Safety and Virologic Effect of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), With Broad HIV-1 Neutralizing Activity, Administered Intravenously to Adults During Early Acute HIV Infection
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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PROTOCOL RV 398 
SAFETY AND VIROLOGIC EFFECT OF A HUMAN MONOCLONAL ANTIBODY,
VRC-HIVMAB060-00-AB (VRC01), WITH BROAD HIV-1 NEUTRALIZING ACTIVITY,
ADMINISTERED INTRAVENOUSLY TO ADULTS DURING  
EARLY ACUTE HIV INFECTION 
Study Agent Provided by  
Vaccine Research Center/NIAID/NIH, Bethesda, Maryland 
Study Conducted By  
U.S. Military HIV Research Program, Silver Spring, Maryland 
Makerere University-Walter Reed Project, Makerere University, Kampala, Uganda 
U.S. Army Medical Research Unit-Kenya and Kenya Medical Research Institute 
Kericho, Kenya 
Mbeya Medical Research Centre, National Institute of Medical Research 
Mbeya, Tanzania 
Department of Retrovirology, U.S, Army Medical Corps (USAMC)/Armed Forces Research 
Institute of Medical Sciences (AFRIMS) and Royal Thai Army AFRIMS Bangkok, Thailand 
In Collaboration with 
Vaccine Research Center, NIAID, NIH 
Study Sponsored By 
National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS), 
National Institutes of Health (NIH) 
Bethesda, Maryland 
IND Number: 126,001 
DAIDS-ES ID 12002 
Protocol Chair: 
Julie Ake, MD, MSc 
Protocol Co-Chair:  
Merlin Robb, MD 
DAIDS Medical Officer: 
Randall Tressler, MD, MSc 

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TABLE OF CONTENTS 
SCHEMA ..................................................................................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................................................... 8 
1.0 
INTRODUCTION ................................................................................................................................. 12 
1.1 
BACKGROUND .................................................................................................................................... 12 
1.2 
RATIONALE FOR VRC01 AS A STUDY AGENT ................................................................................... 13 
2.0 
STUDY AGENT ................................................................................................................................... 15 
2.1 
BACKGROUND .................................................................................................................................... 15 
2.2 
DESCRIPTION OF STUDY AGENT VRC-HIVMAB060-00-AB (VRC01) ........................................... 15 
2.3 
PRECLINICAL GLP TOXICOLOGY STUDY .......................................................................................... 15 
2.4 
TISSUE CROSS-REACTIVITY GLP STUDY OF VRC01 WITH HUMAN TISSUES IN VITRO .................... 17 
2.5 
NONHUMAN PRIMATE (NHP) STUDIES OF VRC01 ........................................................................... 17 
2.6 
PHASE 1 AND PHASE 2 CLINICAL TRIALS OF VRC01 ........................................................................ 18 
2.6.1 
Initial Pharmacokinetic Data .......................................................................................................... 20 
2.6.2 
Viral Load Effects ........................................................................................................................... 20 
3.0 
STUDY OBJECTIVES .......................................................................................................................... 22 
3.1 
PRIMARY OBJECTIVES ....................................................................................................................... 22 
3.2 
SECONDARY OBJECTIVES .................................................................................................................. 22 
3.3 
EXPLORATORY OBJECTIVES .............................................................................................................. 22 
4.0 
ENDPOINTS ........................................................................................................................................ 23 
4.1 
PRIMARY ............................................................................................................................................ 23 
4.2 
SECONDARY ....................................................................................................................................... 23 
4.3 
EXPLORATORY ................................................................................................................................... 23 
5.0 
STUDY DESIGN AND POPULATION ................................................................................................... 25 
5.1 
SOURCE COHORTS ............................................................................................................................. 25 
5.1.1 
RV 217 ECHO ................................................................................................................................ 25 
5.1.2 
RV 254/SEARCH 010 .................................................................................................................... 26 
5.2 
STUDY DURATION .............................................................................................................................. 27 
5.3 
ELIGIBILITY ........................................................................................................................................ 27 
5.3.1 
Inclusion Criteria ............................................................................................................................ 27 
5.3.2 
Exclusion Criteria ........................................................................................................................... 28 
6.0 
STUDY PROCEDURES ........................................................................................................................ 30 
6.1 
ENROLLMENT AND RANDOMIZATION ................................................................................................ 30 
6.1.1 
Entering from RV 217 .................................................................................................................... 30 
6.1.2 
Entering from RV 254 .................................................................................................................... 30 
6.1.3 
RV 398 Visit 1 ................................................................................................................................ 30 
6.2 
ANTIRETROVIRAL THERAPY .............................................................................................................. 31 
6.3 
NEUROPSYCHOLOGICAL TESTING ..................................................................................................... 31 
6.4 
OPTIONAL PROCEDURES .................................................................................................................... 32 
6.4.1 
Mucosal secretions .......................................................................................................................... 32 
6.4.2 
Rectosigmoid biopsy ...................................................................................................................... 33 
6.4.3 
Lymph node biopsy ........................................................................................................................ 33 
6.4.4 
Leukapheresis ................................................................................................................................. 33 
6.4.5 
Lumbar puncture ............................................................................................................................. 33 
6.5 
CLINICAL AND LABORATORY EVALUATIONS .................................................................................... 34 
6.5.1 
Assessing Primary Endpoints: Safety and Virologic Impact .......................................................... 34 
6.5.2 
Assessing Secondary Endpoints ..................................................................................................... 34 
6.5.3 
Assessing Exploratory Endpoints ................................................................................................... 35 

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6.6 
CONCOMITANT MEDICATIONS ........................................................................................................... 37 
6.7 
SOLICITED ADVERSE EVENTS ............................................................................................................ 37 
6.8 
STUDY DISCONTINUATION ................................................................................................................ 38 
6.8.1 
Early Discontinuation or Withdrawal of Study Participants .......................................................... 38 
6.8.2 
Premature Termination of the Study ............................................................................................... 38 
6.8.3 
Management of Volunteers Who Become Pregnant ...................................................................... 39 
6.8.4 
Unblinding Procedure ..................................................................................................................... 39 
7.0 
STUDY TREATMENT ......................................................................................................................... 40 
7.1 
STUDY TREATMENT REGIMENS, ADMINISTRATION, AND DURATION ............................................... 40 
7.1.1 
Regimens ........................................................................................................................................ 40 
7.1.2 
Administration ................................................................................................................................ 40 
7.1.3 
Duration .......................................................................................................................................... 40 
7.2 
STUDY PRODUCT FORMULATION AND PREPARATION ....................................................................... 40 
7.2.1 
Formulation .................................................................................................................................... 40 
7.2.2 
Preparation of Study Products ........................................................................................................ 41 
7.3 
PHARMACY: PRODUCT SUPPLY, DISTRIBUTION, AND ACCOUNTABILITY ......................................... 42 
7.3.1 
Study Product Acquisition/Distribution ......................................................................................... 42 
7.3.2 
Study Product Accountability ......................................................................................................... 43 
7.3.3 
Disposition ...................................................................................................................................... 43 
7.4 
ANTIRETROVIRAL THERAPY .............................................................................................................. 43 
8.0 
PHARMACOVIGILENCE, SAFETY, AND ADVERSE EXPERIENCE REPORTING ................................ 44 
8.1 
DEFINITIONS ...................................................................................................................................... 44 
8.2 
ADVERSE EVENT GRADING AND RECORDING ................................................................................... 44 
8.3 
PROTOCOL SAFETY REVIEW TEAM (PSRT) AND PSRT REVIEWS .................................................... 45 
8.4 
SAFETY MONITORING COMMITTEE (SMC) REVIEWS ....................................................................... 46 
8.5 
CRITERIA FOR STUDY PAUSE OR TERMINATION ............................................................................... 46 
8.6 
EXPEDITED REPORTING TO IND SPONSOR (DAIDS) ........................................................................ 48 
8.6.1 
Study Agents for Expedited Reporting to DAIDS ......................................................................... 48 
8.6.2 
Study Recording Period for SAEs .................................................................................................. 49 
8.6.3 
Timeframe for Expedited Reporting of Individual Adverse Events ............................................... 49 
8.7 
REPORTING SERIOUS AND UNEXPECTED ADVERSE EVENTS TO THE DOD IN ADDITION TO DAIDS 49 
8.7.1 
Social Harms Reporting .................................................................................................................. 50 
8.7.2 
Unanticipated Problems Reporting to WRAIR .............................................................................. 50 
8.8 
REPORTING REQUIREMENTS TO THE LOCAL IRB .............................................................................. 50 
8.9 
MODIFICATION TO THE DAIDS AE GRADING TABLE ....................................................................... 50 
9.0 
STATISTICAL CONSIDERATIONS ...................................................................................................... 52 
9.1 
POWER AND SAMPLE SIZE ................................................................................................................. 52 
9.2 
ANALYSIS ........................................................................................................................................... 53 
9.2.1 
Primary Endpoints: ......................................................................................................................... 53 
9.2.2 
Secondary Endpoints: ..................................................................................................................... 54 
9.2.3 
Exploratory Endpoints: ................................................................................................................... 55 
10.0 
DATA COLLECTION ........................................................................................................................ 57 
11.0 
ETHICAL CONSIDERATIONS ........................................................................................................... 58 
11.1 
PARTICIPATION OF CHILDREN ......................................................................................................... 58 
11.2 
PARTICIPATION OF PRISONERS ........................................................................................................ 58 
11.3 
RISKS ................................................................................................................................................ 58 
11.4 
BENEFITS .......................................................................................................................................... 62 
11.5 
INFORMED CONSENT ........................................................................................................................ 62 
11.6 
LANGUAGE ....................................................................................................................................... 63 
11.7 
COMPENSATION ............................................................................................................................... 63 
11.8 
DOD RESEARCH MONITOR .............................................................................................................. 63 

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11.9 
SUBJECT INSURANCE ....................................................................................................................... 63 
11.10 
PARTICIPANT CONFIDENTIALITY ................................................................................................... 64 
11.11 
INSTITUTIONAL REVIEW BOARD ................................................................................................... 64 
11.12 
FUTURE USE AND STORAGE OF BLOOD SAMPLES ......................................................................... 64 
11.13 
STUDY DOCUMENTATION AND STORAGE ..................................................................................... 64 
12.0 
ADMINISTRATIVE AND LEGAL PROCEDURES ............................................................................... 66 
12.1 
PROTOCOL DEVIATION REPORTING ................................................................................................. 66 
12.2 
PROTOCOL MODIFICATIONS ............................................................................................................ 66 
12.3 
CONTINUING REVIEWS /CLOSEOUT REPORT ................................................................................... 67 
12.4 
VOLUNTEER REGISTRY DATABASE ................................................................................................. 68 
12.5 
SITE-SPECIFIC ADDENDUM ............................................................................................................... 68 
12.6 
USE OF INFORMATION AND PUBLICATION ...................................................................................... 68 
13.0 
CONDUCT OF THE RESEARCH STUDY ........................................................................................... 70 
13.1 
REGULATORY AUDITS ..................................................................................................................... 70 
13.2 
SPONSOR STUDY MONITORING ....................................................................................................... 70 
14.0 
PRINCIPAL INVESTIGATOR AGREEMENT ..................................................................................... 71 
15.0 
REFERENCES ................................................................................................................................... 73 
APPENDIX I: CASE DEFINITION FOR ACUTE RETROVIRAL SYNDROME (ARS) ............... 76 
APPENDIX II: SCHEDULE OF EVALUATIONS ............................................................................... 77 
APPENDIX III: TEST OF UNDERSTANDING ................................................................................... 79 
ATTACHMENT I: STUDY TEAM ROSTER ....................................................................................... 82 
ATTACHMENT II: ROLES AND RESPONSIBILITIES ................................................................... 88 
ATTACHMENT III: LIST OF COLLABORATORS .......................................................................... 91 
ATTACHMENT IV: DAIDS AE GRADING TABLE .......................................................................... 97 
 

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SCHEMA 
Title 
Safety and Virologic Effect of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB 
(VRC01), With Broad HIV-1 Neutralizing Activity, Administered Intravenously to Adults 
During Early Acute HIV Infection 
Clinical Phase 
Phase I 
Study Duration 
Study duration is 25 weeks. 
Study Design 
This is a placebo controlled study of the safety and impact of broadly neutralizing monoclonal 
antibody (mAb) therapy with VRC01 on viral dynamics in acute HIV infection, alone or in 
combination with antiretroviral therapy (ART). Twenty-four subjects will be enrolled during 
early acute HIV infection (AHI): defined either as two positive nucleic acid amplification tests 
(NAATs) for HIV-1 RNA within 21 days of a prior negative NAAT OR as a positive NAAT or 
positive 4th generation HIV EIA in the context of a negative 2nd or negative 3rd generation EIA. 
They will be subsequently randomized to one of three groups: 
• Group 1, Immediate ART and placebo infusion (n=8): start ART with a single infusion 
of placebo on day 0 during AHI  
• Group 2, Immediate ART and mAb Therapy (n=8): start ART with a single infusion of 
40 milligrams/kilograms (mg/kg) VRC01 on day 0 during AHI  
• Group 3, Immediate mAb Therapy and Subsequent ART (n=8): a single infusion of 40 
mg/kg VRC01 on day 0 during AHI followed by ART initiation on day 7 
 Group 
Number of 
Subjects 
Day 0 
Day 7 
1 
8 
ART initiation and 
single placebo 
infusion 
(continued ART) 
2 
8 
ART initiation and 
single infusion 
40mg/kg VRC01 
(continued ART) 
3 
8 
Single infusion 
40mg/kg VRC01 
ART initiation 
 
For groups 1 and 2, participants and study team will be blinded to active mAb vs. placebo 
infusion. After day 7, all groups will be on ART and be followed for an additional 24 weeks. 

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Sample Size 
Sample size is 24 participants; 8 per group 
Participants 
Adults aged 18-50 years enrolled at the time of early acute HIV infection in Thailand, 
Kenya,Tanzania, and Uganda. 
Intervention 
VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing human IgG1 mAb targeted against 
the HIV-1 CD4 binding site. It was developed by the Vaccine Research Center (VRC)/National 
Institutes of Allergy and Infectious Diseases (NIAID)/ National Institutes of Health (NIH) and 
manufactured under cGMP for the VRC by the Vaccine Pilot Plant operated by Leidos 
Biomedical Research, Inc, formerly Science Applications International Corporation (SAIC)-
Frederick, Inc., Frederick, Maryland, under contract to VRC. Vials are provided at 100 ± 10 
mg/mL. The mAb will be administered intravenously at a dose of 40 mg/kg. 
Antiretroviral therapy will consist of once daily oral combination antiretroviral therapy. 
Study Objectives 
Primary Objectives 
1. Safety of VRC01 in acutely HIV-infected individuals 
2. Impact of VRC01 on plasma viremia in each mAb arm compared to the ART plus placebo 
control at day 7 (+/- 1 day)  
Secondary Objectives 
1. Impact of VRC01 on viral dynamics in plasma over the course of 24 weeks  
2. Impact of VRC01 on reservoir measures in peripheral blood mononuclear cells and plasma 
3. Impact of VRC01 on clinical outcomes/characteristics of AHI 
4. Impact of VRC01 on CD4 + T cell count 
5. Pharmacokinetics of VRC01 in AHI in peripheral blood 
Exploratory Objectives 
1. Impact of VRC01 on reservoir measures in CSF, mucosal, and tissue compartments 
2. Comparison of peripheral blood reservoir measures to those in the CSF, mucosal, and tissue 
compartments 
3. Impact of VRC01 on reservoir measures in T cell subsets 
4. Pharmacokinetics of VRC01 in CSF and mucosal compartments 

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5. Anti-VRC01 antibody detection 
6. Impact of VRC01 on immune responses and activation 
7. Effect of VRC01 on viral sequence, phenotype, and evolution 
8. Predictors of favorable viral dynamics, immune responses, and reservoir seeding 
9. Impact of VRC01 on neuropsychological testing outcomes 
NOTE: Exploratory objectives involving additional specimen collections will only be performed 
on specimens of those participants who consent to these optional procedures. 

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LIST OF ABBREVIATIONS 
TERM 
DEFINITION 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADCP 
Antibody-dependent cell-mediated phagocytosis 
ADCVI 
Antibody-dependent cell-mediated viral inhibition 
AE 
Adverse experience 
AFRIMS 
Armed Forces Research Institute of Medical Sciences 
AHI 
acute HIV infection 
AI 
Associate Investigator 
AIDS 
Acquired immunodeficiency syndrome 
ALP 
Alkaline phosphatase 
ALT/AST 
Alanine aminotranferase and aspartate aminotransferase liver enzymes 
ANOVA 
Analysis of Variance 
APGAR 
American Pediatric Gross Assessment Record 
ART 
Antiretroviral therapy 
ARV 
Antiretroviral 
bnMAb 
Broadly neutralizing monoclonal antibody 
CBER 
Center for Biologics Evaluation and Research (FDA) 
CCR5 
chemokine receptor 5 
CD4+ 
A functional subclass of T cells, helper T lymphocytes (Th) that are 
necessary for augmentation and coordination of innate and adaptive 
effector responses, humoral and cellular 
CD8+ 
Cytotoxic T-Cells that destroy host cells, which have become infected 
by viruses or other intracellular pathogens 
CDR 
complementarity-determining regions 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CHMP 
Committee for Medicinal Products for Human Use 
CHO 
Chinese Hamster Ovary 
CIOMS 
Council of International Organization of Medical Sciences 
Cl 
Clearance 
Cmax 
The maximum concentration of a drug observed after its 
administration 
Cmin 
The minimum concentration of a drug observed after its administration 
and just prior to the administration of a subsequent dose. 
CRF 
Case report form 
CRPMC 
Clinical Research Products Management, NIAID, DAIDS 
CRR 
Continuing Review Report 
CRS 
Cytokine release syndrome 
CSF 
Cerebrospinal fluid 

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DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
U.S. Division of AIDS, NIAID, NIH 
DAIDS CSRC 
DAIDS Clinical Sciences Review Committee 
DAIDS PRO 
Protocol Registration Office, DAIDS 
DCAC 
Data Coordinating and Analysis Center 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
DoD 
United States Department of Defense 
E01 
End of Infusion 
EAE 
Expedited Adverse Events 
ECHO 
Early Capture HIV Cohort (RV 217) 
ELISA 
Enzyme linked immunosorbent assay 
ELISPOT 
Enzyme-Linked Immunospot 
ERC 
Ethical Review Committee 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
gp120 
glycoprotein 120 
H1 
hypervariable loop 1 
H3 
hypervariable loop 3 
HADS 
Hospital Anxiety and Depression Scale 
HIV and HIV-1 
Human immunodeficiency virus, type 1 
HRPO 
Human Research Protection Office, Office of Research Protection, 
USAMRMC 
HSPB 
Human Subjects Protection Branch, WRAIR 
IB  
Investigator’s Brochure 
IC50 
inhibitory concentration (IC50) of <50 micrograms/milliliter (mcg/mL) 
ICH 
International Conference on Harmonization 
ICS 
Intracellular cytokine staining 
ID 
Identification 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug  
IQR 
interquartile range 
IRB 
Institutional Review Board 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
kilogram 
LTR 
long terminal repeat 
mAb 
Monoclonal antibody 
mcg 
microgram 
mg 
Milligram 

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MHRP 
US Military HIV Research Program 
MHRP COO 
U.S. Military HIV Research Program-Clinical Operations Office 
mL 
Milliliter  
mm 
Millimeter 
MO 
Medical Officer 
MOP 
Manual of Operations 
MUWRP 
Makerere University Walter Reed Project 
NAAT 
Nucleic acid amplification tests 
NAb 
Neutralizing antibody 
NHP 
Non-human primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NK 
Natural killer 
NOAEL 
“no observed adverse effect level”  
NOEL 
“no observed effect level”  
NP 
Neuropsychological Testing 
NSAID 
Non-steroidal anti-inflammatory drug 
OHRP 
Office for Human Research Protection 
ORP 
Office of Research Protections, USAMRMC 
ORTA 
WRAIR Office of Research Technology and Applications 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PHQ-9 
Patient Health Questionnaire-9 
PI 
Principal investigator 
PIR 
post-injection reactogenicity 
PK 
pharmacokinetics 
PSRT 
Protocol Safety Review Team 
QA 
Quality assurance 
RAB 
DAIDS Regulatory Affairs Branch 
RBC 
Red blood cell count 
RNA 
Ribonucleic acid 
RSC 
DAIDS Regulatory Support Center 
SAE 
Serious adverse experience 
SAIC-Frederick 
Science Applications International Corporation-Frederick 
SBV 
Small blood volume 
SC 
Subcutaneous injection 
SHIV 
Simian-human immunodeficiency virus 
SIV 
Simian immunodeficiency virus 
SMC 
Safety Monitoring Committee 
SOE 
Schedule of Evaluations 
SSN 
Social security number 

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TILDA 
Tat/Rev Induced Limiting Dilution Assay 
Tmax 
The time after administration of a drug when the maximum plasma 
concentration is reached; when the rate of absorption equals the rate of 
elimination 
U.S. 
United States 
ul 
microliter 
UNAIDS 
The Joint United Nations Programme on HIV/AIDS 
UPIRTSOs 
Unanticipated problems related to the study and involving risk to 
subjects or others 
USA 
United States of America 
USAMRMC 
U.S. Army Medical Research and Materiel Command 
V 
variable 
Vd 
volume of distribution 
VRC 
Vaccine Research Center, National Institute of Allergy and Infectious 
Diseases, National Institutes of Health, Maryland 
WBC 
White blood cell count 
WHO-QOL 
World Health Organization-Quality of Life 
WRAIR 
Walter Reed Army Institute of Research 
Β-HCG 
Β-human chorionic gonadotropin 
 

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1.0 
INTRODUCTION 
1.1 
BACKGROUND 
The global incidence of new human immunodeficiency virus (HIV) infections peaked in the mid-
1990s. The incidence of new infections in 2012 is reported by the Joint United Nations 
Programme on HIV/AIDS (UNAIDS) as 2.3 million new cases, down from 3.4 million in 2001, 
with an estimated global total of 35.3 million people living with HIV. The reduction of HIV 
incidence is due to multiple factors that include prevention and treatment programs. The decrease 
in incidence is an encouraging trend, but the scope and cost of the epidemic remain of great 
global concern. The wider availability of antiretroviral therapy (ART), prevention of mother-to-
child transmission programs, and a diverse array of other interventions have all contributed to 
turning the tide of the epidemic [1]. 
The United States (US) Military HIV Research Program (MHRP) and The National Institute of 
Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) are committed to 
the development of safe, effective methods to prevent and treat HIV infection and acquired 
immunodeficiency syndrome (AIDS) worldwide.  
Long-term use of antiretroviral therapy (ART) in HIV-positive persons may be challenged by the 
need for high-level life long adherence to a daily regimen, development of drug resistance and 
cross-resistance, short and long-term toxicities, and cost [2-5]. Even with complete and durable 
viral suppression, standard antiretroviral therapies do not fully restore health, as some degree of 
immunodeficiency and/or chronic immune activation and inflammation persists. Furthermore, 
the large and growing global population of HIV infected individuals and the costs of ART 
present a significant challenge for providing treatment to those in need, particularly through 
public health systems where resources are already constrained. There is, therefore, a growing 
interest and need for the development of curative approaches for HIV that include treatment 
strategies that confer durable virologic control with less frequent dosing or even sustained 
remission in the absence of ART [6]. 
The MHRP has pioneered clinical research methods to establish cohorts of individuals acutely 
infected with HIV, including the RV 217 Early Capture HIV Cohort (ECHO) study and the RV 
254/SEARCH10 study. These cohorts are ideal for evaluating curative strategies, given their 
successes in early diagnosis and treatment of early AHI and the limited establishment of a latent 
reservoir during the time period of very early infection [7-10]. Intervening with single or 
combination treatment modalities during this time period very early in AHI may decrease the 
magnitude of early viremia and profoundly limit establishment of the latent reservoir that gives 
rise to rebound viremia upon ART cessation in chronically treated HIV infection. 
The Vaccine Research Center (VRC)/NIAID, Division of AIDS (DAIDS)/NIAID, and MHRP 
are collaborating to evaluate the clinical uses of VRC01 in these acutely diagnosed populations, 
This broadly neutralizing human mAb has thus far been demonstrated to be safe and generally 
well tolerated in initial Phase 1 studies [11]. It has also been demonstrated to decrease viremia in 
a rhesus macaque model [11] and in viremic HIV-infected individuals [12]. The current study 

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aims to determine the safety and impact of mAb therapy on AHI in humans. It will evaluate the 
effect of VRC01, with and without ART, on viremia and the establishment of an HIV-1 reservoir 
during early acute infection. 
1.2 
RATIONALE FOR VRC01 AS A STUDY AGENT 
Administration of broadly neutralizing monoclonal antibodies has the potential to treat HIV 
infection by preventing viral spread (as with ART), by facilitating clearance of virus particles 
and mediating destruction of virus-producing cells. This may decrease the number of cells with 
HIV DNA incorporated and limit chronic immune activation. Indeed, recent data from 
nonhuman primate (NHP) and humanized mice models demonstrate that broadly neutralizing 
mAbs can control viremia and reduce the persistent cellular HIV DNA in infected animals in the 
absence of ART [13-15].  
This proof of concept study will evaluate the impact of VRC01 on viremia in acute HIV 
infection and explore its impact on the establishment of the latent reservoir, informing 
considerations for the development of the VRC01 mAb for use in therapeutic settings, including 
administration in early and chronic HIV infection. 
The VRC01 mAb was originally isolated from an adult who had been infected with HIV-1 for 
more than 15 years and had maintained viral control without ART [16]. Using novel methods to 
isolate and screen memory B lymphocytes from the peripheral blood mononuclear cells (PBMC) 
of HIV infected donors, investigators at the VRC were able to clone out this antibody that 
neutralized more than 90% of genetically diverse heterologous strains of HIV-1 at a 
concentration of 50 mcg/mL[17]. Since the initial isolation and characterization of the VRC01 
mAb, subsequent investigations on longitudinal serum samples from HIV-1 infected individuals 
have shown that VRC01-like epitopes are induced during HIV-1 infection but only in a subset of 
HIV-infected individuals and may take years to develop [18].  
The structure of VRC01 in complex with the HIV glycoprotein (gp)120 core glycoprotein has 
also been determined. It is highly affinity-matured, has a disulfide link between 
complementarity-determining regions (CDR) hypervariable loop 1 (H1) and hypervariable loop 3 
(H3) and has a glycan in the variable (V) region of the light chain. However, none of these 
features appears to affect its binding affinity or neutralization activity [19].  VRC01 does not 
have an unusually long CDR-H3 region like some other HIV-1 neutralizing antibodies. It is not 
self- or poly-reactive, lacks anti-phospholipid antibody activity [13], and it does not bind to 
human adult or fetal tissue. These features suggest that mAb administration will not precipitate 
adverse immune phenomena. The VRC01 mAb has been safe in multiple NHP studies, and first-
in-human studies (VRC 601 and 602) conducted in HIV-infected and -uninfected individuals, 
respectively, have demonstrated the product to be safe and well tolerated across a range of doses 
(1 to 40 mg/kg) and delivery methods (IV and SC). These studies have observed no drug-related 
serious adverse events, discontinuations due to drug-related adverse events, nor dose-related 
toxicities. 
From in vitro testing, it has been observed that VRC01 has a half-maximal inhibitory 
concentration (IC50) of <50 micrograms/milliliter (mcg/mL) against 91% of primary isolates of 
various HIV-1 clades and <1 mcg/mL against 72% of primary isolates [17].  Several proof-of 

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concept studies have been conducted to determine whether the in vitro neutralization capabilities 
of VRC01 translate into protecting NHPs from challenge with virulent chimeric simian-human 
immunodeficiency virus (SHIV), which contains the HIV envelope in an simian 
immunodeficiency virus (SIV) background. Rhesus macaques that received a single dose of IV 
VRC01 at 20mg/kg or 5mg/kg were fully or partially protected, respectively, against a single 
high-dose rectal challenge of SHIV-SF162P3 (a chemokine receptor 5 (CCR5) tropic strain of 
HIV). Rhesus macaques were protected against vaginal challenge if they had received 20mg/kg 
IV the mAb. VRC01 at the same dose also protected infant macaques from oral SHIV challenge.  
Additional NHP work with VRC01 is exploring the impact of the mAb on viremia and the latent 
reservoir in acute SHIV infection. Rhesus macaques were challenged intravenously with SHIV 
SF162P3 and subsequently administered VRC01 (40 mg/kg IV, VRC01 group) or started on a 
daily antiretroviral drug regimen (ARV group) at day ten following challenge. A control group 
was left untreated. Both VRC01 and antiretroviral (ARV) groups demonstrated a substantial 
antiviral effect compared to the control group, with reduced peak viremia [11].  
 

