Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE
Phase: PHASE3
Conditions: HIV, Cardiovascular Diseases
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
 
 
Principal Investigators: 
 
Steven Grinspoon, MD 
Pamela Douglas, MD 
Michael Lu, MD, MPH 
Heather Ribaudo, PhD  
 
AIDS Clinical Trials Group  
Investigators:  
 
 
Carlos Malvestutto, MD, MPH 
 
 
 
 
 
Carl Fichtenbaum, MD 
 
 
 
 
 
Judith Aberg, MD 
 
 
 
 
 
Markella Zanni, MD 
 
Data Coordinating Center:   
Harvard School of Public Health 
 
Study Funders: 
 
 
National Heart, Lung, and Blood Institute  
 
 
 
 
 
National Institute of Allergy and Infectious Diseases 
 
National Institute of Diabetes and Digestive and 
Kidney Diseases 
 
Office of AIDS Research, National Institutes of Health 
 
Industry Support: 
 
 
Kowa Pharmaceuticals America 
 
 
 
 
 
Gilead Sciences 
 
 
 
 
 
ViiV Healthcare  
 
NHLBI Program and Medical 
Officer: 
 
 
 
Patrice M. Desvigne-Nickens, MD 
 
 
DAIDS Medical Officer:  
 
 Christine Chiou, MD 
 
 
IND Sponsor:  
 
 
 Division of AIDS, NIAID, NIH  
 
 
IND Number:  
 
 
119127 
 
 
 
 
FINAL Version 6.0 
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REPRIEVE (A5332) 
 
 
FINAL Version 6.0 
 
 
16May2022 
 
 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (eg, US National Institutes of Health, Division of AIDS) and institutional 
policies. 
 
 
 
 
 
Principal Investigator: __________________________________________________ 
Print/Type 
 
 
 
 
 
Signed:  
 
___________________________________ Date: ________________ 
Name/Title 
 

 
 
REPRIEVE (A5332) 
 
 
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TABLE OF CONTENTS 
Page 
 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 11 
EXECUTIVE SUMMARY .......................................................................................................... 12 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 14 
1.1 
Clinical Hypotheses ........................................................................................... 14 
1.2 
Clinical Objectives .............................................................................................. 14 
2.0 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background ........................................................................................................ 15 
2.2 
Rationale ........................................................................................................... 27 
3.0 
STUDY DESIGN ........................................................................................................... 28 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 29 
4.1 
Inclusion Criteria ................................................................................................ 29 
4.2 
Exclusion Criteria ............................................................................................... 32 
4.3 
Study Enrollment Procedures............................................................................. 33 
4.4 
Mechanistic Substudy of REPRIEVE (A5333s) Enrollment Procedures ............. 34 
4.5 
Coenrollment Guidelines .................................................................................... 35 
4.6 
Retention Procedures ........................................................................................ 35 
5.0 
STUDY TREATMENT ................................................................................................... 35 
5.1 
Regimens, Administration, and Duration ............................................................ 35 
5.2 
Study Product Formulation and Preparation ....................................................... 36 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 36 
5.4 
Concomitant Medications ................................................................................... 37 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 39 
6.1 
Schedule of Evaluations..................................................................................... 39 
6.2 
Timing of Evaluations ......................................................................................... 45 
6.3 
Instructions for Evaluations and Data Collection ................................................ 46 
6.4 
Endpoint Assessments....................................................................................... 54 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 56 
7.1 
Toxicity Management ......................................................................................... 57 
7.2 
Requirement for Precautionary or Prohibited Medications (see PSWP) ............. 60 
7.3 
Pregnancy.......................................................................................................... 60 
7.4 
Unblinding Procedures ....................................................................................... 60 

 
 
REPRIEVE (A5332) 
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CONTENTS (Cont’d) 
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Page 
 
 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 61 
8.1 
Premature and Permanent Treatment Discontinuation ....................................... 61 
8.2 
Premature Study Discontinuation ....................................................................... 61 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 62 
9.1 
General Design Issues ....................................................................................... 62 
9.2 
Outcome Measures ............................................................................................ 63 
9.3 
Randomization and Stratification ........................................................................ 65 
9.4 
Sample Size and Accrual ................................................................................... 65 
9.5 
Monitoring .......................................................................................................... 70 
9.6 
Analyses ............................................................................................................ 73 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 77 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 78 
11.1 
Records to Be Kept ............................................................................................ 78 
11.2 
Role of Data Management ................................................................................. 78 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 78 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 78 
12.0 
PARTICIPANTS ............................................................................................................ 80 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 80 
12.2 
Participant Confidentiality ................................................................................... 80 
12.3 
Study Discontinuation ........................................................................................ 80 
12.4 
Women and Minorities ....................................................................................... 80 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 80 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 81 
15.0 
STUDY GOVERNANCE ................................................................................................ 81 
16.0 
REFERENCES .............................................................................................................. 82 
APPENDIX I: SAMPLE INFORMED CONSENT ....................................................................... 93 
APPENDIX IA: SAMPLE INFORMED CONSENT ADDENDUM............................................. 108 
APPENDIX II: THE MECHANISTIC SUBSTUDY OF REPRIEVE (A5333s) ........................... 111 
APPENDIX III:  SAMPLE INFORMED CONSENT .................................................................. 136 
APPENDIX IV: REPRIEVE OBJECTIVES TO DECIPHER SEX-SPECIFIC MECHANISMS OF 
CVD RISK AND RISK REDUCTION ............................................................................ 146 
APPENDIX V: REPRIEVE ANCILLARY STUDY: EFFECT OF PITAVASTATIN ON KIDNEY 
FUNCTION IN HIV-INFECTED PERSONS ................................................................. 153 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
REPRIEVE (A5332) is a multicenter study open to US clinical research sites and select 
international sites that have been approved for participation by the protocol team. Refer to the 
Site tab on the protocol-specific Web page on the ACTG Member website for the list of eligible 
sites. 

 
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PROTOCOL TEAM ROSTER  
 
Chair 
Steve Grinspoon, MD 
Metabolism Unit 
Harvard Medical School 
55 Fruit Street 
Longfellow 5, Room 207 
Boston, MA  02114 
Phone: 617-724-9109 
E-mail: sgrinspoon@partners.org 
 
Co-Chair 
Pamela Douglas, MD  
Duke University Medical Center 
7022 North Pavilion 
Durham, NC  27715 
Phone: 919-681-2690 
E-mail: pamela.douglas@duke.edu 
 
Vice Chairs 
Judith Aberg, MD 
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box 10190 
New York, NY  10029 
Phone: 212- 241-6741 
E-mail: Judith.aberg@mountsinai.org 
 
Carl Fichtenbaum, MD 
University of Cincinnati 
200 Eden Avenue, Room 3114  
Mail Location 405 
Cincinnati, OH  45267 
Phone: 513-584-6361  
E-mail: fichtecj@ucmail.uc.edu 
 
Carlos Malvestutto, MD, MPH 
Ohio State University Medical Center 
410 West 10th Avenue 
Columbus, OH  43205 
Phone: 614-366-5405 
E-mail: carlos.malvestutto@osumc.edu 
 
Vice Chairs (Cont’d) 
Markella V. Zanni, MD 
Metabolism Unit 
Harvard Medical School,  
55 Fruit Street, Longfellow 5, Room 209 
Boston, MA  02114  
Phone: 617-724-6926 
E-mail: mzanni@mgh.harvard.edu 
 
Vice-Chair and Co-Project Manager 
Kathleen V. Fitch, MSN 
Metabolism Unit 
Harvard Medical School 
55 Fruit Street 
Longfellow 5, Room 207 
Boston, MA 02114 
Phone: 617-724-8015 
E-mail: kfitch@mgh.harvard.edu 
 
Mechanistic Substudy  
Michael T. Lu, MD, MPH 
MGH Cardiovascular Imaging Research 
Center, Harvard Medical School 
165 Cambridge Street, Suite 400 
Boston, MA  02114 
Phone: 617-726-1255 
E-mail: mlu@mgh.harvard.edu 
 
DAIDS Medical Officer 
Christine Chiou, MD 
HIV Research Branch 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9F41 
Rockville, MD  20852 
Phone: 240-507-9611 
E-mail: cchiou@niaid.nih.gov  
 
NHLBI Program and Medical Officer 
Patrice M. Desvigne-Nickens, MD 
Heart Failure and Arrhythmias Branch 
DCS, NHLBI, NIH  
6705 Rockledge Drive, Room 312-B2 
Bethesda, MD  20817 
Phone: 301-435-0504 
E-mail: desvignp@nhlbi.nih.gov 

 
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Clinical Trials Specialists 
Laura E. Moran, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3373 
E-mail: laura.moran@dlhcorp.com 
 
Nada Saleh, MS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-0204 
E-mail: nada.saleh@dlhcorp.com 
 
Statisticians 
Amy Kantor  
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-7129 
E-mail: akantor@sdac.harvard.edu 
 
Jorge Tomas Leon-Cruz 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-7469 
E-mail: jleoncru@sdac.harvard.edu 
 
Heather Ribaudo, PhD 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-2897 
E-mail: ribaudo@sdac.harvard.edu 
 
Statisticians (Cont’d) 
Triin Umbleja, MSc 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 512A 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-0118 
E-mail: tumbleja@sdac.harvard.edu 
 
Project Manager 
Kayla Paradis, BA 
Cardiovascular Imaging Research Center 
Department of Radiology, Massachusetts 
General Hospital 
165 Cambridge Street, Suite 400  
Boston, MA 02114 
Phone: 978-870-4535 
E-mail: kparadis@mgh.harvard.edu 
 
Data Managers 
Mark Byroads 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7341 
E-mail: byroads@frontierscience.org 
 
Kenneth Wood, MA 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7235 
E-mail: wood@frontierscience.org 
 
DAIDS Pharmacist 
Oladapo Alli 
5601 Fishers Lane 
Room 9E18, MSC #9829 
Rockville, MD  20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov 
 

 
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Investigator 
Gerald Bloomfield, MD 
Associate Professor of Medicine 
Duke University School of Medicine 
200 Morris Street 
Durham, NC 27701 
Phone: 919-668-8702 
E-mail: gerald.bloomfield@duke.edu 
 
Field Representative 
Erin Elizabeth Hoffman, BS 
UNC AIDS CRS 
130 Mason Farm Road 
Chapel Hill, NC  27599 
Phone: 919-843-0720 
E-mail: Erin_Hoffman@med.unc.edu 
 
Laboratory Technologist 
Francoise Giguel 
Division of Infectious Diseases 
Partners AIDS Research Center 
Massachusetts General Hospital 
65 Landsdowne Street, Room 435 
Cambridge. MA  02139 
Phone: 617-768-8374 
E-mail: fgiguel@mgh.harvard.edu 
 
Community Scientific Subcommittee (CSS) 
Representatives 
Karl Shaw, BBA 
19140 Ohio Street 
Detroit, MI 48221 
Phone: 313-861-1979 
E-mail: kedshaw@hotmail.com  
 
Kate Starr, BS 
Ohio State University CRS 
6285 Rygate Drive 
Reynoldsburg, OH 43068 
Phone: 614-353-2944 
E-mail: borloglou@gmail.com 
 
International Program Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., A DLH 
Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3318 
E-mail: akbar.shahkolahi@dlhcorp.com 
 
Industry Representatives 
Kathy Melbourne, PharmD 
Gilead Sciences 
333 Lakeside Drive 
Foster City, CA 94404 
Phone: 401-261-7360 
E-mail: kathy.melbourne@gilead.com 
 
James Rooney, MD 
Gilead Sciences, 333 Lakeside Drive 
Foster City, CA  94404 
Phone: 650-522-5708 
E-mail: jim.rooney@gilead.com 
 
Craig Sponseller, MD 
Kowa Pharmaceuticals America, Inc. 
530 Industrial Park Boulevard 
Montgomery, AL  36117 
Phone: 334-288-1288 x127 
E-mail: csponseller@kowapharma.com 
 
Laboratory Data Managers 
Frederic Bone 
Frontier Science and Technology Research 
Foundation. 4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7306 
E-mail: bone@frontierscience.org 
 
David Vlieg 
Frontier Science and Technology 
Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7333 
Email: vlieg@frontierscience.org 

 
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STUDY MANAGEMENT 
 
This section provides important instructions on how to attempt to have questions about 
REPRIEVE (A5332) answered. Following these instructions will help you receive an answer as 
quickly as possible, generally within 24 hours. Sites are responsible for documenting phone 
calls made to team members. 
 
Protocol E-mail Group 
The protocol logon is the primary vehicle for distributing important information about the study to 
sites. It is the site’s responsibility to add all relevant personnel to this e-mail group as soon as 
possible. Contact actg.user.support@fstrf.org to be added to the “actg.protA5332” e-mail group 
and, for sites participating in the mechanistic substudy, to the “actg.prota5333s” substudy e-mail 
group.  
 
IND (Investigational New Drug) Number or Questions  
E-mail Regulatory@tech-res.com. 
 
To Request Study Product Package Inserts and/or Investigator Brochures 
E-mail RIC@tech-res.com. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 1+ 301-294-0741. 
 
Questions about Study Product, Dose, Supplies, Records, and Returns 
E-mail protocol pharmacist Oladapo Alli at PABREPRIEVEPEP@mail.nih.gov.  
 
Protocol Registration Questions 
E-mail Protocol@tech-res.com or call 1+ 301-897-1707.  
 
Participant Registration and Randomization Issues and Study Identification Number (SID) Lists 
E-mail rando.support@fstrf.org or call 1+ 716-834-0900 x7301.   
 
FSTRF Portal Problems and Data Management Questions 
• 
E-mail actg.support@fstrf.org or call 1+ 716-834-0900 x7302 (US sites) or 1+ 716-834-0900 
x7200 (non-US sites).  
• 
For nonclinical questions about randomization/registration, inclusion/exclusion criteria, 
OpenClinica, electronic case report forms (eCRFs), transfers, and other data management 
issues, e-mail reprieve.dmc@fstrf.org. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 1+ 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 

 
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Other Questions 
• 
For all other questions about REPRIEVE (A5332), e-mail actg.corea5332@fstrf.org.  
• 
For all questions about the Mechanistic Substudy A5333s, including coronary computed 
tomography angiography (CCTA), e-mail actg.corea5333s@fstrf.org. 
 
Protocol-Specific Web Page (PSWP) 
Additional information about protocol management can be found on these PSWPs: 
• 
A5332: https://member.mis.s-3.net/cms/study/53278/10260 
• 
A5333s: https://member.mis.s-3.net/cms/study/53279/10264 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ACC 
American College of Cardiology 
ACTG 
AIDS Clinical Trials Group 
AHA 
American Heart Association 
AMI 
acute myocardial infarction 
ART 
antiretroviral therapy 
ASCVD 
atherosclerotic cardiovascular disease 
CAD 
coronary artery disease 
CCTA 
coronary computed tomography angiography 
CEC 
Clinical Events Committee  
CKD 
chronic kidney disease 
CVD 
cardiovascular disease 
DAIDS 
Division of AIDS 
DM 
diabetes mellitus 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
EDC 
electronic data capture system 
FDG-PET 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
FIB-4 
Fibrosis 4 Score 
HDL 
high-density lipoprotein 
IVUS 
intravascular ultrasound 
LDL 
low-density lipoprotein 
MACE 
major adverse cardiovascular events 
NAC 
non-AIDS complications 
NCEP 
National Cholesterol Education Panel  
NHLBI 
National Heart, Lung, and Blood Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
PAB 
Pharmaceutical Affairs Branch (DAIDS) 
PAD 
peripheral arterial disease  
PSWP 
protocol-specific web page 
PWH 
people with HIV 
RCT 
randomized controlled trial 
SAP 
Statistical Analysis Plan 
TIA 
transient ischemic attack

 
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EXECUTIVE SUMMARY 
 
Title 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
Indication 
To study the efficacy of statins to reduce the risk of cardiovascular disease 
(CVD) in people with HIV (PWH). 
Location 
Multicenter trial conducted at US trial sites and select international sites 
Brief 
Rationale 
PWH face an increased risk of CVD morbidity and mortality, yet no preventive 
strategies for CVD risk reduction have been proven for this population. Among 
PWH, immune activation may contribute in unique ways to atherosclerosis and 
ensuing cardiovascular events. Statins affect both traditional CVD risk factors 
(LDL cholesterol) and have pleiotropic effects to reduce inflammation and 
immune activation. Thus, statins may target the unique mechanisms of 
cardiovascular disease in HIV. 
Study 
Design and 
Duration 
Prospective, double-blind, randomized, placebo-controlled, multicenter efficacy 
study in 6500 participants, with individual participants to be followed for up to 72 
months. The sample size was increased to approximately 7500 participants with 
follow-up for up to 84 months per the December 2017 Data and Safety 
Monitoring Board (DSMB) recommendations. Follow-up was further increased to 
96 months, which was endorsed at the December 2018 DSMB meeting. Follow-
up is now planned to continue, up to Month 120, until the study reaches its 
target of 288 primary MACE endpoints or is otherwise recommended for 
closure by the DSMB. 
Treatment 
Pitavastatin 4 mg PO daily or placebo for pitavastatin. 
Primary 
Objective 
To determine the effects of pitavastatin as a primary prevention strategy for major 
adverse cardiovascular events (MACE) in HIV. 
Key 
Secondary 
Objectives 
1. The effects of pitavastatin on the components of MACE and all-cause 
mortality. 
2. The effects of pitavastatin on LDL and non-HDL in relationship to MACE. 
3. Whether baseline traditional risk factors and time updated HIV-specific 
immunological risk factors are predictive of MACE and pitavastatin effects on 
MACE. 
4. The effects of pitavastatin on the incidence of serious non-CVD events.  
5. The safety of pitavastatin in the HIV population. 
Ancillary 
Objectives 
1. To assess the influence of sex/reproductive aging status on immune 
activation and statin induced immunomodulation in relation to clinical CVD 
events. 
2. To determine the effects of pitavastatin on the incidence of changes in kidney 
function. 
Primary 
Endpoint 
Major adverse cardiovascular events (MACE) 
Secondary 
and Safety 
Endpoints  
Primary components of MACE, all-cause mortality, LDL cholesterol, immune 
function, non-CVD events (malignancy, end stage liver and kidney disease, 
AIDS-defining events), and safety endpoints, including diabetes mellitus 

 
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Abbreviated 
Study Flow 
 

 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Clinical Hypotheses  
 
1.1.1 Primary Clinical Hypothesis 
 
Statin therapy will prevent atherosclerotic cardiovascular disease (ASCVD)-
related MACE (major adverse cardiovascular events) in PWH on antiretroviral 
therapy (ART) in whom traditional cardiovascular disease (CVD) risk is not 
significantly increased.  
 
1.1.2 Secondary Clinical Hypotheses 
 
1.1.2.1 Statin therapy will be associated with reductions in specific CVD-related 
events and all-cause mortality. 
 
1.1.2.2 Decreases in LDL and non-HDL cholesterol levels associated with statin 
therapy will be predictive of reduction in CVD events. 
 
1.1.2.3 Statin therapy will reduce serious non-cardiovascular events, including 
malignancies, end stage kidney or liver disease.   
 
1.1.2.4 Statin therapy will be safe and well tolerated in PWH. 
 
1.2 
Clinical Objectives 
 
1.2.1 Primary Clinical Objective 
 
To determine the effects of pitavastatin as a primary prevention strategy for 
MACE in HIV. 
 
1.2.2 Secondary Clinical Objectives  
 
1.2.2.1 To evaluate the effects of pitavastatin on each of the components of the 
primary composite MACE endpoint and all-cause mortality. 
 
1.2.2.2 To determine the effects of pitavastatin on LDL and non-HDL 
cholesterol in the HIV population and assess the relationship of changes 
in LDL and non-HDL to the incidence of MACE. 
 
1.2.2.3 To evaluate whether baseline traditional risk factors (including smoking, 
hypertension, dyslipidemia, glucose) and time updated HIV-specific 
(immunological and virological) risk factors are predictive of MACE and 
pitavastatin effects on MACE in the HIV population. 
 

 
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1.2.2.4 To evaluate whether baseline and time updated inflammatory and 
immune activation biomarkers are predictive of MACE and pitavastatin 
effects on MACE in the HIV population.  
 
1.2.2.5 To determine the effects of pitavastatin on the incidence of serious non-
cardiovascular events and AIDS-defining events.  
 
1.2.2.6 To determine the safety of pitavastatin in the HIV population, including 
the development of diabetes mellitus (DM), liver dysfunction, and 
myopathy. 
 
1.2.2.7 To collect blood to enable the evaluation of the relationship of host 
genetics to study endpoints in subsequent ancillary studies. 
 
1.2.2.8 Characterize the epidemiology and pathobiology of SARS-CoV-2 
infection, particularly with respect to CVD, among individuals 
aging with HIV globally. 
 
1.2.2.9 Identify which host factors influence risk with respect to SARS-
CoV-2 infection and COVID-19-related CVD outcomes. 
 
1.2.2.10 Determine whether statin therapy protects against SARS-CoV-2 
infection and/or mitigates the severity of COVID-19-related CVD 
complications. 
 
1.2.3 Ancillary Objectives 
 
1.2.3.1 To assess the influence of sex/reproductive aging status on immune 
activation and statin induced immunomodulation in relation to clinical 
CVD events.  
 
1.2.3.2 To determine the effects of pitavastatin on the incidence of changes in 
kidney function.  
 
2.0 
INTRODUCTION 
 
2.1 
Background  
 
Over 34 million people worldwide, including 1.7 million people in the US, are chronically 
infected with HIV-1 [WHO 2012]. Due to the remarkable success of ART, PWH are now 
living longer [Lewden 2007]. By the year 2015, greater than half of the population living 
with HIV in the US is expected to be 50 or older [WHO 2012; Greene 2013]. Yet, even 
while ART has reduced AIDS-related deaths [Palella 2006], CVD and CVD-related 
deaths have increased in PWH, who have 1.5-2 times increased risk compared with 
HIV-negative individuals [Antiretroviral Therapy Cohort Collaboration 2010; Data 
Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group 2010; Sackoff 

 
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2006]. Currently, there are no treatment strategies proven to prevent CVD in PWH, 
despite the higher risk. A State of the Science Conference on CVD in HIV sponsored by 
the American Heart Association (AHA) highlighted the critical need to test preventive 
therapies for CVD in HIV and to develop HIV-specific guidelines [Grinspoon 2008]. 
Experts agree that existing strategies for CVD prevention in the general population are 
likely inadequate with increasing evidence suggesting HIV-associated immune activation 
accelerates the process of atherosclerosis and atherothrombosis [Hsue 2012; Zanni 
2012] such that relatively young PWH with modest traditional CVD risk factor scores still 
face high CVD risk. Most of these patients would not meet current guidelines for 
preventive CVD therapies. The imperative to identify a safe and efficacious strategy for 
CVD prevention in HIV is best met by a randomized controlled trial (RCT) of an 
intervention addressing both traditional and immune CVD risk factors.  
 
2.1.1 Increased Risk of CVD in HIV  
 
CVD-related deaths—including sudden cardiac death—are increased in PWH 
compared with people without HIV [Antiretroviral Therapy Cohort 
Collaboration 2010; Tseng 2012]. With respect to acute myocardial infarction 
(AMI), the most common cause of CVD-related deaths, studies show a 1.5- to 2-
fold increased relative risk of this in PWH versus people without HIV [Currier 
2003; Durand 2011; Freiberg 2013; Klein 2002; Lang 2010; Obel 2007; Triant 
2007]. Controlling for traditional CVD risk factors does not fully mitigate the 
heightened CVD risk among PWH [Freiberg 2013; Triant 2007], suggesting a 
unique pathobiology of atherosclerosis in HIV and highlighting the need for an 
effective, tailored primary CVD prevention strategy. 
 
2.1.2 Unique Biology of CVD in HIV  
 
2.1.2.1 Inadequate Explanation of CVD Risk in HIV by Traditional CVD Risk 
Factors  
 
Early studies of CVD in HIV suggested that heightened risk stemmed, 
indirectly, from an effect of ART to exacerbate traditional CVD risk 
factors (eg, diabetes, hypertension, dyslipidemia, and abdominal fat 
accumulation). For example, in the Data Collection on Adverse Events 
of Anti-HIV Drugs (D:A:D) study, use of protease inhibitors was 
associated with increased AMI risk, and this risk was partially attenuated 
after controlling for dyslipidemia [Friis-Moller 2003]. In contrast, recent 
studies demonstrate no independent association of ART with AMI and 
indicate that higher rates of AMI persist with HIV infection despite 
controlling for traditional CVD risk factors [Freiberg 2013; Triant 2007]. 
In large epidemiologic studies, immune dysfunction (low CD4 count) and 
degree of viremia have been identified as important independent 
contributors to CVD risk in HIV [Triant 2010]. Moreover, data from the 
Strategies for Management of Antiretroviral Therapy (SMART) study 
suggest a protective effect of continuous and intensive ART on CVD 

 
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risk: In the SMART study, patients were randomized to continuous ART 
or to an ART conservation strategy based on a CD4-guided algorithm. 
CVD occurred 60% more often in the drug conservation group, 
highlighting a benefit from more continuous and suppressive ART 
[Strategies for Management of Antiretroviral Therapy (SMART) 
Study Group 2006]. Subsequent studies from the SMART group have 
focused on specific markers of inflammation and coagulation that are 
significantly increased with drug conservation, related to viremia, and 
independently associated with increased CVD rates [Kuller 2008]. Work 
from the SMART group thus reinforces the principle that chronic viral 
infections and the subsequent immune response contribute to CVD, 
independently of traditional risk pathways highlighting the need to 
consider a possible role for an immune modulating strategy to prevent 
CVD.  
 
2.1.2.2 Relationship between HIV-Associated Systemic Immune Activation and 
CVD Risk 
 
HIV infection induces a paradoxical state of both immune suppression 
(low CD4 count and increased risk of opportunistic diseases) and 
immune activation [Deeks 2011]. A paucity of CD4+ T regulatory cells in 
the gut mucosa enables heightened microbial translocation and ensuing 
activation of both the innate and adaptive arms of the immune system 
[Brenchley 2006]. Concomitantly, depletion of circulating CD4+ T 
regulatory cells, coupled with opportunistic co-infection (hepatitis, 
cytomegalovirus), results in further immune activation. The net result, in 
PWH, is persistent activation of circulating monocytes and T-cell 
subsets [Deeks 2011]. Such chronic immune activation translates into 
an exhausted T-cell phenotype and a pro-inflammatory milieu that is 
manifest by higher circulating levels of soluble inflammatory and 
immune activation markers in PWH versus HIV-negative controls. 
Elevated inflammatory and immune activation biomarkers in PWH 
include pro-inflammatory cytokines (eg, IL-6), acute phase proteins (eg, 
CRP), leukocyte adhesion molecules (eg, sICAM-1), and fibrin 
degradation products (eg, d-dimer) [Dolan 2005; Ross 1999; Ross 
2008]. 
 
Immune activation in HIV is highly relevant to atherosclerosis [Hsue 
2012; Zanni 2012]—an inflammatory disease [Libby 2002] resulting in 
AMI and sudden cardiac death. Atherosclerosis as a process features 
an intricate interplay between activated immune cells―particularly 
monocytes―and vascular endothelial cells [Hulten 2009; Koenen 2010; 
Libby 2002; Libby 2011; Packard 2009]: Circulating monocytes target 
the tunica intima of affected coronary arteries in response to 
chemokines and adhesion molecules produced by activated endothelial 
cells. There, monocytes transform to macrophages and then, upon 

 
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internalization of oxidized LDL, to foam cells which form the lipid core of 
the developing atheroma. Plaque macrophages, along with resident T 
cells, also secrete cytokines and matrix metalloproteinases, which can 
degrade the fibrous cap overlying an atheroma, thus precipitating 
plaque rupture/AMI [Hulten 2009; Koenen 2010; Libby 2002; Libby 
2011; Packard 2009]. With HIV infection―a state of persistently 
activated circulating monocytes and T cells and increased circulating 
levels of pro-inflammatory cytokines―all stages of atherogenesis and 
atherothrombosis are likely exacerbated. 
 
2.1.2.3 Novel Atherosclerotic Phenotype in HIV  
 
Initial studies to radiographically characterize subclinical atherosclerosis 
in HIV focused on carotid intima media thickness (cIMT) [Hulten 2009], 
which has been found in this population to relate largely to traditional 
CVD risk factors and not to inflammatory indices [Stein 2013]. In contrast, 
studies employing coronary computed tomography angiography (CCTA) 
and cardiac fluorodeoxyglucose-positron emission tomography (FDG-
PET) have shown PWH to have 1) predominantly non-calcified coronary 
atherosclerotic plaque [Burdo 2011], 2) a higher prevalence of high-risk 
morphology features (including low attenuation and positive remodeling) 
[Zanni 2013], and 3) vascular inflammation reflected in clustering of 
glucose-avid macrophages in the subendothelial matrix [Subramanian 
2012; Yarasheski 2012]. The clinical relevance of these observations is 
that inflamed vulnerable plaque which has yet to calcify is more prone to 
rupture, resulting in AMI [Hou 2012; Kitagawa 2009; Rominger 2009]. Of 
note, in PWH, non-calcified, vulnerable, and inflamed coronary 
atherosclerotic plaque has been found to relate to specific markers of 
monocyte activation, including soluble CD163, and has been observed 
even in those ART-treated PWH with low traditional CVD risk factors 
[Burdo 2011; Subramanian 2012; Zanni 2013]. 
 
2.1.3 Rationale for Statin Therapy to Prevent Primary CVD in HIV 
 
An ideal intervention to prevent CVD in HIV would affect both conventional lipid 
and HIV-specific immune mediators of CVD and would have minimal risk. Statin 
therapy uniquely meets these criteria. 
 
2.1.3.1 LDL, Immunomodulatory, and Plaque Stabilizing Effects of Statins  
 
Statins, which address both conventional and inflammatory mechanisms 
for atherosclerosis, may have unique utility for primary CVD prevention 
in HIV. In the general population, statins have long been known to 
potently reduce LDL cholesterol and to prevent CVD events [Downs 
1998; Sacks 1996; Scandinavian Simvastatin Survival Study (4S) 
1994; Shepherd 1995]. In addition, statins are known to have pleiotropic 

 
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anti-inflammatory and immunomodulatory characteristics, which may 
also contribute to cardio-protective effects [Greenwood 2007]. Indeed, in 
vitro, animal, and human studies have shown that statins decrease 
monocyte activation - reflected in a) decreased monocyte chemotaxis 
and endothelial adhesion [Fujino 2006; Han 2005; Montecucco 2009], b) 
reduced monocyte uptake of oxidized LDL cholesterol [Han 2004], and 
c) decreased monocyte secretion of cytokines/chemokines and matrix 
metalloproteinases [Guo 2009; Waehre 2003]. Moreover, statins 
decrease T-cell activation [Bu 2010; Kwak 2000; Singh 2009] while 
recruiting regulatory T cells [Mira 2008], suppress endothelial cell 
activation [Mulhaupt 2003; Romano 2000; Veillard 2006; Zheng 2013; 
Zineh 2006], and decrease lipid oxidation [Aviram 1992; Giroux 1993; 
Vasankari 2001]. Further, data from cardiovascular imaging studies in 
HIV-negative participants reveal that statins stabilize vulnerable 
coronary atherosclerotic plaque and even induce plaque regression. 
Specifically, statins have been shown to decrease atherosclerotic 
plaque vulnerability features on CCTA and intravascular ultrasound 
(IVUS) [Inoue 2010; Kodama 2010; Nakamura 2008; Shimojima 2012], 
to reduce atherosclerotic plaque inflammation on cardiac FDG-PET 
[Tawakol 2013], and to reduce non-calcified plaque volume [Burgstahler 
2007; Hiro 2009]. Based on these data, statins may be uniquely tailored 
to address important mechanisms of CVD in HIV. 
 
