Clinical trial NCT01815580
Conditions: HIV
Keywords: HIV Treatment as Prevention Seek, Test, Treat, Retain Strategies
Sponsor: Fred Hutchinson Cancer Center
Start date: 2013-07-01; Completion date: 2021-06-30
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will recruit men and transgender women with acute or recent HIV infection. It wil look at how HIV medicines (ART) when given very early after HIV infection affect the amount of HIV in the blood, semen and rectal secretions. In addition, Investigators will be using modeling studies to look at whether or not this kind of HIV treatment can decrease the risk that a man will infect a person he has sex with and to find out how failure to take medications will impact spreading the virus to other people.

In this study, one group will be randomized (like a coin toss) to start ART immediately (just at the time of the enrollment visit) and the other group will wait until week 24 of the study to start ART. Both groups will be followed for a total of 48 weeks and will continue to receive ART from local sources after the study is over.

Detailed description:
This is three-step study. Step 1 will screen men who have sex with men (MSM) and transgender women who are unaware of their HIV status and 1) report high risk behaviors for acquiring HIV-1 infection or 2) who have symptoms of acute retroviral syndrome or 3) who have a sexual partner with newly-diagnosed acute or recent HIV infection. HIV testing will be conducted for several thousand MSM and transgender women from study opening until July 2015. In Step 2, high risk HIV-1 uninfected MSM and transgender women with high risk for acquiring HIV will be tested at regular intervals for incident HIV-1 (using tests for HIV p24 and/or HIV RNA). (During this period, men will receive standard HIV prevention interventions.) In Step 3, individuals with acute or recent HIV-1 infection will be enrolled in a 48-week randomized, open-label study of the effects of immediate vs. deferred ART on the decay dynamics of HIV viral load in plasma, semen and rectal secretions. (ART will be provided prior to 24 weeks for any participant in the deferred ART arm who meets initiation criteria.) All participants will be followed for 48 weeks after which they will continue ART from other sources.

Arms: arm 1: Daily Atripla or Stribild will be provided to these patients for the duration of the study beginning at enrollment. arm 2: Daily Atripla or Stribild will be provided to these patients for the duration of the study beginning at 24 weeks.
Interventions: intervention 1: Atripla or Stribild
Intervention descriptions: intervention 1: Antiretroviral therapy

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
HIV Testing and Treatment to Prevent Onward HIV 
Transmission among MSM and Transgender Women in 
Lima, Peru 
NCT number: 
NCT01815580 
Date of the 
Document: 
July 10, 2019 
 


• 
Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
RECI) JUN 2 6 2019 
HIV Testing and Treatment to Prevent Onward HIV Transmission 
among MSM and Transgender Women in Lima, Peru 
Project "4SABES?" 
Sponsored by: 
National Institute on Drug Abuse (NIDA) 
U. S. National Institutes of Health (NIH), 
Protocol Chair and Principal Investigator 
Ann Duerr, M.D., Ph.D., M.P.H. 
Fred Hutchinson Cancer Research Center 
Seattle, WA, United States 
Protocol Co-Chair 
Javier Lama, M.D., M.P.H. 
Asociacion Civil lmpacta Salud y Educacion 
Lima, Peru 
January 4, 2016 
(Amendment 2) 
FHCRC IRB Approval 
JUL 10 2019 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
TABLE OF CONTENTS 
LIST OF ACRONYMS  
7 
1  PROTOCOL TEAM AND SITES  
7 
1.1  PROTOCOL TEAM ROSTER  
7 
1.1.1  Fred Hutchinson Cancer Research Center  
 7 
1.1.2  Asociacion Civil Impacta Salud y Educacion  
 7 
1.1.3  Epicentro (EPICENTRO)  
8 
1.1.4  Via Libre (VIA LIBRE)  
 9 
1.1.5  University of Connecticut  
 10 
1.1.6  University of California Los Angeles  
 10 
1.2  NATIONAL INSTITUTE ON DRUG ABUSE, US NATIONAL INSTITUTES OF HEALTH 11 
1.3 CLINICAL LABORATORIES  
 11 
1.4 RESEARCH FACILITIES  
 11 
1.5  INSTITUTIONAL REVIEW BOARDS  
12 
1.6 MEDICAL DIRECTOR (ON-SITE PHYSICIAN RESPONSIBLE FOR MEDICAL 
DECISION-MAKING)  
12 
2 SUMMARY  
13 
3 BACKGROUND  
17 
3.1  INTRODUCTION [1]  
 17 
3.2 RATIONALE  
17 
3.3 FEASIBILITY  
 19 
3.3.1  Testing Coverage and Frequency  
 19 
3.3.2  Time from HIV Diagnosis to Initiation of Antiretroviral Therapy  
20 
3.3.3  Extent of Reduction in Infectivity with Antiretroviral Therapy and Durability of Viral Load 
Suppression  
20 
3.4 RISKS  
21 
3.4.1  Drug Resistance  
21 
3.4.2  Increased Sexual Risk Behaviors  
 21 
3.4.3  Ethical Issues  
22 
3.4.4  Mathematical Models  
22 
3.4.5  Conclusion  
 23 
3.5 ACUTE HIV INFECTION [110]  
 24 
3.5.1  The HIV-1 Transmission Event  
24 
3.5.2  Detection of HIV Infection  
 28 
3.5.3  Public Health Consequences of Acute HIV-1 Infection  
 28 
3.6  TREATMENT OF ACUTE AND RECENT HIV INFECTION [163]  
 30 
3.6.1  Treatment for Acute HIV Infection  
 30 
3.6.2  Treatment for Recent but Non-acute HIV Infection or Infection of Undetermined 
Duration  
 31 
3.6.3  Treatment Regimen for Acute or Recent HIV Infection  
 31 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
4  STUDY DESIGN  
31 
4.1  OVERALL STUDY DESIGN  
31 
4.2  CRITERIA FOR OFFERING TO INITIATE TREATMENT IN STEP 3  
32 
4.3 MANAGEMENT OF RESISTANCE  
32 
4.4 MANAGEMENT OF SUBJECTS WITH VIROLOGIC FAILURE OR PREMATURE 
TREATMENT DISCONTINUATION  
32 
4.5 MANAGEMENT OF SUBJECTS WHO DO NOT REACH 48 WEEKS IN THE ASSIGNED 
STUDY ARM  
33 
5  SELECTION AND ENROLLMENT OF SUBJECTS  
33 
5.1 STEP 1  
33 
5.1.1  Description of Population  
 33 
5.1.2  Inclusion Criteria  
 34 
5.1.3  Exclusion Criteria  
 35 
5.2  STEP 2  
35 
5.2.1  Inclusion Criterion  
 35 
5.2.2  Exclusion Criterion  
 35 
5.3  STEP 3  
35 
5.3.1  Description of Population  
 35 
5.3.2  Inclusion Criteria  
 35 
5.3.3  Exclusion Criteria  
 36 
6  STUDY TREATMENT  
37 
6.1  STEP 1  
37 
6.2  STEP 2  
37 
6.3  STEP 3  
38 
6.3.1  Regimens, Administration, and Duration  
 38 
6.3.1.1 Regimen  
38 
6.3.1.2 Administration  
 38 
6.3.1.3 Duration  
 38 
6.3.2  Product Formulation and Preparation  
 39 
6.3.3  Product Supply  
39 
6.3.4  Pharmacy Facilities  
 39 
6.3.5  Drug Inventory  
40 
6.3.6  Drug Dispensing  
40 
6.3.7  Concomitant Medications  
40 
6.3.7.1 Precautionary Medications  
40 
6.3.7.2 Prohibited Medications  
40 
6.3.7.3 Options for Medication Substitutions Due to Intolerance/Toxicity  
 42 
6.3.7.4 Options for Medication Substitutions for Virologic Failure  
42 
6.3.8 Adherence Assessment  
42 
7  STUDY PROCEDURES  
43 
7.1  STUDY DIAGRAM  
43 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
7.2 STEP 1  
43 
7.2.1  Clinical Procedures  
43 
7.2.2  Laboratory Evaluations  
45 
7.3  STEP 2  
45 
7.3.1  Regular Follow-Up Visit  
45 
7.3.2  Interim Contacts and Visits  
46 
7.3.3  Laboratory Evaluations  
46 
7.4 STEP 3  
47 
7.4.1  Timing of Visits  
47 
7.4.2  Timing of Evaluations  
49 
7.4.2.1 Screening Evaluations  
 Error! Bookmark not defined. 
7.4.2.2 Entry Evaluations (Week 0 Visit)  
 49 
7.4.2.3 On-Study Evaluations  
49 
7.4.2.4 Evaluations for Subjects Randomized to Arm 1 Who Do Not Start Study Treatment   49 
7.4.2.5 Evaluations for Subjects Who Start Treatment without Meeting Eligibility Criteria   49 
7.4.2.6 Premature Treatment Discontinuation Evaluations  
49 
7.4.2.7 Premature Study Discontinuation Evaluations  
49 
7.4.3  Definitions of Evaluations and Special Instructions  
 50 
7.4.3.1 Medical History  
 50 
7.4.3.2 Medication History  
 50 
7.4.3.3 Concomitant Medications  
 50 
7.4.3.4 Study Treatment Modifications  
 50 
7.4.3.5 Clinical Assessments  
50 
7.4.3.6 Laboratory Evaluations  
 51 
7.4.3.7 Immunologic Studies  
 52 
7.4.3.8 Virologic Studies  
 52 
7.4.3.9 Genotype  
53 
7.4.3.10 Semen and Rectal Secretions  
 53 
7.4.3.11 Stored Plasma  
53 
7.4.3.12 Questionnaires  
54 
8  WARNINGS AND PRECAUTIONS  
54 
8.1  LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS  
54 
8.2  PATIENTS WITH HIV AND HBV COINFECTION  
55 
8.3 PSYCHIATRIC SYMPTOMS  
55 
8.4 NERVOUS SYSTEM SYMPTOMS  
56 
8.5 RENAL IMPAIRMENT  
56 
8.6 SKIN RASH  
57 
8.7 LIVER ENZYMES  
57 
8.8 BONE EFFECTS  
58 
8.9 CONVULSIONS  
58 
8.10 FAT REDISTRIBUTION  
58 
8.11 IMMUNE RECONSTITUTION SYNDROME  
59 
8.12 CO-ADMINISTRATION WITH RELATED DRUGS  
59 
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9  TOXICITY MANAGEMENT  
59 
9.1  PROCEDURES FOR MODIFICATIONS FOR SPECIFIC SYMPTOMS  
60 
9.1.1  Rash  
60 
9.1.1.1 Grade 1 or 2 Rash  
60 
9.1.1.2 Grade 3 Rash  
60 
9.1.1.3 Grade 4 Rash  
60 
9.1.2  Nausea and Vomiting  
60 
9.1.2.1 Grade 1 or 2  
60 
9.1.2.2 Grade > 3  
60 
9.1.3  Diarrhea  
 61 
9.1.3.1 Grade 1 or 2  
61 
9.1.3.2 Grade 3 Diarrhea  
61 
9.1.4  Symptomatic Hyperlactatemia  
61 
9.2 TOXICITY MANAGEMENT FOR LABORATORY ABNORMALITIES  
62 
9.2.1  Increases in Values for Liver Function Tests  
62 
9.2.1.1 Asymptomatic  
62 
9.2.1.2 Symptomatic or Grade 4  
62 
9.2.2 Lipase  
62 
9.2.2.1 Grade 2 Asymptomatic  
62 
9.2.2.2 Symptomatic Pancreatitis (Regardless of Lipase Grade)  
63 
9.2.3  Trig lycerides/Cholesterol  
 63 
9.2.4 Hyperglycemia  
63 
9.2.5  Renal Insufficiency  
63 
9.2.6 Hypophosphatemia  
64 
9.3  FOR ALL OTHER GRADE 3 OR 4 TOXICITY  
64 
10 CRITERIA FOR DISCONTINUATION  
65 
10.1 PERMANENT TREATMENT DISCONTINUATION  
65 
10.2 PREMATURE STUDY DISCONTINUATION  
65 
11 STATISTICAL CONSIDERATIONS  
65 
11.1 OBJECTIVES  
65 
11.1.1 Primary Objectives  
 65 
11.1.2 Secondary Objectives  
 66 
11.2 ENDPOINTS  
66 
11.2.1 Primary Endpoints  
 66 
11.2.2 Secondary Endpoints  
 66 
11.3 SAMPLE SIZE AND ACCRUAL  
67 
11.4 MONITORING  
67 
11.5 ANALYSES  
67 
11.5.1 Viral Phylogenetic Analysis  
 67 
11.5.2 Effect of HIV Seek and Test Strategies and Impact of Substance Use on Clustered 
Transmission-  
 68 
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11.5.3 The Impact of Immediate and Early (6 Months after Diagnosis) Antiretroviral Therapy 
on the Decay Dynamics of HIV Viral Load  
69 
11.5.4 Modeling the Expected Intervention Impact at Population Level  
69 
12 DATA COLLECTION, MONITORING AND ADVERSE EXPERIENCE REPORTING  70 
12.1 DEFINITION OF AN ADVERSE EVENT  
70 
12.2 GOVERNANCE  
71 
12.3 CLINICAL ADVERSE EVENTS  
71 
12.4 LABORATORY ADVERSE EVENTS  
0  71 
12.5 DISCONTINUATION OF STUDY AGENT DUE TO AN ADVERSE EVENT  71 
12.6 SOCIAL ADVERSE EVENTS  
71 
12.7 ASSESSMENT OF RELATIONSHIP TO STUDY AGENT  
72 
12.8 FOLLOW-UP ON ADVERSE EVENTS  
72 
12.9 REVIEW OF ADVERSE EVENTS  
72 
12.10EXPEDITED ADVERSE EVENTS REPORTING TO NATIONAL INSTITUTE ON DRUG 
ABUSE  
72 
12.10.1 Study Agents for Expedited Reporting to National Institute on Drug Abuse Program 
Official  
 73 
12.10.2 Grading Severity of Events  
73 
12.10.3 Adverse Events Reporting Periods  
 73 
12.11CONTACT FOR QUESTIONS ABOUT EXPEDITED ADVERSE EVENTS REPORTING 73 
12.11.1 Assuring Reporting of Suspension of the Clinical Trial  
 73 
13 HUMAN SUBJECTS PROTECTION  
73 
13.1 INSTITUTIONAL REVIEW BOARDS AND ETHICS COMMITTEE REVIEW  73 
13.2 SUBJECT CONFIDENTIALITY  
74 
13.3 STUDY DISCONTINUATION  
74 
14 PUBLICATIONS OF RESEARCH FINDINGS  
75 
15 REFERENCES  
76 
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1  PROTOCOL TEAM AND SITES 
1.1  PROTOCOL TEAM ROSTER 
1.1.1 Fred Hutchinson Cancer Research Center 
Ann Duerr, MD, PhD, MPH 
Principal Investigator and Protocol Chair 
Director (Scientific Affairs), HIV Vaccine Trials Network Member, Vaccine and Infectious 
Disease & Public Health Science Divisions, Fred Hutchinson Cancer Research Center 
Affiliate Professor, Departments of Global Health and Epidemiology, University of Washington, 
Seattle, WA 
Phone: +1-206-667-7938 
e-mail address: aduerrfhcrc.orq 
Carolyn Bain, MPH 
Project Coordinator 
Duerr Clinical Trials: TNT Peru Project 
Fred Hutchinson Cancer Research Center, Seattle, WA 
Phone: +1-206-667-7858 
e-mail address: cebaina,fhcrc.orq 
1.1.2 Asociacion Civil Impacta Salud y Educacion 
Javier R. Lama, MD, MPH 
Protocol Co-Chair, Site Principal Investigator IMPACTA San Miguel 
Director, HIV Prevention Studies, IMPACTA PERU Clinical Trials Unit 
Asociacion Civil Impacta Salud y Educacion 
Affiliated Assistant Professor, University of Washington Department of Global Health 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru 
Phone: +51-1-206-7800 Ext 407 
e-mail address: jrlamaimpactaperu.orq 
Pedro Gonzales, MD, MAS 
Co-Investigator 
IMPACTA PERU Clinical Trials Unit. 
Asociacion Civil Impacta Salud y Educacion 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru 
Phone: +51-1-206-7800 Ext 402 
e-mail address: pgonzalesimpactaperu.orq 
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Jorge Sanchez, MD, MPH 
Co-Investigator, Site Principal Investigator IMPACTA Barranco 
Principal Investigator, IMPACTA PERU Clinical Trials Unit 
Director of Research and President, Asociacion Civil lmpacta Salud y Educacion 
Affiliated Associate Professor, University of Washington Department of Global Health 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru 
Phone: +51-1-206-7800 Ext 401 
e-mail address: jsanchezimpactaperu.orq 
Martin Llancare, PharmD 
Protocol Pharmacist 
Unidad de Ensayos Clinicos IMPACTA PERU 
Asociacion Civil Impacta Salud y Educaci6n, Lima, Peru 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peril 
Phone: +(51-1) 206-7800 Ext. 316 
Email address: mllancare@impactaperu.org  
Jessica Rios, CNM. 
Study Coordinator 
IMPACTA PERU Clinical Trials Unit 
Asociacion Civil Impacta Salud y Educacion 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru. 
Phone: +51-1-206-7800 Ext 210 
e-mail address: iriosimpactaperu.orq 
1.1.3 Epicentro (EPICENTRO) 
Mey Leon, MD 
Study Medical Director, Site Principal Investigator EPICENTRO 
Jr. Jaen No. 250-A, Lima 4, PERU 
Phone: +51-1 247-4148 
e-mail address: mleonimpactaperu.orq 
Hugo Sanchez, BSc 
Co-Investigator 
Executive Director, Epicentro, Lima, Peru 
Jr. Jaen No. 250-A. Lima 4, Peru 
Phone: +51-1-247-4158 
e-mail address: hsanchezebicentro.oro.pe  
Gino Calvo, CNM 
Study Counselor 
Counseling Area Director, Epicentro, Lima, Peru 
Jr. Jaen No. 250-A. Lima 4, Peru 
Phone: +51-1-247-4158 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
e-mail address: bcalvoepicentro.orp.be  
1.1.4 Via Libre (VIA LIBRE) 
Jorge Alave, MD 
Site Principal Investigator Via Libre 
Jr. Paraguay No. 478, Lima 1, Peru 
Phone: +51-1-203-9900 
e-mail address: jorge.alave.r@upch.edu  
Robinson Cabello, MD 
Co-Investigator 
Director of Research and Executive Director, Via Libre, Lima, Peru 
Jr. Paraguay No. 478, Lima 1, Peru 
Phone: +51-1-203-9900 Ext.110 
e-mail address: rcabellovialibre.oro.pe  
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
Carlos Medrano, RN 
Study Nurse 
Health Center Director, Epicentro, Lima, Peru 
Jr. Jaen No. 250-A. Lima 4, Peru 
Phone: +51-1-247-4158 
e-mail address: cmedrano@ebicentro.orq.pe  
Joel Roque, MD 
Clinical Coordinator, Study Physician 
Via Libre, Lima, Peru 
Jr. Paraguay No. 478, Lima 1, Peru 
Phone: +51-1-203-9900 Ext.143 
e-mail address: jroquevialibre.oro.be  
1.1.5 University of Connecticut 
K Rivet Amico, PhD 
Research Associate Professor 
School of Public Health 
1415 Washington Heigths 
Ann Arbor, Michigan 48109-2029 
Correo electronico: ramico@umich.edu  
1.1.6 University of California Los Angeles 
Jesse L. Clark, MD, MSc 
Assistant Professor of Medicine 
Division of Infectious Diseases 
Program in Global Health 
David Geffen School of Medicine at University of California Los Angeles 
Office (US): +1-310-601-7798 
Office (Peru): +51-1-446-1845 
e-mail address: jIclarkmednet.ucla.edu  
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1.2 NATIONAL INSTITUTE ON DRUG ABUSE, US NATIONAL INSTITUTES OF HEALTH 
William Aklin, Ph.D. 
Project Officer 
National Institute on Drug Abuse 
6001 Executive Boulevard, 
Bethesda, MD 20892 
e-mail address: aklinwm4mail.nih.ciov 
Redonna Chandler, Ph.D. 