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2.0 
STUDY AGENT 
2.1 
BACKGROUND 
The study agent, VRC-HIVMAB060-00-AB, was produced under current Good Manufacturing 
Practice (cGMP) by SAIC-Frederick, Inc., Frederick, Maryland, under contract to VRC. Specific 
manufacturing information is included on the product vial labels and Certificates of Analysis and 
can be found in the Investigator’s Brochure (IB). Quality Assurance (QA) lot release testing by 
the manufacturer and ongoing stability programs verify conformance to product specifications 
prior to use in clinical trials. 
2.2 
DESCRIPTION OF STUDY AGENT VRC-HIVMAB060-00-AB (VRC01) 
VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing human mAb targeted against the 
HIV-1 CD4 binding site. It was developed by the VRC/NIAID/NIH. VRC01 is of the 
Immunoglobulin G1 (IgG1) subtype and is highly somatically mutated from its germ-line 
precursor. The heavy chain CDR3 region is 14 amino acids long, which is an average length 
relative to natural antibodies, and the glycosylation pattern is derived from its production in a 
Chinese Hamster Ovary (CHO) mammalian cell line. 
The study agent was produced using recombinant DNA technology. The mammalian Glutamine 
Synthetase Gene Expression System in the CHO cell line developed by Lonza Biologics (Slough, 
UK) was used to produce the VRC01 mAb. The methods by which VRC01 was isolated and 
produced have been described previously in detail [20]. Briefly, PBMC from HIV-1 infected 
adults stained with specific antigenic probes and passed through a flourescence activated cell 
sorter (FACS) through which single B lymphoctyes were isolated. Heavy and light chain variable 
regions of single B cell receptors were amplified by polymerase chain reaction (PCR) and 
sequenced. Heavy and light chains were intially expressed in an HEK 293 suspension cell 
culture.  
The bulk lot of the mAb was manufactured under cGMP using a stably transfected CHO cell 
line. The product was then purified and labeled at the VRC Vaccine Pilot Plant (Frederick, 
Maryland), operated by Leidos Biomedical Research, Inc., Frederick, Maryland. There are two 
fill volumes available-- a 3 ml glass product vial contains 2.25 mL ± 0.10 mL volume and a 10 
ml glass product viral containing 6.25 ± 0.10 mL fill volume at a concentration of 100 ± 10 
mg/mL VRC01 in an isotonic, sterile solution. Vials contain a clear, colorless to yellow liquid, 
essentially free of visible particles; some opaque or translucent particles may be present. The 
formulation buffer is composed of 25 mM Sodium Citrate, 50 mM Sodium Chloride, and 150 
mM L-Arginine Hydrochloride at pH 5.8.  
More details on the VRC-HIVMAB060-00-AB composition and manufacturing can be found in 
the IB. 
2.3 
PRECLINICAL GLP TOXICOLOGY STUDY 
A single-dose pharmacokinetics (PK) study and repeat-dose toxicity study of IV and 

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subcutaneous (SC) administration of VRC-HIVMAB060-00-AB (VRC01) was performed by 
SRI International (Menlo Park, CA) in male and female Sprague-Dawley rats according to U.S. 
Food and Drug Administration (FDA) “Good Laboratory Practice (GLP) for Nonclinical 
Laboratory Studies.” This study was conducted with a pre-GMP pilot lot of VRC01 
manufactured at a smaller scale using a purification process similar to that of the GMP clinical-
grade drug product. 
For the safety assessment, vehicle control, 4 mg/kg VRC01, 40 mg/kg VRC01, and 400 mg/kg of 
VRC01 were administered by tail vein injection on Days 1 and 8 to Groups 1 through 4, 
respectively. The vehicle consisted of the VRC01 formulation buffer containing 25mM sodium 
citrate, 50mM sodium chloride and 150mM L-arginine-HCl at pH 5.8. An additional group 
(Group 5) received 40 mg/kg VRC01 via SC administration to the dorsal scapular region on 
Days 1 and 8. Each group contained 10 male and 10 female rats. Five of each sex were sacrificed 
on Day 9, one day after the second administration; the remaining animals were sacrificed on Day 
30, 22 days after the second administration. 
Results obtained showed that both routes of administration were well tolerated in the rats. All 
animals survived until their scheduled necropsy. No findings or changes were seen in general 
clinical condition, body weight, food consumption, body temperature, injection site irritation, 
organ weight or in hematologic or coagulation factor measurements that could be attributed to 
VRC01. However, VRC01 administration resulted in small, transient, dose-dependent increases 
in aspartate aminotransferase (AST) and alkaline phosphatase (ALP) on Day 9. By Day 30, AST 
values had returned to normal, and ALP values were returning to normal.  
Other than red discoloration of the administration site in one male in the SC group on Day 9, 
there were no other gross necropsy observations attributable to VRC01 administration. There 
were no histopathology findings that were considered related to IV administration of VRC01. 
However, histopathology evaluation revealed subacute inflammation at the SC injection site on 
Day 9, one day after injection, in all 10 SC administered rats; dermal inflammation was usually 
minimal or mild while SC inflammation was usually mild, moderate, or marked. By Day 30, this 
inflammation had completely resolved, and the SC dose site was normal in all rats.  
A “no observed effect level” (NOEL) was not determined in this study because transient 
elevations of AST and ALP were observed on Day 9 after IV administration and transient 
inflammation at the dose site was observed on Day 9 after SC administration. Because the 
elevated AST and ALP levels were transient and minor and did not correlate with histopathology 
findings, the “no observed adverse effect level” (NOAEL) for VRC01 by the IV route of 
administration in rats was 400 mg/kg, the highest dose used in this study. The systemic NOAEL 
for the SC route of administration of VRC01 in rats was 40 mg/kg, the only SC dose level 
examined in this study. 
For the PK analysis, a separate cohort of rats received VRC01 on Day 1 at 4 mg/kg and 40 
mg/kg by the IV route of administration and at 40 mg/kg by the SC route of administration. 
VRC01 levels in serum were determined by enzyme-linked immunosorbent assay (ELISA) on 
pre-dose samples collected from each animal. Untreated control samples were collected from and 
tested on an additional 3 males and 3 females. Blood was collected from 3 rats/sex/PK group for 
a total of 4–5 collections per PK animal at each of the following post-dose time points: 1, 4, 8, 

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24, 48, and 72 hours and 7, 14, 21, and 29 days.  
VRC01 administration by the IV route resulted in dose-proportional exposure. The terminal 
elimination phase half-life (t1/2) was about 10 days, with clearance (Cl) of approximately 
20 ml/day/kg and volume of distribution (Vd) that was about 0.28 l/kg, indicating that the drug 
was distributed primarily in the serum and eliminated slowly. 
2.4 
TISSUE CROSS-REACTIVITY GLP STUDY OF VRC01 WITH HUMAN 
TISSUES IN VITRO 
A tissue cross-reactivity study of VRC-HIVMAB060-00-AB (VRC01) using normal adult and 
neonatal human tissues in vitro (Testing Facility Study No. A255-12) was performed by Charles 
River Laboratories (Reno, NV) in accordance with U.S. FDA “Good Laboratory Practice (GLP) 
for Nonclinical Laboratory Studies.” The tissue panels used as the test system for this in vitro 
cross-reactivity study included all of the tissues on the “Suggested list of human tissues to be 
used for immunohistochemical or cytochemical investigations of cross reactivity of monoclonal 
antibodies” in Annex I of the “European Medicines Agency Guideline on Development, 
Production, Characterisation and Specifications for Monoclonal Antibodies and Related Product, 
Adopted by the Committee for Medicinal Products for Human Use (CHMP) on December 18, 
2008” and all of the tissues recommended in the FDA/Center for Biologics Evaluation and 
Research (CBER) “Points to Consider in the Manufacture and Testing of Monoclonal Antibody 
Products for Human Use (February 28, 1997).”  
To determine the cross-reactivity of VRC01 binding, VRC01 was applied to cryosections from a 
full panel of tissues from normal human adults and a limited panel of human neonatal tissues, 
immunohistochemically detected using a biotinylated rabbit anti-human immunoglobulin G 
(IgG) secondary antibody and binding visualized with a streptavidin-horseradish peroxidase 
complex and a diaminobenzidine chromogen substrate. VRC01 binding was evaluated at 
concentrations of 5 and 50 mcg/mL. 
Specific VRC01 staining was not observed in any normal adult human or neonatal human tissues 
evaluated. Therefore, in vitro evaluation of cross-reactivity in tissue specimens did not identify 
potential tissue sites or organ systems to more thoroughly evaluate in subsequent preclinical 
studies, thus supporting the use of VRC01 in humans. 
2.5 
NONHUMAN PRIMATE (NHP) STUDIES OF VRC01 
Several non-GLP studies of VRC01 have been completed in NHPs to assess for preclinical 
evidence of potential efficacy for prevention of HIV infection. Table 1 is a brief summary of the 
studies performed [11]. 
Table 1. Preclinical proof-of-concept studies performed with VRC01 in NHP  
Study Purpose 
Study Outcome 
Demonstration of plasma and secretion 
concentrations of VRC01 given by IV or 
SC routes in female rhesus macaques 
Kinetics of decay of 40 mg/kg of VRC01 
given IV or SC in plasma, rectal, vaginal and 
nasal secretions established 

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Demonstration of challenge-protection 
against intrarectal high-dose SHIV 
SF162P3 in male rhesus macaques 
100% protection from challenge 
demonstrated at 20 mg/kg dose administered 
IV 
Demonstration of challenge-protection 
against intravaginal high-dose SHIV 
SF162P3 in female rhesus macaques 
100% protection from challenge 
demonstrated at 20 mg/kg dose administered 
IV  
Demonstration of challenge-protection 
against intrarectal high-dose SHIV-BaL 
in male rhesus macaques 
100% protection from challenge 
demonstrated at 20, 5, and 1.25 mg/kg dose 
administered IV 
Demonstration of effect of VRC01 during 
the acute and chronic phases of SHIV 
SF162P3 infection in rhesus macaques 
The administration of VRC01 (40 mg/kg 
dose administered IV) during the acute phase 
of infection led to a reduction of peak 
viremia during the chronic phase of infection 
2.6 
PHASE 1 AND PHASE 2 CLINICAL TRIALS OF VRC01 
Evaluation of VRC01 as an investigational drug began in humans with the initiation of the VRC 
601 study in September 2013. Initial development of VRC01 was based on an intended 
indication for the prevention of HIV-1 infection in infants at risk for HIV-1 infection through 
maternal transmission at birth or during breastfeeding. The safety, tolerability, PK and antiviral 
effect of VRC01 are assessed in HIV-1 infected adults, healthy adults and infants in the United 
States (U.S.) and internationally. Additional studies in HIV-unifected adults and HIV-infected 
adults are on going to evaluate potential HIV prevention and therapeutic indications, 
respectively.  
Cumulatively, across all studies as of January 2017, VRC01 has been administered either IV or 
SC to over 840 HIV-uninfected and HIV-infected adults and 33 HIV-uninfected infants. There 
have been no SAE related to VRC01 requiring expedited safety reporting to the FDA or other 
regulatory authorities. There were no study safety pauses for adverse events. Although 
experience in HIV-infected, viremic adults is limited (n=8), there is evidence of a statistically 
significant antiviral effect of VRC01. 
Protocols VRC 601, VRC 602, HVTN 104, P1112, HVTN 704/HVTN 085, HVTN 703/HVTN 
081, HVTN 116, and VRC 606 - Prevention Indication: VRC 601 [12] and VRC 602 [21] were 
the first Phase 1 studies of VRC-HIVMAB060-00-AB (VRC01) administered to HIV-infected 
and HIV-uninfected adults, respectively. Both the IV or SC routes of administration were 
evaluated on schedules with 1 or 2 administrations.  
HVTN 104 is a Phase 1 clinical trial of VRC01 administered IV or SC on schedules with 
multiple administrations to HIV-uninfected adults.  
P 1112 is a Phase 1 study of VRC01 administered SC one time or up to 19 times (maximum until 
72 month of age) to HIV-1-exposed infants.  
HVTN 704/HPTN 085 is a Phase 2b study to evaluate the safety and efficacy of VRC01 in 
reducing acquisition of HIV-1 infection among men and transgender persons who have sex with 
men.  

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HVTN 703/HPTN 081 is a Phase 2b study to evaluate the safety and efficacy of VRC01 in 
reducing acquisition of HIV-1 infection in women in sub-Saharan Africa.  
HVTN 116 is a Phase 1 study to evaluate the safety, pharmacokinetics, and anti-viral activity of 
VRC-HIVMAB060-00-AB (VRC01) and VRC-HIVMAB080-00-AB (VRC01LS) in the serum 
and mucosa of healthy, HIV-uninfected adult participants.  
VRC 606 is a Phase 1, dose-escalation study to evaluate the safety and pharmacokinetics of 
VRC-HIVMAB080-00-AB (VRC01LS), and VRC-HIVMAB060-00-AB (VRC01), administered 
IV or SC to healthy adults. 
The doses, routes evaluated and protocol statuses for these studies are summarized in the 
Investigator’s Brochure. Overall, as of January 10, 2017, VRC01 infusions in the dose range 
from 1 to 40 mg/kg IV and 5 to 40 mg/kg SC have been assessed as well-tolerated in adults and 
infants and safe for further evaluation. Cumulatively, across all studies, there have been no SAE 
related to VRC01 that required expedited reporting to the FDA or other regulatory authorities. A 
non-serious AE of urticaria was submitted to regulatory authorities as a safety report because 
urticaria, at the grade 3 severity, was not reported in the IB, Version 6.0, dated October 5, 2016. 
The HVTN 104 study has expanded experience with repetitive administration of VRC01 beyond 
the two doses per subject that was the maximum administered in the VRC 601 and VRC 602 
protocols. HVTN 704/HPTN 085 and HVTN 703/HPTN 081 studies are further expanding on 
experience with infusion of VRC01 or placebo every 2 months for up to 72 weeks, with 
approximately 2,500 infusions administered and no related SAEs reported as of January 2, 2017.  
Protocols RV 397, RV 398, A 5340, A 5342, 15-I-0140, and IMPAACT 2008 - THERAPEUTIC 
INDICATION: Protocols RV 397, RV 398 (this study) A 5340, A 5342 and 15-I-0140 evaluate 
the safety and virologic effect of VRC01 in HIV-infected adults. Protocol IMPAACT 2008 
evaluate the safety and antiviral activity of VRC01 administered to HIV-1-infected infants. Each 
protocol was designed to address different aspects of the effect of VRC01, including virologic 
effect when administered during acute HIV infection, effect on the HIV reservoir and effect 
when administered during an analytical treatment interruption (ATI).  
RV 397 is a Phase 1 placebo controlled study evaluating the safety and therapeutic efficacy of 
VRC01 during ATI in patients who initiated ARV during early HIV infection.  
A 5340 is a Phase 1, open-label study of the safety, pharmacokinetics, and antiviral activity of 
VRC01 administered IV to HIV-infected adults undergoing a brief ATI.  
A 5342 is a Phase 1 study evaluating the safety, tolerability, and effect of VRC01 on markers of 
HIV persistence in ART-treated, HIV-infected adults.  
15-I-0140 is a Phase 1 study evaluating the safety, tolerability, and effect of VRC01 on markers 
of HIV persistence in ART-treated, HIV-infected adults undergoing ATI.  
IMPAACT 2008 is a Phase 1/2, randomized, controlled study to evaluate the safety and antiviral 
activity of VRC01 administered in addition to combination antiretroviral therapy (cART) to 
HIV-1-infected infants to promote clearance of HIV-1-infected cells.  

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The dose, routes evaluated and protocol statuses these and other ongoing studies with therapeutic 
indications are shown in the Investigator’s Brochure.  
Overally, as of January 10, 2017, VRC01 infusions at 40 mg/kg IV have been safe and well-
tolerated in these studies in about 80 HIV-infected adults. There have been no SAE related to 
VRC01 that required expedited reporting to the FDA or other regulatory authorities. RV 397 
reported an infusion reaction consisting of Grade 3 urticaria and grade 1 pruritis and nausea that 
required early termination of study infusion and discontinuation from the study intervention. 
Emergence of VRC01-resistant HIV has been detected during plasma viral rebound in subjects 
undergoing analytic treatment interruption, however resumption of ART routinely results in re-
suppression of the viral load. Additional detail on the safety profile of VRC01 administration is 
contained in the Investigator’s Brochure. 
2.6.1 INITIAL PHARMACOKINETIC DATA 
The pharmacokinetic (PK) parameters of passively administered VRC01 have been evaluated in 
HIV-infected and healthy uninfected adults in the VRC 601 and VRC 602 studies, respectively. 
The Investigator’s Brochure shows PK parameters by population, dose and administration route.  
In these initial studies of VRC01 no more than two doses were administered and, by study 
design, many subjects received only one dose. At 28 days after second administration at 20 
mg/kg and 40 mg/kg IV, mean VRC01 serum levels were 55.9±16.8 and 88.9±40.4 mcg/mL in 
uninfected adults, and were 46.0±26.7 and 64.9±56.7 mcg/mL in HIV-infected adults, 
respectively. The time to maximum concentration (Tmax) is about 1-3 hours after IV 
administration and about 1-3 days after SC administration.  
The PK of VRC01 by the IV and SC routes of administration after repeat dosing in adults is 
under investigation in ongoing clinical trials. Evaluation of the SC route of administration in 
adults has been limited to the 5 mg/kg dose due to limitation on the volume that can be 
administered to adults. This is expected to be the primary route of administration to infants, but 
there are not yet any PK data from pediatric studies.  
2.6.2 VIRAL LOAD EFFECTS 
Analysis of the VRC 601 viral load data obtained from 8 viremic adults shows that VRC01 has a 
statistically significant effect on HIV viral load when administered as a single 40 mg/kg IV dose. 
None of these adults had been taking antiretroviral therapy (ART) when enrolled into the study 
and had not started ART during the time period when the viral load data were collected. Six of 
the eight adult subjects had ≥1 log10 copies/mL decrease in viral load and two subjects had a 
viral load drop of 0.26 and 0.18 log10 copies/mL respectively [12]. 
These data indicate the following for a single dose of VRC01 at 40 mg/kg IV:    
• A statistically significant change from baseline viral load post-infusion days 5 to 16;  
• The median time to reach ≥0.5 log decrease in viral load is 5 days; and,   

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• The median time to greatest decrease in viral load is 7 days. 
A 0.5 log10 copies/mL or greater decrease in viral load is considered to be a positive response to 
ART [22] - the data from 8 viremic adults who received VRC01 indicate an in vivo virological 
effect of VRC01 on HIV viral load. VRC 601, subjects were administered only one dose of 
VRC01 at 40 mg/kg, thus, would not expect a sustained effect on viral load,importantly, there 
was no evidence of an adverse response or an exaggerated viral rebound in subjects escaping 
VRC01-mediated VL supression. 

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3.0 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
1. Safety of VRC01 in acutely HIV-infected viremic individuals 
2. Impact of VRC01 on plasma viremia in each mAb arm compared to the ART plus placebo 
control at day 7 (+/- 1 day)  
3.2 
SECONDARY OBJECTIVES 
1. Impact of VRC01 on viral dynamics in plasma over the course of 24 weeks. 
2. Impact of VRC01 on HIV reservoir measures in peripheral blood mononuclear cells and 
plasma 
3. Impact of VRC01 on clinical outcomes/characteristics of AHI 
4. Impact of VRC01 on CD4 + T cell count 
5. Pharmacokinetics of VRC01 in AHI in peripheral blood 
3.3 
EXPLORATORY OBJECTIVES 
1. Impact of VRC01 on reservoir measures in CSF, mucosal, and tissue compartments 
2. Comparison of peripheral blood reservoir measures to those in the CSF, mucosal and tissue 
compartments 
3. Impact of VRC01 on reservoir measures in T cell subsets 
4. Pharmacokinetics of VRC01 in CSF and mucosal compartments 
5. Anti-VRC01 antibody detection 
6. Impact of VRC01 on immune responses and activation 
7. Effect of VRC01 on viral sequence, phenotype, and evolution 
8. Predictors of favorable viral dynamics, immune responses, and reservoir seeding 
9. Impact of VRC01 on neuropsychological testing outcomes 
 
NOTE: Exploratory objectives involving additional specimen collections will only be 
performed on specimens of those participants who consent to these optional procedures. 
 