2.1.3.2 Statin Effects on Non-CVD Events in HIV 
 
Due to the efficacy and widespread use of potent combination ART, 
mortality patterns among HIV patients have changed, with a decline in 
the proportion due to AIDS and a concomitant rise in the proportion due 
to non-AIDS-related diseases [ARTCC 2010; DAD 2010; French 2009; 
Lewden 2008; Marin 2009; Neuhaus 2010; Palella 2006; Wada 2013; 
Weber 2013]. In this regard, cardiovascular, end-stage liver and renal 
disease, and non-AIDS-related malignancies represent important 
causes of mortality among HIV patients in the current era of potent ART. 
Based on animal models and in-vitro and in-vivo data that statins may 
decrease the systemic inflammation that has been associated with many 
of these events, and epidemiologic data suggesting statins alter the risk 
of these events, including these key comorbidities in a secondary 
endpoint analysis of REPRIEVE (A5332) is warranted. 
 
Beyond an excellent safety record in persons with liver disease, current 
data suggest that statins may improve various aspects of liver disease. 
In animal models of non-alcoholic fatty liver disease, several different 
statins, including pitavastatin, have improved hepatic steatosis and 
decreased fibrosis mediated by anti-inflammatory and antifibrotic effects 
[Hyogo 2012; Miyaki 2011; Tarantino 2012; Wang 2013]. Human trials 

 
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have demonstrated similar improvements in steatosis and liver fibrosis 
[Ekstedt 2007; Foster 2011; Gomez-Dominguez 2006; Simon 2015]. 
 
Statins appear to have a beneficial effect on kidney function, particularly 
among persons with pre-existing microalbuminuria, a common finding 
among PWH [Amarenco 2014; Colhoun 2009]. Meta-analyses have 
demonstrated either a modest benefit or uncertain effects of statins on 
renal function [Douglas 2006; Nikolic 2013; Palmer 2014]. The limited 
data in HIV patients indicated improvement in renal function with 
rosuvastatin that correlated with reductions in inflammatory biomarkers 
and T-cell activation [Longenecker 2014]. 
 
HIV infection remains associated with an increased risk of cancer 
[Crum-Cianflone 2009; Deeken 2012]. While there are numerous factors 
that contribute to the excess risk of cancer, persistent inflammation and 
alterations in the immune system, particularly altering normal tumor 
surveillance, are considered key contributors to the excess risk, even in 
the setting of viral suppression and partial immunologic reconstitution 
experienced with ART [Borges 2014; Tenorio 2014]. Statins have been 
demonstrated to have anticancer activity which have been related to 
consequences of blocking the mevalonate pathway, including arresting 
cell cycle progression, inducing apoptosis, reducing oxidative stress, 
and decreasing systemic inflammation [Carlberg 1996; Wong 2002; 
Yasui 2007]. While the data from observational studies and post-hoc 
analyses for cancers in the general population have failed to 
consistently demonstrate an anticancer effect for statins, data from 
studies including PWH, while limited, suggest potential anticancer 
effects of statins due to the fact that persistent inflammation is likely an 
important driver [Galli 2014; Overton 2013]. 
 
Despite a declining incidence, AIDS events continue to occur and 
remain the leading cause of death among PWH. Clearly, advanced 
immunosuppression and a maladaptive inflammatory response, both 
related to uncontrolled HIV infection, are important drivers of the 
underlying mechanisms of AIDS events. While there are limited data 
regarding the impact of statins on the risk of developing AIDS events, 
the effects of statins on markers of both cellular and soluble markers of 
inflammation indicate that there may be benefit to assess the effect of 
statins on AIDS events, in conjunction with end stage renal and liver 
disease, as well as cancers in REPRIEVE (A5332). These data are 
critical to obtain in order to understand the potential overall impact of 
statins on PWH. 
 

 
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2.1.3.3 Efficacy of Statin Therapy in HIV 
 
In PWH, statins safely and effectively lower LDL cholesterol [Calza 
2012; Ganesan 2011; Silverberg 2009]. and also exert 
immunomodulatory effects to 1) decrease monocyte activation - 
reflected in decreased circulating levels of sCD14 and the macrophage-
derived phospholipase, Lp-PLA2 [Eckard 2014; Funderburg 2014, 2015] 
and 2) decrease T-cell activation in some studies [De Wit 2011; 
Ganesan 2011]. Statins are generally well tolerated among PWH and 
introduce minimal risks balanced against their significant potential to 
prevent CVD in this population [Singh 2011]. In a large cohort study, 
Silverberg et al. demonstrated that statins can be safely administered to 
PWH. Increased relative rates of grade III myositis (1.9% vs. 0.5%) and 
liver function test (LFT) abnormalities (1.1% vs. 0.3%) were seen in 
PWH versus control participants, but absolute rates were low [Silverberg 
2009]. With respect to the potential to induce DM development with 
statin use in PWH, non-randomized cohort studies recently reported 
contrasting results, with one study showing increased DM risk 
[Lichtenstein 2015] and two others suggesting no increased risk 
[Overton 2013; Spagnuolo 2017]. Unlike other agents with immune 
suppressant effects [Paton 2012], statins have not been shown to have 
adverse effects on viral replication [Moncunill 2005; Negredo 2006]. 
Indeed, in vitro studies suggest numerous mechanisms through which 
statins may actually reduce viral replication although clinical data 
suggests little impact on measured changes in plasma HIV viral loads 
while on statin therapy [Amet 2008; del Real 2004; Giguere 2004; 
Gilbert 2005; Nabatov 2007]. 
 
2.1.3.4 Selection of Pitavastatin 
 
Several statins are currently FDA approved and commercially available, 
with a limited number available in generic form; however, the use of 
select statins in PWH is complicated by, or in some cases 
contraindicated based on, complex interactions with antiretroviral agents 
[Aberg 2017; Ahmed 2012; Eckard 2014; Funderburg 2014, 2015]. Most 
statins are primarily metabolized by the CYP3A4 system. HIV protease 
inhibitors inhibit CYP3A4 and thus markedly increase exposure to these 
statins, as reflected in the area under the plasma drug concentration-
time curve (AUC) [Chauvin 2013]. As such, simvastatin and lovastatin 
are contraindicated in PWH taking protease inhibitors. Atorvastatin is 
partially metabolized by the CYP3A4 system, and the exposure to this 
statin is moderately increased by protease inhibitor therapy. Pravastatin 
exposure may be decreased by co-administration with ritonavir, but 
increased with co-administration with ritonavir-boosted darunavir. 
Similarly, rosuvastatin exposure is increased by co-administration with 
ritonavir-boosted darunavir [Samineni 2012]. In contrast, no clinically 

 
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significant effects of darunavir or lopinavir/ritonavir on pitavastatin were 
seen [Aberg 2017; Eckard 2014; Funderburg 2014, 2015; Malvestutto 
2014]. Other effects are also seen, for example between efavirenz, a 
widely prescribed ART, on the AUC of various common statins, 
including atorvastatin (-43% AUC), pravastatin (-40% AUC), and 
simvastatin (-58% AUC) [Gerber 2005], in contrast there was only an 
11% change in pitavastatin AUC with efavirenz [Malvestutto 2014]. 
 
Pitavastatin is a relatively new statin with comparable efficacy in terms 
of LDL reduction and anti-inflammatory effects as other potent statins 
[Eriksson 2011a]. It is an excellent choice for PWH as it is not 
metabolized by the CYP3A4 system but is instead metabolized primarily 
by glucuronidation [Gotto 2010]. Consequently, there are minimal 
documented interactions between pitavastatin and antiretroviral agents, 
including minimal effects of pitavastatin on exposure to ritonavir (+8% 
AUC), darunavir (+3% AUC), atazanavir (+6% AUC), lopinavir (-9% 
AUC) [FDA package insert]. Similarly, relatively modest effects of 
individual antiretroviral drugs are seen with respect to pitavastatin AUC 
[FDA package insert]. Indeed, there is no contraindication or 
recommendation for dose adjustment when pitavastatin is used in 
concert with any specific antiretroviral agent. Importantly, pitavastatin 4 
mg/day has been shown to effectively decrease LDL cholesterol among 
ART-treated PWH: the INTREPID study randomized PWH to 
pitavastatin 4 mg/day versus pravastatin 40 mg/day [Aberg 2017]. 
Results demonstrated that pitavastatin was superior to pravastatin with 
respect to LDL cholesterol lowering (-49.4 mg/dL (-31.1%) vs. -33.6 
mg/dl (-20.9%)) over a 12-week period with results sustained over 52 
weeks [Aberg 2017]. Moreover, relative to pravastatin, pitavastatin 
showed significantly greater ability to lower total cholesterol, non-HDL 
cholesterol, TC:HDL ratio, and Apo B lipoprotein levels. Tolerability and 
toxicity profiles were similarly benign for both agents: myalgias and LFT 
abnormalities were rare in both groups; no effects on HIV RNA or CD4 
were seen. Of note, pitavastatin, like pravastatin, had a neutral effect on 
blood glucose and HgbA1c levels in PWH [Aberg 2017]. Pitavastatin 
has compared favorably to other statins in randomized trials among 
people without HIV as well [Eriksson 2011a; Eriksson 2011b; 
Gumprecht 2011; Maruyama 2011]. Additionally, pitavastatin has 
demonstrated little impact on glucose metabolism and may even 
improve insulin resistance, an additional benefit when compared with 
other statins [Aberg 2017; Eckard 2014; Funderburg 2014, 2015; 
Teramoto 2010; Yamakawa 2008; Yokote 2009]. 
 
2.1.4 Opportune Timing for Randomized Control Trial of Statin Therapy in HIV  
 
The JUPITER trial demonstrated that among individuals in the general population 
with LDL cholesterol <130 mg/dL and moderate inflammation (defined as high 

 
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sensitivity C-reactive protein >2 mg/L), statin therapy resulted in a 44% reduction 
in CVD events [Ridker 2008]. To date, there are no large scale randomized trials 
of statin therapy to prevent CVD among PWH. Non-randomized studies in PWH 
demonstrate that use of statins is associated with reduced overall mortality 
[Moore 2011], especially among those diagnosed with co-morbidities 
[Rasmussen 2013]. Moore et al. showed that statin use was associated with a 
with a three-fold reduction in hazard ratio for all-cause mortality among PWH, 
adjusting for age, CD4, HIV-1 RNA, cholesterol levels, and prior ART use [Moore 
2011]. Observational studies also show a trend toward reduction in non-AIDS 
complications among ART-treated PWH on high potency statins [Drechsler 
2017]. 
 
Despite the potential appeal of statins, their use is relatively low in PWH―19.6% 
in a 2013 survey commissioned from the ACTG. Another recent analysis 
reported significant clinical inertia for the utilization of statin therapy in well 
controlled people living with HIV highlighting that both patient and provider 
factors weigh into the decision whether to utilize statins [Willig 2008]. The low 
use of statins in PWH reflects in part the relatively low prevalence of increased 
LDL cholesterol in this group [Freiberg 2013], but more importantly, the uncertain 
efficacy for CVD prevention and the potential side effects and ART interactions. 
These factors suggest equipoise and opportune timing for a large randomized 
trial to assess efficacy and safety of a statin therapy strategy for primary CVD 
prevention in HIV among those not meeting recommendations for statins under 
the 2013 American College of Cardiology/American Heart Association 
(ACC/AHA) guidelines.  
 
In 2013, the ACC/AHA released Blood Cholesterol Guidelines to replace the 
guidelines from the Third Report of the Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 
Novel aspects of the guidelines included 1) delineation of four statin benefit 
groups—patients age ≥21 with clinical ASCVD and/or with LDL cholesterol ≥190 
mg/dL and patients age ≥40 and ≤75 with diabetes and/or with 10-year ASCVD 
risk estimated to be ≥7.5% by the Pooled Cohort Equations and 2) abandonment 
of LDL cholesterol and non-HDL cholesterol treatment goals. In addition, the new 
guidelines deemphasized the use of non-statin lipid lowering therapies and 
focused exclusively on the use of statins for primary CVD prevention [Stone 
2014]. In this regard, pitavastatin is included as a recommended therapy in the 
new guidelines for primary prevention. Although these guidelines are now 
recommended for general use in clinical practice, they do not incorporate into risk 
prediction novel HIV-specific factors, including degree of systemic immune 
activation. REPRIEVE (A5332) provides a critical opportunity, in line with the 
hypothesis of the grant, to test whether patients without significant traditional risk, 
eg, those with ASCVD scores <7.5%, are an appropriate group for statin primary 
prevention. The currently proposed trial achieves equipoise by testing the 
efficacy and safety of statin therapy for primary CVD prevention in HIV among 
those not meeting recommendations for statins under the 2013 ACC/AHA 

 
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guidelines and speaks directly to critical knowledge gaps identified by the 
recently published ACC/AHA guidelines for cholesterol management and the 
AHA sponsored State of the Science Conference on CVD in HIV. In alignment 
with these guidelines, individuals aged 40-75 will be recruited for REPRIEVE 
(A5332). In order to be fully aligned with the 2013 ACC/AHA Guidelines, persons 
with diabetes and LDL <70mg/dL or ASCVD risk score ≥7.5% and LDL 
<70mg/dL are not recommended to initiate statins, thus these two groups will be 
included in the study. 
 
Although we do not anticipate a change in the guidelines occurring during the 
REPRIEVE (A5332) study, we will address any future changes in the guidelines 
by obtaining Data and Safety Monitoring Board (DSMB) review to determine 
whether equipoise has been disturbed and whether any changes to the study 
should be made as a result, updating the informed consent documents to inform 
participants about the change, and providing participants with a letter describing 
the new guidelines to take to their personal physicians to determine whether they 
should continue to participate in the study in light of the change. 
 
2.1.5 Rationale for the Change in 10-Year ASCVD Risk Score  
 
Following the launch of REPRIEVE (A5332), the team found that a number of 
candidates were being excluded from the trial in the moderate risk category with 
an ASCVD risk score ≤10%. These individuals were not otherwise being offered 
statins clinically, and equipoise exists for their entry into this randomized, 
placebo-controlled trial. Moreover, it was noted by the team that certain 
demographic and risk factor groups were being excluded from the trial 
disproportionately based on higher ASCVD risk scores, despite relatively low 
LDL cholesterol levels. For example, black/African American men and smokers 
were often excluded at very young ages, despite uncertainty about the efficacy of 
statins among HIV+ individuals with such risk factors. The exclusion from the 
study of certain demographic groups overrepresented in the US HIV epidemic 
reduces the generalizability of the study and precludes from study a large 
number of individuals with moderate risk for whom the question of statin use for 
primary CVD prevention was critical.  
 
During a DSMB meeting on June 8, 2015, the REPRIEVE (A5332) team leadership 
reported these findings and proposed a change in the ASCVD risk score entry 
criteria in order to improve the generalizability of the study results and the 
enrollment of participants for whom statins are not generally offered. The DSMB 
agreed with the study team’s assessment and proposal to raise the upper bound 
for the enrollment ASCVD risk score from <7.5% to ≤10%, if those individuals 
between 7.5% and 10% had an LDL <160 mg/dL. The rationale for having a lower 
threshold for the LDL cholesterol for persons with an ASCVD risk score between 
7.5% and 10% was to focus study enrollment on those persons with low or 
moderate risk who were unlikely to be prescribed statin therapy. The comments 
from the DSMB affirm their agreement with this assessment and proposal and 

 
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noted: “1) there are no trial data validating the ASCVD risk prediction equations in 
PWH; 2) there are no definitive data for PWH with ASCVD risk scores of 7.5%-10% 
regarding the use of statins; 3) the use of statins in this group is not mandated by 
clinical experience or guidelines, allowing for the necessary equipoise for inclusion 
of this group in REPRIEVE (A5332); 4) the consent should ensure the opportunity 
for an informed discussion between patients and providers with ASCVD risk scores 
between 7.5%-10% and patients/providers could elect not to pursue the trial; and 
5) raising the ASCVD risk score might permit enrollment of study populations, 
including smokers and minority patients, that would be more representative of the 
actual HIV population in the United States.” The DSMB further agreed that the 
2013 guidelines were designed to encourage a discussion of the relative risk and 
benefits of statins for persons with an ASCVD risk score between 7.5%-15% 
(considered the moderate risk category), and that prescription of statins was not 
mandatory in this group, especially in the case of PWH for whom there were no 
trial data. Furthermore, the requirement to limit trial participants in the range of 
7.5%-10% ASCVD risk category to those with an LDL cholesterol <160 mg/dL 
would help to ensure that those with relatively higher ASCVD risk and elevated 
LDL levels were not enrolled into the trial. This level of LDL cholesterol was 
selected based on the recently updated National Lipid Association 
Recommendations that suggest consideration for initiating statin therapy for 
moderate risk individuals (ie, risk score <15%) [Jacobson 2014]. 
 
During a DSMB meeting on June 24, 2016, the REPRIEVE (A5332) team 
proposed a further change in the 10-year ASCVD risk score entry criteria after 
finding that a partial increase in the risk score cutoff from 7.5% to 10% only slightly 
increased the median risk of the study population. Approximately 6 months after 
the change, the median risk remained low at 3.6%. Moreover, persons of black 
race tended to be disproportionately excluded as the scoring is weighted such that, 
for this racial group, the ASCVD risk score is higher for a given set of parameters. 
The net result of the use of the score at the current level has been: 
• 
Enrollment of a low-risk population with fewer black participants and smokers 
than would be representative of the relevant at-risk population. 
• 
Enrollment of a non-representative, low-risk population for whom prevention 
is less relevant.  
• 
An adverse impact on enrollment and perhaps a reduction in event rates to a 
level that was not envisioned.  
 
REPRIEVE (A5332) is the first prospective study to assess the accuracy of the 
ASCVD scoring system in HIV+ individuals, but will be limited in its utility if participants 
are clustered at the very low end of this risk scale. Moreover, the 2013 ACC/AHA 
Prevention Guidelines are designed to assess 10-year and lifetime risk, and it is not 
yet known how well it will predict rates over 3 to 5 years in a trial. To rectify this 
situation, the team proposed, and the DSMB approved, an increase in the threshold for 
exclusion from ≤10% to ≤15%, requiring an LDL <130 mg/dL for those with a risk score 
>10% and ≤15%. Recent data [Nayor 2016] highlight the uncertainty of the correct 

 
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threshold for statin initiation to be used with the ASCVD criteria, and this change is in 
line with the recommendation of at least one major guideline, from Canada.  
 
In alignment with the guidelines, this change in the risk score threshold will 
facilitate enrollment of the intended population of intermediate risk participants for 
whom uncertainty and equipoise exist, and will permit a more generalizable and 
relevant study population, representative of the at-risk HIV population. Enrollment 
of participants with a broader range of scores will also better permit REPRIEVE 
(A5332) to assess the relative utility of the ASCVD score in the HIV population, 
leveraging the study for a critical purpose. The graded LDL requirement will 
further ensure equipoise, and will help to prevent any significant crossover rate. 
 
2.1.6 Rationale for the Enrollment Cap for 10-Year ASCVD Risk Score <2.5% 
 
Based on recommendations of the REPRIEVE (A5332) DSMB following their 
December 2017 review, the REPRIEVE team has capped enrollment of persons 
with a very low cardiovascular risk (10-year ASCVD risk score <2.5%) at 
approximately 2000 participants to ensure that final study population reflects the 
targeted low-to-moderate-risk population that the study is intending to enroll. 
Despite the previous expansion of the upper bound of the allowable entry criteria 
to allow enrollment of persons with 10-year ASCVD risk score ≤15%, the DSMB 
noted that median ASCVD risk score for the entire cohort remained low at 3.4% 
with approximately 2000 participants with a 10-year ASCVD risk score <2.5%. 
 
The cessation of enrollment of persons with very low 10-year ASCVD score will 
ensure that the study enrolls a study cohort that is more reflective of the entire 
HIV population at risk for ASCVD and ensures that the study maintains adequate 
power to determine the efficacy of pitavastatin for primary ASCVD prevention in 
the setting of HIV infection over a broad range of scenarios for the rate of events 
of interest. 
 
2.1.7 Rationale for the Enrollment Cap for 10-Year ASCVD Risk Score <5% 
 
Based on a recommendation from the National Institutes of Health (NIH) (the 
National Heart, Lung, and Blood Institute [NHLBI] and the Division of AIDS 
[DAIDS] at the National Institute of Allergy and Infectious Diseases [NIAID]) in 
April 2018, the REPRIEVE team is capping enrollment of persons with low 
cardiovascular risk (10-year ASCVD risk score <5%) at approximately 4200 
participants to ensure that the final study population reflects the targeted low-to-
moderate-risk population. 
 
2.1.8 Rationale for the Study of SARS-CoV-2 
 
The COVID-19 pandemic gripped the globe in 2020 and continues to have 
significant impact, with SARS-CoV-2 predicted to infect a large percentage of 
the global population and cause significant morbidity and mortality [Walker 

 
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2020]. Cardiovascular (CV) involvement is common, including myocarditis, 
heart failure, ischemic events due to thromboembolism and supply/demand 
mismatch, and arrhythmias [Madjid 2020; Zheng 2020]. The impact of COVID-
19 on the large global population of persons with HIV who have excess risk for 
CV disease is unknown. REPRIEVE is uniquely positioned to serve as a 
platform to understand the epidemiology, genetics, and pathobiology of 
COVID-19-related CVD in HIV, as well as the effects of statins on COVID-19 in a 
large, global RCT.  
 
COVID-19 may increase CVD through immunological pathways that have been 
characterized as part of the cytokine release syndrome [Saghazadeh 2020]. 
Even without such advanced disease presentations, the HIV population is 
particularly important to study, given that PWH concomitantly experience 
reduced immune function and increased innate immune activation [Lederman 
2013]. Investigation in this population may provide insights into COVID-19 of 
relevance to the general population.  
 
REPRIEVE will be used to identify host factors influencing risk for SARS-CoV-2 
infection, COVID-19 disease, and CV complications of COVID-19. 
 
The randomized design of REPRIEVE is ideal to study whether statins’ 
pleotropic immune-modulatory actions and known protection against virally-
mediated myocardial injury [Guan 2010] and acute lung injury [Brett 2011] 
impact COVID-19 infection. Statins have been shown to reduce 
hyperinflammatory subphenotype of acute respiratory distress syndrome, 
increasing 28-day survival [Calfee 2018], and thus may be particularly useful to 
reduce inflammatory conditions in other systems, including CVD. Moreover, 
ongoing use of statins, rather than as acute therapy, may be protective and 
help to prevent such disease before it becomes advanced and difficult to treat. 
Pitavastatin therapy―the statin used in REPRIEVE―has the most potent 
immune modulatory effects in PWH [Toribio 2017], affects multiple potentially 
relevant immune pathways in this population [deFilippi 2020], and has 
inhibitory activity against SARS-CoV-2 proteins [Xu 2020]. In this regard, we 
will test whether the therapy in REPRIEVE will ameliorate COVID-19-related 
hospitalization and ensuing COVID-19-related cardiovascular events including 
myocardial infarction and/or heart failure.  
 
2.2 
Rationale 
 
PWH face an increased risk of CVD morbidity and mortality, yet no preventive strategies 
for CVD risk reduction have been proven for this population. Existing primary CVD 
preventive strategies for the general population cannot simply be extrapolated to PWH, 
in whom immune dysfunction/activation contributes in unique ways to atherosclerosis 
and ensuing cardiovascular events. The rationale of testing statins for primary CVD 
prevention in HIV is multifold: First, statins affect both traditional CVD risk factors (LDL 
cholesterol) and have beneficial pleiotropic “off-target” effects, i.e., reduction in immune 

 
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activation. The latter effect is critical, as immune activation and persistent inflammation 
in HIV are thought to contribute importantly to the development of non-calcified, 
vulnerable, and inflamed coronary atherosclerotic plaque even in relatively young PWH 
on ART with low traditional CVD risk indices [Subramanian 2012; Yarasheski 2012; 
Zanni 2013]. In such patients, statin therapy may stabilize high-risk coronary 
atherosclerotic plaque, precluding rupture and AMI. Moreover, statins are generally safe 
in the HIV population, exerting anti-inflammatory properties without enhancing viremia 
[Aberg 2017; Eckard 2014; Funderburg 2014, 2015; Ganesan 2011; Nabatov 2007; 
Negredo 2006; Silverberg 2009]. Based on this rationale, the REPRIEVE (A5332) study 
was designed to assess the efficacy of statins as a primary prevention strategy for CVD 
events in PWH on ART not meeting 2013 ACC/AHA guideline thresholds for 
recommended statin initiation. The study will also definitively determine the safety of 
statins in PWH, including statin effects on non-CVD events such as incident diabetes, 
malignancies, kidney or liver failure, and AIDS-defining events in PWH. In addition to 
enrolling participants in the main study, select sites will have the option of coenrolling 
participants in a Mechanistic Substudy of REPRIEVE (A5333s). As part of this substudy, 
described in detail in Appendix II, coenrolled patients will undergo detailed coronary CT 
angiography and biochemical immunophenotyping. The Mechanistic Substudy of 
REPRIEVE (A5333s) will allow for determination of statin effect on non-calcified 
coronary atherosclerotic plaque burden and morphology, as well as lipid and immune 
parameters predictive of this effect. REPRIEVE (A5332) addresses an urgent national 
healthcare priority to prevent CVD among persons living with HIV.  
REPRIEVE will address critical knowledge gaps regarding SARS-CoV-2 infection and 
COVID-related CV complications among PWH. We will focus on three interrelated but 
independent key topics: epidemiology and scope of COVID-19-related CVD in HIV, 
host factors, and protective strategies. Uniform study-wide eCRF assessment tools to 
ascertain symptoms (including long-term COVID-19 effects) and antibody testing will 
allow for an objective and unbiased determination of epidemiology of COVID-19, its 
effects on CVD in HIV, and statin effects across the globe for the first time in HIV. The 
results of this work will provide critical information on COVID-19-related CVD in HIV, 
and critical effects of statins to mitigate effects of the SARS-CoV-2 virus-related 
infection, disease severity, and MACE. These results will be broadly generalizable to 
the large population of PWH simultaneously at risk for COVID-19 and CVD and also to 
other populations at risk for CVD experiencing COVID-19 infection.   
 
3.0 
STUDY DESIGN 
 
REPRIEVE (A5332) is a prospective, double-blind, randomized, placebo-controlled, 
multicenter phase III efficacy study that will examine the effects of 4 mg daily pitavastatin 
on cardiovascular-related events among adults with HIV who are currently on ART. The 
randomization in the study will be stratified by sex at birth, CD4+ T-cell counts (≤500 vs. 
>500 cells/mm3), and by whether or not a participant has elected to participate in the 
Mechanistic Substudy of REPRIEVE (A5333s) (yes/no). 
 

 
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Men and women ≥40 and ≤75 years of age, on any ART regimen (ART not provided by 
the study) for at least 6 months prior to study entry, with any plasma HIV-1 RNA level, 
with CD4+ T-cell count >100 cells/mm3 considered low-to-moderate risk using the 2013 
ACC/AHA guideline thresholds for recommended statin initiation will be enrolled into this 
study. Per the December 2017 DSMB recommendations, the study sample size was 
increased to approximately 7500 participants, follow-up was extended to approximately 
84 months from the time the first participant enrolled, and on 01/19/18, total enrollment 
of individuals with very low cardiovascular risk (10-year ASCVD risk score <2.5%) was 
capped at approximately 2000 participants to ensure that final study population reflects 
the targeted low-to-moderate-risk population. Subsequent to a new recommendation 
from the NIH, the total enrollment of individuals with low cardiovascular risk (10-year 
ASCVD risk score <5.0%) was capped at approximately 4200 participants to ensure that 
the final study population reflects the targeted low-to-moderate-risk population. At this 
same time the NIH recommended to increase follow-up to 96 months. This increase was 
endorsed by the DSMB at the December 2018 meeting. Follow-up is now up to 120 
months in order to continue until the study reaches its target of 288 primary 
MACE endpoints or is otherwise recommended for closure by the DSMB (see 
section 9.1 for more details). 
 
At study entry, participants will be randomized to one of the following arms: 
ARM A:  At Day 0, initiate pitavastatin at a daily dose of 4 mg. 
ARM B:  At Day 0, initiate placebo for pitavastatin daily. 
 
Clinical assessments will be performed at month 1, month 4, and then every 4 months 
for the duration of the study.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Documentation of HIV-1 infection by means of any one of the following: 
• 
Documentation of HIV diagnosis in the medical record by a licensed health 
care provider;  
• 
OR HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating 
>1000 RNA copies/mL; 
• 
OR any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a HIV-
1 Western blot confirmation or HIV rapid Multispot antibody differentiation 
assay. 
 
NOTE: A “licensed” assay refers to a US FDA-approved assay, which is required 
for all IND studies. Non-US sites are encouraged to use FDA-approved methods; 
if not available, then each non-US site must use an assay that has been certified 
or licensed by an oversight body within that country and validated internally.  
 

 
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WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. 
 
4.1.2 Combination antiretroviral therapy (ART) for at least 180 days prior to study 
entry. 
 
NOTE: Treatment interruptions for up to 30 days total in the last 180 days are 
permitted as long as the participant has been continuously on therapy for the 30 
days prior to study entry. 
 
4.1.3 CD4+ cell count >100 cells/mm3 obtained within 180 days prior to study entry at 
any US laboratory that has a Clinical Laboratory Improvement Amendments 
(CLIA) certification or its equivalent, or at any network-approved non-US 
laboratory that operates in accordance with Good Clinical Laboratory Practices 
and participates in appropriate external quality assurance programs. 
 
4.1.4 Laboratory values drawn at screen and/or obtained from clinical care (as 
indicated in section 6.1 Schedule of Evaluations) within 90 days prior to study 
entry at any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, or at any network-approved  
non-US laboratory that operates in accordance with Good Clinical Laboratory 
Practices and participates in appropriate external quality assurance programs. 
 
• 
Fasting LDL cholesterol as follows: 
o If ASCVD risk score <7.5%, LDL cholesterol must be <190 mg/dL 
o If ASCVD risk score ≥7.5% and ≤10%, LDL must be <160 mg/dL 
o If ASCVD risk score >10% and ≤15%, LDL must be <130 mg/dL 
 
NOTE: If LDL <70 mg/dL, participant is eligible regardless of 10-year ASCVD 
risk score in line with the ACC/AHA 2013 Prevention Guidelines. 
 
• 
Fasting triglycerides <500 mg/dL 
• 
Hemoglobin 8 g/dL for female participants and 9 g/dL for male participants 
• 
Glomerular filtration rate (GFR) ≥60 mL/min/1.73m2 or creatinine clearance 
(CrCl) ≥60 mL/min 
NOTE: See the A5332 Manual of Procedures (MOPS) for links to GFR and 
CrCl calculators. 
• 
ALT ≤2.5 x ULN  
NOTE: Participants co-infected with chronic active hepatitis B or C must have 
ALT ≤2 x ULN.  
 
4.1.5 For persons with known chronic active hepatitis B or C, calculated FIB-4 score 
must be ≤3.25. 
 

 
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NOTE: Active is defined as hepatitis B surface antigen positive, hepatitis B DNA 
positive, or hepatitis C RNA positive. 
 
NOTE: Refer to the calculator for the FIB-4 equation in the MOPS. 
 
4.1.6 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, ie, who have had 
menses within 24 months prior to study entry, and women who have not 
undergone surgical sterilization, specifically hysterectomy or bilateral 
oophorectomy) must have a negative serum or urine pregnancy test within 48 
hours prior to entry by any US laboratory or clinic that has a CLIA certification or 
its equivalent, or is using a point-of-care (POC)/CLIA-waived test, or at any 
network-approved non-US laboratory or clinic that operates in accordance with 
Good Clinical Laboratory Practices and participates in appropriate external 
quality assurance programs. 
 
NOTE: Participant-reported history is considered acceptable documentation of 
hysterectomy, bilateral oophorectomy, and menopause. Women are considered 
menopausal if they have not had a menses for at least 12 months and have a 
FSH (follicle stimulating hormone) of greater than 40 IU/L or, if FSH testing is not 
available, they have had amenorrhea for 24 consecutive months. 
 
4.1.7 For women of reproductive potential, willingness to use contraceptives as 
described in the product information for pitavastatin. Contraceptives must be 
used at least two weeks before initiation of study drug and must be continued 6 
weeks after cessation of study drug. 
If participating in sexual activity that could lead to pregnancy, women must use a 
form of contraceptive. At least one of the following methods must be used 
appropriately: 
• 
Condoms (male or female) with or without spermicidal agent 
• 
Diaphragm or cervical cap with spermicidal agent 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
• 
Tubal ligation 
• 
Tubal micro-inserts 
 
Women who are not of reproductive potential as defined above are eligible 
without the use of contraception. 
 
