactions with Nucleoside Reverse Transcriptase InhibitorsAZT (Zidovudine) (Retrovir®)

Ganciclovir/ Valganciclovir

Pharmacodynamic interaction/Additive toxicity.

Enhanced bone marrow toxicity.

Delayed Moderate Monitor CBC frequently. May require 

switch to alternative antiretroviral or use concomitant G-CSF. 

AZT Acetaminophen Competitive inhibition of 

glucuronidation

May rarely result in granulocytopenia and hepatotoxicity

Delayed Minor Intermittent use of acetaminophen is 

considered safe. Adverse effects not consistently reported.

AZT Stavudine In vitro and in vivo 

antagonism

Decreased antiviral efficacy Immediate Major Concomitant administration not 

recommended.

AZT Rifampin Enzymatic induction 

resulting in increased glucuronidation of AZT

Increased clearance of AZT Delayed Moderate Clinical significance unknown.

AZT Ribavirin In vitro ribavirin inhibits 

phosphorylation of AZTPharmacodynamic interaction

Antagonism in vitro but not in vivoAdditive anemia

ImmediateDelayed Moderate/

Severe

Avoid combination if possible or closely monotor virologic response.Anemia may be severe. May require treatment or change in drugs.

AZT Doxorubicin Pharmacodynamic interaction Additive bone marrow 

suppression

Delayed Moderate Additive bone marrow suppression. 

Consider alternative to AZT or support with G-CSF.

AZT Zalcitabine Low potency combination Non-responsive regimen Delayed Moderate Avoid combination.AZT Myelosuppressive 

drugs (e.g., interferon, pyrimethamine)

Pharmacodynamic interaction Additive bone marrow 

suppression

Delayed Moderate Use with caution.

Monitor for bone marrow suppression.

AZT Atovaquone Inhibition of AZT 

glucuronidation

AZT: AUC increased 31% decreased clearance

Immediate Moderate Clinical significance unknown. Use 

standard dose.
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ddI (Didanosine) (Videx®)

Ganciclovir/ Valganciclovir

Unknown ddI AUC increased by 

>100% with concomitant dosing (or when oral ganciclovir is administered 2 hours after ddI); ganciclovir AUC decreased 21%

Delayed Moderate Monitor for ddI toxicity (i.e. peripheral 

neuropathy, pancreatitis). Appropriate doses for combination of ddI and ganciclovir not established. Dose adjustment may be required.

ddI Tenofovir Unknown ddI AUC increased by 40–

60%. Suboptimal response in 91% of patients with ddI/TDF/3TC only

Delayed Major May increase rate of peripheral 

neuropathy and pancreatitis. Lower dose of ddI EC to 250 mg qd with TDF coadministration for pts >60kg. Dose for pts <60kg 200 mg qd.

ddI Indinavir Ritonavir 

Delavirdine

Increase in gastric pH due to the buffer in ddI formulation

Decreased absorption of indinavir, ritonavir, and delavirdine

Immediate Moderate Separate administration time by at least 

2 hours or use ddI EC formulation.

ddI Dapsone Increase in gastric pH due to 

the buffer in ddI formulation

No significant interaction Immediate Mild Use standard dose.

ddI Itraconazole 

Ketoconazole

Increase in gastric pH due to the buffer in ddI formulation

Decreased absorption of antifungal agent

Immediate Major Separate administration time by at least 

2 hours or use ddI EC formulation. Fluconazole may be preferred as an alternative azole antifungal.

ddI Fluoroquinolones, 

Tetracyclines

Chelation of fluoroquinolones and tetracyclines by the divalent cation in DDI formulation

Significant decrease in antibiotic absorption resulting in sub-therapeutic levels

Immediate Major Administer quinolones or tetracyclines 

2 hours before or 6 hours after DDI administration or use ddI EC formulation.

ddI Pentamidine IV 

Ethambutol

Pharmacodynamic interaction / additive toxicity

May increase the risk of pancreatitis

Delayed Moderate Should avoid in patients with current 

alcohol use. Use caution when administering to patients with a history of alcoholism.

ddI Atazanavir Decreased absorption of 

ATV due to buffer in ddI formulation

ATV AUC decreased 87% with buffered ddI given simultaneously; no significant interaction expected with ddI EC

Immediate Severe buffered ddI: Take ATV with food 2 hr 

before or 1 hr after ddI (if this timing of dosing not followed, 90% reduction in ATV level); ddI EC: take at different times (ATV with food and ddI on empty stomach).
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Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

ddI ddC,hydroxyurea, 

INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, and long-term metronidazole. 

Pharmacodynamic interaction/ Additive toxicity

May increase the risk of peripheral neuropathy.

Delayed Moderate Avoid co-administration or give with 

careful monitoring for symptoms of peripheral neuropathy. Incidence of peripheral neuropathy increases with low CD4 count.

ddI d4T Pharmacodynamic 

interaction/ Additive toxicity

Increased risk lactic acidosis in pregnant women. Peripheral neuropathy and pancreatitis also reported with this combination.

Delayed Major Avoid co-administration especially during 

pregnancy, unless no other antiretroviral options are available and potential benefits outweigh risks.

ddI Methadone Unknown buffered ddI AUC decreased 

by 63%, methadone levels remains unchanged. No interaction with ddI EC

Delayed Moderate Consider using ddI EC. May consider 

buffered ddI increase.

ddI Allopurinol Unknown ddI levels increased by 

120%

Immediate Moderate Avoid co-administration.

ddI Ribavirin Inhibition of mitochondrial 

DNA polymerase gamma

ddI intracellular triphosphate levels increased

Delayed Major Increased of risk of pancreatitis and lactic 

acidosis. Avoid co-administration. 

ddC (Zalcitabine) (Hivid®)

ddI, d4T, INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, pyridoxine, and longterm metronidazole. 

Pharmacodynamic interaction/ Additive toxicity

May increase the risk of peripheral neuropathy.

Delayed Moderate Avoid or give with careful monitoring of 

symptoms of peripheral neuropathy. Risk of peripheral neuropathy increases with total exposure and low CD4 count.

ddC Lamivudine Pharmacodynamic interaction Non-suppresive regimen Delayed Moderate To be avoided.ddC Al or mg containing 

antacid

Interference with absorption ddC absorption decreased 

by 25%

Immediate Moderate Do not take simultaneously.
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ddC Pentamidine I.V. Pharmacodynamic interaction Additive toxicity Delayed Moderate May increase the risk of development of 

fulminant pancreatitis.

ddC Probenecid Inhibition of tubular secretion May decrease elimination 

of ddC. ddC AUC increased by 54%

Delayed Moderate Monitor signs of toxicity.

d4T (Stavudine) (Zerit®)

ddC, INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, pyridoxine, and longterm metronidazole.

Pharmacodynamic interaction/Additive toxicity

May increase the risk of peripheral neuropathy

Delayed Moderate Avoid or give with careful monitoring 

of symptoms of peripheral neuropathy. Peripheral neuropathy increases with total exposure and low CD4 count.

d4T ddl Pharmacodynamic 

interaction/ Additive toxicity

Increased risk lactic acidosis in pregnant women. Peripheral neuropathy and pancreatitis also reported with this combination.

Delayed Major Avoid coadministration use during 

pregnancy, unless no other antiretroviral options are available and potential benefits outweigh risks.

d4T Methadone Unknown d4T drug levels decreased 

by 23%. Methadone levels unchanged

Delayed Mild Clinical significance unknown, no dose 

adjustment needed (unlikely to be significant).

d4T Zidovudine In vitro and in vivo 

antagonism

Decreased efficacy of the combination therapy

Immediate Major Concomitant administration not 

recommended due to antagonism.

d4T Ribavirin In vitro ribavirin interacts 

with thymidinephosphorylated nucleoside analogs

Antagonism in vitro but not in vivo

Immediate Minor Not clinically significant.

3TC (Lamivudine) (Epivir®)

Bactrim Trimethoprim competitively 

inhibits renal tubular secretion.

AUC of lamivudine increased by 44%

Immediate Minor No dosage adjustment required due to 

the safety profile of 3TC (not clinically significant).

3TC Abacavir + tenofovir Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an 

NNRTI or a PI.
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Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

3TC Emtricitabine Overlapping resistance profile Non-suppressive regimen Delayed Major Avoid use together.3TC Tenofovir + 

didanosine

Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an 

NNRTI or a PI.

3TC Zalcitabine Pharmacodynamic interaction Non-suppressive regimen Delayed Moderate Consider alternative combination.

FTC (Emtricitabine) (Emtriva®)

– In vitro data suggest potential for 

CYP450-mediated interactions involving emtricitabine with other agents is low; in human studies, no significant PK changes in either drug with tenofovir, indinavir, famciclovir, or stavudine.

FTC Lamivudine Overlapping resistance profile Non-suppressive regimen Delayed Major Avoid.

Abacavir (Ziagen®)

Alcohol Unknown Alcohol increases ABC 

levels by 41%. No effect on alcohol levels

Immediate Minor Clinical significance unknown. No dose 

adjustment recommended.

Abacavir Tenofovir + 

didanosine

Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid us of this combination without an 

NNRTI or a PI.

Drug Interactions with Nucleotide Reverse Transcriptase InhibitorsTenofovir (Viread®)

Atazanavir Possible interference with 

absorption

Atazanavir AUC decreased by 25%; decreased Cminby 23%

Immediate Moderate Clinical significance unknown. Consider 

dosing tenofovir 2 hours before atazanavir or “boosting” with RTV dose: (ATV 300 mg + RTV 100 mg).

Tenofovir ddI Unknown

Low potency combination

ddI AUC increased by 40–60%.

Delayed Major May increase rate of peripheral 

neuropathy and pancreatitis. Lower dose of ddI to 250 mg qd with TDF co-administration for pts >60kg. Dose adjustments for pts <60kg 200 mg qd. Preliminary data shows low potency.
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Tenofovir Cidofovir, ganciclovir, 

valganciclovir

Possible competition for active tubular secretion

May increase concentration of TDF or these drugs

Immediate Moderate Monitor for dose-related toxicities.

Tenofovir Lamivudine + 

Abacavir

Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an 

NNRTI or a PI.

Tenofovir Lamivudine + 

didanosine

Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an 

NNRTI or a PI.

Tenofovir Didanosine Increased ddI serum level ddI AUC increased by 44% 

may result in increased toxicity

Immediate Major Monitor for ddl associated toxicities for 

patients ≥ 60 kg, decrease ddl EC dose 250 mg qd for patients < 60 kg.

Drug Interactions with Non-Nucleoside Reverse Transcriptase InhibitorsNevirapine (Viramune®) (NVP)

Ethinyl estradiol (Oral contraceptives)

Induction of hepatic metabolism

Ethinyl estradiol AUC decreased by 23%

Delayed Major Patients should be aware of the potential 

interaction. Alternative or additional birth control method should be recommended.

NVP Methadone Induction of hepatic 

metabolism

Substantially decreased methadone AUC by 46%

Delayed Moderate Opiate withdraw may occur. May need to 

increase dose of methadone by 15–25% (some patients may required doses of greater than 150 mg per day).

NVP Ketoconazole Induction of hepatic 

metabolism by nevirapine. Inhibition of hepatic metabolism by ketoconazole

Ketoconazole levels decreased by 72%. Nevirapine levels increased by 15–30%

Delayed Moderate Co-administration not recommended. 

Ketoconazole dose may need to be increased. Fluconazole may be preferred as alternative azole agent.

NVP Rifampin/ Rifabutin Induction of hepatic 

metabolism

Nevirapine levels decreased by 37% with rifampin and 16% with rifabutin

Delayed Major Co-administration not recommended 

with rifampin. Rifabutin is the preferred alternative agent.
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Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

NVP Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism by both NVP and anticonvulsants.

May decrease serum levels of NVP and anticonvulsants

Delayed Moderate Consider alternative anticonvulsants 

(i.e valproic acid, levetiracetam, or topiramate).

NVP Clarithromycin Induction of hepatic 

metabolism by nevirapine

Clarithromycin AUC decreased by 30%, but active hydroxy-metabolite is increased

Delayed Minor No dose modification needed. Use 

standard doses of nevirapine and clarithromycin.

NVP Inhibition of hepatic 

metabolism by clarithromycin

Nevirapine AUC increased by 26%

Immediate Minor 

NVP St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

NVP clearance increased by 35%

Delayed Major Co-administration is contraindicated.

NVP Saquinavir Induction of hepatic 

metabolism

Saquinavir AUC decreased by 38%. NVP level not affected.

Delayed Moderate Avoid concurrent use unless saquinavir is 

“boosted” with ritonavir (SQV 1000 mg/ RTV 100 mg bid.

NVP Ritonavir Induction of hepatic 

metabolism

Ritonavir AUC decreased by 11%. NVP level not affected

Delayed Minor Use standard doses.

NVP Indinavir Induction of hepatic 

metabolism

Indinavir AUC decreased by 28%. NVP level not affected

Delayed Minor Clinical trials demonstrated good efficacy 

with standard dose. Consider increasing IDV to 1000 mg q8h (or IDV 800 mg/RTV 100 mg q12h) with NVP coadministration.

NVP Nelfinavir Induction of hepatic 

metabolism

Nelfinavir levels increase by 10%. NVP level not affected

Delayed Minor Use standard doses.
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NVP Lopinavir/r Induction of hepatic 

metabolism

LPV/r AUC decreased by 22%. Cmin decreased by 55%. NVP level not affected

Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid 

with food (NVP standard dose).

NVP Efavirenz Induction of hepatic 

metabolism

EFV AUC decreased by 22%. NVP AUC not affected

Delayed Moderate Though pharmacokinetic data exist, coadministration is not recommended due 

to overlapping resistance.

NVP Atazanavir No data Consider using ATV 300 mg/ RTV 100 

mg qd.

NVP Fluconozole Inhibition of NVP metabolism May increase NVP serum 

level

Immediate Moderate Monitor NVP-associated side effects.

NVP Voriconozole Potential for bi-directional 

inhibition

May significantly decrease voriconazole serum level

Delayed Moderate/

Severe

Monitor frequently for toxicites and voriconazole efficacy. Dose adjustment may be needed.

NVP Norethindrone Induction of northindrone 

metabolism

May decrease norethindrone Delayed Major Use additional method of contraception.

NVP Rifapentine Induction of NVP metabolism May significantly decrease 

NVP serum level

Delayed Major Avoid use together; consider rifabutin.

Delavirdine (Rescriptor®) (DLV)

Indinavir Induction of hepatic 

metabolism

Indinavir AUC increased by 40%. DLV no change

Immediate Moderate May reduce indinavir dose to 600 mg 

q8h. DLV standard dose.

DLV Nelfinavir Inhibition of hepatic 

metabolism by delavirdine; Induction of hepatic metabolism by nelfinavir

NFV AUC increased by 72%. DLV AUC decreased by 42% Cmin decreased by 52%. 

Immediate; delayed

Moderate Do not co-administer.

DLV Ritonavir Inhibition of hepatic 

metabolism

Ritonavir AUC increased by 61%. DLV no change

Immediate Minor Standard doses likely (no data).

DLV Saquinavir Inhibition of hepatic 

metabolism

Invirase® Cmin increased by 500%; DLV AUC decreased by 15%.

Delayed Minor A beneficial interaction. No dose 

adjustment necessary. Monitor transaminase levels.
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Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

DLV Amprenavir Inhibition of hepatic 

metabolism by DLV. Induction of hepatic metabolism by APV

Amprenavir AUC increased by 125%. DLV AUC decreased by 60%

Delayed Major Co-administration not recommended.

DLV Lopinavir/r Inhibition of hepatic 

metabolism

LPV AUC increased by 8–134%. DLV no change

Immediate Minor Limited data. No dose adjustment.

DLV ddI and antacid Decreased delavirdine 

absorption due to antacid content in DDI

Delavirdine AUC decreased by 41%

Immediate Moderate Separate administration by at least 1 

hour or use ddI EC.

DLV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism

Increased serum levels of simvastatin and lovastatin

Immediate Moderate Avoid concurrent administration. 

Consider alternatives such as atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.

DLV H2 blockers, Proton 

pump inhibitors (i.e. omeprazole)

Decreased delavirdine absorption due to antacid content in DDI

May decrease delavirdine concentration

Immediate Moderate Concurrent administration 

contraindicated.

DLV Terfenadine, 

Astemizole, Cisapride

Inhibition of hepatic metabolism

Increased levels of terfenadine, astemizole, cisapride

Immediate Major Concurrent administration 

contraindicated due to potential for serious cardiac arrhythmias.

DLV Midazolam, Triazolam Inhibition of hepatic 

metabolism

Midazolam and triazolam AUCs increased

Immediate Major Concurrent administration 

contraindicated due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.

DLV Ergot alkaloid Inhibition of hepatic 

metabolism

Possible acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.
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DLV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease serum level of delavirdine

Delayed Major Co-administration is contraindicated.

DLV Clarithromycin Inhibition of hepatic 

metabolism

Clarithromycin levels increased by 100% and delavirdine levels increased by 44%

Immediate Minor May require clarithromycin dose 

adjustment, based upon CrCl.

DLV Ethinyl estradiol Unknown Ethinyl estradiol levels 

decreased by 20%

Delayed Major Patients should be aware of the potential 

interaction. Alternative or additional birth control method should be recommended.

DLV Quinidine Inhibition of hepatic 

metabolism

May increase quinidine serum concentration

Immediate Major No data. Use with caution with close 

EKG monitoring and serum levels of quinidine.

DLV Ketoconazole Inhibition of hepatic 

metabolism by delavirdine

Ketoconazole AUC increased by 50%

Immediate Minor Consider dose reduction of ketoconazole. 

DLV 200–400 mg tid.

DLV Rifampin Inhibition of hepatic 

metabolism

Delavirdine Cmin decreased below the level of detection AUC decreased by 96%

Delayed Major Concurrent administration 

contraindicated due to sub-therapeutic level of delavirdine.

DLV Rifabutin Inhibition of hepatic 

metabolism by delavirdine

Rifabutin AUC increased by 100%

Immediate Moderate Concurrent administration 

contraindicated due to sub-therapeutic level of delavirdine.

DLV Rifabutin Induction of hepatic 

metabolism by rifabutin

Delavirdine AUC decreased by 80%

Delayed Major Concurrent administration 

contraindicated. 

DLV Warfarin Potential inhibition of 

warfarin metabolism

May increase warfarin Immediate Moderate Monitor INR.

DLV Voriconazole Potential for bi-directional 

inhibition

May increase voriconazole and DLV serum level

Immediate Moderate Monitor frequently for toxicities.

DLV Bepridil Potential inhibition of bepridil 

metabolism

May increase bepridil serum level

Immediate Moderate Use with caution; monitor for cardiac 

arrhythmias.
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508 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

DLV Tadalafil Potential inhibition of 

tadalafil metabolism

May substantially increase in tadalafil AUC and half life

Immediate Moderate Start tadalafil 5 mg dose; do not exceed a 

single 10 mg dose of tadalafil in 72 hours.

DLV Vardenafil Potential inhibition of 

vardenafil metabolism

May substantially increase vardenafil AUC

Start with a 2.5 mg dose; do not exceed a single 2.5 mg dose of vardenafil in 72 hours.

Efavirenz (Sustiva®) (EFV)

Saquinavir Induction of hepatic 

metabolism

Invirase® AUC decreased by 60%. Efavirenz AUC decreased by 12%

Delayed Moderate Avoid using SQV as sole protease 

inhibitor with efavirenz. If RTV/SQV/efavirenz regimen used: dose SQV 1000 mg/RTV 100–200 mg bid plus EFV 600 mg qhs or RTV/SQV 400 mg/400 mg bid plus EFV 600 mg qhs.

EFV Nelfinavir Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 21%

Immediate Minor A beneficial pharmacokinetic interaction. 

No dose adjustment needed.

EFV Amprenavir Induction of hepatic 

metabolism

Amprenavir AUC decreased by 36%

Delayed Moderate Dose: APV 600 mg/ RTV 100 mg q12h + 

EFV 600 mg qhs.

EFV Indinavir Induction of hepatic 

metabolism

Indinavir AUC decreased by 31%

Delayed Moderate May need to increase indinavir dose to 

1000 mg q8h or consider IDV “boosted” with 200 mg RTV.

EFV Ritonavir Dual inhibition of hepatic 

metabolism

Efavirenz AUC increased by 21%. Ritonavir AUC increased by 17%

Immediate Minor No adjustment needed.

EFV Lopinavir/r Induction of hepatic 

metabolism

LPV AUC decreased by 19%. Cmin decreased by 39%

Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid 

+ EFV 600 mg qhs.

EFV Ergot alkaloid Induction of hepatic 

metabolism

Potential acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.
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EFV Midazolam, Triazolam Induction of hepatic 

metabolism

AUCs of midazolam and triazolam increased

Immediate Major Concurrent administration 

contraindicated due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.

EFV Terfenadine, 

Astemizole, Cisapride

Induction of hepatic metabolism

Levels of terfenadine, astemizole, cisapride increased

Immediate Major Concurrent administration 

contraindicated due to potential for serious cardiac arrhythmia.

EFV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease efavirenz serum level

Delayed Major Co-administration is contraindicated.

EFV Clarithromycin Induction of hepatic 

metabolism

Clarithromycin AUC decreased by 39%

Immediate Moderate Incidence of rash increased to 46% with 

concurrent administration. No interaction with azithromycin, a better alternative.

EFV Ethinyl estradiol Inhibition of hepatic 

metabolism

Ethinyl estradiol AUC increased by 37%

Immediate Minor No dose changes recommended. Clinical 

significance of interaction unknown. No data on progestin component of oral contraceptive available. Alternative or additional form of birth control recommended.

EFV Rifabutin Inhibition of hepatic 

metabolism

Rifabutin AUC decreased by 35%. No effect on Efavirenz AUC

Delayed Moderate If concurrent administration required, 

increase dose of rifabutin to 450 mg or 600 mg po qd.

EFV Rifampin Inhibition of hepatic 

metabolism

Efavirenz AUC decreased by 26%. No change in rifampin levels

Delayed Moderate Consider increasing EFV to 800 mg 

qhs with rifampin co-administration. An alternative is to use rifabutin dose adjusted to 450–600 mg qd (or 600 mg 3x/week) with standard dose EFV.

EFV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism by both EFV and anticonvulsants.

May decrease serum levels of EFV and anticonvulsants

Delayed Moderate Consider alternative anticonvulsants 

(i.e valproic acid, levetiracetam, or topiramate). Consider increasing EFV to 800 mg po qd with co-administration. Monitor anticonvulsant level.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

510 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

EFV Nevirapine Induction of hepatic 

metabolism

EFV AUC decreased by 22%. NVP AUC not affected

Delayed Moderate Though pharmacokinetic data exist, coadministration is not recommended due 

to overlapping resistance.

EFV Methadone Induction of hepatic 

metabolism

Decrease methadone AUC by 57%

Delayed Moderate Opiate withdrawal may occur. May need 

to increase dose of methadone. 

EFV Atazanavir Induction of hepatic 

metabolism

ATV decreases AUC by 74% Delayed Major Use ATV 300 mg + RTV 100 mg qd with 

food. Standard EFV dose.

EFV Fosamprenavir Induction of hepatic 

metabolism

fAPV Cmin decreases 36% when dosed at fAPV 1400 mg + RTV 250 mg qd

Delayed Major Use fAPV 700 mg + RTV 100 mg bid,

OR fAPV 1400 mg + RTV 300 mg with EFV co-administration.

EFV Indinavir Induction of hepatic 

metabolism

IDV decreases 31% Delayed Major Increase IDV dose to 1000 mg q8h or 

consider IDV 800 mg + RTV 200 mg q12h.

EFV Warfarin Unknown Potential increase or 

decrease in warfarin levels

Delayed Moderate Monitor INR.

Drug Interactions with Protease InhibitorsIndinavir (Crixivan®) (IDV)

ddI Impairment of indinavir 

absorption by DDI buffer

Decreases absorption of indinavir

Immediate Moderate Separate indinavir and ddI dosing by at 

least 2h or use ddI EC formulation.

IDV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism

Increased serum levels of simvastatin and lovastatin

Immediate Moderate Avoid concurrent administration. 

Possible alternative include atorvastatin, pravastatin, fluvastatin. Monitor for adverse effect due to limited clinical data with these agents.

IDV Rifabutin Inhibition of hepatic 

metabolism by indinavir

Rifabutin AUC increased by 2 fold. 

Immediate Moderate Decrease rifabutin dose by half (150 mg 

once a day) or 300 mg 3x/week.
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IDV Rifabutin Induction of hepatic 

metabolism by rifabutin

Indinavir AUC decreased by 32%

Delayed Moderate May need to increase indinavir dose to 

1000 mg tid. When IDV “boosted” with RTV, adjust rifabutin 150 mg qod.

IDV Rifampin Induction of hepatic 

metabolism

Indinavir AUC decreased by 90%

Immediate Major Concurrent administration 

contraindicated.

IDV Terfenadine, 

Astemizole, Cisapride

Inhibition of hepatic metabolism

Drug levels increased by 3-fold or greater

Immediate Major Concurrent administration 

contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide. 

IDV Ergot alkaloid Inhibition of hepatic 

metabolism

Potential acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.

IDV Ketoconazole, 

Itraconazole

Inhibition of hepatic metabolism

Indinavir AUC increased by 70%

Immediate Moderate Dose Indinavir at 600 mg Q8h. No dose 

adjustment when “boosted” with RTV.

IDV Midazolam, Triazolam Inhibition of hepatic 

metabolism

AUCs of midazolam and triazolam are increased

Immediate Major Concurrent administration 

contraindicated due to potential for prolonged sedation.

IDV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

Indinavir AUC decreased by 57%.

Delayed Major Co-administration is contraindicated.

IDV Clarithromycin Inhibition of hepatic 

metabolism

Clarithromycin AUC increased by 53%

Immediate Minor No dose adjustment.

IDV Oral contraceptives Inhibition of hepatic 

metabolism

Ethinyl estradiol AUC increased by 24% and norethindrone AUC increased by 26%.

Immediate Minor No dose adjustment.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

512 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

IDV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism

May decrease serum levels of IDV. IDV may increase anticonvulsant serum level.

Delayed Moderate Consider alternative anticonvulsants (i.e 

valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. 

IDV Sildenafil Inhibition of hepatic 

metabolism

Sildenafil AUC increased 3-fold.

Immediate Moderate The maximum dose of sildenafil is 25 

mg/48h.

IDV Nelfinavir Inhibition of hepatic 

metabolism.

Indinavir AUC increased by 50% Nelfinavir AUC increased by 80%

Immediate Minor Limited dosing data using IDV 1200 mg 

bid + NFV 1250 mg bid.

IDV Amprenavir Inhibition of hepatic 

metabolism

Amprenavir AUC increased by 26%. Indinavir AUC increased by 38%.

Immediate Minor No dose adjustment recommended. Dose 

APV 800 mg tid /IDV 800 mg tid.

IDV Ritonavir Inhibition of hepatic 

metabolism

Indinavir AUC increased by 2 to 5-fold.

Immediate Minor Interaction allows indinavir to be dosed 

twice a day. Dose: IDV 400 mg/RTV 400 mg or IDV 800 mg bid/RTV100 bid. IDV 1200 mg/RTV 400 mg qd (limited data).