Director, Health Services Branch 
National Institute on Drug Abuse 
6001 Executive Boulevard, 
Bethesda, MD 20892 
e-mail address: rchandlenida.nih.gov  
1.3 CLINICAL LABORATORIES 
IMPACTA PERU Clinical Trials Unit Central Laboratory 
Carmela Ganoza, MD 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru 
Phone: +51-1-206-7800 Ext 306 
e-mail address: cganozaimpactaperu.orq 
University of Washington Molecular Genetics Laboratory 
Dr. James Mullins 
Rosen Building, Box 358070 
1959 NE Pacific St. 
Seattle WA 98195 
Phone: +1-206-732-6163 
e-mail address: imullins4uw.edu 
 
University of Washington Virology Laboratory 
Dr. Robert Coombs 
Box 359690 
University of Washington 
Harborview Medical Center/ Virology 
325 9th Ave., 
Seattle, WA 98104-2420 
Phone: +1-206-598-3706 
e-mail address: bcoombs4u.washington.edu  
1.4 RESEARCH FACILITIES 
VIA LIBRE 
Jr. Paraguay No. 478. Lima 1, Peru 
Phone: +51-1-203-9900 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
EPICENTRO 
Jr. Jaen No. 250-A. Lima 4, Peru 
Phone: +51-1-247-4158 
IMPACTA San Miguel Clinical Research Site 
Asociacion Civil Impacta Salud y Educacion 
Jr. Putumayo No. 177. Lima 32, Peru 
Phone: +51-1-562-1600 
IMPACTA Barranco Clinical Research Site 
Asociacion Civil Impacta Salud y Educacion 
Av. Almirante Miguel Grau No. 1010. Lima 4, Peru 
Phone: +51-1-206-7800 
1.5 INSTITUTIONAL REVIEW BOARDS 
Fred Hutchinson Cancer Research Center Institutional Review Board 
Institutional Review Office 
PO Box 19024, J6-110 
Seattle, WA 98109-1024 
Tel: +1-206-667-5900 
e-mail address: jsutherl@fhcrc.orq 
Comite Institucional de Bioetica 
Via Libre 
Jr. Paraguay No. 478. Lima 1, Peru 
Phone: +51-1-203-9900 
e-mail address: opshiayialibre.oro.pe  
Comite Institucional de Bioetica 
Asociacion Civil Impacta Salud y Educacion 
Phone: +51-1-206-7800 Ext 318 
e-mail address: eticaimpactaperu.orq 
1.6 MEDICAL DIRECTOR (ON-SITE PHYSICIAN RESPONSIBLE FOR MEDICAL 
DECISION-MAKING) 
Mey Leon, MD 
Study Medical Director 
Jr. Jaen No. 250-A, Lima 4, PERU 
Phone: +51-1 247-4148 
e-mail address: mleon@impactaperu.orq 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
2 SUMMARY 
Protocol Title: HIV Testing and Treatment to Prevent Onward HIV Transmission Among MSM 
and Transgender Women in Lima, Peru. 
Short Protocol Title: Test and treat early HIV among MSM and Transgender Women in Lima, 
Peru 
Study Name: "6SABES?" 
Sites: EPICENTRO; VIA LIBRE; and IMPACTA San Miguel and Barranco Clinical Research 
Sites at IMPACTA PERU Clinical Trials Unit in Lima, Peru. 
Planned Starting Date: July 2012 
Planned Ending Date: July 2016 
Study Rationale: -This research will expand upon Seek-Test-Treat-Retain (STTR) strategies 
based on HIV testing and treatment of individuals with acute and recent HIV infection. The 
overall objective is to improve the efficacy of STTR strategies by specifically intervening to 
reduce the impact of viral load on HIV transmission among individuals with acute and recent 
HIV infection. This research will be conducted in Lima, Peru. We will investigate the 
population-level impact of drug and alcohol use on HIV transmission by examining the role of 
men who have sex with men (MSM) and transgender women who report substance use (mostly 
alcohol) in transmission clusters identified through partner tracing and phylogenetic analysis. 
This analysis will investigate the feasibility of incorporating tests for acute HIV infection into 
routine HIV testing and will model the contribution of men with acute and recent HIV infection to 
transmission among networked populations, such as MSM and transgender women. 
The overall aim of this project is to model STTR strategies that specifically intervene to reduce 
HIV transmission through reductions in HIV-1 viral load and sexual risk behavior among 
individuals with early HIV infection, including both acute and recent infections. 
Primary Objectives 
1. To estimate the impact of immediate and deferred (24 weeks after study enrollment) 
antiretroviral therapy (ART) on the decay dynamics of HIV viral load in plasma, semen 
and rectal secretions from individuals with early HIV infection; 
2. To investigate the impact of drug and alcohol use on HIV transmission by examining and 
modeling the role of MSM and transgender women with substance abuse disorders in 
transmission clusters identified through partner tracing and phylogenetic analysis. 
Secondary Objectives 
1. To determine HIV incidence and associated risk factors among high-risk HIV-1 
uninfected MSM and transgender women who participate in a program of frequent 
routine HIV testing. 
2. To attempt to identify transmission clusters in phylogenetic trees constructed using early 
viral specimens from study participants with acute or recent HIV infection. 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
3. To determine other characteristics (sexual risk behavior, partner characteristics, use of 
entertainment venues, and reason for HIV testing) in MSM and transgender women 
within clusters compared to those outside of clusters. 
4. To assess the feasibility and acceptability of re-contacting HIV-negative individuals with 
evidence of acute infection (HIV-1 RNA positive) for further HIV testing and linkage to 
care. 
5. To evaluate the frequency of HIV testing among recent sexual partners of participants 
diagnosed with early HIV-1 infection, comparing strategies such as partner tracing and 
notification, and general and targeted community outreach. 
6. To evaluate retention in care, including adherence to ART and study procedures, among 
individuals with early HIV-1 infection receiving immediate and deferred ART. 
Primary endpoints 
1. To quantify HIV viral load in plasma, semen and rectal secretions in individuals with 
early HIV infection in immediate versus deferred treatment groups. 
2. To identify transmission clusters through phylogenetic analysis among participants with 
early HIV infection receiving immediate and deferred ART; Construction of models to 
assess the potential population impact of a seek-test-treat-retain strategy. 
Secondary endpoints 
1. To identify risk factors associated with incident HIV-1 infection. 
2. To identify sequence clusters using phylogenetic analysis among participants with early 
HIV infection. 
3. To compare sexual risk behavior, partner characteristics, entertainment venue 
attendance, and method of referral in MSM and transgender women within clusters to 
those outside of clusters. 
4. To determine the proportion of individuals with evidence of acute infection (HIV-1 RNA-
positive) who are successfully contacted for confirmatory HIV testing and are then linked 
to care. 
5. To determine the proportion of newly identified HIV-positive men willing to name at least 
one recent sexual partner, and the proportion of named partners subsequently contacted 
and tested. 
6. To determine the proportion of men retained in care, including adherence to ART and 
study procedures, among individuals with early HIV-1 infection receiving immediate and 
deferred ART. 
Design: This is three-step trial. In Step 1, we will screen MSM and transgender women, 
unaware of their HIV status and with evidence of high risk for acquiring HIV-1 infection, 
including risky sexual behavior, a partner of a newly-diagnosed person with acute or recent HIV 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
infection or with symptoms of acute retroviral syndrome. We anticipate testing a approximately 
2400 MSM and transgender women until July 2015. In Step 2 high risk HIV-1 uninfected MSM 
with high risk sexual behavior will be tested at variable times (during which they will receive 
standard HIV prevention education) for incident HIV-1. Roughly, we anticipate re-testing 
approximately 800 MSM and transgender women per month until July 2015. In Step 3, 
individuals with acute and recent HIV-1 infection detected at Step 1 or 2; or individuals who 
have been diagnosed with HIV in any health clinic or laboratory authorized by the Ministry of 
Health, and that have had a documented negative result in the past three months, will be 
enrolled in a 48-week randomized, open label clinical trial of the effects on the decay dynamics 
of HIV viral load in plasma, semen and rectal secretions of immediate vs. deferred (by 24 
weeks) ART, unless ART initiation criteria are met earlier. We expect approximately 200-250 
MSM and transgender women (roughly 100-125 individuals with acute and 100-125 with recent 
HIV-1 infection). 
Those participants, who have started their participation in the study before the approval of 
Amendment Letter #1 in this study protocol, will continue their participation as originally 
programmed. 
Once the Amendment Letter #1 is approved for this study protocol, the participants who are 
eligible for Step 3 will be given treatment the following way: 1) those people diagnosed with 
acute HIV infection will be offered immediate ART (just at time of the enrollment visit or during 
the next 48 to 72 hours) for the duration of 48 weeks. 2) The people who are diagnosed with 
recent HIV infection will be randomized to start immediate ART or defer ART initiation until 24 
weeks after HIV diagnosis, all of them followed for 48 weeks after which they will continue ART 
from other sources. 
Intervention: This is a study of timing of antiretroviral therapy(ART) initiation. This study will not 
compare one ART medication to another .The ART medications that will be used can be taken 
as one pill a day so that number of pills taken each day is not a burden for people in the study. 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (STRIBILDO) or 
emtricitabine/tenofovir disoproxil fumarate/efavirenz (Atripla TM). When STRIBILD and AtriplaTM 
are not available, co-formulated Truvada TM (emtricitabine 200 mg / tenofovir disoproxil fumarate 
300 mg) plus efavirenz 300 mg may be used. Elvitegravir is an HIV integrase strand transfer 
inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir DF are 
both HIV nucleoside analog reverse transcriptase inhibitors (NRTI)and efavirenz is a non-
reverse transcriptase inhibitor. All these medications have been licensed for the treatment of 
HIV-1 infection in humans by the U.S. Food and Drug Administration (FDA). 
Duration: In Step 1, volunteers will have a cross-sectional evaluation. In Step 2, study 
participants will have variable times of participation in re-testing until July 2015. In Step 3, 
individuals with acute and recent HIV-1 infection detected at Step 1 or 2 will be followed for 48 
weeks. 
Inclusion/Exclusion Criteria: 
In Step 1, potential participants must be MSM and transgender women , have sex with men, 
HIV status, at high-risk for HIV acquisition. Each potential participant must have the ability and 
willingness to provide informed consent for study participation, including being tested for HIV-1. 
If HIV infection is not diagnosed, he must be willing to be enrolled in Step 2, and if diagnosed 
with acute or recent HIV infection be willing to consider participation in Step 3. In particular, if 
they are HIV seronegative on antibodies analysis, but with evidence of acute infection (HIV-1 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
RNA-positive confirmed by HIV antigen analysis), they should be willing to be re-contacted for 
further HIV testing and linkage to care. 
In Step 2, volunteers who were found to have no HIV infection from Step 1 will be re-tested at 
variable times for incident HIV-1. Roughly, we anticipate testing 800 MSM and transgender 
women per month and follow-up until July 2015. 
In Step 3, men with acute or recent HIV-1 infection detected at Step 1 or Step 2; or individuals 
who have been diagnosed with HIV in any health clinic or laboratory authorized by the Ministry 
of Health, and that have had a documented negative result in the past three months with no 
prior ART exposure, with normal hematological, renal and liver function, will be enrolled in a 
randomized clinical trial for immediate vs. deferred ART, unless ART initiation criteria are met 
earlier. 
Treatment Regimen: In Step 1 and Step 2, no study treatment is offered. All participants will 
receive standard risk reduction counseling, condoms, and management of STIs. In Step 3, 
subjects will receive treatment as described above. 
Two ART regimens are available: 
• 
STRIBILD, co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate 
• 
ATRIPLA,emtricitabine/tenofovir,DF/efavirenz 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate will be the 
preferred regimen for newly enrolled participants because of the early benefit of integrase 
inhibitors on the decline of plasma viraemia and co-formulated emtricitabine/tenofovir 
DF/efavirenz will be an alternative regimen. Participants who have already initiated therapy with 
emtricitabine/tenofovir DF/efavirenz will continue on this regimen unless they develop clinical 
indications warranting change in medication. 
Evaluations: In Step 1, volunteers will have a cross-sectional evaluation. In Step 2, all 
participants will be tested quarterly. In Step 3, all participants will be evaluated at regular 
intervals for primary and secondary outcomes. 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
3 BACKGROUND 
3.1 INTRODUCTION [1] 
Despite two decades of HIV preventive initiatives the global prevalence of HIV continues to rise. 
At the end of 2010, an estimated 34 million people were living with HIV worldwide, up 17% from 
2001. This reflects the continued large number of new HIV infections and a significant 
expansion of access to antiretroviral therapy (ART), which has helped reduce AIDS-related 
deaths, especially in more recent years [2]. 
Currently, HIV-prevention strategies are only partly effective, condoms remain severely 
underused, no cure is available, and the discovery of an effective preventive vaccine remains 
elusive. Randomized controlled trials (RCTs) have provided evidence that male circumcision 
reduces the risk of heterosexual men becoming infected with HIV [3-5]. A glimmer of hope 
comes from the CAPRISA 004 trial which recently reported that a 1% vaginal gel formulation of 
tenofovir reduces HIV acquisition by an estimated 39% overall, and by 54% in women with high 
gel adherence [6], and as well as promising results from recent pre-exposure prophylaxis trials 
using antiretrovirals to prevent HIV among populations at risk [7-10]. Despite these important 
findings, the international community needs to think about additional effective prevention 
strategies in order to try to suppress the spread of HIV. 
One potential approach to prevention is to build on the success of antiretroviral therapy, which 
has effectively suppressed HIV viral load of those on treatment [11, 12] and which appears to 
lead to a substantial reduction in HIV transmission [13-17]. This proposed 'test-and-treat' 
approach involves very high levels of population coverage of frequent HIV testing and 
immediate initiation of ART upon diagnosis. While the potential strategy has received 
attention for its possible adoption in developing countries, there is also interest in its application 
in developed countries. 
3.2 RATIONALE 
Transmission of HIV from an infected person to an uninfected one occurs through exposure to 
the infected person's bodily fluids, mainly semen, vaginal secretions, breast milk or blood [18-
20]. HIV transmission risk in unprotected sexual intercourse depends on a number of factors, 
including the type of sexual practice [21], the stage of HIV infection of the infected partner [22-
25], the presence of sexually transmitted infections [22], the susceptibility of the uninfected 
partner [26] and HIV RNA viral load in the infected partner [13, 27, 28]. This last factor in 
particular has been shown to be the main predictor of the risk of sexual transmission of HIV-1 
[27]. 
HIV testing is fundamental to HIV prevention, treatment, and care. Studies have showed that 
those who are found positive modify their behavior in order to reduce the risk of HIV 
transmission [29-31]. This is likely to be particularly the case for sex with long-term partners. 
Widespread use of ART has led to a dramatic decrease in morbidity and mortality among HIV-
infected patients both in low-income and developed countries [32-35]. Antiretroviral therapy 
reduces levels of HIV-1 RNA in infected persons, and reduced levels have been measured in 
plasma [15, 36], female genital tract secretions [37], semen [12] and rectal secretions [38]. Due 
to the strong association between plasma viral load and risk of transmission, there is the 
potential for ART to prevent sexual transmission of HIV by reducing the infectiousness of HIV-
infected patients [27], and there is increasing evidence to support this [13-17]. There is much 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
support for the principle that extension of ART treatment could play a role in curbing the 
advance of the HIV/AIDS pandemic, but many [39-43] have doubts over such a strategy, citing 
concerns such as whether it could be practically implemented at a level sufficient to produce a 
significant impact on incidence, whether it should be implemented due to inherent ethical 
difficulties, and whether it would be cost-effective. 
Evidence of effectiveness of ART in preventing HIV transmission comes from different sources: 
Use of ART to prevent mother-to-child transmission (MTCT) [44-46], studies on sero-discordant 
heterosexual couples [13-15, 17, 25, 27] and ecological studies [47-49]. Randomized clinical 
trials have demonstrated that reducing maternal plasma HIV-1-RNA concentrations with ART 
drastically reduces MTCT [44-46]. Several studies of HIV sero-discordant heterosexual couples 
[14, 15, 17, 25, 27] have reported that transmission is rare in patients on ART, particularly in 
those with low HIV-1 RNA concentrations. A recent meta-analysis [13] on the risk of HIV 
transmission through unprotected sexual acts according to HIV-1-RNA concentrations and 
treatment with ART showed that among heterosexual HIV sero-discordant couples no 
transmissions were observed in patients treated with ART and with HIV-1RNA levels below 400 
copies/ml, and that data were compatible with one transmission per 79 person-years. A word of 
caution comes from a Chinese study of sero-discordant couples [50], where they observed no 
statistical difference in the seroconversion rates between those couples in which the partner 
was receiving ART or not. 
Recently, HPTN 052 RCT reported that suppression of HIV VL by early initiation of ART limits 
sexual transmission within HIV sero-discordant couples. In fact, 1763 couples in which one 
partner was HIV-1—positive and the other was HIV-1—negative were enrolled in nine countries; 
54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1—infected 
subjects with CD4 counts between 350 and 550 cells/mm3  were randomly assigned in a 1:1 
ratio to receive ART either immediately (early therapy) or after a decline in the CD4 count or the 
onset of HIV-1—related symptoms (deferred therapy). The primary prevention end point was 
linked HIV-1 transmission to HIV-1—negative partners. The primary clinical end point was the 
earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health 
Organization stage 4 event, or death. As of February 21, 2011, a total of 39 HIV-1 
transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence 
interval [Cl], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence 
rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 
occurred in the early therapy group (hazard ratio, 0.04; 95% Cl, 0.01 to 0.27; P<0.001). 
Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% Cl, 
0.40 to 0.88; P = 0.01). The authors concluded that early initiation of antiretroviral therapy 
reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and 
public health benefits from such therapy [51]. 
The anti-retroviral medications available have their actions at distinct stages of the viral cycle. 
Integrase inhibitors act before viral integration into host DNA, reverse transcriptase inhibitors 
and protease inhibitors act later in this cycle. Both integrase inhibitor based regimen (Stribild: 
co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) and NRTI based 
regimen (Atripla: co-formulated emtricitabine/tenofovir DF/efavirenz) result in high rates of viral 
suppression and increases in CD4 cell count But patients receiving 
elvitegravir/cobicistat/emtricitabine/tenofovir exhibit a more rapid decline in HIV-1 RNA and a 
greater proportion had viral load suppressed to less than 50 copies/ml as compared to patients 
receiving emtricitabine/tenofovir DF/efavirenz Both these regimens have once daily dosing but 
faster rates of viral suppression and comparatively favorable safety profile make co-formulated 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
elvitegravir/cobicistat/emtricitabine/tenofovir a preferred option for initiation of treatment during 
acute HIV infection. 
At a population level, several ecological studies reported a reduction in incidence following an 
increase in ART availability. An ecological study from Taiwan [48] reported a reduction of 53% 
in new positive HIV tests after the introduction of free access to ART; this occurred despite no 
change in rates of syphilis (which is used as an indicator of sexually transmitted disease 
transmission). Another study, based on a large cohort of MSM in San Francisco [49] showed a 
60% reduction in HIV incidence that the authors attribute to availability of ART. Again in San 
Francisco, amongst MSM an uptake of 72% of HIV voluntary counseling test (VCT) was 
observed and it was followed by 95% acceptance of immediate ART for those diagnosed with 
HIV. This produced a reduction in 'community viral load' (i.e. the viral load of the whole 
community of those with diagnosed HIV) of 45% between 2004 and 2008 and an estimated 33% 
fall in HIV incidence between 2006 and 2008 [47]. A similar pattern was reported in British 
Columbia, Canada, between 1996 and 2009, where a 52% reduction in the number of new HIV 
diagnoses was observed against an increase of 547% in the number of patients actively 
receiving ART and despite a syphilis epidemic, strongly indicating increased risky behavior [52, 
53]. However, earlier ecological studies investigating the effect of widespread use of ART on 
HIV incidence among MSM obtained contrasting results [54, 55], suggesting that any decrease 
in risk of HIV transmission due to ART could possibly be counterbalanced by increases in the 
number of unsafe sexual episodes. Particular caution needs to be taken when considering 
ecological studies, because they have serious limitations. In particular, ART could be not the 
only factor causing a reduction in HIV transmission in the region under study. 
3.3 FEASIBILITY 
So is it reasonable to consider that use of ART could reduce incidence of HIV to zero, and 
hence end the epidemic? This would require that testing coverage were 100%, ART initiation 
were immediate for all people diagnosed, that ART immediately reduces infectivity to zero 
(regardless of sexual risk behavior), and that nobody ever stops taking ART or suffers virologic 
failure while on ART. Below we consider how close or far away from these ideal conditions we 
are. 
3.3.1 Testing Coverage and Frequency 
One hundred percent coverage of testing is not feasible, at least not without coercion which is 
unacceptable. It remains unclear how many individuals in different settings have ever been 
tested for HIV infection and indeed how often individuals should be tested. 
Among 19 countries in sub-Saharan Africa, the number of individuals aged over 15 who 
received HIV testing and counseling in 2008 varies from 210 per 1000 people in Botswana to 
two per 1000 people in Somalia [56]. It is estimated that in this region, 80% of people living with 
HIV are not aware of their HIV status and 90% do not know their partner's status [57]. In the 
UK, the rate of HIV testing, despite a dramatic increase between 1995 and 2005, remained low 
at 71.3 and 61.2 tests per 100 000 person-years for men and women in 2005 [58]. It is 
estimated that one-third of those infected with HIV in the UK are unaware of their diagnosis [59, 
60]. In USA the situation is definitely better; in the last 12 months 16% of the population aged 
18-64 years reported having been tested for HIV [61], but the U.S. Centers for Disease Control 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
and Prevention estimated that 21% of people living with HIV in USA and 27% of those in 
Canada are unaware of their HIV status [62]. 
A further indication of failure to test regularly, if at all, is the proportion of HIV diagnoses classed 
as 'late', that is having a CD4 cell count value of less than 350 cells/ml or AIDS within 3 months 
of diagnosis [63]. In Europe, the incidence of late diagnosis ranges from 15% to 45% [64]. In 
particular, in the UK, an estimated 32% of adults diagnosed with HIV in 2008 had CD4+ cell 
count less than 200 cells/mlwithin 3 months of diagnosis [59]. 
Many of those diagnosed late in the course of their disease have not previously been offered 
HIV testing. It has been shown in a number of studies that most newly detected cases of HIV 
have had contact with medical services in the last years but were not offered HIV testing [65, 
66], and the same was true for late presenters [66, 67]. 