4.1.8 Men and women age ≥40 and ≤75 years of age.  
 
4.1.9 Ability and willingness of participant or legal representative to provide written 
informed consent. 
 

 
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4.2 
Exclusion Criteria 
 
4.2.1 Clinical ASCVD, as defined by 2013 ACC/AHA guidelines, including a previous 
diagnosis of any of the following:  
• 
AMI  
• 
Acute coronary syndromes 
• 
Stable or unstable angina  
• 
Coronary or other arterial revascularization 
• 
Stroke  
• 
TIA  
• 
Peripheral arterial disease presumed to be of atherosclerotic origin  
4.2.2 Current diabetes mellitus if LDL ≥70 mg/dL 
 
NOTE: Current diabetes is defined by patient report of physician diagnosis. 
Participants with a history of diabetes that has resolved and no longer requires 
therapy are not considered to have current diabetes, eg, women with a history of 
gestational diabetes, steroid-induced or medication-induced. 
 
4.2.3 10-year ASCVD risk score estimated by Pooled Cohort Equations >15% 
 
NOTES: 
• 
If LDL <70 mg/dL, participant is eligible regardless of risk score in line with 
the ACC/AHA 2013 Prevention Guidelines. 
• 
See inclusion criterion 4.1.4 for LDL requirements by risk score. 
• 
See section 6.3.4, Cardiovascular Risk Assessment Tool, for detailed 
instructions concerning access and use of the 10-year ASCVD risk score 
calculator. 
 
4.2.4 Active cancer within 12 months prior to study entry. 
 
NOTE: Exceptions: 
• 
Successfully treated non-melanomatous skin cancer 
• 
Kaposi sarcoma without visceral organ involvement 
 
4.2.5 Known decompensated cirrhosis. 
 
4.2.6 History of myositis or myopathy with active disease in the 180 days prior to study 
entry. 
 
4.2.7 Known untreated symptomatic thyroid disease. 
 
4.2.8 History of allergy or severe adverse reaction to statins. 
 
4.2.9 Use of specific immunosuppressants or immunomodulatory agents, including but 
not limited to tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, 

 
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TNF-alpha blockers or antagonists, azathioprine, interferon, growth factors, or 
intravenous immunoglobulin (IVIG), in the 30 days prior to study entry. 
 
NOTE: Use of oral prednisone ≤10 mg/day or equivalent dosage is allowed.  
 
NOTE: Refer to the MOPS for clarification regarding medications in these 
categories. 
 
4.2.10 Current use of erythromycin, colchicine, or rifampin. 
 
4.2.11 Use of any statin drugs, gemfibrozil, or PCSK9 inhibitors in the 90 days prior to 
study entry. 
 
4.2.12 Current use of an investigational new drug that would be contraindicated. 
 
NOTE: Please contact the protocol core team via e-mail as described in the 
Study Management section for guidance on coenrollment of participants on 
investigational new drugs. 
 
4.2.13 Serious illness or trauma requiring systemic treatment or hospitalization in the 30 
days prior to study entry. 
 
4.2.14 Known active or recent (not fully resolved within 30 days prior to study entry) 
systemic bacterial, fungal, parasitic, or viral infections (except HIV, HBV, human 
papillomavirus [HPV], or HCV). 
 
4.2.15 Current breastfeeding. 
 
4.2.16 Alcohol or drug use that, in the opinion of the site investigator, would interfere 
with completion of study procedures. 
 
4.2.17 Other medical, psychiatric, or psychological condition that, in the opinion of the 
site investigator, would interfere with completion of study procedures and or 
adherence to study drug. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 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. 
 

 
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Initial 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 approvals 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 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-protocol-registration-policy-
and-procedures-manual. 
 
Once a candidate for study entry has been identified, details including risks and 
benefits will be carefully discussed with the participant. The participant (or, when 
necessary, the legal representative if the participant is under guardianship) will 
be asked to read and sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, a 
REPRIEVE Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System. 
 
4.3.2 Participant Randomization 
 
Participants will be randomized according to standard data management 
procedures. For participants from whom informed consent has been obtained, 
but who are deemed ineligible or who are not randomized into REPRIEVE 
(A5332), a Screening Outcome form must be recorded in the Electronic Data 
Capture system (EDC).  
 
4.4 
Mechanistic Substudy of REPRIEVE (A5333s) Enrollment Procedures  
 
If applicable, the Mechanistic Substudy of REPRIEVE (A5333s) enrollment will occur at 
the same time as enrollment into REPRIEVE (A5332), ie, completion of enrollment into 
A5333s should occur no later than one business day after enrollment into REPRIEVE 
(A5332). Please see Appendix II for additional information regarding substudy 
enrollment procedures. 

 
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NOTE: The Mechanistic Substudy of REPRIEVE (A5333s) closed to accrual on 
02/06/18. 
 
4.5 
Coenrollment Guidelines  
 
US ACTG sites are encouraged to coenroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Non-US ACTG sites are encouraged to coenroll participants in 
A5243, “Plan for Obtaining Human Biological Samples at Non-US Clinical Research 
Sites for Currently Unspecified Genetic Analyses.” Coenrollment in A5128, observational 
studies, or studies that do not involve a random treatment assignment does not require 
permission from the REPRIEVE (A5332) protocol team. 
 
For specific questions and approval for coenrollment in other studies (including HCV or 
HIV treatment trials and adjunctive treatment trials), sites should first check the PSWP or 
contact the protocol core team via e-mail as described in the Study Management 
section. 
 
4.6 
Retention Procedures  
 
Participants who miss visits should be contacted to make up the visit and to permit 
determination of whether a major event occurred. If a participant refuses to communicate 
with study staff in any context and avoids further participation in the study after repeated 
attempts or the site is unable to contact the participant by phone, mail, primary care 
physician, next of kin, home visits, or emergency contact numbers after repeated 
attempts, then the participant should be taken off study.  
 
Participants who self-withdraw from study medications should be followed (if they agree) 
and evaluated.  
 
See MOPS for recruitment and retention procedures, including contact and data 
collection for participants in the event of missed visits. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as pitavastatin and placebo for pitavastatin, both of which will 
be provided by the study. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
At study entry (day 0), participants will be randomized to one of the following 
arms: 
 
ARM A: Pitavastatin 4 mg one tablet once daily taken orally with or without food. 

 
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ARM B: Placebo for pitavastatin one tablet once daily taken orally with or without 
food. 
 
5.1.2 Administration  
 
The appropriate dose of pitavastatin or placebo for pitavastatin can be 
administered at any time of the day, with or without food. The drug should be 
taken as close to the same time of day as possible. With the exception of 
participants enrolled in the Mechanistic Substudy (A5333s) or select other 
approved REPRIEVE (A5332) ancillary studies, participants must begin 
treatment within 72 hours after randomization. 
 
NOTE: For participants coenrolled in the Mechanistic Substudy (A5333s) or other 
specified approved REPRIEVE (A5332) ancillary studies with ancillary study 
procedures, the initiation of treatment must be held until after the entry CCTA or 
relevant ancillary study procedure (see the A5332 MOPS for more details), even 
if the CCTA or relevant ancillary study procedure occurs more than 72 hours 
after randomization but not more than 14 days after randomization. See the 
A5332 MOPS for more details regarding the specified ancillary studies. 
 
Study product will be dispensed in accordance with the Drug Dispensation 
schedule as described in the MOPS.  
 
NOTE: The drug dispensation schedule described in the MOPS is a preferred 
guidance schema. Sites should notify the DAIDS Pharmaceutical Affairs Branch 
(PAB) at PABREPRIEVEPEP@mail.nih.gov of any deviation from this schema 
and document such occurrences in dispensation/accountability logs. 
 
5.1.3 Treatment Duration 
 
Participants will remain on study treatment for approximately 120 months 
depending on the time they enrolled in the study. 
 
5.2 
Study Product Formulation and Preparation  
 
Pitavastatin and placebo for pitavastatin should be stored at room temperature between 
15–30°C (59–86°F). The product should be stored out of direct sunlight. The container 
should be kept tightly closed retaining the silica gel desiccant in the bottle. Dispense only 
in the original container. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Pitavastatin and placebo for pitavastatin will be provided by Kowa 
Pharmaceuticals America, Inc. These study products will be available through the 

 
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NIAID Clinical Research Products Management Center (CRPMC). The clinical 
research site (CRS) pharmacist can obtain the study products for this protocol by 
following the instructions in the manual Pharmacy Guidelines and Instructions for 
Division of AIDS (DAIDS) Clinical Trials Networks. 
 
5.3.2 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 must be returned to the NIAID CRPMC (or as otherwise directed by the 
sponsor) after the study is completed or terminated. The procedures to be 
followed are provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities. At non-US CRSs, the site pharmacist must follow the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks for the destruction of unused study products. 
 
5.4 
Concomitant Medications  
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. Site 
staff are encouraged to contact the core protocol team via e-mail with any questions 
about required, prohibited, or precautionary medications. Refer to MOPS section 5.0 for 
additional information.  
 
Additional drug information may be found on the updated ACTG Precautionary and 
Prohibited Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search. 
This database was created to assist investigators and research staff to access the most 
current pharmacokinetic data on drug interactions with antiretrovirals. You do not need to 
register or login to use this resource. 
 
5.4.1 Required Medications 
 
Combination ART for at least 180 days prior to study entry.  
 
NOTE: Treatment interruptions for up to 30 days total in the last 180 days are 
permitted as long as participant has been continuously on therapy for the 30 
days prior to study entry. 
 
5.4.2 Recommended Medications 
 
Prophylaxis for HIV-related opportunistic infections should be administered as 
per the “Guidelines for the Prevention and Treatment of Opportunistic Infections 
in Adults and Adolescents with HIV: Recommendations from the Centers for 

 
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Disease Control and Prevention, the National Institutes of Health, and the HIV 
Medicine Association of the Infectious Diseases Society of America.” 
 
5.4.3 Prohibited Medications 
 
Refer to the PSWP for a list of prohibited medications. 
 
5.4.4 Precautionary Medications 
 
Refer to the PSWP for a list of precautionary medications.    

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations  
 
Table 6.1a: Screening – Months 96 
Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Documentation of 
HIV-1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x3 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medication history 
x 
x3 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Myalgia symptom 
assessment 
 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COVID-19 
assessment 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Calculate 10-year 
ASCVD risk score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CVD risk factor 
assessment  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x16 
x16 
x16 
REAP & DASI 
questionnaires 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Screening physical 
exam 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Targeted physical 
exam 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Height  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Waist circumference 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
ECG4 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense lifestyle 
information 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Labs captured from clinical care 
CD4+/CD8+5 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Plasma HIV-1 RNA6 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
CBC7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Serum creatinine7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Calculated 
creatinine clearance 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel 7,8 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST 10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIB-410 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs to be collected (drawn) 
ALT (local lab) 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Pregnancy testing 
x 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fasting lipid panel 
(stored)9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Fasting glucose9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Fasting 
plasma/serum for 
biomarkers – stored9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Urine 
albumin/creatinine11 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
genetic testing12 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety labs if 
indicated13 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense study drug 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Medication 
adherence 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Vital status and 
endpoint follow-up14  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Endpoint 
assessments15 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1 
For the purposes of the study, 1 month equals 30 days. 

 
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2 
 If a participant is not fasting for a visit for which fasting blood is obtained, reschedule the appointment within 30 days of the original 
appointment date. See section 6.2.3.  
3 
 Update any changes from the screening assessment (medical and medication history). 
4  ECG available to site PI, all ECGs will be sent for central read and storage until end of study, no specific ECG findings are 
exclusionary, except findings which in the judgment of PI render the participant clinically unstable as per clinical read, central readings 
will not be available to sites, see MOPS. 
5  At the screening visit, CD4+/CD8+ from clinical care within 180 days prior to entry will be used; if not available, this will be drawn as 
part of the study. For post-entry CD4+/CD8+, the most recent values obtained since the last annual visit will be used. At discontinuation 
visits, CD4+/CD8+ from clinical care within 180 days of that visit will be used.  
6  For the entry visit, an HIV-1 RNA from clinical care from the prior 180 days will be used; if not available, do not collect. For post-entry 
evaluations, the most recent viral load obtained from clinical care since the last annual visit will be used. At discontinuation visits, 
plasma HIV-1 RNA from clinical care within 180 days of that visit will be used. 
7  At the screening visit, results of CBC, creatinine, lipid panel, and ALT (and when needed per footnote #10, AST) will be obtained from 
clinical care if available within 90 days prior to entry; if not available, draw as part of the study. At discontinuation visits, CBC and 
creatinine from clinical care within 180 days of that visit will be used. 
8  At the screening visit, direct LDL must be determined if triglyceride 400-500 mg/dL.  
9  Fasting lipid panels, glucose, and plasma/serum for biomarkers from entry visit forward will be performed centrally. Participants may 
choose to opt out of these entry and post-entry labs.  
10 
 AST is only required for persons with known chronic active HCV and/or HBV in order to calculate FIB-4 at screening. Use results from 
clinical care if available within 90 days prior to entry; if not available, draw as part of the study. 
11  The urine for creatinine/albumin is required of all participants at entry. At months 12, 24, and 48, collect only for participants at ACTG 
sites who enrolled in REPRIEVE (A5332) prior to 01/01/2018. 
12  Whole blood for genetic testing will be drawn at ACTG sites only. 
13  Additional safety labs will be checked at the discretion of site investigator based on participant symptoms (see section 7.1). 
14  Please refer to section 6.3.10 for details. 
15  Please refer to section 6.4 for details. 
16 Hormonal/reproductive health assessments relevant to CVD risk will be determined at study termination/discontinuation 
visits. 
 
 
 

 
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Table 6.1b: Months 100–120 
Evaluation 
Post-Entry Evaluations (months)1 
Study 
Termination 
Visit2 
Discontinuation Visits2 
 
Visit Window 
±7 days for month 1; ±30 days for 
all other visits 
 
Prem. 
Treatment 
D/C Evals 
±30 days2 
Prem. Study D/C 
Evals2 
 
100 
104 1082 112 
116 1202 
 
 
 
Medical history 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medication history 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Myalgia symptom assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COVID-19 assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV risk factor assessment  
 
 
 
 
 
 
x10 
x10 
x10 
REAP & DASI questionnaires 
 
 
 
 
 
 
x 
x 
x 
Targeted physical exam 
 
 
x 
 
 
x 
x 
x 
x 
Weight 
 
 
x 
 
 
x 
x 
x 
x 
Waist circumference 
 
 
 
 
 
 
x 
x 
x 
Dispense lifestyle information 
 
 
x 
 
 
x 
x 
x 
x 
Labs captured from clinical care 
CD4+/CD8+3 
 
 
x 
 
 
x 
x 
x 
x 
Plasma HIV-1 RNA4 
 
 
x 
 
 
x 
x 
x 
x 
CBC5 
 
 
 
 
 
 
x 
x 
x 
Serum creatinine5 
 
 
 
 
 
 
x 
x 
x 
Labs to be collected (drawn) 
Pregnancy testing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fasting lipid panel (stored)6 
 
 
x 
 
 
x 
x 
x 
x 
Fasting glucose6 
 
 
x 
 
 
x 
x 
x 
x 
Fasting plasma/serum for biomarkers – stored6 
 
 
x 
 
 
x 
x 
x 
x 
Safety labs if indicated7 
x 
x 
x 
x 
x 
x 
x 
x 
x 

 
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Evaluation 
Post-Entry Evaluations (months)1 
Study 
Termination 
Visit2 
Discontinuation Visits2 
 
Visit Window 
±7 days for month 1; ±30 days for 
all other visits 
 
Prem. 
Treatment 
D/C Evals 
±30 days2 
Prem. Study D/C 
Evals2 
 
 
100 
104 
108 
112 
116 
120 
 
 
 
Dispense study drug 
x 
x 
x 
x 
x 
x 
 
 
 
Medication adherence 
x 
x 
x 
x 
x 
 
 
 
 
Vital status and endpoint follow-up8  
 
 
 
 
 
 
x 
 
x 
Endpoint assessments9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1  For the purposes of the study, 1 month equals 30 days. 
2 
 If a participant is not fasting for a visit for which fasting blood is obtained, reschedule the appointment within 30 days of the 
original appointment date. See section 6.2.3.   
3  For post-entry CD4+/CD8+, the most recent values obtained since the last annual visit will be used. At discontinuation visits, 
CD4+/CD8+ from clinical care within 180 days of that visit will be used.  
4  For post-entry evaluations, the most recent viral load obtained from clinical care since the last annual visit will be used. At 
discontinuation visits, plasma HIV-1 RNA from clinical care within 180 days of that visit will be used. 
5  At discontinuation visits, CBC and creatinine from clinical care within 180 days of that visit will be used. 
 
6  Fasting lipid panels, glucose, and plasma/serum for biomarkers will be performed centrally. Participants may choose to opt 
out of these post-entry labs.  
7  Additional safety labs will be checked at the discretion of site investigator based on participant symptoms (see section 7.1). 
8  Please refer to section 6.3.10 for details. 
9  Please refer to section 6.4 for details. 
10 Hormonal/reproductive health assessments relevant to CVD risk will be determined at study termination/discontinuation 
visits. 
 
 

 
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6.2 
Timing of Evaluations  
 
NOTE: For the purposes of the study, 1 month = 30 days. 
 
6.2.1 Screening Evaluations  
 
• 
Screening evaluations must occur prior to randomization and any study 
treatment or intervention. 
• 
Screening evaluations to determine eligibility must be completed within 90 
days prior to entry unless otherwise specified. 
• 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be 
captured in a Screening Outcome form in the EDC.  
 
6.2.2 Entry Evaluations 
 
• 
Entry evaluations will normally occur at least 24 hours after screening 
evaluations unless otherwise specified. In certain circumstances, screening 
and entry visits may occur sequentially in real time as long as all screening 
criteria are confirmed prior to entry. 
• 
Entry evaluations must occur after randomization and be completed before 
initiating study treatment. 
• 
Participants must begin treatment within 72 hours after randomization. 
 
NOTE: For participants coenrolled in the Mechanistic Substudy (A5333s) and 
other specified approved REPRIEVE (A5332) ancillary studies with ancillary 
study procedures, treatment must be held until after the entry CCTA or 
relevant ancillary study procedure (see MOPS for more details) even if that 
occurs more than 72 hours but not more than 14 days after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
On-Study Evaluations  
All on-study evaluations must be scheduled as per section 6.1 with a ±7-day 
window for the month 1 visit and a ±30-day window for all other visits. 
 
Participants who miss visits should be contacted to make up the visit and to 
permit determination of whether a major event occurred. See section 6.4 for 
additional considerations for endpoint assessments in the event of missed visits. 
 
Return Fasting Visit (as needed) 
This visit is only required for participants who are in a non-fasting state for visits 
that require fasted assessments. Participants should return for fasted 
assessments within 30 days for a fasting evaluation. 
 

 
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Study Termination Evaluation  
The study termination evaluation will be completed as the participant’s final on-
study visit.  Please follow the Schedule of Evaluations (SOE) regarding data 
collection for the Study Termination Visit.  
 
Since REPRIEVE is an endpoint-driven trial, the study termination will be 
when the target number of endpoints has been reached or when 
determined by the DSMB at a later date. The study team will notify all sites 
of when to begin conducting the Study Termination Visit. 
 
Event-Driven Evaluations  
Evaluations must be scheduled as per section 7.0. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered or Randomized Participants Who Do Not Start Study 
Treatment 
For participants who withdraw from the study before initiating study treatment, 
complete all eCRFs for the period up to and including the entry visit. 
 
Premature Treatment Discontinuation Evaluations 
Participants who discontinue the study treatment before the end of the study will 
have the premature treatment discontinuation evaluations completed within 30 
days after stopping the study drug. At this visit, study drug will not be dispensed 
but adherence assessment will be performed for these individuals. After 
completion of the premature treatment discontinuation evaluations and until the 
study termination visit, participants will follow the clinical assessment and 
laboratory schedules as per section 6.1. Medication adherence will be assessed.  
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue from the study will have the premature 
study discontinuation evaluations performed as per section 6.1 prior to being 
taken off study. 
 
NOTE: Sites will capture and document reasons for premature discontinuation 
(eg, related to AE), and whether premature discontinuation pertains to consent 
for follow-up and/or treatment.  
 
For participants who prematurely discontinue from the study for reasons other 
than withdrawal of consent, sites will attempt to obtain information regarding vital 
status and endpoints annually (see section 6.3.10).  
 
6.3 
Instructions for Evaluations and Data Collection  
 
Each study site and laboratory involved in this study will comply with the DAIDS 
policy on Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical 

 
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Trials Policy, which is available at 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is required to be maintained in 
the source documents (see MOPS for additional details). Sites must refer to the Source 
Document Guidelines on the DAIDS website for information about what must be included in the 
source document: https://www.niaid.nih.gov/sites/default/files/score-source-documentation-
requirements.pdf. 
 
All stated evaluations are to be recorded in the EDC unless otherwise specified. This 
includes events that meet the International Conference on Harmonization (ICH) 
definitions for a serious adverse event: 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above). 
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), corrected Version 2.1, July 2017, is available on the DAIDS RSC website 
at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
The protocol team and/or study monitoring entity may determine that additional 
source data associated with procedures or evaluations performed per protocol 
should be entered into eCRFs so that the data can be used for analysis or to 
otherwise assist with interpretation of study findings. In such cases, sites will be 
officially instructed to enter the additional data into eCRFs from available source 
documentation.  
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies requirements for HIV-1 documentation. HIV-1 
documentation is not recorded in the EDC. 
 
6.3.2 Medical History 
 
The following diagnoses should be recorded in the EDC at screening and 
updated at entry, regardless of when the diagnosis was made: 
• 
Hypertension 
• 
Diabetes mellitus 
• 
AIDS-defining events  

 
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• 
Any malignancy (exclusive of basal/squamous cell skin cancer) 
• 
Prior history of dialysis or renal transplantation 
• 
Chronic active hepatitis C 
• 
Chronic active hepatitis B 
• 
Venous thromboembolism (VTE) 
• 
Pulmonary thromboembolism (PTE) 
• 
Nadir CD4 cell count (verbal history accepted) 
• 
COVID-19 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Medication History 
 
A limited medication history must be performed at screening and updated at 
entry and post-entry visits as per Table 6.3.3-1 below. Record all modifications to 
ART, including participant-initiated modifications (more than 7 consecutive 
missed days), provider-initiated modifications, and permanent discontinuation. 
See Table 6.3.3-1 below and MOPS for more details. 
 
Table 6.3.3-1: Medication History  
Medication Category 
Complete History or Timeframe 
Record in 
EDC 
(Yes/No) 
Antiretroviral therapy 
Cumulative duration of protease inhibitor, 
thymidine analogs, abacavir, tenofovir, and 
overall ART duration 
Yes 
Current ART therapy 
Current  
Yes 
Blinded study therapy (other 
than for REPRIEVE) 
Current 
Yes 
Statin therapy  
Any prior or current exposure  
Yes 
Nonstatin lipid lowering 
therapy 
Current 
Yes 
Antidiabetic medications 
Current 
Yes 
Aspirin therapy (ongoing 
regular therapy) and 
anticoagulant medications 
Current  
Yes 
Antihypertensive 
medications* 
Current  
Yes 
Antihepatitis medications  
Current 
Yes 
Hormonal contraceptives or 
hormone replacement 
therapy* 
Current  
Yes 
Testosterone therapy* 
Current 
Yes 

 
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Medication Category 
Complete History or Timeframe 
Record in 
EDC 
(Yes/No) 
COVID-19 medications 
(including vaccines)* 
Any prior or current exposure 
Yes 
*Refer to the MOPS for more information about recording these classes of drugs. 
Study Treatment Modifications 
The study drugs are pitavastatin and placebo for pitavastatin. Record all study 
drug modifications, participant-initiated and protocol-mandated modifications, 
inadvertent and deliberate interruptions of more than 7 consecutive days. Record 
any permanent discontinuation of treatment. 
 
6.3.4 Clinical Assessments 
 
Signs and Symptoms 
At entry, all grades that occurred ONLY within the 30 days before entry are to be 
collected and maintained in the source documents but are not required to be 
recorded in the EDC at this time. If a participant develops future signs and 
symptoms, the signs and symptoms recorded in source documents at entry can 
be referred to, in order to see if they are truly incident or recurrent.  
 
After entry, only the following signs and symptoms are to be recorded in the EDC: 
• 
Signs and symptoms Grade 3. 
• 
All signs and symptoms that led to a change in treatment (pitavastatin or 
placebo) regardless of grade. 
 
NOTE: If signs and symptoms are related to a diagnosed event, record the 
primary event in the EDC and do not grade or record related signs and 
symptoms. If Grade 3 signs and symptoms occur independent of a related 
diagnosis, they should be recorded in the EDC.  
 
Further evaluation will be required for those events that meet EAE or ICH 
reporting requirements. 
 
Diagnoses 
All incident diagnoses listed in section 6.3.2 will be assessed at all visits post entry; 
refer to section 6.4 for requirements for intervening medical history review related 
to primary MACE and other secondary serious non-cardiovascular events.  
 
Assessment of Potential Myalgia Toxicity 
Potential statin effects on the liver will be assessed with ALT at month 1 and 
month 12 visits; potential effects on muscle will be assessed by a myalgia 
symptom assessment at entry and onward.  
 

 
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Cardiovascular Risk Assessment Tool 
The ACC/AHA 2013 10-year ASCVD risk score should be performed as part of 
screening. MOPS section 2.1, Atherosclerotic Cardiovascular Disease Risk 
Assessment Tool, provides detailed instructions concerning access and use of 
the 10-year ASCVD risk score calculator. It is important to use only the 10-Year 
ASCVD Risk Score, not the “risk with optimal risk factors” or the “lifetime ASCVD 
Risk calculator” results. 
 
NOTE: For the purposes of calculation of the 10-year ASCVD risk score using 
the Pooled Cohort Equations: 
• 
For participants whose values of HDL cholesterol, total cholesterol, and/or 
systolic blood pressure fall below or above the acceptable calculator bounds 
for those parameters, values at the lower or upper bounds, respectively, will 
be entered.  
• 
Participants of mixed race will be asked to identify themselves as 
predominantly African American or predominantly other, and the race of 
predominant identification will be entered; as per calculator guidelines, non-
African American race is entered as White or other race. 
• 
Participants will be asked to report sex at birth, and this sex will be entered.  
• 
Only participants currently on 1 or more antihypertensive medications will be 
counted as undergoing treatment for high blood pressure.  
• 
Only participants who report current active smoking will be counted as smokers.  
 
NOTE: When calculating the ASCVD risk score, the use of e-cigarettes is not 
considered as current active smoking. Please mark “no” for persons who 
report only the use of e-cigarettes. 
 
Cardiovascular Risk Factor Assessment 
An assessment of general cardiovascular risk factors, current smoking, alcohol 
use, substance use, and family history of premature CVD. will be assessed at 
screen. Hormonal/reproductive health assessments relevant to CVD risk 
will be assessed at screening and study termination visits. 
 
Diet and Functional Capacity Assessment 
Diet (Rapid Eating and Activity Assessment for Patients [(REAP] questionnaire), 
functional capacity (Duke Activity Status Index [DASI] questionnaire), will be 
completed at entry, and study termination visits.  
 
Screening Physical Exam 
A screening physical examination is to include auscultation of the chest, cardiac 
exam, examination of the lower extremities for edema, and vital signs. 
 
Targeted Physical Exam 
A targeted physical examination is to include vital signs, and is to be driven by 
any previously identified or new signs or symptoms, including muscle aches, 
pains, tenderness, weakness, malaise, or fever. A targeted physical exam will 

 
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also be driven by any diagnoses that the participant has experienced since the 
last visit. The targeted physical exam will occur at month 1 and each annual visit. 
 
Height 
Measurement of height will occur at screening. 
 
Weight 
Measurement of weight will occur at screening and each annual visit. 
 
Waist Circumference 
Measurement of iliac waist circumference will occur at screening and study 
termination visits. Please see MOPS for instructions on waist circumference 
measurement. 
 
ECG 
Resting 12-lead ECG results, including heart rate will be performed at entry. 
Please see MOPS for instructions. 
 
6.3.5 Lifestyle Information 
 
Participants will be provided information regarding healthy diet and activities in 
the Lipid-Lowering Diet, Activity Guide, and Smoking Cessation located on the 
REPRIEVE (A5332) PSWP. In addition, participants will be reminded to adhere 
to prescribed antiretroviral regimen and study medication. This is to be provided 
at entry and annual visits. 
 
6.3.6 Laboratory Evaluations 
 
All laboratory values collected for REPRIEVE (A5332) must be recorded in the 
EDC. This includes laboratory values performed as part of toxicity 
management (eg, all CK assessments performed as part of management of 
myalgias and myopathy). 
 
Post entry, all Grade 3 laboratory values and all laboratory values regardless of 
grade that led to a change in treatment must be recorded as adverse events. 
Further evaluation will be required for those events that meet EAE or ICH 
reporting requirements. 
 
Laboratory testing for screening or safety assessment must be performed in a 
CLIA or equivalent certified laboratory or at any network-approved non-US 
laboratory that operates in accordance with Good Clinical Laboratory Practices 
and participates in appropriate external quality assurance programs. 
 
When labs are being captured from clinical care, the most recent lab value 
should be the value recorded in the EDC. Screening labs captured from clinical 
care should be within 90 days prior to entry unless otherwise indicated. 

 
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Fasting is defined as nothing to eat or drink except water and required 
prescription medications for at least 8 hours. Drinking black decaffeinated coffee 
without sweetener or creamer is permissible, but is not advised. Participants 
must be evaluated in a fasting state for those evaluations indicated as “fasting” 
unless otherwise specified. Participants will be asked whether they have fasted, 
and if not, they should be scheduled to return in a fasting state within 30 days to 
complete the fasting evaluations. 
 
Participants should be instructed with the exact time beyond which they are to be 
fasting, such as: “Your visit is scheduled for 8:00 a.m. You should not have any 
food or drink by mouth except water and medication after 12 a.m.” 
 
In order to minimize diurnal variation, fasting samples for individual participants 
should be obtained consistently in the morning, if possible. Participants will be 
encouraged to take the study drug consistently at the same time and this 
information will be collected in the medication adherence assessment. 
 
CD4+/CD8+ 
Screen: Absolute CD4+/CD8+ count and percentages will be obtained from 
clinical care within 180 days prior to entry; if not available, draw as part of study. 
 
Post-entry evaluations: CD4+/CD8+ obtained from clinical care since the last 
annual study visit. For post-entry evaluations, all laboratories must possess 
a CLIA certification or equivalent (US sites) or IQA certification (non-US 
sites). 
 
NOTE: If CD8+ cell count is not available, CD4+ cell count alone is acceptable. 
 
Plasma HIV-1 RNA 
At all visits indicated on the Schedule of Evaluations, collect results of plasma 
HIV-1 RNA determinations that are obtained through clinical care. For the entry 
visit, a viral load from the prior 180 days should be recorded in the EDC. If not 
available, it will not be collected. For all post-entry evaluations, the most recent 
viral load obtained since the last annual study visit should be recorded in the 
EDC. For post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent (US sites) or must be VQA certified (non-US 
sites).  
 
Hematology  
At screening, hemoglobin, hematocrit, white blood cell count (WBC) and platelets 
will be captured from clinical care within 90 days prior to entry; if not available, 
draw as part of the study. At study termination visits, results must be within 
180 days prior to that visit. 
 
Serum creatinine and calculated creatinine clearance/GFR: at screening, 
creatinine result will be obtained from clinical care within 90 days prior to entry; if 

 
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not available, draw as part of the study. At study termination visits, results 
must be within 180 days prior to that visit; calculated creatinine clearance/GFR 
is not required at study termination visits.  
 
NOTE: See the A5332 MOPS for links to GFR and CrCl calculators. 
 
Fasting Lipid Panel  
Screen: Total cholesterol, HDL cholesterol, direct or calculated LDL cholesterol if 
triglycerides are ≤400 mg/dL (direct LDL must be determined if triglycerides are 
>400 mg/dL and <500 mg/dL), and triglycerides will be collected from clinical 
care within 90 days prior to entry; if not available, draw as part of the study. 
 