IDV Lopinavir/r Inhibition of hepatic 

metabolism

Indinavir AUC increased by 3-fold

Immediate Moderate Dose: IDV 600 mg or 666 mg bid plus 

LPV/r 400 mg/100 mg bid.

IDV Saquinavir Inhibition of hepatic 

metabolism

Saquinavir AUC increased 4 to 7 fold. No effect on Indinavir level

Immediate Moderate In vitro antagonism. Avoid coadministration.

IDV Nevirapine Induction of hepatic 

metabolism

Indinavir AUC decreased by 28%. NVP level not affected.

Delayed Minor Clinical trials demonstrated good efficacy 

with standard doses. Some experts recommend increasing the dose of IDV to 1000 mg q8h. When using “boosted” IDV consider RTV dose 200 mg bid.

IDV Efavirenz Induction of hepatic 

metabolism

Indinavir AUC decreased by 31%

Delayed Moderate May need to increase indinavir dose to 

1000 mg q8h or IDV 800/ RTV 100 q12h.

IDV Delavirdine Inhibition of hepatic 

metabolism

Indinavir AUC increased by 40%. DLV no change.

Immediate Moderate May reduce indinavir dose to 600 mg 

q8h. DLV standard dose.
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XIV

IDV Methadone No change in serum level No interaction. Use standard dose

IDV Voriconazole When IDV is boosted 

with RTV, potential for bidirectional interaction

Voriconazole levels may be decreased with IDV/RTV

Delayed Moderate No interaction with IDV but voriconazole 

may be decreased with RTV coadministraion. Monitor for toxicities and therapeutic efficacy.

IDV Tadalafil Inhibition of hepatic 

metabolism

May substantially increase tadalafil AUC

Immediate Moderate Start with 5 mg dose and do not exceed 

a single dose of 10 mg in 72 hrs.

IDV Vardenafil Inhibition of hepatic 

metabolism

Vardenafil increases 16-fold IDV unboosted decreases 30% 

Immediate Moderate For unboosted IDV, consider using 

sildenafil instead; for IDV + RTV, do not exceed 2.5 mg vardenafil in 72 hrs.

IDV Atorvastatin Inhibition of hepatic 

metabolism

Potential for atorvastatin AUC increase

Immediate Moderate Use lowest possible starting dose of 

atorvastatin with careful monitoring or avoid use together.

Saquinavir (Invirase®) (Fortovase®) (SQV)

Ritonavir Inhibition of hepatic 

metabolism

Saquinavir AUC increased by 20-fold.

Immediate Minor Dual protease inhibitor combination 

with the most clinical experience. Recommended doses: RTV 400 mg bid plus SQV 400 mg bid. RTV 100 mg bid plus SQV 1000 mg bid. RTV 100 mg plus SQV 1600 mg qd.

SQV Indinavir Inhibition of hepatic 

metabolism

Saquinavir AUC increased 4 to 7- fold No effect on Indinavir

Immediate Moderate In vitro antagonism. Avoid coadministration.

SQV Nelfinavir Inhibition of hepatic 

metabolism

Fortovase®AUC increased by 3 to 5-fold. Nelfinavir AUC increased by 20%

Immediate Minor Recommended doses are nelfinavir 750 

mg tid and Fortovase® 800 mg tid or 1200 mg bid.

SQV Amprenavir Induction of hepatic 

metabolism

Saquinavir level decreased by 18%. Amprenavir level decreased by 36%.

Delayed Moderate Limited data: SQV (FTV) 800 mg tid plus 

APV 800 mg tid.

SQV Lopinavir/r Inhibition of hepatic 

metabolism

Saquinavir Cmin increased by 3..6-fold

Immediate Minor Dose: SQV 800–1000 mg bid plus LPV/r 

400/100 mg bid.
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514 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

SQV Ketoconazole Inhibition of hepatic 

metabolism

Saquinavir level increased by 3-fold.

Immediate Minor Beneficial pharmacokinetic interaction. 

Use standard doses. If ketoconazole dose is >200 mg/da, monitor for GI side effects and adjust doses accordingly.

SQV Midazolam, Triazolam Inhibition of hepatic 

metabolism

Midazolam and triazolam AUCs increased

Immediate Major Concurrent administration 

contraindicated due to potential for prolonged sedation.

SQV Terfenadine, 

Astemizole, Cisapride 

Inhibition of hepatic metabolism 

Drug levels increased by 3-fold or greater.

Immediate Major Concurrent administration 

Contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide. 

SQV Dexamethasone Induction of hepatic 

metabolism

May decrease SQV serum levels

Delayed Moderate Clinical significance unknown.

SQV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism

May decrease serum levels of SQV

Delayed Moderate Consider alternative anticonvulsants 

(i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. 

SQV Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.

SQV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism.

Simvastatin and lovastatin serum level increased

Immediate Moderate Avoid co-administration. Recommended 

alternatives include atorvastatin, pravastatin (but pravastatin AUC decreased by 50% with SQV/r), fluvastatin. Monitor for adverse effects due to limited clinical data with these agents. 
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SQV Clarithromycin Inhibition of hepatic 

metabolism

Clarithromycin increases SQV AUC 177% and SQV increases clarithromycin AUC 45%

Immediate Minor Beneficial pharmacokinetic interaction. 

Use standard doses.

SQV Rifabutin/ Rifampin Induction of hepatic 

metabolism

Rifabutin and rifampin decrease AUC of saquinavir by 40% and 80% respectively.

Delayed Major Concurrent administration 

contraindicated unless using RTV/SQV. Consider RTV/SQV 400 mg/400 mg with rifabutin 150 mg 3x/week or rifampin 600 mg qd or 3x/week.

SQV Sildenafil Inhibition of hepatic 

metabolism.

Sildenafil AUC increased by 2-fold.

Immediate Moderate Caution with concurrent use, Do not exceed 

25 mg of sildenafil in a 48-hour period.

SQV Oral contraceptives No data.SQV Methadone Induction of hepatic 

metabolism

8–10% reduction in methadone level.

Delayed Minor Insignificant interaction. No dose 

adjustment needed.

SQV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease SQV serum level

Delayed Major Co-administration is contraindicated.

SQV Garlic supplement 

(3.5 mg bid)

Unknown SQV Cmin decreased by 

49%

Delayed Moderate Avoid concurrent administration.

SQV Delavirdine Inhibition of hepatic 

metabolism

SQV increases 5-fold Immediate Minor Decrease SQV-sgc dose to 800 mg tid, 

and monitor transaminase levels.

SQV Efavirenz Induction of hepatic 

metabolism

SQV decreases 62%, EFV decreases 12%

Delayed Moderate Use SQV-sgc 400 mg + RTV 400 mg.

SQV Nevirapine Inhibition of hepatic 

metabolism

SQV decreases 25% Delayed Moderate SQV-sgc 400 + RTV 400 mg or SQV-sgc 

1000 mg + RTV 100 mg bid or SQV-hgc 1000 mg + RTV 100 mg bid.

SQV Warfarin Unknown Increases or decreases 

warfarin

Dealyed Moderate Monitor INR.

SQV Amitryptiline 

Imipramine

Inhibition of hepatic metabolism

May increase tricyclics Immediate Minor Monitor tricyclic antidepressant 

concentration.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

516 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

SQV Voricanazole Potential for bi-directional 

inhibition

With SQV/RTV voriconazole serum level may be decreased

Delayed Moderate Monitor for toxicities and therapeutic 

efficacy.

SQV Tadalafil Inhibition of hepatic 

metabolism

May substantially increase tadalafil AUC

Immediate Moderate Start with a 5 mg dose and do not 

exceed a single 10 mg dose of tadalafil in 72 hrs.

SQV Vardenafil Inhibition of hepatic 

metabolism

Vardenafil AUC may increase substantially

Immediate Moderate Start with a 2.5 mg dose, and do not 

exceed a single 2.5 mg dose in 72 hrs.

SQV Atorvastatin Inhibition of hepatic 

metabolism

Atorvastatin increases 450% when combined with SQV/RTV

Immediate Moderate Use lowest possible starting dose of 

atorvastatin with careful monitoring.

Ritonavir (Norvir®) (RTV)

Metronidazole Alcohol in ritonavir liquid 

may precipitate a disulfiramlike reaction.

Unexpected nausea Immediate Moderate Warn patient of the alcohol content in 

ritonavir liquid.

RTV Voriconazole Hepatic induction Decreased voriconazole by 

82% when administered with RTV 400 mg bid

Delayed Major Do not co-administer with standard dose 

RTV 400 bid; no data with boosting doses of RTV.

RTV Oral contraceptives Induction and increase in 

glucuronosyl transferase activity.

Ethinyl estradiol level decreased by 40%

Delayed Major Warn patient of interaction. Use 

alternative or additional method of contraception.

RTV Sildenafil Inhibition of hepatic 

metabolism.

Sildenafil AUC increased by 2 to 11-fold.

Immediate Major Caution with concurrent use, Do not 

exceed 25 mg of sildenafil in a 48-hour period.

RTV Theophylline Induction of glucuronosyl 

transferase activity.

Theophylline AUC decreased by 43%

Delayed Moderate Monitor theophylline levels; dose may 

need to be increased if subtherapeutic.

RTV Ketoconazole Inhibition of hepatic 

metabolism

Ketoconazole AUC increased by greater than 3-fold.

Immediate Moderate May need to decrease ketoconazole dose.
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RTV Rifabutin Inhibition of hepatic 

metabolism

Rifabutin AUC increased 4-fold

Immediate Moderate Dose rifabutin 150 mg qod or 150 mg 

3x/week with standard ritonavir.

RTV Rifampin Induction of hepatic 

metabolism

Ritonavir AUC decreased by 35%

Delayed Moderate There may be an increased risk of liver 

toxicity. Dose RTV 400 mg/ SQV 400 mg bid with rifampin 600 mg qd.

RTV Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration contraindicated.

RTV Terfenadine, 

Astemizole, Cisapride 

Inhibition of hepatic metabolism 

Drug level increased by 3- fold or greater.

Immediate Major Concurrent administration contraindicated 

due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative prokinetic agent includes metoclopramide. 

RTV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease RTV serum level Delayed Major Co-administration is contraindicated.

RTV Benzodiazepines Inhibition of hepatic 

metabolism

Prolonged sedation due to accumulation of benzodiazepine

Delayed Major Concurrent administration of midazolam and 

triazolam are contraindicated. Alternative benzodiazepines that can be used: Temazepam, oxazepam, and lorazepam.

RTV Antiarrhythmics Inhibition of hepatic 

metabolism

AUC of antiarrhythmics increased

Immediate Major Concurrent administration of 

propafenone, quinidine, flecainide, encainide, amiodarone, and bepridil are contraindicated. 

RTV Methadone Induction of hepatic 

metabolism

Methadone levels decreased by 37%.

Delayed Moderate Clinical significance unknown. 

RTV Ketoconazole Inhibition of hepatic 

metabolism

Ketoconazole levels increased by 3-fold.

Immediate Moderate Use with caution; do not exceed 200 mg 

ketoconazole per day.

RTV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism

May decrease serum levels of RTV. RTV may increase serum level of anticonvulsants

Delayed Moderate Consider alternative anticonvulsants 

(i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. Carbamazepine toxicity has been reported. 
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518 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

RTV Antidepressant 

(TCAs: desipramine, amitriptyline.) SSRIs, Bupropion

Inhibition of hepatic metabolism

Desipramine AUC increased by 145%.Increased serum levels of SSRIs, bupropion

Immediate Major Monitor desipramine levels. Consider 

citalopram, sertraline, or fluoxetine.Monitor for increased effects from SSRIs, bupropion. Doses of RTV used in boosted PI regimens may have minimal effects.

RTV Antipsychotic 

(Olanzapine)

Induction of hepatic metabolism

Olanzapine AUC decreased by 50%.

Delayed Moderate Olanzapine dose may need to be 

increased.

RTV Antipsychotic 

(Pimozide)

Inhibition of hepatic metabolism

May significantly increase pimozide serum level resulting in QTc prolongation

Immediate Major Concurrent administration of pimozide is 

contraindicated.

RTV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism.

Serum levels of simvastatin and lovastatin are increased.

Immediate Moderate Avoid co-administration, alternatives 

that may be used inlcude atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.

RTV Opioid analgesic Inhibition of hepatic 

metabolism.

Prolonged sedation and possible respiratory depression

Immediate Major Avoid concurrent administration of 

meperidine, propoxyphene, and fentanyl. Morphine may be a safer alternative.

RTV Clarithromycin Inhibition of hepatic 

metabolism.

Clarithromycin AUC increased by 77%

Immediate Minor Reduce clarithromycin dose for renal 

failure. Consider using azithromycin.

RTV Didanosine (buffered) Interference with absoption Decreased ritonavir 

absorption.

Immediate Major Consider using ddI EC or separate 

administration by >2 hours.

RTV Saquinavir Inhibition of hepatic 

metabolism.

Saquinavir AUC increased by 20-fold.

Immediate Minor Dual protease inhibitor with the most 

clinical experience. Recommended doses: ritonavir 400 mg bid and SQV (Fortovase® or Invirase®) 400 mg bid or SQV 1000 mg + RTV 100 mg bid or SQV 1600 mg + RTV 100 mg qd. 
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RTV Indinavir Inhibition of hepatic 

metabolism.

Indinavir AUC increased by 2 to 5-fold.

Immediate Minor Interaction allows indinavir to be dosed 

twice a day, which may reduce renal stones associated with higher dose indinavir. Dose: IDV 400 mg bid and RTV 400 mg bid or IDV 800 mg bid + RTV 100 bid.

RTV Nelfinavir Inhibition of hepatic 

metabolism.

Nelfinavir AUC increased by 2.5-fold.

Immediate Minor Only marginal PK benefit. Clinical trials 

have used ritonavir 400 mg bid and nelfinavir 500 mg or 750 mg bid.

RTV Amprenavir Inhibition of hepatic 

metabolism.

Amprenavir AUC increased by 2.5-fold.

Immediate Minor Dose: APV 600 mg bid plus RTV 100 mg bid 

or APV 1200 mg qd plus RTV 200 mg qd.

RTV Atazanavir Inhibition of hepatic 

metabolism

ATV increases AUC by 238% Immediate Minor A beneficial PK interaction, use ATV 300 

mg + RTV 100 mg qd.

RTV Fosamprenavir Inhibition of hepatic 

metabolism

fAPV increases AUC by 100%, Cmin by 400% when combined with 200 mg RTV

Immediate Minor A beneficial PK interaction, use RTVboosted regimen (fAPV 700 mg + RTV 

100 mg bid) in ARV-experienced patients.

Nelfinavir (Viracept®) (NFV)

Ketoconazole Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 35%

Immediate Minor No dose adjustment needed.

NFV Fluconazole Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 30%

Immediate Minor May be beneficial. No dose adjustment 

needed.

NFV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism.

Increased serum level of simvastatin and lovastatin

Immediate Moderate Avoid co-administration: Alternatives 

includes pravastatin (but pravastatin AUC decreased by 47%), and fluvastatin. Monitor for adverse effects due to limited clinical data. Atorvastatin levels increased by 74%.

NFV Methadone Induction of hepatic 

metabolism

Decreased serum level of inactive methadone (S)-isomer. No change in active methadone (R)-isomer

Delayed Minor Use standard dose. No withdrawal 

symptoms observed.

NFV Rifampin Induction of hepatic 

metabolism

Nelfinavir AUC decreased by 82%

Delayed Major Concurrent administration 

contraindicated.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

520 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

NFV Rifabutin Induction of hepatic 

metabolism by rifabutin

Nelfinavir AUC decreased by 32%

Delayed Moderate If co-administration required, increase 

nelfinavir to 1000 mg po tid.

NFV Inhibition of hepatic 

metabolism by nelfinavir

Rifabutin levels increased by 2-fold

Immediate Moderate If co-administration required, decrease 

rifabutin to 150 mg po qd or 300 mg 3x/week.

NFV Benzodiazepines Inhibition of hepatic 

metabolism

Prolonged sedation due to accumulation of benzodiazepine

Immediate Major Midazolam and triazolam are 

contraindicated. Alternative benzodiazepines include temazepam and lorazepam.

NFV Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.

NFV Terfenadine, 

Astemizole, Cisapride 

Inhibition of hepatic metabolism 

Drug levels increased by 3- fold or greater.

Immediate Major Concurrent administration 

contraindicated due to potential cardiac arrhythmia. Recommended alternative antihistamine: loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent: metoclopramide.

NFV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease NFV serum level

Delayed Major Co-administration is contraindicated.

NFV Oral contraceptives Induction of hepatic 

metabolism

Ethinyl estradiol AUC decreased by 47%

Delayed Major Advise patient to use alternative or 

additional method of contraception.

NFV Sildenafil Inhibition of hepatic 

metabolism.

Sildenafil AUC increased by 2-11 fold.

Immediate Major Caution with concurrent use. Do not exceed 

25 mg of sildenafil in a 48-hour period.
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XIV

NFV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism

May decrease serum levels of NFV. NFV may increase serum levels of anticonvulsants

Delayed Moderate Consider alternative anticonvulsants (i.e 

valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. 

NFV Indinavir Inhibition of hepatic 

metabolism.

Indinavir AUC increased by 50% Nelfinavir AUC increased by 80%

Immediate Minor Limited data for dosing IDV 1200 mg bid 

+ NFV 1250 mg bid.

NFV Saquinavir Inhibition of hepatic 

metabolism

Fortovase® AUC increased by 3–5 fold. Nelfinavir AUC increased by 20%

Immediate Moderate Dose nelfinavir 750 mg tid and Fortovase 

800 mg tid or 1200 mg bid.

NFV Amprenavir Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 15%, Amprenavir AUC increased by 50%.

Immediate Minor Limited data: NFV 1250 mg bid plus APV 

1200 mg bid.

NFV Ritonavir Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 1.5 fold. Increase in Nelfinavir metabolite.

Immediate Moderate Limited data: ritonavir 400 mg bid 

and nelfinavir 500 mg or 750 mg bid. Boosting with ritonavir will yield only minimal pharmacokinetic enhancement of nelfinavir serum concentration.

NFV Lopinavir/r Induction of hepatic 

metabolism by NFV. Inhibition of hepatic metabolism by LPV/r.

LPV decreased by 33%. NFV increased 25%

Delayed Moderate Consider increasing LPV/r dose to 4 caps 

bid with NFV co-administration.

NFV Nevirapine No significant drug interaction. Use 

standard dose.

NFV Delavirdine Induction of hepatic 

metabolism

Delavirdine AUC decreased by 50%. NFV AUC increased by 2-fold.

Immediate Minor Consider increasing DLV dose to 600 mg 

tid with standard dose NFV 1250 mg bid (limited data).

NFV Efavirenz Inhibition of hepatic 

metabolism

NFV AUC increased by 20%. EFV levels unchanged.

Immediate Minor No significant drug interaction. Use 

standard dose.

NFV Voriconazole Potential for bi-directional 

interaction

NFV and voriconazole may be increased

Immediate Moderate Monitor for toxicities.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

522 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

Amprenavir(Agenerase®)(APV)

Rifampin Induction of hepatic 

metabolism

Amprenavir AUC decreased by 80%

Delayed Major Concurrent administration 

contraindicated.

APV Rifabutin Induction of hepatic 

metabolism

Amprenavir AUC decreased by 14%.Rifabutin AUC increased by 204%

Delayed Moderate Dose rifabutin 150 mg qd or 300 mg 3x/

week. No change in amprenavir dose.

APV Ketoconazole Inhibition of hepatic 

metabolism

Amprenavir AUC increased by 32%.Ketoconazole AUC increased by 44%.

Immediate Minor May be beneficial. No dose adjustment 

needed.

APV Clarithromycin Inhibition of hepatic 

metabolism

Amprenavir AUC increased by 18%

Immediate Minor No dose adjustment needed.

APV Oral contraceptives Induction of hepatic 

metabolism

Potential decreases in ethinyl estradiol level.

Delayed Major Advise patient of potential risk and the 

use of an alternative or additional method of contraception.

APV Sildenafil Inhibition of hepatic 

metabolism.

Sildenafil AUC increased by 2-11 fold.

Immediate Major Caution with concurrent use, Do not exceed 

25 mg of sildenafil in a 48-hour period.

APV Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism.

Simvastatin and lovastatin levels increased.

Immediate Moderate Avoid concurrent administration. 

Alternative agents include atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.

APV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease APV serum level

Delayed Major Co-administration is contraindicated.
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XIV

APV Saquinavir Induction of hepatic 

metabolism

Saquinavir level decreased by 18%.Amprenavir level decreased by 36%.

Delayed Minor No dose adjustment. Insufficient data for 

dose recommendation.

APV Indinavir Inhibition of hepatic 

metabolism

Amprenavir AUC increased by 33%.Indinavir AUC decreased by 38%.

Immediate Minor No dose adjustment. IDV 800 mg tid plus 

APV 800 mg tid.

APV Nelfinavir Inhibition of hepatic 

metabolism

Nelfinavir AUC increased by 15%, Amprenavir AUC increased by 50%.

Immediate Minor No dose adjustment. NFV 750 mg tid plus 

APV 800 mg tid.

APV Ritonavir Inhibition of hepatic 

metabolism

Amprenavir AUC increased by 2.5-fold.

Immediate Minor Dose: APV 600 bid/RTV 100 bid or APV 

1200 mg qd /RTV 200 mg qd.

APV Lopinavir/r Induction of hepatic 

metabolism by APV. Inhibition of hepatic metabolism by LPV/r

APV Cmin increased 5-fold. LPV AUC decreased 30–50%.

Delayed Moderate Dose: LPV/r 533 mg/133 mg (4 caps) + 

APV 750 mg bid (+/- EFV).

APV Efavirenz Induction of hepatic 

metabolism

Amprenavir AUC decreased by 36%.Efavirenz AUC increased by 15%

Delayed Moderate Dose: APV 600 mg/ RTV 100 mg bid + 

EFV 600 mg qHS.

APV Nevirapine Induction of hepatic 

metabolism

APV level may be significantly decreased

No data. 

APV Delavirdine Induction of hepatic 

metabolism by APV. Inhibition of hepatic metabolism by DLV

DLV AUC decreased by 60% and trough decreased by 90%. APV AUC increased by 25%.

Delayed Major Co-administration not recommended. 

APV Methadone Induction of hepatic 

metabolism

Decreased serum level of inactive methadone (S)-isomer. No change in active methadone (R)-isomer

Delayed Minor Use standard dose. No withdrawal 

symptoms observed. 
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Pharmacologic Considerations in HIV-Infected Pregnant Patients

524 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

APV Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration contraindicated

APV Midazolam,

Triazolam

Inhibition of hepatic metabolism

AUC of midazolam and triazolam are increased.

Immediate Major Concurrent administration contraindicated 

due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.

APV Terfenadine

AstemizoleCisapride

Inhibition of hepatic metabolism 

Cardiotoxic drug level increased by 3-fold or greater.

Immediate Major Concurrent administration contraindicated 

due to potential for cardiac arrhythmias. Alternatives include loratidine, fexofenadine, or cetirizine. Alternative prokinetic agent includes metoclopramide.

APV Amiodarone, lidocaine 

(systemic), quinidine, and bepridil

May increase serum level of antiarrhythmics.

Immediate Moderate Use with caution. Monitor antiarrhythmic 

serum level.

APV Pimozide May increase serum level of 

pimozide.

Immediate Major Contraindicated. Potential for lifethreatening cardiac arrhythmia.

APV Calcium channel 

blocker

May increase serum level of calcium channel blocker

Immediate Moderate Use with caution. Close monitoring 

recommended.

APV Dexamethasone May decrease APV serum 

level.

Delayed Moderate Use with caution. 

APV Cyclosporine, 

tacrolimus, rapamycin

May increase immunosuppressant serum level.

Immediate Moderate Therapeutic drug monitoring of 

immunosuppressant highly recommended.

APV Amitriptyline, 

imipramine, and desipramine

May increase TCA serum level.

Immediate Moderate Consider therapeutic drug monitoring 

or use SSRI (i.e. citalopram, sertraline, or fluoxetine).
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XIV

APV Phenytoin, 

carbamazepine, and phenobarbital

May significantly decrease APV serum level.

Delayed Moderate Consider alternative anticonvulsant 

(i.e. valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level.

APV Didanosine May interfere with absorption APV serum level may be 

decreased

Immediate Moderate Dosing should be separated by 1 hour.

APV Warfarin Unknown Increase or decrease in 

warfarin

Immediate Moderate INR must be monitored.

APV Voriconazole Potential for bi-directional 

interaction (or induction with RTV co-administration)

Voriconazole may be decreased with RTV coadministration. APV may be increased

Immediate Moderate Monitor for toxicities and therapeutic 

efficacy.

APV Bepridil Inhibition of hepatic 

metabolism

May increase bepridil Immediate Moderate Use with caution.

APV Tadalafil Inhibition of hepatic 

metabolism

May substantially increase tadalafil AUC and half life

Immediate Moderate Start with 5 mg dose; do not exceed a 

single 10 mg dose of tadalafil in 72 hrs.

APV Vardenafil Inhibition of hepatic 

metabolism

May increase vardenafil AUC Immediate Moderate Start with a 2.5 mg dose; do not exceed 

a 2.5 mg dose of vardenafil in 72 hrs.

APV Atorvastatin Inhibition of hepatic 

metabolism

May increase atorvastatin substantially

Immediate Moderate Use lowest possible starting dose of 

atorvastatin with careful monitoring.

Fosamprenavir drug-drug interactions Since fosamprenavir is converted to amprenavir, all drug interaction data for “unboosted” amprenavir should also apply to “unboosted” fosamprenavir. However, there are some interactions that are more pronounced with fosamprenavir. fAVP LPV/r Enzyme induction Significant decrease in levels 

of both LPV and APV

Delayed Major Boosting with RTV still resulted in 

significant reduction of APV trough at standard dose. Best PK data with fAPV 1400 mg bid and LPV/r 533 mg/133 mg bid.

fAPV/r EFV Enzyme induction APV Cmin decreased by 17% 

(90% CI 4–29%) with bid vs. 36% (90% CI 8–56%) with qd fAPV dosing

Delayed Moderate Recommended Dose: fAPV 700 mg 

bid/RTV 100 mg bid or fAPV 1400 mg qd/RTV 300 mg qd.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

526 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

fAPV Atorvastatin Enzyme inhibition Atorvastatin AUC increased 

by 130% (with fAPV 1400 mg bid) and 150% (with fAPV 700 mg/RTV 100 mg bid). No change in APV AUC.

Immediate Moderate Close monitoring recommeded. Do not 

exceed 20 mg per day of atorvastatin.

fAPV/r Ritonavir Enzyme inhibition Amprenavir AUC increased 

by over 2-fold. Cminincreased by 4-fold with daily administration and 6-fold with twice daily administration compared to fAPV 1400 mg bid.

Immediate Minor Dose: fAPV 700 mg bid/RTV 100 mg bid 

or fAPV 1400 mg qd/RTV 200 mg qd.