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4.0 
ENDPOINTS 
4.1 
PRIMARY 
1. Safety: ≥ grade 3 mAb-related reactogenicity and mAb-related AEs  
2. Plasma viral load change from day 0 to day 7 (+/- 1 day) 
4.2 
 SECONDARY 
1. Time to virologic suppression (<50 copies/ml) in plasma 
2. Total viremic copy days (area under viral load curve) from day 0 to week 24 
3. Plasma viremia including single copy HIV RNA quantification in samples with HIV RNA < 
50 copies/ml at day 7, day 14 and week 24 
4. Cell-associated HIV RNA and DNA in the peripheral compartment  
5. Frequency, severity and duration of acute retroviral syndrome 
6. Frequency of hospitalization and incidence of opportunistic infections and non-AIDS related 
conditions 
7. CD4 + T cell decrease from baseline to nadir, increase from nadir to week 24, and overall 
change from baseline to week 24 
8. VRC01 levels in peripheral blood 
4.3 
EXPLORATORY 
1. HIV RNA quantification in the CSF and mucosal compartment (to include single copy 
measurements from samples with HIV RNA < 50 copies/ml)  
2. Cell-associated HIV RNA and DNA in the CSF, mucosal and tissue compartments 
3. Correlation of HIV RNA and DNA measurements across biologic compartments that include 
the peripheral blood, CSF, mucosal, and tissue compartments 
4. HIV RNA and DNA in sorted memory CD4+ T cell subsets (for subjects with sufficient 
PBMC collections) 
5. Viral outgrowth in total CD4+ T cells and sorted memory CD4+ T cell subsets (for subjects 
with sufficient PBMC collections) 
6. VRC01 levels across biologic compartments that include the CSF and mucosal secretions 
7. Presence of anti-mAb antibody  
8. Biomarkers of immune activation (soluble and cellular markers, gene expression) 

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9. Neutralization sensitivity of virus isolates (including to VRC01) 
10. Binding and neutralizing activities of elicited antibodies 
11. Non-neutralizing antibody functional assays including antibody-dependent cell-mediated 
cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), antibody-
dependent cell-mediated viral inhibition (ADCVI), and viral capture  
12. Cellular immune responses: percentage of peptide specific T cell responses as measured by 
enzyme-linked immunospot (ELISPOT); breadth and magnitude of epitope-specific T cell 
responses; polyfunctionality of cellular responses 
13. Innate immune response characterization including assessment of natural killer cell activity 
14. Viral sequence evolution and the development of VRC01 escape mutations  
15. Host genetic determinants of virologic suppression 
16. Neuropsychological battery performance at week 24 compared to cohort data from pre-
infection and baseline AHI timepoints, where available. 
 

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5.0 
STUDY DESIGN AND POPULATION 
This is a placebo-controlled study of the safety and impact of broadly neutralizing monoclonal 
antibody therapy with VRC01 on viremia in acute HIV infection, alone or in combination with 
antiretroviral therapy (ART). Twenty-four subjects will be enrolled during early acute HIV 
infection, as defined by either 1) two positive nucleic acid amplification tests (NAATs) for HIV-
1 RNA within 21 days of a prior negative NAAT, or 2) a positive NAAT or a positive 4th 
generation EIA in the context of a negative 2nd or negative 3rd generation HIV EIA. They will be 
randomized to three groups:  
 Group 
Number of 
Subjects 
Day 0 
Day 7 
1 
8 
ART initiation and 
single placebo 
infusion 
(continued 
ART) 
2 
8 
ART initiation and 
single infusion 
40mg/kg VRC01 
(continued 
ART) 
3 
8 
Single infusion 
40mg/kg VRC01 
ART 
initiation 
For groups 1 and 2, participants and the study team will be blinded to active mAb vs. placebo 
infusion.  Product safety and day 7 viral load in each mAb-containing arm (Groups 2 and 3) will 
be compared to the control arm (Group 1). Secondarily, viral dynamics across the duration of the 
study, sequential evaluations of the reservoir, evolution of CD4+ T cell count, and clinical 
characteristics will be compared along with exploratory evaluations of the impact of the mAb on 
the immune response to HIV infection, viral sequence, and on the reservoir in T cell subsets and 
optional specimen collections. 
Study participants from acute infection cohorts will be co-enrolled in the cohort studies and RV 
398, although study visits for the acute infection cohorts will be suspended during the RV 398 
study participation. Once the study participant has completed their participation in RV 398, they 
will resume cohort study activities.  
5.1 
SOURCE COHORTS  
5.1.1 RV 217 ECHO 
RV 217, entitled HIV Prevalence, Incidence, Cohort Retention, Host Genetics and Viral 
Diversity in Cohorts in East Africa and Thailand - Short Title: Early Capture HIV Cohort 
(ECHO), is an ongoing acute infection cohort study enrolling in Kenya, Uganda, Tanzania, and 
Thailand. The purpose of the study is to characterize recruitment, retention, human 
immunodeficiency virus (HIV) prevalence, HIV incidence, and biological characteristics of acute 
HIV infection in high-risk volunteers in Africa and Southeast Asia. The study incorporates two 

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phases. The main study activity, or phase I, is the observational cohort or surveillance activity 
during which the study collects very small blood samples via finger stick. These frequent “small 
blood volume” (SBV) visits afford the opportunity to diagnose HIV infection by nucleic acid 
amplification testing (NAAT) prior to the advent of detectable antibody by the most sensitive 
techniques available. Volunteers are also screened for viral hepatitis and other sexually 
transmitted infections; hematology and chemistry parameters are also recorded. Participants with 
incident HIV infections observed during phase I are the source of potential volunteers for this 
mAb intervention study. They will be briefed about this study as well as other acute HIV 
intervention studies during this surveillance phase.  
Based on accumulating RV 217 data, those testing with 2 positive NAATs within 21 days of last 
negative NAAT correspond to diagnosis in Fiebig Stages I, II, and III. The RV 217 study has 
defined early Priority 1 cases as those with a known last negative NAAT and having at least 2 
positive NAATs within Fiebig stage I or II. Those Priority 1 volunteers have had a median 
interval of 4 days between last negative to first positive NAAT, and the median day of EIA 
positivity from the day of first NAAT is day 15 (Interquartile (IQR) 13.5-18).  
Following acute HIV infection, RV 398 participants recruited from RV 217 may elect to 
continue frequent visits for small blood volume draws at the RV 217 study site for masking 
purposes to avoid stigma associated with disclosure of new HIV positive status.  
 
Figure 1: RV 217 Priority 1 Viral Loads (n = 42) 
 
5.1.2 RV 254/SEARCH 010 
RV 254/SEARCH010, entitled “Establish and characterize an acute HIV infection cohort in a 
high risk population,” is an ongoing acute infection cohort study enrolling adult volunteers at the 
0
20
40
60
80
100
0
2
4
6
8
10
Days From First RNA Positive
VL  (log10 cps/ml)
days to Nadir
day to EIA 
days to peak
42
15
13
4.2
6.7

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Thai Red Cross AIDS Research Centre (TRCARC) in Bangkok, Thailand. The primary 
objectives of the study are to describe clinical, immunological and virological characteristics of 
persons with acute HIV infection and to identify and follow volunteers who may be candidates 
for future HIV intervention or treatment protocols due to diagnosis of HIV during acute 
infection. 
In this cohort, patients presenting for HIV testing at the Thai Red Cross are consented for their 
phlebotomy specimens to be tested for HIV by nucleic acid testing well as by serologic assays. 
Those with a positive NAAT or positive 4th generation HIV EIA with a negative 2nd or negative 
3rd generation EIA are classified as having acute HIV infection (this corresponds to Fiebig stages 
I-III of HIV infection) and return for the study’s Week 0 visit. They will be briefed about this 
study (RV 398) as well as other acute HIV intervention studies at this Week 0 visit.  
5.2 
STUDY DURATION  
After the first 7 days of the study, all groups will be on ART and followed for 24 weeks for a 
total study duration of 25 weeks.  
5.3 
 ELIGIBILITY 
5.3.1 INCLUSION CRITERIA 
1. Able and willing to complete the informed consent process.  
2. Passes Test of Understanding 
3. 18 to 50 years of age. 
4. Experiencing early acute HIV-1 infection as defined by  
blood samples on at least two separate days positive by nucleic acid testing within 21 days of 
a negative nucleic acid HIV-1 test.  
OR 
by a positive nucleic acid test or a positive 4th generation EIA in the context of a negative 
2nd or negative 3rd generation HIV EIA test 
 
5. No history of antiretroviral therapy for any indication in the last 30 days. 
6. In general good health  
7. Willing to have blood samples collected and stored. 
8. Able to participate for 25 weeks for study visits 
9. Willing to have photo or fingerprint taken for identification purposes 
Female-specific Criteria: 
10. Agrees not to become pregnant from the time of study enrollment until the last study 
visit. If a woman has no history of hysterectomy, tubal ligation or menopause, she must 

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agree to use an effective birth control method: abstinence; male or female condoms; 
diaphragm or cervical cap with spermicide; intrauterine device; contraceptive hormones 
delivered by pills, patch, injections, or vaginally; and hormonal implants under the skin; 
or a male partner who has previously undergone a vasectomy. 
11. Negative β-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day 
of enrollment for any woman unless she is post-menopause for 24 consecutive months or 
has undergone a surgical procedure that precludes pregnancy. 
5.3.2 EXCLUSION CRITERIA 
1. Weight < 46 kg or >115kg 
2. Previous receipt of humanized or human monoclonal antibody whether licensed or 
investigational. 
3. Ongoing AIDS-related opportunistic infection (including oral thrush or active 
tuberculosis). 
4. Severe acute retroviral syndrome (as defined in Appendix I) or clinical condition (other 
than HIV infection) constituting an indication for immediate antiretroviral therapy per 
local country guidelines. 
5. Active injection drug use within previous 12 months. 
6. History of a severe allergic reaction with generalized urticaria, angioedema or 
anaphylaxis in the 2 years prior to enrollment. 
7. History of chronic urticaria 
8. Physical finding on examination considered indicative of significant disease such as 
murmur (other than functional), hepatosplenomegaly, focal neurological deficit. 
9. Hypertension that is not well controlled by medication. 
10.  Positive Hepatitis B surface antigen at any time in the past 
11.  History of hepatitis C infection 
12.  Untreated syphilis infection 
13. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x the upper 
limit of normal (ULN). 
14. Absolute neutrophil count (ANC) <740 cells/mm3  
15. Estimated GFR < 50 ml/min within the past 90 days 
16. Breast-feeding. 
17. Pregnancy 
18. Receipt of licensed vaccine or other investigational study agent within 28 days prior to 
enrollment or past participation in an investigational HIV vaccine study with receipt of 
active product. 

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19. Current or planned participation in another interventional clinical trial during the study 
period. 
20. Chronic or recurrent use of medications that modify host immune response, e.g., oral or 
parenteral steroids, cancer chemotherapy. 
21. Any other chronic or clinically significant medical condition that in the opinion of 
investigator would jeopardize the safety or rights of the volunteer. Including, but not 
limited to: diabetes mellitus type I, chronic hepatitis, renal failure; OR clinically 
significant forms of: drug or alcohol abuse, mental illness, severe asthma, autoimmune 
disease, psychiatric disorders, heart disease, or cancer. 
22. Study site employee 
There are no inclusion/exclusion criteria based on CD4 count because the delay of ART by 7 
days does not incur significant risk to the subject compared to immediate ART. Additionally, we 
have not observed sustained low CD4 counts in the early Fiebig Stages thus far in RV 217. 
Among 42 early acute cases in RV 217, low CD4 counts rebounded rapidly and the lowest 
observed CD4 count at mean day 17 post positive NAAT was 395 cells/ul. 

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6.0 
STUDY PROCEDURES 
6.1 
ENROLLMENT AND RANDOMIZATION 
6.1.1 ENTERING FROM RV 217 
RV 217 ECHO volunteers, at the time of their first positive HIV test will be re-briefed about this 
study and other acute HIV infection intervention studies, including an early ART-only protocol, 
such that participation in this study will not be the only available avenue for accessing 
antiretroviral therapy in acute HIV. After determination of acute HIV infection according to RV 
398 inclusion criteria, interested volunteers will be referred to Visit 1 of this study. 
6.1.2 ENTERING FROM RV 254 
RV 254 volunteers determined to have acute HIV infection return for the RV 254 Week 0 visit, 
during which they undergo medical history and physical; hematology, chemistry, HIV RNA and 
lymphocyte profiles are also obtained. Volunteers also undergo neuropsychological testing and 
questionnaire administration, are screened for viral hepatitis and other sexually transmitted 
infections, and have the option of consenting for procedures to further characterize their acute 
HIV infection (genital secretion collection, CSF collection, brain MRI, colon biopsy, and lymph 
node biopsy). They will be informed about RV 398 as well as other acute HIV intervention 
studies at this Week 0 visit. Those volunteers interested in this study will then be referred to RV 
398 visit 1 procedures within 5 days. To avoid duplication of study procedures between the 
Week 0 visit for RV 254 and Visit 1 of RV 398, volunteers enrolling from RV 254 will have a 
reduced schedule of events for visit 1 of RV 398 (Appendix II). 
6.1.3 RV 398 VISIT 1 
At RV 398 Visit 1, volunteers will undergo the informed consent process with a test of 
understanding (TOU) and verification of eligibility, with same visit enrollment and 
randomization of eligible volunteers on day 0 of the study into one of three groups: 
• Group 1: Immediate ART Only (n=8): start ART with single infusion of placebo in AHI 
on day 0  
• Group 2: Immediate ART and mAb Therapy (n=8): start ART with single infusion of 40 
mg/kg VRC01 in AHI on day 0 
• Group 3: Immediate mAb Therapy and Subsequent ART (n=8): single infusion of 40 
mg/kg VRC01 in AHI on day 0 followed by ART initiation on day 7 
Participants are allowed to take the TOU three times but must have a passing score (90% or 
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The randomization list will be prepared by the study statistician according to a separate 
randomization plan generated by the statistician. The site pharmacist will be responsible for 
maintaining access to the list in a secure manner. The total number of treatment assignments may 
not be the same for each site, in order to accommodate differences in each site’s eligible 
population, pace of enrollment and operational issues. Furthermore, randomizations by arm at 
each site will likely not be equal and the Protocol Chair may reallocate enrollment slots during 
the course of the study. 
Volunteers will undergo IV infusion of either mAb or placebo during the enrollment visit at the 
clinic site. The infusion will typically last an hour, however the infusion rate may be reduced to 
mitigate infusion-related side effects. Following infusion, the volunteers will be observed for a 
minimum of one hour at the clinic site, longer if indicated by demonstrated signs and symptoms. 
The infusion will occur prior to the first dose of oral ART. Enrollment (Visit 1) procedures may 
encompass two days. Day 0 is the day of first product administration. 
6.2 
ANTIRETROVIRAL THERAPY 
Antiretroviral therapy is described in each Site Specific Addendum and consists of country 
guideline-recommended first line combination therapy: either efavirenz 600 mg/emtricitabine 
200 mg/tenofovir disoproxil fumarate 300 mg or efavirenz 600 mg/lamivudine 300 mg/tenofovir 
disoproxil fumarate 300 mg. The only regimen difference between the sites would be the use of 
lamivudine or emtricitabine, nucleoside reverse transcriptase inhibitors that are generally 
considered to have equivalent clinical and virological efficacy and safety profiles [23-24]. 
Volunteers with ART regimen intolerance or inadequate virologic response may require 
prescription of an alternate regimen recommended by local country guidelines, typically based 
on the boosted protease inhibitor lopinavir/ritonavir. Genotype resistance testing will be 
performed as clinically indicated, including failure to achieve virologic suppression to <1,000 
copies/mL after 12 weeks or confirmed viral load over 1,000 copies/mL after initial suppression. 
Results will be used to guide subsequent regimen choice. 
Following the study, antiretroviral therapy will be continued either at the study site or through 
local referral, with procedures detailed in the site-specific addenda. Volunteers may also be 
offered enrollment into an early ART study or other intervention studies upon completion of this 
protocol. For those volunteers electing local referral, site investigators have confirmed with local 
HIV care program authorities that continued treatment of volunteers beginning ART during this 
study will be supported. Upon local referral, volunteers will continue treatment with locally 
available ART regimens.  
6.3 
NEUROPSYCHOLOGICAL TESTING 
The week 24 visit will include a set of thinking tests (neuropsychological (NP) testing), 
questions about mood, and questions about ability to function in day-to-day activities. During 
this testing patients will be asked to do easy tasks as fast as possible (such as put pegs in holes 
and draw lines between sequential circled numbers). Mood and anxiety measures are necessary 
for the accurate interpretation of the neuropsychological measures and will be captured as 
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capture a brief assessment of quality of life and stress as it may be impacted by treatment. 
A trained psychometrist completes this cognitive testing using a modification of published 
international neuropsychological battery [25]. For this study we will use a brief NP battery 
consisting of Non-Dominant Hand Grooved Pegboard Test, Trails A Test, and Color Trails 1 and 
2. To assess stress and depression the following tools will be used: the Hospital Anxiety and 
Depression Scale (HADS), the Patient Health Questionnaire-9 (PHQ-9), the World Health 
Organization-Quality of Life (WHO-QOL), and the Distress Thermometer. 
Neuropsychological test results, mental health and quality of life measures for these participants 
will be compared to similar data collected in RV 217 and RV 254. 
6.4 
OPTIONAL PROCEDURES 
Volunteers will have the option of participating in separately consented collections and 
procedures to characterize the impact of VRC01 and ART on the HIV-1 reservoir and 
pathogenesis. The availability of these procedures varies across sites, and is detailed in each site-
specific addendum. If any of the procedures provides evidence of an abnormal finding, the 
participant will be referred for diagnosis and care. Specifics on referral are provided in the site-
specific addendum. 
6.4.1 MUCOSAL SECRETIONS 
Collection of these samples will be offered at all sites at baseline and subsequent intervals per the 
SOE. 
• Female participants 
Consenting women will be instructed on how to use a Softcup device to collect cervical 
and vaginal secretions. The cup will remain in place for 4 -12 hours. Pregnant women 
and those with a history of toxic shock syndrome will be excluded. Date of last menstrual 
period will be measured/recorded at each collection visit. Collection will not take place if 
the woman is menstruating or has symptoms of active inflammation or infection of the 
vagina or cervix. Blood samples will be drawn for hormone levels at each collection visit. 
Rectal sponge secretions will also be collected, however will be deferred if there are 
signs or symptoms of perianal inflammation. Volunteers may participate in 
cervicovaginal secretion collection if they choose to defer rectal sponge secretion 
collections. 
• Male participants 
Consenting men will be asked to ejaculate into a sterile container for semen collection. 
Rectal sponge secretions will also be collected. Semen and rectal sponge collections will 
be deferred from men if there are signs or symptoms of urethral or perianal inflammation, 
respectively. Volunteers may participate in semen collection if they choose to defer rectal 
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6.4.2 RECTOSIGMOID BIOPSY 
Gut mucosal biopsy will be performed on consenting individuals at baseline, day 14, and week 
24 visits. This will most commonly be a clinic-based rectal biopsy procedure. In Thailand, at the 
Pattaya site, volunteers may be referred to Bangkok for flexible sigmoidoscopy with biopsy. This 
will be conductd by a licensed physician trained in the procedure. The biopsy is anticipated to 
take 5 hours. 
6.4.3 LYMPH NODE BIOPSY 
Inguinal lymph node biopsy will be offered at the 24 week visit and performed by a qualified 
surgeon. The procedure will be performed under local anesthesia and last approximately 30-40 
minutes. Subjects will then be asked to rest under observation for another 4 hours.  
Subjects agreeing to inguinal lymph node biopsy may be asked to undergo photography of the 
biopsy wound in order to provide an objective reference for assessment of wound healing and for 
possible use as volunteers’ educational material. Subjects are free to refuse photography of their 
wound at any point should they not be amenable for any reason.  
6.4.4 LEUKAPHERESIS 
At baseline, day 7, and the week 24 visit, volunteers at capable sites will have the option of 
undergoing apheresis to collect PBMC and plasma. Leukocytes and plasma will be obtained 
using automated apheresis techniques conducted by a qualified apheresis nurse/technician. 
During apheresis, whole blood is withdrawn through a catheter placed in an antecubital vein and 
channeled into a cell separator where cellular and plasma fractions are separated by 
centrifugation. The component to be harvested (i.e. leukocytes) will be directed into a collection 
bag while the erythrocytes, platelets, and other plasma components are returned to the donor. 
The return is accomplished through a second needle placed at another site, usually in the other 
antecubital vein. Approximately 50 mL of red blood cell volume will be lost as residual loss in 
the machine during the procedure. Those volunteers who undergo leukapheresis will have a 
reduced volume of blood (only one 8.5 mL tube) collected via peripheral blood phlebotomy for 
the PBMC and plasma storage and additional testing blood draw scheduled at the same visit. 
Leukapheresis will not be performed on participants with platelet counts <150,000 or with 
hemoglobin < 12.0 mg/dL. 
6.4.5 LUMBAR PUNCTURE  
Volunteers will undergo lumbar puncture at baseline, day 7 and at the week 24 visit via standard 
clinical procedure using a standard needle or a specialized atraumatic needle, at sites with 
capability, to capture up to 20cc of CSF. All individuals will undergo neurological examination 
by a physician prior to the procedure to ensure no focal neurologic findings that would preclude 
the procedure. Neurologic examination by the physician will also take place after the lumbar 
puncture. The full neurologic exam and lumbar puncture is anticipated to take 1.5 hours. The 
participant will be advised to lie prone in the clinic for one (1) hour after the procedure has 
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6.5 
CLINICAL AND LABORATORY EVALUATIONS 
This study is exploratory and will evaluate safety and virologic impact (including on the 
reservoir) of a mAb therapeutic intervention during acute HIV infection. The primary safety and 
virologic endpoints will be assessed by medical history, physical exam and collection of 
peripheral blood at intervals throughout the study. Additional study visits may be required if, in 
the investigator’s opinion, repeat laboratory or additional clinical assessment is indicated. After 
Day 0, deviations from the visit windows are discouraged and will be recorded as protocol 
deviations, but will be permitted at the discretion of the site Principal Investigator (or designee) 
in the interest of obtaining subject safety evaluations following exposure to the investigational 
product. 
The study will also include optional collections of peripheral blood mononuclear cells 
(PBMC) and plasma via apheresis, of mucosal secretions, of cerebrospinal fluid (CSF) via 
lumbar puncture, and of tissue samples from other compartments (inguinal lymph node, 
rectosigmoid tissue), which will contribute to evaluation of additional objectives. Please refer to 
the Schedule of Evaluations (SOE) in Appendix II for more details. 
6.5.1 ASSESSING PRIMARY ENDPOINTS: SAFETY AND VIROLOGIC IMPACT 
• Safety and tolerabililty of the study product will be assessed along the following 
parameters:  
• History and physical exam 
• Adverse events during the course of the study 
• mAb reactogenicity  
• Serum chemistry: Creatinine, ALT, AST, ALP 
• Hematology safety parameters: hemoglobin, hematocrit, white blood cell (WBC) and 
differential count, red blood cell count, platelet count 
• Plasma HIV RNA and lymphocyte subsets (CD4+ T cell count) 
• CD4+ T cell count, chemistry and hematology safety parameters will be performed at 
baseline (day 0); on days 3, 7, 14, and 28; and then every 4 weeks until study termination. 
HIV RNA will be measured on days 0, 1, 3, 7, 10, 14, 18, 21, 25 and 28, 42, 56 and then 
every 4 weeks until study termination. These viral load measurements also evaluate the 
second primary objective: impact of VRC01 on plasma viremia.  
6.5.2 ASSESSING SECONDARY ENDPOINTS 
• Secondary objectives, such as the impact of VRC01 on clinical outcomes/characteristics 
of AHI, viral dynamics, and CD4 + T cell preservation, will be assessed by periodic 
monitoring of HIV-1 plasma RNA and CD4 + T cell count as described above. 
Assessment of clinical outcomes such as the incidence of acute retroviral syndrome, 
hospitalization, opportunistic infections, and non-AIDS related conditions will be 
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• Viral dynamics will also be assesed via single copy HIV RNA assay in plasma samples 
with HIV RNA<50 copies/mL. 
• The impact of the mAb on reservoir seeding in the peripheral compartment will be 
evaluated by assessments of the HIV reservoir at baseline, on day 7 and week 24. 
Additional timepoints may also be explored. These evaluations will be done on total 
PBMC and total CD4+ T cells. Reservoir measurements will include:  
• Cell associated HIV RNA  
• Total and integrated HIV DNA and 2 long terminal repeat (LTR) circles 
• Viral out-growth assay (a 100 mL collection is included at the week 24 visit for this 
assay) 
• TILDA (Tat/Rev Induced Limiting Dilution Assay) to measure frequency of CD4+ 
cells producing multi-spliced HIV RNA upon maximal stimulation 
• Digital droplet PCR targeting highly conserved regions of the integrated HIV-1 
genome  
• Blood samples for PK analysis will be collected pre-dose and at the end of infusion (EOI) of 
the mAb administration; and then days 3, 7, 14, 21, 28, and 56 after mAb administration.  
• Plasma and PBMC will be collected for storage on enrollment (day 0), and days 3, 7, 14, 21, 
and 28, 56 and then every 4 weeks for the remainder of the study. These stored specimens 
will be used to evaluate the remainder of the study objectives. 
6.5.3 ASSESSING EXPLORATORY ENDPOINTS 
• The impact of the mAb on reservoir seeding will also be assessed in tissue and CSF, when 
available, among participants who separately consent to collection of those specimens. In 
participants with sufficient PBMC collection (as with leukapheresis), measurement of cell-
associated HIV RNA and HIV DNA, as well as viral outgrowth, may be performed in 
memory CD4+ T cell subsets, as well as other cell subsets that could contribute to latency. 
Larger volume PBMC/plasma and 20mL CSF collections are scheduled for day 0, 7, and 
week 24 to support these analyses, although other timepoints may also be explored.  
• The impact of VRC01 on immune responses and activation will be evaluated by humoral and 
cellular immunoassays as well as by measurement of biomarkers of immune activation, 
conducted at baseline and following mAb administration. These will be evaluated across 
biological compartments as specimen availability permits. 
! Biomarkers 
• Activation and functional markers (as measured by intracellular cytokine staining 
(ICS))  
• Frequency and phenotype of virus-harboring cells among collected PBMCs 
• Flow cytometric sorting of CD4+ T-cells, combined with quantitative PCR, to assess 
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• Soluble markers of immune activation 
• Cellular gene expression profiles of total PBMC and cell-sorted compartments  
! Humoral immunity 
• Neutralization sensitivity of founder vs post-VRC01 virus 
• Binding (host-generated) antibodies to relevant antigens, including HIV envelope 
proteins 
• Neutralizing antibody activity using a representative panel of tier 1 and tier 2 HIV 
strains with emphasis on the subtype infecting the participants and, where possible, the 
infectious molecular clone and pseudovirus expressing the participant’s founder virus 
and, if relevant, breakthrough virus. 
• Non-neutralizing antibody functional assays including antibody-dependent cell-
mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis 
(ADCP), antibody-dependent cell-mediated viral inhibition (ADCVI), and viral capture  
• Cellular immune responses 
• ELISPOT and polyfunctional ICS of collected PBMC  
• Epitope mapping of CD4+ and CD8+ T lymphocyte responses 
• Immunophenotyping and functional characterization of cellular subsets of interest, 
including natural killer (NK) cells 
• Viral evolution 
• The effect of VRC01 on virus evolution will be assessed via viral sequencing, to 
include envelope, whole genome, and targeted deep sequencing, on baseline and post-
mAb specimens, with a particular focus on poor responders as compared to those who 
have favorable viral load responses to VRC01. 
• Exploratory, hypothesis-generating data analysis will identify potential predictors of 
favorable viral dynamics and reservoir seeding. 
• Host genetics: Host immune-genotyping will be performed as resources are made 
available. Existing host genetic data from the parent RV 217 or RV 254 cohort will also 
be employed. 
• Optional Specimen Collection Assessments:  
Mucosal secretion samples will be assayed for HIV RNA by nucleic acid amplification. Residual 
samples will be stored at –80°C and will be used to detect VRC01 levels, to isolate and sequence 
HIV, to assay cytokines and inflammatory markers, and to detect sexually transmitted infections. 
Other HIV-specific immune responses may also be evaluated. Gut biopsy specimens will be 
cryo-preserved on the day of collection for mucosal mononuclear cell isolation and phenotyping 
by flow cytometry and immunohistochemistry. Specimens will also be analyzed for HIV 
RNA/DNA, cytokine expression by ICS, ELISPOT, and transcriptomics. Inguinal lymph nodes 
will be divided and sent for immuno-fluorescence confocal microscopy, flow cytometry, HIV 
RNA/DNA measurement, gene expression/whole transcriptome analysis, cytokine production, 
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may also be evaluated. CSF will be pelleted to obtain samples of cellular product, which, along 
with supernatant, will be stored for markers of neuronal damage, other immunologic and 
virologic studies as well as for measurement of VRC01 levels. 
Anti-VRC01 antibody will be quantified by bridging electrochemiluminescence technique or 
alternative sensitive assay. The anti-VRC01 B cell response will also be characterized. 
NP data will be summarized using z-scores based on age-matched normative data when such 
data is available or as raw scores when not available. With either approach, individual 
performance can be compared longitudinally to determine the impact of the intervention 
on cognitive performance, the primary interest of the neuropsychological testing portion of this 
study. Results from the week 24 of this study will be compared to NP battery results from pre-
infection and AHI baseline timpoints in the RV 217 and RV 254 studies.  
6.6 
CONCOMITANT MEDICATIONS 
Participants will be asked about concomitant medication use during the 45 days prior to study 
enrollment and at every study visit. Study participants can receive medications such as 
acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), or antihistamines as required, 
although they must be documented.  
6.7 
SOLICITED ADVERSE EVENTS 
All participants receiving infusions (VRC01/placebo), temperature and solicited systemic 
symptoms will be recorded in the clinic prior to infusion and at a minimum of 30 minutes post 
procedure and then daily by the participant for 3 days.  
All participants will be given a diary card on which to record temperature and systemic 
symptoms daily for 3 days. The diary card will act as a memory tool for the subject but is not 
considered a source document.  
For this study, solicited adverse events occurring during the 3 days after receipt of study agent 
will include: unusually tired/feeling unwell, muscles aches, headache, chills, nausea and joint 
pain. Subjects will also record highest measured temperature daily. The diary cards are reviewed 
for accuracy and completeness at follow-up visits and are recorded without an attribution 
assessment (unless they are Grade 3 or higher in severity in order to assess whether the event is 
relevant to the study pause criteria). Clinicians will collect resolution information for any 
systemic symptoms that are not resolved after 3 days. 
Clinician assessment of the local IV administration site will be conducted on day of study agent 
administration and during the scheduled follow-up timepoints on days 1, 3 and 7 after 
administration. 
At every visit all participants will be asked about other adverse experiences, which will be 
recorded and entered the same day into the study database. The local PI will assess the 
relationship of the study products to the events.  