NOTE: If the screening lipid values to determine study eligibility are taken from 
existing clinical care assessments and are within the range specified by inclusion 
criterion 4.1.4, fasting status and documentation of fasting status are not required.  
 
The screening lipid panel will be reviewed with the potential participant and 
shared with his or her medical provider along with the study rationale to confirm 
support of participant participation. Specimens from entry onward will be stored 
to be tested centrally. Participants may opt out of these entry and post-entry labs. 
 
Liver Function Tests 
Screen: ALT (SGPT) will be obtained from clinical care within 90 days prior to 
entry; if not available; draw as part of the study. Persons with HCV or HBV 
should also have AST (SGOT) obtained from clinical care within 90 days prior to 
entry to facilitate calculation of fibrosis by the FIB-4 equation. 
 
At month 1 and month 12, ALT will be drawn as part of the study.  
 
NOTE: Refer to the MOPS for link to the FIB-4 calculator.  
 
Pregnancy Testing 
For women with reproductive potential: serum or urine -HCG (urine test must 
have a sensitivity of <25 mIU/mL) will be performed as part of the study at each 
visit and whenever pregnancy is suspected. Record pregnancy and pregnancy 
outcome. Refer to the MOPS for guidance. 
 
Fasting glucose at entry and onward will be performed as part of the study. 
Specimens will be tested centrally. Participants may opt out of these entry and 
post-entry labs.  
 
NOTE: Fasting is defined as above (see 6.3.6 for Fasting Lipid Panel). 
 
Urine Albumin/Creatinine Ratio 
Urine for urine albumin/creatinine ratio will be collected from all participants at 
entry. Specimens will be tested centrally. 

 
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ACTG sites will collect urine at subsequent visits per section 6.1 only from 
participants who enrolled in REPRIEVE (A5332) prior to 01/01/2018. These 
specimens will be tested centrally. 
 
6.3.7 Immunologic, Hormonal, and Biomarker Studies 
 
Additional serum and plasma will be batched and stored in the ACTG Specimen 
Repository for analyses by a central core laboratory. Refer to the Laboratory 
Processing Chart (LPC) for details. Participants may opt out of these entry and 
post-entry labs. 
 
6.3.8 Stored Whole Blood for Future Genetic Studies  
 
A single whole blood sample will be obtained from all study volunteers for human 
genotyping of selected polymorphisms that may predispose to CVD or alter 
pitavastatin levels or effectiveness. This sample will be drawn at ACTG sites only 
and will be collected in addition to any samples collected for participants in 
A5128 or A5243. 
 
6.3.9 Medication Adherence Assessment 
 
Site personnel will perform an assessment of adherence to study medication at 
every visit after the entry visit. 
 
6.3.10 Vital Status and Endpoint Follow-up 
 
For participants who prematurely discontinue study for reasons other than 
withdrawal of consent, site personnel will attempt to obtain information regarding 
vital status (including date last seen alive, date of death, and primary cause of 
death) and endpoints (see sections 6.4.1-6.4.2) from participant or other sources 
(such as family members, other designated contacts, or clinic records) annually 
from the time off study. Please see MOPS for additional information.  
 
6.4 
Endpoint Assessments 
 
At entry and onward, a comprehensive review of the intervening medical history of the 
participant will be performed to capture the data for adjudication of the primary and 
secondary endpoints, including diagnoses and any hospitalization. Participants will be 
specifically asked about hospitalization, emergency room visits, urgent care visits, 
physician visits, and any symptoms that are suggestive of CVD. Information regarding 
potential events will be recorded in the EDC and via source documents and prepared for 
transmission after de-identification to the Clinical Event Committee (CEC) for 
adjudication, as appropriate. Participants who miss visits will be contacted to make up 
the visit and to permit determination of whether major event occurred, the assessment 
will be completed using other sources such as designated contact, physician contact, or 
medical records (refer to the MOPS for details). Events will be reviewed and categorized 

 
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by a CEC unaware of the treatment assignment based on established definitions 
described below.  
 
Non-CVD events as described below will be assessed but will not be formally 
adjudicated by the CEC. 
 
6.4.1 Definitions of Major Adverse Cardiovascular Events (MACE) Components  
 
The primary endpoint of Major Adverse Cardiovascular Events (MACE) includes 
the composite of Cardiovascular Death, Myocardial Infarction, Hospitalization for 
Unstable Angina, Coronary, Carotid or Peripheral Arterial Revascularization, 
Transient Ischemic Attack, Stroke, and Peripheral Arterial Ischemia. 
 
Formal definitions for each of these components and additional secondary and 
exploratory endpoints are contained within the CEC charter, and are based on 
the Standardized Definitions for Cardiovascular and Stroke End Point Events in 
Clinical Trials [Hicks 2015]. 
 
General principles guiding these definitions are described below.  
 
CVD death: includes death resulting from an acute myocardial infarction (MI), 
sudden cardiac death, death due to heart failure (HF), death due to stroke, death 
due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death 
due to other CV causes. 
 
Myocardial infarction: The diagnosis of MI requires the combination of: evidence 
of myocardial necrosis (either changes in cardiac biomarkers or post mortem 
pathological findings); and supporting information derived from the clinical 
presentation, electrocardiographic changes, or the results of myocardial or 
coronary artery imaging suggesting an event consistent with coronary ischemia. 
 
The totality of the clinical, electrocardiographic, and cardiac biomarker 
information will be considered to determine whether or not an MI has occurred. 
Specifically, timing and trends in cardiac biomarkers and electrocardiographic 
information will be included whenever possible, but the diagnosis can still be 
determined if these results are not available. 
 
Unstable angina hospitalization: ischemic discomfort or equivalent requiring 
hospitalization within 24 hours with objective signs of coronary ischemia in 
absence of MI. ECG, angiographic and imaging criteria will be considered.  
  
Coronary, carotid, or peripheral arterial revascularization: invasive percutaneous 
or surgical procedure intended to restore or improve blood flow in a coronary or 
peripheral artery including but not limited to angioplasty, stent, stent graft, or 
bypass graft. 
 

 
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Stroke: an acute episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction. 
 
Transient Ischemic Attack: a transient episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without stroke. 
 
Peripheral Arterial Ischemia (PAD): Peripheral arterial ischemia hospitalization: 
Urgent hospitalization for insufficiency of the peripheral arterial circulation, 
including but not limited to, acute limb ischemia, chronic limb ischemia, 
amputation, or other vascular abnormality of an ischemic and noninfectious 
nature.  
 
6.4.2 Causes of Death  
 
In addition to CVD death which is a component of the primary endpoint, all 
deaths will be adjudicated by the CEC to determine likely cause.  
 
6.4.3 Cardiac Events to be adjudicated but not included in REPRIEVE (A5332) MACE 
Definition: 
• 
Heart Failure, including all COVID-19-related events resulting in 
hospitalization (see CEC Charter) 
 
6.4.4 Non-CVD Events 
 
Clinical assessments will also include assessing the participant regarding the 
occurrence of the following diagnoses: 
• 
AIDS-defining events  
• 
Non AIDS defining cancers (except squamous/basal cell of the skin) 
• 
End stage kidney disease, requiring initiation of dialysis or renal 
transplantation 
• 
End stage liver disease (incident cirrhosis or hepatic decompensation 
requiring hospitalization) 
• 
Incident diabetes mellitus requiring use of diabetes medications 
• 
Venous thromboembolism (VTE) 
• 
Pulmonary thromboembolism (PTE) 
 
For diagnostic criteria for these non-CVD events, refer to the MOPS. All identified 
events should be reported in the EDC regardless of grade. These events do not 
undergo CEC adjudication. 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
Only toxicities related to the study drug (pitavastatin and placebo for pitavastatin) are 
subject to the guidelines outlined in the toxicity management section. In the case of 

 
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multiple toxicities or AEs, the guidelines pertaining to the most severe event should take 
precedence.  
 
The grading system is located in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
Please refer all questions to the REPRIEVE (A5332) core protocol team via email. 
 
7.1 
Toxicity Management 
 
7.1.1 General Reactions 
 
Grade 1 or 2 
Participants who develop a Grade 1 or 2 toxicity may continue study treatment. 
 
Grade 3 
Participants who develop a Grade 3 toxicity that is judged by the site investigator 
to be study drug-related should have the study drug held and the study team 
should be consulted. The participant should be followed closely and if the toxicity 
does not return to Grade 2 within 2 weeks, the study drug must be permanently 
discontinued with participant evaluations as per section 6.2.4. 
 
If the study drug is resumed and the same Grade 3 toxicity recurs within 4 weeks 
of reintroduction, and the site investigator considers this AE related to the study 
drug, the drug must be permanently discontinued. 
 
With a Grade 3 toxicity that is judged not related to the study drug by the site 
investigator, the study drug may be continued at the discretion of the site 
investigator in consultation with the study team. 
 
Grade 4 
Participants who develop a Grade 4 toxicity will have the study drug held and the 
study team should be consulted. Participants experiencing Grade 4 toxicities 
should be followed closely with additional clinical assessments and laboratory 
testing as clinically indicated.  
 
If the investigator feels that the toxicity is clearly related to another cause and 
that the toxicity is not caused by the study drug, and after consultation with the 
study team, dosing may continue. 
 
Otherwise, if the toxicity does not return to Grade 2 within 2 weeks, the study 
drug must be permanently discontinued with participant evaluations as per 
section 6.2.4. 
 

 
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NOTE: Direct and indirect bilirubin elevations that reach Grade 4 elevations 
according to the DAIDS AE Grading Table and are related to atazanavir are 
excluded from reporting. 
 
7.1.2 ALT Elevations  
 
ALT levels will be routinely evaluated at visits at month 1 and month 12. All other 
evaluations of ALT will be performed at the discretion of the site investigator 
based on participant symptoms.  
Grade 3 
Participants who develop asymptomatic >5 x ULN ALT elevations (Grade 3), 
study drug should be held for 1 week and the individual should be re-evaluated 1 
week after drug discontinuation. If at that time the ALT elevation is 5 x ULN and 
participants remain asymptomatic, the participants are eligible to continue on 
study treatment at the discretion of the site investigator. If the ALT does not 
return to ≤5 x ULN within the 1-week period, the study drug must be permanently 
discontinued unless the ALT elevations are deemed not related to study drug 
upon further assessment as per the discretion of the PCP (ie, acute hepatitis A or 
other clear causation). 
 
For any symptomatic (eg, fatigue, nausea and vomiting, right upper quadrant 
pain, rash or eosinophilia) ALT >5 x ULN (Grade 3), study drug should be held. 
Participants should be asked to return to the research site for repeat testing 1 
week later. If repeat ALT is ≤3 x ULN and the participant is no longer 
symptomatic, study drug can be resumed. 
 
Grade 4 
For any ALT >10 x ULN (Grade 4), study drug should be discontinued. The 
participant should be brought back for repeat testing every 1 week until the ALT 
≤5 x ULN.  
 
NOTE:  If the Grade 3 or 4 elevation is clearly related to another cause and not 
related to study drug (eg, acute hepatitis A infection), the participant should be 
brought back for repeat testing every 2 weeks for Grade 3 or every 1 week for 
Grade 4 until the ALT ≤3 x ULN. The local site investigators should contact the 
study team for approval before resuming study drug. Participants who 
permanently discontinue study drug will be followed on study, off treatment 
through the study termination visit with participant evaluations as per section 
6.2.4. 
 
NOTE: For those participants with ALT >3 x ULN upon repeat testing, whether 
symptomatic or not, AST, alkaline phosphatase, and total bilirubin or INR, should 
also be performed as part of the study to help determine etiology of increased 
LFTs. For participants on atazanavir, performance of INR rather than bilirubin is 
preferred. Other labs including hepatitis serologies may also be indicated and 
performed in the context of clinical care by PCP.  

 
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NOTE: If the participant has recurrent elevations of ALT >3 x ULN but the site 
investigator deems the elevation not related to study drug, the site investigator 
must contact the study team to discuss continuation of study drug.  
 
Abnormal ALT determinations occurring in the course of clinical care should be 
repeated by the treating clinician. Persistently abnormal values which would 
trigger the toxicity guidelines above should be reported to the REPRIEVE 
(A5332) team. If the ALT abnormality is not due to another cause, eg, acute 
hepatitis, the REPRIEVE (A5332) site PI will follow the toxicity algorithm above. 
7.1.3 Myalgias and Myopathy 
 
Persons who present with significant myalgias (Grade ≥3, ie, muscle pain 
causing inability to perform usual social and functional activities) should be 
evaluated with a clinical assessment that includes an evaluation of CK, serum 
creatinine, potassium, and urinalysis. Myopathy is defined as muscle aches, 
soreness, tenderness, or weakness with CK >10 x ULN not related to exercise or 
other causes, including trauma. If the symptoms are associated with Grade 3 
elevation in CK (10 x ULN) (See Table 7.1.3-1 below) that is not related to 
exercise or other cause, study medications should be permanently discontinued. 
Participants will be followed on study, off treatment through the study termination 
visit with participant evaluations as per section 6.2.4.  
 
NOTE:  Mitochondrial toxicity related to nucleoside therapy and not related to 
study medication is a possibility, and evaluations for lactic acidosis should be 
considered by the participant’s primary care provider. 
 
Table 7.1.3-1: Serum CK Toxicity Grading* 
Toxicity Grade 
Value 
Grade 1 
3 – <6 x ULN 
Grade 2 
6 – <10 x ULN 
Grade 3 
10 – <20 x ULN 
Grade 4 
≥20 x ULN 
 
 
*Not related to exercise or other cause 
 
7.1.4 Rhabdomyolysis 
 
Rhabdomyolysis is defined as the presence of myopathy as per section 7.1.3 
plus one or more of the following: 
• 
Hematuria on urine dipstick in the absence of microscopic hematuria 
(myoglobinuria) 
• 
Grade 2 hyperkalemia 
• 
Grade 2 creatinine elevation 
 
If rhabdomyolysis occurs, study medications should be permanently 
discontinued. The team should be consulted. Participants will be followed on 

 
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study, off treatment through the study termination visit with participant 
evaluations as per section 6.2.4. In addition, CK will be added to the laboratory 
evaluations performed until it has declined to ≤1 x ULN. 
 
7.2 
Requirement for Precautionary or Prohibited Medications (see PSWP) 
 
Participants who need to initiate therapy with erythromycin, colchicine, systemic (oral or 
intravenous) cyclosporine, or rifampin should be asked to hold study drug. If use of one 
of these precautionary medications is anticipated to be short-term, the site investigator 
may consider restarting study drug after use of prohibited medication is discontinued. 
Participants who begin a statin medication provided through clinical care should 
discontinue study drug. Taking two statins can increase the risk of toxicity.  
 
Participants who temporarily or permanently discontinue study treatment will be followed 
on study, off treatment through the study termination visit with participant evaluations as 
per section 6.2.4. 
 
7.3 
Pregnancy  
 
If the pregnancy test is positive at entry, then the participant should not start study 
treatment. No further evaluations are necessary, provided that the participant did not 
initiate study drug. 
 
Participants who become pregnant after study entry must discontinue study treatment 
immediately. These participants should be seen for a premature treatment 
discontinuation evaluation within 7 days. Participants will be followed on study, off 
treatment through the study termination visit with participant evaluations as per section 
6.2.4. The core team must be notified of any pregnancies that occur in participants on 
study. Management of the background ART is at the discretion of the site investigator.  
 
All pregnancies should be followed until the final outcome can be determined. In the 
event that the pregnancy has not been completed by the final study visit, the site should 
contact the participant through monthly phone calls and review of medical records, if 
possible, until the pregnancy outcome can be ascertained. See the MOPS for guidance 
on documenting pregnancy outcomes. 
 
Pregnancies that occur on study should be reported prospectively to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Phone: 800-
258-4263; Fax: 800-800-1052 (Non-US sites: Fax: 44-1628-789-666 or 910-246-0637; 
phone: 910-679-1598.) 
 
7.4 
Unblinding Procedures 
 
For unblinding requests, including emergency unblinding, refer to the ACTG Unblinding 
Participants Standard Operating Procedure (SOP) 123 at   
https://member.mis.s-3.net/cms/dl/10466 

 
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Note: Unblinding is rarely allowed as study medications can most often be withdrawn in 
a participant experiencing adverse effects without the need for unblinding. Any decision 
on unblinding should be made with reference to the ACTG SOP. 
 
In the event that emergency disclosure of treatment assignment is thought to be 
required, the site investigator must follow the ACTG Unblinding Participants SOP 123. 
 
The protocol chairs and DAIDS Medical Officer will be notified of such a request through 
the ACTG DMC unblinding program. All site e-mails to the team should be carefully 
worded to prevent unblinding the team, if possible. 
Unblinding of all study participants will take place after the last participant has completed 
the study, all data have been entered into the database and cleaned for primary and 
secondary endpoints, and MACE endpoint verification is complete. The time necessary 
to finalize the data can be up to 3 months or more after study closure. 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Premature and Permanent Treatment Discontinuation 
 
• 
Participant refusal to continue study treatment. 
• 
Drug-related toxicity per section 7.0. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
section 7.0. 
• 
Pregnancy or breast-feeding. 
• 
Use of prohibited and some precautionary medications per section 7.0. See PSWP 
for precautionary and prohibited medication list for further information. Please 
contact the study team if you have questions. 
 
NOTE: Participants who permanently discontinue study treatment will be followed on 
study, off treatment through the study termination visit with participant evaluations per 
section 6.2.4. 
 
8.2 
Premature Study Discontinuation 
 
• 
Refusal by the participant of further study follow-up. 
• 
Request by the participant to withdraw consent. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
• 
At the discretion of the ACTG, IRB/EC, Food and Drug Administration (FDA), Office 
for Human Research Protections (OHRP), NHLBI, NIAID, other government 
agencies as part of their duties, investigator, or pharmaceutical supporter.  
 
If a participant misses clinic visits for >1 year, it is at the discretion of the site PI whether 
or not to discontinue the participant from study participation. Participants who 

 
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prematurely discontinue from the study will have the premature study discontinuation 
evaluations performed as per section 6.1 and then be taken off study. 
 
In the event that a participant prematurely discontinues from the study, unless they have 
withdrawn consent, sites will attempt to obtain information regarding vital status 
(including date last seen alive, date of death, and primary cause of death) and MACE 
events from other sources (such as family members, other designated contacts, or clinic 
records) per section 6.2.4. 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
REPRIEVE (A5332) is a prospective, randomized, double-blind, placebo-controlled, 
phase III study of the effect of pitavastatin on major cardiovascular events in PWH who 
do not meet current guidelines for statin therapy. The study was originally designed to 
enroll 6500 participants with HIV on stable ART and not eligible for statins as per the 
2013 ACC/AHA guidelines. Enrollment was anticipated to take 30 months with study 
follow-up continuing for approximately 72 months after the enrollment of the first 
participant. Based on recommendations of the REPRIEVE (A5332) DSMB following their 
December 2017 review, the study sample size was increased to approximately 7500 
participants with follow-up continuing for approximately 84 months after the enrollment of 
the first participant. Based on recommendations of the NIH and the REPRIEVE DSMB 
following their December 2018 review, follow-up was extended to 96 months. Follow-up 
will now continue until the study reaches the targeted 288 primary MACE events 
or is otherwise recommended for closure by the DSMB. 
 
Further, a cap of approximately 2000 participants total enrollment of individuals with very 
low cardiovascular risk (estimated 10-year ASCVD risk score <2.5%) was implemented 
to ensure that the final study population reflects the targeted low-to-moderate-risk 
population. Subsequent to a new recommendation from the NIH, the total enrollment of 
individuals with low cardiovascular risk (10-year ASCVD risk score <5.0%) was capped 
at approximately 4200 participants, to ensure that the final study population reflects the 
targeted low-to-moderate risk population. 
 
All primary analyses will be performed as intention-to-treat and include all participants as 
randomized. 
 
A complete firewall will be maintained to ensure that investigators have no access to the 
data. All data will be kept on secure systems at Frontier Science & Technology 
Research Foundation (FSTRF). A complete description of the firewall procedures, data 
organization, and security is included in the final statistical analysis plan. The plans and 
procedures will be consistent with NHLBI and NIAID policy with respect to maintenance 
of data integrity. 
 

 
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Ancillary studies are investigations that are not part of REPRIEVE (A5332), but that 
propose questions and test hypotheses that are relevant to and further the goals and 
purposes of REPRIEVE (A5332). It is recognized that well-designed ancillary studies, 
consistent with the goals of REPRIEVE (A5332), can leverage the trial’s resources to 
provide critical answers to highly relevant questions for the field. Successful ancillary 
studies should have secured adequate funding through peer review, through either the 
ACTG, NIH, or other funding sources. To protect the integrity of REPRIEVE (A5332), 
ancillary study proposals are reviewed and approved by the REPRIEVE Ancillary 
Studies Committee and the DSMB prior to implementation. In addition to meeting the 
standard for high scientific merit, the major criterion for approval of an ancillary study is 
that it does not negatively affect the conduct of the parent REPRIEVE trial. 
For more details regarding the ancillary studies approved for implementation as part of 
REPRIEVE (A5332), please see Appendices IV and V. 
 
9.2 
Outcome Measures 
 
For all time to event study endpoints, time will be measured from the date of 
randomization to the onset date of the event of interest. 
 
9.2.1 Primary Endpoint 
 
The primary endpoint will be time to the first event of a composite of major 
cardiovascular events (primary MACE) including:  
• 
Atherosclerotic or other CVD death 
• 
Nonfatal myocardial infarction 
• 
Unstable angina hospitalization  
• 
Coronary or peripheral arterial revascularization 
• 
Nonfatal stroke or TIA 
• 
Urgent PAD ischemic event (acute or chronic limb ischemia, amputation, etc.) 
 
All primary events will be prospectively determined and adjudicated by an expert 
Clinical Events Committee based on standardized criteria used in prior 
cardiovascular trials and developed by consensus groups and the FDA [Hicks 
2015] (see section 6.4.1). Deaths adjudicated as of undetermined cause will 
be included as primary MACE endpoints. 
 
Participants discontinuing follow-up without experiencing the event will be 
considered censored at the time of their contact at which an assessment for 
primary endpoints was made; deaths from known non-CVD causes will be 
treated as competing risk events in the primary analysis. See section 9.6 for 
additional supportive analyses.  
 

 
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9.2.2 Supportive and Secondary Endpoints  
 
9.2.2.1 Time to the first of each individual component of the primary endpoint. 
 
For each event, participants discontinuing follow-up without 
experiencing the event will be considered censored; deaths from other 
causes will be considered competing risk events. 
 
9.2.2.2 Time to death (all-cause mortality)  
 
Based on independent review, death will be classified as cardiovascular 
event or non-cardiovascular event. Non-cardiovascular events will be 
further characterized as HIV-associated clinical diagnosis, non-AIDS 
malignancy, accidental, suicide, homicide, other sudden death of 
unknown etiology, or other. See Statistical Analysis Plan (SAP) for 
further details. 
9.2.2.3 Time to death (all-cause mortality) and/or MACE 
 
Participants discontinuing follow-up without experiencing the event 
(death from any cause or MACE) will be considered censored. A 
supportive outcome measure including data from vital status and 
endpoint follow-up (see section 6.3.10) will also be conducted. See SAP 
for further details. 
 
9.2.2.4 Time to any (composite) or each (individual) of the following incident 
clinical diagnoses (including recurrent diagnoses as appropriate) 
 
• 
Non AIDS-defining cancers (excluding basal cell and squamous cell 
carcinomas of the skin) 
• 
AIDS-defining events (based on CDC 2014 classification) 
• 
Initiation of dialysis or renal transplantation. 
• 
Cirrhosis, or hepatic decompensation requiring hospitalization  
 
For specific case definitions, see MOPS. 
 
For each event, participants discontinuing follow-up without 
experiencing each event will be treated as censored; deaths from other 
causes will be treated as competing risk events. 
 
9.2.2.5 Calculated fasting LDL and non-HDL cholesterol level at study entry and 
annually thereafter as well as change from baseline expressed as 
absolute change and as a percentage of baseline. For participants with 
triglycerides >400 mg/dL and <500 mg/dL, direct LDL will be determined 
and use in the statistical analysis. 
 

 
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9.2.2.6 Time to any of the following adverse events (including recurrent events 
as appropriate) 
 
• 
Serious adverse event as defined by ICH criteria 
• 
Incident Diabetes mellitus (DM) 
• 
Grade 3 or 4 ALT 
• 
Grade 3 or 4 myopathy 
• 
COVID-19 diagnosis 
• 
Serious COVID-19 diagnosis (ie, a COVID-19 diagnosis that is 
Grade 4 or results in hospitalization or death)  
 
All events will be included regardless of relationship to treatment as 
determined by sites. 
 
Grading will be defined per the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, corrected Version 2.1, July 2017. 
See section 11.4 for link to the document. 
For COVID-19 outcomes, time will be measured from January 1, 2020. 
 
9.2.2.7 Antibody-positive COVID-19 infection assessed cross-sectionally 
at specific calendar time points from samples collected annually. 
 
9.2.3 Exploratory Endpoints  
 
9.2.3.1 Fasting Total and HDL cholesterol and LDL-C/HDL-C ratio at study entry 
and annually thereafter. 
 
9.2.3.2 Time to heart failure  
 
9.3 
Randomization and Stratification 
 
At study entry, participants will be assigned with equal probability to one of the two 
treatment arms. Randomization will use permuted blocks with stratification by sex 
(male/female) and screening CD4+ T-cell counts (≤500 vs. >500 cells/mm3). Additionally, 
to ensure balanced treatment allocation for the Mechanistic Substudy of REPRIEVE 
(A5333s), randomization will also be stratified by whether or not a participant has elected 
to participate in the mechanistic substudy (yes/no). Total enrollment of individuals with 
low cardiovascular risk (10-year ASCVD risk score <5.0%) was capped at approximately 
4200 participants, to ensure that the final study population reflects the targeted low-to-
moderate risk population. It is anticipated that the study will take 48 months to fully 
enroll.  
 
9.4 
Sample Size and Accrual 
 
The original target sample size of REPRIEVE (A5332) was 6500 individuals. This was 
increased by approximately 1,000 participants or to approximately 7500 following the 

 
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December 2017 DSMB. Sample size considerations for the original target are provided 
below. Additional considerations providing justification for the increased sample size and 
duration of follow-up are also provided.  
 
9.4.1 Original Sample Size Considerations 
 
The original sample size for the main study was determined to provide 90% 
power to detect a 30% reduction in the composite CVD endpoint with statins 
(statin effectiveness equating to Hazard Ratio (HR) of 0.70). This desired effect 
size equates to a 5-year number needed to treat of 47. The effect size is more 
than the 22% based on LDL reduction alone seen in the Cholesterol Treatment 
Trialists’ collaboration [Cholesterol Treatment Trialists’ (CTT) Collaboration 
2010], consistent with the hypothesis of REPRIEVE (A5332), that statins will 
have an effect beyond LDL lowering. The HR is a more conservative effect size 
than was observed in JUPITER (a primary CVD prevention trial in people 
without HIV)―an HR of 0.56 or 44% reduction in the composite endpoint 
[Ridker 2008]. This more modest clinical effect is felt justified based on the higher 
absolute risk of CVD outcomes in PWH as well as some anticipated cross-over 
between the two study groups.  
 
Assuming a fixed sample size of 6500 individuals and total follow-up of 6 years, 
Table 9.4.1-1 shows the power under a range of alternative scenarios. For 
example, under the baseline assumption of an event rate of 15/1000 PY and 
accrual duration of 2.5 years, the sample size of 6500 participants will ensure 
90% power to detect a 30% reduction in event rates (HR = 0.70; 5-year NNT = 
47). However, with slower accrual (2.75 yrs) and lower event rates (14/1000 PY) 
REPRIEVE (A5332) will still have adequate power at 89% and 88%, respectively. 
Moreover, while power will be reduced to 83% in the case of severely reduced 
event rates of 12/1000 PY and a slower accrual rate of 2.75 years, contingencies 
to extend REPRIEVE (A5332) for a total follow up of 6.5 years while remaining 
within the scope of the current budget, will ensure a reasonable 85% power. 
 
Table 9.4.1-1: Power to Detect Given Hazard Ratio (HR) with Total Sample Size of 6500 Based 
on 2.5 Years of Accrual and 6 Years Maximal Follow-up 
 
The assumptions and justification underpinning the original REPRIEVE (A5332) 
study sample size are as follows:  
 
Design Assumptions 
Power to Detect 
Given HR 
Control rate 
of MACE 
5y event rates 
5y NNT for given 
HR 
Control 
Statin (for given HR) 
0.65 
0.70 
0.75 
0.65 
0.70 
0.75 
0.65 
0.70 
0.75 
18/1000 PY 
8.7% 
5.7% 
6.1% 
6.5% 
34 
39 
48 
99% 
94% 
83% 
15/1000 PY 
7.3% 
4.8% 
5.1% 
5.5% 
41 
47 
57 
97% 
90% 
76% 
12/1000 PY 
5.8% 
3.8% 
4.1% 
4.4% 
50 
58 
70 
93% 
83% 
67% 

 
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A composite CVD event rate of 15/1000 PY in the absence of statin therapy: 
Event rates for a similar composite endpoint were queried in the Partners 
Research Patient Data Registry (RPDR) for individuals ≥ 40 years of age, and 
determined for 3,213 thousand PWH and 26,309 thousand people without HIV 
matched on age/gender/race followed over 10 years from 2000-2009 (14,942 
person-years for PWH and 106,853 person-years for non-HIV). Event rates were 
21/1000 PY in PWH and 15/1000 PY in the non-HIV group. Further refining the 
Partners database query for incident MI, stroke, angina, revascularization among 
PWH ≥40 years, without diabetes mellitus and no recent history of statin use 
demonstrated (in alignment with the LDL independent definition of potentially 
eligible participants for REPRIEVE (A5332)) a MACE rate of 13/1000 PY. Since 
CVD death could not be obtained as part of this query, this rate likely 
underestimates the rate that could be expected in REPRIEVE (A5332). In 
JUPITER, CVD death represented 20% of all MACE. A similar adjustment would 
bring the HIV CVD event rate in Partners to 16.2/1000 PY. The placebo rate for 
MACE in JUPITER, among people without HIV was 13.6/1000 PY. The assumed 
event rate of 15/1000 PY for REPRIEVE (A5332) was felt to be a reasonable 
compromise between these rates. 
Enrollment will be completed in 30 months: Given the total study duration of 6 
years after enrollment has begun, individual participant follow-up will range from 
3.5 to 6 years, with a median follow-up of 4.75 years. REPRIEVE (A5332) will be 
conducted at approximately 100-130 sites including the majority of all domestic 
ACTG sites, and selected non-US ACTG sites as well as protocol specific sites. 
The assumed enrollment period of 30 months requires an average enrollment 
rate of 2.2 participants per site per month. Given a staggered rate of site 
activation, actual site enrollment will need to be between 3 to 4 participants per 
site per month. This enrollment rate is consistent with enrollment rates observed 
in recent large ACTG trials and with the expectations of the study sites based on 
a site survey. Further, a site survey conducted in early 2014 has suggested 
broad availability of the target study population. As of May 29, 2014, of sites 
queried, a total of 153 sites have expressed an interest in participating in 
REPRIEVE (A5332) and estimated being able to enroll 10,551 out of an 
estimated pool of 46,395 eligible participants. 
 
An annual 5% loss to follow-up rate: Since 1999, the ACTG has actively followed a 
large cohort of individuals on a limited visit schedule. During that time, the annual 
rate of lost to follow up was observed to be around 5.6%. We believe that we will be 
able to achieve a rate lower than this in REPRIEVE (A5332) since participants may 
also be receiving active treatment. Indeed, while this conservatively high estimate 
maintains power of study even in the event of 25% rate of loss over the duration of 
the study, it is desired that the observed rate will be no more than 15% over 6 years. 
 