3.3.2 Time from HIV Diagnosis to Initiation of Antiretroviral Therapy 
Immediate initiation of ART in those found to be HIV positive is fraught with difficulties, 
especially if, in order to increase HIV test uptake, these tests are not conducted where HIV care 
is delivered. At the moment no data are available on the feasibility, acceptability or deliverability 
of tightly linking HIV testing with treatment initiation. A RCT [68] is currently ongoing in the USA 
investigating the possibility of delivering this approach: the feasibility of enhanced community-
level testing, and the capacity of linking HIV positive patients to care and treatment. 
Unfortunately these results will not be generalizable to African or any developing country 
context. In any case, it is important to bear in mind that although current guidelines recommend 
ART initiation in HIV-infected patients when CD4+ cell count reaches 350 cells/ml, worldwide 
only 30% of those currently in need (with 'need' defined by a CD4+ cell count < 200 cells/m1) are 
receiving treatment [69] and the situation is worse in many developing countries. The 
implementation of a policy of test-and-treat would dramatically increase the number of people 
starting treatment, and the source of resources to fund such initiatives is not obvious. However, 
the current paradigm of care is not sustainable and it will become ever more difficult to sustain 
without a large increase in treatment funding [70]. 
A further key issue is whether starting ART at higher CD4+ cell counts confers individual health 
benefit. At the moment this is not clear. Findings from observational studies suggest that there 
should be a benefit on AIDS progression and death in those who start treatment early [71, 72], 
but there is ongoing debate about appropriate methods for analyzing observational data and, 
unlike RCTs, none can be relied on to eliminate all confounding. The START trial is currently 
recruiting worldwide ART-naive patients with CD4+ cell counts greater than 500 cells/ml. The 
aim of the study is to evaluate whether immediate ART initiation is associated with reduced risk 
of serious AIDS-associated illness, serious non-AIDS illness and death, compared to those who 
defer ART initiation until CD4+ cell count reaches below 350 cells/ml [71]. This is a major 
component of global efforts to assess the potential impact of a test-and-treat strategy, as most 
strategies propose that ART be given immediately regardless of CD4 count. 
3.3.3 Extent of Reduction in Infectivity with Antiretroviral Therapy and Durability of Viral 
Load Suppression 
The potential reduction in infectivity for patients on ART has been described above, but it takes 
time to achieve viral load suppression and therefore a reduction in infectivity. It is estimated that 
90% of patients achieve viral suppression to less than 50 copies/m1 in 4 months after starting 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
ART, but 20% of them will at some point experience viral load rebound [73]. There is also the 
potential for variations in viral load on a regular basis which do not constitute failure, that is viral 
load 'blips' above the limit of detection in people for whom re-suppression subsequently occurs 
[74, 75]. In addition, failure of treatment and often large increases in viral load will go 
undetected and unknown by individuals until the next clinical review and viral load 
measurement. The impact of recognized variations of HIV-RNA in genital secretions despite 
undetectable serum viral load [72] is unclear. Studies have shown that ART suppresses 
seminal shedding of HIV [12, 75], but breakthrough genital tract HIV shedding has been 
observed [76]. Additionally, antiretroviral agents currently in use have different penetration into 
the male and female genital tracts, so can potentially lead to different rates of infectiousness 
[77-79]. The level of plasma HIV-RNA below which transmission does not occur (in particular in 
MSM) is also currently unknown. Therefore, it is necessary that patients on ART continue to be 
advised to avoid unprotected sex with people of unknown or negative HIV status. 
3.4 RISKS 
There is also a lack of information on potential negative effects of a universal test-and-treat 
policy, in particular the risk of increasing transmission of drug-resistant strains [80-82] induced 
by poor adherence to ART, the risk of sexual disinhibition [83-85] and the risk of stigmatization. 
3.4.1 Drug Resistance 
Although concerns have been expressed with regards to the potential risk of HIV drug 
resistance acquisition induced by suboptimal adherence in settings where scale-up of ART is 
taking place [81], recent data suggest that good adherence can be attained in resource-limited 
settings and in marginalized populations in developed nations [70]. 
This contrasts with data from some mathematical models which suggests that if antiretroviral 
treatment was offered to most HIV-positive individuals in South Africa eligible for treatment, 
drug-resistant strains could increase to up to 20% of circulating HIV strains [86]. It is likely that 
the risk of increased HIV-resistance caused by such a strategy has been overestimated, given 
that ART suppresses in most people who are adherent. In addition observational data from 
British Columbia has shown that the number of new cases and identified drug resistant isolates 
dropped when ART was extended to all intravenous drug users [53], in contrast to concerns 
previously expressed regarding the risk of an epidemic of drug resistant HIV. Although not an 
immediate concern for ART programs (relative to priorities of providing ART for those in need), 
in the long term, significant transmission of drug resistant virus is likely to occur if ART is used 
for decades without monitoring of viral load to guide switches to second line therapy [87], and 
this phenomenon could be more marked if ART coverage is very high. When considering the 
overall impact of a test-and-treat policy on transmission of drug-resistant HIV it is important to 
consider the incidence of infection with drug resistant virus, not the proportion of new infections 
with drug resistance. 
3.4.2 Increased Sexual Risk Behaviors 
The risk of sexual disinhibition that the wide scale use of ART could cause has been raised by 
some researchers [83-85, 88-91]. 
Most studies, but not all [92], did not find an association between use of ART and risky sexual 
behavior [14, 93-96] and in fact interrupting ART or low adherence were correlated with greater 
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risk behavior [83, 96-98]. Studies from Africa, where positive prevention was promoted, showed 
that 6 months and 1 year after initiation of ART risky sexual behavior was reduced [99, 100] and 
there was no sign of sexual disinhibition even after 2 years [93]. The concern is higher with 
regard to MSM. Studies showed that since 1996 there has been a substantial increase in 
unprotected sex among HIV-positive and HIV-negative MSM in Europe, Australia, Canada and 
the USA, but in the last years it seems to be leveling off [101]. The reason for this is not clear 
[101]; some studies showed that MSM could change to unprotected sex when perceiving less 
threat of HIV/AIDS since availability of highly active antiretroviral therapy [102-104] or if they 
believe that having suppressed viral load reduces their infectiousness [83]. In any case, a recent 
meta-analysis [105] investigating this issue among MSM in the USA found that being on 
antiretroviral therapy, having an undetectable viral load, and reporting more than 90% 
medication adherence were not associated with unprotected sex. Mathematical models warned 
that the effect on incidence of decrease in infectiousness induced by treatment could be easily 
counterbalanced by much more modest increases in unsafe sex or a decrease in adherence to 
treatment, although this will depend on exactly how low is the risk of transmission through 
unprotected sex from people with suppressed viral load. 
3.4.3 Ethical Issues 
The test-and-treat strategy is not without ethical concerns as it potentially involves a move from 
medical treatment for individual benefit to medical treatment for public health benefit [40]. 
Although the benefits of treating an individual with advanced HIV disease obviously outweigh 
any potential treatment-related risks, such as development of drug resistance and adverse 
effects of ART, the benefits to an individual diagnosed early with an intact immune system are 
still far from clear. Indeed, if trials were to show that early use of ART does not lead to any 
individual health benefit, or the toxicity and inconvenience of early ART for patients outweighs 
clinical benefits, then initiation of treatment at diagnosis in people with high CD4 cell count 
would only be justified in people well informed of the health risks who nevertheless wish to 
reduce their infectiousness. There is also a danger of stigmatization of groups in which HIV 
prevalence is high and of coercion of individuals to be tested. These issues are considerable 
and require due consideration. 
3.4.4 Mathematical Models 
Mathematical models can be useful for evaluating the potential efficacy of a strategy of test-and-
treat. By definition, models are based on assumptions, upon which the validity of the inferences 
derived depend, but they provide an important means of explicitly relating a set of assumptions 
to a predicted outcome in terms of reduced HIV incidence. Models have varied in the degree of 
detail with which they have modeled this process. 
The first mathematical simulation models produced conflicting findings regarding the effect of 
ART on the spread of HIV [80, 84, 85, 88-91, 106, 107]. Although most of them concluded that 
an increase in use of ART could lead to a decrease in HIV incidence, the likely realistic 
magnitude of the effect remains poorly characterized. The Granich model [108] advocating that 
universal voluntary HIV testing and immediate ART treatment with combined prevention 
interventions could potentially eradicate HIV infection has received lots of interest, but some 
underlying assumptions are highly controversial [109] because they assume virtually everyone 
could be tested and treated immediately if found HIV-positive and that accompanying prevention 
interventions would also be highly effective. This is not likely to be feasible [41]. Some argued 
[39] that a test-and-treat policy would not be the most cost-efficient strategy in some settings 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
and found that if it does not reach full implementation or coverage could paradoxically increase 
long-term ART costs [39]. Others have argued that acute infections have a major role in driving 
the epidemic and doubt that this strategy could diminish transmission during the acute phase 
[42, 109]. 
A recent study [43] forecast outcomes of different combinations of HIV screening and ART 
initiation strategies, if were implemented in Washington, District of Columbia, using a 
mathematical model. They showed that an intensive test-and-treat strategy (annual screening 
with ART initiation at diagnosis) may have a population benefit, reducing overall life-years spent 
with transmissible HIV infection over the next 5 years by 15%, but they concluded that such a 
program could not eradicate the epidemic in the District of Columbia. It is important to note that 
this model projects the clinical course of HIV disease but does not model new transmissions, so 
it does not take into account the potential reduction in risk behavior following diagnosis. 
Additionally, it assumes imperfect linkage and loss to follow-up among patients detected by a 
screening program, whereas those detected outside of the screening program are all linked to 
care. 
3.4.5 Conclusion 
We do not know 
1. How effective ART that suppresses HIV-RNA in plasma will be in reducing risk of 
transmission on a population level. The impact of variations of HIV-RNA in genital 
secretions despite undetectable plasma viral load is not fully understood. 
2. Whether ART has individual health benefits at higher CD4 cell counts and if not, whether 
people with high CD4 cell counts will accept treatment simply to reduce transmission. 
3. Whether individuals will be adherent enough to ART to sustain predicted prevention 
benefits. 
4. Whether individuals will increase their sexual risk behavior, in particular once they 
become aware of the reduction in infectiousness induced by virally suppressive ART. 
5. Whether such a strategy would be feasible in the face of limited resources. 
So even if observational studies and trials demonstrate that ART can successfully prevent 
transmission of infection in high-risk populations and that individuals remain highly adherent and 
do not experience sexual disinhibition, the critical issue remains the feasibility of such a 
strategy. The success of any test-and-treat strategy depends on being able to offer frequent HIV 
testing, on achieving a high level of acceptability in the population, on linking all detected cases 
to care and on having the ability to initiate ART immediately. 
Cluster randomized trials that compare HIV incidence in areas that adopt a test-and-treat policy 
with those that do not are planned and will provide the best means of evaluating the impact of 
such strategies. In the meantime, models that incorporate more real life details are now needed 
to better understand the potential of this strategy and to assess its likely cost-effectiveness. 
Given that many people with HIV who are in immediate need of treatment are undiagnosed, and 
that a reduction in risk behavior has been observed after diagnosis, which is likely to be 
particularly significant for sex with longer term partners, it is already clear that a key priority for 
all countries should be to instigate high levels of testing, particularly in higher prevalence 
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V iral Load (virions/m1 of plasma) 
 
Eclipse,  I 
VI 
Viral RNA + 
Gag p24 antigen + 
ELISA + 
Western blot ± 
Western blot + p31-
-• Western blot + p31+ 
•• 
10  
40  50  
100  1000 
Days since Infection 
Viral load 
Strain-specific neutralizing antibodies 
gP41 Antibodies 
Antibody-antigen complexes 
Inflammatory cytokines 
CD8 T-cell responses 
Acute-phase reactants 
Viral latency 
103 
106-1 
105-
104-
103-
102-
101  
Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
groups. Whether countries should then take the next step and also have a policy of initiating 
ART in those with high CD4 cell count at diagnosis is yet to be established but should continue 
to be actively studied. 
3.5 ACUTE HIV INFECTION [110] 
3.5.1 The HIV-1 Transmission Event 
More than 80% of adults infected with HIV-1 became infected through the exposure of mucosal 
surfaces to the virus; most of the remaining 20% were infected by percutaneous or intravenous 
inoculations [2]. The risk of infection associated with different exposure routes varies [111], but 
no matter what the transmission route, the timing of the appearance of viral and host markers of 
infection is generally uniform and follows an orderly pattern [112]. Immediately after exposure 
and transmission, as HIV-1 is replicating in the mucosa, submucosa, and draining 
lymphoreticular tissues [113, 114], the virus cannot be detected in plasma; this so-called eclipse 
phase generally lasts 7 to 21 days [115, 116]. Once HIV-1 RNA reaches a concentration of 1 to 
5 copies per milliliter in plasma, the virus can be detected with the use of sensitive qualitative 
methods of nucleic acid amplification [117]; at concentrations of 50 copies per milliliter, HIV-1 
can be detected by means of quantitative clinical assays used to monitor viral load [118]. The 
stages that define acute and early HIV-1 infection are characterized by the sequential 
appearance of viral markers and antibodies in the blood (Fig. 1) [112]. More sensitive, fourth-
generation tests, which detect both antigens and antibodies, shrink the virus-positive—antibody-
negative window by about 5 days [119]. Testing for viral RNA in plasma closes this gap by an 
additional 7 days. 
Figure 1. Natural History and Immunopathogenesis of HIV-1 Infection (from [110]). 
The progression of HIV-1 infection can be depicted as six discrete stages [1 1 3] (indicated by Roman numerals). These stages are 
defined according to the results of standard clinical laboratory tests (listed above the curve for viral load). The stages are based on 
the sequential appearance in plasma of HIV-1 viral RNA; the gag p24 protein antigen; antibodies specific for recombinant HIV-1 
proteins, detected with the use of an enzyme-linked immunosorbent assay (ELISA); and antibodies that bind to fixed viral proteins, 
including p31, detected on Western immunoblot. A plus sign indicates a positive test result, a minus sign a negative result, and a 
plus—minus sign a borderline-positive result. The lines below the viral-load curve show the timing of key events and immune 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
responses that cannot be measured with standard clinical laboratory assays, beginning with the establishment of viral latency. 
Acute-phase reactants include elevated levels of serum amyloid protein A. CD8 T-cell responses lead to the appearance of escape 
mutants concurrently with inflammatory cytokines in plasma. Immune complexes of antibodies with viral proteins, such as the HIV-1 
envelope glycoprotein (gp41), precede the first appearance of free antibodies to gp41. Strain-specific antibodies to gp41 that 
neutralize the virus do not appear until sometime close to day 80. The portion of the line for viral latency that is dotted reflects 
uncertainty as to exactly when latency is first established; the dotted line for acute-phase reactants indicates that not all patients 
have elevated levels of reactants at this early point in the process of infection; the gray segment of the black line for viral load 
reflects the inability to measure very low viral loads. 
The characteristic appearance in the blood of viral markers of acute HIV-1 infection belies an 
extremely complicated and still poorly understood series of virus—host cell interactions in the 
tissues [111, 120]. Given the varied routes of viral transmission — cervicovaginal, penile, rectal, 
oral, percutaneous, intravenous, in utero — and the distinctly different histologic features of 
these tissues, it is not surprising that several cell types are candidates for early infection. More 
is known about vaginal transmission than about other routes, and the study of human tissue 
explants [121, 122] and the Indian rhesus macaque model of vaginal transmission of the simian 
immunodeficiency virus (SIV) [120, 123-125] have been informative. The preponderance of 
evidence implicates CD4 T cells and Langerhans' cells as the first targets of the virus [121, 
122], but other dendritic cells may play an important accessory role [126]. However, recent 
observations of mucosally transmitted strains of HIV-1 reveal that monocyte-derived 
macrophages are generally poor targets for infection as compared with CD4 T cells [127, 128]. 
Regardless of the route of viral transmission and the first cells infected, within a few days, viral 
replication converges on the lymphoreticular system of the gastrointestinal tract (i.e., gut 
associated lymphoid tissue) [129-132]. In this tissue, in both humans and macaques, the 
phenotype of most productively infected cells appears to be the resting CD4 T cell lacking 
activation markers and expressing low levels of the chemokine receptor CCR5 [123-125]. Many 
of these cells express a4137 integrin receptors and type 17 helper T—cell surface markers [133, 
134]. Since these receptors are also detected on T cells harvested from the genital mucosa, 
they may play an important role in HIV acquisition [135]. The rapid expansion of HIV-1, first in 
gut-associated lymphoid tissue and then systemically [132, 136], along with a sharp rise in 
plasma levels of viral RNA, is clinically important because of the coincident irreversible 
destruction of reservoirs of helper T cells and the establishment of viral latency (defined as the 
silent integration of HIV-1 DNA into the genomes of resting T cells, an effect that has stymied 
curative treatment efforts [137, 138]. 
Rather than being genetically homogeneous, RNA viruses, including HIV-1, consist of complex 
mixtures of mutant and recombinant genomes called quasi-species. Genetic studies of the HIV-
1 quasi-species in patients with chronic infection as compared with patients with acute infection 
have brought some clarity to the qualitative and quantitative aspects of HIV-1 transmission 
[115]. Figure 2 depicts the HIV-1 transmission event [115, 116, 139, 140], in which the inoculum 
(e.g., semen, cervicovaginal secretions, or blood) contains a complex genetic quasi-species of 
viruses, of which only a very small number are likely to broach mucosal barriers and establish 
infection. Lee and colleagues9 developed a model that allows transmitted viral genomes to be 
inferred from a phylogenetic analysis of the viral quasi-species that replicate in the weeks after 
infection. Empirical analyses based on single-genome amplification of HIV-1 RNA in plasma or 
HIV-1 DNA in blood lymphocytes have provided robust evidence to support this model [115, 
123, 127, 140-145]. A single virion is responsible for HIV-1 transmission in approximately 80% 
of heterosexuals but in only about 60% of men who have sex with men and about 40% of 
injection-drug users [115, 127, 128, 140, 144, 145]. In injection-drug users, as many as 16 
transmitted virions have been found to be responsible for productive infection [141], which 
would be consistent with the absence of a mucosal barrier to transmission. The phenotypes of 
cloned proviruses corresponding to transmitted (or founder) viruses are nearly always CD4 and 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
CCR5 T-cell tropic variants and exhibit neutralization-sensitivity patterns that are typical of 
primary viral strains. These phenotypic properties are present at the moment of transmission, 
when the virus encounters the first target cell; they are not the consequence of viral adaptation 
to the new host [115, 127, 128]. 
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HIV-1 tranilocation through female epithelium, s. • 
HIV-1— 
infected 
cells 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
B  HIV-1 translocation through male epithelium • 
Stratified squamous epithelium of inner side of penile foreskin 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
Figure 2. Progression of HIV Transmission to Productive Clinical Infection (from [110]). 
HIV-1 must traverse several tissue layers in the female vagina or rectal mucosa to come into contact with appropriate receptive cells 
(Panel A). The CCR5 (R5) viral strain has selective transmission advantages that remain poorly explained, and R5 variants make up 
the majority of transmitted and founder viruses. CXCR4 (X4) variants are transmitted only rarely. Founder viruses come into contact 
with Langerhans' cells or CD4 T cells in squamous epithelium; CD4 T cells can also be infected by viruses bound to submucosal 
dendritic cells. It is not clear whether submucosal macrophages are an initial target, since most founder viruses poorly infect 
macrophages in vitro. The challenge for HIV-1 transmission in the male genital tract differs somewhat from that in the vagina 
because of differences in anatomy, but the penile foreskin and urethra harbor critical virus-receptive cells (Panel B). Virus—cell 
interactions in the male submucosa are likely to be similar to those in female submucosa, with viral targets including Langerhans' 
cells, other submucosal dendritic cells, and CD4 cells. Removal of the foreskin through elective circumcision can prevent at least 
60% of HIV-1 infections in men [114]. Although the time required for HIV-1 virions or virus-infected cells to traverse epithelial 
barriers is short (hours), it probably takes as long as 3 to 6 days for HIV-1 infection and propagation to occur and for the virus to 
spread beyond submucosal CD4 T cells (Panel C). Dissemination into draining lymph nodes and the systemic circulation rapidly 
follows, with establishment of the CD4 T-cell viral reservoirs. Studies in nonhuman primates of the timing of response to 
postexposure prophylaxis with antiretroviral drugs suggests that the time to establishment of the CD4 T-cell reservoir may be as 
short as 24 hours [113]. 
3.5.2 Detection of HIV Infection 
In the absence of a high degree of clinical suspicion, the symptoms associated with acute HIV-1 
infection are often too vague or nonspecific to lead to a diagnosis [146]. In the absence of 
antibody seroconversion, confirmation of acute infection requires detection of HIV-1 RNA or p24 
antigen, but tests designed for this purpose have heretofore not been routinely available. In 
public health settings, a cross-sectional screening strategy that involves searching for HIV RNA 
in pooled, antibody-negative samples has been used to increase detection [146]. This approach 
has been used to detect acute HIV-1 infection, with a prevalence of 0.5 cases detected per 
1000 persons tested, in North Carolina, to 4.0 cases per 1000, in San Francisco; acute infection 
accounted for 5 to 10% of all cases of HIV in both places. 