Lopinavir/r Methadone Induction of hepatic 

metabolism

Methadone AUC decreased by 53%

Delayed Minor No withdrawal symptoms observed 

in 2 out of 3 studies. Standard dose recommended. Monitor and increase dose of methadone if needed.

LPV/r Rifampin Induction of hepatic 

metabolism

LPV AUC decreased 75% Delayed Major Concurrent administration 

contraindicated. Consider using rifabutin with LPV/r.

LPV/r Rifabutin Inhibition of hepatic 

metabolism by LPV/r

Rifabutin serum level increased by 3-fold. LPV serum level not affected

Immediate Moderate Dose: LPV/r 3 caps bid plus rifabutin 150 

mg qod or 150 mg 3x/week.

LPV/r Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities

Immediate Major Concurrent administration 

contraindicated.
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XIV

LPV/r Terfenadine

AstemizoleCisapride

Inhibition of hepatic metabolism 

Drug level increased by 3-fold or greater.

Immediate Major Concurrent administration contraindicated 

due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide. 

LPV/r St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease LPV serum level

Delayed Major Co-administration is contraindicated.

LPV/r Benzodiazepines Inhibition of hepatic 

metabolism

Prolonged sedation due to accumulation of benzodiazepine

Delayed Major Concurrent administration of midazolam 

and triazolam are contraindicated. Alternative benzodiazepine that can be used: Temazepam, oxazepam, and lorazepam.

LPV/r Antidepressants (TCA, 

SSRIs, Bupropion)

See RTV section

LPV/r Antiarrhythmics Inhibition of hepatic 

metabolism

AUC of antiarrhythmics increased

Immediate Major Concurrent administration of 

propafenone, flecainide, and encainide are contraindicated. 

LPV/r Antipsychotic 

(Pimozide)

Inhibition of hepatic metabolism

May significantly increase pimozide serum level resulting in QTc prolongation

Immediate Major Concurrent administration of pimozide is 

contraindicated.

LPV/r Simvastatin/ 

Lovastatin

Inhibition of hepatic metabolism.

Serum levels of simvastatin and lovastatin are increased.

Immediate Moderate Avoid co-administration, alternatives 

that may be used include pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.

LPV/r Phenytoin 

(also carbamazepine and phenobarbital).

Induction of hepatic metabolism

LPV decreased by 33%. Phenytoin decreased by 31%.

Delayed Major Consider alternative anticonvulsants. 

Consider TDM. Monitor anticonvulsant levels with co-administration.
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Pharmacologic Considerations in HIV-Infected Pregnant Patients

528 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

LPV/r Atorvastatin Inhibition of hepatic 

metabolism

Atorvastatin AUC increased by 6-fold. 

Immediate Moderate Clinical significance unknown. Use with 

caution. Starting dose atorvastatin 10 mg qd.

LPV/r Indinavir Inhibition of hepatic 

metabolism

Indinavir AUC increased by 3-fold

Immediate Moderate Dose: IDV 600 mg or 666 mg bid plus 

LPV/r 400 mg/100 mg bid.

LPV/r Amprenavir Induction of hepatic 

metabolism by APV. Inhibition of hepatic metabolism by LPV/r

APV Cmin increased 5-fold. LPV AUC decreased 30–50%.

Delayed Moderate Dose: LPV/r 533 mg/133 mg (4 caps) + 

APV 750 mg bid.

LPV/r Efavirenz Induction of hepatic 

metabolism

LPV AUC decreased by 40%. Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid 

+ EFV 600 mg qhs.

LPV/r Delavirdine Inhibition of hepatic 

metabolism.

LPV AUC increased by 8–134%. DLV no change

Immediate Minor Limited data. No dose adjustment.

LPV/r Nevirapine Induction of hepatic 

metabolism

LPV Cmin decreased by 55%. NVP level not affected.

Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid 

(NVP standard dose).

LPV/r Saquinavir Inhibition of hepatic 

metabolism

Saquinavir Cmin increased by 3–6-fold

Immediate Minor Dose: SQV 1000 mg bid plus LPV/r 400/

100 mg bid.

LPV/r Nelfinavir Induction of hepatic 

metabolism by NFV. Inhibition of hepatic metabolism by LPV/r.

LPV decreased by 33%. NFV increased 25%.

Delayed Moderate Consider increasing LPV/r dose to 4 caps 

bid with NFV co-administration.

LPV/r Itraconazole Inhibition of hepatic 

metabolism

May increase itraconazole serum level

Immediate Moderate Use with caution; do not exceed 200 mg 

itraconazole.

LPV/r Voriconazole Potential for bi-directional 

inhibition and/or induction 

May decrease voriconazole serum level

Immediate Moderate Monitor for toxicities and therapeutic 

efficacy. Co-administration not recommended by manufacturer.

LPV/r Vardenafil Inhibition of hepatic 

metabolism

May substantially increase vardenafil AUC

Immediate Moderate Start with a 2.5 mg dose; do not exceed 

a 2.5 mg dose of vardenafil in 72 hrs.
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XIV

LPV/r Ethinyl estradiol Induction of hepatic 

metabolism

EE AUC decreases 42% Use alternative or additional method.

Atazanavir (ATV)

Clarithromycin Inhibition of hepatic 

metabolism

ATV AUC increased by 28%. Clarithromycin AUC increased by 94%. Clarithromycin hydroxymetabolite AUC decreased by 30%

Immediate Major QTc prolongation observed with coadministration. 50% of clarithromycin 

dose recommended.

ATV ddI (buffered) Interference with absorption No effect on ddI serum 

level. ATV AUC decreased by 87%.

Immediate Major Administer ATV 400 mg one hour after ddI 

(buffered) administration. Consider ddI EC.

ATV EFV Induction of hepatic 

metabolism (Inhibition of hepatic metabolism with RTV boosting)

ATV AUC decreased by 74%. EFV not measured(ATV AUC increased by 39% with RTV boosting)

Delayed(Immediate)

Major(Minor)

Co-administration of ATV as a sole PI with EFV is not recommended. Boosting ATV 300 mg with 100 mg RTV recommended with EFV co-administration (doubles total ATV exposure and increases ATV trough by 300%).

ATV Oral contraceptives Inhibition of glucuronidation. Ethinyl estradiol AUC 

increased by 48%. Norethindrone AUC increased by 110%. ATV not measured.

Delayed Minor Clinical significance unknown. 

Monitor for adverse reactions with oral contraceptive; consider alternative method of contraception. 

ATV Diltiazem Inhibition of hepatic 

metabolism

Diltiazem AUC increased by 125%. Desacetyl diltiazem (active metabolite) AUC increased by 165%. ATV not affected.

Immediate Major Increase in PR interval observed. 

Use with caution. Start with 50% of diltiazem dose and titrate slowly. Monitor BP and pulse.

ATV Atenolol Inhibition of hepatic 

metabolism

Atenolol AUC increased by 25%. ATV not affected.

Immediate Moderate No effect on PR or QTc interval with coadministration. 

Monitor BP and pulse.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Pharmacologic Considerations in HIV-Infected Pregnant Patients

530 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

ATV Rifabutin Inhibition of hepatic 

metabolism

Rifabutin AUC increased. ATV not affected

Immediate Moderate Dose: ATV 400 mg qd plus rifabutin 150 

mg 3x/week.

ATV SQV Inhibition of hepatic 

metabolism

SQV AUC increased by 5.5-fold. ATV not affected

Immediate Minor Beneficial PK interactions which allows 

once-a-day administration of SQV 1200 mg.

ATV AZT/3TC No effect AZT and 3TC not affected. 

ATV not measured

Standard dose AZT/3TC with ATV.

ATV Ketoconazole No effect ATV not affected. 

Ketoconazole not measured

Standard dose ATV with ketoconazole co-administration.

ATV Tenofovir Interference with absorption ATV AUC decreased by 

25%. TDF not measured

Immediate Moderate Interaction likely to occur due to 

interference with absorption. ATV dose 300 mg qd + RTV 100 mg qd with coadministration.

ATV Rifampin Induction of hepatic 

metabolism

ATV may be decreased Delayed Moderate Rifabutin may be a safer alternative. 

Dose: ATV 400 mg qd plus rifabutin 150 mg 3x/week.

ATV Ergot alkaloid Inhibition of hepatic 

metabolism

Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities may be observed

Immediate Major Concurrent administration contraindicated 

until more data become available.

ATV Terfenadine

AstemizoleCisapride

Inhibition of hepatic metabolism 

Drug level may be increased by 3-fold or greater.

Immediate Major Concurrent administration contraindicated 

until more data become available.

ATV St. John’s wort Induction of hepatic 

metabolism by St. John’s wort

May decrease ATV serum level

Delayed Major Concurrent administration contraindicated 

until more data become available.
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XIV

ATV Benzodiazepines Inhibition of hepatic 

metabolism

May prolong sedation due to accumulation of benzodiazepine

Delayed Major Concurrent administration of midazolam 

and triazolam are contraindicated until more data become available. Alternative benzodiazepine that can be used: Temazepam, oxazepam, and lorazepam.

ATV Antiarrhythmics Inhibition of hepatic 

metabolism

AUC of antiarrhythmics increased

Immediate Major Concurrent administration of propafenone, 

quinidine, flecainide, encainide, amiodarone, and bepridil are contraindicated until more data become available. 

ATV Proton-pump 

inhibitors 

Decreased absorption ATV Significantly decreases ATV 

levels

Immediate Major Avoid concomitant use.

ATV Phenobarbital, 

phenytoin, and carbamazepine

Induction of hepatic metabolism 

May decrease serum levels of ATV. ATV may increase serum levels of anticonvulsants

Delayed Moderate Consider alternative anticonvulsant 

(i.e. valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. Carbamazepine toxicity has been reported.

ATV Methadone No data.ATV Nevirapine No data Consider using ATV 300 mg + RTV 100 

mg qd.

ATV Ritonavir Induction of hepatic 

metabolism

ATV AUC increases by 238% Immediate Minor Use ATV 300 mg + RTV 100 mg.

ATV Warfarin Unknown May increase in warfarin 

concentration

Delayed Moderate Monitor INR.

ATV Amitryptiline 

Imipramine

Inhibition of hepatic metabolism

May increase tricyclic concentration

Immediate Minor Monitor tricyclic antidepressant 

concentration.

ATV Voriconazole Potential for bi-directional 

inhibition and/or induction 

May decrease voriconazole serum level with RTV coadministration

Delayed Moderate Monitor for toxicities and therapeutic 

efficacy.

ATV Sildenafil Inhibition of hepatic 

metabolism

May increase sildenafil AUC Immediate Moderate Use with caution; start with reduced dose 

of 25 mg q48h and monitor for adverse affects.
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Pharmacologic Considerations in HIV-Infected Pregnant Patients

532 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 

Table 14-6 Drug Interactions of Antiretrovirals (continued)

Primary drug Interacting drug Mechanism of interaction Effect Time 

course

Severity Comments/ management 

recommendation

ATV Tadalafil Inhibition of hepatic 

metabolism

May substantially increase tadalafil AUC

Immediate Moderate Start with 5 mg dose; do not exceed a 

single 10 mg dose of tadalafil in 72 hrs.

ATV Vardenafil Inhibition of hepatic 

metabolism

May substantially increase vardenafil AUC

Immediate Moderate Start with a 2.5 mg dose; do not exceed 

a 2.5 mg dose of vardenafil in 72 hrs.

ATV H2 receptor 

antagonist

Interference with absorption May significantly decrease 

ATV concentration

Immediate Moderate Separate ATV concentration by 12 hrs.

ATV Atorvastatin Inhibition of hepatic 

metabolism

May increase atorvastatin substantially

Immediate Moderate Use lowest possible starting dose (10 mg) 

of atorvastatin with careful monitoring.

Tipranavir/ritonavir(currently in Phase III trials)

Efavirenz No change in EFV PK,. TPV 

PK (at 500/100 mg dose)

Phase II trials are currently using TPV500/200 mg with the co-administration of EFV (Roszko, 2003).

TPV/r AZT AZT AUC decreased by 40%. 

No change in TPV PK.

Minor Clinical significance unknown.

TPV/r ddI EC No Interactions Separate administration time by 4 hours 

due to potential interaction of self emulsifying drug delivery system (SEDDS) of TPV and the ddI EC outer coat.

TPV/r Tenofovir TPV AUC decreased by 20% 

(with TPV 500 mg/100 mg)

Minor Reduction of TPV may be due to decrease 

in RTV. TPV 500 mg/200 mg should be considered.

TPV/r LPV/r LPV AUC decreased by 49% Major Do not co-administer.TPV/r APV APV AUC decreased by 45% Major Do not co-administer.TPV/r SQV SQV AUC decreased by 70% Major Do not co-administer.
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Drug Interactions with Fusion InhibitorsFuseon No significant drug 

interactions

AUC= Area Under the Concentration Time CurveCmax = Peak serum concentrationCmin = Trough serum concentrationCrCl = Creatinine clearanceTDM = Therapeutic drug monitoringTime course: 

Delayed = maximal interaction occurring at 14 daysImmediate = interaction occurring immediately

Severity: 

Major = Do not co-administer; contraindicated.Moderate = Can be co-administered with caution and possible dose adjustment.Minor = Can be co-administered.
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Table 14-7: Clinically Pertinent Food-Drug Interactions

Valganciclovir / Itraconazole Capsule / Ritonavir / Atazanavir: 

Should be taken with food or within 2 hr of eating.

AZT:

Can be taken with food to decrease GI side effects.

Saquinavir1 (Fortovase® and Invirase®) / Atovaquone / Nelfinavir: 

Should be administered with a high-fat meal.

Efavirenz / Amprenavir: 

High-fat meal should be avoided.

Didanosine2 / Indinavir3 / Itraconazole Solution / EFV: 

Should be taken on an empty stomach (1 hr before or 2 hr after meals).

Grapefruit Juice: 

Increases saquinavir levels 40–100% but decreases indinavir AUC by 26%.

1 No food restriction when saquinavir is co-administered with RTV.

2 No food restriction when ddI is co-administered with TDF.

3 No food restriction when IDV is co-administered with RTV.

Table 14-8: Drugs of Special Consideration in Pregnant Women

Drug Name FDA 

Class

Comments

Terbutaline B Terbutaline has produced significant increases in birth weights 

(Briggs et al, 1998). Follow-up studies did not show increased 

adverse fetal outcomes (Svenningsen,1982).

Ritodrine B The manufacturer reports that ritodrine administration after 

the 20th wk of gestation has not been associated with an 

increase in fetal abnormalities. 

Methergine C Indicated for postpartum uterine bleeding due to atony. 

According to the manufacturer, oral methylergonovine .2 mg 

3–4 times daily may be administered to nursing mothers for a 

MAXIMUM of 1 wk postpartum to control uterine bleeding. 

Should not be given during antenatal period. Should not be 

used in women with hypertension (including pre-eclampsia) or 

heart disease.

Pain Medication

Acetaminophen B Acetaminophen is considered safe for shortterm use in all 

stages of pregnancy.

Aspirin C Use of aspirin, especially of chronic or intermittent high 

doses, should be avoided in pregnancy. May increase risk for 

maternal or newborn hemorrhage. Full dose aspirin in 3rd 

trimester may result in premature closure of ductus arteriosus 

and may prolong gestation and labor. Acetaminophen is 

preferred analgesic/antipyretic during pregnancy.

Nonsteroidal 

antiinflammatory 

drugs (NSAIDs)

C Avoid in pregnancy. Due to prostaglandin synthesis inhibition, 

constriction of ductus arteriosus has been reported. Persistent 

pulmonary hypertension in the newborn has occurred when 

NSAIDs were used in 3rd trimester or near term. NSAIDs have 

been shown to inhibit labor and prolong pregnancy and have 

been associated with decreases in amniotic fluid volume.

Narcotic 

analgesic

B Narcotic analgesics can be used short term in pregnancy. 

Avoid the use of high doses for prolonged periods near term 

as neonatal withdrawal can occur.
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Table 14-9: Alternative/Complimentary Medication to Avoid in Pregnancy

Drug Name Animal Data Human Experience in Pregnancy Comments

Vitamin A A known 

teratogen at high doses in animal data.

A double-blind randomized trial of low-dose supplementation with vitamin A or betacarotene (7000 μg retinol equivalent) in malnourished pregnant women reported a 40% decrease in newborn mortality (West, 1999). In a prospective case-controlled study of 423 exposures to 10,000 IU vitamin A during the first 9 wk an increased risk of major malformations was not reported (Mastroiacovo, 1999).

Until more data are available it is prudent to consume only the recommended dietary allowance of 8000 IU (which can be obtained by a balanced diet).

Vitamin B6 (in doses above 100 mg/day)

None None Avoid use of high doses in pregnancy. Possible health hazard: ataxia and 

peripheral neuropathy. *

Niacin (in doses above 500 mg immediate-release or 750 mg sustained-release)

None None Avoid use of high doses in pregnancy. Possible health hazard: GI symptoms 

(nausea, vomiting, diarrhea, abdominal cramps); liver disease.*

Selenium (in doses of greater than 800–1000 μg per day)

None None Avoid use of high doses in pregnancy. Possible health hazard: tissue damage.*

Ma-huang (Ephedra sinica)

None None Avoid use in pregnancy. The FDA warns against using Ma-huang (Ephedra 

sinica) due to possible health hazards including: high blood pressure, irregular heartbeat, nerve damage, injury, insomnia, tremor, headache, seizure, heart attack, stroke, and death.* Over 500 reports of adverse events including 8 fatalities have been reported to the FDA (CDC, 1996).

St. John’s wort (Hypericum perforatum)

None None Metaanalysis of St. John’s wort suggests that it was more effective than 

placebo and as effective as low-dose tricyclic antidepressants for short-term management of mild to moderately severe depression (Kim, 1999). Due to the lack of data in pregnancy the routine use of St. John’s wort cannot be recommended. Major drug interaction: Indinavir trough concentration (Cmin) decreases by 81% when co-administered with St. John’s wort.
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Table 14-9: Alternative/Complimentary Medication to Avoid in Pregnancy (continued)

Drug Name Animal Data Human Experience in Pregnancy Comments

Chaparral herb (traditional American Indian medicine)

None None Avoid use in pregnancy. Possible health hazard: liver disease, possibly 

irreversible.*

Comfrey herb None None Avoid in pregnancy. Possible health hazard: obstruction of blood flow to liver, 

possibly leading to death.*

Slimming/dieter’s tea None None Avoid in pregnancy. Possible health hazard: nausea, diarrhea, vomiting, 

stomach cramps, chronic constipation, fainting, possibly death.*

Germander herb None None Avoid in pregnancy. Possible health hazard: liver disease, possibly leading to 

death.*

Lobelia herb (Indian tobacco)

None None Avoid in pregnancy. Possible health hazard: respiratory distress, tachycardia, 

hypotension, and possibly coma and death at higher doses.*

Magnolia-Stephania herb None None Avoid in pregnancy. Possible health hazard: renal failure which may be 

irreversible.*

Willow bark herb None None Avoid in pregnancy. Possible health hazard: allergic reaction (marketed as 

aspirin-free product, although it actually contains a precursor of aspirin with subsequent conversion to aspirin).*

Wormwood herb None None Avoid in pregnancy. Possible health hazard: neurological symptoms, 

paresthesia, delirium and paralysis.*

Germanium mineral None None Avoid in pregnancy. Possible health hazard: kidney damage, possibly death.*L-tryptophan amino acid None None Avoid in pregnancy. Possible heath hazard: eosinophilic myalgia syndrome, a 

potentially fatal blood dyscrasia. (FDA has limited its import into the US).*

* Note: Folic acid deficiency has been associated with increased risk of neural tube defects in the fetus and megaloblastic anemia in the mother. All pregnant women should receive sufficient dietary 

or supplementary folic acid to maintain normal maternal folate levels. The CDC recommends daily consumption of 0.4 mg of folic acid from diet and/or supplements for all women of childbearing age before the onset of pregnancy.
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Table 14-10: Dosing of Antiretroviral Agents in Renal Insufficiency and/or Hepatic Insufficiency 

Drug Name Usual adult 

dose

Dosing for 

GFR >50 

mL/min

Dosing for 

GFR 10-50 

mL/min

Dosing for GFR 

<10 mL/min

Dosing in 

Hemodialysis 

(HD)

Dosing in 

Peritoneal 

dialysis (PD)

Hepatic clearance/

Comments

Zidovudine (Retrovir®; AZT) 300 mg bid, or 200 mg tid 300 mg bid 300 mg bid 300 mg qd 300 mg qd 300 mg qd, a very small amount 

removed in PD (no supplemental dose needed) (Gallicano, 1992)

Extensive with significant first pass liver metabolism to GAZT. Excreted in urine as 14–18% unchanged drug and 60–74% GAZT. With GFR <20 mL/min half life is increased from 1.1–1.4 hr to 0.9 to 8 hours (with high inter patient variation).

Didanosine (Videx®; (Dideoxyinosine, ddI) 

Wt >60kg dose: 400 mg qd (tabs) or 500 mg qd (powder). Wt <60kg dose: 250 mg qd (tabs) or 334 mg qd (powder). Dose can also be taken in two divided doses

Usual dose 50% of usual 

dose

25% of usual dose 25% of usual 

dose qd, on days of dialysis give post dialysis. 30% removal after a 3-hours session (Knupp, 1996)

25% of usual dose qd. Not removed with PD (Knupp, 1996)

Metabolism not fully evaluated. 20–40% excreted unchanged in the urine. 

Stavudine (Zerit®; d4T)

Wt >60kg dose: 40 mg bid. Wt <60kg dose: 30 mg bid

Wt >60kg dose: 40 mg bid. Wt <60kg dose: 30 mg bid

Wt >60kg dose: 20 mg q12–24h. Wt <60kg dose: 15 mg q12–24

Wt >60kg dose: 20 mg q24h. Wt <60kg dose: 15 mg q24h

Wt >60kg dose: 20 mg q24h. Wt <60kg dose: 15 mg q24h, on days of dialysis dose post dialysis. (Grasela, 2000)

No data: Wt >60kg dose: 20 mg q24h. Wt <60kg dose: 15 mg q24h

Some hepatic metabolism and degradation by pyrimidine pathway. 40% of drug excreted unchanged.

Zalcitabine (Hivid®; (Dideoxycytidine, ddC)

0.75 mg tid 0.75 mg tid 0.75 mg bid 0.75 mg qd No data: 0.75 mg 

qd, on days of dialysis dose post dialysis (likely to be dialysed out)

No data: 0.75 mg qd, on days of dialysis dose post dialysis 

Insignificant liver metabolism. 62–75% excreted unchanged in the urine. 10% excreted unchanged in the feces.
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Table 14-10: Dosing of Antiretroviral Agents in Renal Insufficiency and/or Hepatic Insufficiency (continued)

Drug Name Usual adult dose Dosing for 

GFR >50 

mL/min

Dosing for 

GFR 10-50 

mL/min

Dosing for GFR 

<10 mL/min

Dosing in 

Hemodialysis (HD)

Dosing in Peritoneal 

dialysis (PD)

Hepatic clearance/Comments

Lamivudine (Epivir®; 3TC) 150 mg bid or 300 mg qd 150 mg bid 150 mg qd 150 mg x1 then 50 mg qd (some 

recommend 150 mg qd due to good safety profile and convenience)

150 mg x 1 then 25–50 mg qd; Dose after HD

50 mg qd; Limited data 

Intermittent hemodialysis does not warrant a further change in dose from that defined by CrCl (Johnson, 1996).

Emtricitabine (Emtriva®) (FTC) 200 mg qd 200 mg qd 30–49 mL/min: 200 mg q 48hr. 

15–29 mL/min: 200 mg q 72 hr. < 15 mL/min: 200 mg q 96 hr

200 mg qd 200 mg q 96 hr. 

(30% of dose removed with 3 hr. HD; on days of dialysis, dose postHD)

Abacavir (Ziagen®)ABC 

300 mg bid or 600 mg qd

300 mg bid 300 mg bid 300 mg bid Usual dose [In 4 

patients undergoing HD or PD, the pharmacokinetics of abacavir were not altered (Thompson, 1998)

Usual dose [In 4 patients undergoing HD or PD, the pharmacokinetics of abacavir were not altered (Thompson, 1998)

Pharmacokinetics are unchanged in renal failure (Izzedine, 2001b). Animal studies: 12% unchanged Abacavir in the urine. Only 2% metabolized to carbovir. Consider ABC 200 bid with hepatic insufficiency.

Tenofovir (Viread®) 300 mg qd 300 mg qd

30–49 mL/min: 300 mg q48h. 

<30 mL/min: 300 mg q72–96h

300 mg q7days 300 mg q 7 days 

following dialysis (54% removed with 4 hours high flux HD-healthy volunteer PK data) May require more if patient requires more than three 4-hour HD sessions. 

No data: Not recommended by manufacturer. Interval adjustment likely.

Note: Dosing recommendations based on single dose PK data in healthy volunteer. HIV infected patients with Cr Clearance less than 60 mL/min were excluded from clinical trials. 
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Efavirenz (Sustiva®) 600 mg qhs Usual dose** Usual dose 

likely**

Usual dose likely** 600 mg qhs, No 

significant removal with HD (Izzedine, 2000a)

600 mg qhs, Not removed with PD (Gill, 2000)

Data limited in renal failure. Extensive liver metabolism 14–34% excreted in urine as glucuronide metabolite and 16–61% excreted in stool.

Nevirapine (Viramune®) 200 mg qd x 14 days then 200 

mg bid

Usual dose Usual dose Usual dose Usual dose postHD. Small amount 

removed (Izzedine, 2001a)

Usual dose post dialysis. 16 mg removed in dialysate in a 24 hour period.

Extensive liver metabolism to hydroxylated metabolites which are renally cleared. Less than 5% excreted unchanged in the urine. 

Delavirdine (Rescriptor®) 400 mg tid Usual dose** Usual dose likely** Usual dose likely** No data: Unlikely to be removed in 

dialysis due to high protein binding**

No data: Unlikely to be removed in dialysis due to high protein binding**

Extensive liver metabolism.

Nelfinavir (Viracept®) 750 mg tid or 1250 mg bid Usual dose Usual dose Usual dose Usual dose. Removed with HD, MUST 

be given post-HD on days of dialysis (Izzedine, 2000a)

Usual dose. Not removed with PD (Tillotson, 2000)

Pharmacokinetics are unchanged in renal failure (Izzedine, 1999). Extensive liver metabolism to active oxidative metabolites. Major biliary excretion with less than 2% renal excretion.

Indinavir (Crixivan®) 800 mg tid* or 

IDV 800/RTV 100–200 mg bid (increased incidence of kidney stones with RTV 200 mg–generally recommended only in pt also on EFV or NVP)

Usual dose* Usual dose Usual dose Usual dose. Very 

small amount removed in dialysis (Izzedine, 2000b)

No data: Usual dose likely** (Low probability of significant amount being removed in dialysis due to low protein binding)

Pharmacokinetics are unchanged in renal failure (Izzedine, 2000b). Extensive liver metabolism to glucuronide and oxidative metabolites. Major biliary excretion with approximately 10% renal excretion.
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Table 14-10: Dosing of Antiretroviral Agents in Renal Insufficiency and/or Hepatic Insufficiency (continued)

Drug Name Usual adult dose Dosing for 

GFR >50 

mL/min

Dosing for 

GFR 10-50 

mL/min

Dosing for GFR 

<10 mL/min

Dosing in 

Hemodialysis (HD)

Dosing in Peritoneal 

dialysis (PD)

Hepatic clearance/Comments

Ritonavir (Norvir®) 600 mg bid (High 

dose not well tolerated, dose may be lowered if used with another PI)

Usual dose Usual dose Usual dose Small amount 

dialyzed out, dose post HD (Izzedine, 2001b)

No data: Usual dose likely**, dose post dialysis on days of dialysis. (Unlikely to be removed in dialysis due to high protein binding, however due to low volume of distribution small amount possibly removed)**

Pharmacokinetics are unchanged in renal failure (Izzedine, 2001b). Extensive liver metabolism to isopropylthiazole (active metabolites) and other inactive metabolite. Major biliary excretion with approximately 4–10% renal excretion.