Estimated treatment cross-over rates of 10%: REPRIEVE (A5332) is powered to 
detect a statin effectiveness equating to a HR of 0.70. The influence of treatment 
switching (crossover) on the effectiveness of statin treatment for the prevention 
of MACE and impact of this crossover on the power of the REPRIEVE (A5332) 

 
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study to detect a statin benefit as currently designed was broadly assessed via a 
simulation study. Briefly, clinical trials were simulated according to the 
REPRIEVE (A5332) design and analysis considerations. Simulated MACE times 
were accelerated and decelerated for discontinuation or initiation of statin 
treatment (for active and placebo groups respectively) over a range of crossover 
rates that were varied according to underlying MACE risk—simulated cases in 
the placebo group of higher underlying CVD risk as well as those in the statin 
group with the lowest CVD risk were assumed to have the highest rate of 
crossover. Average statin effectiveness over 6 years was estimated based on 
uncensored follow-up over >3,000,000 simulated cases. Under the base case, an 
overall rate of crossover of 10% resulted in an estimated statin effectiveness at 
the target of 0.70 for an underlying statin efficacy of 0.66. For the same statin 
efficacy, a 16% overall rate of crossover was associated with an estimated statin 
effectiveness of 0.74.  
 
9.4.2 Design Considerations following December 2017 and 2018 DSMB Reviews 
 
In follow-up to their December 2017 review, the REPRIEVE (A5332) DSMB 
recommended the following actions: 1) to cease study enrollment of patients with 
10-year ASCVD risk score less than 2.5%; 2) increase study sample size by 
approximately 1,000 participants of higher risk population; and 3) increase the 
follow-up by 1 year now and consider re-evaluation of an additional follow-up 
extension in the future [implemented following the December 2018 DSMB 
Review]. These recommendations respond to the higher than anticipated 
enrollment of participants with very low risk and ensure that REPRIEVE (A5332) 
will maintain power to detect the targeted effect of interest under a broader range 
of scenarios for the rate of MACE in the absence of a pitavastatin (control rate). 
Specifically, a total of 288 primary MACE endpoints are needed to ensure 
that the study will have 85% power to detect a hazard ratio of 0.7.  
 
9.4.3 Power Considerations for non-MACE Clinical Endpoints 
 
Since the composite rate of serious non-MACE of interest (see section 9.2.2.4) in 
the absence of statin is expected to exceed the rate of MACE, REPRIEVE 
(A5332) will be well powered to detect statin effectiveness equating to a 25% 
reduction in non-MACE or higher. 
 
If the incidence of any specific class of non-MACE in the absence of statin 
therapy is 5/1000 PY or higher, REPRIEVE (A5332) will have 90% power to 
detect a statin effect equating to a 50% reduction in the non-MACE event rate or 
higher. Published data from the ALLRT cohort [Overton 2013] suggest that the 
incidence of each of these events of interest will exceed this 5/1000 PY 
threshold. 
 

 
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9.4.4 Power Considerations for COVID-19 Objectives 
 
In March 2020, when SARS-CoV-2 infections and COVID-19 diagnoses were 
emerging in REPRIEVE enrollment areas, approximately 6650 REPRIEVE 
participants remained in follow-up.  
 
It was hypothesized that 30% of REPRIEVE participants will be antibody 
positive for exposure to SARS-CoV-2. This rate is considered a 
conservative estimate based on widespread successful implementation of 
mitigation strategies. Recent studies from NYC and other large US urban 
areas indicate infection rates of up to 30%, and this is anticipated to 
increase further, especially in less-developed Global Burden of Disease 
regions that recruited into REPRIEVE. With the use of comprehensive 
sensitive and specific state of the art antibody testing, as proposed in this 
supplement, we will be well-poised to capture a significant number of 
cases, independent of any differences in more localized testing rates. 
 
Allowing for 5% additional losses to follow-up, this will yield approximately 
2000 cases and 4650 controls for analyses, including about 200 
hospitalizations (10% of infections, ie, serious disease), and will provide 
ample numbers for the proposed epidemiology, pathobiology, genetic, and 
clinical investigations (see Table 9.4.4-1). For example, with this rate of 
antibody positivity, we will be able to estimate infection risk with a 
precision of at least ±1.2%, and will have 90% power to show a 12% 
reduction in the infection risk in the pitavastatin group (RR=0.88, 30% risk 
in the placebo group compared to 26% risk in the pitavastatin group), and 
80% power to detect a 35% relative risk reduction (RR=0.65) in serious 
disease (see table cells in blue font). Detectable effect sizes for antibody 
positivity rates of 15%-30% and power of 80%-90% are shown in the table 
below. 
 
Table 9.4.4-1: Detectable Effect Sizes for Antibody Positivity Rates of 15%-30% and 
Power of 80%-90% 
 
Power Proportion of Participants COVID-19 Antibody Positive (Control) 
30% 
20% 
15% 
Precision to 
estimate 
infection risk 
- 
±0.012% 
±0.0135% 
±0.015% 
Detectable risk 
reduction with 
given power 
90% 
12% (RR=0.88) 
15% (RR=0.85)  
18% (RR=0.82) 
85% 
11% (RR=0.89) 
14% (RR=0.86) 
17% (RR=0.83) 
80% 
10% (RR=0.90) 
13% (RR=0.87) 
16% (RR=0.84) 
 
 
Proportion of COVID-19 antibody positives experiencing serious disease 
 
 
10% 
20% 
10% 
20% 
10% 
20% 

 
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Detectable risk 
reduction with 
given power 
90% 
40% (0.60) 29% (0.71) 48% (0.52) 
35% (0.65) 
55% (0.45) 
40% (0.60) 
85% 
38% (0.62) 27% (0.73) 45% (0.55) 
33% (0.67) 
51% (0.49) 
38% (0.62) 
80% 
35% (0.65) 25% (0.75) 43% (0.57) 
31% (0.69) 
48% (0.52) 
35% (0.65) 
* Assumes sample size of 6650 with evaluable COVID-19 antibody results equally distributed 
between pitavastatin and placebo groups (see text for rationale for this number). 
 
9.5 
Monitoring 
 
The following is a summary of the data and safety monitoring plan for REPRIEVE 
(A5332). Prior to enrollment of the first participant, a detailed study monitoring and 
analysis plan document will be prepared that will more fully describe these data 
monitoring aspects including timelines and responsibilities for preparation.  
 
Summaries of accrual rates, deaths, SAEs, and targeted AEs across regimens as well 
as study conduct (in terms of off-study rates, and completeness of study visits) will be 
reviewed on a regular basis by the protocol core team with all data pooled across study 
arms. Further, in line with the NHLBI Accrual Guidelines of observed against target 
accrual benchmarks will be reviewed by NHLBI program staff at a minimum of 25%, 
50%, and 75% of the anticipated accrual period. Additional accrual reporting to NHLBI 
will be provided as requested. The timing and anticipated enrollment by 25%, 50%, and 
75% of the accrual period are shown in Table 9.5-1. 
 
Table 9.5-1: Accrual Benchmarks at 25%, 50%, and 75% of the Accrual Period 
Recruitment Period 
Time after First Patient 
Enrollment 
Projected Accrual 
25% 
7.5 months 
767 
50% 
15 months 
2740 
75% 
22.5 months 
4635 
 
The study will undergo at least annual review by an NIH appointed DSMB for study 
conduct, continued feasibility, safety, and efficacy.  
 
Unless otherwise noted, the unblinded REPRIEVE (A5332) statisticians will be 
responsible for all data analysis and report preparation to the DSMB. The DSMB will be 
appointed by NHLBI in consultation with DAIDS. For each review, the statisticians will 
prepare 3 summary reports: 1) a closed report containing all information broken down by 
masked treatment group distributed only to the DSMB; 2) a report for REPRIEVE 
(A5332) PIs and the NIH (NHLBI and DAIDS) team that will include MACE endpoint 
information pooled over both treatment groups; and 3) an open administrative report with 
administrative and safety information pooled over treatment groups. Specific contents of 
reports will be discussed with the DSMB prior to the first review. An outline of the focus 
of each review is provided in Table 9.5-2 below; further details and rationale are 
provided in the text below. These details are provided in broader detail in the Statistical 
Analysis Plan. 
 

 
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Table 9.5-2: Overview of DSMB Monitoring Focus 
Focus 
Timeframe 
Feasibility and 
conduct 
Site activation, enrollment, data and visit 
completeness, rates of loss to follow-up 
and cross-over 
At all interim reviews occurring at 
least annually 
Safety 
Rates of adverse events by treatment 
group 
At all interim reviews occurring at 
least annually 
Event rate 
evaluation 
Pooled rates of events observed to date; 
predicted confidence interval of the 
pooled event rate under a range of 
realistic scenarios* 
At all interim reviews occurring at 
least annually 
Formal 
efficacy and 
futility review 
Treatment group comparison for the 
primary endpoint utilizing group 
sequential methods 
Interim looks for efficacy are 
planned at approximately 50% 
and 75% statistical information, 
or as otherwise 
recommended**.  
* To be conducted if the pooled rate falls below a specified target (see Statistical Analysis 
Plan). 
** Statistical information for the MACE endpoint is based on the total number of expected 
MACE endpoints (see Statistical Analysis Plan for more details). 
 
The first feasibility review will occur approximately one year after the accrual of the first 
participant with a focus on site activation and patient accrual and retention as well as 
rates of treatment crossover. Benchmarks for these aspects are provided in detail in the 
Statistical Analysis Plan that will be reviewed and agreed upon by the DSMB.  
In addition to these aspects, pooled rates of events observed to date will be reviewed by 
the DSMB at all reviews to evaluate the adequacy of the sample size assumptions. 
Given the expected rate of accumulation of events it is anticipated that sufficient events 
will have been accrued to the study by the time of reviews occurring 2-2.5 years after 
enrollment of the first participant to allow reasonable determination of whether the 
underlying rate of event accumulation is inconsistent with observing the required total 
number of events to achieve 90% power to detect a HR of 0.70 at the study conclusion. 
This is illustrated by the anticipated rate of event accumulation dependent on the interim 
review timing shown in Table 9.5-3. 
 
Table 9.5-3: Anticipated Data and Event Accumulation Dependent of Interim Review Timing 
Timing of 
review (y) 
Number of 
participants 
enrolled* 
Accumulated 
person years of 
follow-up* 
Expected total accumulation of events under 
given event rate in control group (all cases 
assume the target HR of 0.7) 
15/1000 
12/1000 
10/1000 
1 
508 
127 
2 
1 
1 
1.5 
1944 
972 
12 
10 
7 
2 
3609 
707 
34 
28 
21 
2.5 
5414 
5685 
72 
58 
43 
3 
6500 
8125 
103 
82 
62 
3.5 
6500 
11375 
143 
115 
86 
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The event rate evaluation will be performed by a blinded REPRIEVE (A5332) statistician. In 
the event that the observed number of events falls short of the predetermined benchmarks 
providing in the statistical analysis plan, a predicted confidence interval analysis will be 
performed for the total expected number of MACE at trial conclusion based on accumulated 
data to date and a range of scenarios for accumulation of future data. These will include but 
not be limited to continued accumulation as observed and, under the target effect size of 
HR = 0.70, control MACE rate of 12/1000 PY and 15/1000 PY. Unless otherwise requested 
by the DSMB, these assessments along with recommendations for any study design 
changes will be presented only in the closed study report, and thus available only to 
members of the DSMB. Release of the information to the REPRIEVE (A5332) Executive 
Committee will be at the discretion of the DSMB.  
 
If any of these assessments suggest that the anticipated total number of events appear 
substantially smaller than the rate assumed for sample size considerations or if accrual 
is below anticipated, consideration will be given to modifying the design of the study. 
Such considerations may include (but will not be limited to) extending the study duration, 
increasing the target sample size, and broadening the study entry criteria to include 
individuals with low/moderate traditional CVD risk who are willing to be randomized to 
statin therapy or placebo, for example, participants who have an ASCVD risk score of 
≥7.5%. 
 
Unless there are emerging feasibility or safety concerns, guidelines for stopping or 
modifying the trial will be guided by formal efficacy review to occur once sample size 
adequacy for the study has been established. A total of four interim looks were 
planned originally: at 20% (if requested by DSMB), 40%, 60%, and 80% 
information. Per recommendation of NHLBI, endorsed by the DSMB at the 
December 2019 meeting, the timing of interim looks was changed to 50% and 75% 
information to allow for the best possible decision about extending study follow-
up duration. Inference at each interim efficacy review will be guided by a Lan-
DeMets implementation of the O’Brien-Fleming sequential stopping boundary with 
information measured on the cumulative number of primary MACE endpoints at the 
time of the review. This implementation permits early stopping only for very strong 
positive or negative effects and maintains most of the nominal power for when the 
majority of information has accrued. For example, under the hypothesized effect 
size (HR=0.7), the cumulative probability that the interim result will cross a 
boundary at 50% information is 33% compared to a 78% probability at 75% 
information. The ultimate recommendation of all reviews—irrespective of whether 
boundary p-values have been achieved—will be at the discretion of the DSMB. 
 
9.5.1 Monitoring of COVID-19-Related Outcomes 
 
The incidence of COVID-19 diagnoses and hospitalizations (pooled over 
treatment groups) will be described as part of the routine (monthly) 
REPRIEVE adverse event monitoring reports and as targeted events at 
each DSMB review. 
   

 
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9.6 
Analyses 
 
9.6.1 General Analysis Considerations 
 
The following sections provide a brief overview of the analysis considerations for 
REPRIEVE (A5332). Prior to the start of enrollment, a detailed Statistical 
Analysis Plan fully delineates all planned statistical analyses. In the event of a 
DSMB recommendation to stop the trial for efficacy at interim review, full 
analysis and publication of the primary trial results will be prepared based 
on the frozen data for the DSMB meeting. Subsequent analyses (including 
a database prepared for future data-sharing requests) will be performed 
based on the final trial database including all final study termination visits. 
In the event of a DSMB recommendation to stop for futility, full analysis 
and publication of the primary trial results will be performed based on the 
final trial database including all final study termination visits. 
 
All major treatment comparisons between the randomized groups will be 
performed according to the principle of "intention-to-treat;" that is, participants will 
be analyzed (and endpoints attributed) according to the randomized treatment 
assigned regardless of subsequent changes to that treatment; as-treated 
analyses will also be performed. Descriptive summaries of the distribution of 
continuous baseline variables will be presented in terms of percentiles (eg, 
median, 25th and 75th percentiles), while discrete variables will be summarized 
in terms of frequencies and percentages. Statistical comparisons will be 
performed using two-sided significance tests with a 5% Type I error. 
 
Unless otherwise noted, comparison of time to event outcomes will use methods 
for competing risks, notably Cox proportional hazards models for estimation of 
cause-specific hazard ratios and Gray’s test for comparison of cumulative 
incidence curves. 
 
Treatment group comparisons of continuous outcomes will use t-tests with 
transformation as needed. In the event of non-Normal distributions even after 
transformation, Wilcoxon rank sum tests will be preferred. With respect to 
discrete outcomes, Wilcoxon rank sum tests with be used for ordinal outcomes; 
Chi-squared test will be used otherwise; Fisher’s exact test will be preferred in 
the event of small cell numbers. All testing will be stratified by sex and CD4 cell 
count per randomization: while the primary analyses will not be further stratified 
by enrollment in the Mechanistic Substudy of REPRIEVE (A5333s), sensitivity 
analyses will be performed including this stratification. Additional perspective 
regarding the interpretation of the data will be provided through extensive use of 
confidence intervals and graphical displays. 
 
Given the strong plans for participant follow-up as part of the study, it is 
anticipated that missing data will be minimized. Unless examination of the data 
suggest otherwise, missing data will be assumed to be ignorable; participants 

 
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lost to follow-up before experiencing a prior endpoint will be considered non-
informatively censored. For all participants lost to follow-up, cardiovascular risk 
factors at the time of their final study visit will be described. In addition, a 
supportive analysis of time to death from any cause or MACE (outcome measure 
9.2.2.3), including data from vital status and endpoint follow-up following 
premature study discontinuation will be conducted. 
 
With the primary clinical and mechanistic hypotheses and the various secondary 
endpoints that have been outlined, it is recognized that there is a multiplicity of 
analyses to be performed, which leads to an increased probability that at least 
one of the comparisons could be "significant" by chance. Although the overall 
level of significance for all treatment comparisons will be 0.05, we will be 
conservative in the interpretation of our supporting analyses, taking into account 
the degree of significance, and looking for consistency across endpoints. 
Assessment will be made for any differences in major disease indices between 
participants in the Mechanistic Substudy of REPRIEVE (A5333s) and REPRIEVE 
(A5332). Such differences are unlikely, given that all participants in the 
Mechanistic Substudy will be eligible for REPRIEVE (A5332) and vice versa. 
Moreover, a subset of sites will be performing both and there will be overlap in 
the capacity to do both studies at selected sites. Nonetheless, we will analyze for 
any differences in the main and Mechanistic Substudy populations and account 
for any such differences in our interpretation of the Mechanistic Substudy and 
main study results. 
 
9.6.2 Primary MACE and Supportive Analyses 
 
The primary comparison of study arms for the primary composite endpoint will be 
time to event analyses and therefore based on the time from randomization to 
the first of any of the components of the primary composite endpoint. Deaths 
from non-CVD causes will be treated as competing risk events and participants 
completing follow-up without experiencing the event will be considered censored 
at the time of their last contact at which an assessment for primary endpoints 
was made. 
 
A Stratified cause-specific Cox proportional hazards model will be the primary 
analytic methods used for assessing outcome differences between the two 
treatment groups with stratification by sex and CD4 cell count at screening as 
previously noted. The relative cause specific hazard of pitavastatin versus 
placebo for MACE will be estimated with a repeated 95% confidence interval and 
compared via a Wald test; modification of the statin effect over time (non-
proportional hazards) will be evaluated with treatment by time interaction. In 
supportive analyses, the cumulative incidence of MACE will be estimated using 
the Breslow estimators of the cause-specific hazard from the Cox model 
and plotted over time by treatment group and compared via a stratified Gray 
test. 
 

 
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To complement the primary analyses, the same analytic approach will be used 
for evaluation of individual components of the primary MACE endpoint. In the 
absence of a competing risk event, treatment comparisons of all-cause mortality 
and a composite of MACE and all-cause mortality will use a stratified log-rank 
test.  
 
Poisson regression with robust variance estimates will also be used to 
incorporate multiple and repeated events in evaluation of event incidence rates 
by treatment group and rate ratios. Sensitivity analyses will be performed that 
censor individuals for whom critically significant CAD was identified as a result of 
the Mechanistic Substudy of REPRIEVE (A5333s) CCTA evaluation; censoring 
will occur at the date of the apparent CCTA study findings. 
 
9.6.3 Secondary MACE and Lipid Analyses 
 
Analyses of targeted serious clinical diagnoses (see section 9.2.2.4) will use the 
same methods as described for the primary MACE endpoint for the composite 
and individual outcomes. Analyses of a further composite outcome including the 
primary MACE outcomes (the START endpoint) will also be performed. 
 
Summary statistics (means and quantile distributions) will be provided to 
describe the distributions of LDL and non-HDL cholesterol from study entry and 
12 month intervals over time. At each annual post-entry time point, the mean 
difference in levels between treatment groups will be estimated with 95% 
confidence interval. Mixed effects models adjusted for sex and screening CD4 
cell count will be used for repeated measurements over time to estimate 
annual treatment group differences; the same analyses will be applied for other 
lipid fractions.  
 
Prognostic Factors of MACE: Important secondary aims of REPRIEVE (A5332) 
are to evaluate whether baseline traditional risk factors and time updated HIV-
specific risk factors are predictive of MACE and pitavastatin effects on MACE in 
the HIV population.  
 
Targeted risk factors of interest at (or prior to) study entry and time-updated (as 
indicated) are as follows: 
 
At study entry/screening: 
• 
Age, sex, race  
• 
ASCVD risk score 
• 
HIV-1 RNA level 
• 
CD4 cells count 
• 
Nadir CD4 cell count 
• 
Duration of ART exposure and any exposure to thymidine analogs, protease 
inhibitors, or abacavir 

 
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• 
Weight, BMI, waist circumference 
• 
Fasting lipid (TC, HDL-C and LDL-C, HDL:LDL ratio, TG) and glucose 
• 
Smoking status 
• 
Systolic and diastolic BP and use of antihypertensive agents 
• 
Presence of metabolic syndrome defined according to current guidelines at 
the time of the analysis. 
• 
Self-reported level of physical activity 
• 
Family history of heart disease 
 
Time-updated (annually unless otherwise noted): 
• 
HIV-1 RNA level 
• 
CD4 cells count 
• 
Fasting lipid (TC, HDL-C and LDL-C, HDL:LDL ratio, TG) and glucose and 
their changes expressed as absolute change and as percent of baseline 
 
Analyses will use stratified Cox proportional hazards models to estimate the 
cause-specific hazard of MACE with respect to the risk factors of interest, 
including the selected biomarkers representing surrogates from plaque 
progression as described above. In the full cohort we will include the baseline 
risk factors and evaluate modification of the statin effect by key subgroups (ie, 
race/ethnicity sex, and CD4 cell count at screening as well as HIV-related and 
CV risk factors including age, hypertension, LDL and non-HDL cholesterol at 
entry, BMI, metabolic syndrome (as defined by current NCEP guidelines at the 
time of the analysis) and smoking) by interaction terms in these models. 
  
This approach will investigate associations with LDL and non-HDL levels and 
changes from baseline as a time-updated covariate. The same approach to 
analysis will be used to assess the effects of other longitudinal outcomes. With 
respect to HIV-1 RNA levels over time, it is of particular interest to examine 
whether there is evidence of the modification of the effect of statins according to 
whether participants maintain full suppression of HIV-1 RNA levels. This will be 
examined in a 12-month landmarked Cox proportional hazards models assessing 
an interaction between continued HIV-1 RNA suppression (<400 copies/mL) over 
the first 12 months of the study as well as time-updated analysis. The analysis 
approach for assessment of effect of selected biomarkers for MACE will be 
determined based on the sampling approach to biomarker testing. Depending on 
power consideration, sampling may involve testing of the entire REPRIEVE 
(A5332) study population or a restricted sampling approach such as a case-
cohort sampling. In this case, the same analytic approach as described above 
would be utilized with appropriate weighting for the sampling fractions; an 
alternative would be case-control sampling with analyses performed using 
logistic regression. 
 
The frequency with which serious adverse events (excluding study defined 
clinical endpoints) occur will be tabulated and descriptively summarized. 

 
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Additional targeted and pre-specified adverse events that will be summarized will 
include incident diabetes, elevated liver function tests, and myositis. Statistical 
comparisons of the randomized arms with respect to adverse events will use chi-
square or other appropriate two-sample methods depending on the nature of the 
event, interpreting such comparisons in the context of differences between the 
two randomized arms in the primary and major secondary clinical endpoints.  
 
9.6.4 COVID-19 Analyses  
 
All analyses will be restricted to participants who remained in REPRIEVE 
study follow-up as of January 1, 2020. Person years of follow-up will be 
measured from January 1, 2020. 
 
The incidence of COVID-19 diagnoses and COVID-19 hospitalizations will 
be estimated, including the statin effect on the incidence of COVID-19 and 
serious COVID-19 disease via estimation of the incidence rate ratio by 
randomized treatment group. Log binomial regression will be utilized to 
assess host factors associated with COVID-19 infection as defined by a) 
SARS-CoV-2 antibody positivity and b) severe disease requiring 
hospitalization. 
 
Analyses will be stratified by global burden of disease region and 
randomized treatment and control for comorbid conditions (including 
hypertension, diabetes, kidney disease, and obesity). Further extension of 
these analyses will evaluate the influence of targeted concomitant 
medications (such as lopinavir/ritonavir and of ACE inhibitors and ARBs), 
and COVID-19 vaccination on rates of SARS-CoV-2 infection. 
 
In all analyses, death (not due to COVID-19) will be considered a censoring 
event. Discontinuation of randomized treatment will be ignored in primary 
analyses; a supportive analysis will censor at randomized treatment 
discontinuation and use inverse probability of censoring weights (IPCW) to 
estimate the statin effect when statins are being taken per protocol. 
Likewise, COVID-19 vaccination will be ignored in the primary analysis; a 
supportive analysis will censor at COVID-19 vaccination and use IPCW to 
estimate the statin effect in the absence of COVID-19 vaccination.  
 
More detailed analysis plans are provided in the REPRIEVE Statistical 
Analysis Plan. 
 
10.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 

 
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11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Electronic case report forms (CRF) are available on the DMC website. Participants must 
not be identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID), screening number (SN), and study identification number 
(SID) provided by the DMC upon randomization. 
 
11.2 
Role of Data Management 
 
Instructions concerning the recording of study data on eCRFs will be provided by the 
DMC. Each CRS is responsible for recording the data in a timely fashion. 
 
It is the responsibility of the DMC to ensure the quality of computerized data for each 
study. This role extends from protocol development to generation of the final study 
databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or in 
addition to, onsite visits to ensure the safety of study participants and data 
integrity [FDA, 2021]. The site will make available study documents for site 
monitors to review utilizing a secure platform that is HIPAA and 21 CFR Part 11 
compliant. Potential platform options include: Veeva SiteVault, site-controlled 
SharePoint or cloud-based portal, direct access to Electronic Medical Record 
(EMR), and Medidata Rave Imaging Solutions. Other secure platforms that are 21 
CFR Part 11 compliant may be utilized, as allowed by the DAIDS Office of Clinical 
Site Oversight (OCSO).   
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
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. For questions about DAERS, please contact 
DAIDS-ES (now part of the NIAID Clinical Research Management System) at 

 
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CRMSsupport@niaid.nih.gov. Site queries may also be sent from within the 
DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current 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 EAE reporting, please contact the 
RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study with certain exceptions as noted below. 
Unless the site investigator considers the following events to be study drug-
related, DO NOT REPORT them as EAEs:  
• 
AIDS-defining events (see MOPS for a listing) 
• 
REPRIEVE MACE (see section 9.2.1 for complete listing) and related CVD 
events: CVD death, MI, stroke, TIA, unstable angina, peripheral ischemia, 
coronary or peripheral reperfusion procedures, heart failure, and all deaths 
(because they are components of the primary endpoint or additional 
adjudicated CVD endpoint). See MOPS for details about reporting CVD 
Endpoints). 
• 
COVID-19 hospitalizations. 
 
NOTE: COVID-19 is a novel disease that has emerged since protocol 
version 5.0 was distributed. Given our evolving understanding of this viral 
infection, and the likelihood of subclinical cardiac injury during COVID-19 
hospitalization, the requirement for reporting COVID-19 infection has been 
outlined in greater detail in the MOPS.  
 
The study agents for which expedited reporting are required are pitavastatin and 
placebo for pitavastatin. 
  
11.4.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, is 
available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
11.4.4 Expedited AE Reporting Period 
 
The expedited AE reporting period for this study is the entire study duration for 
an individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
 

 
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After the protocol-defined AE reporting period, unless otherwise noted, only 
SUSARs (suspected unexpected serious adverse reactions) as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
12.0 
PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB/EC responsible for oversight of 
the study. A signed consent form will be obtained from the participant (or legal 
representative). The consent form will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant or legal representative, and this fact will be documented in the 
participant’s record. Risks, including potential risks of pitavastatin, and protection against 
risk are described in the accompanying sample informed consent form. 
 
12.2 
Participant Confidentiality  
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NHLBI, 
NIAID, OHRP, and other local, US, and international regulatory entities as part of their 
duties, or the industry supporters or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, NHLBI, 
OHRP, or the industry supporter, or other government agencies as part of their duties to 
ensure that research participants are protected. 
12.4 
Women and Minorities  
 
REPRIEVE (A5332) will aim to recruit women and minority participants commensurate 
with the population demographic for HIV in the US. The prevalence of HIV among 
women in the US is approximately 22%, while over half of PWH in the US are minorities 
(CDC 2014). 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by NHLBI and NIAID policies. 
 

 
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14.0 
BIOHAZARD CONTAINMENT  
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  
 
15.0 
STUDY GOVERNANCE 
 
• 
There is an Executive Committee, a DSMB, and an External Advisory Board. 
• 
There are various other operational committees to ensure that the trial progresses 
smoothly.  
• 
There is a Clinical Events Committee (CEC) charter.  
 
 

 
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16.0 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
For the REPRIEVE (A5332) Protocol, FINAL Version 6.0, 16May2022 
 
Randomized Trial to Prevent Vascular Events in HIV (The REPRIEVE Study) 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are living with the human 
immunodeficiency virus (HIV), the virus that causes AIDS, and you are taking HIV medications.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
Since people started taking HIV medications, illness from AIDS has decreased, but other 
serious diseases, like heart disease, have increased. HIV causes inflammation (irritation) inside 
the body that cannot be felt but can be measured. These tests will be described later in this 
consent form. Inflammation may contribute to diseases such as heart disease that have become 
some of the leading causes of death in people with HIV (PWH). HIV medications can lower 
inflammation somewhat, however sometimes the levels of inflammation can remain higher 
compared to people without HIV. 
 
Statins are a group of medicines used to lower the levels of cholesterol and triglycerides (fat in 
the blood) that people make and to prevent heart-related disease events such as heart attacks 
in persons with high risk for heart attacks. Studies have shown that statins may have other 
benefits. For example, by decreasing levels of inflammation, statins may have an effect to 
protect against heart disease and its related events. In addition, statins may have some 
beneficial effects on some other diseases like some cancers or kidney problems. 
 
The most recent guidelines from the American College of Cardiology and the American Heart 
Association (ACC/AHA) recommend the use of statins if someone is at risk of heart-related 
disease based on many different factors, including the use of a risk calculator based on known 
risk factors including gender, age, race, cholesterol levels, tobacco use, diabetes, and 
hypertension that estimates the 10-year risk of heart attack, stroke, or other event (the ASCVD 
risk score). HIV infection is not included in the risk calculator. The current risk calculators may 
not accurately predict the risk in PWH. However, HIV infection, HIV medications, and chronic 
inflammation may put you at higher risk for these diseases, although we do not know if you 
would benefit from taking a statin. You are eligible for this study because you are in a low-to-
moderate-risk group for heart disease under the current guidelines, and there is no consensus 
about whether PWH in this group should take statins. Your participation in this study will help us 

 
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determine if the use of statins can prevent heart-related disease among PWH. The results of 
this study may help to create guidelines for the prevention of heart disease in HIV infection. 
For HIV-negative individuals with an ASCVD risk score between 7.5% and 15%, the current 
guidelines recommend a discussion between the health care provider and patients about the 
risks and benefits of statin therapy and recommend initiating statins based on available clinical 
trial data. However, for PWH with a moderate-risk for heart disease (a risk score between 7.5% 
and 15%), no currently available data clearly tell us whether the benefits of statin therapy 
outweigh the risks, including adverse effects and potential drug-drug interactions. Some health 
care providers may elect to treat PWH in this moderate-risk range with statin therapy, and this 
option may be available to you, rather than participating in the trial. Ultimately, the results of this 
trial will provide data to guide the use of statins for PWH. 
 
Pitavastatin is a statin that, along with a diet, has been approved by the US Food and Drug 
Administration for the treatment of high cholesterol. It also lowers triglyceride levels in the blood. 
It has not been studied to see if it reduces heart-related disease or death. Pitavastatin was 
chosen because there are thought to be few interactions between pitavastatin and commonly 
used HIV medications. 
 
The main purpose of this clinical trial is to see if pitavastatin can prevent heart disease and 
heart-related deaths in PWH who are taking HIV medications. We will also study the safety of 
pitavastatin.  
 
 
HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 7500 people will take part in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Study visits 
If you enter the study, you will be seen in the clinic about 6 times the first year. After that, the 
study visits are every 4 months for the next 6-10 years depending on when you join. The 
study staff will tell you about how long each visit will be. More details about the visits and 
procedures are below. 
 
If you do not enter the study 
If you decide not to take part in this study after signing the consent form, or if you do not meet 
the eligibility requirements, we will still use some of your information. As part of this screening 
visit, some demographic (for example, age, gender, race), clinical (for example, disease 
condition, diagnosis), and laboratory (for example, safety tests) information is being collected 
from you so that AIDS Clinical Trials Group (ACTG) researchers may help determine whether 
there are patterns or common reasons why people do not join a study.  
 