As an alternative and more practical strategy, an enzyme-linked immunosorbent assay that can 
concomitantly detect viral p24 antigen and antiviral antibodies has been developed and 
approved for clinical use [146-148]. This test can increase the number of patients with acute 
HIV-1 infection whose condition is diagnosed at a time when they are most infectious to others 
[148]. It is anticipated that a rapid point-of-care test will also be developed for the purpose of 
detecting acute HIV-1 infection. The implementation of these tests across the United States in 
public health and commercial laboratories can be expected to dramatically increase the number 
of patients with acute HIV-1 infection who will require care. 
3.5.3 Public Health Consequences of Acute HIV-1 Infection 
The per-person probability of transmitting HIV-1 is most closely correlated with the viral burden 
in blood; each time the viral burden in an HIV-1—infected person increases by a factor of 10, the 
risk of transmission is expected to increase by a factor of 2.5 [27]. The risk of contagion from 
patients with acute, early infection appears to be much higher than that from patients with 
established infection [25], at least in part because of the high viral load and the homogeneity of 
viral variants clearly capable of causing infection. In the rhesus macaque SIV model, plasma 
from animals with acute infection is up to 750 times as infectious, on a per-virion basis, as 
plasma from animals with chronic infection [149]. The reduced risk of contagion from patients 
with chronic infection probably results from the presence of neutralizing antibodies, which are 
not evident in acute infection. 
Mathematical models used to estimate the role of patients with acute infection in the spread of 
HIV-1 have produced strikingly different results depending on the population studied and the 
assumptions used (Fig. 3) [23, 150-160]. The epidemic phase used for modeling has been a 
critical determinant [161]. In communities subject to a new epidemic, early infections are held to 
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Pinkerton and Abramson. 
1996 
Kretzschmar and Dietz, 
1998 
Jacquez et al., 
1994 
Xiridou et al., 
2004 
Pinkerton, 
2007 
Prabhu et al., 
2009 
I 
U.S. 	
U.S. 	
Europe 
(heterosexuals or MSM) 	
(MSM) 	
(MSM) 
Population 
Sub-Saharan Africa 
(heterosexuals) 
Koopman et al., 
1997 
Proportion  of New Infections Caused 
by  Early Infections 
 
1.0 
0 9-
0.8-
0.7-
0 6-
0.5-
0.4-
0.3-
0.2--
0.1-, 
0.0 	
 
Hayes and 
White, 
2006 
Salomon and 
Hogan, 
2008 
Powers et al., 
2010 
`,1 
Abu-Raddad 
and Longini.-""' 
2008 IIC " Hollingsworth 
et al., 
2008 
Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
be responsible for a considerable share of HIV-1 transmission, since a larger proportion of 
infected persons have acute or early-stage disease rather than late-stage disease [162]. Sexual 
behavior plays an important role in rates of infection, with high rates of partner change 
increasing the chances of contact with a person who has acute HIV-1 infection. In a recent 
comprehensive study conducted in Lilongwe, Malawi, in which both behavioral and biologic data 
were used, 38% of cases of HIV-1 were ascribed to sexual exposure to patients in the first 5 
months of infection, even though there is a long-established epidemic in Malawi. The results of 
the Malawi study may be most relevant to the HIV-1 pandemic in sub-Saharan Africa. The 
importance of acute HIV-1 infection can also be seen in studies of phylogenetically related 
cases. In Montreal more than half the patients with newly diagnosed early HIV-1 infection are 
infected with viral variants that can be linked through phylogenetic studies, which suggests the 
presence of clusters of transmission, perhaps from patients with acute and early infection [162]. 
Figure 3. Role of Acute and Early HIV-1 Infection in the Spread of HIV-1, According to Population Studies in Sub-Saharan 
Africa, the United States, and Europe (from [1101). 
Acute and early HIV-1 infection is responsible for secondary transmission of HIV-1, which is critical to the epidemic spread of the 
virus. A variety of models [23, 150-160] have generated widely varying estimates of the potential importance of acute and early 
HIV-1 infection, depending on the patient populations studied and the assumptions of the models. These models generally include 
people in whom the virus was detected before and during seroconversion (acute HIV-1 infection) and for several weeks thereafter 
(early infection) [152, 159]. The estimates reflect the proportion of all transmissions during an individual patient's entire infectious 
period. The extent to which this proportion corresponds to the proportion of all transmissions that occur during acute and early HIV-1 
infection at the population level depends on the epidemic phase and the distribution of patterns of sexual contact in the population 
[154, 155, 158]. Transmission probabilities were drawn from the population category shown, but the reported estimates result from a 
range of hypothetical sexual-behavior variables that do not necessarily reflect a specific population [150, 155]. The range of 
estimates shown was extracted from the endemic-phase portion of graphs showing the proportion of new infections resulting from 
early HIV-1 infection over calendar time. I bars represent an estimate of the percentage of new HIV cases caused by people with 
acute or early HIV infection. MSM denotes men who have sex with men. 
The earliest events in acute HIV-1 infection determine the future health of the individual patient 
and the extent of transmission in the general population. Recent studies have unraveled many 
of the initial immune events of acute infection. With improved diagnostic tests, greater numbers 
of persons with acute HIV-1 infection will come to the attention of practicing physicians and 
public health officials. Although considerable progress has been made in understanding the 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
HIV-1 transmission event, more studies are needed to develop optimal treatment and 
prevention strategies for people in the earliest stages of HIV-1 infection. 
3.6 TREATMENT OF ACUTE AND RECENT HIV INFECTION [163] 
3.6.1 Treatment for Acute HIV Infection 
Clinical trials information regarding treatment of acute HIV infection is limited. Ongoing trials are 
addressing the question of the long-term benefit of potent treatment regimens initiated during 
acute infection. Previous studies, especially HPTN 052, that have demonstrated reduced risk of 
HIV transmission associated with ART did not include persons with acute and recent infection 
and were focused on discordant stable heterosexual couples in which the HIV-infected partner 
had an established (chronic) HIV infection. Although this study would be deferring ART for 24 
weeks for some participants, the timing of this treatment initiation would still be earlier than 
initiation of ART in the HPTN 052 study, which initiated ART when CD4 counts were between 
350 and 550 cells per mm3. In addition, deferred study treatment would begin far earlier than 
standard treatment according to the Peruvian guidelines, which do not recommend initiation of 
treatment until CD4 counts fall below 350 cells per mm3. 
Potential benefits and risks of treating acute infection are as follows: 
1. Potential Benefits of Treating Acute Infection. Preliminary data indicate that 
treatment of acute HIV infection with combination ART has a beneficial effect on 
laboratory markers of disease progression [164-168]. Theoretically, early intervention 
could decrease the severity of acute disease; alter the initial viral setpoint, which can 
affect disease progression rates; reduce the rate of viral mutation as a result of 
suppression of viral replication; preserve immune function; and reduce the risk of viral 
transmission during this highly infectious stage of disease. Additionally, although data 
are limited and the clinical relevance is unclear, the profound loss of gastrointestinal 
lymphoid tissue that occurs during the first weeks of infection may be mitigated by the 
early initiation of ART [130, 169]. 
2. Potential Risks of Treating Acute HIV Infection. The potential disadvantages of 
initiating therapy include exposure to ART without a known clinical benefit, which could 
result in drug toxicities, development of drug resistance, continuous need for therapy 
with strict adherence, and adverse effect on quality of life. 
Some of the potential benefits associated with treatment during acute infection remain uncertain 
and of unknown clinical relevance, while the risks are largely consistent with those for initiating 
therapy in chronically infected asymptomatic patients with high CD4 counts. The health care 
provider and the patient should be fully aware that the rationale for therapy for acute HIV 
infection is based on theoretical considerations, and the potential benefits should be weighed 
against the potential risks. For these reasons, treatment of acute HIV infection should be 
considered optional at this time. Because acute or recent HIV infection is associated with a high 
risk of MTCT of HIV, all HIV-infected pregnant women should start a combination ARV regimen 
as soon as possible to prevent perinatal transmission of HIV. Following delivery, considerations 
regarding continuation of the ARV regimen as therapy for the mother are the same as for 
treatment of other non-pregnant individuals. 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
3.6.2 Treatment for Recent but Non-acute HIV Infection or Infection of Undetermined 
Duration 
In addition to patients with acute HIV infection, some HIV clinicians also recommend 
consideration of therapy for patients in whom seroconversion has occurred within the previous 6 
months. Although the initial burst of viremia among infected adults usually resolves in 2 months, 
rationale for treatment during the 2- to 6-month period after infection is based on the probability 
that virus replication in lymphoid tissue is still not maximally contained by the immune system 
during this time [170]. In the case of pregnancy, use of a combination ARV regimen to prevent 
MTCT of HIV is recommended. For non-pregnant patients the current guidelines have provided 
a rationale for recommending initiation of ART in ART-naive patients with CD4 count between 
350 and 500 cells/mm3  as well as a recommendation to consider therapy for those with CD4 
count >500 cells/mm3. Although these recommendations are primarily based upon data from 
patients with chronic infection, the potential benefit of early treatment on immune recovery and 
on attenuation of the pathologic effects of viremia-associated inflammation and coagulation 
could apply to those with early HIV infection as well. Based upon all of these considerations it is 
reasonable that clinicians share with patients the potential rationale for initiating ART during 
early HIV infection and offer treatment to those who are willing and able to commit to lifelong 
treatment. 
3.6.3 Treatment Regimen for Acute or Recent HIV Infection 
If the clinician and patient have made the decision to initiate ART for acute or recent HIV 
infection, the goal of therapy is to suppress plasma HIV RNA levels to below detectable levels. 
Data are insufficient to draw firm conclusions regarding specific drug combinations to use in 
acute HIV infection. Potential combinations of agents should be those used in chronic infection. 
The optimal duration of therapy for patients with acute or recent HIV infection is unknown, but 
ongoing clinical trials may provide relevant data regarding these concerns. Difficulties inherent 
in determining the optimal duration and therapy composition for acute or recent infection (and 
the potential need for lifelong treatment) should be considered when counseling patients prior to 
initiation of therapy. Patients need to know that there are limited data regarding the benefits of 
stopping treatment, whereas strong data from studies in patients with chronic HIV infection 
show that stopping ART may be harmful [170]. 
4  STUDY DESIGN 
4.1  OVERALL STUDY DESIGN 
This is three-step trial. In Step 1 we will screen MSM and transgender women who are 
unaware of their HIV status and with evidence of high risk for acquiring HIV-1 infection, 
including risky sexual behavior, a partner of a newly-diagnosed person with acute or recent HIV 
infection or with symptoms of acute retroviral syndrome. We anticipate testing approximately 
2400 MSM and transgender women until July 2015. In Step 2, high risk HIV-1 uninfected MSM 
and transgender women with high risk for acquiring HIV will be tested at variable intervals 
(during which they will receive standard HIV prevention methods) for incident HIV-1. Roughly, 
we anticipate testing 800 MSM and transgender women monthly for the first three months and 
then every other month for re-testing until July 2015. In Step 3, individuals with acute and 
recent HIV-1 infection detected at Step 1 or 2, or individuals who have been diagnosed with HIV 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
in any health clinic or laboratory authorized by the Ministry of Health, and that have had a 
documented negative result in the past three months, will be enrolled in a 48-week randomized, 
open-label clinical trial of the effects on the decay dynamics of HIV viral load in plasma, semen 
and rectal secretions of immediate —ARM 1- vs. deferred (by 24 weeks) —ARM 2- ART, unless 
ART initiation criteria are met earlier. We expect that approximately 200--250 MSM and 
transgender women (roughly 100-125 with acute and 100-125 with recent HIV-1 infection) will 
participate in the study. Those participants, who have started their participation in the study 
before the approval of Amendment Letter #1 in this study protocol, will continue their 
participation as originally programmed. Once the Amendment Letter #1 is approved for this 
study protocol, the participants who are eligible for Step 3 will be given treatment the following 
way: 1) those people diagnosed with acute HIV infection will be offered immediate ART (just at 
time of the enrollment visit or during the next 48 to 72 hours) for the duration of 48 weeks. 2) 
The people who are diagnosed with recent HIV infection randomized to start immediate ART 
or defer ART initiation until 24 weeks after HIV diagnosis, all of them followed for 48 weeks after 
which they will continue ART from other sources. Roughly half of these participants have been 
enrolled to date. These participants will receive Atripla as study drug; participants enrolled after 
approval of this protocol version will receive Stribild. 
4.2 CRITERIA FOR OFFERING TO INITIATE TREATMENT IN STEP 3 
Clinical, virologic, and immunologic criteria, as specified below, will be used to determine 
whether initiation of ART is indicated in subjects who have been assigned to Arm 2 (ART to be 
initiated at 24 weeks after HIV diagnosis). Subjects who meet these criteria for initiation of 
therapy will be encouraged to start ART. If the subjects agree, they will initiate therapy, which 
will be provided by the study while they are study participants. 
Subjects in Arm 2 (ART initiation at 24 weeks after HIV study enrollment) will be offered therapy 
if: 
1. CD4+ T cell counts fall below 350 cells/mm3  on 2 consecutive determinations at least 4 
weeks apart. 
OR 
2. Participant progresses to WHO clinical stage 3 or 4 irrespective of CD4+ T cell count). 
4.3 MANAGEMENT OF RESISTANCE 
Plasma specimens will be stored for future testing, including HIV genotyping for antiretroviral 
resistance if failure to control viral load is observed during the study. Subjects with resistance to 
one component of the regimen may substitute another antiretroviral agent for that component 
(see Study Specific Procedures for recommended substitutions) but the substituted medication 
will be provided by the study. The substitute medication will be provided by the study while the 
volunteer is participating in the study. 
4.4 MANAGEMENT OF SUBJECTS WITH VIROLOGIC FAILURE OR PREMATURE 
TREATMENT DISCONTINUATION 
For subjects on immediate treatment (Arm 1), suboptimal virologic response will be defined as 
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the following: 
1. Confirmed failure to achieve > 1 logio drop in HIV-1 RNA by week 16 of first antiretroviral 
regimen. If at week 16 there is a < one logio drop in HIV-1 RNA then the HIV-1 RNA test 
must be repeated as soon as possible, preferably within 2 weeks of receipt of the result. 
2. Confirmed failure to achieve HIV-1 RNA level <50 copies/mL by week 24. If at week 24 
HIV-1 RNA remains 50 copies/mL, then the HIV-1 RNA test must be repeated as soon 
as possible, preferably within 2 weeks of receipt of the result. 
3. HIV-1 RNA > 400 copies/mL on 2 consecutive measurements after having achieved 
HIV-1 RNA < 50 copies/mL on 2 consecutive measurements separated by at least 14 
days. 
If suboptimal virologic response occurs, University of Washington Virology Laboratory will 
perform HIV genotypying on a sample drawn before discontinuation of therapy if HIV-1 RNA 
500 copies/mL, in order to determine whether or not resistance has developed and, if so, to aid 
in construction of a new antiretroviral regimen. The substitute medication will be provided by 
the study while the participant remains in the study. If the HIV genotyping reveals no evidence 
of of resistance and compelling arguments (i.e., substantially improved adherence or 
intercurrent illness to possibly explain increased viral load) the original treatment plan can be 
continued.. Any decision to continue medications in the setting of suboptimal virologic response 
must be discussed with the Study Chair/Co-Chair. Further management in terms of whether or 
not to begin a new or altered regimen should proceed at the discretion of the local investigator 
consistent with standards of care, keeping in mind that subjects are previously antiretroviral 
naïve and that potential treatment benefits must be weighed against the risk of further limiting 
antiretroviral treatment options. Subjects will be asked to remain on study to complete all study 
evaluations, during this time and alternative ART regimens will be provided by the Study. 
4.5 MANAGEMENT OF SUBJECTS WHO DO NOT REACH 48 WEEKS IN THE ASSIGNED 
STUDY ARM 
Subjects who do not reach 48 weeks in their assigned study arm will continue to be followed 
and will complete all study evaluations of the final visit. They will be treated in the analysis as 
detailed in Section 11.0. 
5  SELECTION AND ENROLLMENT OF SUBJECTS 
5.1 STEP 1 
5.1.1 Description of Population 
Step 1 will screen MSM and transgender women, unaware of their HIV status and with evidence 
of high risk for acquiring HIV-1 infection, including sexual risk behavior, partner of a newly-
diagnosed person with acute or recent HIV infection, or with symptoms of acute retroviral 
syndrome. These men will have voluntarily visited one of our collaborating testing centers in 
Lima. We will also attempt to increase voluntary testing to help with our recruitment by using 
educational campaigns on acute HIV symptoms, community mobilization for increased 
frequency of testing, advertisements on radio, and recruitment of prior study participants, many 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
of whom in active contact with EPICENTRO, VIA LIBRE and IMPACTA (with its two clinics: San 
Miguel and Barranco). 
5.1.2 Inclusion Criteria 
Individuals will be included in the study if they meet ALL of the following criteria: 
1. Male sex (at birth); 
2. Eighteen years of age or older; 
3. Unaware of their HIV status; 
4. Ability and willingness to provide informed consent for study participation, including 
being tested for HIV-1; for re-testing if HIV negative (Step 2); and to consider enrollment 
in an immediate vs. deferred ART trial (Step 3) if diagnosed with acute or recent HIV 
infection after testing. People diagnosed with HIV infection during participation in Step 2 
will be offered enrollment in Step 3. 
5. Willingness to be re-contacted if HIV seronegative by antibody analysis but with virologic 
evidence of acute infection HIV-1"1" and to be linked to care; 
6.  Evidence of high risk for acquiring HIV-1 infection, including any one of the following: 
a. Sexual behaviors: 
i. Inconsistent condom use during anal intercourse during the last 6 
months; 
ii. Anal intercourse with more than 5 male sex partners during the last 6 
months; 
iii. Self-identification as a sex worker; 
iv. STI diagnosis during the last 6 months or at screening; or 
v. Sexual partner of an HIV-infected man in the last 6 months. 
b. Partner of a newly-diagnosed person with acute or recent HIV infection; 
c. Someone seeking HIV testing because of symptoms of acute retroviral 
syndrome; 
7. Able to provide contact information, including (1) one or more phone numbers (cell 
and/or home) and/or a street address of residence for themselves and (2) personal 
contact information (ideally from two or more people) who would know their whereabouts 
during the study period. 
1 The "1" refers to the footnote which describes the following" "Feibig stage 1 (presence of HIV RNA only) or 
Feibig Stage 2 (presence of HIV RNA and antigen p24) 
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8. Ambulatory performance status 80 on the Karnofsky scale. 
5.1.3 Exclusion Criteria 
1. Any medical, psychological/psychiatric, occupational, or other condition that, in the 
judgment of the investigator, would interfere with, or serve as a contraindication to, 
protocol adherence, assessment of safety, or a participant's ability to give informed 
consent; 
2. Seeking HIV test behavior for routine reasons. 
3. Use of estrogens (or its derivatives) or anti-androgens, administered orally or intra-
muscularly, during the past three months. 
5.2 STEP 2 
In Step 2, high-risk MSM and transgender women with no HIV-1 infection identified in Step 1 will 
be asked to repeat testing every 3 months for incident HIV-1 infection while receiving standard 
risk reduction counseling, condoms, and management of STIs. 
5.2.1 Inclusion Criterion 
Individuals will be asked to participate in repeat testing if they are found to be HIV-negative in 
Step 1. 
5.2.2 Exclusion Criterion 
Any medical, psychological/psychiatric, occupational, or other condition that, in the judgment of 
the investigator, would interfere with, or serve as a contraindication to, protocol adherence, 
assessment of safety, or a participant's ability to give informed consent; 
5.3 STEP 3 
5.3.1 Description of Population 
Step 3 will be conducted among high-risk MSM and transgender women with acute or recent 
HIV infection during their participation in Step 1 or Step 2 willing to be randomized to immediate 
vs. deferred ART, unless ART criteria are met earlier. 
5.3.2 Inclusion Criteria 
1. Determination of acute or recent HIV infection (either in Step 1 or Step 2), as defined by 
the HIV test algorithm described in Section 7.1. (Also see Appendix 1 for Study Flow 
Diagram and Appendix 2 for HIV categories by test results).2  
2 This case definition fulfills the definition of World Health Organization (WHO). According to the 
WHO, HIV case definition among adults and children 18 months or older is as follow: 
• 
Positive HIV antibody testing (rapid or laboratory-based enzyme immunoassay). This is confirmed 
by a second HIV antibody test (rapid or laboratory-based enzyme immunoassay) relying on 
different antigens or of different operating characteristics; 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
a. Acute HIV infection: 
Third-generation HIV test negative (HIV antibody negative), HIV-1 RNA test 
positive, and a confirmatory HIV test positive; 
b. Recent HIV infection: 
Third-generation HIV test positive (HIV antibody positive), HIV negative test 
in Step 2 in the previous 3 months, and a confirmatory HIV positive test. 
Individuals who have been diagnosed with HIV in any health clinic or laboratory 
authorized by the Ministry of Health, and that have had a documented negative result in 
the past three months can also participate in Step 3. 
2. No prior ART, including prior administration of pre- and post-exposure prophylaxis in the 
last 30 days of HIV diagnosis; 
3. Laboratory values obtained within 28 days prior to study entry: 
a. AST (SGOT) and ALT (SGPT) 5 x ULN; 
b. Serum phosphorus > 2.0mg/dI 
c. Serum creatinine < 1.4 x ULN, 
d. Calculated creatinine clearance (CrCI) > 70mUmin (Cockcroft-Gault formula); 
e. Serum lipase 1.5 x ULN. 
4. Ability and willingness to provide written informed consent for being screened and if 
qualifying, to be randomized to immediate vs. deferred ART, to remain in their assigned 
arm and then, continue ART from other sources. 