Saquinavir (Invirase® (capsule); Fortovase® (soft gel capsule)

Invirase 600* mg tid (not recommended as sole PI); Fortovase 1200 mg tid or INV 1000 mg/RTV 100 mg q12h.

Usual dose Usual dose Usual dose Not dialyzed out 

(Izzedine, 2001b)

No data: Usual dose likely** (Unlikely to be removed in dialysis due to high protein binding and large volume of distribution.)

Pharmacokinetics are unchanged in renal failure (Izzedine, 2001b). Extensive first pass metabolism which accounts for saquinavir’s low bioavailability. Major biliary excretion with only 1–3% renal excretion.

Amprenavir (Agenarase®) 1,200 mg bid* or APV 600 mg/RTV 

100 mg q12h.

Usual dose Usual dose likely Usual dose likely No data: Usual dose 

likely

No data: Usual dose likely

Impaired hepatic function moderate—consider dose reduction 450 mg bid; severe—300 mg bid. 

LPV/RTV (Kaletra®) 400/100 mg bid Usual dose Usual dose likely Usual dose likely Usual dose. Not 

removed with HD (Izzedine, 2001c)

No data: Usual dose likely
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Atazanavir (Reyataz®) 400 mg qd* or ATV 300/RTV 100 

qd.

Usual dose Usual dose likely Usual dose likely Usual dose. Dose 

post-HD

Usual dose likely ATV is not recommended in 

patients with severe hepatic insufficiency. ATV AUC increased by 45% with mild to moderate hepatic impairment. Consider decreasing ATV to 300 mg/day in subjects with mild to moderate hepatic impairment. Clinical data using the lower dose in hepatic insufficiency has not been assessed.

Fosamprenavir (Lexiva®) 1400 mg* q12h or fAPV 700/100 

RTV q12h.

usual dose usual dose likely usual dose likely No data. Usual dose 

likely.

No data. Usual dose likely.

Enfuvirtide (Fuzeon®) 90 mg SQ q12h usual dose usual dose likely usual dose likely No data. Usual dose likely. No data. Usual dose likely.

* Approved adult dose, but usually use lower doses with ritonavir boosting for most PIs.** Prediction based on pharmacokinetic principles. Drugs likely to be removed have a Vd <0.7 L/kg, protein binding <80%, and size <1500 Dalton
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Parry E, Shields R, Turnbull A. Transit time in the small intestine in 

pregnancy. J Obstet Gynaecol Br Commonw. 1970;77:900–901.

Perinatal HIV Guidelines Working Group. Public Health Service Task 

Force Recommendations for Use of Antiretroviral Drugs in 

Pregnant HIV-1-infected Women for Maternal Health and 

Interventions to Reduce Perinatal HIV-1 Transmission in the United 

States. Available at: http://www.aidsinfo.nih.gov.guidelines. 

Accessed January, 2005.

Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John’s wort. Lancet. 2000;355:547–548.

Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 

1996;22:336–340.

Rosa F. Azole fungicide pregnancy risks. Presented at the Ninth International Conference of the Organization of Teratology Information Services; May 2-4, 1996; Salt Lake City, Utah.
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Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz (EFV), zidovudine (ZDV), tenofovir (TDF), and didanosine (ddI) may be given with 

tipranavir/ritonavir (TPV/r). 2nd IAS Conference on HIV and pathogenesis; July 14–17, 2003; Paris. Abstract 864. 

Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal 

quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol 

Reprod Biol. 1996;69:83–89.

Schick B, Hom M, Librizzi R, Donnenfeld A. Pregnancy outcome following 

exposure to clarithromycin. Reprod Toxicol. 1996;10:162. 

Schuman P, Kauffman R, Crane LR, et al. Pharmacokinetics of zidovudine during pregnancy. VI International Conference on AIDS; June 20-23, 1990; 

San Francisco, CA. Abstract F.B.17.

Snider DE Jr, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis. 1980;122:65–79.

Sorenson HT, Nielsen GL, Oleson C, et al. Risk of malformations and other 

outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol. 

1999;48:234–238.

Stern JO, Love JT, Robinson PA, et al. Hepatic safety of nevirapine: results of 

the Boehringer Ingelheim Viramune Hepatic Safety Project. 14th International AIDS Conference; July 7-12, 2002; Barcelona, Spain.

Svenningsen NW. Follow-up studies on preterm infants after maternal betareceptor agonist treatment. Acta Obstet Gynecol Scand. 1982;Suppl 108:

67–70.

Tarantal AF, Castillo A, Ekert JE, Bischofberger N, Martin RB. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys 

(Macaca mulatta). J Acquir Immune Defic Syndr. 2002;29:207–220.

Thompson M et al. Single-dose plasma profiles of abacavir (1592, ABC) in renal 

failure. Presented at: 12th World AIDS Conference; June 28–July 3, 1998; 

Geneva, Switzerland. Abstract 42278.

Tillotson GS, Peterson LR. Quinolones and pneumococci. J Antimicrob Chemother. 2000;45:709–710.

van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National 

Institute of Allergy and Infectious Diseases Mycoses Study Group and 

AIDS Clinical Trials Group. N Engl J Med. 1997;337:15–21.

Wang Y, Livingston E, Patil S, et al. Pharmacokinetics of didanosine in antepartum and postpartum human immunodeficiency virus–infected pregnant 

women and their neonates: an AIDS clinical trials group study. J Infect 

Dis. 1999;180:1536–1541.

West KP, Jr, Katz J, Khatry SK, et al. Double blind, cluster randomised trial of 

low dose supplementation with vitamin A or carotene on mortality related 

to pregnancy in Nepal. BMJ. 1999;318:570–575.

Wong S-Y, Remington JS. Toxoplasmosis in pregnancy. Clin Infect Dis. 1994;18:

853–862.
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I. HOW TO USE THIS CHAPTER

A chapter devoted to additional resources is an essential part of this guide. First, 

HIV clinical care evolves so rapidly that some information in the guide will soon 

be out of date. Second, a wealth of information is available that supplements 

these chapters in specialized areas of care. It is our intention to include some of 

the most important resources for clinical care of women with HIV, but the list is 

by no means exhaustive. Readers can explore the links provided on websites to 

find other informative sites. 

In this electronic information age, the term resources includes internet sites 

and electronic documents as well as organizations and published documents, 

so the chapter includes a range of mechanisms for obtaining more information. 

However, the web-based resources are considered primary because they are 

available from anywhere in the world and are usually updated on a periodic 

basis. Phone contact information is provided where available, so that those 

without access to the internet can still obtain information.

The resources are listed alphabetically in a grid that identifies major topics 

addressed by each resource as well as the type of information available. There 

is a brief description of the resource and website and phone contact information. 

The phone numbers with 800, 888, and 866 prefixes are only toll-free in the U.S.

Regarding special populations, the purpose of the resources chapter is to 

supplement the guide itself. We refer the reader to Chapter VIII, Addressing 

Cultural Issues to Improve Quality of Care, to discover tools to enhance the 

cultural competency of service providers and service agencies. In addition, 

many of the resources contain some information, such as fact sheets, about 

or for groups of people with special needs, such as people who are homeless, 

incarcerated, or transgendered. Special populations are usually only one aspect 

of a resource; there are not many resources specifically concerning racial/ethnic 

minorities or other special populations. The search function on many websites is 

a useful tool for locating information on specific topics or special populations. For 

example, providers caring for lesbians with HIV can find relevant information on 

their needs by searching The Body and the American Psychological Association 

Office on AIDS websites. 

XV: RESOURCES

Judith Ellis, MS, and Helen Schietinger, MA, ACRN
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II. RESOURCES WITH TOPIC AREAS 

Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

Adult AIDS Clinical Trials Group* (AACTG) Website for the NIH-funded AIDS Clinical Trials Groups. See Pediatric AIDS Clinical Trial Group for clinical trials in pregnant women. Contact: http://aactg.s-3.com

A 1

AIDS Alliance for Children, Youth & Families National association providing advocacy, education and support for children and families affected by HIV/AIDS. (formerly the AIDS Policy Center for Children, Youth & Families)Contact: http://www.aids-alliance.org1-202-785-3564, 1-888-917-AIDS (2437)

A B 1, 3, 4, 6

AIDS Education Global Information System (AEGIS)Website with HIV information and resources from the mainstream press, professional journals, and legal and legislative sourcesContact http://www.aegis.com

A 1, 5

AIDS Education and Training Centers (AETC)Regional centers that provide HIV training and education, including preceptorships, for health care providers; national and international centers that provide technical assistance in evaluation and specific areas of clinical care, such as hepatitis and palliative care; the resource center that provides resource materials on a wide range of HIV-related topics and links to the other centers.Contact: http://www.aidsetc.org

A 1, 3, 4, 5
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AIDSInfo*Website of U.S. Public Health Service treatment guidelines, continually updated (living documents), clinical trials, and drug and vaccine information. (The AIDS Clinical Trials Information Services and AIDS Treatment Information Services have been integrated into AIDSInfo.) Contact: http://www.aidsinfo.nih.gov1-800-HIV-0440, outside US 1-301-519-0459, TTY 1-888-480-3739 (Spanish speakers; Monday through Friday, 12 to 5 pm Eastern Time)

A B 1, 2, 3, 5

AIDS Info NYCWebsite with information from community-based organizations in New York City for people living with HIV and AIDS.Contact: http://www.aidsinfonyc.org

B 1,3, 

6

AIDSMeds.comWebsite for consumers that provides HIV treatment information and tools for understanding and tracking HIV treatment.Contact: https://www.aidsmeds.com

B 1, 3, 4, 6

AIDS Treatment Data Network (ATDN)Organization with information about HIV treatment for consumers. Provides adherence and case management services in New York City, tracks Medicaid and the AIDS Drug Assistance Program (ADAP) nationwide (provides information to help individuals access drugs), and provides treatment information on the web.Contact: http://www.atdn.org1-212-260-8868, 1-800-734-7104 

B 1, 3, 5, 6

American Academy of HIV Medicine (AAHIVM)*Professional association for HIV specialists that promotes excellence in HIV/AIDS care and offers HIV credentialing for physicians, nurse practitioners, and physicians assistants.Contact: http://www.aahivm.org/new/index.html

A 1, 3, 5

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

American College of Obstetricians and Gynecologists (ACOG)*Professional association for specialists in obstetrics and gynecology that provides guidelines and information in reproductive care of women.Contact: http://www.acog.org

A

1, 

2, 3, 

5, 6

American Foundation for AIDS ResearchOrganization with focus on basic and clinical research, clinical trials information, public and professional education, public policy, prevention science, and global initiatives. Contact: http://www.amfar.org

A B 1, 3, 4, 6

American Psychological Association Office on AIDSOrganization that provides information, training, and technical assistance on HIV/AIDS-related topics associated with coping, mental health services, prevention, community collaboration, and ethics.Contact: http://www.apa.org/pi/aids

A B 3, 6

Association of Nurses in AIDS Care (ANAC)*Professional association that provides information and advises members about clinical and policy issues related to nursing and HIV care and offers HIV credentialing for RNs (ACRN).Contact: http://www.anacnet.org1-800-260-6780 

A 1, 3, 5

The BodyWebsite with comprehensive HIV information and resources for consumers.Contact: http://www.thebody.com

B 1, 4, 5, 6
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The Body Pro*Website with medical treatment information, comprehensive care and prevention information, interactive Q & A, and access to written information.Contact: http://www.thebodypro.com

A 1, 2, 4, 5

Canadian AIDS Treatment Information Exchange (CATIE)Canadian website with comprehensive HIV information and resources for consumers, including drugs, other medical treatments, and complementary therapies, in English and French.Contact: http://www.catie.ca

B

1, 

3, 4, 

5, 6

CDC Division of HIV/AIDS Prevention Website of the Centers for Disease Control and Prevention with guidelines and information on prevention of HIV for providers. Contact: http://www.cdc.gov/hiv/dhap.htm

A 1, 2

CDC National Prevention Information Network (CDCNPIN)Comprehensive reference, referral, and distribution service for information on HIV/AIDS, sexually transmitted diseases (STDs), and tuberculosis (TB), with information specialists who can assist in identifying appropriate resource materials. Contact: http://www.cdcnpin.org1-800-458-5231, TTY/TDD 1-800-243-7012 (Monday through Friday, 9 am to 6 pm Eastern time)

A B

1, 

3, 4, 

5, 6

Critical Path AIDS ProjectWebsite with information on treatment, prevention, policy, and advocacy as well as free internet and email services for consumers. Contact: http://www.critpath.org

A B 1, 4, 5, 6

Community Programs for Clinical Research on AIDS (CPCRA)*Website of a network of research sites composed of community-based health care providers who offer their patients the opportunity to participate in research where they get their health care. Contact: http://www.cpcra.org

A 1

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

Gay Men’s Health Crisis Women and Family Services Organization in New York City that provides information and services for people with HIV. Includes Women and Family Services Department and Lesbian AIDS Project.Contact: http://www.gmhc.org

B 1, 3, 6

Growth House Website with comprehensive database on end-of-life issues, including death with dignity, hospice, palliative care, grief, bereavement, and related topics. Contact: http://www.growthhouse.org

A B 1, 3, 5, 6

Healthy Initiatives for Youth (HIFY)Organization that provides information to youth about HIV prevention and training and technical assistance to professionals providing services to youth. Contact: http://www.hify.com

A B 3

HEPP Report (HIV and Hepatitis Education Prison Project)Publication of the HIV and Hepatitis Education Prison Project (HEPP) that contains in its archives numerous articles about HIV in incarcerated women.Contact: http://www.hivcorrections.org1-401-277-3651 

A 1, 3

HIVandHepatitisWebsite of clinical information and resources on hepatitis and HIV.Contact: http://www.hivandhepatitis.com

A B 1, 4, 5, 6
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HIVdentWebsite with information on the dental manifestations of HIV and AIDS, including information for persons living with HIV/AIDS and their dental care providers. Contact: http://www.hivdent.org

A B 1, 2, 5, 6

HIVInSite: University of California at San FranciscoWebsite with detailed medical treatment information as well as prevention and policy information.Contact http://hivinsite.ucsf.edu

A 1, 6

HIV Medication GuideWebsite with drug information and software to assess for potential drug interactions.Contact: http://www.hivmedicationguide.com

A B 1, 6

HIV Medicine Association (HIVMA)*hProfessional association within the Infectious Diseases Society of America (IDSA) for HIV specialists that provides guidelines and information on HIV treatment and care.Contact: http://www.hivma.org/HIV/toc.htm

A 1, 2, 3, 5

HRSA HIV/AIDS BureauWebsite of the HIV/AIDS Bureau in the Health Resources and Services Administration (HRSA), the Federal agency that administers the Ryan White CARE Act funding. Information and publications supporting care of people with HIV, including Special Projects of National Significance (SPNS).Contact: http://hab.hrsa.gov

A B 1, 3, 4

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

HRSA Information CenterClearinghouse of free publications on HIV, nutrition, maternal and child care, and numerous other health-related topics of concern to HIV providers.Contact: http://www.ask.hrsa.gov1-800-400-2742, 1-888-275-4772 

A B 1, 3

International Association of Physicians in AIDS Care (IAPAC)*Professional association for physicians that provides information and medical education, and advocates to expand access to health care services and life-saving drugs and technologies. Contact: http://www.iapac.org1-312-795-4930 

A 1, 3, 5, 6

International Center for Research on Women (ICRW)Organization that conducts research, capacity building, and advocacy on issues affecting women’s economic, health, and social status in low- and middle-income countries.Contact: http://www.icrw.org

A 1, 3, 4, 5

International HIV/AIDS AllianceOrganization that supports communities in developing countries to play a full and effective role in the global response to AIDS.Contact: http://www.aidsalliance.org

A 1, 3
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Johns Hopkins University AIDS ServiceWebsite with detailed medical treatment information as well as comprehensive care and prevention information, interactive Q & A, and access to written information.Contact: http://www.hopkins-aids.eduTo order Medical Management of HIV Infection or write The Johns Hopkins University AIDS Service, PO Box 5252, Baltimore MD 21224. 

A 1, 3, 6

Kaiser Family FoundationOrganization that informs the U.S. HIV/AIDS policy discussion and funds global HIV prevention.Contact: http://www.kff.org

A 1, 3

MedscapeWebsite of medical information and education tools for medical specialists, primary care physicians, and other health professionals.Contact: http://www.medscape.com

A 1, 5

National AIDS HotlineA website and phone hotline to answer consumer questions and provide referrals about HIV and AIDS. Confidential inquiries about prevention, risk, testing, treatment, and other HIV/AIDS-related concerns.Contact: http://www.ashastd.org/nah1-800-342-AIDS (1-800-342-2437), TTY 1-800-243-7889, Spanish 1-800-344-7432 (24 hours a day)

B 1, 3, 4, 6

National Association of People with AIDS (NAPWA) Organization that advocates for and provides information and support to people living with HIV/AIDS.Contact: http://www.napwa.org1-202-898-0414

B 1, 3, 5, 6

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

National Association on HIV Over Fifty (NAHOF)Organization that promotes the availability of a full range of educational, prevention, service, and health care programs for persons over age fifty affected by HIV.Contact: http://www.hivoverfifty.org

A B 1, 3, 5

National Clearinghouse for Alcohol & Drug Information (NCADI)Website of Federal agencies that provides drug and alcohol information as well as descriptions of Federal prevention initiatives.Contact: http://www.health.org

A B 1, 3, 6

National Clearinghouse on Child Abuse/Neglect InformationWebsite for professionals and others seeking information on child abuse and neglect and child welfare; national child abuse hotline.Contact: http://nccanch.acf.hhs.govHotline: 1-800-422-4453 (24 hours a day)

A B

1, 

3, 4, 

5, 6

National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) National toll-free hotline counsels health care workers with job-related exposure to HIV, hepatitis, and other blood-borne pathogens and offers treating clinicians up-to-the-minute advice on managing occupational exposures (i.e., needlesticks, splashes, etc.). Contact: http://www.ucsf.edu/hivcntr/pepline1-888-448-4911 (24 hours a day)

A 1, 4
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National Network to End Domestic Violence (Hotline) Organization that provides national domestic violence hotline and local resources for women and advocates legally, legislatively, and educationally against domestic violence. Contact: http://www.nnedv.org1-800-799-SAFE (7233), TDD 1-800-787-3224 (24 hours a day)

A B 1, 3,4

National Library of Medicine (NLM)Website that enables readers to conduct literature searches of the professional medical and HIV/AIDS-related literature including abstracts from relevant conferences. Contact: http://www.nlm.nih.gov

A 1

National Minority AIDS CouncilOrganization dedicated to developing leadership within communities of color to address the challenges of HIV/AIDS. Contact: http://www.nmac.org1-202-483-6622

A B 1, 3, 5, 6

National Minority AIDS Education and Training CenterCenter of the AIDS Education and Training Centers that builds capacity for HIV care and training among minority health care professionals and health care professionals serving communities of color.Contact: http://www.nmaetc.org

A 1, 4

New Mexico AIDS InfonetWebsite with non-technical fact sheets on treatment for consumers.Contact: http://www.aidsinfonet.org

B 1, 3, 6

New York Online Access to HealthWebsite for consumers with a range of topics relevant to HIV/AIDS and women. Contact http://www.noah-health.org

B 1

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

NIAID Database for Anti-HIV CompoundsWebsite with computerized databases of chemical structures and biologic data on antiretroviral drugs.Contact http://www.niaid.nih.gov/daids/dtpdb

A 1

Partnership for CaringOrganization that provides resources, education, advocacy, and a hotline on palliative care and end-of-life issues such as living wills.Contact: http://www.partnershipforcaring.org1-202-296-8071, hotline 1-800-989-9455 (Monday through Friday, 9 to 5 pm Eastern time)

A B

1, 2, 3, 4, 

5, 6

Pediatric AIDS Clinical Trials Group (PACTG)Website for NIH-funded HIV clinical trials in children and pregnant women. Contact: http://www.pactg.s-3.com

A 1

Population CouncilOrganization that conducts research and develops policy on reproductive health and family planning, including HIV-related issues, internationally. Contact: http://www.popcouncil.org

A 1, 2, 3
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Project InformOrganization that provides consumers with treatment information and tools for living with HIV, including confidential treatment information by phone and Project Wise, a program focused on HIV/AIDS treatment information and advocacy for women.Contact: http://www.projectinform.orgTreatment hotline 1-800-822-7422 (toll-free in the United States), 1-415-558-9051 (in the San Francisco Bay area or internationally), (Monday through Friday, 9 am to 5 pm; Saturday, 10 am to 4 pm Pacific time)

B

1, 

3, 4, 

5, 6

Reproductive Health Online (Reproline)Website for JHPIEGO, affiliate of Johns Hopkins University, with information and training tools on reproductive health topics in low resource settings. Spanish, French, Portuguese, and Russian.Contact: http://www.reproline.jhu.edu

A

1, 

2, 3, 

4, 5

San Francisco AIDS FoundationOrganization that provides consumers with information about prevention, care, and experimental treatments.Contact: http://www.sfaf.org

B 1, 3, 6

Trevor Project HelplineNational 24-hour suicide prevention hotline for gay, lesbian, bisexual, transgender and questioning youth in crisis. The Trevor Project provides a training film for providers to promote tolerance for gay and questioning youth.Contact: http://www.thetrevorproject.org1-866-4 U Trevor, 1-866-450-8078.

A B 1, 4, 6

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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Provider and Consumer Resources

Type User

Type Info

Epidemiology

Treatment and Care

Prevention

Pediatrics and 

Adolescents

Obstetrics and 

Gynecology

Adherence 

Psychosocial Support 

and Quality of Life

Substance Abuse

Research and 

Clinical Trials

Nutrition

Occupational 

Exposure

Quality Improvement

Palliative Care

Care in Resource 

Poor Settings

UNAIDS: Joint UN Programme on AIDS International program of the United Nations that provides technical assistance and global information to countries and communities to address HIV/AIDS.Contact: http://www.unaids.org

A 1, 3, 5, 6

Warmline: The National HIV Telephone Consultation ServiceTelephone consultation service for health care professionals with questions on any topic related to HIV care. Contact: http://www.ucsf.edu/hivcntr/warmeline/index.html1-800-933-3413 (Monday through Friday, 6 am to 5 pm Pacific Time)

A 1, 4

The Well ProjectWeb portal for women living with HIV with treatment information, discussion groups, organizational tools, slide sets, searchable clinical trials listings, and resource information.Contact: http://www.thewellproject.com

A B

1, 

3, 4, 

5, 6

WhatUDoOrganization targeting youth for HIV prevention (information, activities, chat rooms).Contact: http://whatudo.org

B 1, 6

Women AliveOrganization by and for women living with HIV, with local services in Los Angeles as well as internet services.Contact: http://www.women-alive.org1-800-554-4876, 1-323-965-1564

B 3,4,

6
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Women, Children, and HIVWebsite with information for providers on prevention of perinatal HIV transmission and HIV preganancy and pediatric care, with a global focus, created by the National Pediatric Resource Center.Contact: http://www.womenchildrenhiv.org

A 1, 2

Women Organized to Respond to Life-threatening Disease (WORLD)Organization in Oakland, CA for women with HIV that provides peer advocacy, treatment education training, and retreats. Contact: http://www.womenhiv.org1-510-986-0340 (Monday through Friday, 10 am to 6 pm Pacific Time)

A B

1, 

3, 4, 

5, 6

World Health Organization HIV/AIDS DepartmentWebsite of the WHO HIV/AIDS Department, which provides technical support in HIV/AIDS treatment and prevention to countries and providers.Contact: http://www.who.int/hiv/en

A 1, 2, 3, 5

Type of UserA: Health Care ProviderB: Consumer

Type of information1: Website2: Guidelines

3: Printed Material4: Phone/Email/Chat/Consultation5: Meetings/Conferences

6: Consumer Education* Must be member to access some informationNote: Websites were accessed 3/04.
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I. INTRODUCTION

Of the estimated 40 million individuals living with HIV/AIDS around 

the world, approximately 95% live in resource-constrained settings and 

have fragmented health care systems and of these, over 50% are women 

(UNAIDS, 2003). This represents what Peter Piot, the Executive Director 

of UNAIDS, has called the “increased feminization of the epidemic.” 

In a recent address to the World Bank, he said “Every year we see an 

increase in the number of women infected with HIV...Because of global 

inequality, women living with HIV/AIDS often experience more stigma 

and discrimination. And since women are the main care givers and 

source of household labour, their illness means the collapse of family 

community care systems and household protection.” (Piot, 2003). One 

of the legacies of HIV in the developing world and especially in women 

is the millions of orphans, estimated to comprise 15% of all children 

in the worst affected countries by 2010. Recognizing the global burden 

of HIV disease and the inequity in availability of resources, including 

antiretroviral drugs, and the resulting erosion of decades of progress in 

health and economic indicators, there has been a growing consensus 

that international response and collaboration are critical and growing 

political momentum. In the 2003 State of the Union address President 

Bush committed US$15 billion to fight HIV/AIDS over the next five 

years and in November 2003 the US Congress allocated US$2.4 billion 

to international AIDS activities for the 2004 budget year. These funds 

are managed by the Global AIDS Coordinator’s office by the newly 

appointed Ambassador, Randall Tobias. The Global Fund to Fight AIDS, 

TB and Malaria represents a partnership between governments around 

the world, civil society, the private sector, and affected communities to 

provide resources directly to resource-constrained countries to address 

their specific HIV care and prevention needs. The United Nations 3 by 5 

initiative is led by WHO and UNAIDS with the goal of getting 3 million 

people on antiretroviral treatment by 2005. 

This chapter includes a discussion of the special considerations and 

challenges for HIV+ women in three representative countries from 

three representative regions. While this cannot represent all countries 

and regions struggling with the HIV pandemic, each of the countries 

discussed presents a unique perspective on the HIV/AIDS pandemic 

from resource-constrained settings: India is the second most populous 

country in the world with over one billion people; although HIV 

prevalence there is currently only approximately 0.7%, this translates 

into almost 4 million persons living with HIV/AIDS and trends show 

prevalence to be increasing. It is one of the few countries that initiated 

XVI. INTERNATIONAL ISSUES

Suniti Solomon, MD; Dorothy Kasonde, MBCHB, MMed; 

Valdiléa Gonçalves Veloso dos Santos, MD, MSc; Jean R. Anderson, MD
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HIV prevention activities in the very early stages of the epidemic. In 

2002, India started prevention of HIV transmission from mother to child 

on a large scale using single dose nevirapine. In April 2004, there is 

planned a roll out of combination antiretroviral therapy (d4t, 3TC, and 

nevirapine) to all those who need it in the six states of India with the 

highest prevalence. 