 
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Study drugs 
If you enter the study, you will be randomly assigned (as if by the toss of a coin) to get either 
pitavastatin or a placebo for pitavastatin. The placebo is a tablet that looks just like pitavastatin 
but does not contain any active medication. Therefore, there is a chance that if you are 
randomized to the placebo you will receive no treatment during your participation in the study. 
We use placebos in clinical studies to learn if the effects seen in the trial are truly from the study 
medicine or from other reasons. Neither you nor the study staff will know your assignment. You 
will not find out your assignment until after the entire study is over and the results of the study 
are known. You and your doctor can be told of the assignment at any point if it is necessary for 
your health. 
 
You will take the study medicine (either pitavastatin or the placebo for pitavastatin) once a day, 
every day, throughout the study period, with or without food. The dose is 4 mg. We recommend 
that you take the study medicine at the same time each day. These drugs are provided by the 
study. It is very important that you take your medicines as directed. At every visit after entry, we 
will ask you about how you have been taking your study drugs. Antiretroviral drugs (treatment 
for HIV) will not be provided by the study. 
 
Study procedures 
The study staff can answer any questions you have about individual study visits and the 
procedures. The table below can be used as a quick reference, along with the explanations that 
follow. 
 
Appendix I, Table 1: Study Procedures 
Procedure 
Screening1 
Entry2 
Month 1 
Visits every 4 
months 
(starting at 
month 4) 
Annual visits 
(starting at 
month 12) 
Final visit 
Physical exam 
X 
 
X 
 
X 
X 
Heart disease risk 
assessment 
X 
 
 
 
 
 
Heart disease risk 
factors  
X 
 
 
 
 
 
Diet and exercise 
questions 
 
X 
 
 
 
X 
Dispense lifestyle 
information 
 
X 
 
 
X 
X 
Health and medicine 
questions 
X3 
X 
X 
X5 
X5 
X3, 5 
Blood collected 
X 
X 
X 
 
X  
X 
Urine collected 
 
X 
 
 
X4 
 
Pregnancy test 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
X 
 
 
 
 
Pills dispensed  
 
X 
 
X 
X 
 
1  Screening visit: before you can enter the study, you will need to come to the clinic to have evaluations 
done to make sure that you can take part in the study. 
2 Entry visit: if you meet the entry requirements, you will enroll in the study. 

 
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3 This will also include hormonal assessment for women.  
4 ACTG Sites ONLY: Urine will be collected at months 12, 24, and 48 only for people enrolled in 
REPRIEVE (A5332) before January 1, 2018. 
5 This will include a COVID-19 assessment for all participants. 
 
If you leave the study early, or have to stop taking the study medication before the study is over, 
you will have the procedures listed in the table below. 
Appendix I, Table 2: Discontinuation Study Procedures  
Procedure 
Stopping the study or the study 
treatment early 
Physical exam 
X 
Health and medicine questions 
X1 
Pregnancy test 
X 
Blood collected 
X 
Fasting blood tests 
X 
1 This will also include hormonal assessment for women and a COVID-19 assessment 
for all participants.   
 
Explanation of study procedures 
 
Physical exam 
You will have a physical exam at screening. At other visits after entry, the extent of the exam will 
depend on how you are feeling at that visit. You will have vital signs taken, including, blood 
pressure and pulse. You will have measurements taken of your waist and height and weight. 
You will be asked questions about your health and medicines.  
 
Heart disease risk assessment 
At screening we will ask specific questions to assess eligibility based on cardiovascular disease 
risk. At screening you will also be asked about cardiovascular risk factors including your family 
history, smoking, alcohol use, substance use, diet, and exercise. 
 
Lifestyle /risk reduction counseling 
If you join the study, you will be given information about a healthy diet and the importance of 
exercise, smoking cessation, and taking your antiretroviral therapy and study medication as 
prescribed. We will provide this information at all annual visits. 
 
ECG 
An electrocardiogram, or ECG, will be done at entry. An ECG is an electrical tracing of your 
heart that can show how hard it is working. You will have to lie very still for up to 10 minutes 
while the ECG is being done. 
 
Blood collected 
Blood will be collected from you for different tests if they are not available as part of your routine 
medical care or for safety reasons. These include routine tests to evaluate your blood counts, 
liver, and kidney function. 
 

 
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At screen we will use the results of your liver function tests done as part of routine care by your 
medical provider. At month 1 and month 12 we will collect blood from you to evaluate your liver 
function. This test is required as part of your participation in the study. Approximately 1 
teaspoon of blood at each of these visits will be collected for this test. 
 
At screen and the end of study visit we will use the results of your CBC (blood count) and kidney 
function done as part of routine care by your medical provider. 
At screen and annual visits we will use the results of your CD4 T-cell count (how many infection 
fighting cells are in your blood) done as part of routine care by your medical provider.  
 
At entry and annual visits we will use the results of your HIV viral load (how much HIV is in your 
blood) done as part of your routine care by your medical provider.  
 
At screen we will use the results of your cholesterol (fat found in your blood) levels done as part 
of routine care by your medical provider. 
 
You will be told the results of these routine tests. 
 
At entry, all annual visits, and the end of study visit, some blood will be collected and stored for 
tests that will be done later on in the study or after the study is over. These tests will measure 
the levels of fat and sugar in your blood. Some of these tests will be used for metabolic blood 
tests (measures how your body uses the food that you eat). You do not need to agree to store 
this blood to join the study and you may change your mind about storing your blood at any time. 
Your blood may be stored (with usual protectors of identity) for an indefinite length of time. You 
will not be told of the results of the research done on your blood.  
 
At each of these visits, approximately 2 teaspoons of your blood will be collected and stored for 
these purposes.  
 
Do you agree to let us store your samples for tests to measure the levels of fat and sugar in 
your blood? 
 
________ YES ________ NO 
_______Initials 
 
At entry, all annual visits (as indicated in the Study Procedures table), and the end of study visit, 
some of your blood will be collected and stored for future REPRIEVE-approved research on 
conditions including cardiovascular disease, HIV, inflammation, cancer or statin medications. 
You do not need to agree to store this blood to join the study and you may change your mind 
about storing your blood at any time. Your blood may be stored (with the usual protectors of 
identity) for an indefinite length of time. You will not be told of the results of the research done 
on your blood.  
 
Up to 15 teaspoons of blood will be collected at each of these visits for these purposes.  
 
Do you agree to let us store your samples for future research on conditions including 
cardiovascular disease, HIV, inflammation, cancer, and statin medications? 

 
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________ YES ________ NO 
_______Initials 
 
 
 
 
 
 
If at a later date you change your mind and want your samples destroyed, contact the research 
staff. There are two ways to withdraw your permission. You could allow researchers to remove 
all your personal identifiers from your samples, so that they are not linked to you anymore. 
These samples will then become anonymous. Or, you can ask researchers to destroy your 
samples, so that they cannot be used for future research. However, in either case, researchers 
will not be able to destroy samples or information from research that is already underway. 
 
 
 
All ACTG sites will add to their local consent: Approximately 1 teaspoon of blood will be collected 
to look at genes that may affect your risk for cardiovascular disease and how statins work in your 
body. Genetic testing is a laboratory test that looks at differences in people’s genes. Your body, 
like all living things, is made up of cells, and cells contain deoxyribonucleic acid, also known as 
“DNA.” DNA is like a string of information put together in a certain order. Parts of the string make 
up “genes.” Genes contain instructions on how to make your body work and fight disease. The 
testing in this study will focus on certain genes that are known to have an effect on cardiovascular 
disease and how your body uses statins. New genes of interest may be identified in the future and 
may also be looked at.  
 
Your body’s genetic makeup is unique to you, so there is a risk with genetic research that even 
with all of the security measures in place, someone using your samples or genetic information 
may still find out which information is yours. However, this risk today is very small, but it may 
increase with time since science and technology are developing rapidly.  
ONLY ACTG sites in the US will add to their local consent: In the event that your genetic 
information becomes linked to your name, the US federal law called the Genetic Information 
Nondiscrimination Act (GINA) helps protect you. This law prohibits health insurance companies, 
group health plans, and most employers from denying services based on your genetic information. 
However, GINA does not protect against discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance. 
All ACTG sites will add this participant opt-out to their local consent: We would like to use some of 
the blood we collect to look at your genes (DNA). Do you agree to this genotyping? 
 
________ YES ________ NO 
_______Initials 
For all Non-US sites to add to their local consent: Your samples may be shipped and stored 
outside of your country and may be used by researchers outside of your country. 

 
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Urine collected 
Urine will be collected at entry to check for protein in your urine. The results from this test will 
not be known immediately; therefore we cannot make sure that you will be told the results of this 
test. 
 
Fasting blood tests 
Before the screen, entry and all annual visits you should not eat or drink anything, including 
food, beverages, candy, or gum for 8 hours before your visit. You are encouraged to drink water 
before your visits. If you are not fasting we will ask you to return while fasting to have your blood 
drawn within 30 days of the study visit.  
 
Study drugs given to you 
Study drugs will be given to you at entry and every 4 months. No study drugs will be given to 
you at your final study visit. 
 
Questionnaires 
You will be asked questions about your diet and exercise at entry and this will be repeated the 
final study visit. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study about 6-10 years (72-120 months) depending on when you join.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the doctor thinks it is in your best interest 
• 
the study is cancelled 
• 
you are not able to attend the study visits as required by the study 
  
The study doctor may also need to take you off the study drug without your permission if: 
• 
you are not able to take the study drug as required by the study 
• 
continuing the study drug may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you become pregnant 
 
If you must stop taking the study drug before the study is over, we will ask you to continue to be 
part of the study and return for some study visits and procedures. 
 
Only ACTG Sites will add to their local consent: For participants enrolled in RERIEVE 
(A5332) before January 1, 2018, urine will also be collected at months 12, 24, and 48 to 
check measures of kidney function. 

 
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If you have to permanently stop taking the study drug, or if you leave the study, how would 
pitavastatin be provided? 
 
During the study: 
If you must permanently stop taking study-provided pitavastatin before your study participation 
is over, the study staff will discuss other options that may be of benefit to you. If you discontinue 
active participation in the study, study staff will contact you, your provided contacts, the medical 
records department, or your health care provider annually to determine if you have had any 
heart disease, stroke, or vascular-related disease events or procedures, or if you have died (and 
the cause of death since last contact). 
 
After the study: 
After you have completed your study participation, the study will not be able to continue to 
provide you with the pitavastatin you received on the study. If continuing to take this or a similar 
drug would be of benefit to you, the study staff will discuss how you may be able to obtain the 
drug. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with this drug. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious or life-threatening side effects when non-study medications are taken 
with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
  
Risks of Pitavastatin 
• 
Muscle problems. Pitavastatin can occasionally cause serious muscle problems that can 
lead to kidney problems, including kidney failure and rarely, death.  
• 
Liver problems. Pitavastatin can occasionally cause liver problems that may rarely be 
serious or cause death. Your study nurse or doctor will do blood tests to check your liver 
before you start taking pitavastatin and while you take it. 
• 
Be sure to let your doctor or study nurse know immediately if you have any of these 
problems:  
▪ 
Muscle problems like weakness, tenderness, or pains that happen without a good reason, 
especially if you also have a fever or feel more tired than usual. 
▪ 
Nausea and vomiting. 
▪ 
Passing brown or dark-colored urine. 
▪ 
Feeling more tired than usual. 
▪ 
Noticing the skin and whites of your eyes become yellow.  

 
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▪ 
Having stomach pain. 
Other problems that have been caused by pitavastatin include headaches, rash (which rarely 
may be severe or fatal), severe allergic reaction or swelling, constipation, gas, diarrhea, pain or 
numbness in arms or legs, tendon rupture, urinary tract infection, dizziness, memory 
impairment, and depression. All of these problems are uncommon to rare. 
 
Risks of drawing blood 
Taking blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of fasting 
Some people find fasting to be bothersome. It may make some individuals feel anxious, irritable, 
or hungry. Patients who are required to take their morning medications with food should wait 
until after the visit has been completed to take their medications. 
 
Risks of ECG 
You may experience mild irritation, slight redness and itching on your skin where the electrodes 
from the electrocardiogram machine are placed. 
 
 
 
Unknown risks 
Other side effects that are not known at this time could happen during the study. All drugs have 
a possible risk of an allergic reaction, which if not treated right away, could become life-
threatening. During the study, you will be told about any new information that may affect your 
decision to stay in the study. If you decide to stay in the study, you will be asked to sign an 
updated consent form. If you decide to leave the study early, the study staff will talk with you 
about your treatment options. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Pitavastatin is unsafe for unborn babies. The risks to the unborn baby include birth defects, 
premature delivery, or death. If you are having sex that could lead to pregnancy, you must 
agree not to become pregnant. 
ALL ACTG sites will add to their local consent:  
 
Genetic Testing 
The results of your genetic tests are for research purposes only and no individual results will be 
given back to you. The results of the genetic studies will never become a part of your medical 
record. We will protect your confidentiality to the fullest extent. Blood samples for genetic studies 
will be identified in a way in order to maintain your confidentiality. 
 
Research study results will not be given to your family members, insurance companies, 
employers, or third parties without your written permission and approval of the Institutional Review 
Board at _________.  

 
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If you can become pregnant, you must have a pregnancy test before you enter this study and at 
every visit (1 teaspoon of blood or a urine specimen will be collected) and at any time that 
pregnancy is suspected. This test must show that you are not pregnant. If you become pregnant 
or think you may be pregnant at any time during the study, tell your study staff right away. The 
study staff will talk to you about your choices. 
 
Because of the risk involved, you and your partner must use at least one accepted form of birth 
control that you discuss with the study staff. You must start an accepted form of birth control at 
least two weeks before you start study drug and continue to use an accepted form of birth 
control until at least 6 weeks after you stop the study drug. If you are having sex that could lead 
to pregnancy, and do not use an accepted form of birth control, your study doctor will take you 
off of the study drug. You may choose from the birth control methods listed below: 
• 
Condoms (male or female), with or without a spermicidal agent 
• 
A diaphragm or cervical cap with spermicide 
• 
An IUD (intrauterine device) 
• 
Tubal ligation 
• 
Tubal micro-inserts 
• 
Hormone-based contraceptive 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
Breastfeeding 
It is not known whether the study drug pass through the breast milk and may cause harm to 
your infant. Women who start breastfeeding must stop taking the provided study drug. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
Studies have shown statins to provide a benefit in terms of preventing heart disease in people 
without HIV with inflammation, but the effects of statins to prevent heart disease in PWH is not 
known. If you take part in this study, there may be a direct benefit to you, but no guarantee can 
be made. You may benefit from learning about your risk of a cardiovascular event, but it is also 
possible that you may receive no benefit from being in this study either because the drug may 
not work or because you are assigned to placebo. Information learned from this study may help 
others who have HIV and are at risk of cardiovascular disease. 
 
 

 
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WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
Treatment with prescription drugs available to you 
• 
Treatment with experimental drugs, if you qualify  
• 
No treatment 
• 
Continue routine medical care from your primary care provider 
• 
Joining another trial if you qualify 
• 
Not getting medical care 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
 
For ALL US sites: We will do everything we can to protect your privacy. In addition to the efforts of 
the study staff to help keep your personal information private, we have gotten a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. Also, any publication of this study will not use your name or identify you 
personally. 
 
People who may review your records include the AIDS Clinical Trials Group (ACTG), Office for 
Human Research Protections (OHRP) or other government agencies as part of their duties, Food 
and Drug Administration (FDA) (insert name of site) IRB/EC (a group that protects the rights and 
well-being of people in research), National Institutes of Health (NIH), other local, US, and 
international regulatory entities, study staff, study monitors, the drug companies supporting this 
study, and their designees. Having a Certificate of Confidentiality does not prevent you from 
releasing information about yourself and your participation in the study.  
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities.  

 
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OR 
 
 
 
A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required 
by US law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
 
WHAT IF WE CAN NO LONGER REACH YOU DURING THE STUDY? 
 
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained at screening and updated at each visit. If you are unable to be reached 
through the alternate contacts we will attempt to obtain information about you from other 
sources such as family members, other designated contacts, or clinic records. The purpose of 
obtaining this information is to determine if you have died and the cause of death since last 
contact and if you have had any heart disease, stroke, or vascular-related disease events or 
procedures. 
 
Contacting Your Health Care Providers 
Sites to modify per local requirements for obtaining health care records: As mentioned above, 
we do not currently have data to tell us if PWH with moderate cardiovascular disease risk by the 
ASCVD risk calculator should be treated with statins. If you are in this moderate-risk group, with 
a risk score between 7.5% and 15%, we would like to inform your health care provider(s) about 
the rationale for the trial, but we need your permission to share this information. 
 
Also, with your permission, for which you would need to sign a waiver, study staff may contact 
your health care providers regarding any clinical diagnoses you may develop during the study, 
For ALL Non-US sites: Efforts will be made to keep your personal information confidential. We 
cannot guarantee absolute confidentiality. Your personal information may be disclosed if required 
by law. Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, OHRP, FDA, (insert name of site) IRB/EC, National 
Institutes of Health (NIH), other local, US, and international regulatory entities, national 
regulatory/health agencies, study staff, study monitors, and the drug company supporting this 
study and its designees. 
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with information 
from other study participants and statistical analysis of study results. Your name and other 
personal identifiers will not be sent. Your research site is responsible for sending your 
information in accordance with the laws, regulations, and policies of your country and 
research site. (No new procedures in data collection) 

 
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including heart related diagnoses and other diagnoses, such as HIV, kidney, liver or cancer 
diagnoses.  
 
Will you allow us to contact your health care provider(s) to share information regarding your 
cardiovascular risk score and rationale for the trial, and to provide information regarding clinical 
diagnoses and to let your doctor know that he/she could object to your taking part in this study 
since you have a chance of getting placebo instead of treatment with statins? 
 
 
________ YES ________ NO 
_______Initials 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases, it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study.  
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be paid ________ at the entry visit, the month 1 visit, and annual visits thereafter for 
participation in the study. (The team recommends compensation to participants of $25 at every 
annual visit and study termination visit). Sites will be reimbursed for the expense.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  
 
For all sites: NIH does not have a mechanism to provide direct compensation for 
research-related injury.   
 
[Sites: Please modify (if necessary) and insert one of these two statements, as 
appropriate to your site. If your site is required to carry CTI, this must be indicated in the 
informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you 
with monetary compensation if you suffer harm as a result of participating in this 
research study.  
OR 

 
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• 
The cost for this treatment will be charged to you or your insurance company. There 
is no program for compensation either through this institution or the NIH.] 
 
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
  
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
name or title of person on the Institutional Review Board (IRB/EC) or other organization 
appropriate for the site 
• 
telephone number of above 
 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 

 
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APPENDIX IA: SAMPLE INFORMED CONSENT ADDENDUM 
 
For the Randomized Trial to Prevent Vascular Events in HIV ‒ (REPRIEVE) (A5332) 
FINAL Version 6.0, 16May2022 
 
 
SHORT TITLE FOR THE STUDY: REPRIEVE 
 
You are being asked to sign this consent addendum because you are participating in a 
research study at _____________, entitled “Randomized Trial to Prevent Vascular Events 
in HIV ‒ REPRIEVE (A5332).” 
 
The purpose of this addendum is to include information about sharing your de-identified 
genetic information. “De-identified” means that all information that identifies you, for 
example, your name, medical record number, and date of birth, has been removed. 
 
The genetic information was obtained from the blood sample that was collected from you 
at the entry visit. You consented to provide this sample in the original consent. 
 
Except for the activities described in this addendum, the terms of your original consent 
form remain in full effect, including that research study results will not be given to your 
family members, insurance companies, or employers without your written permission 
and approval of the Institutional Review Board/Ethics Committee at 
____________________.  
 
Please read this consent addendum carefully and take your time making your decision. 
As your study doctor or study staff discusses this addendum with you, please ask them 
to explain any words or information that you do not clearly understand.   
You do not have to sign this addendum to remain in REPRIEVE (A5332). 
 
SHARING OF YOUR GENETIC INFORMATION 
Illness and health are affected by the genes or genetic information we have inside of us. 
The genetic information we collect in this study may help advance other types of 
research. The National Institutes of Health (NIH) has established a program to let 
researchers share genetic information from different studies to help us learn more from 
each study that is funded by the NIH. Your genetic information will be shared with other 
researchers through a secure, controlled-access database supported by the NIH.   
 
When we share your genetic information with other researchers through a secure, 
controlled-access database supported by the NIH, including whole genome studies (such 
as determining your complete DNA sequence at a single time), we will remove all 
information that identifies you. This de-identified information may be used in other 
research. We do not think that there will be further risks to your privacy and 
confidentiality by sharing your genetic information with this controlled-access 
database. However, we cannot predict how genetic information will be used in the future. 

 
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Your name or other directly identifiable information will not be given to the controlled-
access database supported by the NIH. There are many other safeguards in place to 
protect your information while it is stored in the controlled-access database and used for 
research. Even so, it may become possible in the future that someone can re-identify 
your information. Also, using the controlled-access database, researchers may publish 
or present combined results of their research, but they will not include your name or 
other information that can identify you. 
 
There is no expected direct benefit to you from research using your genetic information. 
You can withdraw consent for sharing your genetic information at any time. However, we 
cannot get back any information that has already been shared. 
 
Do you agree to share your genetic information? 
 
________YES ___________NO _________Initials 
 
OTHER 
All other information that is contained in the REPRIEVE (A5332) consent that you signed 
also applies to this consent addendum. A copy of this signed consent will be provided 
for you as a reference at the time you consent to the information in this addendum. 
 
QUESTIONS REGARDING THIS CONSENT ADDENDUM  
If you have any questions, concerns, or complaints concerning this consent addendum, 
please contact Dr. (name) at (number) during regular business hours, and at (pager) after 
hours and on weekends and holidays. 
 
For questions about your rights as a research participant, or to discuss questions, 
concerns, or suggestions related to the research or this consent addendum, or to obtain 
information or offer input about the research, please contact the 
_____________Institutional Review Board/Ethics Committee Office at (number). 
 
STATEMENT OF CONSENT 
“The purpose of this consent addendum has been explained to me. I have been allowed 
to ask questions, and my questions have been answered to my satisfaction. I have been 
told whom to contact if I have questions, to discuss problems, concerns, or suggestions 
related to the research or this addendum, or to obtain information or offer input about the 
research. I have read this addendum and agree to the choices I have indicated above, 
with the understanding that I may withdraw my consent at any time. I have been told that 
I will be given a signed and dated copy of this addendum.” 
 
 
 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have 
been answered, and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Representative (print) Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 

 
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APPENDIX II: THE MECHANISTIC SUBSTUDY OF REPRIEVE (A5333s) 
 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: 
Mechanistic Substudy of REPRIEVE 
 
 
Principal Investigators: 
Steven Grinspoon, MD 
 
Pamela Douglas, MD 
 
Udo Hoffmann, MD, MPH 
 
Heather Ribaudo, PhD 
 
 
AIDS Clinical Trials Group  
Investigators: 
Turner Overton, MD 
 
Carl Fichtenbaum, MD 
 
Judith Aberg, MD 
 
Markella Zanni, MD 
 
 
Data Coordinating Center: 
Harvard School of Public Health 
 
 
Study Funders: 
National Heart, Lung, and Blood Institute 
 
National Institute of Allergy and Infectious Diseases 
 
Office of AIDS Research, National Institutes of Health 
 
 
Industry Support: 
Kowa Pharmaceuticals America 
Gilead Sciences 
ViiV Healthcare 
 
NHLBI Program and Medical 
Officer: 
Patrice M. Desvigne-Nickens, MD 
 
 
DAIDS Medical Officer: 
Karin L. Klingman, MD 
 
 
IND Sponsor: 
Division of AIDS, NIAID, NIH 
 
 
IND Number: 
119127 
 
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SITES PARTICIPATING IN THE MECHANISTIC SUBSTUDY of REPRIEVE (A5333s) 
 
The Mechanistic Substudy of REPRIEVE (A5333s) is open to selected sites that are 
participating in the REPRIEVE (A5332) study. 
 
EXECUTIVE SUMMARY 
 
Title 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers:  
Mechanistic Substudy of REPRIEVE (A5333s) 
Indication 
Assess the effects of statins on critical plaque and inflammatory characteristics to understand 
mechanism of action in HIV 
Location 
Selected sites of the REPRIEVE (A5332) study 
Brief 
Rationale 
The Mechanistic Substudy of REPRIEVE (A5333s) will determine, among HIV-infected persons, 
potential statin effects to halt progression of non-calcified atherosclerotic plaque and to stabilize 
morphologic features of plaque vulnerability. Moreover, the study will identify biological factors 
mediating these changes – be it lipid parameters, such as LDL cholesterol, or markers of 
inflammation and immune activation. 
Study Design 
and Duration 
Randomized, placebo-controlled multicenter substudy of REPRIEVE (A5332) in 800 subjects, 
with individual subjects participating in the substudy for 2 years. 
Treatment 
Pitavastatin 4 mg PO daily or placebo for pitavastatin. 
Primary 
Objective 
To determine the effects of pitavastatin on the morphology and composition of non-calcified 
coronary atherosclerotic plaque (NCP), including the progression of plaque volume and whether 
these effects are modulated by markers of inflammation and immune activation. 
Key 
Secondary 
Objectives 
1. The effects of pitavastatin on the progression of high risk plaque features including low 
attenuation plaque and positive remodeling. 
2. The effects of pitavastatin on detailed markers of immune activation, immune activation, 
inflammation, coagulation, and traditional CVD risk indices including detailed parameters of 
glucose homeostasis (insulin, glucose and related indices of insulin resistance such as 
HOMA-IR, HgbA1c). 
3. The relative contributions of baseline and pitavastatin induced changes in HIV-specific 
immune activation and traditional risk factors, including LDL, on the presence and 
progression of coronary plaque and high risk morphological features in HIV. 
Primary 
Endpoint 
Noncalcified plaque volume on coronary computed tomography angiography (CCTA) 
Secondary 
Endpoints 
High risk plaque features on CCTA 
Detailed immune phenotyping measures and inflammatory and coagulation indices as well as 
detailed measures of glucose homeostasis 
Abbreviated 
Study Flow 
Subjects will be coenrolled at specific sites participating in the Mechanistic Substudy of 
REPRIEVE (A5333s). Enrollment and treatment will be identical as in REPRIEVE (A5332), but 
endpoints will be collected over 2-year study duration for each enrolled patient. 

 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES  
 
1.1 
Primary Mechanistic Hypothesis  
 
Statin therapy will reduce progression of non-calcified coronary atherosclerotic plaque 
volume over two years as measured by serial coronary computed tomography 
angiography (CCTA) as compared with placebo in HIV-infected patients on ART in 
whom traditional CVD risk is not significantly increased. The mechanisms underlying the 
effect of statins will include a) reduction in non-calcified coronary atherosclerotic plaque, 
b) reduction in vulnerability features of non-calcified coronary atherosclerotic plaque, and 
c) improvement in critical indices of immune activation and inflammation. 
 
1.2 
Secondary Mechanistic Hypotheses  
 
1.2.1 Decreases in LDL cholesterol levels associated with statin therapy will be 
predictive of improvement in non-calcified coronary atherosclerotic plaque 
burden and/or vulnerability features. 
 
1.2.2 Statin therapy will reduce indices of general inflammation, coagulation, monocyte 
activation, and arterial inflammation. 
 
1.2.3 Statin therapy will reduce levels of pro-inflammatory monocyte populations. 
 
1.2.4 Statin therapy will reduce levels of T-cell activation and exhaustion. 
 
1.2.5 Changes in levels of immune activation and inflammatory markers will be 
associated with changes in morphology and composition of non-calcified 
coronary atherosclerotic plaque. 
 
1.2.6 Statin therapy will not have a clinically significant effect on glucose and insulin 
resistance. 
 
1.3 
Primary Mechanistic Objective 
 
To determine the effects of pitavastatin on the morphology and composition of non-
calcified coronary atherosclerotic plaque (NCP), including the progression of plaque 
volume and whether these effects are modulated by markers of inflammation and 
immune activation. 
 
1.4 
Secondary Mechanistic Objectives 
 
1.4.1 To determine the effects of pitavastatin on the progression of high risk plaque 
features including low attenuation plaque and positive remodeling. 
 
1.4.2 To determine the effects of pitavastatin on detailed markers of immune 
activation, including immune function (CD4, viral load), immune activation 

 
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(%CD14+CD16+ monocytes, sCD163, sCD14, MCP-1 and T-cell markers), 
inflammation (Lp-PLA2, hsCRP, IL-6), coagulation (D-Dimer and tissue factor) 
and traditional CVD risk indices including detailed parameters of glucose 
homeostasis (insulin, glucose and related indices of insulin resistance such as 
HOMA-IR, HgbA1c). 
 
1.4.3 To determine the relative contributions of baseline and pitavastatin induced 
changes in HIV-specific immune activation and traditional risk factors, including 
LDL, on the presence and progression of coronary plaque and high risk 
morphological features in HIV. 
 
1.4.4 To collect blood to enable the evaluation of the relationship of host genetics to 
study endpoints in subsequent ancillary studies. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
HIV-infected persons face a 1.5- to 2-fold risk of myocardial infarction (MI), even after 
controlling for increased prevalence of traditional CVD risk factors [Triant 2007; Freiberg 
2013]. This increased risk is thought to be mediated, in large part, by immune activation 
and inflammation as emerging major contributors to the markedly increased prevalence 
of high risk coronary atherosclerosis in the HIV-infected population [Hsue 2012; Zanni 
2012], such that young patients without known CVD and with relatively low Framingham 
risk scores may still be high-risk. Traditional CVD prevention paradigms tested in the 
HIV-negative population fail to adequately assess and specifically target HIV-associated 
immune-mediated CVD risk. The proposed randomized trial of statin therapy in HIV-
infected individuals with minimal traditional cardiovascular risk leverages the LDL-
lowering [Silverberg 2009] and immunomodulatory properties of statins [Kwak 2000], 
targeting both traditional CVD risk factors (dyslipidemia), and HIV-specific immune 
activation. Embedded in the larger events trial is a mechanistic sub-study in which 
coenrolled participants will undergo coronary CT angiography for determination of 
atherosclerotic plaque morphology and composition, as well as detailed profiling of lipid 
and inflammatory/immune parameters. The mechanistic sub-study will provide several 
key scientific insights of crucial relevance to predicting and preventing CVD in HIV. Data 
from the mechanistic sub-study will highlight whether CCTA-based plaque morphology 
relates to CVD events in HIV, independent of lipid and inflammatory/immune 
parameters, and whether potential effects of statins to stabilize atherosclerotic plaque 
morphology – rendering plaques less likely to rupture and cause acute myocardial 
infarction – are mediated primarily through lipid-lowering or through immunomodulatory 
effects.  
 

 
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2.1.1 HIV-infected patients have a novel phenotype of atherosclerotic plaque linked to 
immune activation  
 
HIV-infected individuals without known CVD have been shown to have more non-
calcified coronary atherosclerotic plaque relative to HIV-negative controls 
matched on traditional cardiovascular risk factors [Burdo 2011]. The significance 
of non-calcified plaque – namely, the higher likelihood it has to rupture, relative to 
calcified plaque – is highlighted by the MACE trial of over 5000 HIV-negative 
outpatients. This study showed that over 3 years of follow-up, 22.7% of patients 
with non-calcified plaque experienced a major adverse cardiac event compared 
with 5.5% of patients with calcified plaque [Hou 2012]. HIV-infected individuals 
without known CVD also have more vulnerable atherosclerotic plaque on 
coronary CTA relative to HIV-negative controls matched on traditional CVD risk 
factors. Features used to characterize vulnerability include low CT attenuation 
(correlating with necrotic lipid core) and positive remodeling (reflecting eccentric 
plaque extension) [Zanni 2013]. Among HIV-negative individuals with suspected 
CVD, low attenuation and positively remodeling have been demonstrated to 
prospectively predict the development of acute coronary syndrome (ACS). In a 
large study of over 1000 patients, Motoyama et al. demonstrated that in patients 
without significant CAD the occurrence of either low CT attenuation or positive 
remodeling was accompanied by a 22 fold increase in relative risk for suffering 
from an adverse cardiovascular event [Motoyama 2009]. These results were 
confirmed in another study that demonstrated that those persons with 
atherosclerotic plaques characterized by two vulnerability features were far more 
likely than individuals with atherosclerotic plaques absent of vulnerability features 
to develop ACS (22.2% vs. 0.5%, respectively) [Kitagawa 2009; Motoyama 
2009]. Importantly, non-calcified and vulnerable plaque in HIV-infected 
individuals relates to levels of soluble CD163, a monocyte/macrophage activation 
marker [Burdo 2011; Zanni 2013]. This latter finding suggests that immune 
activation in HIV may be contributing to the development of a novel 
atherosclerotic plaque phenotype which is prone to rupture and result in acute 
MI. Numerous other studies have linked immune activation markers – including 
monocyte activation markers LPS, sCD14, sMCP-1, and sCD163, as well as T-
cell activation markers – to subclinical atherosclerosis, cardiovascular events, 
and mortality [Merlini 2012; Kelesidis 2012; Sandler 2011; Kaplan 2011; Liu 
1997; Hunt 2011; Giorgi 1999; Burdo 2011; Zanni 2013; Subramanian 2012]. 
 