5.3.3 Exclusion Criteria 
1. Presentation with WHO clinical stage 3 or 4 irrespective of CD4 count. 
2. Use within 21 days prior to study entry of drugs that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with life-
threatening adverse events or drugs that strongly induce CYP3A and lead to lower 
exposure of one or more components and loss of efficacy of STRIBILD and possible 
resistance: alfuzosin, astemizole cisapride, ergot aklaloids and derivatives, flecainide, 
St. John's wort, lovastatin, simvastatin, triazolam, oral midazolam, pimozide, 
propafenone, rifampin, • simvastatin, sildenafil terfenadine, and fluticasone-containing 
and/or; 
• 
Positive virological test for HIV or its components (HIV-RNA or HIV-DNA or ultrasensitive HIV p24 
antigen) confirmed by a second virological test obtained from a separate determination. 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
compounds..  
Check  the  most  recent  co-formulated 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (STRIBILD®) or co-
formulated emtricitabine/tenofovir DF/efavirenz package inserts for other exclusionary 
medications. Estimated creatinine clearance below 70 mL per minute 
3. 
Prior receipt of investigational anti-HIV vaccine. 
4. Ongoing therapy with any of the following: 
a. Systemic corticosteroids. Short course less than or equal to 21 days of 
corticosteroids is allowed; 
b. Systemic chemotherapeutic agents; 
c. Nephrotoxic systemic agents, including aminoglycosides, amphotericin B, 
cidofovir, cisplatin, foscarnet, pentamidine; 
d. Immunomodulatory treatments including Interleukin-2; 
e. Investigational agents; 
5. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their 
formulations; 
6. Active drug or alcohol use or dependence that, in the opinion of the site investigator, 
would interfere with adherence to study requirements; 
7. Serious medical or psychiatric illness that, in the opinion of the site investigator, would 
interfere with the ability to adhere to study requirements; 
8. Chronic (HBsAg positive, anti-HBc positive, Ig M anti-HBc negative, and anti-HBs 
negative) or acute (HBsAg positive, anti-HBc positive, Ig M anti-HBc positive, and anti-
HBs negative) hepatitis B infection. 
9. Use of estrogens (or its derivatives) or anti-androgens, administered orally or intra-
muscularly, during the past three months. 
6  STUDY TREATMENT 
6.1  STEP 1 
No study treatment is offered. 
6.2  STEP 2 
No study treatment is offered. 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
6.3 STEP 3 
6.3.1 Regimens, Administration, and Duration 
6.3.1.1 Regimen 
Those participants, who have initiated their participation in the study before the approval of 
Amendment Letter #1 in this study protocol, will continue their participation as originally 
programmed. 
Once the Amendment Letter #1 is approved for this study protocol, the participants who are 
eligible for Step 3 will be given treatment the following way: 
• 
Those people diagnosed with acute HIV infection will be offered immediate ART (just at time of 
the enrollment visit or during the next 48 to 72 hours) for the duration of 48 weeks. 
Weeks 0-48: Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate (or co-formulated emtricitabine/tenofovir DF/efavirenz) orally once daily. 
Those people diagnosed with recent HIV infection will be randomized to one of the following 
arms: 
1. Arm 1: 
Weeks 0-48: Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate (or co-formulated emtricitabine/tenofovir DF/efavirenz) orally once daily. 
2. Arm 2: 
Week 0-24: No treatment unless Peruvian criteria for initiation of treatment are met. 
Week 25-48: Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate (or co-formulated emtricitabine/tenofovir DF/efavirenz) orally once daily. 
6.3.1.2 Administration 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate will be 
administered as one tablet orally once daily with food. Co-formulated emtricitabine/tenofovir 
DF/efavirenz) will be administered as one tablet orally once daily at bedtime with or without 
food. 
6.3.1.3 Duration 
Those participants, who have started their participation in the study before the approval of 
Amendment Letter #1 in this study protocol, will continue their participation as originally 
programmed. 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
Once the Amendment Letter #1 is approved for this study protocol, the participants who have 
been diagnosed with acute HIV infection, and decide to participate in the study will receive 
treatment duration of 48 weeks. 
For the people who are diagnosed with recent HIV infection and decide to participate, 
treatment will depend on which arm they are assigned to: 
Arm 1 will receive study treatment for 48 weeks. Arm 2 will receive no treatment for 24 weeks 
and then receive 24 weeks of study treatment. However, if during the first 24 weeks of no 
treatment, clinical, virologic, or immunologic criteria of treatment initiation are met, subject will 
be offered treatment initiation. ART will be provided by the study for the duration of the time that 
the participant remains in the study. At the end of study, participants will continue ART from 
other sources. 
6.3.2 Product Formulation and Preparation 
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (STRIBILDO) is co-formulated 
to contain 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of 
tenofovir disoproxil fumarate. in each tablet. Emtricitabine/tenofovir DF/efavirenz (AtriplaTM) is 
co-formulated to contain 200 mg of emtricitabine, 300 mg of tenofovir DF and 600 mg of 
efavirenz in each tablet. Each bottle contains a silica gel desiccant canister that should remain 
in the original container to protect the product from humidity. Dispense in the original container. 
Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). 
Co-formulated emtricitabine/tenofovir (Truvada Tm) contains 200 mg of emtricitabine and 300 mg 
of tenofovir DF in each tablet. Each bottle contains a silica gel desiccant canister that should 
remain in the original container to protect the product from humidity. Dispense in the original 
container. Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F). 
Efavirenz of 600 mg in each tablet, will be dispensed in blister packs of 10 tablets. Store at 25 
°C (77°F), excursions permitted to 15°-30°C (59°-86°F). 
6.3.3 Product Supply 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (STRIBILDO) will 
be provided by Gilead Sciences, Inc while co-formulated emtricitabine/tenofovir DF/efavirez 
(Atripla Tm) will be provided by Merck & Co., Inc., under previous agreement with Gilead 
Sciences. Co-formulated emtricitabina/tenofovir DF (TruvadaTm) will be provided by Gilead 
Sciences. Efavirenz will be purchased locally from commercially available sources. 
6.3.4 Pharmacy Facilities 
The pharmacy facilities are located at the IMPACTA Barranco and IMPACTA San Miguel 
Clinical Research Sites and both are staffed by registered trained pharmacists.  Both 
pharmacies will have adequate space to store sufficient quantities of study agent to assure 
continuous access to all study participants. The study drug will be stored in accordance with the 
drug manufacturer's recommendations. Both pharmacies' storage and the study pharmacies will 
be locked by a secure door. The pharmacies and storage facilities have climate-controlled 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
environments, with controlled humidity and temperature to remain within limits allowed by the 
manufacturer for drug storage. 
6.3.5 Drug Inventory 
The pharmacists at the IMPACTA Barranco and IMPACTA San Miguel Clinical Research Sites 
will receive the study agent and store it in the pharmacy. Access will be restricted to authorized 
pharmacy personnel only. The pharmacists will be responsible for keeping accurate records of 
the material received. At the end of the study, the pharmacists will perform the final drug 
accounting of unused study material on the proper log documents. Unused study agent will be 
disposed of in accordance with local regulations. 
6.3.6 Drug Dispensing 
The Study Pharmacist will be responsible for dispensing the drug to the Study Nurse who will 
deliver it to the participant. At each visit, the pharmacist will receive the prescription that 
includes the participant's enrollment ID number. The pharmacist will dispense drug according to 
the randomization procedure below. For bottle dispensed, the pharmacist will enter the packed 
label information and date in a Drug Dispensation Log, to be kept secure in the Pharmacy. 
6.3.7 Concomitant Medications 
To avoid adverse events caused by drug interactions, investigators must refer to the most 
recent package insert for study drug and concomitant agents whenever a concomitant 
medication is initiated or a dose is changed. 
Sites must also refer to the study product's most recent package insert or investigator brochure 
to access additional current information on prohibited and precautionary medications. 
Below are lists of selected concomitant medications. These lists are only current as of the date 
of this protocol. Therefore, whenever a concomitant medication or study agent is initiated or a 
dose changed, investigators must review the concomitant medication's and study agent's most 
recent package inserts or investigator brochure to obtain the most current information on drug 
interactions, contraindications, and precautions. 
6.3.7.1 Precautionary Medications 
Package inserts of antiretroviral drugs and concomitant agents should be referenced whenever 
a concomitant medication is initiated or a dose is changed to avoid drug interaction AEs. 
6.3.7.2 Prohibited Medications 
Co-administration with drugs that are highly dependent on CYP3A for clearance and for 
which elevated plasma concentrations are associated with serious and/or life-threatening 
events is contraindicated. These drugs and other contraindicated drugs (which may lead to 
reduced efficacy of STRIBILD and possible resistance) are listed in the table below. 
Drugs that are Contraindicated with STRIBILD 
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Test and Treat Early HIV among MSM and Trans gender Women in Lima, Peru 
MEDICATION CLASS 
ALPHA 1-
ADRENORECEPTOR 
ANTAGONIST 
ANTIMYCOBACTERIAL 
ERGOT DERIVATIVES 
GI MOTILITY AGENT 
HERBAL PRODUCTS 
HMG-COA REDUCTASE 
INHIBITORS 
NEUROLEPTIC 
PHOSPHODIESTERASE-5 
(PDE5) INHIBITOR 
SEDATIVE/HYPNOTICS 
PROHIBITED MEDICATIONS 
Alfuzosin 
Rifampin 
Dihydroergotamine 
Ergotamine 
Methylergonovine 
Cisapride 
St. John's wort (Hypericum 
perforaturn) 
Lovastatin 
Simvastatin 
Pimozide 
Sildenafil when dosed as 
REVATIO for the treatment of 
pulmonary arterial hypertension 
Triazolam 
Orally administered midazolam 
Drugs that are contraindicated with Atripla 
Medication Class 
Prohibited Medications* 
ANTIHISTAMINES 
astemizole (Hismanal)  . 
terfenadine (Seldane) 
ANTI-INFECTIVES 
rifampin (Rifadin, Rimactane) 
GASTROINTESTINAL- 
cisapride (Propulsid) 
MOTILITY 
HYPOLIPEMICS 
lovastatin (Mevacor) 
simvastatin (Zocor) 
PSYCHIATRIC 
pimozide (Orap) 
St. John's wort (Hypericum perforatum) 
MEDICATIONS 
SEDATIVES 
midazolam (Versed)** 
triazolam (Halcion) 
OTHER 
alfuzosin (Uroxatral) 
dexamethasone 
dihydroergotamine (Migranal, Cafergot) 
eletriptan (Relpax) 
ergonovine (Ergotrate, Ergostat) 
ergotamine (Ergostat, Gotamine, Bellergal) 
fluticasone containing compounds (e.g., flonase, 
Flovent, Advair) 
methylergonovine (Methergine, Wigraine) 
* Some brand names are showed, but attention must be taken about the generic name. 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
**A single dose of midazolam may be used for sedation in subjects undergoing procedures in a 
monitored setting. 
NOTE: Subjects receiving the medications listed above who are randomized to receive 
immediate or deferred ART during the course of the study must agree to receive an alternative 
antiretroviral regimen that has been approved by the Protocol Chair. 
6.3.7.3 Options for Medication Substitutions Due to Intolerance/Toxicity 
If intolerance or toxicity occurs, substitutions may be made to the study regimen, after 
discussion with the Protocol Chair, as long as the new regimen is consistent with current 
guidelines for potent ART. The substituted medications will be provided by the study for the 
duration of time that the participant remains in the study. The purpose of the study is to 
determine whether ART in general, not necessarily this specific regimen, affects the impact of 
immediate and deferred ART on the decay dynamics of HIV viral load in plasma, semen and 
rectal secretions of individuals with acute or recent infection. 
6.3.7.4 Options for Medication Substitutions for Virologic Failure 
If a subject develops virologic failure on the study regimen further management based in clinical 
judgment should proceed at the discretion of the On-Site Principal Investigator in consultation 
with the Protocol Chair. . 
Substitutions in antiretroviral regimens during the course of the study are at the discretion of the 
site investigator. It is the site investigator's responsibility to review all concomitant medications 
to ensure safety. The protocol pharmacist is available for discussion if questions arise. 
The substituted medications will be provided by the study for the duration of time that the 
participant remains in the study. 
6.3.8 Adherence Assessment 
Adherence will be assessed via validated self-report measures, pharmacy refill-based 
measures, and unexpected increases in HIV plasma viral load. Specifically, the Visual Analogue 
Scale [171] and the Ability Likert item [172] will be used to collect self-reported adherence over 
the past 30 days, collected monthly. These measures have demonstrated consistent 
associations with viral load in other studies [173]. Because self-report has a number of 
limitations, including a tendency of over-estimate adherence in comparison to electronic drug 
monitoring measures as well as potentially high demands on other cognitive processes to 
produce accurate reports [174], we also will monitor pharmacy dispensation records to produce 
medication possession ratios (days covered by a script/days between scripts) in approximately 
3-month intervals. Pharmacy-based measures of adherence have consistently been associated 
with clinical outcomes in previous research [175, 176]. We will not monitor ART blood levels 
because a) this is not done as part of routine clinical practice, b) the tests would only refer to 
recent adherence rather than adherence over time, and c) it is rather expensive to conduct 
these tests. 
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STEP 2 
Quarterly re-testir g 
HIV testing 
301 gen HIV ah- 
3rd gen HIV ab+ 
confirm test + 
MStvi at high risk  for HIV infection 
STEP 1 
Consent to FIN testing? 
31  generation NW antibody test, confirmatory HIV antigen/RNA, 
testing, re-contact, sequencing & specimen storage. 
Wiling to consider enrollment in STEP 3 if diagnosed with acute or 
recent infection 
IMSIv1 at low 'sk f or FIN if potion 
Cohort of high-risk men 
recruited by the study 
from the community for 
repeat testing for HIV 
Not eligib e for study 
No 
let 
HIV RNA testing 
Not eligible for study 
Prior HIV- test in 
STEP 2 within 
past 6 months 
res 
110 
NAAT RNA + 
Confirm test + 
NAAT RNA- 
(for cohort 
only) 
Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
7  STUDY PROCEDURES 
7.1  STUDY DIAGRAM 
CHRONIC HI,/ INFECTION 
RECENT HIV INFECTION 
ACUTE HIV INFECTION 
Refer to regular FIN 
care or other studies 
STEP 3 
Screen, enroll, randomize to immediate vs deferred treatment 
Patient Flow Diagram 
7.2 STEP 1 
Written informed consent will be obtained prior to the conduct of any study procedure. Potential 
study participants will undergo eligibility screening (see Section 5.2.1.) by an interviewer. 
Eligibility will be determined based on participant responses to an interviewer-administered 
eligibility checklist. Study Step 1 activities will be conducted at the following sites: EPICENTRO, 
VIA LIBRE and IMPACTA San Miguel Clinical Research Site and IMPACTA Barranco Clinical 
Research Site. 
7.2.1 Clinical Procedures 
The following procedures will be performed at Step 1 Visit: 
1. Explain the purpose of the visit and the informed consent and eligibility determination 
processes; 
2. Determine eligibility, using Screening Eligibility Checklist (interviewer-administered); 
3. Ascertain participant identity and assign Participant ID (PID) number; 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
4. Obtain written informed consent for willingness to consider study participation; 
5. Deliver HIV and STD pre-test and risk reduction counseling; obtain written informed 
consents for HIV testing and stored blood for future testing. HIV and STD counseling 
includes encouraging, training in, and negotiation of condom use with partners and 
provision of lubricated condoms. Counselors will also discuss risk reduction by 
discussion of HIV serostatus and risks with new and existing partners, reduction of 
number of sexual partners, and the importance of prompt treatment for STDs; 
6. Collect participant contact and locator information; 
7. Administer Screening Questionnaires 
8. Obtain 18.5 ml of venous blood for HIV and syphilis testing; and if acute or recent HIV 
infection is detected, other blood tests to evaluate overall health. These tests include 
liver function, Hepatitis B serology and HIV RNA; 
9. Administer complete physical exam; 
10. Provide results on HIV rapid test (per study HIV diagnosis algorithm —Section 7.1.) and 
syphilis test (diagnosis following Ministry of Health of Peru guidelines); and deliver post-
test counseling; 
11. Deliver counseling on potential strategies for re-contacting HIV seronegative individuals 
with evidence of acute infection (HIV-1 RNA positive) for further HIV testing and linkage 
to care; 
12. Provide study site contact information and instruct the participant to contact the study 
site for additional information or counseling, if needed; 
13. Refer for STD treatment or treat according to Ministry of Health of Peru guidelines 
14. If no HIV infection is diagnosed and eligibility criteria are met (see Section 5.2.), refer to 
Step 2and schedule a First Visit to occur in 30 days (+1- 15 days); 
15. If acute or recent HIV infection is diagnosed, refer to Step 3: Participants will be asked to 
come to the IMPACTA Barranco or IMPACTA San Miguel Clinical Research Site as 
described in the Study Specific Procedures; 
16. If chronic HIV infection is diagnosed, participant is not eligible for study participation. 
Participant should be referred to other sources of HIV care, including standard care at no 
charge under Peruvian guidelines or to other studies if available; 
17. Document all referrals; 
18. Complete and enter all required data collection forms. 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
7.2.2 Laboratory Evaluations 
1. HIV testing 
The following tests will be used for establishing HIV status in this protocol: Determine TM  
HIV-1/2 [Alere/Abbott Laboratories] (third-generation HIV test), GS HIV Combo Ag/Ab 
EIA [Bio-Rad] (fourth-generation HIV test) and LiatTM HIV Quant Assay [IQuum] (HIV-1 
RNA test) will be used in this algorithm (see Section 7.1). 
2. Sexually Transmitted Infection Testing 
Syphilis screening testing will be conducted by RPR and confirmed by MHA-TP if 
reactive. Syphilis diagnosis and treatment will follow Ministry of Health of Peru 
guidelines. 
7.3  STEP 2 
7.3.1 Regular Follow-Up Visit 
Participants who test HIV-uninfected in Step 1 and still meet eligibility criteria (see Section 
5.2.2.) will be followed in a prospective cohort study. Study Step 2 activities will be conducted 
at the following sites: EPICENTRO, VIA LIBRE,IMPACTA San Miguel Clinical Research Site 
and IMPACTA Barranco Clinical Research Site. The follow-up of participants will be every 30 
days. At each follow-up visit, the following procedures will be performed: 
1. Confirm participant identity and PID number; 
2. Update locator information; 
3. Administer Follow-up Questionnaire for assessment of sexual risk behavior and 
socialization venues; 
4. Deliver HIV and STD pre-test and risk reduction counseling; obtain written informed 
consents for HIV testing.. HIV and STD counseling includes encouraging, training in, 
and negotiation of condom use with partners and provision of lubricated condoms. 
Counselors will also discuss risk reduction by discussion of HIV serostatus and risks with 
new and existing partners, reduction of number of sexual partners, and the importance 
of prompt treatment for STDs; 
5. Obtain 18.5 ml of venous blood for HIV and syphilis testing (every 3 months) and if acute 
or recent HIV infection is detected, other blood tests to evaluate overall health. These 
tests include liver function, Hepatitis B serology and HIV RNA; 
6. Administer targeted physical exam, if symptoms are reported; 
7. Provide results on HIV rapid test (per study HIV diagnosis algorithm — Section 7.1), and 
syphilis test (diagnosis following Ministry of Health of Peru guidelines); and deliver post-
test counseling; 
8. Deliver counseling on potential strategies for re-contacting HIV seronegative individuals 
with evidence of acute infection (HIV-1 RNA positive) for further HIV testing and linkage 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
to care; 
9. Provide study site contact information and instruct the participant to contact the study 
site for additional information or counseling, if needed; 
10. Refer for STD treatment or treat according to Ministry of Health of Peru guidelines; 
11. If no HIV infection diagnosis schedule a Step 2 Follow-up Visit to occur in 30 days (+/-
15 days). 
12. If acute or recent HIV infection diagnosed, participants will be asked to come to the 
IMPACTA Barranco or IMPACTA San Miguel Clinical Research Site as described in the 
Study Specific Procedures; 
13. If chronic HIV infection is diagnosed, participant is not eligible for inclusion in the study. 
Participant should be referred to other sources of HIV care, including regular care or 
other studies if available; 
14. Document all referrals; 
15. Confirm schedule for next quarterly visit; 
16. Complete and enter all required data collection forms. 
7.3.2 Interim Contacts and Visits 
Interim contacts and visits may be conducted at participant request at any time during Step 2. 
Interim HIV/STD counseling and testing should be provided as needed in response to 
participant reports a potential high risk sexual exposure, STD symptoms, partner of a newly-
diagnosed person with acute or recent HIV infection; symptoms of acute retroviral syndrome. 
All interim contacts and visits will be documented in participants' study records. 