Zambia is a high-prevalence country (approximately 16%) in the highest 

prevalence region in the world, sub-Saharan Africa. Among Zambians 

15-24 years of age, women are two-and-a-half times as likely to be HIVinfected as men (Zambia Demographic and Health Survey, 2001-2002). 

Each of these three discussions is anchored by women who have a long 

and distinguished history as care providers and/or advocates for women 

living with HIV in these three countries. 

Brazil is a country with limited resources that has made the political 

commitment to provide antiretroviral therapy for all of its citizens with 

HIV infection and has seen decreases in morbidity and mortality equal to 

that seen in resource-rich countries.

II. INDIA

In India 85% of women with HIV were infected through heterosexual 

contact and over 90% reported a single lifetime partner, generally 

their spouse (John, 1993; Gangakhedkar, 1997; Newman, 2000). Blood 

transfusion was the source of infection in almost 8% of women; single 

unit transfusions are commonly given during childbirth and abortion to 

manage hemorrhage. Common clinical manifestations in HIV-infected 

women include vaginal and oral candidiasis, pulmonary tuberculosis, 

skin lesions, genital ulcers, weight loss, and diarrhea.

There are a number of cultural beliefs and practices that present special 

challenges to HIV care and prevention. In India there are different values 

placed on the birth of a female and a male child. A woman’s primary social 

function is to assure caste community and continuity of property through 

the birth of sons. Only sons can perform certain rituals, such as funeral 

rites for their parents. Furthermore, parents must often pay large dowry 

amounts for their daughters’ marriage. This has resulted in overwhelming 

importance given to bearing sons, resulting in use of prenatal ultrasound 

commonly for sex determination with elective termination of female 

fetuses and a low overall female to male ratio of 100:144. Therefore, 

women begin life as devalued and considered a liability. 

In ancient times India offered to the world the renowned treatise on 

sexuality The Kamasutra. Sexual imagery found a pride of place in 

temple sculptures and elaborate rituals covered marriage, nuptial nights, 

pregnancy, and childbirth, recognizing sex and reproduction as part of 

the social process. Such openness about sex and sexuality is now nearly 

absent. As a woman attains puberty, she is expected to maintain a culture 

of silence when confronted with issues of her own sexuality, preventing 
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access to information. There is a great deal of pressure to maintain virginity 

until marriage. Many women engage in alternative and even risky sexual 

behaviors, such as anal sex, in an effort to maintain their virginity. When 

women do engage in sex, their ignorance and the continued culture of 

silence make them unable to negotiate safer sex practices. 

As with virginity, motherhood is considered a virtue and using barrier 

methods or non-penetrative sexual practices is seen as an affront to the 

concept of motherhood. The worst offense a woman is held guilty of is 

the inability to bear children. Her life is reduced to violence, rejection, 

and misery. The pressure to have children is equally great among HIV 

serodiscordant couples. In one study from an HIV care center in south 

India, 44% of couples were serodiscordant for HIV, but many women 

were willing to risk acquiring HIV in order to conceive a child (Solomon, 

2003). “I would rather be HIV positive than a barren woman,” said Aruna, 

one HIV-uninfected woman whose husband has HIV infection. “If my 

neighbor sees me as she goes out to work, she considers it so inauspicious 

that she will go back home to cleanse herself under the shower.” Parentsin-law of these women may extend threats that their sons will marry a 

second time and produce a child by his second wife. 

Violence against women is a fact of life in India. A woman has the duty 

of pleasing her husband; if she refuses sex, she risks violence, abuse, 

and abandonment. These women tolerate their husband’s infidelity and 

abuse and submit to their demands to avoid further abuse, remaining 

in these relationships for fear of abandonment. The culture of silence 

is maintained and many view this violent relationship as “normal.” A 

woman is raped every 34 minutes in India and a woman is burnt to death 

over dowry every 93 minutes (UNIFEM, 2000).

AN INNOVATIVE PROGRAM FOR WOMEN

YR Gaitonde Center for AIDS Research and Education (YRG CARE) is an 

innovative program for women that offers a number of services to women 

with or at risk for HIV. Couples counselling and testing promotes open 

communication between genders and can reduce practices of blaming 

the woman and can encourage both partners’ involvement in decisionmaking, help them plan their future together, reduce risks and improve 

their quality of life. Family counselling is also offered to help other 

family members realise that the couple needs all their support to achieve 

a better quality of life. 

In India marriages are not “made in heaven”. Parents arrange them, 

usually within the same caste and religion. The first step is to match 

horoscopes; if the majority of the houses in the astrological charts of the 

prospective groom and bride match, their parents meet and finally the 

couple are introduced to each other. This usually occurs when the man 

is 24–25 years of age and the woman is 18–21 years. At YRG Care there 

is a marriage counseling center where HIV seropositive men or women 

who are under pressure to marry are counseled, their needs assessed, and 

efforts made to introduce them to suitable partners.
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There is a cohort of 1908 women followed at YRG CARE, of which 693 

are HIV-negative married to husbands with HIV. These women are under 

great pressure from the parents-in-law to bear children, but neither the 

husband or wife is able to discuss HIV-related issues, including the need 

for safe sex, because of the stigma attached to HIV disease. Through 

counseling services at the center, these couples are given various 

options including adoption; artificial insemination using donor semen; 

antiretroviral therapy for the husband to reduce plasma viral load, in 

turn decreasing HIV transmission from husband to wife while trying 

to conceive; or artificial insemination with washed semen from the 

husband. This service allows these couples hope, while helping protect 

the woman both from rejection and from HIV.

Other services offered through YRG CARE include provision of at least 

one balanced meal daily to a woman and her husband when he is in 

the hospital through a novel scheme called “365 Good Friends,” in which 

people donate money on their birthday, sufficient for 50 meals. This 

saves the woman from having to cook and bring food from home to the 

hospital, as would usually occur. This initiative is presently assisted by 

the Andrew Ziegler Foundation, which is helping YRG CARE to find 

‘Good Friends’ who will donate $100 towards daily meals to improve the 

nutrition of our patients. 

YRG CARE also provides HIV and sexuality education to industrial 

employees. This has resulted in many requests to also conduct such 

programs for the employees’ family members and for women in the 

neighboring community. It was felt that such knowledge would empower 

these individuals in their efforts to prevent the spread of HIV.

There remain many challenges for HIV prevention and management 

for women in India. Girls must be provided with the same educational 

opportunities as boys, both in terms of general academics and in the area 

of sexuality. Because gender inequities and power dynamics inherently 

involve both sexes, it is important that men be included when addressing 

issues affecting women. It may be helpful to better educate and sensitize 

both young women and young men about sexuality and about gender 

with the goal of reducing risky behaviors and violence, while enhancing 

information-seeking behavior and female equality. . Another important 

source of power is access to economic resources and assets. Educational 

programs along with skills training programs and microcredit loan 

schemes can help women to achieve economic independence. 

Women in sex work have historically been disempowered and are at 

risk for exploitation, violence, and infection. Programs that organize and 

mobilize sex workers have been successful in increasing the power of these 

women and their communities. Organizations from all over India have 

combined into The National Network of Sex Workers to improve social, 

economic, and health conditions. These programs must be strengthened 

and expanded. The development of female-controlled methods of HIV/

STI prevention, particularly those that can be used in secrecy, should be 

a major research priority and has significant implications both for sex 
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workers and for women in primary relationships. In one study 89% of 

men would allow their non-primary sexual partners to use microbicides 

to prevent HIV and STI transmission and only 42% would allow their 

primary sexual partners to use them (Srikrishnan, 2001).

Although over 48% of Indians are women, they represent less than 10% of 

individuals in the parliament, the State High Courts and Supreme Courts, 

and in Civil Service administration. Political representation of women 

will be important to further advance many issues relating to women’s 

health and empowerment (Rao Gupta, 2002). 

Lack of access to health care prevents women from having control 

over their lives. Since it is often difficult to access services without the 

permission or monetary support of their husbands and in-laws, steps 

must be taken to provide services to women in convenient, low cost, and 

discreet environments. In YRG CARE 61% of men and 76% of women 

who needed antiretroviral therapy were not able to secure the drugs. In a 

family wherein both husband and wife require antiretroviral therapy and 

the finances are sufficient for one person only, the man is usually the one 

who accesses the medications. HIV-infected women are also less likely 

to have laboratory investigations such as CD4 counts or viral loads. The 

Government of India currently has a project funded by the Global Fund 

for AIDS, TB and Malaria for prevention of mother-to-child transmission 

(PMTCT) which will supply ARV therapy not only to prevent MTCT but 

also for treatment of parents with CD4 counts less than 200/mm3 in 11 

centers in the country.

III. ZAMBIA

It is estimated that some 1.2 million Zambians are living with HIV/AIDS 

and prevalence in women is 12.9%, with significantly higher rates in 

women as compared to men throughout most of the reproductive years. 

The prevalence rates for both men and women are two-fold higher in 

urban than in rural areas. Although awareness about HIV/AIDS is high, 

this does not translate into positive action for prevention and both uptake 

of voluntary counseling and testing (VCT) and condom use are low 

(Zambia Demographic and Health Survey, 2001-2002). Women are most 

often offered VCT during antenatal care, after a spontaneous abortion 

or stillbirth, with death or failure to thrive in a child, with presentation 

of a sick child or partner to the clinic, after death of a partner, or when 

seeking treatment for frequent illnesses.

In sub-Saharan Africa tuberculosis (TB) is the most common HIV-related 

opportunistic infection (OI) and a leading cause of death. TB has special 

implications for the health of women: a study of 775 maternal deaths at 

the University Teaching Hospital of Zambia (Ahmed, 1999) found that 

255 were due to TB and in 92% of these cases the woman was HIV+. 

TB endometritis is a major cause of infertility. The most recent national 

statistics indicate that 70% of TB patients have HIV infection (Zambia 

Demographic and Health Survey, 2001-2002).
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Sexually transmitted infections (STIs) are a major problem in sub-Saharan 

Africa in general, including Zambia. STI prevalence is 56% among sex 

workers in Zambia (Family Health International, unpublished data, 2003) 

The East, Central, and Southern African Commonwealth region has 

adopted syndromic management of STIs, in which immediate treatment 

is given for all major causes of certain presenting symptoms (e.g., genital 

ulcers), based on local information about etiologies of the symptom and 

drug susceptibility patterns. Etiologic diagnosis with cultures and other 

laboratory tests is not generally available. Syndromic management is 

cost-effective and encourages people to access treatment at all levels of 

care. However, it does not identify those individuals with asymptomatic 

infection, which is more common in women. Contact tracing may help 

identify sexual partners, especially wives, who may be asymptomatic. 

Presumptive treatment should be offered to all sexual partners of persons 

being treated syndromically.

Invasive cervical cancer is the most common gynecologic malignancy 

in Zambia and is considered an AIDS-defining condition in the presence 

of HIV infection. Rates of preinvasive cervical lesions are significantly 

increased in the presence of HIV and both prevalence and severity 

increase with progressive immunosuppression. Routine Pap smear 

screening is not generally available throughout Africa, in either urban or 

rural areas, and women usually present in advanced stages of disease. As 

antiretroviral treatment becomes more available, invasive cervical cancer 

may become a still greater problem as women with HIV live longer with 

their infection but still suffer the consequences of HPV infection and 

progressive cervical dysplasia.

Although malaria does not appear to be more severe or more prevalent 

in HIV-infected individuals in general, in HIV+ pregnant women HIV 

hinders the ability to control Plasmodium falciparum infection and peak 

parasite prevalence occurs earlier in pregnancy. While in the HIVuninfected pregnant woman a single dose of sulfadioxine pyrimethamine 

(SP) is sufficient to clear parasitemia, two to three doses are required in 

the HIV+ woman (Schulman, 1999). Malaria is a principal cause of severe 

anemia and intrauterine growth restriction in pregnancy (Steketee, 

1996); in the HIV+ woman anemia related to malaria is exacerbated 

by nutritional deficiencies or wasting, other infections, and HIV-related 

illnesses. Malaria is estimated to be responsible for more than 20% of all 

maternal deaths in sub-Saharan Africa. Placental parasitemia is increased 

in the presence of HIV and may increase risk of MTCT.

CHALLENGES TO PREVENTION AND TREATMENT:

• The environment of poverty (these issues apply to sub-Saharan 

Africa in general): Literacy and education levels are low, 

particularly for women, and these factors are associated with 

lower use of condoms (Zellmir, 2003; Zambia Demographic and 

Health Survey, 2001-2002). Because of high unemployment levels, 

women may turn to sex work in exchange for favors or money 
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needed to feed and educate their children, further increasing their 

risk of acquiring HIV. Lack of clean accessible water increases 

the incidence of diarrheal diseases and risk of malnutrition in 

those with HIV. Overcrowding in households occurs with several 

generations in an extended family often living together in small 

houses because of unemployment and because of incorporation 

of AIDS orphans into these families. Women and girls in these 

settings may be at increased risk for domestic and sexual violence 

and for neglect of their own health care needs. In several countries 

in Africa there is civil unrest and war. This has led to increased 

HIV risk for women, who are vulnerable to rape and intentional 

impregnation. Where there have been peacekeeping soldiers 

from high-HIV prevalence areas sent to low-prevalence countries, 

women in those countries have been at increased risk for 

contracting HIV. Women who are refugees from war and drought 

or famine are also at increased risk for HIV because of their 

vulnerability to violence and to sexual coercion and because of 

extreme economic dependence. Finally, health care infrastructures 

and resources are inadequate for the diagnosis and management of 

HIV disease and other general health conditions.

• Violence against women and sexual violence occurs in 4.4% 

of ever-married women (50% in the last 12 months). (Zambia 

Demographic and Health Survey, 2001-2001)

• Cultural issues (many of these issues apply to other countries 

in Africa, not just Zambia): Women are care providers but their 

work is not considered in monetary terms. When the husband 

dies his relatives come to claim the property because the woman 

did not contribute money for the purchase of land, house, or 

household goods. Because of their lack of monetary resources, 

women are economically dependent on their partners. They have 

no bargaining power to negotiate for safe sex, as the man will go 

outside the home for sex. Married women who demand the use of 

condoms are accused of not trusting their husbands and female 

condoms cannot be used without the permission of the husband. 

Even with condom use, some men believe they can be made sick 

if the semen does not flow out, so they make a small hole at the 

tip of the condom. It is believed that wives who are faithful cannot 

get HIV or other STIs. Often, even if a man receives STI treatment 

or HIV testing, his wife will refuse, as she will be blamed for 

bringing disease to the marriage. Certain sexual practices increase 

the risk of HIV infection for women. Dry sex is considered more 

pleasing and women use herbs or other substances to dry the 

vaginal mucosa, increasing risk of trauma during intercourse and 

risk of HIV transmission. Female genital mutilation is commonly 

practiced in many areas throughout Africa in order to reduce the 

woman’s libido, as it is believed that a respectable woman does 

not enjoy sex. Infertile couples seek the wife’s sister as a surrogate 

mother without regard to HIV status. In many African cultures 

polygamy is practiced and legally supported; it is commonly 

believed that a man will become impotent if they are in a 
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monogamous sexual relationship. “Sexual cleansing” after the death 

of the husband is practiced in some Zambian communities. With 

this practice the widow is expected to have sex with her husband’s 

chosen relative in order to remove the husband’s shadow from the 

woman’s body; otherwise, any man who has sex with the widow 

will die. In South Africa sexual assault of children has increased 

dramatically because many men believe that they can be cured 

of HIV by having sex with a child. Older men (who may already 

be HIV-infected themselves) often seek out very young women or 

girls because they believe that older women are likely to be HIV+. 

In one study, 66% of women had unprotected sex in their last sex 

act with a non-regular partner.

• Stigma: Stigma concerning HIV is widespread throughout Africa 

and leads to a vicious cycle of fear and denial. The consequences 

of this cycle include discrimination, rejection, increased risk 

of HIV transmission, and decreased likelihood that infected 

individuals will appropriately access care and treatment for HIV 

and related opportunistic infections, such as TB. Health care 

providers who worry about stigma or fear becoming infected 

through work activities may have problems with disclosure of VCT 

results to patients (Zambia Nursing Council, 2001) and may be 

unwilling to care for those known or suspected to have HIV. Stigma 

is cited as the primary reason for the low VCT uptake in PMTCT 

programs. In most hospitals doctors and nurses will not write HIV 

as the cause of death on a death certificate because of stigma.

INNOVATIVE INITIATIVES

• In village initiation ceremonies traditional women counselors 

(“Alangizi”) are being trained to incorporate couple counseling to 

promote HIV knowledge and use of condoms.

• The Forum for African Women Educationists (FAWE) has trained 

teachers to counsel girls, many in boarding schools during their 

adolescent years, about HIV/AIDS, and advocates for pregnant 

girls to remain in school and to return to school after giving birth.

• Home-based care (HBC) is supported by faith-based and 

community organizations to provide care within the home for 

chronically ill persons using community volunteers. These 

programs offer VCT, spiritual care, help in writing wills, assistance 

with chores, administration of medicine, and assistance with 

personal hygiene. Although volunteers were at first stigmatized, 

they now have the respect of the community and are often called 

upon for advice because of their knowledge about HIV and care. 

• Programs that provide access to water and sanitation have 

incorporated HIV awareness and basic hygiene information. 

• PLWHA networks have started income-generation activities at 

various centers, with money raised used to improve nutrition and 

help pay school tuition for children.
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• An initiative in Southern Africa supported by Family Health 

International, including partnerships with international and local 

non-governmental and community-based organizations, provides 

commercial sex workers in border areas with HIV information, 

condoms, VCT, and STI treatment.

IV. BRAZIL

It is estimated that approximately 623,000 individuals are living with 

HIV/AIDS in Brazil (Szwarcwald, 2001); women account for 30% of cases 

reported and are now the fastest-growing segment of the population in 

terms of AIDS cases. The male:female ratio for AIDS has fallen from 24:

1 in 1985 to 2:1 in 1997 and among adolescents is now 1:1. (Brasil, 2003). 

The HIV/AIDS epidemic began to explode in Brazil in the 1980s when 

the country was emerging from a military dictatorship and in the midst 

of a redemocratization process. In 1988 the country’s new constitution 

recognized health as a constitutional right for all citizens; this facilitated 

the adoption of the prevention and care policy that characterizes the 

Brazilian approach to fighting HIV/AIDS and paved the way to the 

successful implementation of universal and free access to highly active 

antiretroviral therapy (HAART) for all HIV-infected citizens in Brazil. 

Currently more than 115,000 people have had access to free ARV treatment 

provided through government financing and generic versions of a number 

of ARV agents are produced by several publicly-owned companies. Since 

the introduction of HAART, a sharp decline in the incidence of AIDS and 

an 80% decrease in AIDS-related mortality has occurred in Brazil, similar 

to that seen in the most developed countries (Levi, 2002; Gotlieb, 2003). 

The median survival after a diagnosis of AIDS has increased from 5.8 

months for patients diagnosed between 1982 and 1989 (Chequer, 1992) 

to 58 months for those diagnosed in 1996 (Marins, 2003). The decrease 

in hospitalizations has saved more than US$2.2 billion from 1997 to 2001, 

more than offsetting the US$1.8 billion invested in fighting HIV/AIDS 

during the same period. Today Brazil provides technical assistance on 

HIV/AIDS to Portuguese-speaking African countries.

However, the reduction in AIDS deaths among women has lagged behind 

the reduction in deaths among men with AIDS, and this is true in all 

regions of the country (Fonseca, 2002; Gotlieb, 2003). The epidemic began 

later in women and women with HIV continue to experience delays in 

diagnosis and treatment. Health care providers may be less likely to 

think about HIV infection in women and women themselves often do 

not perceive themselves to be at risk. In a study conducted in Sao Paulo, 

53% of HIV-infected women interviewed did not perceive themselves 

to be at risk before learning of their HIV status and, of those who did 

perceive themselves at risk before testing, 29% believed they were at risk 

only after their partners became ill (Ventura-Filipe, 2000). Women may 

also prioritize the health care of their children and infected partners over 

that of their own care, potentially postponing care and compromising 

adherence to antiretroviral therapy. 
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Once women are diagnosed with HIV, health care providers are frequently 

not prepared to provide the needed support with HIV-infected women 

reporting limited receptiveness for discussing sexuality and childbearing 

wishes with their providers (Paiva, 2002). Furthermore, the fact that 

gynecologic care and family planning services are often located in places 

separate from those providing HIV/AIDS care is a barrier to integrated 

care for women.

The most frequent clinical manifestations in a cohort of 297 women with 

HIV/AIDS followed in Rio de Janeiro included oral candidiasis, weight 

loss >10%, vaginal candidiasis, recurrent bacterial sinusitis, tuberculosis, 

and multidermatomal herpes zoster. Tuberculosis, Pneumocystis carinii 

pneumonia, and espophageal candidiasis were the most common AIDSdefining illnesses (Grinsztejn, 2001). In the same cohort, prevalence of 

sexually transmitted infections (STIs) were high, including HPV (51.2%), 

syphilis (10.8%), hepatitis B (14.7%), and trichomoniasis (9.8%). Among 

HPV-infected women, 92% were infected with oncogenic subtypes. 

Vaginal candidiasis was identified in 20.9% and bacterial vaginosis in 

18.2%. (Grinsztejn, 2001). The high rate of HPV infection has special 

relevance in Brazil, since cervical cancer is still a major cause of morbidity 

and mortality and is the most frequent cancer in Brazilian women, with 

approximately 20,000 new cases of cervical cancer and 6000 deaths due 

to cervical cancer each year. Overall, survival and disease progression 

rates appear to be similar in HIV-infected women and men, with initially 

observed differences largely explained by differences in stage of disease, 

access to care and treatment, and initiation of timely therapy. 

Because of gender and social inequities and prejudices, Brazilian women 

continue to face enormous barriers in prevention of HIV; it is difficult 

to discuss safer sex with partners and women have very little bargaining 

power when trying to introduce and sustain condom use. Frequently, 

women who do use condoms use them primarily for contraception, 

not as a means to prevent sexually transmitted infections or HIV, and 

HIV-infected women who use more effective contraceptive methods 

are less prone to use condoms (Fernandes, 2000; Magalhaes, 2002). In 

a cross-sectional study designed to assess safe sexual behavior among 

heterosexual couples, women who had known about their partner’s 

HIV infection for a longer period of time were less likely to report safe 

behavior than those who had recently found that their partner was HIVinfected (Guimaraes, 2001). The partner’s desire not to use a condom is a 

frequently reported reason for inconsistent use, even among HIV-infected 

women with HIV-uninfected partners. In a study conducted in Sao Paulo 

25% of HIV-negative men did not use condoms even after knowing about 

their female partner’s HIV infection (Magalhaes, 2002). In 1999 the 

favorable results of an acceptability study conducted in six urban areas 

led the Ministry of Health to purchase and distribute female condoms 

free of charge, prioritizing HIV-infected women, commercial sex workers, 

and women attending selected reproductive health services. In 2002 a 

total of 4 million female condoms were purchased for distribution. 
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Poverty, lack of family or social support, sexual abuse, and domestic 

violence are problems frequently faced by women in Brazil and represent 

a major public health problem. These problems increase risk of acquiring 

HIV and other STIs and increase the likelihood that HIV-infected women 

will not receive the care they need. In interviews conducted among HIVinfected women being followed in Rio de Janeiro, domestic violence 

was reported by 24.2% and sexual abuse by 24.6%. The monthly family 

income was US$330 or less in over 60% of women, and 56% of women 

were unemployed at the time of the interview. Twenty-five percent of 

women had no support from family or friends and 20% had lost at least 

one child to AIDS (Friedman, 2002 ). In 2001 the Ministry of Health began 

to provide antiretroviral prophylaxis for victims of rape and a special 

training program to sensitize health care providers about violence against 

women was developed.

In the last several decades women’s access to and use of contraception 

has increased dramatically in Brazil, resulting in a sharp drop in the 

fertility rate from 6.3 in the 1950s to 2.3 in 2001 (IBGE, 2003). However, 

approximately 10 million women have unwanted pregnancies, either due 

to inadequate use of contraceptive methods or to a lack of knowledge and/

or access to them. The high pregnancy rate among teenagers in Brazil, 

especially among those from poorer social strata, is of special concern. 

In 1998 32% of 15-year-old girls had had sexual intercourse and in 2002 

adolescent pregnancies accounted for approximately 25% of all deliveries 

in the country. Some studies in Brazil suggest that the knowledge of 

HIV infection increases the prevalence of contraceptive use, including 

use of condoms, among women of reproductive age (Magalhaes, 2002; 

Santos, 2002). There was also a significant increase in dual method use 

after knowledge of HIV infection, with more than 70% of HIV-infected 

women choosing hormonal methods also using condoms; however, 

only 46% of women with tubal ligation also used condoms (Magalhaes, 

2002). Nevertheless, HIV infection has not changed women’s desire 

to have children and with interventions available to prevent perinatal 

transmission of HIV and the increase in survival of HIV-infected people, 

many women with HIV are choosing to have children. If the health care 

provider adopts a judgmental attitude about childbearing in the context of 

HIV infection, this will represent a barrier for care for most HIV-infected 

women (Santos, 2002; Paiva, 2002). 

The Ministry of Health has established the prevention of mother-to-child 

transmission of HIV as a top priority. Antiretroviral drugs for prophylaxis 

and treatment, infant formula, and referral for cesarean delivery are 

widely available (Veloso, 1999). However, in 2002 it is estimated that 

of the 17,000 HIV-infected women who delivered, only about 35% were 

identified and received ARV prophylaxis. Many doctors still do not offer 

HIV testing during prenatal care and test results often take too long to 

receive, resulting in many deliveries in women of unknown HIV serostatus 

and missed opportunities to prevent mother-to-child transmission. In a 

cross-sectional study conducted between November 1999 and April 2000 
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in 12 Brazilian cities highly affected by the HIV/AIDS epidemic, 77.5% 

of 2,234 postpartum women who were interviewed reported being HIV 

tested and the HIV test acceptance rate was 92.5%. However, 49.1% 

reported that they did not receive counseling about HIV prevention 

during prenatal care and over 50% did not receive explanations about the 

meaning of their test results (Veloso, 2002). Considering these barriers to 

diagnosis of HIV and counseling about HIV prevention during pregnancy, 

and because 95% of all deliveries in Brazil take place in hospitals, the use 

of rapid HIV testing in labor has become a major strategic intervention for 

prevention of mother-to-child HIV transmission (Santos, 2001; Nogueira, 

2001). However, the overall low quality of prenatal care, as reflected by 

an unacceptably high maternal mortality rate (161–260/100,000) and 

incidence of congenital syphilis (24/1000 live births) (Brasil, 1993), 

remains a primary barrier to both prevention of HIV and appropriate 

care and treatment for women with HIV living in Brazil.