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6.8 
STUDY DISCONTINUATION 
6.8.1 EARLY DISCONTINUATION OR WITHDRAWAL OF STUDY PARTICIPANTS 
A participant will be taken out of the study entirely under the following circumstances: 
• Repeated failure to comply with protocol requirements 
• Decision by the study sponsor (DAIDS) or the Protocol Chair to stop or cancel the 
study 
• Decision by Walter Reed Army Institute of Research Institutional Review Board (IRB) 
and the United States Army Medical Research and Materiel Command’s (USAMRMC) 
Office of Research Protections (ORP), Human Research Protection Office (HRPO), 
DAIDS, the U.S. FDA, the Office for Human Research Protection (OHRP), or local 
regulatory authorities and IRBs to stop or cancel the study 
• Participant requests withdrawal 
Each subject has the right to withdraw from the study at any time for any reason without 
affecting the right to treatment by the investigator. The investigator should make an attempt to 
contact subjects who did not return for scheduled visits or follow-up. Although the subject is not 
obliged to give reason(s) for withdrawing prematurely, the investigator should make a reasonable 
effort to ascertain the reason(s) while fully respecting the subject’s rights. 
For those subjects who are unable to continue participation in the study, but who do not 
withdraw consent, an exit visit will be conducted (refer to SOE for list of procedures to be 
conducted). Any subject who withdraws consent will not have any further data collected after 
consent has been withdrawn. However, data that was collected prior to a subject’s withdrawal of 
consent will be included in data analysis. 
The investigator also has the right to withdraw a subject, e.g., because of worsening health status, 
intercurrent illness, or AEs. 
If a participant withdraws from the study, the next available participant will be placed in the 
vacated randomization slot. A study participant will be considered non-evaluable for the primary 
virologic endpoint if they miss the Visit 4 (day 7) visit window and will be replaced. 
Replacements for participants who withdraw from the study will only be permitted while 
enrollment is open. 
6.8.2 PREMATURE TERMINATION OF THE STUDY 
Walter Reed Army Institute of Research IRB and the USAMRMC ORP, HRPO, DAIDS, the 
U.S. FDA, and OHRP, and other applicable regulatory authorities reserve the right to terminate 
the study. The investigator will notify reviewing IRBs in writing of the study’s completion or 
early termination. 

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6.8.3  MANAGEMENT OF VOLUNTEERS WHO BECOME PREGNANT 
Pregnant women are excluded from enrollment, however if a volunteer becomes pregnant during 
the course of the study, any volunteer who has not yet initiated ART per protocol will be offered 
ART and referred for maternal and child health services. Volunteers will continued to be 
followed for the remainder of the study period for safety and the study team will follow the 
course of the pregnancy until the outcome is documented. During subsequent study visits, blood 
draws will be conducted for safety and HIV disease monitoring purposes only. No optional 
collections or procedures will be performed. Pregnant volunteers prescribed ART will also be 
advised to enroll in the antiretroviral pregnancy registry (http://www.apregistry.com/) 
The site PI or designated associate investigator will be responsible for reporting any pregnancy 
to the PSRT. This information will be reviewed by the PSRT weekly in aggregate with other 
safety data. The PSRT will forward notification as necessary to IRBs, study sponsors, and 
regulatory agencies. 
Pregnancy outcomes will be recorded via a standardized case report form. Information 
documented on this form will include date of last menstrual period, date pregnancy confirmed, 
history of complications during prior pregnancies (such as congenital abnormalities or 
spontaneous abortions), and the outcome of the pregnancy including date of termination or 
delivery, any complications of pregnancy, and the status of the child. A separate case report form 
will be completed for the delivered child to document date of delivery, gender, weight, presence 
of any congenital abnormalities, American Pediatric Gross Assessment Record (APGAR) score, 
HIV status, and any other complication of delivery. 
6.8.4 UNBLINDING PROCEDURE 
Once all study visits have completed and the study safety database lock is approved by the 
sponsor, the site investigators will contact blinded study participants by phone or through home 
visit to invite them to come back to the clinic to find out whether they received the study product 
or placebo. When the participant returns to the clinic, they will be given a letter, which indicates 
their study arm. Site investigators, in consultation with the PSRT, may elect to unblind a study 
participant if treatment group information would substantively inform the clinical management 
of an adverse event. 
 

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7.0 
STUDY TREATMENT  
Study treatment is defined as VRC-HIVMAB060-00-AB (VRC01) or placebo for VRC01. 
Standard first line combination ART will be provided to participants as part of the study but is 
not an investigational product (Section 6.2). 
7.1 
STUDY TREATMENT REGIMENS, ADMINISTRATION, AND DURATION 
7.1.1 REGIMENS 
Twenty-four men and women 18 to 50 years of age, in early acute HIV infection (AHI) will be 
randomized to one of three groups: Group 1: Participants will start ART and receive placebo for 
VRC01 (0.9% sodium chloride for injection, USP) administered intravenously at Day 0; Group 
2: participants will start ART and receive 40 mg/kg VRC01 administered intravenously in 100 
ml of 0.9% sodium chloride for injection, USP, at day 0; Group 3: Participants will receive 40 
mg/kg VRC01 administered intravenously in 100 ml of 0.9% sodium chloride for injection, USP, 
at day 0 followed by ART initiation at day 7. 
7.1.2 ADMINISTRATION 
VRC01 or placebo for VRC01 will be administered as an intravenous infusion over 30 to 60 
minutes using a volumetric pump. The infusion rate may vary based on the total volume needed 
to administer the full dose The total time needed to administer the dose may be longer based on 
factors such as participant tolerance. 
An in-line filter infusion set must be used for IV administration. 
The in-line filter must comply with the following specifications:  
-       1.2 micron PES (polyethersulfone) filter membrane  
-       DEHP-free  
-       Latex-free 
When the in-line filter is added to the tubing, prime the administration set. Flush the 
administration set with about 30 mL or appropriate volume of normal saline at the end of product 
administration.  
7.1.3 DURATION 
Participants will be followed for a total of 25 weeks. 
7.2 
STUDY PRODUCT FORMULATION AND PREPARATION 
7.2.1 FORMULATION 
VRC01 (labeled as VRC01 HIV MAb Drug Product VRC-HIVMAB060-00-AB) is supplied at a 

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concentration of 100 ± 10 mg/mL in an isotonic, sterile solution. Two fill volumes are available: 
10 mL glass vials with a 6.25 ± 0.10 mL fill volume and 3 mL glass vials with a 2.25 ± 0.10 mL 
fill volume.VRC01 is a sterile clear, colorless to yellow liquid, essentially free of visible 
particles; some opaque or translucent particles may be present. The formulation buffer is 
composed of 25 mM sodium citrate, 50 mM sodium chloride, and 150 mM L-arginine 
hydrochloride at pH 5.8. Vials are intended for single use only and thus do not contain a 
preservative. 
VRC01 is a highly concentrated protein solution and may develop white, opaque to translucent 
particles after thawing. When particles are observed, they may disappear after a few hours at 
room temperature or storage at 2°C to 8°C. 
Note: All dose calculations should be based on a concentration of VRC01 of 100 mg/mL and a 
volume of 2 mL per vial (200 mg per vial) or 6ml per vial (600 mg per vial) that may be 
withdrawn. 
Placebo for VRC01 will be sodium chloride for injection 0.9%, USP.  
7.2.2 PREPARATION OF STUDY PRODUCTS 
VRC01 Thawing Instructions 
Please refer to the RV398 pharmacy SSP for detailed instructions on VRC01 thawing 
instructions.  
IV infusion preparation instructions 
The pharmacist must receive a prescription that states the participant’s weight obtained at the 
most recent visit where weight was measured. Participants’ screening weight, entry weight, or 
last obtained weight may be used for estimating the dose to thaw vials. Calculate the total 
milligrams of VRC01 required based on the participants weight and the dose of 40 mg/kg and 
the total number of vials required based on a 6 mL withdrawal volume containing 600 mg of 
VRC01 or 2 ml withdrawal volume containing 200 mg of VRC01 
1. Prior to preparation for administration, vials should be swirled for 30 seconds with 
sufficient force to resuspend any visible particles, yet avoiding foaming. DO NOT 
SHAKE THE VIALS. Keep the vials upright at all times until ready to withdraw the 
contents. Do not invert the vial during inspection. 
2. Add the required volume for the calculated total milligrams needed to 0.9% Sodium 
Chloride Injection, USP 100 mL using aseptic technique. 
3. The prepared IV bag should  then be covered with an amber bag and labeled to maintain 
blinding. The IV bag will be labeled as “VRC01 or Placebo in Normal Saline, total 
volume in ml (eg: 128 ml)”, participant weight used for calculating the dose, and a DO 
NOT INFUSE AFTER date and time. A bag cover will be placed over the bag and should 
not be removed by the clinic staff. 

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Placebo 
Placebo for VRC01 will be 0.9% sodium chloride for injection, USP and should be added to a 
100 mL bag of 0.9% sodium chloride for injection, USP, using aseptic technique.. The volume of 
placebo to be infused will be approximately 100 mL plus 0.4 mL/kg to be consistent with the 
volume infused in the active VRC01 arms. The IV bag should then be covered with an amber 
bag. The IV bag will be labeled as “VRC01 or Placebo in Normal Saline, total volume in ml (eg: 
128 ml)”, participant weight used for calculating the dose and a DO NOT INFUSE AFTER date 
and time. A bag cover will be placed over the bag and should not be removed by the clinic staff. 
ASSIGNING THE DO NOT INFUSE AFTER DATE AND TIME 
After product preparation in IV bags:  
VRC01 IV bags or Placebo for VRC01 may be stored at 2°C to 8°C for up to 48 hours 
(equilibrate to room temperature for a minimum of 30 minutes prior to product 
administration). 
VRC01 IV bags or Placebo for VRC01 may be stored at room temperature (maximum 27°C) for 
no longer than 4 hours, including infusion time. 
Product may not be stored in direct sunlight. 
Storage of Vials of VRC01 
VRC01 vials should be stored in a qualified, continuously monitored, temperature-controlled 
freezer at -35°C to -15°C. Freezer temperature from -45°C and -10°C is acceptable. 
Placebo for VRC01 (0.9% sodium chloride for injection, USP) should be stored as per 
manufacturer instructions . 
7.3 
PHARMACY: PRODUCT SUPPLY, DISTRIBUTION, AND ACCOUNTABILITY 
7.3.1 STUDY PRODUCT ACQUISITION/DISTRIBUTION 
VRC01 is manufactured by the VRC and will be available through the National Institute of 
Allergy and Infectious Diseases (NIAID) Clinical Research Products Management Center 
(CRPMC). The site pharmacist should obtain the VRC01 product(s) for this protocol by 
following the instructions in the manual Pharmacy Guidelines and Instructions for DAIDS 
Clinical Trials Networks. 
The placebo for VRC01 (0.9% sodium chloride for injection, USP) can be obtained locally.  
Sodium chloride for injection 0.9%, USP, 100 ml bags required to prepare the dose for VRC01 and 
placebo for VRC01, can be obtained locally. 
For the sites that are unable to obtain the Sodium chloride for injection 0.9%, USP,MHRP will 
supply the Sodium chloride for injection 0.9%, USP and will be distributed to the sites by 
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7.3.2 STUDY PRODUCT ACCOUNTABILITY 
The site pharmacist is required to maintain complete records of all study products received from 
the NIAID CRPMC and subsequently dispensed. All unused study products at the study sites 
must be returned to the NIAID CRPMC or destroyed (as directed by the sponsor) after the study 
is completed or terminated. The procedures to be followed are in the Pharmacy Guidelines and 
Instructions Manual. 
7.3.3 DISPOSITION 
The empty vials and the unused portion of a vial will be discarded in a biohazard containment 
bag and incinerated or autoclaved. Any unopened vials that remain will be returned to the 
production facility or discarded at the discretion of DAIDS in accordance with policies that apply 
to investigational agents. Partially used vials will not be administered to other subjects or used 
for in vitro experimental studies. They will be disposed of in accordance with institutional or 
pharmacy policy. 
Vials or IV infusion bags of VRC01 with particles should be quarantined and stored at 2-8⁰C. 
Contact the protocol pharmacist for further instructions regarding management of VRC01 vials 
or infusion bags VRC01 with particles.. 
7.4 
ANTIRETROVIRAL THERAPY 
Antiretroviral therapy is described in each Site Specific Addendum and consists of country 
guideline-recommended, available first line once-daily oral combination therapy: currently either 
efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg or efavirenz 600 
mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg. This initial ART regimen may be 
adjusted or switched to an alternate regimen as clinically indicated for regimen intolerance or 
failure. ART will be prescribed by study clinicans, pharmacy-dispensed and labelled for each 
individual participant. It will be provided at the study site and stored at 15-30°C with continuous 
temperature monitoring. The site pharmacist is required to maintain complete records of all ART 
that is dispensed to study participants.  

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8.0 
PHARMACOVIGILENCE, SAFETY, AND ADVERSE EXPERIENCE 
REPORTING 
8.1 
DEFINITIONS  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and does not necessarily have a causal 
relationship with this product. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (International Conference on Harmonization (ICH) E6) (Synonym: 
Adverse Experience).  
A serious adverse event (SAE): An adverse event or suspected adverse reaction is considered 
"serious" if, in the view of either the investigator or sponsor, it results in any of the following 
outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32). 
“Life-threatening” refers to an adverse event that at occurrence represents an immediate risk of 
death to the subject. An event that may cause death if it occurs in a more severe form is not 
considered life-threatening. Similarly, a hospital admission for an elective procedure is not 
considered an SAE. 
8.2 
ADVERSE EVENT GRADING AND RECORDING 
Recording of all AEs will occur during the period from study agent administration through 175 
days after study agent administration.  
All recorded AE and lab data will be coded for severity using the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), Version 2.0 dated November 2014 included as Attachment IV and found on the website 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables, and 
modification to the DAIDS AE Grading table as per Section 8.9. 
For adverse events not identified in the grading table, the following guidelines will be applied:  
 

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Table 2. Additional category for grading the AE 
Mild 
Grade 1 
Symptoms causing no or minimal interference with 
usual social & functional activities 
Moderate 
Grade 2 
Symptoms causing greater than minimal interference 
with usual social & functional activities 
Severe 
Grade 3 
Symptoms causing inability to perform usual social & 
functional activities 
Potentially 
Life-Threatening 
Grade 4 
Symptoms causing inability to perform basic self-care 
functions OR medical or operative intervention 
indicated to prevent permanent impairment, persistent 
disability or death 
Death 
Grade 5 
Symptoms resulting in fatal outcome 
The site clinical research team will ascertain accurate recording of AEs during the study. AE 
case report forms (CRFs) will be completed by the research staff on a daily basis as the data 
become available from the clinic or laboratory.  
The clinical investigators will monitor and analyze study data including all AE and lab data as 
they become available and will make determinations regarding the severity of the adverse 
experiences and their relation to study product. To insure that all AEs are captured in a timely 
manner, CRFs will be entered in real-time and also subjected to analysis to identify AEs that 
may invoke study pause rules. 
Although post injection reactogenicity (PIR)/Solicited AEs are documented separately from 
unsolicited AEs, they are reported to DAIDS if they meet SAE or study pause rule definitions as 
noted below. Therefore the PI or designee must review both PIR and AE CRFs to insure prompt 
and complete identification of all events that require expedited reporting as SAEs, study pause 
rules or other serious and unexpected events.  
AEs will be followed by the clinical research team until resolved or stable. 
8.3 
PROTOCOL SAFETY REVIEW TEAM (PSRT) AND PSRT REVIEWS 
The PSRT will review all AEs (including reportable AEs) on a regular and expedited basis as 
needed. In addition, the PSRT will review aggregate safety data reports from all sites on a 
weekly basis. This team includes the following: Study Chair, Site PIs, a research monitor, and 
the DAIDS medical officer or their designees. Additional participants could include associate 
investigators, and senior clinical research nursing staff. A quorum is established with the 
Protocol Chair, 2 of 4 site PIs and the DAIDS medical officer (MO) or their designee. 

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8.4 
SAFETY MONITORING COMMITTEE (SMC) REVIEWS 
The SMC for this study will be comprised of an independent group of experts established with 
consultation of DAIDS to review safety data during the clinical trial. The Protocol Chair (or 
designee) will submit written recommendations and cumulative safety data to the SMC 
Executive Secretary after the first enrollee has completed 90 days of the study. Subsequently, the 
SMC will convene every six months to review the completeness of the study data collected, the 
adherence to the protocol, and the Protocol Chair’s review summaries. The SMC will request 
review of unblinded data if needed to evaluate a safety signal or serious adverse event. The SMC 
will also meet as needed to deliberate upon the initial interim safety data, the disposition of study 
pauses, and/or to provide other recommendations regarding the safe conduct of the study as 
requested by the Protocol Chair and/or DAIDS. The SMC Executive Secretary will provide the 
Protocol Chair and DAIDS Medical Officer with SMC recommendations, and the Protocol Chair 
and site PIs will inform IRBs and regulatory authorities as appropriate. 
8.5 
CRITERIA FOR STUDY PAUSE OR TERMINATION  
If the trial is placed on safety pause, all enrollment and infusions will be suspended until further 
notice. Study pauses should not delay the initiation of ART according to study schedule. 
Table 3 summarizes the AEs, which when experienced by at least one participant will lead to a 
safety pause or prompt PSRT AE review. For any AE where the outcome is death, the severity of 
the AE is classified as Grade 5. Related AEs refer to AEs deemed to be definitely, probably, or 
possibly related to the study; Not related AEs refer to AEs deemed to be unlikely related or not 
related to the study. 
Grade 5 or 4 events that are judged related to study product administration should be reported 
immediately (within hours of the site learning of the event). These events require immediate 
pause. 
Grade 3 events that are judged related to study product administration should be reported 
promptly i.e., within 24 hours. These events require prompt review by the PSRT.  
All events that are related to study product administration and are similar grade 2 AEs in two or 
more participants will be routinely reviewed by the PSRT but will not necessarily prompt a 
pause. The PSRT may take that action in consultation with DAIDS after review.  
When the administration of study products has been paused, mAb administration and 
enrollments would resume only if review of the triggering AEs by the PSRT, DAIDS, (and 
where applicable, the SMC), result in a recommendation to permit further study product 
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Table 3. ADVERSE EVENT NOTIFICATION AND INFUSION PAUSING GUIDELINES 
Toxicity 
Post-Injection Reactogenicity (PIR) and Study 
Treatment Related Adverse Events (AEs) 
Action 1 
Grade 5/Grade 4 
Related2 
 
“Verified” 3 abnormal laboratory values, systemic 
reactogenicity, or other study mAb infusion related AEs 
(if fever, must persist for ≥ 48 hours) 
Automatic pause 
Immediate reporting2 
(Concurrent with 
observation or report) 
Grade 3 
Related 
“Verified”3 abnormal laboratory values, fever for ≥ 48 
hours, vomiting or other clinical study mAb infusion 
related AEs 
 (Except subjective symptoms) 
PSRT considers pause 
Prompt reporting (within 
24 hours of observation or 
report) 
1Follow-Up and Resolution: All promptly or immediately reportable AEs are followed until resolution or condition is medically stable. 
 2Related AEs refer to AEs deemed to be definitely, probably, or possibly related to the study; Not related AEs refer to AEs deemed to 
be unlikely related or not related to the study 
3If no evidence of disease is present other than the abnormal laboratory value, the test must be repeated at least one time in order to be 
considered “verified”. The verification period will be a maximum of 48 hours after initial awareness of the abnormal laboratory value. 
When signs and symptoms are present, repeat test WILL NOT be needed. 
For events in the table above, the Site PI notifies the PSRT, which includes the Study Chair and 
DAIDS MO, within a few hours after the site is aware of the AE. The PSRT will convene within 
one business day to review these adverse events and determine disposition (including whether 
the SMC needs to review the event). 
If a decision to resume study enrollment and study treatment administration is made, the PSRT 
and/or SMC will record its judgment in a memorandum to the study file and notify DAIDS. 
MHRP COO will then forward the memorandum to the principal investigators. The clinical sites 
will be allowed to resume activities upon receipt of written notification from DAIDS. As needed, 
the appropriate regulatory authorities will be informed in writing of the decision to resume or 
discontinue study activities. Sites are responsible for notifying their respective IRBs according to 
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8.6 
EXPEDITED REPORTING TO IND SPONSOR (DAIDS) 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are 
outlined in Version 2.0 of the DAIDS Expedited Adverse Events (EAE) Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-
expedited-reporting-adverse-events-daids. Reporting AEs to DAIDS will be conducted according 
to this Manual. 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
used for this study. All SAEs will be reported by the site PI or designee to the DAIDS RSC 
Safety Office and MHRP COO (email: reportable_events@hivresearch.org).  
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for expedited AE reporting to DAIDS. In the event of system outages or 
technical difficulties, expedited AEs may be submitted via the DAIDS EAE Form. This form is 
available on the RSC website: https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-
reporting.  
For questions about DAERS, please contact DAIDS-ES at CRMSSupport@niaid.nih.gov. Site 
queries may also be sent from within the DAERS application itself. For questions about EAE 
reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com).  
At the time of SAE submission, any supplemental forms as required by local and U.S. 
Department of Defense (DoD) IRBs must also be submitted to DAIDS RSC and MHRP COO. 
Outcomes of the SAE will need to be provided as updates through DAERS or on the EAE form 
until the adverse event is resolved, is stable, or chronicity has been established and documented.  
For questions or other communication with RSC on SAEs, please note the following:  
 Website:  
https://rsc.niaid.nih.gov/ 
 Office Phone*:  
1-800-537-9979 (U.S. only) or +1-301-897-1709  
 Office Fax*:  
1-800-275-7619 (U.S. only) or +1-301-897-1710  
Office Email:  
DAIDSRSCSafetyOffice@tech-res.com  
Office Hours:  
Monday through Friday, 8:30 AM to 5:00 PM (U.S. Eastern 
Time) 
Mailing Address:  
DAIDS Safety Office 6500 Rock Spring Drive Suite 650 
Bethesda, Maryland 20817 
*Office phone and fax are accessible 24 hours per day 
8.6.1 STUDY AGENTS FOR EXPEDITED REPORTING TO DAIDS 
The study agents that must be considered in determining relationships of AEs requiring 
expedited reporting to DAIDS is the VRC01 MAb (VRC-HIVMAB060-00-AB) and placebo for 
VRC01 (0.9% sodium chloride for injection, USP). 