7.3.3 Laboratory Evaluations 
Laboratory evaluation will follow what is described in Section 7.2.2. 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
7.4 STEP 3 
7.4.1 Timing of Visits 
Those participants, who have initiated their participation in the study before the approval of Amendment Letter #1 in this study protocol, will continue their participation as originally 
Procedure 
Study Visit 
Week 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Enrolment and 
sample storage 
informed consents 
X 
Acute or recent HIV-1 
counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB screening 
X*** 
CBC 
X 
X 
X 
X 
X 
X 
Chemistry/LFT 
X 
X 
X 
X 
X 
Lipid panel 
X*** 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis B serology 
STI testing 
X 
X 
X 
X 
CD4+/CD8+ cells 
count 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Semen and rectal 
secretion collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening 
questionnaire - 
Demographics 
X 
AUDIT 
X 
Interviewer— Monthly 
questionnaire* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quarterly 
questionnaire** 
X 
X 
X 
X 
X 
Pharmacy Refills 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood volumes (m1) 
60.0 
10 
10 
21.5 
10 
21.5 
21.5 
10 
10 
21.5 
0 
0 
13 
0 
0 
21.5 
*Monthly interviewer-administered questionnaire containing: Timeline Follow Back (alcohol use and sexual behavior), Visual analog scale for ART adherence, and Medication 
adherence program choices 
**Quarterly questionnaire containing: Drug and alcohol use (drug use history, DAST 10, drinking expectancies); Mental health and wellbeing (RAND 12, Social support scale, Stigma 
scale, Stigma and disclosure, Partner notification, Intimate partner violence, 10 item CES-D, CID Mental health items on anxiety, stress & coping; Medical care (Hospitalization and ER 
use, Barriers to care, Access to care, Self-efficacy for ART use). *** These will be done within 72 hours. 
prog 
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Test and Treat Early HIV among MSM and Transgender Women in Lima, Peru 
Once the Amendment Letter #1 for this study has been approved, the participants who are eligible will enter Step 3 and they will be 
participate in the following way: 
Procedure 
Week 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
40 
4 
4 
48 
Enrolment and sample 
storage informed 
consents 
X 
Acute or recent HIV-1 
counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB screening 
X*** 
CBC 
X 
X 
X 
X 
X 
X 
Chemistry/LFT 
X 
X 
X 
X 
X 
Lipid panel 
X*** 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Hepatitis B serology 
STI testing 
X 
X 
X 
X 
C04+/CD8+ cells count 
X 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Semen and rectal 
secretion collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening 
questionnaire - 
Demographics 
X 
AUDIT 
X 
Interviewer — Monthly 
questionnaire* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quarterly 
questionnaire** 
X 
X 
X 
X 
X 
Pharmacy Refills 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hair Sample 
X 
x 
x 
x 
x 
Blood volumes (ml) for 
participants with 
immediate treatment 
160 
60 
60 
71.5 
10 
121.5 
21.5 
110 
10 
121.5 
50 
50 
50 
100 
13 
100 
0 
121.5 
Blood volumes (m1) for 
participants with deferred 
treatment 
230 
60 
60 
71.5 
0 
201.5 
21.5 
190 
10 
201.5 
50 
50 
50 
100 
13 
100 
0 
121.5 
*Monthly interviewer-administered questionnaire containing: Timeline Follow Back (alcohol use and sexual behavior), Visual analog scale for ART adherence, and Medication 
adherence program choices 
**Quarterly questionnaire containing: Drug and alcohol use (drug use history, DAST 10, drinking expectancies); Mental health and wellbeing (RAND 12, Social support scale, Stigma 
scale, Stigma and disclosure, Partner notification, Intimate partner violence, 10 item CES-D, CID Mental health items on anxiety, stress & coping; Medical care (Hospitalization and ER 
use, Barriers to care, Access to care, Self-efficacy for ART use). *** These will be done within 72 hours. 
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7.4.2 Timing of Evaluations 
7.4.2.1 Entry Evaluations (Week 0 Visit) 
Subjects diagnosed with acute HIV infection must begin treatment within 72 hours after 
randomization, and preferably within 24 hours.Subjects randomized to Arm 1 must begin 
treatment within 72 hours after randomization, and preferably within 24 hours. 
7.4.2.2 On-Study Evaluations 
On-study evaluations will occur according to the schedule of events as specified in Section 
7.4.1. On-study evaluations will occur according to the schedule of events as specified in 
Section 7.4.1. according to whether the participant was enrolled before or after the approval of 
Amendment 1, of this protocol. A study visit will be considered missed if it is not completed 
before half of the time between the current and next study visit has elapsed. 
. Study visit windows will be +1- 5 days for scheduled study visits. 
7.4.2.3 Evaluations for Subjects Randomized to Arm 1 Who Do Not Start Study Treatment 
Subjects with recent HIV infection randomized to Arm 1 (immediate treatment) who do not start 
study treatment will be followed according to the originally specified schedule of evaluations. 
7.4.2.4 Evaluations for Subjects Who Start Treatment without Meeting Eligibility Criteria 
Subjects with recent HIV infection randomized to Arm 2 (deferred treatment to be started at 24 
weeks after HIV-1 diagnosis) who elect to start treatment despite not meeting criteria for 
treatment initiation will be invited to continue to be followed according to the originally specified 
schedule of evaluations. Study medication will not be provided to these subjects. The ART 
treatment will not be provided by the study in this case. 
7.4.2.5 Premature Treatment Discontinuation Evaluation Provided by the Study 
Subjects who voluntarily discontinue treatment provided by the study will be advised to 
continue anti-retroviral treatment with public or private sources. The study investigators will take 
necessary steps to ensure that the subjects continue ART. Counseling will be provided with a 
special emphasis on safety, and later efficacy options to use in the future if the participant 
decides to discontinue ART provided by the study and not continue with any other. All the 
participants will be invited to continue with the follow-up evaluations according to the originally 
specified "Timing of Visits". 
7.4.2.6 Premature Study Discontinuation Evaluations and Voluntary Treatment Provided 
by the Study 
Subjects who elect to withdraw from participation in the study prior to completion of the study 
will have all final evaluations performed for the end of the study as described in visit for Week 
48. 
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7.4.3 Definitions of Evaluations and Special Instructions 
7.4.3.1 Medical History 
A medical history must be present in source documents. The medical history should be 
comprehensive and include HIV-1 related and non-related diagnoses. Details of acute HIV 
seroconversion signs and symptoms and HIV risk behaviors should be included. Any allergies 
to any medications and their formulations must be documented. 
7.4.3.2 Medication History 
A medication history must be present in source documents, including any history of antiretroviral 
medication, immune-based therapy, or HIV-1-related vaccines, including blinded study 
medications. 
All prescription medications taken within 30 days prior to study entry, including actual or 
estimated start and stop dates, should be included in both the source documents and on the 
case report forms (CRFs). 
All nonprescription medications taken within 30 days prior to study entry, including actual or 
estimated start and stop dates, should also be included in source documents. 
7.4.3.3 Concomitant Medications 
All concomitant medications taken since the last report must be recorded in the source 
documents and CRFs and must include start dates and stop dates. 
7.4.3.4 Study Treatment Modifications 
All modifications to study drug(s) including initial doses, subject-initiated and/or protocol-
mandated interruptions, modifications, and permanent discontinuation of treatment must be 
recorded at each visit in the source documents and CRFs. 
7.4.3.5 Clinical Assessments 
1. Complete physical exam  
A complete physical exam is to be performed at study entry and study completion. 
2. Targeted physical exam  
A targeted physical examination is required as clinically indicated. 
3. Height to be collected at study entry. 
4. Weight to be collected at all study visits. 
5. Vital signs  
Oral temperature, pulse, and blood pressure to be collected at all visits. 
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6. Sims and symptoms 
All signs, symptoms, and toxicities at entry must be documented in the subject's record 
and on the CRFs. Unless otherwise specified, after entry, only grade 3 and all signs 
and symptoms that led to a change in treatment, regardless of grade, must be recorded 
on the CRFs. The "Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events Version 1.0, December, 2004; Clarification August 2009" must 
be used and is available at http://rsc.tech-res.com/safetyandpharmacoviqilance 
 
7. Tuberculosis screening 
Potential participants will be taken to a nearby clinic for TB screening (sputum acid fast 
bacilli stain and chest X-ray). Chest X-rays will be offered as part of the study 
procedures. Tuberculosis prophylaxis will be provided to participants according to 
Ministry of Health of Peru guidelines. 
8. Leukapheresis procedure  
A subset of SABES? participants (N = 40) will undergo leukapheresis. There is a 
separate consent form and only those who are newly enrolled and volunteer for this 
procedure will have it performed. Qualitative assessment of the HIV reservoir (including 
its localization in different CD4+ T cell subsets) will require large numbers of cells, which 
is important as both size and distribution of the HIV reservoir will be key factors in 
strategies to induce a functional cure. Thus, we will use leukapheresis to collect large 
samples at critical time points (baseline, 24 and 48 weeks). 
9. Diagnoses  
All confirmed and probable diagnoses made since the last visit must be recorded in the 
source documents and CRFs. The following diagnoses will be recorded in source 
documentation and CRFs: U.S. Center for Disease Control and Prevention Category B 
and C diagnoses, major organ disease including but not limited to diabetes, 
cardiovascular disease and stroke, hepatitis, avascular necrosis, fat redistribution 
including central fat accumulation and peripheral fat wasting (as noted by subject and 
site staff and/or primary care provider). Please refer to AIDS Clinical Trials Group 
Appendix 60 for specific diagnoses and definitions which can be found at 
http://www.hptn.orq/web%20documents/HPTN052/Appendix60V1.123Feb2007.pdf.  
7.4.3.6 Laboratory Evaluations 
The "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Version 1.0, December, 2004; Clarification August 2009" must be used and is available at 
http://rsc.tech-res.com/safetyandpharmacovigilance.  
All laboratory values must be documented in the subject's record and recorded on the CRFs. 
Subsequently, all laboratory values must be documented in the subject's record, but unless 
otherwise specified, only laboratory values Grade 3 must be recorded on the CRFs. Any 
laboratory toxicity that led to a change in treatment, regardless of grade, must be recorded on 
the CRFs. Laboratory evaluations that do not have a grading scale in the "Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0, December, 
2004; Clarification August 2009" must be collected on the CRFs if the values are outside the 
upper or lower limit of normal. All values for total HDL and LDL cholesterol, and triglycerides 
should be recorded on the CRFs at baseline and every 12 weeks, regardless of toxicity grade. 
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1. Hematology 
Hemoglobin, white blood cell count, absolute neutrophil count, platelets; 
2. Blood chemistries  
Serum amylase, lipase, bicarbonate, phosphorus, creatinine, AST (SGOT), ALT (SGPT), 
alkaline phosphatase. 
3. Lipid panel 
Subjects should be fasting for at least 8 hours when possible. Triglycerides, total 
cholesterol, HDL, LDL; 
4. Urinalysis  
Dipstick, and microscopic exam if dipstick positive; 
5. Hepatitis B serology 
Potential participants will be tested for hepatitis B infection through HBsAg, anti-HBc and 
anti-HBs. The interpretation of the results will be based in the US Center for Diseases 
Control and Prevention Hepatitis B Serology Interpretation (available at http://www.U.S.  
Center for Disease Control and Prevention.qov/hepatitis/HBV/HBVfaci.htmltoeneral). 
Individuals with chronic or acute hepatitis B infection will not be eligible to participate. 
Hepatitis B susceptible participants will be offered hepatitis B vaccination according 
Ministry of Health of Peruvian guidelines. 
6. Sexually transmitted infection testing 
Syphilis screening testing will be conducted by RPR and confirmed by MHA-TP if 
reactive. Syphilis diagnosis will follow Ministry of Health of Peru guidelines. A positive 
leukocyte esterase test by a urine dipstick will trigger a microscopic examination. 
Further confirmation with a nucleic acid amplification test for N. gonorrhoeae and C. 
trachomatis will follow if a diagnosis of urethritis is made. 
7.4.3.7 Immunologic Studies 
1. CD4+/CD8+ T-cell subsets 
A CD4+ T-lymphocyte percent of total lymphocytes and CD8+ T-lymphocyte percent of 
total lymphocytes should be performed in addition to the absolute CD4+ and CD8+ T cell 
counts at screening and for all visits at which CD4+/CD8+ T cell counts are required. 
Because of the diurnal variation in CD4+ and CD8+ cell counts, determinations for 
individual subjects should be obtained consistently in either the morning or the afternoon 
throughout the study, if possible. 
NOTE: Each time a CD4+/CD8+ measurement is obtained, the local laboratory must 
perform a WBC and differential from a sample obtained at the same time. 
7.4.3.8 Virologic Studies 
1. Plasma HIV-1 RNA 
All HIV-1 RNA testing will be performed using the Abbott m2000 RealTime System 
(Abbott Molecular) at the IMPACTA PERU Clinical Trials Unit Central Laboratory, which 
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is certified by the U.S. NIH/NIAID/DAIDS Virology Quality Assurance (VQA) Program. 
The baseline value will be the HIV-1 RNA level at the entry evaluation. 
The results from the analysis of Plasma HIV-1 RNA for the visits 0, 12, 24, 36, and 48 
will be available at the next follow-up visit to guide the medical management decision-
making for each participant, according to the HIV management standards. 
The plasma samples for RNA HIV-1 determination from visits 1, 2, 4, 6, 8, 16, and 20 will 
not be processed in real time. Since these determinations are exlusively research 
purposes, the samples will be processed at a later time. 
2. Phylooenetic Analyses  
HIV-1 sequencing and phylogenetic analysis will be performed at The University of 
Washington Molecular Genetics Laboratory 
7.4.3.9 Genotype 
HIV-1 genotype in stored samples will be performed by the University of Washington Virology 
Specialty Laboratory at the end of the study or when required per clinical judgment at time of 
suboptimal virologic response. 
7.4.3.10 Semen and Rectal Secretions 
Semen and rectal secretion specimens will occur according to the schedule of events as 
specified in Section 7.4.1. Samples will be initially processed and stored as stated in the 
Protocol Study Specific Procedures. HIV-1 viral load in semen and rectal secretions will be 
tested at the University of Washington Retrovirology Laboratory at the end of the study. 
7.4.3.11 Stored Plasma 
At all-time points for which an HIV-1 RNA level is required the remaining plasma after the HIV-1 
RNA assay is performed will be stored. 
7.4.3.12 Hair. This section has been created to describe the following: 
The collection of a snip of hair (approximately 80 or 120 individual hairs) will be obtained from 
the scalp of the participants using a pair of scissors, as specified in section 7.4.1. If it is not 
possible to obtain hair from the scalp, then hair from face, extremities or pubic region may be 
obtained, also using a pair of scissors. The hair samples will be analyzed in ethyl glucuronide 
(marker for chronic alcohol consumption)3 and a commercially available kit will be used for the 
analysis of cocaine, marijuana, phencyclidine, amphetamines, and opioid consumption. 
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7.4.3.12 Hair. As a result of the above change, the following foot note has been added: 
3 Drug Testing: A white paper of The American Society of Addiction Medicine. 2013. 
http://www.asam.oro/docs/default-source/public-policy-statements/drua-testino-a-white-paper-byasam.odf  
7.4.3.13 Questionnaires 
Interviews will either be administered by interviewers (monthly) or self-administered by 
participants (quarterly). 
The AUDIT will be administered at the first visit only, along with a short questionnaire, including 
demographics, health literacy, and another short questionnaire. 
A questionnaire (roughly 60 minutes) will be administered at the first study visit and then 
quarterly. It will contain several modules as follows: 
1. Drug and alcohol use (drug use history, DAST 10, drinking expectancies); 
2. Mental health and well being (RAND 12, Social support scale, Stigma scale, Stigma and 
disclosure, Partner notification, Intimate partner violence, 10 item CES-D, CID Mental 
health items on anxiety, Stress & Coping; 
3. Medical care (Hospitalization and ER use, Barriers to care, Access to care, Self efficacy 
for ART use). 
In addition, there will be a monthly interviewer-administered questionnaire containing the 
following items: Timeline Follow Back (alcohol use and sexual behavior), Visual analog scale for 
ART adherence, and Medication adherence program choices. 
The Timeline Follow Back questionnaire includes questions on sexual partners. We will collect 
anonymous interview data about partners (including number of partners, type of partner [main, 
casual, anonymous], etc.). We will also counsel men on the need to inform recent sexual 
partners that they may have been exposed to HIV. Scripts have been developed to guide this 
process. In brief, all participants will be provided with intensive one-on-one partner notification 
counseling with a trained member of the staff. First party partner notification (notification of 
partners by the index HIV-infected MSM and transgender women) will be encouraged and 
supported by use of a printed referral card. Third party notification (notification by the provider 
that a person may have been exposed to HIV) will be offered as an option in situations where 
the participant does not want to or does not feel comfortable notifying their partner directly. All 
third party notifications will be anonymous (i.e., will not reveal participants' names or other 
identifying information). Any partners who wish to be tested for HIV will be offered free HIV 
testing at IMPACTA Barranco or IMPACTA San Miguel Clinical Research Site (the study sites). 
8 WARNINGS AND PRECAUTIONS 
8.1  LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS 
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Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been 
reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A 
majority of these cases have been in women. Obesity and prolonged nucleoside exposure may 
be risk factors. Particular caution should be exercised when administering nucleoside analogs 
to any patient with known risk factors for liver disease; however, cases have also been reported 
in patients with no known risk factors. 
Treatment with co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate 
or co-formulated emtricitabine/tenofovir DF/efavirenz should be suspended in any patient who 
develops clinical or laboratory findings suggestive of lactic acidosis or pronounced 
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked 
transaminase elevations). 
8.2  PATIENTS WITH HIV AND HBV COINFECTION 
It is recommended that all patients with HIV be tested for the presence of hepatitis B before 
initiating antiretroviral therapy.  Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir 
disoproxil fumarate or co-formulated emtricitabine/tenofovir DF/efavirenz is not indicated for the 
treatment of chronic HBV infection and the safety and efficacy of co-formulated 
emtricitabine/tenofovir DF/efavirenz have not been established in patients co-infected with 
hepatitis B virus and HIV. Severe acute exacerbations of hepatitis B have been reported in 
patients after the discontinuation of emtricitabine and tenofovir DF. Hepatic function should be 
closely monitored with both clinical and laboratory follow-up for at least several months in 
patients who discontinue co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil 
fumarate or co-formulated emtricitabine/tenofovir DF/efavirenz and are co-infected with HIV and 
HBV. 
HIV-1/hepatitis B co-infected individuals will not be enrolled in this study. 
8.3 PSYCHIATRIC SYMPTOMS 
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. 
In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 
years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency of 
specific serious psychiatric events among patients who received efavirenz or control regimens, 
respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal 
suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 
0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted 
above were combined and evaluated as a group in a multifactorial analysis of data from Study 
A1266006 (006), treatment with efavirenz was associated with an increase in the occurrence of 
these selected psychiatric symptoms. Other factors associated with an increase in the 
occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, 
and receipt of psychiatric medication at study entry; similar associations were observed in both 
the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric 
symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. 
One percent of efavirenz-treated patients discontinued or interrupted treatment because of one 
or more of these selected psychiatric symptoms. There have also been occasional post-
marketing reports of death by suicide, delusions, and psychosis-like behavior; although a causal 
relationship to the use of efavirenz cannot be determined from these reports. 
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Patients with serious psychiatric adverse experiences should seek immediate medical 
evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, 
and if so, to determine whether the risks of continued therapy outweigh the benefits 
8.4 NERVOUS SYSTEM SYMPTOMS 
Fifty-three percent of patients receiving efavirenz in controlled trials reported central nervous 
system symptoms compared to 25% of patients receiving control regimens. These symptoms 
included dizziness (28.1%), insomnia (16.3%), impaired concentration (8.3%), somnolence 
(7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were 
euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The 
majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of 
patients. Overall, 2.1% of patients discontinued therapy as a result. These symptoms usually 
begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of 
therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least 
moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz 
and from 3% to 5% in patients treated with a control regimen. Patients should be informed that 
these common symptoms were likely to improve with continued therapy and were not predictive 
of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve 
the tolerability of these nervous system symptoms. 
Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 
weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz +indinavir, and 
indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the 
incidences of new-onset nervous system symptoms among efavirenz-treated patients were 
generally similar to those in the indinavir-containing control arm. Patients receiving co-
formulated emtricitabine/tenofovir DF/efavirenz should be alerted to the potential for additive 
central nervous system effects when co-formulated emtricitabine/tenofovir DF/efavirenz is used 
concomitantly with alcohol or psychoactive drugs. 
Patients who experience central nervous system symptoms such as dizziness, impaired 
concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or 
operating machinery. 
8.5 NEW ONSET OR WORSENING RENAL IMPAIRMENT 
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal 
tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir 
DF, and it's formulations. Estimated creatinine clearance, urine glucose and urine protein 
should be documented in all patients prior to initiating therapy. Initiation of co-formulated 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in patients with estimated 
creatinine clearance below 70 mL per minute is not recommended. 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate and co-
formulated emtricitabine/tenofovir DF/efavirenz should be avoided with concurrent or recent 
use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs 
(NSAIDs)). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have 
been reported in HIV-infected patients with risk factors for renal dysfunction who appeared 
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stable on tenofovir DF. Some patients required hospitalization and renal replacement 
therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal 
dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or 
muscular pain or weakness may be manifestations of proximal renal tubulopathy and should 
prompt an evaluation of renal function in at-risk patients. 
Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein 
should be performed during co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir 
disoproxil fumarate therapy in all patients. Additionally, serum phosphorus should be 
measured in patients at risk for renal impairment. 
Although cobicistat (a component of STRIBILD) may cause modest increases in serum 
creatinine and modest declines in estimated creatinine clearance without affecting renal 
glomerular function, patients who experience a confirmed increase in serum creatinine of 
greater than 0.4 mg per dL from baseline should be closely monitored for renal safety. 