It is of utmost importance for Brazil that health care providers be better 

trained and sensitized about gender issues in order to provide a high 

quality of care and to address unmet needs. The integration of HIV/AIDS 

care with gynecologic, obstetrical, and family planning services and the 

availability of social support must be improved so that women in Brazil 

can be freed from many of the competing needs and other barriers they 

now face which prevent them from taking full control of their lives, 

including prevention of HIV and other sexually transmitted infections 

and access to HIV care and treatment.

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Brasil. Ministério da Saúde. Bases Técnicas para a Eliminação da Sífilis 

Congênita. Brasília: Coordenação Nacional de DST/AIDS, Secretaria de 

Políticas de Saúde, MS; 1993.

Brasil. Ministério da Saúde. Bol Epidemiol AIDS. 2003—abril a dezembro de 

2002. Available at http://www.aids.gov.br. Accessed July 1, 2004.

Chequer P, Hearst N, Hudes ES, et al.Determinants of survival in adult Brazilian AIDS patients, 1982-1989. The Brazilian State AIDS Program CoOrdinators. AIDS. 1992;6:483–437.

Fernandes AM, de Gaspari Antonio D, Bahamondes LG, Cupertino CV. 

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Fonseca MG, Szwarcwald CL, Bastos FI. A sociodemographic analysis of the 

AIDS epidemic in Brazil, 1989-1997. Rev Saude Publica. 2002;36:678–685.
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Friedman,RK, Lourenço,MC, Veloso,VG, Grinsztejn,B, Schechter,M, Bastos, 

FI. HIV-infected marginalized and abused women from Rio de Janeiro, 

Brazil (BR), are heavily coinfected with HPV but have low/ moderate 

prevalences for other sexually transmitted infections (STIs). XIV International Conference on AIDS; July 2002; Barcelona, Spain. Abstract 

ThPeC7595.

Gangakhedkar RR, Bentley ME, Divekar AD, et al. Spread of HIV infection in 

married monogamous women in India. JAMA. 1997;278:2090–2092.

Gotlieb SLD, Castilho EA, Buchalla CM. The impact of AIDS on life expectancy, Brasil, 2000. Bol Epidemiol AIDS. 2003—Abril a dezembro de 2002. 

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Grinsztejn, BGJ. Prevalence of sexually transmited infections and study of risk 

factors for the HPV infection in a cohort of HIV infected women in Rio 

de Janeiro [doctoral thesis]. Federal University of Rio de Janeiro; 2001.

Guimaraes MD, Boschi-Pinto C, Castilho EA. Safe sexual behaviour among 

female partners of HIV-infected men in Rio de Janeiro, Brazil. Int J STD 

AIDS. 2001;12:334–341.

John TJ, Bhushan N, Babu PG, et al. Prevalence of HIV infection in pregnant 

women in Vellore region. Indian J Med Res. 1993;97:227–230. 

Levi GC, Vitoria MA. Fighting against AIDS: the Brazilian experience. AIDS. 

2002;16:2373–2383.

Magalhaes J, Amaral E, Giraldo PC, Simoes JA. HIV infection in women: 

impact on contraception. Contraception. 2002;66:87–91.

Marins JR, Jamal LF, Chen SY, et al. Dramatic improvement in survival 

among adult Brazilian AIDS patients. AIDS. 2003;17:1675–1682.

Newman S, Sarin P, Kumarasamy N et al. Marriage, monogamy and HIV: 

a profile of HIV-infected women in South India. Int J STD AIDS. 

2000;11:250–253.

Nogueira SA, Lambert JS, Albuquerque AL, et al. Assessment of a rapid HIV 

test strategy during labor: a pilot study from Rio de Janeiro. Brazil J 

Hum Virol. 2001;4:278–282.

Paiva V, Latorre Mdo R, Gravato N, et al. Enhancing Care Initiative - Brazil. Sexuality of women living with HIV/AIDS in SaoPaulo. Cad Saude 

Publica. 2002;18:1609–1620.

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Available at: http://www.unaids.org/en/about+unaids/speeches.asp. 

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Rao Gupta G, Whelan D, Allendorf K. 2002 expert consultation on integrating 

gender into HIV/AIDS programmes. Washington, DC: ICRW; 2002.

Santos NJ, Buchalla CM, Fillipe EV, Bugamelli L, Garcia S, Paiva V. Reproduction and sexuality in HIV-positive women, Brazil. Rev Saude Publica. 

2002;36(4 Suppl):12–23.

Santos VV, Bastos FI, Nielsen K, et al. A prospective study of feasibility of 

rapid HIV testing in pregnant women during the peripartum period in 

Rio de Janeiro, Brazil. 8th Conference on Retroviruses and Opportunistic Infection; February 4-8, 2001; Chicago, USA. Abstract 695.
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Shulman CE, Dorman EK, Cutts F, et al. Intermittent sulphadoxine-pyrimethamine to prevent severe anemia secondary to malaria in pregnancy: a 

randomised placebo-controlled trial. Lancet. 1999;353:632–636.

Solomon S, Buck J, Chaguturu S, Ganesh AK, Kumarasamy NK. Stopping 

HIV before it begins: issues faced by women in india. Nat Immunol. 

2003;4:719–721.

Steketee RW, Wirima JJ, Hightower AW, Slutsker L, Hiymann DL, Breman 

JG. The effect of malaria and malaria prevention in pregnancy on offspring birth weight, prematurity and intrauterine growth retardation. 

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Srikrishnan AK, Morrow K, Ganesh AK et al. Same risks, disparate perceptions: challenges to microbicide acceptability in the Chennai community. 6th International Conference on AIDS in Asia and the Pacific; 

October 5-10, 2001; Melbourne, Australia. Abstract 0777.

Szwarcwald CL, Barbosa Júnior AB, Fonseca MG. Estimativa do número 

de crianças (0-14 anos) infectadas pelo HIV, Brasil, 2000. Bol Epidemiol AIDS. 2001—julho a setembro de 2001. Available at http://

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UNAIDS. AIDS epidemic update-December 2003. Available at: http://

www.unaids.org/wad/2003/Epiupdate2003_en. Accessed January 4, 2004.

VelosoVG, Vasconcelos ML, Matzenbacher LL, Vasconcelos A, GrangeiroA, 

Portella M. Evaluation of HIV counselling and testing during antenatal 

care in Brazil. XIV International Conference on AIDS; July 2002; Barcelona, Spain. Abstract WePeB5949.

Veloso VG, Vasconcelos AL,Grinsztejn B. Prevenção da transmissão vertical 

no Brasil. Bol Epidemiol AIDS. 1999—junho a agosto de 1999. Available 

at http://www.aids.gov.br. Accessed June 13, 2004.

Ventura-Fillipe EM, Bugamelli LE, Leme B, et al. Risk perception and counselling among HIV-positive women in Sao Paulo, Brazil. Int J STD AIDS. 

2000;11:112–114.

Zambia Demographic and Health Survey, 2001-2002.

Zambia Nursing Council. Needs assessment study on HIV/AIDS for Zambian 

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Zellner SL. Condom use and the accuracy of AIDS knowledge in Cote 

d’Ivoire. Int Fam Plan Perspect. 2003;29:41-47.
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EDITOR’S NOTE:

The following chapter is part of a series of modules being developed by the 

World Health Organization (WHO) and its partners on the care, treatment, 

and support of HIV-infected women and their children in resource-constrained 

settings. We are grateful to WHO for allowing us to reproduce this chapter 

on nutrition in its entirety for this guide. Although it is focused on the needs 

of women living in areas with limited resources, it is a valuable review of 

the current evidence base for the inter-relationship of HIV and nutrition 

and resulting recommendations, with relevance for HIV-infected women in 

all settings. Following this chapter are a series of tables, adapted from or 

developed by other sources, providing additional information which may be 

useful in areas with greater resources.

We want to acknowledge the following contributors to this chapter: Ellen 

Piwoz, Support for Analysis and Research in Africa Project, Academy for 

Educational Development, USA; the WHO Technical Advisory Group on 

Nutrition and HIV/AIDS; and, the Writing Committee Working Group 

who contributed to the module on HIV-related care, treatment, and support 

interventions for HIV-infected women (for a complete list of individuals, see 

the full report at http://www.who.int/hiv/pub/prev_care/nutrition/en/).

INTRODUCTION TO CHAPTER

The relationship between nutrition and HIV/AIDS is complex and not fully 

documented to date. The HIV/AIDS epidemic poses a challenge to the health 

and overall socioeconomic development in countries that have been greatly 

affected by the disease, which in turn may affect nutrition and food security. 

Healthy nutrition plays a role in alleviating the symptoms—e.g., diarrhea, 

anorexia, sore mouth, muscle wasting—common with HIV disease. There 

are, however, many gaps in current scientific knowledge on the impact 

that HIV/AIDS and malnutrition have on each other, the role of nutrition 

in the management of HIV/AIDS, and interactions between nutrition and 

ARV treatment. This document reviews the relationship between nutrition 

and HIV/AIDS and scientific evidence on the role of nutrition in HIV 

transmission, disease progression, morbidity, and disease management; and 

makes recommendations on nutrition counseling, care, and support for HIVinfected women, based on current evidence. 

XVII. NUTRITION COUNSELING, 

CARE AND SUPPORT

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I BACKGROUND

A INTRODUCTION

HIV infection affects nutritional status by causing increased energy 

requirements, reductions in dietary intake, nutrient malabsorption and 

loss, and complex metabolic alterations that culminate in the weight loss 

and wasting that are common in AIDS (Babameto, 1997; Macallan, 1999; 

WHO, 2003). The effect of HIV on nutritional status begins early in the 

course of infection, possibly even before the individual in question is 

aware of being infected (Beach, 1992; Bogden, 2000; Friis, 2001a; Friis, 

2001b, Semba, 1999). 

B MALNUTRITION AND HIV 

Nutrition is an important component of comprehensive care for the HIVinfected woman, and is particularly so in resource-limited settings where 

malnutrition and food insecurity are endemic. Pre-existing malnutrition, 

i.e. malnutrition occurring before HIV infection, compromises the 

immune system. The cellular effects of malnutrition on the immune 

system are similar to those of HIV. They include decreases in CD4 T-cells, 

suppression of delayed hypersensitivity, and abnormal B-cell responses 

(Beisel, 1996; Gorbach, 1993; Scrimshaw, 1997). 

The impact of nutrition on HIV and disease progression is difficult to 

study. A systematic review of the literature is being conducted by the 

WHO Technical Advisory Group on Nutrition and HIV/AIDS. Early studies 

demonstrated that reduced body cell mass and decreased serum albumin 

levels were associated with shorter survival in AIDS patients, which 

was independent of the CD4 cell count (Kotler, 1989; Suttmann, 1995). 

Community-based research studies in the USA revealed that moderate 

weight loss (< 5%) and severe weight loss (5−10%) over a four-month 

period were associated with a subsequent increased risk of opportunistic 

infections, including Pneumocystis jiroveci (formerly P. carinii) pneumonia, 

cytomegalovirus, and the Mycobacterium avium complex, and with 

mortality (Wheeler, 1998). Other studies showed that clinical outcome 

was comparatively poor and that the risk of death was comparatively high 

in HIV-infected patients with compromised micronutrient intake or status 

(Baum, 1997; Baum, 1998; Semba, 1994a; Tang, 1993; Tang, 1996; Tang, 

1997a; Tang, 1997b). 

C VITAMIN AND MINERAL DEFICIENCIES AND HIV 

Deficiencies of vitamins and minerals, such as vitamins A, B-complex, C, 

and E, and selenium and zinc, which are needed by the immune system 

to fight infection, are commonly observed in people living with HIV in all 

settings (Baum, 1995; Friis, 2001a; Friis, 2001b; Kupka, 2002; Semba, 1999). 

Deficiencies of antioxidant vitamins and minerals contribute to oxidative 

stress, a condition that may accelerate immune cell death (Banki, 1998; 

Romero-Alvira, 1998) and increase the rate of HIV replication (Allard, 

1998; Rosenberg, 1990; Schwarz, 1996). 
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Short-term antioxidant supplementation has been shown to improve 

body weight and body cell mass (Shabert, 1999), reduce HIV RNA levels 

and improve CD4 cell counts (Muller, 2000), and reduce the incidence of 

opportunistic infections (Mocchegiani, 2000) in small studies of adults 

with AIDS, including those on ARV treatment. In Thailand a larger 

placebo-controlled randomized trial on 481 ARV-naive HIV-positive men 

and women revealed that daily micronutrient supplementation for one 

year reduced mortality in persons with baseline CD4 cell counts below 

200 x 106/L, although supplementation had no effect on the CD4 cell 

count or on the plasma viral load. Further research is necessary in order 

to elucidate possible mechanisms for increased survival associated with 

micronutrient supplementation (Jaimton, 2003). 

D. NUTRITION, PREGNANCY AND LACTATION, AND HIV 

An HIV-infected woman’s nutritional status before and during pregnancy 

influences both her health and survival and those of her newborn 

children. The physiological changes that occur during pregnancy 

require extra nutrients for adequate gestational weight gain in order to 

support the growth and development of the fetus (National Academy of 

Sciences, 1989). For women who are malnourished, daily energy-protein 

supplementation during pregnancy may improve maternal weight 

gain, increase infant birth weight, and reduce the risks of stillbirth and 

perinatal mortality (Ceesay, 1997). 

HIV infection increases energy requirements because of elevated resting 

energy expenditure (Grunfeld, 1992; Melchior, 1991; Mulligan, 1997). 

These additional needs, as well as the nutritional consequences of 

common HIV-related infections and illnesses, place HIV-infected pregnant 

and lactating women at greater nutritional risk than HIV-uninfected 

pregnant and lactating women. A meta-analysis of 31 studies conducted 

in developed and developing countries reported that intrauterine growth 

retardation, preterm delivery (< 37 weeks), and low birth weight (< 2500 

g) were more common in infants born to HIV-positive mothers than in 

infants with HIV-negative mothers (Brocklehurst, 1998). The effects of 

HIV infection on pregnancy outcomes are likely to be more pronounced 

in women with symptomatic HIV infection, as has been observed in 

Tanzania (Coley, 2001). 

Wasting during pregnancy is also more common in HIV-infected women 

than in the general population (Villamar, 2002a). A high plasma viral load, 

which is a marker of advanced disease, has been associated with lower lean 

and fat body mass in pregnancy (Friis, 2002). Several studies conducted in 

Africa indicate that an HIV-infected mother’s nutritional status, measured 

by body mass index (BMI), mid-upper arm circumference, and/or weight 

loss, is an important predictor of mortality during the postnatal period 

(Lindan, 1992; Nduati, 2001; Zvandasara, 2002). Studies are planned in 

Malawi and Zambia to determine whether providing adequate nutrition 

to HIV-infected breastfeeding women can prevent the weight loss and 

nutritional depletion associated with both HIV infection and lactation. 
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E. MICRONUTRIENTS AND MOTHER-TO-CHILD TRANSMISSION OF HIV 

Malnutrition during pregnancy results in low fetal stores of some 

nutrients. This impairs immune function and fetal growth and may 

increase the vulnerability of infants to HIV. Furthermore, poor nutrition 

during pregnancy may impair the integrity of the placenta, the genital 

mucosal barrier, and the gastrointestinal tract. In each of these cases the 

transmission of HIV from mother to infant may be facilitated, although 

data confirming such relationships independently of maternal HIV 

disease progression are limited (Dreyfuss, 2002). 

Low serum retinol, used as an indicator of vitamin A status, is associated 

with the shedding of HIV in genital tract secretions and in breast milk 

(John, 1997; Mostad, 1999; Nduati, 1995). Low serum retinol has also 

been associated with an increased risk of cervical disease in HIV-infected 

women (French, 2000). Serum retinol levels decline during infections, 

however, and consequently it is difficult to interpret correlations between 

them and HIV. 

In randomized clinical trials, daily vitamin A supplementation with 

10 000 IU of retinyl palmitate had no effect on vaginal HIV shedding 

among non-pregnant women in Mombasa (Baeten, 2002 ) or on maternal 

antenatal and postnatal morbidity in Durban (Kennedy, 2000). However, 

a randomized trial among HIV-positive pregnant women in Dar es Salaam 

indicated that daily vitamin A supplementation increased viral shedding 

in the lower genital tract (Fawzi, 2004). 

Early observational studies found that low serum retinol levels were 

associated with an increased risk of Mother-to-child transmission (MTCT) 

(Semba, 1994b; Semba, 1997). Randomized controlled clinical trials with 

vitamin A and beta-carotene, however, revealed no significant impact 

on HIV transmission during pregnancy and delivery (Coutsoudis, 1999; 

Fawzi, 2000; Kumwenda, 2002). The following positive benefits of vitamin 

A supplementation on birth outcomes were observed. 

• In Durban, daily supplementation with vitamin A (5000 IU) and 

beta-carotene (30 mg) during the third trimester of pregnancy, 

combined with 200 000 IU vitamin A after delivery, reduced the 

risk of preterm delivery and was associated with improved maternal 

postpartum weight retention (Coutsoudis, 1999; Kennedy-Oji, 2001). 

• In Blantyre, Malawi, daily supplementation with vitamin A (10 000 

IU), beginning at 18−28 weeks of gestation, was associated with 

increased birth weight, increased weight and length at six weeks, 

and reduced rates of infant anemia at six weeks (Kumwenda, 2002). 

Not all vitamin A supplementation trials have produced positive results. 

In a randomized trial in Dar es Salaam, mothers received daily vitamin A 

(5000 IU) and beta-carotene (30 mg) from 12−27 weeks of gestation until 

the end of lactation, and 200 000 IU of vitamin A were given at delivery. 

MTCT at 24 months increased by 38% (34.2% versus 25.4%; P = 0.009) 

in infants of mothers randomized to vitamin A. The comparison group 

received daily multivitamins with no vitamin A (Fawzi, 2002). 
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This was the only supplementation trial in which daily vitamin A and 

beta-carotene supplements were provided during breastfeeding. Current 

WHO recommendations for maternal vitamin A supplementation in highrisk areas do not extend to the breastfeeding period (WHO, 1997). 

It is important to emphasize that, in the above studies, vitamin A 

supplements were given to women and that there were no findings on 

vitamin A supplementation in children. Studies on such supplementation 

for HIV-exposed and HIV-infected children aged 6 to 60 months have 

consistently shown positive effects on morbidity, nutritional status and 

mortality (Coutsoudis, 1995; Fawzi, 1999; Villamor, 2002b). 

In Tanzania, women were randomized to receive a multivitamin product 

daily containing high levels of vitamins B1 (20 mg), B2 (20 mg), B6 (25 

mg), niacin (100 mg), B12 (50 μg), C (500 mg), E (30 mg), and folic acid (0.8 

mg). This supplementation was associated with reductions of 39% in fetal 

deaths, 44% in low birth weight, 39% in preterm delivery before 34 weeks, 

and 43% in small size for gestational age at birth. Although multivitamin 

supplementation did not affect the risk of MTCT overall (RR = 1.04) it was 

associated with reduced transmission in subgroups of women who were 

nutritionally or immunologically compromised (Fawzi, 2002). 

In Zimbabwe, pregnant women were randomized to daily doses of 

vitamin A (10 000 IU) and 11 other vitamins and minerals (at single 

RDA levels) or placebo from 22−35 weeks of gestation until delivery. 

Micronutrient supplementation was associated with increases in birth 

weight of about 100 g in infants born to HIV-positive mothers. The effects 

of the supplement on outcomes such as HIV disease progression and 

transmission were not assessed (H. Friis, personal communication). 

F. ANEMIA, IRON SUPPLEMENTATION, AND HIV 

Anemia, defined as hemoglobin < 110 g/L, affects more than half of all 

pregnant women in resource-limited settings, but is more common and 

often more severe in HIV-infected women than in other women (Meda, 

1999; Ramon, 1999; Van den Broek, 1998). Severe anemia, defined as 

hemoglobin < 70g/L, is associated with many dangerous outcomes for 

mothers and infants, including the risks of premature delivery and low birth 

weight in infants, and maternal mortality (Bothwell, 1981; Schorr, 1994). 

Premature delivery and low birth weight are associated with increased risks 

of MTCT (Ioannidis, 2001; João, 2003; Moore, 1998; Fawzi, 2001). 

For HIV-infected women, anemia is evidently an independent predictor 

of more rapid HIV progression and mortality (Moore, 1998; Moore, 

1999; Zvandasara, 2002) and of increased risk of MTCT (Bobat, 1996; 

St. Louis, 1993) after controlling for other indicators of maternal disease 

progression. Iron stores in tissues, on the other hand, typically measured 

by blood ferritin concentrations, have been associated with increased 

HIV load in pregnant women in some studies (Friis, 2003) but not in all 

(Semba, 2001a). 
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The causes of anemia in HIV infection are complex (Semba, 2001b). In 

resource-limited settings, anemia during HIV infection may result from: 

• cytokine-induced suppression of red blood cell production; 

• the use of cotrimoxazole for OI prophylaxis; 

• the use of some ARVs (e.g. zidovudine) or drugs for AIDSassociated OI treatment (e.g. gancyclovir) which suppress bone 

marrow function and red blood cell synthesis; 

• coincidental issues such as coinfections with malaria and hookworm; 

• poor dietary intake and absorption of iron, folate, vitamin A, 

riboflavin, and vitamin B12. 

Iron-folate supplementation is a standard component of antenatal care 

for the prevention of anemia and the improvement of fetal iron stores 

during pregnancy. Some studies suggest, however, that supplemental 

iron given to individuals with HIV may cause increased iron stores 

in bone marrow and other tissues, oxidative stress, faster HIV disease 

progression, and subsequent increased mortality (Bolaert, 1996; Friis, 

2003). These adverse effects may be more common in individuals with 

haptoglobin 2-2, a specific type of this heme-binding protein (Delanghe, 

1998; Friis, 2003). A recent study in Kenya found no effect on viral load 

of iron supplements (60 mg) taken twice weekly for four months by HIVpositive adults (Olsen, 2004). 

G. NUTRITION AND ARV TREATMENT

Highly active ARV treatment will in almost all adherent patients with 

fully drug sensitive infection result in suppression of viral replication 

and dramatic improvement in clinical, immunological, and nutritional 

status. However, weight loss and wasting may still be observed in some 

patients on ARV treatment (Wanke, 2000) and are associated with reduced 

survival (Tang, 2003). This may be complex and relate to poor adherence 

to therapy, virus resistance, or poor nutrition. 

Lipodystrophy in HIV-infected patients (sometimes referred to as fat 

redistribution, including peripheral lipoatrophy, central fat accumulation, 

or lipomatosis) is common in adults and also has been recently described in 

children taking protease inhibitors (PI), analog reverse-transcriptase inhibitors 

(NRTI), or both, for HIV infection (HIV Lipodystrophy Case Definition Study, 

2003; Temple, 2003). This syndrome was first described in 1998 and is 

characterized by loss of subcutaneous fat from the face, arms, and legs, but 

some patients may have concomitant deposition of excess fat in the neck and 

upper back, causing a double chin and a buffalo hump, respectively, and in 

the trunk (HIV Lipodystrophy Case Definition Study, 2003). 

Most HIV-infected patients with lipodystrophy are otherwise relatively 

healthy, but insulin resistance, hypertriglyceridemia, low serum levels 

of high-density lipoprotein cholesterol, and occasionally hyperglycemia 

may develop. Hepatic steatosis with hyperglycemia has been reported, 

but acanthosis nigricans with lactic acidosis seems extremely rare. 
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Although several hypotheses have been put foreword to account for 

lipodystrophy, the etiology and pathogenesis of this syndrome remain 

ill-defined. There is no internationally agreed case definition for HIVassociated lipodystrophy syndrome, which has led to substantial variations 

in reports of prevalence (20–80%) (Garg, 2004). Epidemiological and 

prospective studies suggest that lipodystrophy may be attributable to 

multiple factors, including the ARV drug that has been used, the stage of 

the HIV disease, and host risk predispositions. Stavudine-based regimens 

have a higher cumulative prevalence of lipoatrophy than other NRTIor tenofovir-based regimens. Combinations based on nelfinavir are 

associated with more rapid fat loss than efavirenz (Temple, 2003). 

Some studies indicate that protease inhibitors impair the differentiation 

of peripheral adipocytes by targeting specific mediators that regulate 

the expression of adipocyte-specific markers. In general, thymidinebased nucleoside analogues have been most associated with lipoatrophy 

and protease inhibitors most associated with metabolic syndrome. HIVassociated lipodystrophy probably involves multiple drug-associated events 

in metabolic pathways and in different tissues, as well as host predispositions 

(such as age, genetics, HIV stage, and inflammatory stage) (Temple, 2003). 

The morphological changes associated with lipodystrophy are disfiguring 

and potentially stigmatizing, and thus can hinder adherence, cause 

discomfort and psychological morbidity, and reduce effectiveness of 

antiretroviral treatment. Furthermore, the frequent associated lipid and 

glucose metabolic abnormalities might increase the risk of cardiovascular 

disease. It is not clear to what extent lipodystrophy will emerge in 

nutritionally challenged groups, or the impact this will have on adherence 

to therapy. To date most studies have been done in industrialized settings 

in nutritionally replete populations. 

Without a full understating of the molecular mechanisms involved, 

management approach should be based on some assumptions about 

probable etiologies and the palliative treatment of specific symptoms. 

Switching some components of antiretroviral treatment (from protease 

inhibitors to non-nucleoside reverse-transcriptase inhibitors or abacavir), 

and use of metformin and recombinant human growth hormone, have 

led to some success with managing the metabolic manifestations and 

local fat accumulation (Temple, 2003). However, lipoatrophy remains 

the most difficult manifestation to manage. Improvement of cosmetic 

appearance with surgical correction and implants for more obvious 

morphological manifestations can be considered. With regards to 

metabolic manifestations, dietary intervention and regular exercises have 

beneficial effects in dyslipidemia in some patients with lipodystrophy 

and should be tried before starting fibrates or statins. It is important to 

note that some statins can interact with antiretrovirals and should be 

avoided. The presence of hyperglycemia may necessitate the use of oral 

hypoglycemic drugs or insulin. 

Research on the metabolic consequences of ARV treatment and 

appropriate strategies for their management is a growing field in 

industrialized countries where HIV-infected adults and children have 
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had access to long-term treatment. However, studies are necessary in 

resource-limited settings where management options and follow-up 

monitoring may be more limited. 

II GENERAL PRINCIPLES

A. NUTRITION ADVICE, COUNSELING, CARE, AND SUPPORT FOR HIVINFECTED WOMEN ARE ESPECIALLY IMPORTANT BECAUSE OF THE

DUAL BURDENS OF HIV AND REPRODUCTION (PREGNANCY AND

BREASTFEEDING) ON NUTRITIONAL VULNERABILITY

Women living in resource-limited settings are at increased risk of poor 

nutrition during pregnancy and lactation. HIV-infected women may 

be at even greater risk because of the effects of HIV on dietary intake, 

the absorption and use of nutrients, and related metabolic processes. 

Moreover, they may be socially and psychologically vulnerable as a 

result of living with HIV. For these reasons they may require enhanced 

follow-up and support so that they can achieve adequate nutrition during 

antenatal and postnatal care. 