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8.6.2 STUDY RECORDING PERIOD FOR SAES 
The protocol-defined expedited event reporting period for this protocol is 175 days after study 
agent administration 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, sites must report serious, unexpected, suspected adverse drug reactions (SUSARs) if the 
study site staff becomes aware of the event on a passive basis (i.e., from publicly available 
information). 
8.6.3 TIMEFRAME FOR EXPEDITED REPORTING OF INDIVIDUAL ADVERSE 
EVENTS  
The timeframe for expedited reporting of an individual AE begins when the site recognizes that 
an event fulfills reportable AE criteria. For SAEs sites must submit adverse events requiring 
expedited reporting to the DAIDS RSC Safety Office as soon as possible, but no later than 3 
reporting days (as defined in the DAIDS EAE Manual v2.0), after the site’s recognition that the 
event fulfills the criteria for SAE reporting. The RSC will submit written IND Safety Reports to 
the FDA in accordance with 21 CFR 312.32 as soon as possible and, in no event, later than 7 or 
15 calendar days following receipt of reportable adverse event information. 
For IND Safety Reports submitted to the FDA and received from DAIDS, the MHRP COO will 
complete the necessary reporting to the Walter Reed Army Institute of Research (WRAIR), 
including telephone contact and a written report generated within 24 hours of the initial safety 
report. WRAIR HSPB will forward to USAMRMC ORP. 
The COO will also submit the necessary AE reporting documents and any study pauses to the 
WRAIR IRB and the USAMRMC ORP.  
8.7 
REPORTING SERIOUS AND UNEXPECTED ADVERSE EVENTS TO THE 
DOD IN ADDITION TO DAIDS 
The WRAIR IRB provides DoD-required human subjects protection review of clinical trials 
involving WRAIR investigators and employees. It is the responsibility of the MHRP COO to 
fulfill the reporting requirements. .The local DoD research monitor should also review the events 
and provide an independent assessment to the WRAIR HSPB (as a DoD research monitor’s 
report). 
Per DAIDS new EAE Manual and 21 CFR 312.32, serious and unexpected adverse events may 
be categorized as related to the study agent or not related. All AEs that are serious and 
unexpected and related to the product are reported as described above and become IND Safety 
reports. Any serious and unexpected adverse events assessed as related to the study agent will be 
reported to the WRAIR HSPB immediately to the Director of HSPB (UWZ-C) (301-319-9940). 
WRAIR HSPB will report SAEs to USAMRMC ORP HRPO as per SOP UWZ-C-636.  

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8.7.1 SOCIAL HARMS REPORTING 
Unanticipated events and social harms may occur during the course of the study. When such 
events are related to study participation, the study staff, informed of these events, will inform the 
PI or his/her designee. The PI or designee will then prepare a narrative summary of the event and 
report to the local IRBs, MHRP COO, and PSRT including DAIDS Medical Officer. WRAIR 
HSPB will then be informed. The DoD research monitor should also review the social harms and 
provide an independent assessment of these to the WRAIR HSPB. WRAIR HSPB will report 
these summaries to USAMRMC ORP HRPO. 
8.7.2 UNANTICIPATED PROBLEMS REPORTING TO WRAIR 
All unanticipated problems related to the study and involving risk to subjects or others 
(UPIRTSOs) and all subject deaths should be promptly reported to the WRAIR IRB (phone +1 
301-319-9940, facsimile +1 301-319-9961) by the MHRP COO. A complete written report 
should follow the initial notification. The complete report will be sent to the Director, Human 
Subjects Protection HSPB, Walter Reed Army Institute of Research, 503 Robert Grant Ave., 
Silver Spring, Maryland 20910-7500. The DoD research monitor should also review the 
unanticipated events and provide an independent assessment to the WRAIR HSPB (as a DoD 
research monitor’s report). WRAIR HSPB will report these summaries to USAMRMC ORP 
HRPO. MHRP COO will forward the report to the Division of AIDS.  
8.8 
REPORTING REQUIREMENTS TO THE LOCAL IRB 
The site PI will be responsible for providing all Safety Reports and reporting all SAEs, study 
pauses, social harms, UPIRTSOs, and major deviations to the local regulatory authority, such as 
a local IRB, and any country-specific regulatory agencies, in a timely manner according to the 
institution’s guidelines. Reporting requirements to the local IRB can be found in the site-specific 
addenda.  
8.9 
MODIFICATION TO THE DAIDS AE GRADING TABLE 
The only modification to the DAIDS AE Grading Table is a change in the grading of absolute 
neutrophil count. Individuals of African descent have lower neutrophil counts than individuals of 
other ethnicities. A study evaluating the reasons for ineligibility in phase I and II HIV vaccine 
trials in East Africa found that approximately one third of subjects were excluded because of 
neutropenia. The phase I and II studies used normal ranges from U.S. populations, not from 
African ones. If neutrophil ranges from East/South Africa populations were used instead, over 
one half of the subjects excluded because of hematologic abnormalities could have been included 
[26]. Since this study will be conducted in part in East Africa, we will use the normal neutrophil 
range from East/South Africa (1.0 – 5.3 x 103 cells/ul, [27]) for subjects in East Africa (Kenya, 
Uganda, Tanzania) or other subjects of African descent. Grades for absolute neutrophil count in 
these subjects will be as follows: 

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Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute 
Neutrophil Count 
(cells/ul) 
750 – 999 
500 – 749 
250 – 499 
<250 
 
 
For other subjects, the usual DAIDS AE grading scale will be used as follows: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Absolute 
Neutrophil Count 
(cells/ul) 
800 - 1000 
600 – 799 
400 - 599 
<400 
 

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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
POWER AND SAMPLE SIZE 
Data from twenty-two RV 254 and RV 217 participants starting ART in AHI and with a viral 
load measurement between days 6 and 8 post-ART initiation show a typical decline of 1.5 logs 
with a standard deviation of 1.  
Table 4. Log Viral Load Prior to ART Initiation and Approximately 7 Days Post-ART 
Initiation in Subjects Receiving Between 6 – 8 Days of ART. 
Measurement 
N 
Mean 
Std Dev 
Median 
Minimum 
Maximum 
Pre-ART Log Viral Load 
Day 7 Log Viral Load 
Change From Pre-ART to Day 7 
22 
22 
22 
5.96 
4.46 
-1.49 
1.08 
0.78 
1.01 
5.88 
4.25 
-1.58 
3.31 
3.23 
-3.33 
7.49 
5.75 
0.70 
 
The study design features 3 arms with varying treatment in the first 7 days: ART only, mAb 
only, and mAb + ART. The ART only arm functions as a control. Pairwise comparisons of the 
mAb only arm to the ART only arm and of the mAb + ART arm to the ART only arm are 
planned. Table 5 shows the approximate detectable effect sizes for various sample sizes using a 
two-sided non-parametric test with 85% power and a 5% Type I Error. The assumed standard 
deviation is 1 in both groups based on the above data. This demonstrates that a sample size of 24 
(8 per arm) would have 85% power to detect a difference in mean viral load decline of 1.7 logs 
between the control arm and a mAb treatment arm. If the assumptions of the t-test are met, this 
represents a conservative estimate of the detectable difference as the asymptotic relative 
efficiency of the non-parametric test to the t-test is approximately 95%. Since this is an early 
phase, exploratory study no adjustment for multiple pairwise comparisons will be made. Given 
the short time between treatment and the primary endpoint, no loss to follow-up for this endpoint 
is anticipated. Note that this study is not powered to detect differences between the two 
monoclonal arms. 
Table 5: Effect Size for Two-Arm Comparison Detectable 
with 85% Power and 5% Type I Error 
N per Arm 
Effect Size 
(Mean Difference/SD)* 
6 
2.1 
7 
1.9 
8 
1.7 
9 
1.6 
10 
1.5 
 
To assess safety, exact two-sided 95% confidence intervals will be constructed for the proportion 
of subjects experiencing a mAb related - grade 3 or greater reactogenicity. Table 6 below shows 
the expected confidence intervals based on number of subjects experiencing an event within arm 
(n=8) and collapsed across arms (n=16). 

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Table 6. Exact Two-Sided 95% Confidence Intervals for Number of Subjects Experiencing a mAb 
Related - Grade 3 or Greater Reactogenicity Within Arm and Across mAB Arms 
Number of Subjects with 
Event 
Single Arm (n=8) 
Combined mAB Arms (n=16) 
0 
(0%, 36.9%) 
(0%, 20.6%) 
1 
(0.3%, 52.7%) 
(0.1%, 30.2%) 
2 
(3.2%, 65.1%) 
(1.6%, 38.5%) 
3 
(8.5%, 75.5%) 
(4.0%, 45.7%) 
4 
(15.7%, 84.3%) 
(7.3%, 52.4%) 
6 
(34.9%, 96.8%) 
(15.2%, 64.6%) 
9.2 
ANALYSIS 
All data from randomized participants will be included in the intention-to-treat analysis. Data 
from all randomized participants who receive the assigned study treatments and complete the 
study through the 24 week visit will be included in the per-protocol analysis. Endpoints are listed 
in section 4.0. 
Baseline characteristics including demographics and laboratory measurements will be 
summarized using descriptive statistics. Summaries of the number and percentage of subjects 
experiencing any AE or reactogenicity will be tallied by group and presented along with exact 
95% confidence intervals for the proportion. For the following continuous endpoints appropriate 
transformations (e.g. log, square root, or arcsin) will be applied as necessary. 
9.2.1 PRIMARY ENDPOINTS: 
1. Safety: mAb related - grade 3 or greater reactogenicity and product related AEs  
For solicited AEs/reactogenicity, number and percentage of subjects experiencing each type of 
solicited sign or symptom will be tabulated by severity. For a given sign or symptom, each 
subject’s solicited AEs will be counted once under the maximum severity for all assessments.  
For unsolicited AEs, number and percentages of participants experiencing each specific adverse 
event will be tabulated by severity and relationship to treatment. For the calculations in these 
tables, each participant’s adverse experience will be counted once under the maximum severity 
or strongest recorded causal relationship to treatment. 
A complete listing of adverse experiences for each participant will provide details including 
severity, solicited or unsolicited, onset, duration, outcome. 
Proportions of subjects experiencing a reaction will be summarized and compared across all 3 
treatment groups using a chi-square test or Fisher’s exact test. 
2. Log change in plasma viral load from day 0 to day 7 
The log change in plasma viral load over the first seven days will be compared among treatment 
groups using an Analysis of Variance (ANOVA) model or the non-parametric equivalent if 

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necessary. Regardless of the significance of the global test, pairwise comparisons between the 
ART arm and the monoclonal arms will be made at the 5% significance level using a two-sided 
t-test or non-parametric methods if assumptions are not met.  
9.2.2 SECONDARY ENDPOINTS: 
1. Time to virologic suppression (<50 cp/mL)  
Time to virologic suppression as defined above will be compared between groups using time to 
event methods (Kaplan-Meier) to account for the possibility of subjects not achieving viremic 
control prior to 24 weeks and will be tested among groups using a log-rank test.  
2. Total area under viral load curve [28] (viral load over time) 
Area under the viral load curve will be calculated as described in the referenced paper and 
compared between groups using an ANOVA model followed by pairwise contrasts (without 
adjustment for multiple comparisons) where appropriate or using non-parametric methods if 
necessary. 
3. HIV RNA quantification, including single copy HIV RNA in samples with HIV RNA < 50 
copies/ml, at week 24 
HIV RNA quantification will be compared among treatment groups using an ANOVA model or 
the non-parametric equivalent if necessary. Pairwise comparisons between the ART arm and the 
monoclonal arms will be made at the 5% significance level using a two-sided t-test or non-
parametric methods if assumptions are not met. 
4. Cell-associated HIV RNA and DNA in the peripheral compartment 
Cell-associated HIV RNA and DNA in the peripheral compartment will be compared among 
treatment groups using an ANOVA model or the non-parametric equivalent if necessary. 
Pairwise comparisons between the ART arm and the monoclonal arms will be made at the 5% 
significance level using a two-sided t-test or non-parametric methods if assumptions are not met. 
5. Frequency, severity, and duration of acute retroviral syndrome 
Frequency and percentage of subjects experiencing acute retroviral syndrome will be tabulated 
by treatment group and severity. For the per subject analysis, maximum severity will be 
considered. Percentage of subjects experiencing ARS will be compared across treatment groups 
using a chi-square test of Fisher’s Exact Test. 
6. Frequency of hospitalization and incidence of opportunistic infections and non-AIDS 
related conditions. 
Frequency and percentage of subjects experiencing a hospitalization will be tabulated by 
treatment group. Similar methods will be used for infections and conditions. Percentage of 
subjects experiencing a hospitalization, infection, or non-AIDS related condition (each endpoint 
will be considered separately) will be compared across treatment groups using a chi-square test 
of Fisher’s Exact Test. 

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7. CD4 + T cell decrease from baseline to nadir, increase from nadir to week 24, and overall 
change from baseline to week 24 
Change from baseline to nadir, change from nadir to week 24, and change from baseline to week 
24 in CD4+ T-Cells will be compared across treatment groups using an ANOVA model or the 
non-parametric equivalent if necessary. Pairwise comparisons between the ART arm and the 
monoclonal arms will be made at the 5% significance level using a two-sided t-test or non-
parametric methods if assumptions are not met. 
8. VRC01 Levels in Peripheral Blood - Pharmacokinetics 
Cmax, Cmin, Tmax, and Tmin will be described by group and overall. Slope of elimination will 
be estimated using WinNonlin PK[Pharsight Corporation, CA, USA] software or comparable 
software and/or methods. 
9.2.3 EXPLORATORY ENDPOINTS: 
Exploratory endpoints will be described over time by treatment arm in tabular and graphical 
format. Continuous variables will be described at each timepoint using means, standard 
deviations, medians and interquartile ranges. Categorical variables will be presented as 
proportions and confidence intervals at each timepoint. If hypothesis testing is possible, similar 
methods to those for the primary and secondary endpoints can be employed. Further for repeated 
measures data (e.g. HIV RNA and DNA collected at 10 timepoints) models will be fit to 
compare treatment groups accounting for within subject correlation. If the number of subjects 
consenting to optional procedures is low, then analysis of exploratory objectives will be 
primarily descriptive. 
More specifically, the key exploratory endpoints will be analyzed according to the following 
plan: 
1. HIV RNA quantification in the CSF and mucosal compartment (to include single copy 
measurements from samples with HIV RNA < 50 copies/ml) at days 0, 7, and 168. Cell-
associated HIV RNA and DNA in the CSF, mucosal and tissue compartments at days 0, 7, 
and 168. 
HIV RNA quantification in the CSF and mucosal compartments will be compared among 
treatment groups using an ANOVA model or the non-parametric equivalent if necessary at days 
7 and 168. Change from baseline will also be considered as an outcome. Pairwise comparisons 
between the ART arm and the monoclonal arms will be made at the 5% significance level using 
a two-sided t-test or nonparametric methods if assumptions are not met. 
2. Correlation of HIV RNA and DNA measurements across biologic compartments (at baseline, 
day 7, day 168) that include the peripheral blood, CSF, mucosal, and tissue compartments. 
Correlation of viral loads across different biologic compartments will be measured using 
Spearman’s correlation coefficient at each time point.  
3. HIV RNA and DNA in sorted memory CD4+ T cell subsets (for subjects with sufficient 
PBMC collections) at each days 0, 3, 7, 14, 21, 28, 56, 84, 112, 168. Viral outgrowth in total 

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CD4+ T cells and sorted memory CD4+ T cell subsets (for subjects with sufficient PBMC 
collections) at day 168. 
HIV RNA and DNA will be compared between treatment groups over time using repeated 
measures models accounting for within subject correlation. Viral outgrowth will be compared 
between treatment groups at day 168. Viral outgrowth will be described and compared between 
groups at day 168. 
4. VRC01 levels across biologic compartments that include the CSF and mucosal secretions at 
days 0, 7 and 168. Presence of anti-mAb antibody at days 0, 7, 14, 28, 56, 84, 112, 168. 
Biomarkers of immune activation (soluble and cellular markers, gene expression). 
As with comparisons of virologic measures, VRC01 levels, anti-mAb levels, and biomarkers of 
immune activation will all be compared across groups using an ANOVA model or the non-
parametric equivalent at days 7 and 168. Pairwise comparisons will be made at the 5% 
significance level using a two-sided t-test or nonparametric methods. Additionally presence and 
magnitude of anti-mAB antibody will be assessed longitudinally adjusting for within subject 
correlation due to repeated measures. 
5. Remaining exploratory outcomes 
The remaining exploratory outcomes that address the predictors of favorable viral dynamics, 
immune responses, and reservoir seeding will be analyzed with the appropriate statistical 
measures as the data become available. 

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10.0 DATA COLLECTION 
Data collection will be conducted on tablets or computers with daily upload to a central database. 
Access to the data collection software is limited by individual username and password. Data is 
stored in encrypted fashion on the local computer. After the data is uploaded to the central 
database it is deleted from the local tablet or computer. 
Data obtained in the conduct of this study are housed in a secure database maintained by the 
DCAC, MHRP, WRAIR. All research data are entered in a secure database with standardized 
quality assurance review procedures in accordance with Good Clinical Practices (GCP).  
The DCAC serves as the central data management facility for MHRP research protocols. Data 
managed by DCAC are entered into and maintained in a password-protected database. Data are 
accessible only to participating sites, DCAC, and Information Technology staff authorized to 
work on the protocol. The database is located at the Bethesda campus of MHRP and is protected 
by a firewall.  
This data does not contain participant names or Social Security or other national identification 
number, but is referenced only by the study specific identification code. All subjects consented 
will be assigned a 9-digit Subject Identification (ID). The first three digits are the protocol 
number (398), followed by a 2-digit site code, and then a 4-digit number which, will be assigned 
sequentially. 
Every attempt must be made to follow the protocol and to obtain and record all data requested 
for each subject at the specified times. However, ethical considerations or other events may 
result in the failure to obtain and record certain data, or to record data at the times specified. If 
this occurs, the events and, the reasons for the event must be clearly documented on the case 
report form for deviations and reported as described above.  
Analysis files are created on a periodic basis and made available to the Protocol Chair, site 
Principal Investigators (PIs), and Associate Investigators (AIs) at the direction of the Protocol 
Chair. Other collaborators may be given access to these analysis files, or data gathered from 
them, at the direction of the Protocol Chair. Data may be made available as a listing, external 
file, or through a query program. 

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11.0 ETHICAL CONSIDERATIONS 
11.1 
PARTICIPATION OF CHILDREN  
Children are not eligible to participate in this clinical trial because it does not meet the guidelines 
for inclusion of children in research. These guidelines (45 CFR 46, Subpart D, 401-409) state the 
Department of Health and Human Services protections for children who participate in research. 
Generally, healthy children can be studied when the research is considered as "not greater than 
minimal risk." Children can be involved in research with greater than minimal risk only when it 
presents the prospect of direct benefit to the individual child or is likely to yield generalizable 
knowledge about the child's disorder or condition. 
11.2 
PARTICIPATION OF PRISONERS 
Participation of prisoners is not planned and any volunteer will be suspended from study visits 
while incarcerated. The IRB will be notified of the period of incarceration. If possible, site teams 
will coordinate with correctional authorities to ensure that antiretroviral therapy is not 
interrupted. 
11.3 
RISKS 
Risks from IV infusions: 
General risks of IV infusion include stinging, discomfort, pain, soreness, redness, bruising, 
swelling or small laceration at the needle insertion site. 
Risks of the VRC01 study agent:  
Safety experience: 
As described in section 2.6 and in the Investigator’s Brochure, as of January 10, 2017, VRC01 
administrations in the dose range from 1 to 40 mg/kg IV and 5 to 40 mg/kg SC have been 
assessed as well-tolerated in adults and infants and safe for further evaluation.  
In phase 2 trials, most subjects had no local or systemic reactogenicity symptoms. When present, 
local and systemic reactogenicity symptoms were of mild or moderate severity. Infusion site pain 
and/or tenderness developed in 26% of study subjects. Infusion site erythema and/or induration 
developed in 9% of study subjects. The 3 most common systemic reactogenicity events were 
malaise (21%), headache (19%), headache followed by nausea (8%) and myalgia (7%). 
In phase 2 trials, there have been 22 related AEs of mild or moderate severity in 15 subjects (2 
AEs of change in sleep pattern, 2 AEs hypogeusia, 5 AEs of urticaria and 1 event each of wheals 
and erythema-left upper arm/right calf/under right breast, urticaria of upper limbs, urticaria of the 
face, infusion site pruritus, generalised body itchiness, low neutrophil count, dizziness during 
infusion, lightheadedness, loose stools, dermatitis, headache, nausea and malaise). There has 
been one related severe (grade 3) AE of urticaria in 1 subject. 