The emtricitabine and tenofovir DF are primarily excreted by the kidney. Co-formulated 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate and co-formulated 
emtricitabine/tenofovir DF/efavirenz should be discontinued if estimated creatinine clearance 
declines below 50 mL per minute as dose interval adjustment required for emtricitabine and 
tenofovir DF cannot be achieved with the fixed-dose combination tablet. 
8.6 SKIN RASH 
In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz 
experienced new-onset skin rash compared with 17% (111/635) of patients treated in control 
groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% 
(9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema 
multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz in all studies and 
expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin 
eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to 
onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, 
rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in 
clinical trials was 1.7% (17/1008). Co-formulated emtricitabine/tenofovir DF/efavirenz can be 
reinitiated in patients interrupting therapy because of rash. 
Co-formulated emtricitabine/tenofovir DF/efavirenz should be discontinued in patients 
developing severe rash associated with blistering, desquamation, mucosal involvement, or 
fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten 
the resolution of rash. 
Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI 
class is limited. Nineteen patients who discontinued nevirapine because of rash have been 
treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving 
therapy with efavirenz, and two of these patients discontinued because of rash. 
8.7 LIVER ENZYMES 
In patients with known or suspected history of hepatitis B or C infection and in patients treated 
with other medications associated with liver toxicity, monitoring of liver enzymes is 
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recommended. In patients with persistent elevations of serum transaminases to greater than 
five times the upper limit of the normal range, the benefit of continued therapy with co-
formulated emtricitabine/tenofovir DF/efavirenz needs to be weighed against the unknown risks 
of significant liver toxicity. 
Because of the extensive cytochrome P450 mediated metabolism of efavirenz and limited 
clinical experience in patients with hepatic impairment, caution should be exercised in 
administering co-formulated emtricitabine/tenofovir DF/efavirenz to these patients. 
8.8 BONE EFFECTS OF TENOFOVIR OF 
Bone Mineral Density: 
In clinical trials in HIV-1 infected adults, tenofovir DF (a component of STRIBILD) was 
associated with slightly greater decreases in bone mineral density (BMD) and increases in 
biochemical markers of bone metabolism, suggesting increased bone turnover relative to 
comparators. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher 
in subjects receiving tenofovir DF. 
The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-
term bone health and future fracture risk are unknown. Assessment of BMD should be 
considered for HIV-1 infected patients who have a history of pathologic bone fracture or 
other risk factors for osteoporosis or bone loss. Although the effect of supplementation with 
calcium and vitamin D was not studied, such supplementation may be beneficial in all 
patients. If bone abnormalities are suspected, then appropriate consultation should be 
obtained. 
Mineralization Defects: 
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain 
or pain in extremities and which may contribute to fractures, have been reported in 
association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have 
also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and 
osteomalacia secondary to proximal renal tubulopathy should be considered in patients at 
risk of renal dysfunction who present with persistent or worsening bone or muscle 
symptoms while receiving products containing tenofovir DF. 
8.9 CONVULSIONS 
Convulsions have been observed in patients receiving efavirenz, generally in the presence of 
known medical history of seizures. Caution must be taken in any patient with a history of 
seizures. 
Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the 
liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels. 
8.10 FAT REDISTRIBUTION 
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement 
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid 
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appearance" have been observed in patients receiving antiretroviral therapy. The mechanism 
and long-term consequences of these events are currently unknown. A causal relationship has 
not been established. 
8.11 IMMUNE RECONSTITUTION SYNDROME 
Immune reconstitution syndrome has been reported in patients treated with combination 
antiretroviral therapy,.. During the initial phase of combination antiretroviral treatment, patients 
whose immune system responds may develop an inflammatory response to indolent or residual 
opportunistic infections (such as 
Mycobacterium avium 
infection, cytomegalovirus, 
Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further 
evaluation and treatment. 
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre 
syndrome) have also been reported to occur in the setting of immune reconstitution, 
however, the time to onset is more variable, and can occur many months after initiation of 
treatment. 
8.12 CO-ADMINISTRATION WITH RELATED DRUGS 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate is indicated for 
use as a complete regimen for the treatment of HIV-1 infection and co-administration with 
other antiretroviral products is not recommended. 
Co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate is not 
recommended for coadministration with the following: 
• 
emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, 
VIREAD) 
• 
products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, 
TRIZIVIR) or adefovir dipivoxil (HEPSERA) 
• 
ritonavir (NORVIR, KALETRA) 
Related drugs not for co-administration with co-formulated emtricitabine/tenofovir DF/efavirenz 
include EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir 
DF), and SUSTIVA (efavirenz), which contain the same active components as the co-
formulation offered in this trial. Due to similarities between emtricitabine and lamivudine, other 
drugs that should not co-administered include those containing lamivudine, like COMBIVIRO, 
EPIVIRTM, EPIVIR-HBVTM, EPZICOMT", or TRIZIVIRT". 
9  TOXICITY MANAGEMENT 
Toxicity management guidelines take into consideration the fact that the subjects are started on 
their first antiretroviral drug regimen very early in the course of their HIV infection when long-
term clinical benefits of antir=etrovirals are unproven. Study treatment may be interrupted or 
discontinued at the discretion of the investigator and according to the severity of the adverse 
experience. However, investigators are reminded that the purpose of this study is to look at the 
effects of early treatment in general, not the effects of this particular regimen. Attempts should 
be made to continue antiretroviral treatment uninterrupted if possible. Thus, substitutions for 
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toxicity are allowed and would be preferable to the discontinuation or interruption of the entire 
regimen, if safety considerations permit. Alternate regimens will be provided for participants by 
the study for the duration of time that the participant remains in the study. 
There will be no mandated drug interruptions or discontinuations for any Grade 1 or 2 toxicity, 
except for elevated creatinine. Subjects with symptomatic toxicity Grade < 2 may continue to 
receive study treatment at the discretion of the investigator. Any allowed medication may be 
used to treat subjects for symptomatic toxicities, at the discretion of the investigator, except 
excluded medications as listed in section 5.3.3. 
9.1  PROCEDURES FOR MODIFICATIONS FOR SPECIFIC SYMPTOMS 
9.1.1 Rash 
9.1.1.1 Grade 1 or 2 Rash 
Study treatment should continue without interruption and the rash may be treated 
symptomatically with permitted antipyretic or antihistamine medications, but should be 
monitored closely by the local investigator. 
9.1.1.2 Grade 3 Rash 
All study treatment should be interrupted until the toxicity grade returns to Grade 5 1, after which 
time study medications can be resumed or alternative antiretroviral medications may be initiated 
at the investigator's discretion upon consultation with the Protocol Chair. If Grade  3 rash 
persists for more than 4 weeks, or if Grade 3 rash recurs, then the offending agent should be 
permanently discontinued. 
9.1.1.3 Grade 4 Rash 
All study treatment should be interrupted for any Grade 4 rash or evidence of a Stevens-
Johnson syndrome. Any resumption of study treatment or alternative antiretroviral medications 
should only be done upon consultation with the Protocol Chair. 
9.1.2 Nausea and Vomiting 
9.1.2.1 Grade 1 or 2 
Study treatment should continue without interruption. Subjects with Grade 1 and 2 nausea or 
vomiting may be treated symptomatically with permitted oral antiemetic therapies or antiemetic 
suppositories provided there is no suspicion of lactic acidosis or pancreatitis. 
9.1.2.2 Grade 3 
Subjects with Grade  3 nausea and vomiting should interrupt all study treatment until the 
toxicity grade returns to Grade 2 or to baseline. However, substitutions to the treatment 
regimen, as opposed to interruption of the entire regimen, may be made at the investigator's 
discretion upon consultation with the Study Chair. If the nausea does not improve with the 
substitution, then all study treatment should be interrupted. Once the toxicity returns to Grade 2 
or baseline, study medications may be resumed. If Grade 3 nausea and vomiting recurs upon 
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the resumption of study treatment, treatment should again be interrupted and alternative ART 
should be considered and discussed with the Study Chair. If Grade 3 nausea or vomiting 
persists for more than 4 weeks, then study treatment should be permanently discontinued. 
9.1.3 Diarrhea 
9.1.3.1 Grade 1 or 2 
All subjects with study drug-related diarrhea should initially be treated symptomatically with 
antidiarrheal medications such as loperamide, diphenoxylate, and/or an aluminum hydroxide 
antacid. Study drug administration may continue at the discretion of the investigator. 
9.1.3.2 Grade 3 Diarrhea 
Grade 3 diarrhea that is unresponsive to antimotility agents should prompt interruption of all 
study treatment until resolution of diarrhea to Grade 5 2 or baseline. However, substitutions to 
the treatment regimen, as opposed to interruption of the entire regimen, may be made at the 
investigator's discretion upon consultation with the Study Chair. If the diarrhea does not 
improve with the substitution, then all study treatment should be interrupted. Once the toxicity 
returns to Grade 2 or baseline, study medications may be resumed. If Grade > 3 diarrhea 
recurs upon the resumption of study treatment, all study treatment should be interrupted and 
alternative ART should be considered and discussed with the Protocol Chair. If Grade 3 
diarrhea persists for more than 4 weeks, then study treatment should be permanently 
discontinued. 
9.1.4 Symptomatic Hyperlactatemia 
Occurrence of lactic acidosis is expected to be very rare with the medication regimen used in 
this protocol. However, if an investigator suspects — due to symptoms or lab abnormality — 
lactic acidosis or symptomatic hyperlactatemia, a lactate level should be drawn. 
Symptomatic hyperlactatemia will be defined as new, otherwise unexplained and persistent 
occurrence for >2 weeks of one or more of the following in addition to an elevated lactate level: 
• 
nausea and vomiting 
• 
abdominal pain or gastric discomfort 
• 
abdominal distention 
• 
increased LFTs 
• 
unexplained fatigue 
• 
dyspnea 
• 
motor weakness 
If the lactate value is > 2 x ULN, obtain a confirmatory lactate value as soon as possible, 
preferably within 1 week.  Study treatment should be discontinued immediately if the 
confirmatory value remains > 2 x ULN or if the site is unable to obtain a confirmatory value 
within 1 week. Determine lactate levels every 4 weeks until the lactate value returns to normal, 
at which time a new antiretroviral regimen may be constructed in consultation with the protocol 
team. 
Management of symptomatic lactate value < 2 x ULN will proceed at the discretion of the local 
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investigator. However, any modification of a subject's antiretroviral regimen should be made in 
consultation with the protocol team. 
9.2 TOXICITY MANAGEMENT FOR LABORATORY ABNORMALITIES 
Grade 3 and 4 laboratory abnormalities should be confirmed by repeat testing preferably within 
3 calendar days of receipt of results and before study drug discontinuation, unless such a delay 
is not consistent with good medical practice. All laboratory abnormalities that would lead to a 
change in treatment should be confirmed as soon as possible. 
9.2.1 Increases in Values for Liver Function Tests 
9.2.1.1 Asymptomatic 
For asymptomatic Grade 3 elevations of total bilirubin, AST, ALT, or alkaline phosphatase, 
study treatment may be continued at the discretion of the site investigator in consultation with 
the Study Chair. Alternatively, the investigator may make substitutions to the antiretroviral 
regimen upon consultation with the Study Chair. 
If asymptomatic abnormalities in liver enzymes of Grade 3 persist for more than 4 weeks, the 
site investigator should consider temporary interruption of study treatment in consultation with 
the Protocol Chair. 
9.2.1.2 Symptomatic or Grade 4 
For symptomatic Grade 3 elevations of total bilirubin, AST, ALT, or alkaline phosphatase or for 
Grade > 3 elevations in AST, ALT, or alkaline phosphatase, all study treatment should be 
interrupted until the toxicity returns to Grade 2 or baseline, after which time all study treatment 
may be resumed. 
If asymptomatic liver enzyme elevations Grade > 3 or symptomatic liver enzyme elevations 
persist for more than 4 weeks, despite the interruption of all study treatment, or if liver function 
abnormalities recur to Grade 3 at any time after the resumption of study treatment, then all 
study treatment should be interrupted or discontinued and the Study Chair should be contacted 
regarding the reintroduction of study treatment or the selection of alternate ART. 
9.2.2 Lipase 
9.2.2.1 Grade a 2 Asymptomatic 
If a Grade  2 elevation of lipase occurs, the subject should be evaluated for signs and 
symptoms of pancreatitis and additional diagnostic evaluation should be performed as clinically 
indicated. For asymptomatic Grade 2 or 3 elevations of lipase, study treatment may be 
continued at the discretion of the site investigator in consultation with the Protocol Chair. 
Alternatively, the investigator may choose to substitute another antiretroviral agent for any of the 
components of the original study regimen. If Grade > 3 toxicity persists for more than 14 days 
despite interruption or substitution of study treatment, or recurs after reintroduction of study 
treatment, all study treatment should be permanently discontinued, and a new potent 
antiretroviral regimen should be selected at the discretion of the local investigator when 
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appropriate resolution of pancreatitis occurs. 
Subjects with Grade 4 elevations in serum lipase without clinical symptoms of pancreatitis 
should have all study treatment interrupted until the toxicity returns to Grade < 1, then all study 
treatment or a substituted regimen may be restarted at full dose. 
9.2.2.2 Symptomatic Pancreatitis (Regardless of Lipase Grade) 
A diagnosis of pancreatitis should be considered if clinical symptoms such as nausea, vomiting, 
or abdominal pain are present. Subjects with these signs and symptoms should be evaluated 
for the presence of pancreatitis through the use of diagnostic testing, which should include 
serum amylase, lipase, and triglyceride measurements and may include pancreatic imaging via 
abdominal ultrasound and/or CT scanning as clinically warranted. If a diagnosis of pancreatitis 
is confirmed, all study treatment should be interrupted immediately. 
9.2.3 Triglycerides/Cholesterol 
Subjects with asymptomatic triglyceride elevations Grade > 3 may continue to receive study 
treatment at the discretion of the local investigator. In consultation with the Protocol Chair, the 
On-Site Principal Investigator may consider the addition of permitted lipid-lowering agents if 
necessary to treat hyperlipidemia. Dose interruptions or discontinuations of study treatment 
should be considered only for confirmed increased fasting triglycerides 1200 mg/dL. 
Elevations in triglycerides 1200 mg/dL: For subjects with a nonfasting triglyceride level 1200 
mg/dL, a fasting triglyceride level and a serum amylase and lipase must be obtained. For Grade 
2 asymptomatic elevations in serum amylase and/or lipase (collected in response to elevated 
triglycerides) in the setting of Grade > 3 hypertriglyceridemia, subjects should be started on a 
fibrate, and amylase and lipase should be monitored every 2 weeks until amylase and lipase are 
Grade < 2. If symptoms of pancreatitis develop, study treatment should be interrupted until 
pancreatitis resolves, amylase, and lipase are Grade < 2 and hypertriglyceridemia is Grade <3. 
Consideration should be given to continuing a fibrate if study treatment is reintroduced. 
Subjects may continue on all study treatment despite Grade 3 triglyceride elevations if they 
remain asymptomatic with close clinical follow-up. In consultation with the Study Chair, the 
concomitant administration of gemfibrozil, clofibrate, or fenofibrate may be considered. 
If Grade 4 triglyceride toxicity persists 4 weeks after the addition of medical intervention 
(addition of lipid-lowering agent), all study treatment should be interrupted. If Grade 4 toxicity 
persists for more than 14 days after all study treatment has been interrupted, consider 
permanent discontinuation of all study treatment and a new potent antiretroviral regimen should 
be selected at the discretion of the local investigator in consultation with the Study Chair. 
9.2.4 Hyperglycemia 
Appropriate dietary modifications and glucose-lowering agents should be initiated for subjects 
with hyperglycemia, at the discretion of the local investigator and in accordance with customary 
medical care. 
9.2.5 Renal Insufficiency 
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Tenofovir DF substitution should occur for a confirmed creatinine clearance < 50 ml/min until an 
underlying etiology is determined. If no other etiology is determined or the renal insufficiency 
improves with holding tenofovir OF, tenofovir DF should be permanently discontinued. 
Baseline serum creatinine will be the mean of the screening and entry values. If at any time 
serum creatinine is increased >1.5-fold above baseline, the serum creatinine should be 
repeated as soon as possible (preferably within one week). Participants with confirmed serum 
creatinine increases >1.5-fold above baseline should undergo an evaluation for potential causes 
of decreased renal function. Participants with confirmed increase in serum creatinine >1.5-fold 
above baseline should have serum creatinine monitored more frequently, at the discretion of the 
site investigator, until serum creatinine either stabilizes or decreases to 51.5-fold above 
baseline. Drug dosing adjustments should be done based on the calculated creatinine 
clearance. 
9.2.6 Hypophosphatemia 
For Grade 1 and Grade 2 hypophosphatemia, phosphorus should be repeated as soon as 
possible (within 2 weeks is optimal), and tenofovir DF may be continued without other signs of 
renal tubular acidosis at the discretion of the site investigator. 
For asymptomatic Grade 3 decreases in phosphorus, subjects may either substitute another 
nucleoside reverse transcriptase inhibitor (NRTI) for tenofovir DF, or may remain on tenofovir 
OF with the following caveats. Subjects should be treated with oral phosphate supplements and 
phosphorus levels should be re-tested weekly until phosphorus returns to Grade 2 or better. If 
Grade 3 or worse phosphorus levels persist, tenofovir DF should be discontinued and another 
NRTI should be substituted. If Grade 4 hypophosphatemia occurs, tenofovir DF should be 
changed to an alternative NRTI in consultation with the Protocol Chair, and serum phosphorus 
levels should be followed weekly until resolution to Grade 2 or better. 
9.3  FOR ALL OTHER GRADE 3 OR 4 TOXICITY 
Subjects who develop a Grade 3 adverse event or toxicity reasonably causally related to the 
study medications (with the exception of asymptomatic laboratory abnormalities) should have all 
their antiretroviral study medication held and the subject rechecked each week until the adverse 
event returns to Grade < 2. If the investigator has compelling evidence that the adverse event 
has not been caused by the study medication or has another acceptable management plan, 
dosing may continue after discussion with the Protocol Chair. Once the adverse event is Grade 
<2, the medications may be reinstated at full dose. If the adverse event recurs after 4 weeks, 
the above management scheme may be repeated. 
Subjects who develop a Grade 4 adverse event or toxicity (with the exception of asymptomatic 
laboratory abnormalities) should have all antiretroviral medication discontinued. The subject 
should be followed weekly until resolution of the adverse event and encouraged to complete the 
protocol study evaluations. Further management of antiretrovirals should proceed at the site 
investigator's discretion. 
Subjects with Grade 3 or 4 asymptomatic laboratory abnormalities may continue therapy if the 
investigator has compelling evidence that the toxicity is not related to study drug, following 
discussion with the sponsor and the Protocol Chair. 
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10 CRITERIA FOR DISCONTINUATION OF THE TREATMENT PROVIDED BY THE STUDY 
10.1 PERMANENT TREATMENT DISCONTINUATION 
• 
Drug-related toxicity (see section 9.0 Toxicity Management); 
• 
Requirement for prohibited concomitant medications (see Section 5.3.3.); 
• 
Clinical reasons believed life threatening by the Study Medical Director, even if not 
addressed in the toxicity management of the protocol; 
• 
Suboptimal virologic response as defined in Section 4.4.; 
• 
Subject repeatedly non adherent, to the extent that the physician believes it would 
not be in the subject's best interest to continue treatment; 
The subjects who permanently discontinue treatment provided by the study according to the 
criteria described should continue a different ART regimen according to the standard of care 
currently in place. The study investigators will take necessary steps to ensure that the subjects 
continue on ART. Counseling will be provided with special emphasis on safety, and on efficacy 
of ART options to use in the future if the participant discontinues study ART, and does not 
continue with any other antiretroviral treatment. 
10.2 PREMATURE STUDY DISCONTINUATION 
• 
Request by the subject to withdraw; 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the subject; 
• 
Subject judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results; 
• 
At the discretion of the Ministry of Health or National Institute of Health of Peru, any 
of the IRBs/ECs responsible for oversight of the study, study sponsor, or On-Site 
Principal Investigator. 
11 STATISTICAL CONSIDERATIONS 
The overall aim of this project is to model seek-test-treat-retain strategies that specifically 
intervene to reduce HIV transmission through reductions in HIV-1 viral load and sexual risk 
behavior among individuals with early HIV infection, including both acute and recent infections. 
11.1 OBJECTIVES 
11.1.1 Primary Objectives 
1. To estimate the impact of immediate and deferred (6 months after diagnosis) ART on the 
decay dynamics of HIV viral load in plasma, semen and rectal secretions from 
individuals with early HIV infection; 
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2. n  To investigate the impact of drug and alcohol use on HIV transmission by examining and 
modeling the role of MSM and transgender women with substance abuse disorders in 
transmission clusters identified through partner tracing and phylogenetic analysis. 
11.1.2 Secondary Objectives 
1. To determine HIV incidence and associated risk factors among high-risk HIV-1 
uninfected MSM and transgender women who participate in a program of frequent 
routine HIV testing. 
2. To attempt to identify transmission clusters in phylogenetic trees constructed using early 
viral specimens from study participants with acute or recent HIV infection. 
3. To determine other characteristics (self-reported sexual risk behavior, partner 
characteristics, use of entertainment venues, and method of referral for HIV testing) in 
MSM and transgender women within clusters compared to those outside of clusters. 
4. To assess the feasibility and acceptability of re-contacting HIV seronegative individuals 
with evidence of acute infection (HIV-1 RNA positive) for further HIV testing and linkage 
to care. 