B. ALL ANTENATAL AND POSTNATAL WOMEN CAN BENEFIT FROM

NUTRITION ADVICE, COUNSELING, CARE, AND SUPPORT AIMED AT

PREVENTING MALNUTRITION DURING PREGNANCY AND IMPROVING

REPRODUCTIVE HEALTH AND CHILD HEALTH OUTCOMES

Nutrition counseling, care and support begin with an assessment of a 

woman’s specific circumstances, including her nutritional status, her diet, 

and the social and other conditions that could prevent her from achieving 

adequate dietary intake. Nutrition counseling should cover: 

• ways of achieving adequate weight gain during pregnancy; 

• the prevention of anemia; 

• the importance of an adequate diet to support lactation and 

prevent nutritional depletion associated with childbearing (Adair, 

1992; Merchant, 1988). 

C. THE FOCUS OF NUTRITION, ADVICE, COUNSELING, CARE, AND SUPPORT

VARIES WITH THE HEALTH STATUS OF THE CLIENT

For HIV-infected women who are asymptomatic, emphasis should be 

placed on the need to stay healthy by improving eating habits and the 

nutritional quality of the diet, maintaining weight (or gaining adequate 

weight during pregnancy), preserving lean body mass, continuing physical 

activity, and ensuring an understanding of food safety. Some women, 

particularly women who are unable to gain adequate weight during 

pregnancy, are losing weight, or are experiencing acute food insecurity 

at home, may require direct food assistance. Food assistance protocols 

depend on the services and food programs that are available locally. For 

women who are experiencing HIV-related infections and illnesses and/or 
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weight loss, the main objective is to minimize the nutritional consequences 

of the infections by obtaining immediate treatment, maintaining the 

greatest possible food intake during acute infection, increasing food 

intake during the recovery period, and continuing physical activity as 

much as possible so as to preserve lean body mass. For women who have 

advanced disease or persistent HIV-related infections and illnesses the 

main objective is to provide comfort and palliative care, with modification 

of the diet according to the symptoms and with encouragement for eating. 

For women on ARV treatment the focus of nutrition counseling, care, and 

support should be the management of drug and food interactions and 

other side effects of treatment. 

D. WOMEN RECEIVING ARV AND OI TREATMENT SHOULD BE GIVEN

ADVICE AND COUNSELING ON RELATED NUTRITIONAL ISSUES AND

SHOULD BE FOLLOWED UP IN ORDER TO MONITOR AND TREAT ANY

ADVERSE NUTRITIONAL COMPLICATIONS

Treatment advice and counseling on nutrition issues related to ARV 

and OI treatment cover the timing of pill ingestion in relation to meals, 

the minimizing and management of nutrition-related side effects of 

prescribed medications (e.g. nausea and vomiting), and the consequences 

of long-term ARV treatment for body fat distribution and metabolism. 

Nutrition advice and counseling should also cover the food and water 

requirements of some ARV drug regimens, e.g. PI-based regimens. The 

role of diet and exercise in managing body fat distribution and the 

metabolic changes associated with the long-term use of ARV drugs is 

not known. However, women should be made aware that, depending on 

the regimens used, physical changes may occur. Advice should be given 

on how to cope with such changes. Underlying or new conditions that 

require dietary modifications, e.g. diabetes mellitus, should be monitored 

during follow-up care. 

III RECOMMENDATIONS

The following recommendations are based on the evidence previously 

reviewed and, where definitive evidence is lacking, on expert opinion. 

Where the basis for a specific recommendation is expert opinion this is 

indicated in the text. See table 17-1 for Summary of Recommendations.

The recommendations cover: 

• nutrition assessment; 

• nutrition counseling and support; 

• use of micronutrient supplements; 

• management of wasting; 

• nutritional considerations for persons on ARV treatment. 

It will be necessary to review these recommendations regularly and to 

update them as new information becomes available. 
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A. NUTRITION ASSESSMENT

These recommendations are based on expert opinion. 

A baseline nutrition and dietary assessment should be carried out when 

a woman is first seen during pregnancy or postnatal follow-up, regardless 

of her HIV status. The purpose of this assessment is to gather information 

about her current nutritional status and dietary practices and to identify 

risk factors for developing future nutritional complications. 

The baseline nutritional status assessment should include at least the 

measurement of weight and hemoglobin. If possible, additional body 

measurements can be taken, such as height (to allow calculation of BMI = 

kg/m2) and mid-upper arm circumference (to allow a crude estimation of 

muscle wasting). WHO reference tables can be used to classify maternal 

nutritional status on the basis of these measurements (WHO, 1995). Data 

from resource-limited settings indicate that non-pregnant women with 

BMI values below 18.5 are nutritionally vulnerable and that women who 

also have mid-upper arm circumference values below 23.0 cm are at even 

greater nutritional risk (Gartner, 2001; James, 1994). 

The dietary assessment should include information on usual eating 

patterns and intake, appetite and eating problems, and household food 

security. Each woman should receive a baseline physical examination 

in order to identify any conditions requiring treatment which affect 

appetite and the ability to eat or involve altered nutrient absorption. 

All medications taken on a daily basis should be noted so that nutrient 

interactions and/or contraindications can be identified. After the baseline 

assessment, HIV-infected women should return for routine antenatal and 

postnatal care in accordance with the same protocols that are used for the 

general population. 

B. NUTRITION COUNSELING AND SUPPORT

These recommendations are based on existing WHO guidance, the evidence 

review, and the report of a WHO technical consultation (WHO, 2003). 

DIETARY RECOMMENDATIONS

Dietary recommendations for women with HIV are similar to those 

for the general population. The following issues have to be taken into 

consideration (WHO, 2003). 

• Energy requirements are increased by 10% for the maintenance of 

body weight and physical activity in asymptomatic HIV-infected 

adults because of increased resting energy expenditure. 

• During symptomatic HIV and subsequently during AIDS there is 

an increase in energy requirements of about 20% to 30% for the 

maintenance of body weight. 

• Currently available data do not provide sufficient support for an 

increase in protein requirements during HIV infection among adults 
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in general and among pregnant and lactating women in particular. 

High-protein supplements alone do not prevent wasting or an 

increase in muscle mass. 

• The available evidence suggests that HIV-infected individuals may 

require more than 1 RDA1 per day in order to reverse deficiencies 

in several nutrients. The current recommendation for HIVinfected women is therefore to consume a diet that is nutritionally 

adequate rather than to rely on high-dose supplements of vitamins 

and minerals. In areas where there are multiple micronutrient 

deficiencies, however, a daily supplement given to HIV-infected 

pregnant and lactating women may improve both birth outcomes 

and maternal health. 

Healthy women require an additional energy intake of 200 kcal/day 

during pregnancy and of 500 kcal/day during lactation. Protein and most 

vitamin and mineral requirements are also increased (National Academy 

of Sciences, 1989). Nutrient requirements are greater in women with low 

pre-pregnancy weight, inadequate weight gain during pregnancy, and 

poor diet quality and diversity, and in women who engage in physically 

demanding activities with high levels of energy expenditure. 

FOOD SAFETY RECOMMENDATIONS

WHO recommendations on food safety for the general population also 

apply to HIV-infected women and should be part of their counseling and 

support. These recommendations cover the following key areas: 

• keeping hands and food preparation areas clean;

• separating raw foods from cooked foods and the utensils used with them; 

• cooking fresh and reheated foods thoroughly; keeping food at safe 

temperatures; using safe water and raw materials. 

More detailed guidance on these areas is available (WHO, 2001). 

RECOMMENDATIONS FOR THE TREATMENT AND MANAGEMENT OF INFECTIONS

Immediate treatment for all conditions and symptoms affecting health 

and nutrition is an important first response in HIV-related care. Moreover, 

symptom-based nutritional management may help to minimize the 

nutritional consequences of HIV-related illnesses and treatments. 

C. IRON SUPPLEMENTATION

These recommendations are based on existing WHO guidance. 

WHO currently recommends daily iron-folate supplementation (400 μg 

folate and 60 mg iron) during six months of pregnancy in order to prevent 

anemia, and twice daily supplements in order to treat severe anemia 

(hemoglobin < 70 g/L). The available data do not support a change in 

this recommendation for women living with HIV. 

1 Recommended daily allowance for nutrients that are essential for health. Daily intakes below RDA levels may 

be associated with negative health outcomes. 
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D. VITAMIN A SUPPLEMENTATION

Well-designed randomized controlled trials have shown that, in HIV-infected 

women, daily antenatal and postnatal vitamin A supplementation does 

not reduce MTCT and that, in some settings, it may increase the risk of 

HIV transmission. Because of the lack of a beneficial effect of vitamin A 

supplementation and, indeed, a harmful effect in one study, the daily vitamin 

A intake during pregnancy and lactation should not exceed the RDA. 

In areas where vitamin A deficiency is endemic, WHO currently 

recommends a single high dose of vitamin A (200 000 IU) for women 

as soon as possible after delivery and not later than 6 − 8 weeks after 

delivery. Research is in progress to assess further the effect of singledose postpartum vitamin A supplementation in HIV-infected women. 

At present the WHO recommendation for postpartum vitamin A 

supplementation should be followed for HIV-positive women. 

E. MANAGEMENT 0F WASTING

These recommendations are based on expert opinion relating to all 

women. 

• Screen for causes of weight loss, including household food 

insecurity and underlying diseases, especially tuberculosis and 

chronic diarrhoea, and treat as needed. 

• Counsel on increased nutritional needs and appropriate local foods. 

For women who are HIV-infected 

• Refer for consideration of commencement of ARV treatment. 

• Refer for additional care, including programs that can provide 

family food assistance in cases where food insecurity is identified. 

• Advise that physical exercise be taken in order to increase strength 

and muscle mass. 

F. NUTRITIONAL CONSIDERATIONS FOR PERSONS ON ARV TREATMENT

These recommendations are based on WHO ARV treatment guidelines 

(WHO, 2003) and expert opinion. 

• Provide treatment advice on dietary needs or restrictions of specific 

ARV drug regimens (e.g. food and water requirements of some PIbased regimens). 

• Provide health education, information, and advice on managing 

common side-effects, such as diarrhea, nausea, and vomiting. 

• Counsel on dietary modifications as needed in response to the 

metabolic syndrome associated with ARV treatment. 
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Table 17-1: Summary of Recommendations

Recommendation HIV+ 

asymptomatic

HIV+ 

symptomatic

On ARV treatment

Nutrition 

assessment

Yes Yes Yes

Dietary 

recommendations

- Energy intake

- Protein intake

- Micronutrient 

intake

Increase by 10%

No Change

At least 1 RDA or 

daily supplement

Increase by 20–30%

No Change

At least 1 RDA or 

daily supplement

Food safety 

counseling

Yes Yes Yes

Symptom-based 

nutritional advice

No Yes Yes

Iron 

supplementation

As per existing 

WHO guidelines

As per existing 

WHO guidelines

As per existing 

WHO guidelines

Vitamin A 

supplementation

As per existing 

WHO guidelines; 

daily intake not to 

exceed 1 RDA.

As per existing 

WHO guidelines; 

daily intake not to 

exceed 1 RDA.

As per existing 

WHO guidelines; 

daily intake not to 

exceed 1 RDA.

Management of 

wasting

No Screen for causes 

and treat as 

needed; counsel 

on increased food 

consumption; refer 

for ARV treatment 

and family food 

assistance as needed

Screen for causes 

and treat as needed; 

counsel on increased 

food consumption; 

refer for review 

of ARV treatment 

as it may indicate 

treatment failure/

need to switch to 

second line therapy; 

refer for family food 

assistance as needed

Nutritional 

considerations for 

persons on ARV 

treatment

No No Provide advice on 

dietary needs and 

restrictions; counsel 

on management 

of nausea and 

related side effects; 

manage toxicity 

and treatment 

failure as per WHO 

guidelines.
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The following tables, compiled by the editor, are provided

as a supplement to the information in this chapter.

Table 17-A: Baseline Nutrition Assessment

History: Usual weight

Weight history since HIV infection

Appetite 

Food intolerances or allergies

Medications and side effects

Use of alternative/complementary therapies (e.g., acupuncture, herbal 

medicines)

Use of nutritional supplements

Use of alcohol, narcotics, stimulants, illicit drugs

Presence/history of opportunistic illnesses or symptoms which may affect 

nutritional status

Other significant medical conditions 

Mental health status/cognitive function, depression, dementia

Social, cultural, financial issues affecting food availability or preparation

Amount of regular exercise

History of eating disorder

Dietary history and intake (e.g., 24 hr recall, 3 day food record; food 

frequency) 

Examination: Height

Weight

Body mass index (BMI kg/m2)

General examination: assess overall nutritional state, look for physical findings 

(e.g., oral thrush, mouth ulcers) which may affect intake

Triceps skinfold and mid-upper arm circumference (used to estimate body 

muscle and fat stores)

Waist, hip, neck circumference (used to document changes/trends in body fat 

distribution)

Laboratory: Hemoglobin

CD4 count/HIV-RNA level

Serum iron, total iron binding capacity (TIBC)

Serum albumin, prealbumin

Renal function

Hepatic enzymes

Fasting lipid profile

Fasting glucose

Magnesium, folate

Micronutrient levels, if indicated (e.g., vitamin B 12, vitamin A, zinc, selenium)

Source: Adapted from Knox TA, Zafonte-Sanders M, Fields-Gardner C, Moen K, Johansen D, Paton 

N. Assessment of nutritional status, body composition, and human immunodeficiency virusassociated morphologic changes. Clin Infect Dis 2003; 36:S63-S68.
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Table 17-B: Screening Tools for Nutritional Risk Assessment – 

The following tools have been adopted and adapted 

for use in the screening of HIV/AIDS patients: 

Scored Patient-Generated Subjective Global Assessment

Revised Subjective Global Assessment for HIV-Infected Individuals

Quick Nutrition Screen

Nutrition Referral Criteria for Adults with HIV/AIDS

Public Awareness Checklist of the Nutrition Screening Initiative

HIV/AIDS Medical Nutrition Therapy Protocols

Source: Nerad J, Romeyn M, Silverman E et al. General nutrition management in patients infected with 

human immunodeficiency virus. Clin Infect Dis 2003;36:S52-62.

(These tools are described in more detail in this review)

Table 17-C: Common Reasons for Problems Eating

Loss of appetite

Feeling full too fast

Oral thrush or mouth sores

Tooth or gum disease

Difficult or painful swallowing

Nausea/vomiting

Bloating/gas/heartburn

Diarrhea/constipation

Dry mouth

Changes in taste or smell

Fatigue

Depression

Dehydration

Source: Adapted from Health Care and HIV: Nutritional Guide for Providers and Clients. Rockville MD: 

HIV/AIDS Bureau, Health Resources and Services Administration; 2002. (Available in English and Spanish 

at http://www.aidsetc.org under Educational and Training Resources).
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Table 17-D: Common Causes of Weight Loss and Wasting

Inadequate intake: Lack of appetite

Depression 

Nausea

Medication side effects

Pain 

Changes in taste or smell

Advanced HIV/AIDS

Difficult or painful chewing or 

swallowing (oral/esophageal thrush, 

mouth sores)

Loss of nutritents Malabsorption

Vomiting/diarrhea

Increased caloric needs HIV-related infections

Advanced HIV/AIDS

Source: Adapted from Health Care and HIV: Nutritional Guide for Providers and Clients. Rockville MD: 

HIV/AIDS Bureau, Health Resources and Services Administration; 2002. (Available in English and Spanish 

at http://www.aidsetc.org under Educational and Training Resources.)

Table 17-E: Nutritional Needs by Stage of HIV Infection

Asymptomatic 

HIV

- Education about nutritional needs

- Balanced intake of macro-nutrients (calories, protein, carbohydrates, fat) and 

micronutrients (vitamins and minerals)

- Education and monitoring for changes in body fat distribution/other metabolic 

changes and management, if indicated

- Education about safe food handling and preparation

- Education about potential food-drug interactions

- Identification/correction of misinformation

Symptomatic 

HIV/AIDS

- Address symptoms/side effects of treatment affecting nutrition

- Prevention of weight loss/wasting

- Monitoring for and management of metabolic changes; addressing changes in 

body fat distribution

- Evaluate for possible food-drug interactions

End-stage 

HIV/AIDS

- Address symptoms/side effects of treatment affecting nutrition

- Maintain hydration

Source: Adapted from Health Care and HIV: Nutritional Guide for Providers and Clients. Rockville MD: 

HIV/AIDS Bureau, Health Resources and Services Administration; 2002. (Available in English and Spanish 

at http://www.aidsetc.org under Educational and Training Resources.)
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Table 17-F: Indications for Nutrition Counseling and/or Referral

Physical evidence of nutritional problem:

- Significant and/or rapid weight loss (>5% unintentional weight loss over 4 weeks or >10%

over 4-6 months)

- Obesity

Nutritional concerns with HIV-related therapies

- Evidence of body fat redistribution

- Possible food/nutrient-drug interactions

- Metabolic abnormalities* (glucose intolerance, elevated lipids)

Symptoms likely to affect nutritional status

- Painful or difficult chewing or swallowing 

- Changes in taste or smell

- Chronic nausea/vomiting

- Chronic diarrhea

- Chronic pain

HIV-related illnesses**

- Chronic oral/esophageal candidiasis

- Oral/esophageal ulcers

- Dental or gingival disease

- Central nervous system disease (especially if associated with decrease in functional or cognitive 

capacity)

- Other active opportunistic illness

Drug and/or alcohol abuse

Depression

Pregnancy

Other medical or psychiatric co-morbidities**

- Diabetes mellitus

- End-stage renal disease

- Hepatic disease

- Cancer

- Other medical conditions which may affect nutritional status or needs: (hypertension, osteoporosis/

osteopenia*, significant psychiatric illness, other intercurrent illness)

Harmful nutritional practices

- Evidence for hypervitaminosis/excessive supplement intake

- Inappropriate use of diet pills, laxatives, other over-the-counter medications

- Eating disorder

Food allergies/intolerance

Enteral or parenteral feedings

Significant food insecurity

Sedentary lifestyle or excessive exercise

* Glucose intolerance and abnormalities in serum lipids may not necessarily be associated with HIV 

therapies; similarly osteoporosis/osteopenia has recently been linked to use of antiretroviral therapy

** Some HIV-related diseases may be seen independently from HIV and some medical co-morbidities may 

be directly or indirectly related to HIV 

The urgency of counseling or referral need is based on the specific problem(s), their severity, and overall 

nutritional and medical status of the woman.

Source: Jean R. Anderson, MD
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Abstract TuPeC4782. 
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A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

INDEX

TOPICS

12-step programs, 392–393

A

abbreviations, 471

abnormal uterine bleeding, 177–181

access to care, 43

acute illness, 14

adherence

among adolescents, 414, 415t

counseling during pregnancy, 304

and depression, 361

improvement, 172, 173–174t

measures of, 171–172

predictors, 168–170

special populations, 169–171

adolescents

and adherence, 171

care requirements, 408–416

epidemiology, 405–408

interview menmonic, 410t

pregnancy counseling, 242

Adult Aids Clinical Trial Group, 548

advance care planning

counseling during pregnancy, 304

at end of life, 440

adverse effects, 169

African American patients, 339–341

AIDS

incidence in US, 1

progression likelihood, 103

AIDS Alliance for Children, Youth & Families, 548

AIDS-defining illness, 120t

AIDS dementia complex

incidence, 362–363

management, 146

AIDS Education and Training Centers, 548

AIDS Education Global Information System, 548

AIDS Info NYC, 549

AIDS Risk Reduction model, 55

AIDS Treatment Data Network, 549

AIDSInfo, 549

AIDSMeds.com, 549

alcohol, 395

alcohol addiction, 390

alcohol intoxication, 384

allergies, topical, 213–214

altered status, 160

amenorrhea, 177–181

American Academy of HIV Medicine, 549

American College of Obstetricians and 

Gynecologists, 550

American Foundation for AIDS Research, 550

American Psychological Association

Office on AIDS, 550

amniocentesis, 272

anal squamous intraepithelial lesions, 183

anemia

management, 151

during pregnancy, 293, 581–582

anovulation, 179

antioxidants, 578–579

Antiretroviral Pregnancy Registry, 299, 470

anxiety

medications, 367t

misperceptions, 359t

aphthous ulcers

genital, image, 238

genital, management, 195

oral, image, 239

ARV therapy. see also individual drugs and 

classes in drugs index

adverse events, 114–118

adverse fetal effects, 289–291

adverse maternal effects, 292–293

adverse pregnancy effects, 291–292

agents, 111–114

indications, 118t

initial regimens, 121–124t

interactions with psychotropics, 368–369t

intrapartum, 306–308

in neonates, 310–311

nutritional considerations, 582–584, 588

nutritional counseling, 585

perinatal HIV transmission, 263

for postexposure prophylaxis, 463t

pregnancy, pharmacokinetics during, 276, 

277–283t

pregnancy, use during, 272, 273–275t

principles, 110

principles, during pregnancy, 294–295, 

296–297t, 298–299

regimen change after treatment failure, 126t

in substance abusers, 395–396

treatment guidelines, 118–131

Asia, 21–22

Association of Nurses in AIDS Care, 550

assumptions, 336t

atypical glandular cells, 187

avascular necrosis, 117

B

B-2 microgloblin, 16t

bacterial vaginosis

management, 196–197

during pregnancy, 252

INDEX OF TOPICS

See page 608 for Index of Drugs

Note: page numbers followed by a “t” indicate tables; page numbers in bold indicate images
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Index of Topics

bad news, 438

barrier contraception

communicating about, 84

and HIV transmission, 77

Bartholin’s abscess, 212

behavioral interventions

models, 55–56

substance withdrawal, 392–393

trial results, 57–60, 58t

Behçet’s syndrome, 194

bereavement. see grief

beta-carotene, 580–581

Bethesda system, 186–187

biophysical profile, 270

bipolar mood disorder

medications, 367t

misperceptions, 359t

vs. depression, 364t

The Body, 550

body fluids, 454t

The Body Pro, 551

bone disorders, 117

boys, 564

Brazil, 571–574

breast cancer, 216

breast-feeding, 264–265, 308

breast lumps, 215–216

C

CAGE survey, 383

Canadian AIDS Treatment Information 

Exchange, 551

candidiasis

images, 232

management, 141, 197–200, 199t

during pregnancy, 251–252

CD4 count

associated complications, 134t

baseline evaluation, 99–100

perinatal transmission, 262

in pregnancy, 250

testing, during pregnancy, 294

CD4 subset analysis, 16t

CDC Division of HIV/AIDS Prevention, 551

CDC National Prevention Information 

Network, 551

cervical cancer

in Brazil, 572

in HIV patients, 183–184

prevalence in Zambia, 568

cervical caps, 245t

cervical dysplasia, 182

cervical ectopy, 5t, 6

cervical intrepithelial neoplasia, 234

cervical lesions, 188–189

cervicitis, 235

cervix development, 407

cesarean delivery, 264, 304–306

chancres, 233

chancroid

image, 236

management, 193

chemistry panel, 102

childbearing imperative, 566

children, and adherence, 171

chlamydia

image, 236

management, 202

chorioamnionitis, 263

chorionic villus sampling, 272

chronic care model, 44–45

circumcision, 6

clinical failure, 125

clinical services pyramid, 41

cocaine addiction, 390–391

cocaine use, 395

coccidiomycosis, 301

colorectal cancer, 219

colposcopy

gential warts, 210

recommendations, 186t

comfort, at end of life, 441

communication

across culture, 334–336, 336–337t

breaking bad news, 438

at end of life, 443–444

essentials of, 35–36

and risk assessment, 48

risk reduction counseling, 66

communicationg about, 336t

Community Program for Clinical Research 

on AIDS, 551

complementary therapies

communicating about, 336t

at end of life, 441

concomitant illness, 572

condoms

counseling during pregnancy, 303

practices in Brazil, 572

practices in Zambia, 569

as prevention tool, 70–76

use influences, 76t, 411t

condoms (female), 245t

condoms (male)

characteristics, 245t

HIV transmission, 248–249

condyloma latum, 237

condylomata acuminata, 234

confidentiality

and adolescents, 408

essentials of, 37

consultations, 302–303

context, in communication, 335
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Index of Drugs Index of Topics

INDEX

TOPICS

contraception

access in Brazil, 573

communicating about, 84

counseling during pregnancy, 303

effect on transmission, 5t

HIV transmission, 6–7

and HIV transmission, 77–78

methods, 243–246t

motivations, 242

prevention effectiveness, 79t

contraction stress testing, 270

core values

African American culture, 339–340

Hispanic culture, 338

cough, 157–158

counseling

about testing, 51, 52t

of adolescents, 409

after occupational exposure, 462

essentials of, 43

influence on prevention, 54–55

initial visit, 94

in practice, 60–65

during pregnancy, 303–304

pregnant patients, 241–242

counselors, 570

Critical Path AIDS Project, 551

Crohn’s disease, 194

cryptococcosis, 301

Cryptococcus neoformans

management, 141–142

prophylaxis, 138t

cultural competence

at end of life, 441

risk reduction counseling, 66

treating HIV patients, 38

cyryptosporidiosis, 145

cytomegalovirus

baseline evaluation, 104

management, 143–144, 194

during pregnancy, 255–256, 299

prophylaxis, 138t

D

death, 444. see also end-of-life issues

delirium

misperceptions, 359t

vs. depression, 364t

dementia, 364t

depression

access to services, 360–361

identification, 358–360

medications, 367t

detoxification, 391

developing countries, 20–21

diaphragms, 245t

diarrhea, 154–156

disclosure, 40

domestic violence

in India, 565

misperceptions, 359t

prevalence in Zambia, 569

and risk reduction counseling, 67

donovanosis, 194

drug dependence, 385t

drug holidays, 131

drug interactions, 293

drug seeking, 433

dry mouth, 435

dysmenorrhea, 206

dysplasia

anal, 183

cervical, 182

dyspnea

management, 436

treatment algorithm, 157–158

E

eating problems, 591t

ectopic pregnancy, 207

education opportunities, 566

embarrassment, 48

emotional milestones, 348, 349–350t

end-of-life issues, 441–447

endometriosis, 206, 207

envelope sequences, 7

episiotomy, 264

evaluation, essentials of, 37–43

eyes, 95

F

Famciclovir Registry, 254

family-centered care, 42–43

fat maldistribution syndrome, 216

fatigue, 424–425

fears, 351

female condoms, 72–75

fertility, 249–250

fetal monitoring

during labor and delivery, 304

perinatal HIV transmission, 264

fetal surveillance, 269–271

fetus, 289–291

fever, 153, 157–158

fibroadenomas, 216

fibrocystitis, 216

fibroid tumors

bleeding cause, 179

management, 206, 207

follow-up visits, 42

forceps use, 264

Forum for African Women Educationists, 570

fungal infection, 213
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Index of Topics