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Potential safety concerns: 
Administration of mAb may have a risk of immune reactions such as acute anaphylaxis, serum 
sickness and the generation of antibodies; however, these reactions are rare and more often 
associated with mAb targeted to human proteins or with the use of murine monoclonal 
antibodies, which would have a risk of human anti-mouse antibodies. In this regard, as VRC01 is 
targeted to a viral antigen and is a human monoclonal antibody, it is expected to have a low risk 
of such side effects.  
Typically, the side effects of mAbs are mild but may include fever, chills, rigors, nausea, 
vomiting, pain, headache, dizziness, shortness of breath, bronchospasm, hypotension, 
hypertension, pruritus, rash, urticaria, angioedema, diarrhea, tachycardia or chest pain. Clinical 
use of monoclonal antibodies that are targeted to cytokines or antigens associated with human 
cells may be associated with an increased risk of infections [20]; however, this is not expected to 
be a risk for a mAb targeted to a viral antigen. 
It is known from published experience with human mAb directed against the cell surface targets 
on lymphocytes, that infusion of a mAb may be associated with cytokine release, causing a 
reaction known as “cytokine release syndrome” (CRS) [29]. Most infusion-related events occur 
within the first 24 hours after beginning administration. Severe reactions, such as anaphylaxis, 
angioedema, bronchospasm, hypotension and hypoxia, are infrequent and more often associated 
with mAbs targeted to human proteins or when a nonhuman mAb, such as a murine mAb, is used 
[20]. The VRC01 mAb is a human mAb that is directed to a viral target rather than a host cell 
target. Severe CRS has not been reported in such pathogen-directed human mAbs, and CRS has 
not been observed in the human experience with VRC01. Specifically, with regard to CRS 
reactions, these most commonly occur within the first few hours of beginning the infusion and 
are more common with the first mAb infusion received. This is because the cytokine release is 
associated with lysis of the cells targeted by the mAb and the burden of target cells is greatest at 
the time of the first mAb treatment. With licensed therapeutic mAbs, CRS is managed by 
temporarily stopping the infusion, administration of histamine blockers and restarting the 
infusion at a slower rate [30].  
Delayed allergic reactions to a mAb may include a serum sickness type of reaction, which is 
characterized by urticaria, fever, lymph node enlargement, and joint pains. These symptoms may 
not appear until several days after the exposure to the mAb and is noted to be more common with 
chimeric types of mAbs [31]. 
There are several FDA-licensed mAbs for which reactions related to the rate of infusion have 
been described. Some symptoms may be treated by slowing or stopping the infusion. Supportive 
treatment may also be indicated for some signs and symptoms.  
A theoretical risk is that receiving VRC01 might affect the subject’s drug sensitivity profile for 
ARV medications that work through entry or fusion inhibition, or may limit eligibility for some 
future monoclonal antibody treatments. 
Risks of Phlebotomy: 
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infection at the phlebotomy site is also a risk of phlebotomy. Rarely, it may cause infection at the 
site where the blood is taken.  
Risks of Antiretroviral Therapy: 
The side effect profiles of the ART regimens in this study are well characterized. Dizziness, 
headache, trouble sleeping, drowsiness, trouble concentrating, and unusual dreams are common 
side effects. These may be reduced by taking the medication at bedtime on an empty stomach 
and tend to resolve after taking the medication for a few weeks. Rash is also a common side 
effect that usually resolves without a change in treatment but can be serious in a small number of 
patients. Other common side effects include nausea, vomiting, and diarrhea. Serious side effects 
are rare and include kidney injury, liver injury, lactic acidosis, allergic reactions, major 
depression and decreased bone mineral density [32-33]. Risks of antiretroviral therapy are 
mitigated by frequent clinical evaluations and monitoring of blood chemistry and liver tests. 
Risk of Delaying Antiretroviral Therapy: 
Although the risk of delaying antiretroviral treatment for seven days among participants 
diagnosed with early, acute HIV infection is real, we believe it to be minimal. Data from acute 
HIV infection studies have shown that antiretroviral therapy initiated later in acute infection still 
reduces the viral reservoir to the same levels as those treated in Fiebig stage I or II [9]. 
Additionally, data from RV 254 suggest HIV reservoirs do not change appreciably over one year 
after infection if ART is initiated in the early Fiebig stages (I-III); a timeframe that covers all 
participants, including those who will have a seven day treatment delay.  
Furthermore, the study is designed to mitigate these risks. Participants will only be enrolled if 
they are in relatively good health. In addition, participants who exhibit signs and symptoms of 
severe acute retroviral syndrome (as defined in Appendix I) during the seven-day delay will be 
started on ART immediately. Participants will be seen three times during the first week and will 
be instructed to return to the clinic for prompt evaluation and potential treatment initiation if they 
exhibit signs and symptoms of acute retroviral syndrome at home.  
Risks Related to Pregnancy: 
The possible effects of VRC01 on a fetus or nursing infant are unknown. Since VRC01 is a 
human monoclonal antibody and not a chemotherapeutic agent, traditional toxicology and animal 
reproduction studies are not possible. However, the antibody is directed against a viral protein 
and showed no cross-reactivity with fetal or adult human tissue in preliminary safety studies. 
Furthermore, anti-HIV antibodies are routinely transferred from the mother to the fetus during 
pregnancy without any adverse affect on the mother or infant [34]. As with the majority of IgG 
antibodies, transfer of anti-HIV antibodies occurs from the mother to the fetus predominantly 
during the third trimester; since VRC01 infusions will be stopped if pregnancy is diagnosed, they 
are unlikely to be present at the time of IgG transfer to the fetus [34].  
This evidence suggests that adverse affects to the infant of a mother exposed to VRC01 are 
unlikely, but pregnant women are still conservatively excluded from participation in this phase II 
study of an investigational new agent. Women who are able to have children must agree to not 
get pregnant during study participation and must use at least one method of effective birth 
control during study participation. Effective birth control includes not having sex; male or female 
condoms; diaphragm or cervical cap with spermicide; intrauterine device; contraceptive 

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hormones delivered by pills, patch, injections or vaginally; and hormonal implants under the 
skin; or a male partner who has previously undergone a vasectomy.  
Women must have a negative pregnancy test before dosing with VRC01 and before collection of 
cervicovaginal secretion samples. Women becoming pregnant during the study will be asked to 
continue with study follow-up visits for clinical evaluation. The outcome of the pregnancy will 
be recorded in the antiretroviral pregnancy registry (http://www.apregistry.com/who.htm).  
Risks related to mucosal secretion collection: 
Mucosal secretion samples collected in the clinic (rectal sponges, semen, and cervicovaginal 
cups) will be obtained noninvasively. Semen will be self-collected and for the collection of 
cervical-vaginal secretions, women may elect to insert and remove cervical cups themselves, as 
well. Inserting an instrument or collection device into the anus or the vagina may cause 
discomfort and slight irritation. There is no evidence of rectal sponge or cervical cup sampling 
contributing to risk of HIV or other sexually transmitted infection. For these non-invasive 
mucosal collections, men and women will be asked to refrain from receptive anal or vaginal, 
intercourse, douching, or inserting any product into the rectum or vagina for 3 days prior to the 
mucosal collection. Men will be asked not to masturbate nor ejaculate 3 days prior to semen 
collection. 
Risks related to colon biopsy (via sigmoidoscopy): 
Rectosigmoid biopsies will be performed through a flexible sigmoidoscopy. Brief cramping and 
gas pains may be felt as air is inserted or as the scope advances. The passing of gas is necessary 
and should be expected after the procedures are terminated. Volunteers may choose to receive 
sedation during the procedure in order to ameliorate the discomfort and anxiety they may feel. 
There may be slight bleeding from the biopsy site, which generally stops spontaneously. There is 
a remote possibility that a biopsy may result in significant bleeding or even perforation requiring 
emergency medical care. A gastroenterologist will perform this procedure in order to minimize 
these risks. All volunteers will be counseled to avoid sexual rectal intercourse for 3 days prior to 
and 7 days following biopsy. Volunteers participating in sigmoidoscopy are not eligible to 
participate in rectal biopsy via anoscopy at the same time point. 
Risks related to rectal biopsy (via anoscopy): 
Rectal biopsies will be performed with the use of an anoscope, the insertion of which may cause 
discomfort and slight irritation. There may be slight bleeding from the biopsy site which 
generally stops spontaneously. There is a remote possibility that a biopsy may result in 
significant bleeding or even perforation requiring emergency medical care. A trained physician 
will perform this procedure in order to minimize these risks. Volunteers will be counseled to 
avoid sexual rectal intercourse for 3 days prior to and 7 days following rectal biopsies. 
Volunteers participating in this rectal biopsy procedure are not eligible to participate in 
sigmoidoscopy at the same time point. 
Risks related to lymph node biopsy: 
Excisional inguinal lymph node biopsy will be performed under local anesthesia by a qualified 
surgeon. As with all surgical procedures, there is a risk of scarring, bruising or bleeding at the 
surgical site; these risks are minimized by the small nature of the incision (approximately 1-2 
centimeters) and by prior clinical and laboratory evaluation to determine any bleeding risks. 

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Subjects may experience some discomfort following the procedure despite use of local 
anesthesia; for subjects who complain of any subsequent discomfort, additional analgesia will be 
made available. There is a possibility of seroma formation at the biopsy site, which may require 
subsequent drainage or further management, or sensory nerve injury during the procedure which 
could result in temporary or permanent local reduction in feeling. Surgical site infection is a 
possible complication of any procedure involving an incision, however the risk is low [35]. 
Finally, there is the unlikely possibility that the procedure will be unsuccessful and no lymph 
node will be recovered. 
Risks related to leukapheresis: 
Adverse reactions to leukapheresis procedure are rare and include vaso-vagal episodes related to 
needle insertions and transient volume shifts, peri-oral paresthesias, chills, nausea, and heartburn 
caused by the citrate anticoagulant used during the procedure. Vaso-vagal reactions are handled 
by postural manipulation and fluid administration. Volunteers will be observed closely by an 
experienced technician during the procedure. Citrate reactions are usually relieved by slowing 
the rate of the anticoagulant infusion and by administering oral calcium carbonate tablets. 
Seizures and allergic reactions are very rare possible reactions.  
Risks related to lumbar puncture: 
The risks of lumbar puncture include local soreness at the site of needle entry. There is a risk of 
headache or decreased blood pressure from removing the small amount of fluid or leaking of 
cerebral spinal fluid after the procedure. About 1 in 4 or 5 people will experience a headache 
following lumbar puncture, and this can sometimes require hospitalization for pain management. 
There is a small risk of infection and a very small risk of damage to nerves in the lumbar spinal 
roots after the procedure, which could cause pain, numbness, or loss of sensation to the legs. In 
order to reduce side effects of the lumbar puncture, the volunteers will be asked to remain lying 
flat for about an hour after the procedure and be given fluid to drink after the procedure. A band-
aid will be placed on the skin where the needle went in and the volunteers will be asked to 
remove it the next day and tell the study doctor right away if any redness or tenderness is 
present. The investigators will ask the volunteers about history of any allergies to anesthetics and 
will not perform lumbar puncture in any volunteer with such history.  
11.4 
BENEFITS 
Although study volunteers may benefit from clinical testing and physical examination, they may 
receive no direct benefit from participation.  
11.5 
INFORMED CONSENT 
The study informed consent describes the investigational product to be used and all aspects 
involved in protocol participation. A properly executed written site specific informed consent 
based on the template provided here, in compliance with the Declaration of Helsinki, guidelines 
of the Council of International Organization of Medical Sciences (CIOMS), the Belmont Report, 
the U.S. Code of Federal Regulations 21 CFR 50, must be obtained from each subject prior to 
entering the subject into trial or prior to performing any unusual or non routine procedure that 
involves risk to the subject. The investigator must provide a copy of the approved informed 

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consent to the subject and a signed copy must be maintained in the subject’s record file. Before a 
subject’s participation in the study, it is the investigator’s responsibility to obtain this written 
informed consent from the subject, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific procedures or study 
medications are administered. 
11.6 
LANGUAGE 
The ICF and other study documents given to participants will be translated into local language as 
detailed in the site specific addenda. 
11.7 
COMPENSATION 
Participants will be compensated for time and inconvenience in accordance with the standards 
and legal obligations for compensation required by each study site. Any applicable guidelines by 
IRBs/ECs for compensation of research subjects will be sought and followed 
There may be compensation for lost time, travel expenses and inconvenience, for each scheduled 
visit. Compensation for unscheduled visits may be provided at the discretion of the site 
investigator. Any applicable guidelines by IRBs/ECs for compensation will be sought and 
followed. Compensation is further detailed in the site specific addenda. 
11.8 
DOD RESEARCH MONITOR 
The role and qualifications of the medical monitor are identified as follows: 
The medical monitor will review all unanticipated problems involving risk to volunteers or 
others, social harms, and all volunteer deaths due to social harms associated with the protocol. 
The DoD research monitor will provide an unbiased written report of the event. At a minimum, 
the medical monitor should comment on the outcomes of the problem, and in the case of a death, 
comment on the relationship to participation in the study. The medical monitor should also 
indicate whether he/she concurs with the details of the report provided by the study investigator. 
11.9 
SUBJECT INSURANCE 
The US DoD and DAIDS/NIAID/NIH are funding this protocol. As stated in the consent form, 
participants who experience illness or injury arising from participation in the study will receive 
medical care for such illness or injury with costs for such care provided by a limited set-aside 
fund and a clinical trials medical insurance policy that will be obtained by the study funder. 
While we anticipate the combination of the set-aside fund and the insurance policy is more than 
enough to pay for the research related injury medical care cost associated with this study, there is 
a limit to the amount of coverage available. If the limit is exceeded, the study subject may have 
to pay non-covered costs. Other than medical care, and other payments as stated in the consent 
form, there is no other compensation available from this research study. 

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11.10 PARTICIPANT CONFIDENTIALITY 
The PI will maintain research records of participant’s participation at the site for this study. All 
participants will receive study numbers that are known only to the investigators and clinic staff. 
Clinical tests will be identified by study number and the specimen bag will be identified by study 
number and/or bar code only. Genetic testing results will not contain enough information to 
independently identify individuals in the study. Clinical and research records may be reviewed 
by the representatives of DAIDS, USAMRMC, WRAIR, representatives of the USAMRMC 
ORP, representatives of the FDA, OHRP, and other local, US, and international regulatory 
entities as part of their responsibilities for insuring the protection of research participants.  
Every effort will be made to keep the records as confidential as possible within the limits of the 
law. All data and medical information obtained about participants as individuals will be 
considered privileged and held in confidence. Research and clinical information relating to 
participants will be shared with other investigators and the scientific community through 
presentation or publication; however, participants will NOT be identified by name or social 
security number. Electronic data will be stored at least as long as the IND remains open. 
11.11 INSTITUTIONAL REVIEW BOARD 
A copy of the protocol, proposed informed consent form, other written participant information, 
and any proposed advertising material will be submitted to the appropriate ethical and scientific 
review committees in each country for review and approval.  
In addition, the protocol will undergo review and approval by both the WRAIR IRB and the 
USAMRMC ORP at Medical Research and Materiel Command, U.S. Army (MRMC).  
11.12 FUTURE USE AND STORAGE OF BLOOD SAMPLES 
Each study participant will be asked to separately, and voluntarily consent to their blood samples 
to be stored for other research studies that may be done after this study is completed. Future 
testing may involve genetic tests. As stated above, the sample will be labeled with the bar code 
of the subject ID that can be linked to their study information.  
All samples for which consent has been obtained and for which additional material is available 
after study specified testing is complete will be stored for future testing at the site. However, 
WRAIR IRB and local IRB approval will be sought before any such samples are used for 
analysis not specified in the protocol or a protocol amendment approved by the IRB. All samples 
belong to the site from which they were obtained and MHRP. 
11.13 STUDY DOCUMENTATION AND STORAGE  
Source documents are original documents, data, and records from which the subject’s data are 
obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence.  
The investigator and staff are responsible for ensuring maintenance of a comprehensive and 

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centralized filing system of all study-related (essential) documentation, suitable for inspection at 
any time by representatives from the WRAIR, MRMC, DAIDS, FDA, and other local, US, and 
international regulatory entities. 

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12.0 ADMINISTRATIVE AND LEGAL PROCEDURES 
12.1 
PROTOCOL DEVIATION REPORTING 
A protocol deviation is defined as an isolated occurrence involving a procedure that did not 
follow the study protocol. 
The timeline for reporting protocol deviations to the Division of Human Subjects Protection/ 
WRAIR IRB is determined by the categorization of the deviation: (1) emergent/significant or (2) 
non-emergent/minor. Unanticipated problems should be reported in the appropriate timeframe 
according to the seriousness of the event as a significant deviation or a minor deviation. 
Emergent/significant deviations are departures from protocol that have a significant impact on 
the welfare or safety of a volunteer or on the integrity of the study data. Examples: providing the 
wrong lab result to a volunteer or failure to obtain a scheduled blood draw for multiple 
participants. Changes in protocol procedures may be initiated without prior IRB/ethical review 
committee (ERC) approval,only in cases where the change (s) is /are necessary to eliminate an 
immediate apparent hazard.  
Non-emergent/minor deviations are routine departures that typically involve a volunteer’s failure 
to comply with the protocol. Examples include missing scheduled visits and failing to complete a 
required questionnaire. Minor deviations will be reported to the sponsor and the Division of 
Human Subjects Protection/IRB in a summary report with the annual continuing review report. 
A cumulative deviation report will be submitted to the HSPB/WRAIR IRB with each protocol 
continuing review report or with the closeout report, whichever comes first. 
12.2 
PROTOCOL MODIFICATIONS 
Amendments to the protocol will be made only after consultation and agreement between 
DAIDS, the protocol chair, and the principal investigators. All protocol modifications (including 
but not limited to changes in the principal investigator, inclusion/exclusion criteria, number of 
participants to be enrolled study sites, or procedures) must be submitted as a written amendment 
to DAIDS, local IRB, and the DoD IRB approval before implementation of the changes. The 
WRAIR IRB will submit protocol amendments and modifications to the USAMRMC ORP 
HRPO.  
Modifications or updates to the investigational brochures (IBs) will also be submitted as protocol 
amendments to the ERCs/IRBS for review and approval. DAIDS does not consider changes to 
the IB as protocol amendments and therefore does not provide approval of IBs. 
The Informed Consent Form must be revised to concur with any significant amendment that 
directly affects volunteers, and must also be reviewed and approved with the amendment. New 
volunteers enrolled in the study will be consented with the most recent approved consent form. 
Volunteers already enrolled in the study will be informed about the revision and, depending on 
the impact of the amendment, may be asked to re consent. This may be accomplished by 

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repeating the consent process with the revised consent form with attention given to the changes, 
or it may be done using an addendum consent that states the revision or new information. The 
new document must be signed, placed in the study record, and a copy given to the volunteer. 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol consent form(s) approved, as appropriate, by their local 
institutional review board (IRB)/ethics committee (EC) and any other applicable regulatory 
entity (RE). Upon receiving final approval, sites will submit all required protocol registration 
documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration packet to ensure 
that all of the required documents have been received. 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the DAIDS 
PRO and sites will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites 
should implement the amendment immediately. Sites are required to submit an amendment 
registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all the required documents have been received. Site-
specific ICF(s) WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a complete registration 
packet. A copy of the Amendment Registration Notification should be retained in the site's 
regulatory files. 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual. 
A list of proposed modifications or amendments to the protocol and an explanation of the need 
for these modifications will be submitted, along with a revised protocol incorporating the 
modifications. The only exception occurs when the investigator considers that a study 
participants’s safety is compromised without immediate action. In these circumstances, 
immediate approval of the chairman of the IRB must be sought, and the investigator should 
inform DAIDS and the IRB within five working days after the emergency occurred. As 
previously mentioned, all study amendments will be submitted as a written amendment to 
DAIDS for possible Clinical Sciences Review Committee (CSRC) review and regulatory 
submission to the local IRB, and WRAIR. In accordance with 21 CFR 312.30 (b) any change in 
a Phase 1 protocol that significantly affects the safety of subjects will be submitted to the FDA.  
12.3 
CONTINUING REVIEWS /CLOSEOUT REPORT 
A continuing review report (CRR) will be submitted to all ERCs/IRBs prior to the anniversary 
date determined at initial IRB review. If the continuing review is not approved by the local 
ERC/IRB and WRAIR IRB by the anniversary date, all protocol activities must stop at that site 
until such time as the approval is obtained. A copy of the approved CRR and local IRB approval 

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notifications will be submitted to the WRAIR HSPB as soon as these documents become 
available. A copy of the approved closeout report and local IRB approval notifications will be 
submitted to the WRAIR HSPB as soon as these documents become available. 
12.4 
VOLUNTEER REGISTRY DATABASE 
It is the policy of the USAMRMC that Volunteer Registry Data Sheets are completed on all 
volunteers participating in greater than minimal risk research for entry into the Command’s 
Volunteer Registry Database. Ordinarily this information would include the individual’s unique 
identifier (e.g. social security number (SSN) in the United States of America (U.S.A.)), study 
name and dates. But because many countries do not have a national identification system that 
would uniquely identify each person in the country, the Volunteer Registry Data Sheets will 
collect the following data on the volunteers:  
names (first and last name) 
date of birth, home district 
study name and study dates 
The intent of the database is two-fold: first, to readily answer questions concerning an 
individual’s participation in research sponsored by USAMRMC; and second, to ensure that the 
USAMRMC can exercise its obligation to ensure research volunteers are adequately warned 
(duty to warn) of risks and to provide new information as it becomes available. The information 
will be stored at USAMRMC for a minimum of 75 years. In countries other than the U.S., social 
security numbers do not exist and cannot be collected; all other data can. If available, country-
specific identity numbers may be used. 
12.5 
SITE-SPECIFIC ADDENDUM 
A site-specific addendum will be employed. The core protocol will be followed by all sites 
except for the differences noted in the site-specific addendum, which must be approved by the 
sponsor prior to submission to the IRBs and regulatory authorities. 
12.6 
USE OF INFORMATION AND PUBLICATION 
It is understood by the investigator that the information generated in this study may be used in 
connection with the development of the product and therefore may be disclosed to government 
agencies in various countries. To allow for the use of information derived from the study, it is 
understood that the investigator is obliged to provide DAIDS with complete test results, all study 
data, and access to all study records.  
WRAIR recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences. Any 
results of medical investigations and or publication/lecture/manuscripts based thereon, shall be 
exchanged and discussed by the investigator and the USAMRMC prior to submission for 
publication or presentation. 

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Results from investigations shall not be made available to any third party by the investigating 
team outside the publication procedure as outlined previously. WRAIR will not quote from 
publications by investigators in its scientific information and/or promotional material without 
full acknowledgment of the source (i.e., author and reference). All publications written by 
WRAIR investigators must be reviewed and approved through the WRAIR publications approval 
process. 

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13.0 CONDUCT OF THE RESEARCH STUDY 
This research study will be conducted in accordance with GCP, ICH guidelines, DOD Directive 
3216.2, the Declaration of Helsinki, the Belmont Report, the U.S. Code of Federal Regulations 
21 CFR 312, 812, 50 and 56, and all applicable local laws and regulations.  
13.1 
 REGULATORY AUDITS 
The knowledge of any pending compliance inspection/visit by the US FDA, OHRP, or other 
local, US or international regulatory entities concerning clinical investigation or research, the 
issuance of Inspection Reports, FDA Form 483, warning letters or actions taken by any 
regulatory agencies including legal or medical actions and any instances of serious or continuing 
noncompliance with the regulations or requirements will be reported immediately to the sponsor 
(DAIDS) and WRAIR HSPB. The WRAIR HSPB will report knowledge of any pending 
inspections/audits by regulatory agencies to the USAMRMC ORP HRPO. 
13.2 
SPONSOR STUDY MONITORING 
Site visits by study monitors will be made in accordance with DAIDS’ policy to monitor the 
following: study operations, the quality of data collected in the research records, the accuracy 
and timeliness of data entered in the database, and to determine that all process and regulatory 
requirements are met.  
Site investigators will allow the study monitors, DAIDS, the IRB/ERCs, MRMC, FDA and other 
local, US, and international regulatory entities to inspect study documents (e.g., consent forms, 
drug distribution forms, case report forms), and pertinent hospital or clinic records for 
confirmation of the study data.  
Study data will be closed and final after data cleaning activities are completed and resolutions 
have been documented. 

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14.0 PRINCIPAL INVESTIGATOR AGREEMENT  
1. I agree to follow this protocol version as approved by the IRBs/ERCs.  
2. I will conduct the study in accordance with applicable IRB/ERC requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare 
of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I will not modify the protocol without first obtaining an IRB/ERC approved amendment 
and new protocol version unless it is necessary to protect the health and welfare of study 
participants.  
5. I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct 
the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable 
ethical principles, the Statement of Investigator (Form FDA 1572), and with local 
regulatory requirements. In accordance with the FDA Modernization Act, I will ensure 
the registration of the trial on the www.clinicaltrials.gov website.  
6. In accordance with Command Policy 2008-35, I will ensure that the Commanding 
General receives a pre-brief (or Executive Summary) and approves the study prior to 
execution.  
7. I will ensure that the data (and/or specimens) are maintained in accordance with the data 
(and/or specimen) disposition outlined in the protocol. Any modifications to this plan 
should first be reviewed and approved by the applicable IRBs/ERCs.  
8. I will promptly report changes to the research or unanticipated problems to the WRAIR 
IRB immediately via the WRAIR Human Subjects Protection Branch at (301) 319-9940 
(during duty hours) or to the usarmy.detrick.medcom-wrair.mbx.hspb@mail.mil and 
submit a written report within 10 working days of knowledge of the event.  
9. I will prepare continuing review reports at an interval established by the IRB/ERC, and a 
study closure report when all research activities are completed.  
10. I will immediately report to the WRAIR Human Subjects Protection Branch knowledge 
of any pending compliance inspection by any outside governmental agency.  