5. To evaluate the frequency of HIV testing among recent sexual partners of participants 
diagnosed with early HIV-1 infection, comparing strategies such as partner tracing and 
notification, and general and targeted community outreach. 
6. To evaluate retention in care, including adherence to ART and study procedures, among 
individuals with early HIV-1 infection receiving immediate and deferred ART. 
11.2 ENDPOINTS 
11.2.1 Primary Endpoints 
1. To quantify HIV viral load in plasma, semen and rectal secretions in individuals with 
early HIV infection in immediate versus deferred treatment groups. 
2. To identify transmission clusters through phylogenetic analysis among participants with 
early HIV infection receiving immediate and deferred ART; Construction of models to 
assess the potential population impact of a seek-test-treat-retain strategy. 
11.2.2 Secondary Endpoints 
1. To identify associated risk factors for incident HIV-1 infection. 
2. To identify sequence clusters using phylogenetic analysis among participants with early 
HIV infection. 
3. To compare self-reported sexual risk behavior, partner characteristics, entertainment 
venue attendance, and method of referral in MSM and transgender women within 
clusters to those outside of clusters. 
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4. To determine the proportion of individuals with evidence of acute infection (HIV-1 RNA-
positive) who are successfully contacted for confirmatory HIV testing and are then linked 
to care. 
5. To determine the proportion of newly identified HIV-positive men willing to name at least 
one recent sexual partner, and the proportion of named partners subsequently contacted 
and tested. 
6. To determine the proportion of men retained in care, including adherence to ART and 
study procedures, among individuals with early HIV-1 infection receiving immediate and 
deferred ART. 
11.3 SAMPLE SIZE AND ACCRUAL 
Our goal is to enroll approximately 75-90 men with AHI and 75-90 with RHI in three years, with 
a target of enrolling 25-50 men with AHI and 25-50 men with RHI per year, or approximately 2-4 
men in each group per month. We expect that another 50 men will be identified with acute or 
recent HIV-1 infection who will either not meet all inclusion requirements or who will not consent 
to enrollment in the study. Specimens for sequencing will be collected from all men. 
Samples for sequencing will be obtained .from all identified HIV+ partners of the 200 men with 
acute/recent infection (we anticipate that not all men will consent to partner tracing). Our initial 
sequencing efforts will focus on the 100 acutely infected men (75 enrolled plus 25 non-enrolled 
in immediate/deferred ART study) and their HIV+ partners (especially those with acute or recent 
HIV infection), testing a total of 400 samples. The first available sample will be sequenced with 
454/pyrosequencing and analyzed as described below. 
Semen HIV VL will be measured in samples from 60 (30 acute/30 recent) men in the immediate 
ART group and 60 (30 acute/30 recent) men in the deferred treatment group using established 
procedures in The University of Washington Virology Laboratory [177, 178]. We will seek 
separate funding to analyze additional samples, including rectal secretions. 
11.4 MONITORING 
All endpoints will be calculated and monitored on a monthly basis throughout the period of 
enrollment and treatment. 
11.5 ANALYSES 
11.5.1 Viral Phylogenetic Analysis 
Viral phylogenetic analysis will be conducted to investigate the occurrence of clustered 
transmission during AHI as evidenced by detection of highly related sequences among men with 
acute infection [162, 179, 180] and their recent partners identified through contact tracing. An 
algorithm for identifying HIV transmission linkages among partnerships has recently been 
developed by our collaborator Dr. Mullins, who analyzed sequences using phylogenetic 
techniques and developed a Bayesian algorithm to evaluate the probability of linkage using 
genetic distance measurements [181]. The same approach will be used here and applied for the 
first time to identifying transmission clusters. 
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Next-generation deep sequencing using the 454/Pyrosequencing platform will be used to 
generate envelope gene sequences from each study participant using plasma from the first 
available time point following infection. Deep sequencing provides us with the opportunity to 
identify relatively low-frequency variants in each infection. This is important because we have 
found that in a significant fraction of the cases, divergent, low-frequency variants are often 
involved in transmission to a new host [181]. To provide context for the identification of linked 
transmissions, we will prepare two HIV-1 envelope gene sequence databases corresponding to 
the same genetic region as Lima. The first dataset will contain all available Peruvian HIV-1 
sequences from the Los Alamos National Laboratory HIV Sequence Database (HIVDB) 
(http://www.hivianl.00v/content/sequence/HIV/mainpaoe.html), as well as subtype B sequences 
from other countries in South America. This will enable us to determine the expected spread of 
genetic relationships from individuals without epidemiologic linkage. Second, a "linked" 
database of corresponding HIV-1 envelope gene sequences from 147 known transmission pairs 
[181] will be generated to enable us to determine the expected spread of genetic relationships 
from individuals with known epidemiologic linkage. HIV-1 linkage will be assigned by requiring 
the following: 1) pair derived HIV-1 env sequences from two or more individuals form 
monophyletic clusters (i.e., originating from the same terminal node) in maximum-likelihood 
phylogenetic trees that include all available sequences from unrelated individuals and 2) the 
pairwise genetic distances are required to be associated with a Bayesian posterior probability 
>50%. Pairs of sequences that meet these two requirements are tentatively classified as linked. 
In this manner, a phylogenetic tree containing clustered and unclustered sequences will be 
constructed for all acutely infected index cases and their HIV+ recent sexual contacts. These 
clusters are due to high-level transmission which occurs early after infection, before sequence 
divergence. (If funding allows or additional funding is available, specimens from men with recent 
infection and their partners will be sequenced and added to this analysis.) 
11.5.2 Effect of HIV Seek and Test Strategies and Impact of Substance Use on Clustered 
Transmission: 
First, initial analysis will assess process measures evaluating, for example, the % HIV infections 
in MSM and transgender women that are detected during AHI compared to our preliminary data 
from 2007-2008 and rates in historical controls [182], and the proportion of MSM and 
transgender women with AHI diagnosed by point-of-care vs. lab-based assays who are 
successfully linked to care. 
Second, summary statistics on the inferred phylogenic tree will be computed, including the 
number of clusters identified, the percentage of MSM and transgender women in the cluster, the 
number of infections in each cluster, and the maximum window periods for onward transmission 
within each cluster. To evaluate the impact of partner services we employ on finding 
transmission clusters, we will also compare the percentage of MSM and transgender women in 
the cluster to that percentage seen in the literature using other approaches, e.g., 49.4% in [162], 
34% in [183]. McNemar's test will be conducted to evaluate the agreement between being in the 
clusters based on partner tracing and being in the clusters based on phylogeny. 
Third, we will compare the sexual behaviors, and use of alcohol or drugs such as cocaine 
between MSM and transgender women clustered by phylogeny and MSM and transgender 
women not clustered by phylogeny (using 2 set of trees: MSM and transgender women with 
acute/recent infection with or without partners). Our analysis of the impact of substance use on 
clustered transmission will include all MSM and transgender women with acute/recent infection 
and their partners. For example, we anticipate that roughly 5% of index cases with AHI will use 
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cocaine and roughly 25% will have AUD based on a recent study of high risk MSM and 
transgender women in Lima [184]— this analysis will assess whether either cocaine use or AUD 
are enriched among men in transmission clusters. For outcomes measured at a single time 
point, we will use Chi-squared tests, Fisher's exact tests or Mann-Whitney U tests, as 
appropriate. For outcomes measured longitudinally, we will use the generalized estimating 
equation approach to account for correlations among repeated measures. 
Fourth, baseline questionnaire data on substance use and sexual behavior will also be 
compared between MSM and transgender women with acute and recent HIV infections after 
stratifying on AUD. Both univariate comparison and multiple regression to explore risk factors 
that are associated with acute/recent infection will be conducted. 
11.5.3 The Impact of Immediate and Early (6 Months after Diagnosis) Antiretroviral 
Therapy on the Decay Dynamics of HIV Viral Load 
For men with acute/recent infection plasma VL will be measured at 0, 1, 2, 4, 6, 8, 12, 16, 24, 36 
and 48 weeks. Semen specimens and rectal secretions will be collected from all men with 
acute/recent infection at 0, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 weeks and stored. Semen HIV VL 
will be measured in these samples from 60 (30 acute/30 recent) ART-treated men and 60 (30 
acute/30 recent) untreated men using established procedures in the University of Washington 
Virology Laboratory [177, 178]. This sample size is adequate to detect a 1.0-1.5 logic) change in 
VL associated with ART based on the following: semen viral load peaks about 30 days after 
infection, with mean 4.5 and standard deviation 1.6 (logio copies/nil) [185]. We compute the 
power of a two-sample t-test comparing two arms (ART vs. no ART) to detect significant 
difference with type I error 5%. With 30/group we have 66% power to detect a 1.0 log change 
and 94% power to detect a 1.5 logio change based on a single viral load measure at peak per 
subject. The power would be greater if we use any summary measure of individual's multiple 
viral loads, e.g., mean across different time points.) We will seek separate funding to analyze 
additional samples, including rectal secretions. VL in semen and rectal secretions will be more 
informative for modeling the potential impact of ART on infectivity during this period than plasma 
VL as these 3 measures are only modestly related [177, 178]. 
The viral load trajectory will be plotted for each subject and for plasma, semen and rectal 
secretions separately. The mean trajectory and its confidence interval will be computed stratified 
by randomized arm and by acute or recent infection. The first-order rate of decay, the area 
under the curve, the peak viral load, and the lowest viral load will be computed for each subject 
and compared across arms. Multiple testing adjustment will be applied to control type I error. 
11.5.4 Modeling the Expected Intervention Impact at Population Level 
Data for model development will come from several sources. We will use data from the study 
testing centers to estimate the percentage of total HIV infections detected during AHI and the 
distribution of testing intervals among MSM and transgender women attending participating VCT 
centers. We will use results of the formative research to modify the baseline questionnaire 
compiled by Dr. Altice from multiple validated surveys such as the Addiction Severity Index, 
Brief Symptom Inventory, etc. and use it to collect extensive data from all enrolled participants 
on sexual risk behaviors, drug and alcohol use, adherence to ART, social support, mental health 
and psychiatric status. Data will be collected from men with Acute and recent HIV infection (and 
consenting HIV+ partners) with or without alcohol use disorder. Data on sexual networks will be 
obtained by partner tracing and phylogenetic analysis. Clinical (CD4+ cell count, HIV viral load) 
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and adherence data (pill count, recall) will be used for analysis and incorporated into models as 
appropriate. Data will be managed at the Data Management Center (DMC) at the IMPACTA 
Barranco Clinical Research site, with experienced staff that participated in multiple NIH-funded 
studies. The DMC will be responsible for forms development, data entry, database 
management, adverse event reporting, specimen tracking, report generation, quality control and 
data security. 
Mathematical modeling will address the potential impact of two strategies to reduce onward HIV 
transmission — treatment of AUD, and detection and treatment for AHI. A sequence of 
deterministic models will be developed to simulate HIV transmission in MSM and transgender 
women populations (with and without interventions) and to evaluate the public-health impact of 
the increased detection and treatment of acute and recent (within 3-6 months) HIV infections on 
the HIV epidemic among MSM and transgender women. Individuals in these models will be 
divided in classes with respect to serostatus, stage of HIV infection, and with respect to their 
ART status (treated/untreated). Men will be additionally stratified by alcohol and drug 
dependency, level of sexual activity, and behavioral risk. The rates at which men acquire HIV, 
i.e., forces of infections, will be expressed as functions of the number of partners per 
susceptible person, the number of sex acts per partnership, and the transmission probability per 
sex act for partners from different classes using standard binomial risk formulas. We expect to 
encounter 300 seropositive men per year with about 10% of them with recent infections. In 
addition, we expect to identify 30-45 acutely infected men per year. Infectivity estimation will use 
plasma and semen VL data from ART treated and untreated men with acute/recent HIV 
infection as well as set-point plasma VL from 200 men with established HIV infection (100 with/ 
100 without AUD). These data will allow us to construct the initial epidemic distribution of the 
MSM and transgender women population and to dynamically calibrate the models. 
12 DATA COLLECTION, MONITORING AND ADVERSE EXPERIENCE REPORTING 
12.1 DEFINITION OF AN ADVERSE EVENT 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical research 
participant who has been administered an investigational product, and that does not necessarily 
have a causal relationship with the investigational product. As such, an AE can be an 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of an investigational product, whether 
or not considered related to the product. This definition will be applied to both study treatment 
groups, even though one group is assigned to receive an investigational product immediately 
and the other not, and will be applied to both groups beginning from the time of random 
assignment. 
Study participants will be provided instructions for contacting the study site to report any 
untoward medical occurrences they may experience, except for possible life-threatening events, 
for which they will be instructed to seek immediate emergency care. Where feasible and 
medically appropriate, participants will be encouraged to seek evaluation where the study 
clinician is based, and to request that the clinician be contacted upon their arrival. With 
appropriate permission of the participant, and whenever possible, records from all non-study 
medical providers related to untoward medical occurrences will be requested and required data 
elements will be recorded on study case report forms and/or in the participant's medical chart. 
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12.2 GOVERNANCE 
The Protocol Chair is ultimately responsible for adherence to all aspects of the study protocol, 
including reporting of AEs. This responsibility is largely delegated to the On-Site Principal 
Investigator, who is responsible of medical decisions. He or his authorized study physicians (all 
of them trained in internal medicine and/or infectious diseases) will prepare all AE reports. In 
addition, there is real-time data checking by the Data Management Unit at the study site, which 
will review data collection forms, including clinic and laboratory reports, from all participants. 
The review will serve to assure that evidence of AEs is identified and reported. 
A Protocol Safety Review Committee will review AE reports and determine appropriate follow-
up, including modifying the study protocol and/or procedures as necessary. 
12.3 CLINICAL ADVERSE EVENTS 
Clinical AEs will be evaluated by the study physicians. Grade 3 and 4 clinical AEs will be 
referred to Study Medical Director (on-site physician responsible for medical decision-making) at 
the time of the visit. A back-up coverage schedule will be developed and posted to assure that 
a study physician is available to the on-site physician responsible for medical decision-making, 
by phone at all times. 
12.4 LABORATORY ADVERSE EVENTS 
Laboratory results will be flagged by the laboratory as abnormal or critical using pre-determined 
criteria at the laboratory. Abnormal values will be confirmed by repeat testing of the same 
specimen. All critical values will be reported to Study Medical Director by cell phone or e-mail. 
All results will be documented in laboratory records. All laboratory test results will be reported. 
Participants who are not present at the study site at the time a critical value is identified will be 
contacted by telephone or in person and asked to come back to the study site for further 
evaluation, referral, and counseling. 
12.5 DISCONTINUATION OF STUDY AGENT DUE TO AN ADVERSE EVENT 
The Study Medical Director or his designee has authority to stop study agent for any participant 
due to clinical or laboratory AEs, and must stop study agent according to criteria defined in the 
safety monitoring section. 
12.6 SOCIAL ADVERSE EVENTS 
This study will be designed to minimize risk and maximize benefit to both study participants and 
their local communities. However, volunteers could experience discrimination or other personal 
problems as a result of being in the study. We will be obliged to provide advocacy for and 
assistance to participants regarding negative social impacts or social AEs associated with the 
study. 
Social AEs may include loss of privacy, stigmatization, interference with gainful employment, 
and coercion. Information regarding social AEs will be solicited during quarterly study visits 
after enrollment in the study and will be recorded in log form on case report forms. In addition, 
social harms may be identified by other study staff, including peer navigator, patient advocates, 
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nurses, physicians, pharmacists, and others. All social adverse events will be brought to the 
attention of the Study Medical Director and reported according to AE reporting guidelines. 
Participants who report social harms will be referred to speak with a social worker and/or a 
study counselor. 
12.7 ASSESSMENT OF RELATIONSHIP TO STUDY AGENT 
The on-site Principal Investigator or his designee will assess whether an AE is related or not 
related to the study agent, using the available information about co-formulated 
elvitegravir/cobicistat/emtricitabine/tenofovir  disoproxil  fumarate(  or  co-formulated 
emtricitabine/tenofovir DF/efavirenz) and his/her clinical judgment. 
The anticipated risks associated with this study are deemed overall to be low. 
The assessment of risk does not, however, preclude the potential for anticipated and/or 
unanticipated AEs, serious or otherwise, since it is not possible to predict with certainty the 
absolute risk in any given individual or in advance of first-hand experience with the proposed 
study methods. 
We will use a Data Safety Monitoring Plan (DSMP) to monitor the overall progress of our study. 
Some of the factors the investigators intend to monitor closely include: 1) Are the treatment 
groups comparable at baseline; 2) Are the accrual rates meeting initial projections and is the 
trial on its scheduled timeline; 3) Are the data of sufficient quality; 4) Are the treatment groups 
different with respect to safety and,  toxicity data; 5) Are the treatment groups different with 
respect to efficacy data; 6) Is there an indication to discontinue the trial due to predefined 
criteria; and 7) Should the protocol be modified in response to any unanticipated outcome or 
change in temporal event?. 
12.8 FOLLOW-UP ON ADVERSE EVENTS 
All participants reporting an untoward medical occurrence will be followed clinically until the 
occurrence resolves (returns to baseline) or stabilizes. Laboratory AEs will be managed 
according to established protocols described in 9.0 Toxicity Management. Laboratory results 
that require action will be documented and a peer navigator will be contacted to schedule a 
repeat visit. 
12.9 REVIEW OF ADVERSE EVENTS 
Summaries of combined AE reports will be reviewed and discussed by the Protocol Team and 
clinic medical staff. All AEs will be tabulated and meeting minutes will be documented. These 
reports will be provided to the NIDA Program Official after review by the Protocol Chair. 
12.10 EXPEDITED ADVERSE EVENTS REPORTING TO NATIONAL INSTITUTE ON DRUG 
ABUSE 
The expedited adverse event (EAE) reporting requirements and definitions for this study and the 
methods for expedited reporting of AEs to the NIDA will be based on "The Manual for Expedited 
Reporting of Adverse Events to DAIDS Version 2.0" dated in January 2010. This manual is 
available on htto://rsc.tech-res.com/safetvandpharmacovioilance. Adverse events reported on 
an expedited basis must be documented on the 2010 NIDA Serious Adverse Event form and 
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reported to the NIDA Program Official within 72 hours by fax (1-301-443-6814) and/or email. 
Investigators will submit a written report to the NIDA Program Official no more than three days 
after site aware. Written follow-up will be sent to the NIDA Program Official 
This study uses the standard level of EAE reporting. In addition, the On-Site Principal 
Investigator will submit AE information as required by local regulatory or other relevant 
authorities. 
12.10.1 Study Agents for Expedited Reporting to National Institute on Drug Abuse 
Program Official 
The study drug on which the relatedness assessment is to be based is co-formulated 
elvitegravir/cobicistat/emtricitabine/tenofovir  disoproxil  fumarate  (or  co-formulated 
emtricitabine/tenofovir DF/efavirenz) and reported to the NIDA Program Official. 
12.10.2 Grading Severity of Events 
All AEs will be graded using the "Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events Version 1.0, December, 2004; Clarification August 2009" available at 
http://rsc.tech-res.com/safetvandpharmacoviq  i lance. 
12.10.3 Adverse Events Reporting Periods 
Adverse events must be reported on an expedited basis at the Standard Level during the 
protocol-defined EAE reporting period, which is: The entire study duration for an individual 
subject (from study enrollment until study completion or discontinuation of the subject from 
study participation for any reason). After the end of the protocol-defined EAE reporting period 
stated above, the study site must report serious, unexpected, clinically suspected AE drug 
reactions if the study site staff becomes aware of the event on a passive bases, i.e., from 
publicly available information. 
12.11 CONTACT FOR QUESTIONS ABOUT EXPEDITED ADVERSE EVENTS REPORTING 
For questions about EAE reporting, contact NIDA Program Official sending an e-mail. 
12.11.1 Assuring Reporting of Suspension of the Clinical Trial 
Any action resulting in a temporary or permanent suspension of the trial will be reported to the 
assigned and responsible NIDA Program Officer and Medical Officer. 
13 HUMAN SUBJECTS PROTECTION 
13.1 INSTITUTIONAL REVIEW BOARDS AND ETHICS COMMITTEE REVIEW 
This protocol and the informed consent forms and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the study. 
Signed consent forms will be obtained from the subject. The consent forms will describe the 
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purpose of the study, the procedures to be followed, and the risks and benefits of participation. 
A copy of the consent forms will be given to the subject, and this fact will be documented in the 
subject's record. 
13.2 SUBJECT CONFIDENTIALITY 
All laboratory specimens, evaluation forms, reports and other records that leave the site will be 
identified by coded number only to maintain subject confidentiality. All records will be kept 
locked. All computer entry and networking programs will be done with coded numbers only. 
Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the Ministry of Health or National Institute of Health of Peru, any of 
the IRBs/ECs responsible for oversight of the study, or the NIDA. 
13.3 STUDY DISCONTINUATION 
The study may be discontinued at any time by the Ministry of Health or National Institute of 
Health of Peru, any of the IRBs/ECs responsible for oversight of the study, or NIDA as part of 
their duties to ensure that research subjects are protected. 
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14 PUBLICATIONS OF RESEARCH FINDINGS 
Presentation and publication of the results of this study will follow the regulations of Fred 
Hutchinson Cancer Research Center and Asociacion Civil Impacta Salud y Educacion. Any 
presentation, abstract, or manuscript must be approved by the Protocol Chair prior to 
submission. 
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