2.1.2 Statin Effects 
 
2.1.2.1 Statins lower LDL cholesterol and dampen immune activation  
In the general population, statins have long been known to potently 
reduce LDL cholesterol and to prevent CVD events [Sacks 1996; 
Shepherd 1995; Downs 1998]. In addition, statins have pleiotropic anti-
inflammatory and immunomodulatory characteristics, which may also 
contribute to cardio-protective effects. Indeed, in vitro, animal, and 
human studies have shown that statins decrease monocyte activation – 

 
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reflected in a) decreased monocyte chemotaxis and endothelial 
adhesion [Montecucco 2009; Fujino 2006; Han 2005] b) reduced 
monocyte uptake of oxidized LDL cholesterol [Han 2004]), and c) 
decreased monocyte secretion of cytokines/chemokines and matrix 
metalloproteinases [Guo 2009; Waehre 2003]. Moreover, statins 
decrease T-cell activation [Kwak 2000; Singh 2009; Bu 2010] while 
recruiting regulatory T cells [Mira 2008], and statins also suppress 
endothelial cell activation [Zheng 2013; Romano 2000; Mulhaupt 2003; 
Veillard 2006; Zineh 2006]. In HIV-infected persons, statins, and 
specifically pitavastatin, effectively lower LDL cholesterol [Silverberg 
2009; Eckard 2014; Funderburg 2014, 2015; Aberg 2017]. In HIV-
infected persons, statins also exert immunomodulatory effects to 1) 
decrease monocyte activation – reflected in decreased circulating levels 
of sCD14 and the macrophage-derived phospholipase, Lp-PLA2 
[Eckard 2014; Funderburg 2014, 2015], and 2) reduce T-cell activation 
[Ganesan 2011; De Wit 2011]. 
 
2.1.2.2 Statins may stabilize rupture-prone coronary atherosclerotic plaque 
 
Findings from observational CT imaging studies and large randomized 
IVUS trials demonstrate that statin therapy results in regression of NCP 
volume and potentially stabilizes coronary atherosclerotic plaque 
morphology in HIV-negative populations [Shimojima 2012; Inoue 2010; 
Kodama 2010; Nakamura 2008]. In addition, statins have been 
demonstrated to reduce atherosclerotic plaque inflammation on cardiac 
FDG-PET [Takawol 2013], and to reduce non-calcified plaque volume 
[Burgstahler 2007; Hiro 2009]. 
 
2.1.2.3  The effect of statins to stabilize rupture-prone atherosclerotic plaque 
may be mediated through LDL lowering and/or through the exertion of 
anti-inflammatory effects  
 
The JUPITER trial was a landmark study in that it showed a significant 
effect of statin therapy to prevent CVD events among non-HIV patients 
without known heart disease, with relatively low LDL cholesterol (<130 
mg/dl), and with evidence of generalized inflammation (CRP >2 mg/L) 
[Ridker 2008]. The CVD preventive benefits seen in JUPITER, 
surprisingly, were found to be proportional to reductions in CRP. This 
observation suggests that in the general population, anti-inflammatory 
pleiotropy may contribute significantly to the cardioprotective effects 
exerted by statins [Ridker 2009]. However, event reduction was also 
consistent with the known magnitude of expected effect from LDL 
lowering. Thus, although the JUPITER trial demonstrated a marked 
reduction in CVD events with statins among patients with relatively low 
LDL cholesterol but generalized inflammation, the lack of mechanistic 
assessment precluded determination of how this effect was achieved. In 

 
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a study of the MESA cohort, a population similar to the JUPITER trial 
cohort, major adverse cardiovascular events correlated better with high 
risk coronary atherosclerotic features than inflammatory markers such 
as hsCRP [Blaha 2011]. This data highlights the importance of 
performing assessments of plaque volume and morphology to 
characterize the mechanisms by which statins have their effect. Hence, 
the currently proposed study will determine, in the HIV-infected 
population, the effects of statins to prevent CVD events and, 
importantly, mechanisms through which statins may achieve this effect 
including a reduction of these high risk morphologic features.  
 
2.2 
Rationale 
 
The proposed REPRIEVE (A5332) study is a multi-center, prospective randomized 
placebo controlled trial testing the effect of statin primary preventive therapy on CVD 
events in HIV-infected patients on ART without significantly increased traditional 
cardiovascular disease risk and no prior history of CVD. The trial described in this 
appendix is a mechanistic substudy embedded in the larger REPRIEVE (A5332) clinical 
events trial. In the Mechanistic Substudy of REPRIEVE (A5333s), coenrolled participants 
will undergo coronary computed tomography angiography (CCTA) for determination of 
atherosclerotic plaque morphology, as well as detailed profiling of lipid and 
inflammatory/immune parameters.  
 
The Mechanistic Substudy of REPRIEVE (A5333s) will determine, among HIV-infected 
persons, potential statin effects to halt progression of non-calcified atherosclerotic 
plaque and to stabilize morphologic features of plaque vulnerability. Moreover, the study 
will identify biological factors mediating these changes – be it lipid parameters, such as 
LDL cholesterol, or markers of inflammation and immune activation. Finally, the study 
will demonstrate whether presence and morphology of subclinical atherosclerotic plaque 
at baseline relates to CVD events independently of traditional CVD risk factors and 
markers of HIV-specific immune activation. 
 
Findings from the study will have implications for predicting CVD risk in HIV-infected 
individuals, for whom traditional risk prediction paradigms such as those used in the 
2013 ACC/AHA guidelines may fall short (for failing to factor in the contributions of HIV-
specific immune activation) [Stone 2013]. Moreover, findings from the mechanistic 
substudy will have implications for the development of targeted CVD preventive 
strategies in the HIV-infected population: If statins stabilize coronary atherosclerotic 
plaques and prevent CVD events primarily via LDL lowering, then further LDL lowering 
strategies may be indicated. On the other hand, if statins stabilize coronary 
atherosclerotic plaques and prevent CVD events primarily through immunomodulation, 
then complementary immune-suppressant therapies in HIV-infected patients – such as 
inhibitors of monocyte activation – will need to be further explored. Overall, the 
mechanistic sub-study will provide new, critical knowledge about the biology of 
atherosclerosis in HIV.  
 

 
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3.0 
STUDY DESIGN 
 
A5333s is an optional mechanistic substudy of REPRIEVE (A5332). Approximately 800 
HIV-infected males and females who are enrolled in REPRIEVE (A5332) will coenroll in 
the Mechanistic Substudy of REPRIEVE (A5333s). To ensure treatment balance in 
treatment assignment in the Mechanistic Substudy of REPRIEVE (A5333s), 
randomization in REPRIEVE (A5332) will be stratified by anticipated substudy 
participation. Participants will be followed for 24 months in the Mechanistic Substudy of 
REPRIEVE (A5333s). 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS  
 
4.1 
Inclusion Criteria  
 
4.1.1 Enrollment in REPRIEVE (A5332). 
 
4.1.2 Willingness to complete procedures required for the study. 
 
4.1.3 Signed informed consent. 
 
4.1.4 Glomerular filtration rate (GFR) ≥60 mL/min/1.73m2 or creatinine clearance 
(CrCl) 60 mL/min, as per REPRIEVE (A5332) 
 
NOTE:  Results of creatinine must be obtained and GFR or CrCl must be 
calculated within 14 days prior to CCTA. The GFR must be ≥60 mL/min/1.73m2 
or the CrCl must be ≥60 mL/min for the subject to proceed with CCTA both at 
entry and at month 24. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Known allergy to iodinated contrast agent. 
 
4.2.2 Currently symptomatic asthma. 
 
4.2.3 Allergy to beta blockers. 
 
4.2.4 Contraindication to beta blockers (ie, taking daily asthma medications). 
 
4.2.5 Positive pregnancy test within 24 hours prior to study entry. 
 
NOTE: Female subjects of reproductive potential (defined as women who have 
not been post-menopausal for at least 24 consecutive months, ie, who have had 
menses within 24 months prior to study entry, and women who have not 
undergone surgical sterilization, specifically hysterectomy or bilateral 
oophorectomy) must have a negative serum or urine pregnancy test within 24 
hours prior to CCTA by any US laboratory or clinic that has a CLIA certification or 
its equivalent, or is using a point-of-care (POC)/CLIA-waived test, or at any 

 
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network-approved non-US laboratory or clinic that operates in accordance with 
Good Clinical Laboratory Practices and participates in appropriate external 
quality assurance programs. 
 
NOTE: Subject reported history is considered acceptable documentation of 
hysterectomy, bilateral oophorectomy, and menopause. Women are considered 
menopausal if they have not had a menses for at least 12 months and have a 
FSH (follicle stimulating hormone) of greater than 40 IU/L or, if FSH testing is not 
available, they have had amenorrhea for 24 consecutive months. 
 
4.2.6 Any condition that prohibits the individual from completing the CCTA. 
 
4.2.7 Body mass index (BMI) ≥40 kg/m2. 
 
NOTE:  Refer to the MOPS for the link to the BMI calculator. 
 
4.2.8 Cardiac arrhythmia at enrollment precluding CCTA; such as atrial fibrillation with 
heart rate >80 beats per minute or frequent ectopic beats. Please see MOPs for 
scanner-specific details. 
 
4.3 
Enrollment Procedures  
 
The Mechanistic Substudy of REPRIEVE (A5333s) will be limited to select sites 
participating in REPRIEVE (A5332). Prior to implementation of the substudy, each site 
must have the protocol and the protocol consent form approved, as appropriate, by their 
local IRB/EC and any other applicable regulatory entity (RE).  
 
Site inclusion criteria for the Mechanistic Substudy of REPRIEVE (A5333s) will include 
the following: 
• 
Site participating in REPRIEVE (A5332). 
• 
Site radiology or cardiology department/facility must conduct >1000 CT/per year.  
• 
MD oversight/supervision of CT scans. 
• 
CT scanner must be at least 2nd generation 64-slice. 
• 
The facility must utilize level III readers. 
• 
The radiology/cardiology facility must be capable of all of the following  
o prospective triggering/gating 
o using low KV 
o have capacity to premedicate subjects  
 
Once a candidate for entry has been identified, details will be carefully discussed with 
the subject. The subject (or when necessary, the legal representative) will be asked to 
read and sign the approved Mechanistic Substudy of REPRIEVE (A5333s) consent 
form. 
 
Enrollment into the Mechanistic Substudy of REPRIEVE (A5333s) will occur concurrently 
with enrollment and randomization into REPRIEVE (A5332), ie, completion of enrollment 

 
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into A5333s should occur no later than one business day after enrollment into 
REPRIEVE (A5332), in recognition that lab results needed to determine eligibility into 
A5333s may not be available on the same day. Note this does not change the 
requirement that CCTA for A5333s must be performed within 14 days after 
randomization. 
 
NOTE: The Mechanistic Substudy of REPRIEVE (A5333s) closed to accrual on 
02/06/18. 
 
4.4 
Subject Registration 
 
Subjects who meet enrollment criteria will be registered to the substudy according to 
standard DMC procedures. 
 
5.0 
STUDY TREATMENT  
 
No medications are provided by the Mechanistic Substudy of REPRIEVE (A5333s). 
Study treatment will be distributed and administered as per REPRIEVE (A5332). See 
section 5.0 of REPRIEVE (A5332) for study treatment requirements and concomitant 
medications. 
 
6.0 
EVALUATIONS 
 
6.1 
Schedule of Evaluations for the Mechanistic Substudy of REPRIEVE (A5333s)  
Evaluation1 
Entry 
Month 4 
±21 days 
Month 24 
± 28 days 
Premature 
Study Disc. 
Evaluations 
Calculate BMI3 
X 
 
X 
 
REAP and DASI Questionnaires 
 
 
X 
X 
QOL assessment 
X 
 
X 
X 
Pregnancy Testing 
X4 
 
X4 
X 
Serum Creatinine 
X5 
 
X5 
X 
CBC with differential 
X5 
 
X5 
X 
CD4+/CD8+ 
X5 
 
X5 
X 
Plasma HIV-1 RNA 
X5 
 
X5 
X 
Fasting Lipid Panel 
 
X6 
 
 
Fasting Plasma/Serum for 
Biomarkers – Planned Analysis7 
X 
X 
X 
X 
Cryopreserved PBMCs for Flow 
Cytometry – Planned Analysis 
X 
 
X 
X 
Whole blood for RNA 
X 
 
X 
X 
CCTA 
X 
 
X 
X2 

 
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1 Subjects in the mechanistic substudy will have all evaluations as per REPRIEVE (A5332) Schedule of 
Evaluations; additional testing and/or unique processing instructions specific to the mechanistic 
substudy are listed here in section 6.1 of the mechanistic substudy. 
2  Premature Study Discontinuation before month 12 should include all evaluations listed except CCTA. 
Premature Study Discontinuation at month 12 or later should include all evaluations including the 
second CCTA.  
3 For BMI calculation at entry, use height and weight obtained at screen from REPRIEVE (A5332). For 
month 24 BMI calculation, use height obtained at screen and weight obtained at month 24 from 
REPRIEVE (A5332). 
4 Pregnancy testing must be performed and reviewed prior to CCTA for mechanistic substudy 
participants at entry and month 24 to ensure subject eligibility.  
5  CD4+/CD8+, HIV viral load, CBC, and serum creatinine at entry and month 24 will be performed as 
part of substudy. Serum creatinine results must be drawn and GFR or creatinine clearance must be 
reviewed within 14 days prior to CCTA to ensure subject eligibility. If drawn more than 14 days before 
CCTA, repeat creatinine must be drawn. The CBC must be drawn on the same day as PBMC. 
6 Fasting lipid panel from month 4 will be performed centrally. 
7  HgbA1c, Lp-PLA2, sCD163, sCD14, MCP-1, IL-6, D-dimer (will not be collected at month 4), hsCRP, 
troponin, insulin, glucose. Related indices of insulin resistance such as HOMA-IR will be calculated.  
 
6.2 
Timing of the Evaluations  
 
6.2.1 Entry 
 
Registration to the Mechanistic Substudy of REPRIEVE (A5333s) will occur at 
the entry visit and is concurrent with enrollment to the main study, ie, completion 
of enrollment into A5333s should occur no later than one business day after 
enrollment into REPRIEVE (A5332), in recognition that lab results needed to 
determine eligibility into A5333s may not be available on the same day. Substudy 
entry evaluations (including CCTA evaluations) must be completed prior to the 
initiation of REPRIEVE (A5332) study medications. The baseline CCTA scan 
should be completed within 14 days after randomization. 
 
6.2.2 Post-entry 
 
Month 4 substudy evaluations must be performed ± 21 days; month 24 substudy 
evaluations must be performed  28 days. 
 
6.2.3 Discontinuation Evaluations 
 
Premature Discontinuation of REPRIEVE (A5332) Study Treatment  
Subjects who prematurely discontinue REPRIEVE (A5332) study treatment may 
continue participation in the substudy with all evaluations performed as per 
section 6.0. 
 

 
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Premature Discontinuation of REPRIEVE (A5332) Study Participation 
Subjects who prematurely discontinue participation in the REPRIEVE (A5332) 
study will be discontinued from the Mechanistic Substudy of REPRIEVE 
(A5333s). 
 
Premature Discontinuation of the Mechanistic Substudy of REPRIEVE (A5333s) 
Participation 
Subjects who discontinue participation in the Mechanistic Substudy of 
REPRIEVE (A5333s) may continue participation in REPRIEVE (A5332). 
 
Subjects who prematurely discontinue participation in the Mechanistic Substudy 
(A5333s) should complete the Premature Discontinuation of Substudy visit. 
Premature Study Discontinuation before month 12 should include all evaluations 
listed except CCTA. Premature Study Discontinuation at month 12 or later should 
include all evaluations including the second CCTA.  
 
Subjects who become pregnant while on the Mechanistic Substudy of 
REPRIEVE (A5333s) must immediately be discontinued from the substudy 
without any further evaluations performed. 
 
6.3 
Instructions for Evaluations 
 
6.3.1 Clinical Assessments 
 
Targeted Physical Exam 
A targeted physical examination as described in REPRIEVE (A5332) will be 
performed as per section 6.1 and findings will be recorded on the REPRIEVE 
(A5332) CRFs. Blood pressure and pulse should also be taken. Blood pressure 
should be recorded on the REPRIEVE (A5332) CRFs at all substudy visits. 
Record any changes that occur after entry on the REPRIEVE (A5332) CRF. 
 
Calculation for Body Mass Index will be performed prior to entry and month 24 
CCTA. See MOPS for link to calculator. 
 
Cardiovascular Risk Factor Assessment 
Diet, using the Rapid Eating and Activity Assessment for Patients (REAP) 
questionnaire and functional capacity using the Duke Activity Status Index (DASI) 
questionnaire will be performed at the month 24 visit.  
 
Quality of Life Assessment using the SF-36v2 questionnaire will be performed at 
entry and month 24. 
 

 
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6.3.2 Laboratory Evaluations 
 
Pregnancy Testing 
For women with reproductive potential: serum or urine beta-HCG (urine test must 
have a sensitivity of 15-25 mIU/mL). A negative pregnancy test result must be 
obtained before the CCTA. 
 
Serum Creatinine 
For entry and month 24, serum creatinine will be performed as part of the 
Mechanistic Substudy of REPRIEVE (A5333s). Serum creatinine must be drawn 
and GFR or CrCl must be calculated within 14 days prior to CCTA. The GFR 
must be ≥60 mL/min/1.73m2 or CrCl must be ≥60 mL/min for the subject to 
proceed with CCTA both at entry and at month 24. 
 
CBC with Differential 
For entry and month 24, a CBC with differential will be performed as part of the 
Mechanistic Substudy of REPRIEVE (A5333s). The CBC must be drawn on the 
same day as the PBMC collection. 
CD4+/CD8+ T-cell Counts  
CD4+/CD8+ T-cell count and percentage assays at entry and month 24 must be 
performed as part of the substudy at a CLIA-certified or equivalent laboratory that 
is certified for protocol testing by the DAIDS Immunology Quality Assurance 
(IQA). 
 
Plasma HIV-1 RNA 
HIV-1 RNA must be performed at entry and month 24 by a laboratory that 
possesses a CLIA certification or equivalent. 
 
Fasting Lipids 
Serum lipid and lipoproteins (total cholesterol, HDL cholesterol, LDL cholesterol, 
non–HDL, triglycerides, particle size, lipid subfractions, oxidized LDL) are 
collected only for the Mechanistic Substudy of REPRIEVE (A5333s) at month 4. 
These samples will be batched and stored in the ACTG Specimen Repository for 
analyses by a central laboratory.  
 
Fasting Insulin  
Fasting insulin samples will be batched and stored in the ACTG specimen 
repository for analyses by a central laboratory. HOMA-IR will be calculated from 
fasting insulin determined from the Mechanistic Substudy of REPRIEVE 
(A5333s) and fasting glucose determined from REPRIEVE (A5332). 
 
HgbA1C 
Samples for HgbA1C will be batched and stored in the ACTG Specimen 
Repository for analyses by a central laboratory. 
 

 
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6.3.3 Immunologic and Biomarker Studies  
 
Fasting Plasma/Serum for Biomarkers – Planned Analysis 
The following primary biomarker assays will be performed using frozen samples: 
Lp-PLA2, sCD163, sCD14, MCP-1, IL-6, D-dimer, hsCRP, troponin. These 
samples will be batched and stored in the ACTG Specimen Repository for 
analyses by a central core laboratory. Refer to the Laboratory Processing Chart 
(LPC) for details. Additional biomarker and coagulation marker assays may be 
performed.  
 
PBMCs for Monocyte and T Lymphocyte Activation – Planned Analysis 
PBMCs for pre-specified flow cytometric analysis on monocytes and T 
lymphocytes will be batched and stored in the ACTG Specimen Repository for 
analyses by a central core laboratory. Refer to the LPC for details. 
 
Whole Blood RNA 
Whole blood will be obtained and processed for RNA. Samples will be batched 
and stored to enable the evaluation of ancillary studies to assess RNA changes. 
 
6.3.4 CT Angiogram and Risks of Radiation Dose 
 
Coronary computed tomography angiography (CCTA) is performed in 
accordance with best practice standards as delineated in the imaging guidelines 
of the Society of Cardiovascular Computed Tomography [Abbara 2009] by 
competent and appropriately credentialed physicians. This includes the 
optimization of the scan protocol to limit radiation dose. Specific protocols for 
each CT scanner, manufacturer, and model will be provided and performed in the 
MOPS. In general, both retrospective and prospective ECG gated protocols are 
permitted. The Core Lab will conduct an initial quality assurance screen to 
ensure correct imaging parameters (kVp, mAs, FOV, slice thickness, slice 
interval, reconstruction kernel). When a data set is received by the CT core lab, 
quality analysis (QA) will be performed and if accepted, a case acceptance notice 
will be sent to the site. If the data set does not pass QA, the site will be sent a 
query to resolve the issue. The CRA will determine if the data set requires 
resubmission or if the correspondence with the site can resolve the query. If the 
site does not respond to the query the CRA will follow the query escalation plan. 
When the query is resolved, the site will be sent a case acceptance notification 
and the data set will be moved to the reader work list. Prior to the follow up 
CCTA, the Core Lab will send the site a reminder including the baseline scan 
parameters with a request to perform the follow up as closely as possible 
resembling the baseline protocol. Refer to the Mechanistic Substudy of 
REPRIEVE (A5333s) MOPS for detailed instructions.  
 
Risks of Radiation Exposure from CT: CT scanning results in a measurable 
radiation exposure. For most patients participation in this study will be associated 
with an estimated cumulative radiation exposure of approximately 11 mSv with a 

 
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maximum dose of about 16 mSv over two years (median radiation exposure per 
exam: 5.6 mSv, range 3-8 mSv).  
 
By comparison, radiation exposure from a single stress nuclear myocardial 
perfusion imaging, another test commonly used to detect heart disease, is about 
14 mSv. The average annual radiation exposure from natural background 
sources in the US is between 2 and 3.6 mSv.  
 
The radiation exposure from this study is only 10% of the maximally allowed 
annual radiation exposure to radiation workers such as radiology technologists, 
radiologists, or workers in nuclear plants (50 mSv per year). Overall, each CT 
scan adds a very small theoretical risk of less than 0.05% to the 7% lifetime risk 
of lung cancer for men and women and to the 12% lifetime risk of breast cancer 
for women. 
 
Pregnant subjects must not have a CCTA scan. 
 
7.0 
TOXICITY MANAGEMENT 
 
See section 7.0 in protocol REPRIEVE (A5332). Specific CCTA-related events should be 
handled as per standard treatment guidelines, eg, for acute contrast-related events. 
 
8.0 
CRITERIA FOR SUBSTUDY DISCONTINUATION 
 
• 
Subjects who discontinue participation in REPRIEVE (A5332). Discontinuation of 
REPRIEVE (A5332) at A5332 study closure does not constitute premature 
discontinuation.  
• 
The subject refuses further participation. 
• 
The site investigator determines further participation would be detrimental to the 
subject’s health or well-being. 
• 
The subject becomes pregnant. 
• 
The subject fails to complete the entry CCTA. 
• 
Subject develops impaired renal function defined as confirmed CrCl <60 mL/min or 
GFR <60 mL/min/1.73m2 at month 24 visit. 
• 
The subject develops new onset clinically significant asthma. 
• 
The subject develops new onset/previously undiagnosed allergy to IV contrast. 
• 
Body mass index (BMI) is ≥40 kg/m2 at month 24 visit. 
 
9.0 
STATISTICAL CONSIDERATION 
 
General Design Considerations 
The overarching aim of the Mechanistic Substudy of REPRIEVE (A5333s) is to better 
understand the modulation of critical features of coronary plaque morphology with statin 
therapy, including the progression of non-calcified coronary atherosclerotic plaque 

 
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(NCP) volume in HIV and the biological factors mediating these effects during statin 
treatment in HIV.  
 
9.1 
Endpoints 
 
9.1.1 Primary Endpoints 
 
9.1.1.1 Evidence of non-calcified coronary atherosclerotic plaque (NCP) at 
study entry and 2 years. 
 
9.1.1.2 Volume of non-calcified coronary atherosclerotic plaque (NCP) at study 
entry and change in NCP over 2 years (expressed as absolute change 
and as a percentage of baseline). 
 
9.1.1.3 Progression of NCP where progression will be defined as follows: 
a) Among subjects with evidence of NCP at entry, any 
progression/increase in NCP volume 
b) Among subjects without evidence of NCP at entry, incident NCP. 
 
9.1.2 Secondary and Supportive Endpoints 
 
9.1.2.1 Number of segments with NCP 
 
9.1.2.2 Presence and number of each of the following high-risk plaque features 
• 
Low Hounsfield Unit attenuation by CT assessment 
• 
Positive remodeling 
 
9.1.2.3 Levels at study entry, 4 months, and 2 years, and changes from study 
entry to 4 months and 2 years in the following biomarkers 
• 
Markers of HIV-1 disease: CD4 cell count, HIV-1 RNA level (entry to 
2 years only) 
• 
Soluble markers of monocyte activation: sCD163, sCD14, MCP-1 
• 
Various monocyte populations including %CD14+CD16+ monocytes 
(entry to 2 years only) 
• 
Markers of T-cell activation and exhaustion (entry to 2 years only) 
• 
Markers of inflammation: Lp-PLA2, hsCRP, IL6, troponin 
• 
Markers of coagulation: D-Dimer and tissue factor (excluding D-
Dimer at month 4; D-Dimer will be available at entry and month 24 
only) 
 
9.1.2.4 Fasting lipid fractions (Total, non-HDL, and HDL cholesterol) and 
LDL:HDL ratio at study entry, month 4 and 2 years. 
 

 
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9.1.2.5 Fasting insulin, HgbA1c, and HOMA-IR at study entry, month 4, and 2 
years (excluding HgbA1c at month 4; HgbA1c will be available at entry 
and month 24 only). 
 
9.1.2.6 Time to the first major cardiovascular events as defined in section 9.2.1 
of REPRIEVE (A5332). 
 
9.2 
Sample Size 
 
The target sample size for the Mechanistic Substudy of REPRIEVE (A5333s) is 800 
participants that will be approximately equally distributed between the study arms. 
 
This sample size was determined to have high power to detect clinically relevant 
differences between the two study groups both with respect to plaque progression 
(among those with plaque at study entry) and rates of incident plaque (among those 
plaque-free at entry). Specifically, the total sample size of 800 subjects will provide 90% 
power to detect a 6% difference between the study groups in the percent change in NCP 
volume over 2 years among those with plaque at entry and 90% power to detect 13 
percentage point difference in the probability of plaque development over 2 years. These 
effect sizes translate to a combined estimated 14 percentage point difference in the 
probability of NCP progression over two years and are based on the following 
assumptions: 
• 
50% of study participants will have evidence of NCP at study entry [Lo 2010] 
• 
A SD of 20% for the percent change over 2 years among participants with evidence 
of plaque at entry 
• 
An annual rate of incident plaque development of 12% among participants without 
plaque at entry 
• 
15% of participants entering the substudy will not be evaluable for study entry or 2 
year NCP volume. 
 
Together, the effects of statins acting in these two groups (those with and without 
evidence of NCP at study entry) will provide for a 7% lower prevalence of NCP after 2-
years of statin treatment. Expectations for NCP prevalence and progression both as a 
whole and according to whether NCP was present at study entry are illustrated in the 
table below. These estimates are based on a simulation that further assumed the 
following: 
• 
Average volume NCP 250mm3 (SD=200) among participants with NCP at entry. 
• 
Average volume NCP 40mm3 (SD=20) at 2 years among participants without NCP at 
entry without statin treatment. 
• 
Average volume NCP 20mm3 (SD=20) at 2 years among participants without NCP at 
entry with statin treatment. 
• 
NCP distributions were also assumed to follow a gamma distribution with size and 
shape parameters determine to provide the desire mean and standard deviations. 
 

 
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Table 9.2-1: Cells constituting the primary targeted group comparisons are shown in bold. 
 
At study entry 
At two 2 years 
 
NCP 
(%) 
NCP volume (mm3) NCP 
(%) 
NCP volume (mm3) 
Change in NCP 
volume (mm3) 
Percent change in NCP 
volume (%)2 
Mean (SD) [P5, P95] 
Mean (SD) [P5, P95] Mean (SD) [P5, P95] Mean (SD) 
[P5, P95] 
Control Overall1 
50% 
121 (186) 
[0, 509] 59% 140 (210) [0, 573] 
19 (51) 
[-21, 103] 17% (33%) [-10%, 100%] 
No plaque at entry 
- 
- 
21% 
9 (19) 
[0, 51] 
9 (19) 
[0, 51] 
21% (41%) [0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
40 (20) 
[17, 79] 
40 (20) 
[17, 79] 100% (0%) [100%, 100%] 
Plaque at entry 
251 (198) [26, 637] 
 
281 (231) [28, 730] 
30 (68) 
[-38, 153] 12% (20%) [-14%, 49%] 
Statin 
Overall1 
50% 
120 (185) 
[0, 507] 52% 127 (198) [0, 536] 
7 (45) 
[-42, 76] 
7% (24%) 
[-17%, 60%] 
No plaque at entry 
- 
- 
8% 
2 (8) 
[0, 14] 
2 (8) 
[0, 14] 
8% (27%) 
[0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
23 (19) 
[2,60] 
23 (19) 
[2,60] 
100% (0%) [100%, 100%] 
Plaque at entry 
250 (197) [26, 633] 
 
262 (216) [26, 682] 
12 (64) 
[-66, 123] 5% (20%) 
[-21%, 43%] 
1  In estimation of overall means, participants without evidence of NCP are assigned a value of 0 for 
volume and change. 
2 In estimation of percentage change, participants without evidence of NCP at study entry with NCP at 2 
years are assigned a value of 100%. 
 
These desired statin effects on NCP volume are similar to those seen in intravascular 
ultrasound (IVUS) studies [Nissen 2006; Nicholls 2005]. Although no data exist to 
directly inform the clinical relevance of these differences, randomized comparisons of 
high vs. low dose statin therapy among non HIV-infected patients have demonstrated 
favorable effects on atherosclerotic plaque of a similar magnitude as well as on adverse 
cardiac events, among non HIV patients [Nissen 2006]. Further, data from the "Coronary 
CT Angiography Evaluation for Clinical Outcomes (CONFIRM) registry suggest that the 
presence of non-obstructive CAD is predictive major adverse cardiac events 
independent of traditional risk factors, degree of stenosis and coronary artery 
calcification (HR 2-5) [Hulton 2013]. The proposed mechanistic study will further add to 
this body of evidence investigating, for the first time in HIV-infected population, the 
association of NCP (both the presence and magnitude) as well as changes in volume 
relate to events. For this exploratory analysis, a larger sample size will be beneficial, in 
order to accrue CVD events to relate to plaque morphology. 
 
9.3 
Randomization/Registration 
 
Participants will be enrolled into the Mechanistic Substudy of REPRIEVE (A5333s) via 
the enrollment system at the same time as they are randomized into REPRIEVE 
(A5332). To ensure balanced treatment allocation in the mechanistic study, REPRIEVE 
(A5332) randomization will be stratified by planned mechanistic substudy participation.  
 
9.4 
Monitoring 
 
Ongoing monitoring of accumulating data for the Mechanistic Substudy of REPRIEVE 
(A5333s) by the study team (pooled by treatment group) will occur for study conduct and 
data completeness. Since scans will be read and biomarkers tested in batch at the end 

 
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of the study, data completeness focus will be for tracking of scan and specimen 
completeness. 
 