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11. I agree to maintain adequate and accurate records in accordance with IRB policies, 
Federal, state and local laws and regulations.  
________________________________ 
 
____________________ 
RV 398 Protocol Chair Signature 
 
 
Date (DD/MM/YYYY) 
________________________________ 
 
____________________ 
RV 398a PI Signature  
 
 
 
Date (DD/MM/YYYY) 
________________________________ 
 
____________________ 
RV 398b PI Signature  
 
 
 
Date (DD/MM/YYYY) 
________________________________ 
 
____________________ 
RV 398c PI Signature  
 
 
 
Date (DD/MM/YYYY) 
________________________________ 
 
____________________ 
RV 398d PI Signature  
 
 
 
Date (DD/MM/YYYY) 
 
 
 
 
 

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15.0 REFERENCES 
1. UNAIDS (2013) UNAIDS Report on the Global AIDS Epidemic 2013. 
2. Milloy MJ, Montaner J, Wood E. Barriers to HIV treatment among people who use injection 
drugs: implications for 'treatment as prevention'. Current opinion in HIV and AIDS 2012 
Jul;7(4):332-8. 
3. Govindasamy D, Ford N, Kranzer K. Risk factors, barriers and facilitators for linkage to 
antiretroviral therapy care: a systematic review. Aids 2012 Oct 23;26(16):2059-67. 
4. Wolfe D, Carrieri MP, Shepard D. Treatment and care for injecting drug users with HIV 
infection: a review of barriers and ways forward. Lancet 2010 Jul 31;376(9738):355-66. 
5. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral 
medication adherence and the development of class-specific antiretroviral resistance. Aids 
2009 Jun 1;23(9):1035-46. 
6. Deeks SG, Autran B, Berkhout B, Benkirane M, et al., Towards and HIV cure: a global 
scientific strategy. Nat Rev Immunol. 2012 Jul 20;12(8):607-14. 
7. Chun TW, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and 
cure. Aids 2012 Jun 19;26(10):1261-8. 
8. Gianella S, von Wyl V, Fischer M, et al. Effect of early antiretroviral therapy during primary 
HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA. Antiviral therapy 
2011;16(4):535-45 
9. Ananworanich J, Schuetz A, Vandergeeten C, et al. Impact of multi-targeted antiretroviral 
treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PloS 
one 2012;7(3):e33948. 
10. Ananworanich J, Puthanakit T, Suntarattiwong P, et al. Reduced markers of HIV persistence 
and restricted HIV-specific immune responses after early antiretroviral therapy in children. 
Aids 2013 Dec 31. 
11. Investigator’s Brochure (IB): VRC01, A Broadly Neutralizing HIV-1 Human Monoclonal 
Antibody: VRC-HIVMAB0600-00-AB. 2nd Ed.; Vaccine Research Center, NIAID. June 25, 
2014. 
12. Lynch RM, Boritz E, Coates EE, DeZure A, et al Virologic effects of broadly neutralizing 
antibody VRC01 administration during chronic HIV-1 infection. VRC 601 Study Team. Sci 
Transl Med. 2015 Dec 23;7(319):319ra206. doi: 10.1126/scitranslmed.aad5752. 
13. Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, et al, HIV-1 suppression and 
durable control by combining single broadly neutralizing antibodies and antiretroviral drugs 
in humanized mice. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16538-43. 

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14. Barouch DH, Whitney JB, Moldt B, Klein F, et al., Therapeutic efficacy of potent 
neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. 
Nature. 2013 Nov 14; 503(7475):224-8. 
15. Shingai M, Nishimura Y, Klein F, Mouquet H, et al., Antibody-mediated immunotherapy of 
macaques chronically infected with SHIV suppresses viraemia. Nature. 2013 Nov 14; 
503(7475):277-80. 
16. Bugelski, P.J., R. Achuthanandam, R.J. Capocasale, G. Treacy, and E. Bouman-Thio, 
Monoclonal antibody-induced cytokine-release syndrome. Expert review of clinical 
immunology, 2009. 5(5): p. 499-521. 
17. Hansel, T.T., H. Kropshofer, T. Singer, J.A. Mitchell, and A.J. George, The safety and side 
effects of monoclonal antibodies. Nature reviews. Drug discovery, 2010. 9(4): p. 325-38. 
18. Vogel, W.H., Infusion reactions: diagnosis, assessment, and management. Clin J Oncol Nurs, 
2010. 14(2): p. E10-21. 
19. Haddad, É., D. Barnes, and A. Kafal, Home therapy with subcutaneous immunoglobulins for 
patients with primary immunodeficiency diseases. Transfusion and Apheresis Science, 2012. 
46(3): p. 315-321. 
20. Wu, X., Z.Y. Yang, Y. Li, C.M. Hogerkorp, W.R. Schief, et al., Rational design of envelope 
identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science, 2010. 
329(5993): p. 856-61. 
21. Ledgerwood, J.E., et al., Safety, pharmacokinetics and neutralization of the broadly 
neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp 
Immunol, 2015. 
22. DHHS. Panel On Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. January 28, 2016; 
Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 
23. Ford N, Shubber Z, Hill A, Vitoria M, Doherty M, et al. (2013) Comparative Efficacy of 
Lamivudine and Emtricitabine: A Systematic Review and Meta-Analysis of Randomized 
Trials. PLoS ONE 8(11): e79981.  
24. WHO (June 2012). Technical Update on Treatment Optimization. Pharmacological 
Equivalence and Clinical Interchangeability of Lamivudine and Emtricitabine: A Review of 
Current Literature. 
25. Maj M, Janssen R, Satz P, et al. The World Health Organization's cross-cultural study on 
neuropsychiatric aspects of infection with the human immunodeficiency virus 1 (HIV-1). 
Preparation and pilot phase. Br. J Psychiatry 1991 Sep; 159:351-6. 

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26. Omosa-Manyonyi GS, Jaoko W, Anzala O, Ogutu H, Wakasiaka S, et al., Reasons for 
Ineligibility in Phase 1 and 2A HIV Vaccine Clinical Trials at Kenya. Aids Vaccine Initiative 
(KAVI), Kenya. PLoS ONE 2011; 6(1): e14580. 
27. Karita E, Ketter N, Price MA, Kayitenkore K, Kaleebu P, et al. CLSI-Derived Hematology 
and Biochemistry Reference Intervals for Healthy Adults in Eastern and Southern Africa. 
PLoS ONE 2009; 4(2): e4401. 
28. Mugavero MJ, Napravnik S, Cole SR, Eron JJ, et al., Viremia Copy-Years Predicts Mortality 
Among Treatment-Naive HIV-Infected Patients Initiating Antiretroviral Therapy. Clinical 
Infectious Diseases 2011;53(9):927–93. 
29. Wu, X., C. Wang, S. O'Dell, Y. Li, B.F. Keele, et al., Selection pressure on HIV-1 envelope 
by broadly neutralizing antibodies to the conserved CD4-binding site. J Virol, 2012. 86(10): 
p. 5844-56. 
30. Lynch, R.M., L. Tran, M.K. Louder, S.D. Schmidt, M. Cohen, et al., The development of 
CD4 binding site antibodies during HIV-1 infection. J Virol, 2012. 86(14): p. 7588-95. 
31. Lobo, E.D., R.J. Hansen, and J.P. Balthasar, Antibody pharmacokinetics and 
pharmacodynamics. J Pharm Sci, 2004. 93(11): p. 2645-68. 
32. WHOPAR. Summary of Product Characteristics. Efavirenz/Lamivudine/Tenoofovir 
disoproxil fumarate. Package Insert August 2011. 
33. ATRIPLA Package Insert Updated October 2013 
34. Kollmann TR, Rubinstein A, Lyman WD, Soeiro R, Goldstein H. Characterization of IgG 
and IgG subclass antibodies present in paired maternal and fetal serum which are directed 
against HIV-1 proteins. AIDS Res Hum Retroviruses 1991; 7(10): 847-54. 
35. Skarda DE, et al Inguinal Lymph Node Biopsy in Patients Infected with the Human 
Immunodeficiency Virus Is Safe. Surg Infect 2007, 8:173-177.  
 

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APPENDIX I: CASE DEFINITION FOR ACUTE 
RETROVIRAL SYNDROME (ARS) 
Case definition must include all of the following: 
·        Occurs within 60 days after diagnosis 
·        Documented fever (temperature >38.5°C) 
·        At least two major criteria 
·        At least two minor criteria 
·        No other cause for signs and symptoms identified 
For severe ARS: at least one major or minor criteria meeting criteria for severe AE per 
DAIDS grading tables 
 
Major criteria: 
·        Pharyngitis 
·        Fatigue 
·        Morbilliform rash 
·        Myalgia/arthralgia 
·        Lymphadenopathy 
·        Subjective fever as reported by subject (may be intermittent) 
 
Minor criteria: 
·        Headache 
·        Nausea/vomiting 
·        Diarrhea 
·        Mucocutaneous ulceration (oral, genital, and/or anorectal) 
·        Meningismus/aseptic meningitis 
·        Night sweats 
·        Thrombocytopenia (platelets <150,000) 
·        Leukopenia (WBC <4,000) 
·        Malaise 
·        Abdominal pain 
·        Weight loss (loss of >5% of body weight) 
 

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APPENDIX II: SCHEDULE OF EVALUATIONS 
 
 

RV 398 Schedule of Evaluations
RV 398/WRAIR 2166
Schedule of Evaluations
Version 4.0
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Visit Number
RV217 
screening
RV254 
screening
1[1]
2
3 
4
5
6
7
8
9
10
11
12
13
14
15/exit [7]
Final
Visit Day
−19 to −1
−5 to −1
0
1
3
7
10
14
18
21
25
28
42
56
84
112
168
175
Visit Window (days)
0
1
3 to 4
6 to 8
9 to 11
12 to 16 17 to 19 20 to 23 24 to 26 27 to 34 35 to 49
50 to 63
77 to 91 105 to 119 161 to 174 175 to 196
Visit Type
RV217 visit 1 [11]
RV254 Week 0 
[11]
ENRL
CLINICAL
Briefing
x
x
Test of Understanding
x
Informed Consent
x
Physical Exam [2]
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Medical history [3]
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Contact information and registry form
x
Enrollment & Randomization
x
Monoclonal Ab/ Pbo Infusion
x
Positive prevention counseling
x
x
x
x
x
x
x
Pregnancy prevention counseling [4]
x
x
x
x
x
x
x
Solicited Adverse Events (Diary Card)
x
x
x
ARV medication record
x
x
x
x
x
x
x
x
x
x
Clinical Labs
Coagulant
CBC w/ diff 
AC
RV217
RV 254 
NB
NB
NB
NB
NB
NB
NB
NB
NB
Creatinine, ALT/AST/ALP
C
RV217 
(Cr/ALT)
RV 254 
(Cr/ALT)
NB
NB
NB
NB
NB
NB
NB
NB
NB
Hepatitis BsAg; Hep C Ab
RV 217 
RV 254
RPR or VDRL
C or AC
RV 217
RV 254
Pregnancy test; urine or serum [4]
RV217
RV 254 
x
x
x
x
x
x
Fiebig staging (EIA/WB/p24)
RV217
4
4
4
HIV PCR [10]
AC
RV217
RV 254
6
4
6
6
4
6
4
4
4
6
4
6
6
6
6
CD4/CD8 
AC
RV217
RV 254
NB
NB
NB
NB
NB
NB
NB
NB
NB
Plasma LH and FSH [5, 9]
NB
NB
NB
NB
NB
NB
Research
PK samples
C
4
2
2
2
2
2
2
Mucosal secretion collection [4,5]
RV 254 
x[12]
x
x
x
x
x
Rectosigmoid biopsy [5]
RV 254 
x[12]
x
x
Lymph Node biopsy (inguinal) [5]
x
Lumbar Puncture(20 ml) [5]
RV 254 
x[12]
x
x
Leukapheresis [5, 14]
RV 254 
x[12]
x
x
Neurocognitive testing
RV217
RV 254 
x
PBMC and plasma for storage and 
additional testing: reservoir, virologic, 
and immune assays [8, 15]
AC
RV217
RV 254 
68
17
85
25.5
25.5
17
34
153
Serum for storage and immune assays C
RV217
RV 254 
8
4
4
4
4
4
4
4
4
6
Daily Volume (mL)
60
70
90
4
29
97
4
41.5
4
10
4
41.5
4
29
44
10
165
0
Cumulative Volume (mL) [6, 13]
150
154
183
280
284
325.5
329.5
339.5
343.5
385
389
418
462
472
637
637
[1] Enrollment visit procedures may encompass two days to allow for optional procedures and/or patient transport. Day 0=day of first product administration.  Evaluations prior to VRC01/placebo administration are the baseline for assessing subsequent AEs.  
[2] Visit 1 includes physical exam with vital signs, height (ht) and weight (wt).  At other visits, if medically indicated, a targeted exam is performed. Otherwise only blood pressure (BP) and temperature are required.
[3] Visit 1 includes past medical history.  At other visits only interval medical history will be obtained.
[4] Pregnancy testing for all females at visit 1 and subsequently with invasive procedure or mucosal secretion collection visits for participating females
[5] Optional procedures.  Schedule the mucosal sample collection visits for women so that they will occur between menstrual periods;  cervical sample collection may be skipped at other mucosal timepoints if blood contamination is likely.
Optional procedures may, at the discretion of the PI, be conducted over 2 days, as long as it fall within the visit window.
 Those participants who consent to optional procedures are allowed to select which time points they  would like to provide samples as long as the collection is within the visit window for that procedure.   
Pre-procedure labs will be drawn according to the requirements of the institutions performing the respective invasive procedures, and the totals listed do not include these volumes.
[6] Residual volume/aliquots will be stored for additional testing and future use 
[7] Volunteers will complete Exit visit procedures if they withdraw or are terminated from the study prior to final visit
[8] Includes 100 mL for QVOA at visit 15
[9] Females participating in mucosal secretion collection, from stored samples
[10]  Genotype resistance testing will be performed at baseline and as clinically indicated
[11] RV 217 Visit 1 = pertinent study activities for the RV 217 Visit 1 following first positive NAAT.  RV 254 Week 0 = shows pertinent study procedures for the RV 254 baseline visit. RV 398 briefs during these visits - remaining activities are conducted under the parent coh
]12] Participants from RV217 only
[13] Participants recruited from RV254 in Thailand will have an additional 10 mL tube of blood drawn during RV254 screening, but will have one less 10 mL tube drawn during visit 1 of RV 398 such that the total blood volume drawn throughout the study is the same as all 
[14] Approximately 50 mL of red blood cell volume will be lost during apheresis
[15] At visits where leukapheresis is performed, participants who undergo the procedure will only have one 8.5mL tube of blood drawn for "PBMC and plasma for storage and additional testing" instead of the listed blood volume. 
If clinical laboratory results from RV 217 visit 1 or RV 254 Week 0 visit are unavailable, they may be drawn at visit 1 of RV 398.  If the participant is not enrolled in RV 217 or RV 254, they must sign the ICF prior to collection of screening labs.
NB = No additional blood required - blood from tubes drawn for other tests on the SOE for that visit will be used to perform these assays

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APPENDIX III: TEST OF UNDERSTANDING 
 
 

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TEST OF UNDERSTANDING 
Please read each question and answer whether the statement is True or False. 
 
True 
 
False 
 
1. 
The VRC01 antibody used in this study will protect you from transmitting 
HIV to others.  
 
True 
 
False 
 
2. 
You will need to come to the clinic for 15 scheduled visits over the next 25 
weeks. 
 
True 
 
False 
 
3. 
This is the first time that the VRC 01 antibody has been given to 
participants newly infected with HIV. 
 
True 
 
False 
 
4. 
One purpose of this study is to determine if VRC01 antibody is safe to 
administer to humans.  
 
True 
 
False 
 
5. 
All study participants will receive antiretroviral therapy immediately.  
 
True 
 
False 
 
6. 
You may take other experimental (test) products while you are taking part 
in this study. 
 
True 
 
False 
 
7. 
You may withdraw from the study at any time if you choose or your 
participation may be stopped if the study team decides it is in your best 
interest. 
 
True 
 
False 
 
8. 
Women are asked to not become pregnant while in the study. 
 
True 
 
False 
 
9. 
Some participants in this study may experience side effects from VRC01 
antibody infusion. 
 
 
True 
 
False 
 
10. Some participants in this study may get placebos or “salt water”. 
 
True 
 
False 
 
11. At the end of this study, I will no longer have access to antiretroviral 
therapy (ART). 
 
True 
 
False 
 
12. The VRC01 antibody infusion is only administered once during the study. 
 
True 
 
False 
 
13. The VRC01 antibody is a cure for HIV so I will not need ART anymore 
once I finish the study. 
 

RV 398/WRAIR 2166 
Page 1 of 1 
Version 4.0 
Test of Understanding Answers 
 
11 October 2018 
TEST OF UNDERSTANDING 
Please read each question and answer whether the statement is True or False. 
 
True 
 
False 
 
1. 
The VRC01 antibody used in this study will protect you from transmitting 
HIV to others.  
 
True 
 
False 
 
2. 
You will need to come to the clinic for 15 scheduled visits over the next 25 
weeks. 
 
True 
 
False 
 
3. 
This is the first time that the VRC 01 antibody has been given to 
participants newly infected with HIV. 
 
True 
 
False 
 
4. 
One purpose of this study is to determine if VRC01 antibody is safe to 
administer to humans.  
 
True 
 
False 
 
5. 
All study participants will receive antiretroviral therapy immediately.  
 
True 
 
False 
 
6. 
You may take other experimental (test) products while you are taking part 
in this study. 
 
True 
 
False 
 
7. 
You may withdraw from the study at any time if you choose or your 
participation may be stopped if the study team decides it is in your best 
interest. 
 
True 
 
False 
 
8. 
Women are asked to not become pregnant while in the study. 
 
True 
 
False 
 
9. 
Some participants in this study may experience side effects from VRC01 
antibody infusion. 
 
 
True 
 
False 
 
10. Some participants in this study may get placebos or “salt water”. 
 
True 
 
False 
 
11. At the end of this study, I will no longer have access to antiretroviral 
therapy (ART). 
 
True 
 
False 
 
12. The VRC01 antibody infusion is only administered once during the study. 
 
True 
 
False 
 
13. The VRC01 antibody is a cure for HIV so I will not need ART anymore 
once I finish the study. 
 

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ATTACHMENT I: STUDY TEAM ROSTER 
 
 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Study Team Roster 
 
Page 1 of 5 
STUDY TEAM ROSTER 
PROTOCOL CO-CHAIR  
LTC Julie Ake, MD 
U.S. Military HIV Research Program (MHRP)/ 
Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF) 
6720A Rockledge Drive 
Bethesda, MD. USA 
Phone: (301) 500-3621 
Email: jake@hivresearch.org 
 
PROTOCOL CO-CHAIR  
Merlin Robb, MD 
U.S. Military HIV Research Program 
6720-A Rockledge Drive, Suite 400 
Bethesda, MD 20817, USA 
Tel: +1 301 500 3602 
Fax: +1 301 762 7460 
Email: mrobb@hivresearch.org  
 
DAIDS MEDICAL OFFICER 
Randall Tressler, MD 
Buliding 5601 RM 9E49 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: (240) 627-3072 
Email: Randall.tressler@nih.gov 
 
SITE PRINCIPAL INVESTIGATORS 
RV 398a--Kampala, Uganda  
Francis Kiweewa, MBChB, MMED, MPH  
Makerere University-Walter Reed Project 
PO 16524, Kampala, Uganda 
Phone: +256-414+534588; Fax: +256-414-534586 
Email: fkiweewa@muwrp.org 
 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Study Team Roster 
 
Page 2 of 5 
RV 398b--Kericho, Kenya 
Josphat Kosgei, MBChB 
Kenya Medical Research Institute/Walter Reed Project HIV Program 
Hospital Road, P.O. Box 1357 
Kericho, 20200; Kenya 
Phone: (254-52) 30686, 30388, Fax: (254-52) 30546 
Mobile phone: 254-729-110122 
Email: josphat.kosgei@usamru-k.org 
 
RV 398c--Mbeya, Tanzania 
Joel Mwakisisile, MD 
Mbeya Medical Research Programme 
P.O.Box 2410, Mbeya, 025, Tanzania 
Phone: 255-25-250-3364; Fax: 255-25-250-3134 
Email: jmwakisisile@nimr-mmrc.org  
 
RV 398d--Pattaya, Thailand 
Somchai Sriplienchan, M.D., M.P.H.  
Royal Thai Army Expert, AFRIMS 
315/6 Rajvithi Road 
Bangkok 10400, Thailand 
Phone: 66-2-644-4888, Fax: 66-2-644-4824 
Email: SomchaiS@afrims.org 
 
 
MHRP ASSOCIATE INVESTIGATORS 
Jintanat Ananworanich MD, PhD  
U.S. Military HIV Research Program 
6720-A Rockledge Drive, Suite 400 
Bethesda, MD 20817, USA 
Tel: +1 301 500 3949 
Fax: +1 301 762 7460 
Email: jananworanich@hivresearch.org  
 
Kavyon Modjarrad, MD, PhD 
U.S. Military HIV Research Program 
6720-A Rockledge Drive, Suite 400 
Bethesda, MD 20817, USA 
301-500-3623 
Email: Kmodjarrad@hivresearch.org 
 

RV 398/ WRAIR 2166 
 
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Protocol Study Team Roster 
 
Page 3 of 5 
LABORATORY INVESTIGATORS 
Victoria Polonis, Ph.D. 
U.S. Military HIV Research Program 
503 Robert Grant Avenue 
Silver Spring, MD 20910 
Phone: 301-500-3600 Fax: 301-500-3666 
Email: Vpolonis@hivresearch.org 
 
Sheila Peel, Ph.D. 
U.S. Military HIV Research Program 
503 Robert Grant Ave.  
Silver Spring, MD 20910 
Phone: 301-500-3600 Fax: 301-500-3666 
Email: speel@hivresearch.org 
 
Leigh Anne Eller, MSc. 
U.S. Military HIV Research Program 
6720-A Rockledge Drive Ste 400  
Bethesda, MD 20817, U.S.A. 
Phone: 301-500-3600 Fax: 301-500-3666 
Email: leller@hivresearch.org  
PROTOCOL STATISTICIAN 
Peter Dawson, Ph.D. 
EMMES Corporation 
401 North Washington St. 
Suite 700 
Rockville, MD 20850 USA 
Main Phone 301-251-1161 
Fax 301-251-1355 
 
OVERALL STUDY PHARMACIST 
Lynette Purdue 
Division of AIDS 
Pharmaceutical Affairs Branch (PAB) 
Building 5601FL RM 9E28 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: 240-627-3061 
Email: lpurdue@niaid.nih.gov 
 
PROTOCOL DATA MANAGEMENT  
 
 
 
Data Coordinating and Analysis Center 
Henry M Jackson Foundation 
6720–A Rockledge Drive; Suite 400 
Bethesda, MD 20817 
 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Study Team Roster 
 
Page 4 of 5 
DAIDS PROGRAM REPRESENTATIVE 
Lawrence Fox, MD 
Building 5601FL RM 9E41 
Rockville, MD 20852 
Phone: 240-627-3069 
Fax: 240-627-3106 
Email: lawrence.fox@nih.gov 
U.S. DEPARTMENT OF DEFENSE/WALTER REED ARMY INSTITUTE OF 
RESEARCH REPRESENTATIVE 
COL Nelson Michael, M.D., Ph.D. 
U.S. Military HIV Research Program 
503 Robert Grant Avenue 
Silver Spring, MD 20910 
Phone: 301-500-3600 Fax: 301-500-3666 
Email: nmichael@hivresearch.org  
 
VRC01 PRODUCT REPRESENTATIVE 
Julie E. Ledgerwood, D.O.  
Chief, Clinical Trials Program 
Vaccine Research Center (VRC) 
BG 10-CRC RM 5-2436 
10 Center Drive 
Bethesda, MD 20814  
Phone: 301-594-8502, 
Fax: 301-451-4651 
Email: Julie.ledgerwood@nih.gov  
 
PARTICIPATING LABORATORIES  
MHRP Laboratories 
508 Robert Grant Avenue  
Silver Spring, MD 20910 
 
AFRIMS Laboratory 
Department of Retrovirology 
315/6 Rajvithi Road 
Bangkok 10400, Thailand 
 
IND SPONSOR  
National Institute of Allergy and Infectious Diseases (NIAID) 
Division of AIDS (DAIDS), National Institutes of Health (NIH) 
Bethesda, Maryland 
 
REVIEWING IRBs 
Walter Reed Army Institute of Research (WRAIR) Institutional Review Board (IRB) 
US Army Garrison-Forest Glen 
503 Robert Grant Avenue 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Study Team Roster 
 
Page 5 of 5 
Silver Spring, MD 20910 
FWA #00000373 
 
RV 398a (Uganda): 
National HIV/ AIDS Research Committee 
Uganda National Council of Science & Technology 
Plot 6 Kimera Road, Ntinda  
P. O. Box 6884, 
Kampala, Uganda 
FWA#000117795 
 
RV 398b (Kenya): 
Kenya Scientific and Ethics Review Unit 
PO Box 54840-00200 
Nairobi, Kenya 
FWA#00002066 
 
RV 398c (Tanzania): 
Mbeya Ethical Review Committee  
Mbeya Medical Research and Ethics Committee 
Hospital Hill Road, P.O. Box 419 
Mbeya, Tanzania 
FWA #00002469 
 
RV 398d (Thailand): 
Royal Thai Army Medical Department Institutional Review Board  
5th floor, Pramongkutklaovejvithaya Building 
Pramongkutklao Medical School 
315 Rajvithi Road, 
Bangkok 10400, Thailand 
Tel: 662-354-7600 ext 94270 
Fax: 662-354-9011 
FWA# 00001813  
 
Chulalongkorn University IRB 
Faculty of Medicine, Chulalongkorn University 
Ananda Mahidol Building, 3rd Floor 
Bangkok, Thailand 
Tel: +66 2256 4455 ext.14, 15 
Fax: +66 2255 4493 
research_affairs@gmail.com 
FWA#: 00000943 
 

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ATTACHMENT II: ROLES AND RESPONSIBILITIES 
 
 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Team Roles and Responsibilities 
 
Page 1 of 2 
PROTOCOL STUDY TEAM RESPONSIBILITIES 
 
Protocol Chair:  
Responsible for study design and serving as a liaison between the sites, the vaccine 
developers including the Sponsor, and contributing support to overall project 
management and the analysis and reporting of study data. Dr. Ake will support the site 
PIs with clinical trial guidance, protocol preparation, protocol review and response to 
regulatory reviews.  
 