G

Gay Men’s Health Crisis Women and Family 

Services, 552

gender inequities, 571–572

gender roles, 332–333

genital masses, 212

genital tract infections, 179

genital warts, 210–211

glucose-6-phosphate dehydrogenase deficiency, 

105–106

goal setting

at end of life, 439–440

risk reduction counseling, 62, 64t, 65

gonorrhea

management, 201–202

screening recommendations, 219

granuloma inguinale, 194

grief

process, 445–447

vs. depression, 364t

Growth House, 552

H

HAART

availability in Brazil, 571

availability in developing countries, 20

as cervical dysplasia therapy, 189

headache, 159

Health Belief model, 55, 56t

health care access, 567

health care system, 340

health literacy, 336t

healthcare workers

grief among, 447

seropositivity, 465

Healthy Intiatives for Youth, 552

hepatic steatosis, 115

hepatitis A, 138t

hepatitis A vaccine, 302

hepatitis B

management, 150

during pregnancy, 257–258

prophylaxis, 137t

hepatitis B vaccine, 301

hepatitis C

among substance abusers, 380–381

baseline evaluation, 105

management, 150–151

during pregnancy, 258–259

hepatotoxicity

in pregnancy, 292

presentation, 115–116

HEPP Report, 552 

herpes (genital), 68 

herpes simplex

lesions, image, 237, 238

management, 142–143, 190–192

during pregnancy, 253–254

hiccups, 435

hidradenitis suppurativa, 195

Hispanic patients, 337–339

Histoplasma capsulatum, 138t

histoplasmosis, 301

history-taking

initial evaluation, 92–95

and risk assessment, 49

HIV

classification, 10t

common symptoms, 422t

diagnostic influences, 14–15

mutations and resistance, 128–129t

natural history, under HAART, 19–20

natural history, untreated, 13–19, 101

progression factors, 18–19t

staging, 8–9, 11–12t, 12–13

transmission factors, 4–8

transmission modes, 3–4

viral detection methods, 98–99

HIV/AIDS

epidemic impact, 21–23

nutritional needs by stage, 592t

regional statistics, 2t

HIV-associated dementia, 362–363

HIV encephalopathy, 146

HIV infection

acute treatment, 132–133

diagnosis in neonates, 310

Pediatric Classification System, 312t

perinatal transmission, 259–265

HIV Medication Guide, 553

HIV Medicine Association, 553

HIV testing

enzyme-linked immunosorbent assay (ELISA), 97

nucleic acid amplification, 98

rapid tests, 99

adolescents, 409

HIVandHepatitis, 552

HIVdent, 553

HIVInSite, 553

home-based care, 570

homeless patients, 171

hope, 439–440

hospice, 419–420

HRSA HIV/AIDS Bureau, 553

HRSA Information Center, 554

human papillomavirus, 181–182

hydrosalpinx, 208

hygiene, 570

hyperglycemia

during pregnancy, 293

presentation, 116

hyperlipidemia, 117

I

immune globulins, 302

immune response, 262
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Index of Drugs Index of Topics

INDEX

TOPICS

immunizations, 301–302

immunologic failure, 125

imunizations, 413t

incarcerated patients, 170

incontinence (urinary), 209

India

HIV prevalence, 563–564

treatment programs, 564–567

inflammation, 6

influenza, 137t

influenza vaccine, 301

injection drug use, 379

insomnia

management, 433–434

medications, 367t

intensification, 127

International Association of Physicians in 

AIDS Care, 554

International Center for Research on Women, 554

International HIV/AIDS Alliance, 554

interstitial cystitis, 209

intrapartum management, 304–308

intrauterine devices

characteristics, 245t

HIV transmission, 78, 248

iron

supplementation during pregnancy, 581–582

supplementation recommendations, 587

itching, 213–214

J

Johns Hopkins University AIDS Service, 555

K

Kaiser Family Foundation, 555

Kaposi’s sarcoma, 147

L

laboratory tests, 16t

lactic acidosis

in pregnancy, 292–293

presentation, 115

lice, 214–215

life review, 443–444

limited resource settings, 40

lipid profile

baseline evaluation, 106

screening recommendations, 219

lipodystrophy

management, 582–583

presentation, 116

listening, 62

long-term survivors, 17

lungs, 96

lymph nodes, 95

lymphocyte count, 16t

lymphogranuloma venereum, 194

lymphoma, 147–148

M

major depressive disorder

diagnosis, 363–364, 364t

medications, 367t

misperceptions, 359t

malaria, 568

malnutrition, 578

mammograms

recommendations, 215

screening recommendations, 219

marriage, 565–566

mastitis, 216

medical orders, 441, 442t

medication toxicity, 124–125

Medscape, 555

membrane rupture, 263

meningitis, 141–142

menopause, 217–218

menstruation

abnormal bleeding, 177–181

communicating about, 84

effect on transmission, 5t

HIV transmission, 6

mental health services, 360–361

mental illness

in adolescents, 416

and subatance abuse, 381–382

microsporidiosis, 145

milestones, emotional, 348, 349–350t

minerals, 578

mitochondrial toxicity, 290–291

mittelschmerz, 206

molluscum contagiosum, 212

mother-to-child transmission. see perinatal 

transmission

motherhood, imperative, 565

multiple loss, 445–446

multiservice programs, 357–358

mutation

perinatal transmission, 260–261

and therapy adherence, 167

Mycobacterium avium complex

management, 144

during pregnancy, 299, 300t

prophylaxis, 137t

Mycobacterium tuberculosis, 136t

N

National AIDS Hotline, 555

National Association of People with AIDS, 555

National Association on AIDS Over Fifty, 556

National Clearinghouse for Alcohol and Drug 

Information, 556
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Index of Topics

National Clearinghouse on Child Abuse/Neglect 

Information, 556

National Clinicians’ Post-Exposure Prophylaxis 

Hotline, 556

National Library of Medicine, 557

National Minority AIDS Council, 557

National Minority AIDS Education and Training 

Center, 557

National Network to End Domestic Violence, 557

needle aspiration, 215

neonatal infection. see also perinatal transmission

care protocol, 310–311, 313

congenital syphilis, 255

cytomegalovirus, 256

hepatitis B, 258

hepatitis C, 259

herpes simplex, 253

toxoplasmosis, 257

neoplasia

abdominal, management, 208

management, 195

neopterin, 16t

nervous system, 96

neurologic deficits, 160

neuropathic pain, 426, 427t

neuropathy

management, 145

treatment algorithm, 161

New Mexico AIDS Infonet, 557

New York Online Access to Health, 557

NIAID Database for Anti-HIV Compounds, 558

nonstress testing, 270

nutrition counseling

assessment, 586, 590t

indications for, 593t

principles, 584–585

recommendations, 586–587

risk assessment, 591t

summary, 589t

O

occupational exposure

counseling, 462

evaluation, 460

magnitude of risk, 456

prevention, 458–459

risk factors, 456–457

testing, 461

odynophagia, 162

opiate addiction, 389–390

opiate intoxication, 384

opiate use, 395

opportunistic diseases

under HAART, 151–152

nutritional counseling, 585

overview, 134–135

during pregnancy, 299–301

prophylaxis, 135–136, 136–139t

oropharynx, 95

osteonecrosis, 117

osteoporosis, 219

ovarian cysts, 206, 207

ovarian torsion, 206

P

p24 antigen, 16t

pain

intensity scales, 423t

scope of, 425–426

pain relief

barriers, 427, 428t

principles, 427–430

WHO ladder, 429t

Pap smears

abnormal, management of, 188t

anal, technique, 186

baseline evaluation, 106

recommendations, 218

use, 184–187, 185t

papillomavirus

image, 234

during pregnancy, 254

Partnership for Caring, 558

patient education, 172

patient evaluation

follow-up visits, 42

initial visit, 41–42

intake flow sheet, 108–109

Pediatric AIDS Clinical Trials Group, 558

Pediatric Classification System, 312t

pelvic examination, 96

pelvic inflammatory disease

image, 236

IUD use, 248

management, 204–206

pelvic mass, 207–208

pelvic pain, 203–206

percutaneous umbilical blood sampling, 272

perimenopause, 179

perinatal transmission

in Brazil, 573–574

factors, 259–265

prevention regimen comparison, 296–297t

prevention strategies, 265

trials review, 276, 284–288t

peripheral neuropathy, 145

pH (vaginal), 5t, 6

pharmacokinetics

ARV/psychotropics interactions, 368–369t

during pregnancy, 276, 277–283t

in pregnancy, 470

physical examination, 95–96

placental abruption, 263

pneumococcal vaccine, 301

Pneumocystis carinii pneumonia

as diagnostic marker, 135
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Index of Drugs Index of Topics

INDEX

TOPICS

management, 140–141

neonatal prophylaxis, 313

during pregnancy, 299, 300t

prophylaxis, 136t

polio vaccine, 302

polymerase chain reaction (PCR), 98

Population Council, 558

post-exposure prophylaxis, 81–82

postexposure prophylaxis

mucous membrane exposure, 455t

percutaneous exposure, 454t

site management, 459

postpartum care, 308–309

poverty

access to care, 331–332

among adolescents, 408

in Brazil, 573

and seeking care, 352–354

treatment barrier in Zambia, 568–569

pregnancy

adverse outcomes, 252t

adverse outcomes, ARV therapy, 291–292

among adolescents, 406

antepartum history, 266

ARV pharmacokinetics, 276, 277–283t

ARV therapy during, 294–295, 296–297t, 

298–299

drug categories, 472

drug pharmacokinetics, 470

HIV natural history, 250–251

laboratory evaluation, 267–269t

nutritional status during, 579

and postexposure prophylaxis, 464

substance abuse, 394–395

testing, 249

vs. amenorrhea, 179

prenatal care

in Brazil, 573–574

nutritional counseling, 584

preterm delivery, 263

prevention messages, 82–85

prevention models, 411–412

priorities, 336t

prisons, substance abusers in, 397–398

prognosis

in depressed patients, 361–362

determining, 436–437

progressive multifocal leukoencephalopathy, 148

Project Inform, 559

provider-patient relationship

and adherence, 169, 174t

cautions for providers, 371–372

communication across culture, 334–336, 

336–337t

providers, 38

pruritus, 435

psychosis

medications, 367t

misperceptions, 359t

psychosocial issues

among adolescents, 415–416

at diagnosis, 334

intervention suggestions, 342–343

puberty, 414

pyosalpinx, 208

Q

quality of life, 420–421

R

rash

as adverse treatment effect, 117–118

in pregnancy, 292

relapse, 393–394

relationships, 348, 351–352

renal stones, 209

reproductive cancer, 179

Reproductive Health Online, 559

resistance

causes, 20

intrapartum nevirapine, 307

perinatal transmission, 260–261

and postexposure prophylaxis, 464

and pregnancy, 293

testing for, 127–131

in treatment-naive patients, 294

resource-poor settings, 59–60

respect, 36

retinitis, 143–144

retinol, 580

risk assessment, 48–49, 49t

risk reduction, 60–65

RNA level

perinatal transmission, 260

in pregnancy, 250

test characteristics, 16t

in tissue, 14

RNA testing, 104t

S

San Francisco AIDS Foundation, 559

scabies, 214

seizures, 160

self-help programs, 392–393

sensitivity, 36–37

serology, 97–98

set points, 14

sex differences, 17

sex information, 564–565

sex workers, 566–567

sexual abuse

misperceptions, 359t

as risk factor, 354–356

sexual activity

among adolescents, 405–406
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Index of Topics

perceived risks, 1

perinatal HIV transmission, 263

as risk factor, 48

sexual mores

adolescents, 407

in Brazil, 572

in Zambia, 569–570

sexually transmitted infections

among adolescents, 406

baseline evaluation, 106

behavioral interventions, 57, 59

communicating about, 83–84

condom use, 71

perinatal HIV transmission, 262

prevalence in Zambia, 568

as risk factor, 67–70

screening recommendations, 218–219

shedding, 580

skin, 96

slim disease. see wasting syndrome

smoking, 263

Social Cognitive Theory, 55, 56t

special populations, 39

spermicides, 78

spirituality

cultural aspects, 340

at end of life, 444

and HIV care, 39

States of Change theory, 55–56, 56t

steatosis, 292–293

sterilization, 78, 246t

stigma

access to care, 332–333

and palliative care, 420

in Zambia, 570

Streptococcus pneumoniae, 137t

substance abuse

abnormal menstruation, 180

among women, 381–382

comorbidities, 380–381

counseling during pregnancy, 303

epidemiology, 378

harm reduction, 387

HIV risk factor, 379–380

identification, 382–386

medications, 367t

in pregnancy, 394–395

prevalence, 377

relapse potential, 393–394

as risk factor, 356–357

social perceptions, 382

treatment, 387–393

substance abusers

adolescents, 416

pain management, 432–433

suicidal ideation, 359t

suicide risk, 370

support systems

access to care, 333

counseling during pregnancy, 303

essentials of, 39–40

symptoms

individual management, 423

quantification, 423

treatment at end of life, 442–443

syncytium-inducing phenotype, 16t

syphilis

baseline evaluation, 102

chancres, image, 233

condyloma image, 237

management, 192–193t

during pregnancy, 254–255

screening recommendations, 218

T

team approach, 37–38

testing

abnormal bleeding protocol, 180–181

availability, 50

baseline evaluation, 99–106

benefits of, 50

evaluation during pregnancy, 267–269t

initial diagnosis, 97–99

for pregnancy, 249

rapid results, 53–54

resistance mutations, 130–131t

tetanus-diphtheria vaccine, 301

Theory of Reasoned Action, 55, 56t

tobacco, 394

toxoplasmosis

baseline evaluation, 104

management, 142

during pregnancy, 256–257, 299, 300t

prophylaxis, 137t

transmission, 564

treatment failure

regimen change, 126t

and regimen selection, 125–127

treatment interruptions, 131

Trevor Project Helpline, 559

trichomonas, 231, 235

trichomoniasis, 200–201

truth, telling, 438

tubal ligation, 78

tuberculosis

baseline evaluation, 105

genital, management, 194

management, 144–145

prevalence in Zambia, 567

urinary, management, 209

in Zambia, 567

U

ulcers (genital), 190–196

ulcers (aphthous)

genital, image, 238
A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

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Index of Drugs Index of Topics

INDEX

TOPICS

genital, management, 195

oral, image, 239

ultrasound, 271–272

umbilical artery Doppler velocimetry, 270

UNAIDS Joint UN Programme on AIDS, 560

universal precautions

described, 458

during labor and delivery, 304

urinary retention, 209

urinary tract infection, 209

urine testing, 386

uterine bleeding, 177–181

V

vaginal cleansing, 308

vaginal discharge, 196–203

vaginal infection, 68

vaginitis, 231

varicella, 104

varicella zoster, 137t

viral load

baseline evaluation, 102

communicating about, 83

perinatal transmission, 260

sex differences, 17–18

and therapy adherence, 168

untreated HIV, 14

viral replication, 4–6

viral shedding, 247

virginity, 564–565

virologic failure, 125

vitamin A

perinatal HIV transmission, 262

supplementation benefits, 580–581

supplementation recommendations, 588

vitamins, 578–579

vulval intraepithelial neoplasia, 233

W

Warmline: The National HIV Telephone 

Consultation Service, 560

warts (genital), 210–211

wasting

causes, 592t

management, 146–147

nutritional recomendations, 588

during pregnancy, 579

The Well, 560

WhatUDo, 560

withdrawal (substance), 367t

Women, Children, and HIV, 561

women, devaluation of

in India, 564

and risk reduction counseling, 66

in Zambia, 569–570

Women Alive, 560

Women Organized to Respond to Life-threatening 

Disease, 561

women who have sex with women, 75

World Health Organization HIV/AIDS Department, 

561

X

xerostomia, 435

Y

YR Gaitonde Center for AIDS Research and 

Education, 565–567

Z

Zambia, 564, 567
608 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau

5-fluorouracil, 189

A

abacavir

characteristics, 473

clearance insufficiency, 538

interactions, 502

pharmacokinetics during pregnancy, 278t

during pregnancy, 273t

ABC. see abacavir

acetaminophen, 534

acyclovir

characteristics, 491

herpes neonatal transmission, 253

Agenerase. see amprenivir

albendazole, 490

Albenza. see albendazole

alprazolam, 369t

alternative/complementary therapies, 133

aminoglycosides, 497

amitriptyline, 368t

amphotericin B, 486

amprenavir

adverse fetal effects, 290

characteristics, 480

clearance insufficiency, 540

food interaction, 534

interactions, 522–525

oral contraceptive interaction, 247

pharmacokinetics during pregnancy, 282t

during pregnancy, 274t

Ancobon. see flucytosine

Antabuse. see disulfiram

antiretroviral drugs

effects buried in cocktail, 469

methadone interactions, 396–397t

APV. see amprenivir

aripiprazole, 369t

atazanavir

adverse fetal effects, 290

characteristics, 480

clearance insufficiency, 541

food interaction, 534

interactions, 529–532

norethindrone interaction, 247

pharmacokinetics during pregnancy, 282t

during pregnancy, 274t

atovaquone, 485

ATV. see atazanavir

azithromycin, 482

azole antifungals, 198–200

AZT. see zidovudine

aztreonam, 497

B

Bactrim. see trimethoprim-sulfamethoxazole

benzodiazepines, 391

Biaxin. see clarithromycin

buprenorphine, 390

bupropion, 368t

C

carbamazepine

ARV interaction, 369t

side effects, 366

caspofungin, 494

cephalosporins, 496

chaparral, 536

chloramphenicol, 497

chlorazepate, 369t

chlordiazepoxide, 369t

chlorhexidine, 308

cidofovir, 493

citalopram, 368t

clarithromycin, 483

clindamycin, 496

clomipramine, 368t

clonazepam, 369t

clotrimazole, 487

codeine, 432t

comfrey, 536

Cotrim. see trimethoprim-sulfamethoxazole

Crixivan. see indinavir

Cytovene. see ganciclovir

D

dapsone, 491

Daraprim. see pyrimethamine

ddC. see zalcitabine

ddI. see didanosine

delavirdine

characteristics, 477

clearance insufficiency, 539

interactions, 505–508

pharmacokinetics during pregnancy, 280t

during pregnancy, 274t

depo-medroxyprogesterone acetate, 244t

desipramine, 368t

diazepam, 369t

didanosine

characteristics, 475

clearance insufficiency, 537

INDEX OF DRUGS

See page 599 for Index of Topics

A GUIDE TO THE CLINICAL CARE OF WOMEN WITH HIV - 2005 EDITION

Note: page numbers followed by a “t” indicate tables; page numbers in bold indicate images
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Index of Topics Index of Drugs

INDEX

DRUGS

food interaction, 534

interactions, 499–500

pharmacokinetics during pregnancy, 278t

during pregnancy, 273t

dideoxycytidine. see zalcitabine

diet teas, 536

Diflucan. see fluconazole

disulfiram, 390

DLV. see delavirdine

DMPA. see depo-medroxyprogesterone acetate

doxepin, 368t

Droxia. see hydroxyurea

d4T. see stavudine

E

efavirenz

adverse fetal effects, 289–290

characteristics, 476

clearance insufficiency, 539

food interaction, 534

interactions, 508–510

pharmacokinetics during pregnancy, 279t

during pregnancy, 274t

EFV. see efavirenz

emtracitabine

characteristics, 475

clearance insufficiency, 538

interactions, 502

pharmacokinetics during pregnancy, 278t

during pregnancy, 273t

Emtriva. see emtracitabine

enfuvirtide

characteristics, 481

clearance insufficiency, 541

pharmacokinetics during pregnancy, 283t

during pregnancy, 275t

ephedra, 535

Epivir. see lamivudine

erythromycin, 496

erythropoietin, 149t

escitalopram, 368t

estazolam, 369t

ethambutol, 485

ethinyl estradiol, 247

F

famciclovir

characteristics, 491

herpes neonatal transmission, 253–254

Famvir. see famciclovir

fluconazole, 487

flucytosine, 486

fluoroquinolones, 497

fluoxetine, 368t

flurazepam, 369t

fluvoxamine, 368t

food interactions, 534

Fortovase. see saquinavir

fosamprenivir

characteristics, 479

clearance insufficiency, 541

interactions, 525–526 (see also amprenivir, 

interactions)

pharmacokinetics during pregnancy, 282t

during pregnancy, 274t

fosAPV. see fosamprenivir

foscarnet, 493

Foscavir. see foscarnet

FTC. see emtracitabine

FTV. see saquinavir

Fungizone. see amphotericin B

fuseon, 533

fusion inhibitors, 114

Fuzeon. see enfuvirtide

G

ganciclovir, 492

germander, 536

H

haloperidol, 368t

Hivid. ¶zalcitabine

hormone replacement therapy, 217–218

Hydrea. see hydroxyurea

hydrocodone, 432t

hydromorphone, 432t

hydroxyurea

adverse fetal effects, 290

characteristics, 485

I

IDV. see indinavir

imipenem, 497

imipramine, 368t

Indian tobacco, 536

indinavir

adverse fetal effects, 290

characteristics, 479

clearance insufficiency, 539

food interaction, 534

interactions, 510–513

pharmacokinetics during pregnancy, 281t

during pregnancy, 274t

INH. see isoniazid

interferon, 494

Intron. see interferon

INV. see saquinavir

Invirase. see saquinavir

isoniazid, 484

itraconazole

characteristics, 487

food interaction, 534
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Index of Drugs

K

Kaletra, 274t, 282t. see lopinavir

L

l-a-acetyl-methadol (LAAM), 389

lamivudine

characteristics, 475

clearance insufficiency, 538

interactions, 501–502

perinatal transmission prevention, 296t

pharmacokinetics during pregnancy, 277t

during pregnancy, 273t

lamotrigine, 369t

levonorgestrel, 246t

levorphanol, 432t

Lexiva. see fosamprenivir

lithium, 366

lobelia, 536

lopinavir

characteristics, 478

clearance insufficiency, 540

clearance insufficiency, plus ritonavir, 540

interactions, 526–529

pharmacokinetics during pregnancy, 282t

during pregnancy, 274t

lorazepam, 369t

Lunelle, 243t

M

Ma huang, 535

magnolia, 536

Mepron. see atovaquone

methadone

dosage equivalence, 432t

interactions with antiretroviral drugs, 

396–397t

methenamine, 497

methergine, 534

metronidazole, 496

metropenem, 497

microbicides, 79–80

midazolam, 369t

mirtazepine, 368t

morphine, 432t

Myambutol. see ethambutol

Mycobutin. see rifabutin

N

narcotic analgesics, 534

nefazodone, 368t

nelfinavir

characteristics, 479

clearance insufficiency, 539

interactions, 519–521

pharmacokinetics during pregnancy, 280t

during pregnancy, 275t

nevirapine

characteristics, 477

clearance insufficiency, 539

hepatotoxicity, 115–116

interactions, 503–505

intrapartum management, 307

for perinatal transmission, 260

perinatal transmission prevention, 297t

pharmacokinetics during pregnancy, 279t

during pregnancy, 274t

NFV. see nelfinavir

niacin, 535

nitrofurantoin, 497

nonnucleoside analogue reverse transcriptase 

inhibitors

characteristics, 112, 113t

pros and cons, 122t

nonoxynol-9, 78

nonsteroidal anti-inflmmatory drugs (NSAIDs), 534

norethindrone, 247

Norplant, 244t

nortriptyline, 368t

Norvir. see ritonavir

nucleoside analogue reverse transcriptase 

inhibitors

characteristics, 111, 112t

pros and cons, 123t

Nuva Ring, 243t

NVP. see nevirapine

Nydrazid. see isoniazid

nystatin, 486

O

olanzapine, 368t

opiate antagonists, 390

opioids

dosage equivalence, 431, 432t

side effects, 430–431, 431t

oral contraceptives

characteristics, 243t

interactions, 247

oxazepam, 369t

oxcarbazepine

ARV interaction, 369t

side effects, 366

oxycodone, 432t

oxymorphone, 432t

P

paroxetine, 368t

peg-interferon, 494

Peg-Intron. see peg-interferon

Pegasys. see peg-interferon

penicillins

safety profile, 496

syphilis during pregnancy, 255

pentamidine, aerosolized, 489
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Index of Topics Index of Drugs

INDEX

DRUGS

pentamidine, intravenous, 490

perphenazine, 368t

primaquine, 490

progestin contraceptives, 243–244t

protease inhibitors. see also individual drugs

characteristics, 113–114t

pros and cons, 123t

psychotropics, 365–366

pyrazinamide, 483

pyrimethamine, 488

Q

quetiapine, 369t

R

Rebetrol. see ribavirin

Rescriptor. see delavirdine

Retrovir. see zidovudine

Reyataz. see atazanavir

ribavirin

characteristics, 493

as teratogen, 259

rifabutin, 484

Rifadin. see rifampin

rifampin, 484

risperidone, 369t

ritodrine, 534

ritonavir

characteristics, 478

clearance insufficiency, 540

clearance insufficiency, plus lopinavir, 540

food interaction, 534

interactions, 516–519

interactions, plus tipranavir, 532

pharmacokinetics during pregnancy, 282t

during pregnancy, 274t, 275t

Roferon. see interferon

RTV. see ritonavir

S

saquinavir

characteristics, 478

clearance insufficiency, 540

interactions, 513–516

pharmacokinetics during pregnancy, 281t

during pregnancy, 275t

selenium, 535

Septra. see trimethoprim-sulfamethoxazole

sertraline, 368t

spermicides

characteristics, 245t

HIV transmission, 248

Sporanox. see itraconazole

SQV. see saquinavir

St. John’s wort, 535

stavudine

characteristics, 474

clearance insufficiency, 537

interactions, 501

pharmacokinetics during pregnancy, 278t

during pregnancy, 273t

Stephania, 536

sulfadiazine, 489

Sulfatrim. see trimethoprim-sulfamethoxazole

Sustiva. see efavirenz

T

T-20. see enfuvirtide

3TC. see lamivudine

TDF. see tenofovir

temazepam, 369t

tenofovir

adverse fetal effects, 290

characteristics, 476

clearance insufficiency, 538

interactions, 502–503

pharmacokinetics during pregnancy, 278t

during pregnancy, 273t

terbutaline, 534

tetracyclines, 496

thalidomide, 495

Thalomid. see thalidomide

thioridazine, 368t

tipranavir/ritonavir, 532

TMP-SMX. see trimethoprim-sulfamethoxazole

trazodone, 368t

triazolam, 369t

trimethoprim-sulfamethoxazole

characteristics, 482

PCP management, 140

L-tryptophan, 536

Tubizid. see isoniazid

V

vaccines, against HIV, 80–81

valacyclovir, 491

Valcyte. see valganciclovir

valganciclovir

characteristics, 492

food interaction, 534

valprioc acid, 366

Valtrex. see valacyclovir

vancomycin, 497

venlafaxine, 368t

Vfend. see voriconazole

Videx. see didanosine

Viracept. see nelfinavir

Viramune. see nevirapine

Viread. see tenofovir

Vistide. see cidofovir
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Index of Drugs

vitamin A, 535

vitamin B3. see niacin

vitamin B6, 535

voriconazole, 488

W

white willow bark, 536

wormwood, 536

Z

zalcitabine

characteristics, 476

clearance insufficiency, 537

interactions, 500–501

pharmacokinetics during pregnancy, 279t

during pregnancy, 273t

ZDV. see zidovudine

Zerit. see stavudine

Ziagen. see abacavir

zidovudine

adverse fetal effects, 289

anemia during pregnancy, 293

characteristics, 473

clearance insufficiency, 537

food interaction, 534

interactions, 498

intrapartum use, 307

neonatal prophylaxis, 310–311

perinatal transmission prophylaxis, 294–295, 

296–297t

pharmacokinetics during pregnancy, 277t

during pregnancy, 273t

ziprasidone, 369t

Zithromax. see azithromycin

zolpidem, 369t

Zovirax. see acyclovir