Protocol Co-Chair:  
Responsible for study design and serving as a liaison between the sites and the vaccine 
developers including the Sponsor, and contributing support to overall project 
management and the analysis and reporting of study data. Dr. Robb will provide support 
with clinical trial guidance, protocol preparation, protocol review and response to 
regulatory reviews.  
 
Site Principal Investigators:  
Responsible for all aspects of the study at their respective site. Primary individual 
responsible for individual subject safety. 
 
Associate Investigators: Assist the Protocol Chairs and Principal Investigators in 
performing specific study tasks and/or procedures under their supervision. 
Laboratory Investigators:  
Responsible for laboratory analysis. Lab investigators will not have contact with study 
subjects or identifiers.  
 
Protocol Statistician:  
Responsible for statistical analysis for this study. The protocol statistician will not have 
contact with study subjects.  
 
Overall Study Pharmacist: qualified pharmacist with responsibility for overseeing the 
import, distribution, inventory, and accountability of vaccine, communication with 
sponsor / MHRP regarding pharmacy related issues, training and consultation with the 
study sites’ pharmacy personnel. 
 
Protocol Data Management:  
Responsible for data management for this study. The data management team will not 
have contact with study subjects.  
 
DAIDS Medical Officer:  
Responsible for protocol development and liason for the submission to the DAIDS 
Clinical Sciences Review Committee review  
The DAIDS medical officer will not have contact with study subjects or identifiers.  
 
DAIDS Program Representative:  
Responsible to all applicable regulatory authorities for conduct of the study through 
exercise of oversight of site PIs, chairs and other investigators. The DAIDS Program 

RV 398/ WRAIR 2166 
 
11 October 2018 
Protocol Team Roles and Responsibilities 
 
Page 2 of 2 
Representative will not have contact with study subjects or identifiers.  
 
U.S. DoD/WRAIR Research Representative:  
Responsible for oversight of this study as it affects DoD interests. The US DoD/WRAIR 
Research Representative will not have contact with study subjects or identifiers.  
 
VRC01 Product Representative:  
Responsible for oversight of this study as it affects VRC interests. The VRC01 Product 
Representative will not have contact with study subjects or identifiers.  
 
 
 

RV 398/WRAIR 2166 
 
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ATTACHMENT III: LIST OF COLLABORATORS 
 
 

RV398 External Collaborator List  
 
Page 1 of 5 
 
 
 
 
Version 4.0 
 
 
 
 
 
11 October 2018 
Row 
# 
Collaborator 
Institution 
Work to be done 
Sample 
types used 
IRB/ 
Determination 
1 
Victor Valcour MD 
Professor of Medicine 
Division of Geriatric 
Medicine and Department of 
Neurology 
Memory and Aging Center 
Vvalcour@memory.ucsf.edu 
(415) 476-3746; fax: (415) 
476-0213 
 
University of 
California San 
Francisco 
Data analysis 
 
 
De-identified 
data 
UCSF 
2 
Serena Spudich, MD 
Associate Professor of 
Neurology 
Yale University Department 
of Neurology 
PO Box 208018 
New Haven, CT 06520 
203-688-5303 
serena.spudich@yale.edu 
 
Yale University 
Data analysis 
 
 
De-identified 
data 
Yale 
3 
Nicolas Chomont, PhD 
Assistant Professor 
Universitéde Montréal 
Centre de recherche du 
CHUM (CRCHUM) 
Address: 900, rue St-Denis, 
Tour Viger 
Montréal, Québec, Canada 
University of 
Montreal 
HIV quantification, 
microarrays, systems 
biology, T cell 
immunology 
TILDA 
Cells/Plasma, 
lymph nodes 
University of 
Montreal 

RV398 External Collaborator List  
 
Page 2 of 5 
 
 
 
 
Version 4.0 
 
 
 
 
 
11 October 2018 
H2X 0A9 
 
4 
Adrian McDermott, MSc. 
Ph.D. 
Director, Advanced Clinical 
Testing, Immunology Core 
Vaccine Research Center, 
NIAID/NIH 
40 Convent Drive, MSC 3015 
Building 40, Room 3508 
Bethesda, MD 20814 
Phone: 301 761-6963 
FAX: 301 480-2779 
 
VRC 
B cell development 
VRC01 levels 
Cells/Plasma, 
CSF, lymph 
nodes, gut 
biopsies, 
mucosal 
specimens 
NIH 
5 
Bob Bailer, Ph.D.  
Vaccine Immunogenicity 
Testing Program, Director  
Vaccine Research Center-
NIH/NIAID  
MDL9BG RM 165C 
9 West Watkins Mill Road 
Gaithersburg, MD 20878 
Phone: 301-594-8481 
FAX: 240-276-0001 
 
VRC/NVITAL 
Cellular and Humoral 
Immune responses, 
VRC01 levels, PK 
Cells/Plasma 
NIH 
6 
Daniel Douek, M.D., MRCP, 
Ph.D. 
Vaccine Research Center 
Bldg 40 Room 3509 MSC 
VRC / NIH 
T cell reservoirs/ 
Pathogen 
Sequencing/TCR 
sequencing 
Plasma, cells, 
lymph nodes 
NIH 

RV398 External Collaborator List  
 
Page 3 of 5 
 
 
 
 
Version 4.0 
 
 
 
 
 
11 October 2018 
3022 
40 Convent Drive 
Bethesda, MD 20814 
Tel: +1 301-594-8484  
Fax: +1 301-480-2565 
 
7 
Sarah Palmer, PhD  
University of Sydney  
Darcy Road, PO Box 412 
Westmead NSW 2145 
Australia  
Tel: +61 2 9845 9107  
Email: 
sarah.palmer@sydney.edu.au 
 
University of 
Sydney 
HIV quantification 
Plasma 
University of 
Sydney 
 
8 
Hendrik Zetterburg, MD, PhD 
Institute of Neuroscience and 
Physiology 
The Sahlgrenska Academy at 
the University of Gothenburg 
S-431 80 Molndal 
Sweden 
Tel : +46 31 3430142 
 
University of 
Gothenburg 
Neurofilament 
CSF 
University of 
Gothenburg/ 
waiver 
9 
Timothy Schacker, MD 
University of Minnesota 
516 Delaware Street 
Minneapolis, MN 55455 
Tel : +1 612 624 9925 
 
University of 
Minnesota 
 
Immunohistochemistry; 
in-situ hybridization 
Gut/Rectal 
biopsies and 
lymph nodes 
University of 
Minnesota 
/ waiver 

RV398 External Collaborator List  
 
Page 4 of 5 
 
 
 
 
Version 4.0 
 
 
 
 
 
11 October 2018 
10 
Jacob Estes, PhD 
Vaccine & Gene Therapy 
Institute 
Chief, Division of 
Pathobiology and 
Immunology 
Oregon National Primate 
Research Center 
Oregon Health & Science 
University 
505 NW 185th Avenue 
Mail Code: VGTI-BD1 
Office: BD1-1119B 
Lab: BD1-1111 
Beaverton, OR 97006 
Phone: (503) 418-2700  
Fax: (503) 418-2701.  
 
Oregon Health & 
Science University 
 
Immunohistochemsitry; 
in-situ hybridization 
Gut/Rectal 
biopsies and 
lymph nodes 
Oregon Health & 
Science 
University 
11 
Robert Paul 
University of Missouri, St. 
Louis 
412 Stadler Hall  
One University Boulevard 
St. Louis, MO 63121-4499 
Phone: (314) 516-5398 and 
(314) 516-7335 
Fax: (314) 516-5392 
Email: paulro@umsl.edu 
 
University of 
Missouri, St. Louis 
 
Data Analysis 
De-identified 
data 
University of 
Missouri, St. 
Louis 
 

RV398 External Collaborator List  
 
Page 5 of 5 
 
 
 
 
Version 4.0 
 
 
 
 
 
11 October 2018 
 
12 
Hendrik Streeck M.D., Ph.D 
Direktor, Institut für 
Medizinische Biologie 
Universitätsklinikum Essen 
Universität Duisburg-Essen 
Hufelandstr. 55 
D-45147 Essen 
Germany 
Phone: +49 (201) 723-4224 
Email: hendrik.streeck@uk-
essen.de 
 
University of 
Essen 
T cell immunology 
Cells 
Univeristy of 
Essen  
13 
Claire Deleage, PhD 
AIDS Cancer Virus Program 
Frederick National 
Laboratory for Cancer 
Research (FNLCR) 
Leidos Biomedical Research 
Inc. 
105 Boyles Street 
Bldg. 535, Rm. 424Frederick, 
MD 21702 
Email: 
Claire.deleage@nih.gov 
 
National Cancer 
Institute 
Frederick/Leidos 
Biomedical 
Research, Inc. 
 
Immunohistochemsitry; 
in-situ hybridization 
Gut/Rectal 
biopsies and 
lymph nodes 
National Cancer 
Institue (NCI) 

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ATTACHMENT IV: DAIDS AE GRADING TABLE 
 
 

 
Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
Version 2.0 
November 2014 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 
 
 

 
 
 

Table of Contents 
Glossary and Acronyms .................................................................................................................. 1 
Introduction ..................................................................................................................................... 3 
Instructions for Use ......................................................................................................................... 4 
Major Clinical Conditions............................................................................................................... 7 
Cardiovascular .......................................................................................................................... 7 
Dermatologic............................................................................................................................. 9 
Endocrine and Metabolic ........................................................................................................ 10 
Gastrointestinal ....................................................................................................................... 11 
Musculoskeletal ...................................................................................................................... 13 
Neurologic............................................................................................................................... 14 
Pregnancy, Puerperium, and Perinatal .................................................................................... 16 
Psychiatric ............................................................................................................................... 17 
Respiratory .............................................................................................................................. 18 
Sensory .................................................................................................................................... 19 
Systemic .................................................................................................................................. 20 
Urinary .................................................................................................................................... 22 
Site Reactions to Injections and Infusions .................................................................................... 23 
Laboratory Values ......................................................................................................................... 24 
Chemistries ............................................................................................................................. 24 
Hematology ............................................................................................................................. 27 
Urinalysis ................................................................................................................................ 29 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates .......................................... 30 
 
 

 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS.  It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency.  
INR 
International normalized ratio  
DAIDS AE Grading Table Version 2.0- November 2014 
Page 1 

Glossary and Acronyms 
Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event.  
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc  Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization  
WNL 
Within normal limits 
 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 2 

 
Introduction 
The Division of AIDS (DAIDS) oversees clinical trials throughout the world which it sponsors 
and supports.  The clinical trials evaluate the safety and efficacy of therapeutic products, 
vaccines, and other preventive modalities.  Adverse event (AE) data collected during these 
clinical trials form the basis for subsequent safety and efficacy analyses of pharmaceutical 
products and medical devices.  Incorrect and inconsistent AE severity grading can lead to 
inaccurate data analyses and interpretation, which in turn can impact the safety and well-being of 
clinical trial participants and future patients using pharmaceutical products.  
 
The DAIDS AE grading table is a shared tool for assessing the severity of AEs (including 
clinical and laboratory abnormalities) in participants enrolled in clinical trials.  Over the years as 
scientific knowledge and experience have expanded, revisions to the DAIDS AE grading table 
have become necessary. 
 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 replaces the grading table published in 2004 and updated in 2009.  In version 
2.0, AEs not previously included, but which now are deemed medically important events, are 
included while other AEs have been removed.  Some AE severity grading descriptions have been 
revised to more appropriately reflect the presentation of these events in clinical settings and their 
impact on clinical trials.  For example, DAIDS performed an extensive literature search and 
reviews of select DAIDS clinical trial data in revising certain hematology parameters (i.e., 
hemoglobin, white cell counts, and absolute neutrophil counts).  DAIDS also took into 
consideration the U.S. Food and Drug Administration’s guidance regarding the use of local 
laboratory reference values and ethnic differences among certain healthy adolescent and adult 
populations in defining parameter limits.  Finally, the revised DAIDS AE grading table also 
contains an updated glossary and acronyms section, an expanded instructions for use section, and 
an appendix that provides more age-specific information for an AE of concern to DAIDS. 
 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS AE grading table. 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 3 

 
Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
 
Clinical sites are encouraged to report parameters in the DAIDS AE grading table as they are 
written to maintain data consistency across clinical trials.  However, since some parameters can 
be reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
 
The DAIDS AE grading table provides an AE severity grading scale ranging from grades 1 to 5 
with descriptions for each AE based on the following general guidelines:  
• Grade 1 indicates a mild event 
• Grade 2 indicates a moderate event 
• Grade 3 indicates a severe event 
• Grade 4 indicates a potentially life-threatening event 
• Grade 5 indicates death (Note: This grade is not specifically listed on each page of the 
grading table). 
 
Other points to consider include: 
• Use parameters defined by age and sex values as applicable. 
• Male and female sex are defined as sex at birth. 
• Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges. 
• Where applicable, Standard International (SI) units are included in italics. 
 
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency.  
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 4 

Instructions for Use 
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions.  
 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
 
Determining Severity Grade for Parameters between Grades  
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the CRFs.  
 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 5 

Instructions for Use 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion.  
• Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies – PDF  
• Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – PDF  
• Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – PDF  
 
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5.  
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Clinical adverse 
event NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability to 
perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 6 

 
Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arrhythmia   
(by ECG or physical 
examination) 
Specify type, if applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention indicated 
Non-life-threatening 
symptoms  AND 
Non-urgent 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1 
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th  
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR Urgent 
intervention indicated 
(e.g., vasoactive 
medications, ventricular 
assist device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion indicated 
Symptoms AND 
Transfusion of  ≤ 2 
units packed RBCs 
indicated  
Life-threatening 
hypotension OR 
Transfusion of  > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-
2107C. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 7 
                                                          

Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Prolonged PR Interval  
or AV Block 
Report only one 
> 16 years  of age 
PR interval 0.21 to < 
0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds 
Complete AV block  
≤ 16 years of age 
1st degree AV block 
(PR interval  
> normal for age and 
rate) 
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, other 
associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention indicated  
Symptoms AND 
Intervention indicated  
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus)  
 
 
2 As per Bazett’s formula. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 8 
                                                          

 
Dermatologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Alopecia (scalp only)  
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities  
NA 
Rash 
Specify type, if applicable 
Localized rash  
Diffuse rash OR 
Target lesions  
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis  
 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 9 
                                                          

 
Endocrine and Metabolic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure)  
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes  
NA 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 10 
                                                          

 
Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention indicated 
(e.g., diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation)  
Constipation 
NA 
Persistent 
constipation requiring 
regular use of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to  6 stools over 
baseline per 24-hour 
period 
Increase of  ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or  
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 11 

Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 to 
48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 12 

 
Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions  
Myalgia (generalized) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6 
≥ 30 years of age 
BMD t-score  
-2.5 to -1 
NA 
NA 
NA 
   < 30 years of age 
BMD z-score  
-2 to -1 
NA 
NA 
NA 
Osteoporosis6 
≥ 30 years of age 
NA  
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences  
 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis 
at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield.  
DAIDS AE Grading Table Version 2.0- November 2014 
Page 13 
                                                          

 
Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below)  
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR  
Obtundation OR  
Coma 
Ataxia  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting 
Headache  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function  
DAIDS AE Grading Table Version 2.0- November 2014 
Page 14 

Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities  
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or  paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA  
1 to  3 seizures  
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with  
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality  
(e.g., severity or  
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope  
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
AND Hospitalization 
or intervention 
required 
NA 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 15 

 
Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Fetal Death or Stillbirth 
(report using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring at 
≥ 20 weeks gestation 
NA 
Preterm Delivery7 
(report using mother’s 
participant ID) 
Delivery at 34 to  
< 37 weeks  
gestational age 
Delivery at 28 to  
< 34 weeks 
gestational age 
Delivery at 24 to  
< 28 weeks 
gestational age 
Delivery at < 24 weeks 
gestational age 
Spontaneous Abortion 
or Miscarriage8 (report 
using mother’s participant 
ID) 
Report only one 
Chemical pregnancy  
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
 
7 Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
8 Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 16 
                                                          

 
Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Insomnia  
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early  
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self or 
others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or intent 
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated 
Suicide attempted 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 17 

 
Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to  
≥ 70 to < 80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second or 
peak flow 50 to  
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to  
< 50% OR Symptoms 
causing inability to 
perform usual social 
& functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation  
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on exertion 
with no or minimal  
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 18 

 
Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Hearing Loss 
≥ 12 years of age 
 
NA 
 
Hearing aid or 
intervention not 
indicated 
 
Hearing aid or 
intervention indicated 
 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 6 
and 8 kHz audiogram) 
> 20 dB hearing loss 
at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss 
at  ≥ 3 kHz in one ear 
with additional speech 
language related 
services indicated 
(where available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related services 
indicated (where 
available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 19 

 
Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acute Allergic 
Reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9 
Mild signs and 
symptoms AND 
Therapy (i.e., antibody 
infusion)  interruption 
not indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe signs 
and symptoms OR 
Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Pain causing inability 
to perform usual social 
& functional activities  
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).   
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 20 
                                                          

Systemic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Underweight12 
> 5 to 19 years of 
age 
NA 
WHO BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score  
< -3 
WHO BMI z-score  
< -3 with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score  
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score  
< -2 to ≤ -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences 
Weight Loss (excludes 
postpartum weight 
loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body weight 
from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
 
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs:  
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 21 
                                                          

 
Urinary 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Urinary Tract 
Obstruction  
NA 
Signs or symptoms of 
urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 22 

 
Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Injection Site Pain or  
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb  
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site Erythema 
or Redness13 
Report only one 
> 15 years of age 
 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤ 2.5 cm in diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area of 
the extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus  
 
Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional activities  
NA 
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 23 
                                                          

 
Laboratory Values  
Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Acidosis 
NA 
pH ≥ 7.3 to < LLN 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0  
≥ 20  to < 30  
< 2.0  
< 20  
NA 
Alkaline Phosphatase,  
High 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT or SGPT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5  
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0  
11.0  to < 16.0  
8.0  to < 11.0  
8.0  to < 11.0  
< 8.0  
< 8.0  
Bilirubin 
Direct Bilirubin14, 
High 
> 28 days of age 
 
 
NA 
 
NA 
 
> ULN  
 
> ULN with life-
threatening 
consequences (e.g., signs 
and symptoms of liver 
failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
 
1.1 to < 1.6 x ULN 
 
1.6 to < 2.6 x ULN 
 
2.6 to < 5.0 x ULN 
 
≥  5.0 x ULN 
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
≥  13.5  
≥  3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
≥  13.5 
≥  3.38 
14 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 24 
                                                          

Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of 
> 0.3 mg/dL above 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase 
of 1.5 to < 2.0 x 
above baseline 
≥ 3.5 x ULN OR 
Increase of  ≥ 2.0 x 
above baseline 
Creatinine Clearance15 
or eGFR, Low 
Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease  
from baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 
OR 
≥ 50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
 
 
110 to 125  
6.11 to < 6.95 
 
 
> 125 to 250  
6.95 to < 13.89 
 
 
> 250 to 500  
13.89 to < 27.75 
 
 
> 500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89  to < 27.75  
> 500 
≥ 27.75  
Glucose, Low  
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64  
3.05  to 3.55  
40  to < 55 
2.22  to < 3.05  
30  to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
< 1 month of age 
50 to 54 
2.78  to 3.00  
40 to < 50 
2.22 to < 2.78  
30 to < 40 
1.67 to < 2.22  
< 30 
< 1.67  
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2). 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 25 
                                                          

Chemistries 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders  
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
 
200  to < 240  
5.18  to < 6.19  
 
240  to < 300  
6.19  to < 7.77  
 
≥  300 
≥  7.77  
 
NA 
< 18 years of age 
170  to < 200  
4.40  to < 5.15  
200  to < 300 
5.15  to < 7.77  
≥  300  
≥  7.77  
NA 
LDL, Fasting, High 
≥ 18 years of age 
 
130  to < 160  
3.37  to < 4.12  
 
160 to < 190  
4.12  to < 4.90  
 
≥ 190  
≥ 4.90  
 
NA 
> 2 to < 18 years of 
age 
110  to < 130  
2.85  to < 3.34  
130 to < 190  
3.34  to < 4.90  
≥ 190 
≥ 4.90  
NA 
Triglycerides, Fasting, 
High 
150 to 300  
1.71 to 3.42  
>300  to 500  
>3.42 to 5.7  
>500 to < 1,000  
>5.7 to 11.4  
> 1,000  
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4  
0.60  to < 0.70  
0.9  to < 1.2  
0.45  to < 0.60  
0.6  to < 0.9  
0.30  to < 0.45  
< 0.6  
< 0.30  
Phosphate, Low  
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81  
1.0 to < 1.4 
0.32 to < 0.65  
< 1.0 
< 0.32  
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13  
2.5  to < 3.0 
0.81  to < 0.97  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45  
2.5  to < 3.5 
0.81  to < 1.13  
1.5  to < 2.5 
0.48  to < 0.81  
< 1.5 
< 0.48  
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0  
6.0  to < 6.5 
6.0  to < 6.5  
6.5  to < 7.0 
6.5  to < 7.0  
≥ 7.0 
≥ 7.0  
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4  
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5  
< 2.0 
< 2.0  
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150  
150  to < 154 
150  to < 154  
154  to < 160 
154  to < 160  
≥ 160 
≥ 160  
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135  
125  to < 130 
125  to < 135  
121  to < 125 
121  to < 125  
≤ 120 
≤ 120  
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59  
10.0  to < 12.0 
0.59  to < 0.71  
12.0  to < 15.0 
0.71  to < 0.89  
≥ 15.0 
≥ 0.89  
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
DAIDS AE Grading Table Version 2.0- November 2014 
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Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
300 to < 400 
300 to < 400 
 
 
 
200 to <  300 
200 to < 300 
 
 
 
100 to < 200 
100  to < 200 
 
 
 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low  
(cell/mm3; cells/L) 
> 5 years of age  
(not HIV infected) 
 
 
 
600  to < 650 
0.600 x 109  to 
< 0.650 x 109 
 
 
 
500  to < 600 
0.500 x 109  to 
< 0.600 x 109 
 
 
 
350 to < 500 
0.350 x 109  to 
< 0.500 x 109 
 
 
 
< 350 
< 0.350 x 109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
 
 
 
600 to 799 
0.600 x 109 to 0.799 x 
109 
 
 
 
400 to 599 
0.400 x 109 to 0.599 x 
109 
 
 
 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109 
750 to 999 
0.750 x 109 to 0.999 x 
109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109 
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100  to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 
x LLN 
75  to < 100 
0.75  to < 1.00  
OR 
≥ 0.50 to < 0.75 
x LLN  
50  to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age  
(male only) 
 
 
10.0 to 10.9 
6.19 to 6.76 
 
 
 
9.0 to < 10.0 
5.57 to < 6.19 
 
 
7.0 to < 9.0 
4.34 to < 5.57 
 
 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
 
17 Male and female sex are defined as sex at birth. 
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor.  For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory. 
 
DAIDS AE Grading Table Version 2.0- November 2014 
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Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
57 days of age to < 13 
years of age  
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin  
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High  
(not on anticoagulation 
therapy) 
1.1  to < 1.66  
x ULN 
1.66 to < 2.33  
x ULN 
2.33 to < 3.00  
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 124,999  
100.000 x 109  to 
< 124.999 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000  
25.000 x 109  to  
< 50.000 x 109 
< 25,000  
< 25.000 x 109 
PT, High  
(not on anticoagulation 
therapy 
1.1  to < 1.25  
x ULN 
1.25  to < 1.50  
x ULN 
1.50  to < 3.00  
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
 
 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
 
 
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109 
 
 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
 
 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109 
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109 
< 2,500 
< 2.500 x 109 
DAIDS AE Grading Table Version 2.0- November 2014 
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Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to   
≤ 500 mg 
> 2+ or > 500 mg 
NA 
Hematuria (not to be 
reported based on dipstick 
findings or on blood 
believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
 
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Appendix A.  
Total Bilirubin Table for Term and Preterm Neonates 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Total Bilirubin19, High 
(mg/dL; µmol/L)20 
 
Term Neonate21 
 < 24 hours of age 
 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10  to < 17  
171  to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of 
age 
5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12  to < 19  
205.2  to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of 
age 
8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15  to < 22  
256.5  to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days 
of age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18  to < 24  
307.8  to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
32 to < 35 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks  
gestational age and  
< 7 days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
≥ 10  
≥ 171  
< 28 weeks 
gestational age and  
< 7 days of age 
NA 
NA 
 5 to < 8  
85.5 to < 136.8  
≥ 8  
≥ 136.8  
7 to  28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of life 
followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4. 
20 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
21 Definitions: Term is defined as ≥ 37 weeks  gestational age; near-term, as ≥ 35 weeks  gestational age; preterm, as < 35 weeks gestational age; 
and neonate, as 0 to 28 days of age. 
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