Such issues will be monitored by the jointly appointed NIAID/NHLBI DSMB at the time of 
DSMB review of REPRIEVE (A5332). 
 
9.5 
Analysis Plan 
 
9.5.1 General analysis considerations 
 
The presence and extent of coronary artery disease (CAD) in this population will 
be described including non-obstructive or obstructive CAD, volume of NCP and 
calcified plaque, and Agatston score, as well as the prevalence of high risk 
plaque features such as positive remodeling and low CT attenuation, and levels 
of inflammatory, and immunomodulatory biomarkers. 95% confidence intervals 
will be provided for CAD characteristic for the mechanistic study subgroup as 
whole and by randomization. 
 
All treatment group comparisons will be performed ITT using a 5% type error. 
Unless otherwise noted, analyses will be performed by subgroups defined 
according to the presence of NCP at study entry. Since CCTA will not be 
available at the time of randomization, balance by treatment arm cannot be 
guaranteed within these subgroups, but given the large sample size and 
stratification according to sex and HIV-1 disease severity relative balance 
between the group sample sizes is expected. 
 
9.5.2 Analysis plan 
 
Statin effects on coronary plaque morphology: Among participants with plaque at 
entry, descriptive statistics for the change and percentage change in NCP 
volume over 2 years will be provided by treatment group with group comparisons 
made with stratified t-test. Among those without NCP at entry, the prevalence of 
incident NCP over 2 years will be compared with stratified chi-squared test. To 
assess the mechanistic study population as a whole patients will be classified as 
progressors (any progression/increase in NCP volume OR incident NCP) or non-
progressors (no progression in NCP volume OR no incident NCP); the probability 
of progression over two years will be compared by treatment group using a 
stratified chi-squared test. 
 
The statin effect on high risk plaque features, including low HU attenuation and 
positive remodeling, will be assessed by comparing differences in the 2-year 
prevalence of high risk plaque morphology features between treatment groups 
using chi-squared (or Fisher’s exact) tests as appropriate; these analyses will be 
performed overall and by subgroups defined by the presence of NCP at study 
entry. Exploratory analysis will be performed for additional high risk plaque 
features that have been described in CCTA and IVUS studies including the 

 
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Napkin Ring Sign, Minimal luminal area, plaque burden, and segments with NCP. 
The analytic approach will be similar as described above. 
 
Statin effects on blood biomarkers: Statin effects on the distributions of blood 
biomarkers belonging to distinct pathways (ie, monocyte activation, generalized 
inflammation, and coagulation) will be assessed via treatment group 
comparisons of these respective markers via t-tests; modification of statin effect 
on these markers by HIV-1 and traditional risk factors (including sex, age, 
screening CD4, duration of suppressive ART, and presence of NCP at study 
entry). Since the hypothesized mechanism is that sustained high levels of 
immune activation and inflammation precede and contribute to progression of 
NCP volume and high risk plaque features, these analyses will relate short term 
changes in these biomarkers (over 4 months) to longer term changes in NCP 
volume and morphology after two years. 
 
LDL and blood biomarkers as mediators for plaque progression: In the event that 
both statin effects on NCP progression and biomarker changes are apparent, the 
association between changes in LDL and these biomarkers and NCP 
progression will be examined using graphical techniques and normal errors and 
logistic regression (for the subpopulations with and without NCP at entry 
respectively. A mediating effect of these biological factors will be evaluated by  
examination of changes in the estimated statin effect on NCP upon adjustment 
for these biological factors. Those biomarkers with the strongest mediating effect 
on plaque progression will be measured in the entire REPRIEVE (A5332) cohort 
to determine their association with MACE.  
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING  
 
Serious adverse events (SAEs) that occur as part of participation in the Mechanistic 
Substudy (A5333s) are reported as expedited adverse events (EAEs) through 
REPRIEVE (A5332). These SAEs are reported on a CRF for the Mechanistic Substudy 
(A5333s); they are not reported on the CRF for REPRIEVE (A5332). There are 
additional non-serious AEs (ie, non-serious contrast reactions) that may occur as part of 
the Mechanistic Substudy (A5333s) that will also be recorded on the CRF. Please see 
the Mechanistic Substudy (A5333s) MOPS for more details regarding AE reporting for 
A5333s. 
 
11.0 
HUMAN SUBJECTS 
 
IRB/EC review, subject confidentiality, and study discontinuation procedures will be the 
same as in REPRIEVE (A5332). Subjects must sign a separate informed consent form 
for the Mechanistic Substudy of REPRIEVE (A5333s). Risks, including potential risks of 
CCTA, and protection against risk are described in the accompanying sample informed 
consent form. 
 

 
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12.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of the Mechanistic Substudy of REPRIEVE (A5333s) will be 
governed by NIH policies. 
 
13.0 
BIOHAZARD CONTAINMENT 
 
Precautions and procedures will be as in REPRIEVE (A5332). 
 
 
 

 
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14.0 
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APPENDIX III:  SAMPLE INFORMED CONSENT 
 
For The Mechanistic Substudy of REPRIEVE (A5333s), FINAL Version 6.0, 16May2022 
 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers:  
Mechanistic Substudy of REPRIEVE  
 
SHORT TITLE FOR THE STUDY: The REPRIEVE Mechanistic Substudy 
 
 
INTRODUCTION 
 
You are being asked to take part in this research substudy because you will be taking 
pitavastatin or the placebo for pitavastatin for REPRIEVE (A5332). This study is sponsored by 
the National Institutes of Health (NIH). The doctor in charge of this substudy at this site is: 
(insert name of Principal Investigator). Before you decide if you want to be a part of this 
substudy, we want you to know about the substudy.  
 
This is a consent form. It gives you information about this substudy. The substudy staff will talk 
with you about this information. You are free to ask questions about this substudy at any time. If 
you agree to take part in this substudy, you will be asked to sign this consent form. You will get 
a copy to keep. 
 
 
WHY IS THIS SUBSTUDY BEING DONE? 
 
The purpose of this substudy is to learn about the effects of pitavastatin on the vessels that 
supply your heart with blood “coronary arteries” and the atherosclerotic plaque within the wall of 
these vessels (known as “hardening of the arteries”), as well as inflammatory biomarkers (blood 
tests that indicate the body’s immune system is active) among people with HIV (PWH). 
 
 
HOW MANY PEOPLE WILL BE IN THIS SUBSTUDY? 
 
About 800 people will take part in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS SUBSTUDY? 
 
If you agree to be in this substudy and sign this consent form, you will be asked to come in for 3 
visits. Each visit will last about 2-3 hours and will occur at the same time as your main study 
visits whenever possible. The visits are at entry (when you join the substudy), month 4, and 
month 24.  
 
Before all visits for the substudy you should not eat or drink anything, including food, beverages, 
candy, or gum for 8 hours before your visit. You are encouraged to drink water before your 

 
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visits. If you are not fasting, we will ask you to return to have your blood drawn within 21 days of 
the study visit.  
 
The procedures described below will be done in addition to your participation in the REPRIEVE 
(A5332) study. 
 
Explanation of study procedures 
You will be asked to fill out a questionnaire about your quality of life at entry and month 24. 
 
Study staff will ask you questions about your diet and physical activity at month 24. 
 
For women capable of having children, a pregnancy test will be done immediately before the CT 
of your heart. This test is required as part of your participation in this study. You will be told the 
results of the pregnancy test. You must notify the research staff if you are pregnant, think you 
may be pregnant, or if you are trying to become pregnant. If do become pregnant while on the 
substudy, you will be taken off the substudy and will not have any more substudy tests. 
 
At entry and month 24 we will check your kidney function, complete blood count (CBC), CD4 T-
cell count (how many infection fighting cells are in your blood), and HIV viral load (how much 
HIV is in your blood). The test to check your kidney function is required as part of your 
participation in this research study. Approximately 3 teaspoons of blood will be collected at each 
the entry and month 24 visits for these tests. 
 
You will be told the results of these tests. 
 
You will have about 1-4 tablespoons of blood drawn in addition to the blood drawn for 
REPRIEVE (A5332) at the entry, month 4 and month 24 visits. This blood will be collected and 
stored for tests that will be done later on in the study or after the study is over. These tests will 
measure various substances in your blood related to cholesterol (fat in your blood), blood sugar, 
metabolic tests (how your body processes food), inflammation, and immune function (how your 
body reacts to infection). You do not need to agree to store this blood to join the study and you 
may change your mind about storing your blood at any time. You will not be told of the results of 
the research done on your blood.  
 
Do you agree to let us store your samples for these tests? 
 
________ YES ________ NO 
_______Initials 
 
Approximately 1 teaspoon of blood collected will be used to look at genes that may affect your 
risk for cardiovascular disease. Genetic testing is a laboratory test that looks at differences in 
people’s genes. Your body, like all living things, is made up of cells, and cells contain 
deoxyribonucleic acid, also known as “DNA.” DNA is like a string of information put together in a 
certain order. Parts of the string make up “genes.” For the substudy, we will do a test to look at 
your RNA. RNA is made from DNA and is short for ribonucleic acid. RNA is a genetic material 
that has a major role in making proteins. Proteins are the building blocks of your body, cells, and 
organs. Genes contain instructions on how to make your body work and fight disease. The 

 
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testing in this study will focus on certain RNA’s that are known to be related to cardiovascular 
disease and effects of statins. New RNA’s of interest may be identified in the future and may 
also be looked at. You do not need to agree to store this blood to join the study and you may 
change your mind about storing your blood at any time. You will not be told of the results of the 
research done on your blood. 
 
Your body’s genetic makeup is unique to you, so there is a risk with genetic research that even 
with all the security measures in place, someone using your samples or genetic information may 
still find out which information is yours. However, this risk today is very small, but it may 
increase with time since science and technology are developing rapidly. 
 
In the event that your genetic information becomes linked to your name, the US federal law 
called the Genetic Information Nondiscrimination Act (GINA) helps protect you. This law 
prohibits health insurance companies, group health plans, and most employers from denying 
services based on your genetic information. However, GINA does not protect against 
discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. 
 
We would like to use some of the blood we collect to look at your genes (RNA). Do you agree to 
this genotyping? 
 
________ YES ________ NO 
_______Initials 
 
If at a later date you change your mind and want your samples destroyed, contact the research 
staff. There are two ways to withdraw your permission. You could allow researchers to remove 
all your personal identifiers from your samples, so that they are not linked to you anymore. 
These samples will then become anonymous. Or, you can ask researchers to destroy your 
samples, so that they cannot be used for future research. However, in either case, researchers 
will not be able to destroy samples or information from research that is already underway. 
 
You will have a computed tomography (CT) scan (“Cat” scan) of your heart at entry and month 
24. A CT scan is a special kind of x-ray that takes pictures of the inside of the body using a 
small amount of radiation. A small amount of dye (intravenous contrast) will be injected into your 
arm during the CT scan to better see the vessels that supply your heart with blood. If your heart 
rate is more than 65 beats per minute, we may inject a drug called a beta-blocker into your arm 
via the intravenous line. A beta-blocker is used to slow down your heart rate. A low heart rate is 
needed in order to make the best pictures of your heart and coronary arteries. In addition, a 
drug called nitroglycerin will be given to you by mouth in order to obtain better images of the 
blood vessels of the heart. We will also check your heart rhythm with an electrocardiogram 
(ECG). To do this, wires with sticky pads attached will be placed on your chest before the scan. 
 
You will be asked to lie quietly while your body is moved inside a large machine and the x-ray is 
taken. The CT scan takes about 15 minutes. For women, a pregnancy test will be performed 
prior to CT scanning. Pregnant women will not be allowed to undergo CT scanning. For all 
patients, a blood test for kidney function will be performed before the CT scan and patients with 
abnormal kidney function will not undergo CT scanning. 

 
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Because the test results are being used for research only, the results created by this study will 
not become part of your hospital record unless we discover an unexpected medical problem that 
must be communicated to the study doctors or your primary care physician. If you are found to 
have a critical blockage of the vessels supplying your heart with blood or another important non-
cardiac abnormality that may affect your health, we will provide the results of the CT to your 
study doctor. The cost of any additional testing will not be covered by the study. 
 
Other Information 
You may withdraw from this substudy at any time and still remain on the main study. If you 
decide to withdraw from the substudy early (before month 24) or if you decide to withdraw from 
the main study you will be asked to return to the clinic to have the procedures listed in the table 
below.  
 
Appendix III, Table 1: Discontinuation Procedures 
Procedure 
Stopping the study  
Fasting Blood 
X 
Blood Collected 
X 
Pregnancy Testing 
X 
Computed Tomography of your Heart (CT scan) 
X 
Quality-of-Life Assessment 
X 
 
If you leave the study before month 12, you will not have a CT scan at the discontinuation visit. 
 
 
HOW LONG WILL I BE IN THIS SUBSTUDY? 
 
You will be in this substudy for about 2 years. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the doctor thinks it is in your best interest 
• 
the study is cancelled 
• 
you are not able to attend the study visits as required by the study 
• 
you are unable to complete the computed tomography of your heart at the entry visit 
• 
you become pregnant 
• 
you have to stop participating in the main study 
• 
your kidney function becomes abnormal during your study participation 
• 
you develop asthma during your study participation 
• 
you develop an allergy to the contrast dye during your study participation 
• 
your body mass index (a measure of body fat based on your height and weight) is greater or 
equal to 40. 
 

 
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WHAT ARE THE RISKS OF THE SUBSTUDY? 
 
The scanning on CT machines will not cause any physical discomfort other than from having to 
lie still on the table for the duration of the test. 
 
Risks of Radiation Dose from CT 
You will have two CTs, one at entry and one at month 24. CT results in a measurable radiation 
dose. For most people the dose from each CT will be approximately twice the amount you get 
from natural background radiation (sun and earth) each year. Your dose may be higher or lower 
based on your size, your heartbeat, and the CT scanner. To put the total dose from the two CTs 
in further context, it is similar to the radiation dose from a cardiac imaging stress test (another 
test commonly used to detect heart disease) and much less (approximately 10%) of the 
maximum allowed exposure for radiation workers such as medical technologists, radiologists, or 
nuclear plant technicians.  
 
The lifetime risk of lung cancer for men and women is 7%. The lifetime risk of breast cancer in 
women is 12%. Each CT scan adds a very small theoretical risk of 0.05%.  
 
Radiation Dose  
Cardiac CT scanning results in a measurable radiation dose. In order to minimize risk for 
participants in this study we have implemented the following measures: 
• 
Exclude subjects <40 years of age 
• 
Exclude pregnant and breast feeding women 
• 
Application of cardiac CT protocols to minimize radiation dose  
• 
Review and approval of these CT protocols by the IRB/EC 
 
Risks of Intravenous Contrast Dye 
You will receive intravenous contrast dye as part of the CT scan and there is a small risk (2 out 
of 1,000) of an allergic reaction. More than 90% of such adverse reactions are very mild and 
allergic-like (itching, rash) and can be effectively treated with available drugs (ie, antihistamine). 
Severe reactions occur in 2 out of 10,000 and one death occurred in approximately 60,000 
contrast dye injections. 
 
Contrast-Induced Nephropathy (CIN)  
CIN is a kidney injury caused by contrast and is usually reversible. CIN almost always occurs in 
people who already have abnormal kidney function. To be enrolled in this study you must have 
normal kidney function, and for this reason CIN is very unlikely (less than 5 out of 1,000). 
  
Risks of IV Needle Placement  
• 
Hemorrhage (bruise at the injection site) 
• 
Infection (catheter related infection) at the injection site (very rare) 
• 
Leaking of contrast agent outside of the vein at the place where the IV is inserted. 
• 
Minor discomfort 
• 
Bleeding 

 
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• 
Infection 
• 
Bruising 
 
Risks of Beta-blockers and Nitroglycerin 
Beta-blockers and nitroglycerin are used by millions of Americans and are generally considered 
safe. These drugs are routinely administered prior to cardiac CT to improve the quality and 
interpretability of the study. 
 
The risk of beta-blockers includes slow heart rate (bradycardia), low blood pressure 
(hypotension), and wheezing (bronchospasm). Allergic reactions to beta-blockers are rare. 
Persons with asthma treated with inhalers should not receive beta-blockers. Study staff will 
assess this and other reasons for you not to have beta-blockers with you prior to the CT. 
 
The side-effects and risks of nitroglycerin are generally mild and of short duration and include 
low blood pressure (hypotension), high heart rate and abnormal rhythm (tachyarrhythmia), 
headache, lightheadedness, and visual disturbance. Persons who take erectile dysfunction 
medications such as Viagra, Cialis, or Levitra (sildenafil, tadalafil, or vardenafil) will need to stop 
these drugs at least 5 days prior to receiving nitroglycerin on the day of the cardiac CT scan. 
Nitroglycerin should not be given to persons with a low blood pressure. Study staff will assess 
this and other reasons for you not to have nitroglycerin with you prior to the CT. 
 
Other Risks/ Additional Risks of CT Scans 
• 
Discomfort 
• 
Claustrophobia 
 
Risks of Drawing Blood 
Having your blood drawn may cause discomfort, bleeding, and bruising where the blood is 
drawn. Occasionally, there is swelling in the area where the needle enters the body and there is 
a small risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 
Risks of Fasting 
Some people find fasting to be bothersome. It may make some individuals feel anxious, irritable, 
or hungry. Patients who are required to take their morning medications with food should wait 
until after the visit has been completed to take their medications. 
 
Genetic Testing 
The results of your genetic tests are for research purposes only and no individual results will be 
given back to you. The results of the genetics studies will never become a part of your medical 
record. We will protect your confidentiality to the fullest extent. Blood samples for genetic 
studies will be identified in a way in order to maintain your confidentiality. 
Research study results will not be given to your family members, insurance companies, 
employers, or third parties without your written permission and approval of the Institutional 
Review Board at _________.  
 

 
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Additional Risks 
The CT scan of your heart is being done to answer research questions, not to examine you 
medically. This scan is not a substitute for one your doctor would order. If the radiologist thinks 
that there may be an abnormality in your scan, we will contact you and will help you get medical 
follow-up for the problem. If you have a primary care doctor, we can contact your doctor, with 
your permission, and help him or her get the right follow-up for you. It is possible that you could 
be unnecessarily worried if a problem were suspected, but not actually found. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS SUBSTUDY? 
 
If you take part in this substudy, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
participating in REPRIEVE (A5332) only 
• 
not participating 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally. 
 
People who may review your records include the AIDS Clinical Trials Group (ACTG), OHRP, 
(insert name of site) IRB/EC, government agencies such as the National Institutes of Health 
(NIH) and Food and Drug Administration (FDA), other local, US, and international regulatory 
entities, study staff, study monitors, the drug company supporting this study, and its designee. 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 

 
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A description of this clinical trial will be available on www.ClinicalTrials.gov. This web site will 
not include information that can identify you. At most, the web site will include a summary of the 
results. You can search this Web site at any time. 
 
 
WHAT IF WE CAN NO LONGER REACH YOU DURING YOUR STUDY PARTICIPATION? 
 
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained at screening and updated at each visit. If you are unable to be reached 
through the alternate contacts we will attempt to obtain information about you from other 
sources such as family members, other designated contacts, or clinic records. The purpose of 
obtaining this information is to determine if you have died and the cause of death since last 
contact. 
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this substudy may lead to added costs to you and your insurance company. In 
some cases it is possible that your insurance company will not pay for these costs because you 
are taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be paid ________ per visit for participation in the substudy. (The team recommends 
compensation to participants of $25 at the entry and the month 24 visits. Sites will be 
reimbursed for the expense.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 

 
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We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB/EC) or other organization 
appropriate for the site 
• 
telephone number of above 
 
 
OTHER 
 
All other information that is contained in the main study REPRIEVE (A5332) consent that you 
signed also applies to this substudy consent. A copy of the signed main study consent will be 
provided for you as a reference at the time you consent to participate in the substudy.  
 
 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
____________________________ 
___________________________________ 
Subject’s Name (print) 
Subject’s Signature and Date 
 
____________________________ 
___________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
___________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
____________________________ 
___________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 

 
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APPENDIX IV: REPRIEVE OBJECTIVES TO DECIPHER SEX-SPECIFIC MECHANISMS OF 
CVD RISK AND RISK REDUCTION 
 
BACKGROUND 
 
HIV-infected individuals face a markedly increased risk of cardiovascular disease (CVD), even 
when viremia is suppressed by combined antiretroviral therapy (cART) [Freiberg 2013; Triant 
2007]. Mechanisms underlying HIV-associated CVD risk are incompletely understood [Zanni 
2014] and specific guidelines on cardioprotective care for this population are not available 
[Stone 2014]. Characterizing and reducing CVD risk among HIV-infected women represents a 
particular challenge. HIV-infected women are less likely than HIV-infected men to be offered 
preventive cardiac care in clinical practice [Willig 2008]. However, data suggest women with HIV 
are just as likely as their male counterparts to incur an MI [Triant 2007]. Indeed, a large-scale 
US epidemiologic study shows that among HIV-infected women, unadjusted rates of MI 
modestly exceed those among HIV-infected men [Triant 2007]. Moreover, the same study 
reveals a significantly higher adjusted relative risk of MI in HIV infected-women versus 
uninfected females (2.89) as compared with HIV-infected men versus uninfected males (1.4) 
[Triant 2007]. The proposed objectives aim to identify sex-specific mechanisms of CVD risk and 
risk reduction in relation to adjudicated clinical CVD events in HIV. Immune activation is 
increased in HIV-infected women (versus HIV-infected men) [Fitch 2013] and especially among 
those HIV-infected women who have undergone menopause [Looby 2015]. Moreover, among 
women with HIV, reduced ovarian reserve has been shown to relate to subclinical 
atherosclerotic plaque even after controlling for traditional CVD risk factors, including age 
[Looby 2015]. Building on these observations, our aims interrogate immune and hormonal 
pathways hypothesized to contribute to CVD risk in HIV-infected women across the reproductive 
aging spectrum. 
 
 
OBJECTIVES  
 
OBJECTIVE 1: To assess among HIV-infected individuals ages 40-75 sex-based differences in 
immune activation and statin-induced immunomodulation in relation to clinical CVD events. 
In order to achieve this objective, we will add to the REPRIEVE trial blood sample collection on 
female and male participants and sample processing for immune activation markers relevant to 
atherogenesis in HIV (beginning with monocyte activation markers including sCD14, and then 
exploring other immune activation markers). HYPOTHESES: Baseline relationships: A) Levels 
of immune activation markers will be higher in HIV-infected women versus men. B) High-level 
immune activation will relate to CVD events in HIV, and this association will be stronger in 
women versus men. Statin effects: C) Statins will decrease levels of immune activation markers 
to a greater extent in HIV-infected women versus men. D) CVD risk-reduction will be mediated 
in part through statin-induced immunomodulation, more so in HIV-infected women versus men. 
 
OBJECTIVE 2: To characterize among HIV-infected women ages 40-75 how menopause status 
and ovarian reserve relate to immune activation, statin-induced immunomodulation, and clinical 
CVD events. In order to achieve this objective, we will add to the REPRIEVE trial blood sample 
collection on female participants and sample processing for hormones including anti-Müllerian 

 
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hormone (AMH) and estradiol (E2). Coupling hormonal data with menstrual history, we will 
categorize women as pre-menopausal and post-menopausal. We will also define the subset of 
pre-menopausal women with reduced ovarian reserve. HYPOTHESES: Baseline relationships: 
A) Post-menopausal HIV-infected women will have higher levels of immune activation markers 
versus pre-menopausal HIV-infected women. B) Among both pre- and post-menopausal HIV-
infected women, reduced ovarian reserve (undetectable AMH) will relate to risk of first CVD 
event. Statin effects: C) Statins will decrease levels of immune activation markers to a greater 
extent in post-menopausal HIV-infected women versus pre-menopausal HIV-infected women. 
D) CVD risk-reduction will be mediated in part through statin-induced immunomodulation, more 
so in post-menopausal (vs. pre-menopausal) HIV-infected women. 
 
 
SIGNIFICANCE 
 
Overall, we will assess whether immune activation contributes uniquely to CVD risk among HIV- 
infected women across the reproductive aging spectrum and how statins may reduce CVD risk 
through effects on this pathway. Answers to these critical questions will influence the 
development of CVD prediction and prevention strategies tailored to the aging female HIV-
infected population worldwide. Maximizing our power to elucidate sex-specific CVD 
mechanisms in HIV, we will also design, implement, and evaluate the effectiveness of an 
evidence-based education/awareness recruitment campaign to enhance female enrollment in 
the REPRIEVE trial. Identification of innovative strategies to recruit women to an interventional 
clinical trial could have far-reaching practical implications for future trial-based, sex-specific 
research across disciplines. 
 
 
INTEGRATION OF OBJECTIVES INTO A5332  
 
In order to address the objectives above, the REPRIEVE trial protocol has been amended to 
permit for additional collection of fasting blood stored for assessment of biomarkers at entry, 1 
year, and at end of study. The end of study blood draw will facilitate future assessment of 
whether observed changes in immune markers at 1 year are sustained. Please see A5332 
protocol section 6.1, Schedule of Evaluations.  
 
 
STATISTICAL CONSIDERATIONS  
 
Overview Considerations 
 
Overall sample size assumptions: The projected sample size is 5446 persons, or approximately 
80% of the total REPRIEVE study sample.  
 
General analysis plans: As comparison groups to address the objectives listed below (eg, 
groups classified by sex for Objective 1 and by menopause/hormone status for Objective 2) will 
not have been assigned by randomization, the distributions of baseline characteristics will be 
compared between groups to help inform the list of characteristics to be included in covariate 

 
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.adjusted models specified below. Baseline covariates anticipated to differ by sex (eg, race, 
hypertension, smoking, substance use, lipids, BMI) [Hatleberg 2014] will be carefully explored 
and considered, particularly when they are hypothesized to be prognostic for the outcome. 
Where treatment effect is included in the analysis plan below (eg, statin effect), this variable will 
use intent-to-treat formulation.  
 
General monitoring considerations: Safety of human participants participating in the objectives 
described will be monitored by the REPRIEVE DSMB as part of the REPRIEVE trial study 
monitoring plan. 
 
Outcome Definition, sample size justification, and analysis plans by objective/hypothesis 
 
Objective 1: To assess among HIV-infected individuals ages 40-75 sex-based differences in 
immune activation and statin-induced immunomodulation in relation to clinical CVD events.  
 
Hypothesis A) Levels of immune activation markers will be higher in HIV-infected women versus 
men. The outcome being tested in this sub-objective is baseline (pre-treatment) immune 
activation, as measured by the levels of each of select immune activation markers such as 
sCD14. A non-parametric alternative to t-test (eg, Mann-Whitney test) will compare the pre-
treatment distribution of each biomarker between groups assigned by sex. If 22% female 
enrollment is achieved, then the comparison group sample sizes to address this hypothesis will 
be 1198 women versus 4248 men (with no adjustments for losses as outcome assessed at 
baseline). Using these sample sizes and the standard deviations of select biomarkers [Fitch 
2013], and adjusting the significance level to 0.0167 by Bonferroni to account for the biomarkers 
being tested, there will be 90% power to detect sex differences of 214 ng/mL for sCD14. 
Covariate adjusted models performed as part of the analysis of this hypothesis will use 
multivariable regression (linear, with log transformation if indicated based on biomarker 
distribution).  
 
Hypothesis B) High-level immune activation will relate to CVD events in HIV, and this 
association will be stronger in women versus men. The primary outcome being tested in this 
sub-objective is the composite clinical outcome of MACE occurring at any time during follow-up. 
The secondary outcome being tested is the time from randomization to first MACE occurring 
any time during follow-up. High-level immune activation with respect to each tested biomarker 
will be classified by the observed highest quartile of the pre-treatment distributions. Fisher’s 
exact test will be used for testing the main effect of immune activation. Taking the sample size 
of 5446 from the overall sample size assumptions above, there is an expectation of 4084 in the 
low immune activation group and 1362 (highest quartile) in the high immune activation group. 
Assuming ~6% of the study sample will experience a MACE event (from control arm incidence 
estimate of 15/1000 person-years and statin effect hazard ratio of 0.70; see REPRIEVE protocol 
section 9.0 for more details), with sample sizes as above and a Bonferroni-adjusted significance 
level of 0.0167, there will be  90% statistical power to detect 5% MACE rate in the low immune 
activation group compared with 7.8% MACE rate in the high immune activation group (ie, 
absolute difference of 2.8% pts in MACE rate between groups). Assessing whether the 
association of baseline immune activation and MACE will be higher in women versus men 
requires testing for an interaction effect between sex and immune activation (high vs. low) for 

 
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the outcome of MACE. To assess power for interaction effect, methods described in 
[VanderWeele 2012] will be used under the following assumptions: 4.9% of men with low 
immune activation will have a qualifying MACE outcome; the main effect odds ratios (OR) for 
sex and immune activation are each 2.1 (eg, 4.9% MACE in one group compared with 9.8% in 
the other); a multiplicative interaction OR of 1.33; association between sex and high/low 
immune activation of 1.33; and 22% female enrollment. Based on these assumptions and using 
a significance level adjusted to 0.0167, the statistical power for additive interaction effect (eg, as 
excess in relative risk attributed to interaction) is estimated as 80%. Testing for interaction 
effects and covariate adjusted models will use multivariable logistic regression (for the primary 
outcome) and Cox proportional hazards regression (for the secondary, time- to-event 
formulation outcome). 
 
Hypothesis C) Statins will decrease levels of immune activation markers to a greater extent in 
HIV-infected women versus men. The outcomes being tested in this sub-objective are the 
changes from pre-treatment to 1 year of follow-up of the immune activation markers tested. For 
this hypothesis, statistical interactions of sex and treatment effects will be tested using linear 
(log transformed as indicated) models, which can also incorporate covariate adjustment. With 
estimates of 5% per year loss to follow-up, the effective sample size for this sub-aim is 5174 
persons. For the biomarker sCD14, standard deviation of the outcome measure for this sub-aim 
is estimated assuming standard deviation of 1-year measurements same as baseline and intra-
person correlation of 0.65. Further, assuming under additivity a 125 ng/mL effect of sex on 
sCD14 differences at 1 year and the same effect of statins on sCD14 differences at 1 year, 
there will be 80% power to detect an additive interaction effect of 220 ng/mL. 
 
Hypothesis D) CVD risk-reduction will be mediated in part through statin-induced 
immunomodulation, more so in HIV-infected women versus men. For this sub-objective, 
structural equation modeling (SEM) will be employed to investigate the pathways and 
mechanisms leading to this clinical outcome while incorporating other prognostic factors. 
Specifically, the SEM model will apply an analysis of covariance structure incorporating multiple 
biomarker data into a single model for CVD clinical outcome. Furthermore, the model will test 
the covariates and directionality of effects with CVD outcome, and include temporal ordering. 
For this sub-objective, some of these pathways include the following: direct effect of sex on 
CVD, direct effect of sex on immunomodulation, direct effect of immunomodulation on CVD, sex 
effect on CVD through immunomodulation, direct effect of statin on CVD and on 
immunomodulation, and sex effect on CVD through statin effect. 
 
Objective 2: To characterize among HIV-infected women ages 40-75 how menopause status 
and ovarian reserve relate to immune activation, statin-induced immunomodulation, and clinical 
CVD events.  
 
The comparison groups will be formulated by combining hormonal data with data on menstrual 
history in order to categorize women as pre-menopausal and post-menopausal. Comparison 
groups will also define the subset of pre-menopausal women with reduced ovarian reserve.  
 
Hypothesis A) Post-menopausal HIV-infected women will have higher levels of immune 
activation markers versus pre-menopausal HIV-infected women. As in Objective 1A, the 

 
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outcome being tested in this sub-objective is baseline (pre-treatment) immune activation, as 
measured by levels of certain biomarkers such as sCD14. A non-parametric alternative to t-test 
(eg, Mann-Whitney test) will compare the pre-treatment distribution of each biomarker within 
women between groups assigned by menopause status. As per Objective 1A, 22% female 
enrollment is assumed. Further assuming a 1:1 ratio between female comparison groups, 
sample sizes for the pre-menopausal and post-menopausal groups will be 599 each. Using 
these sample sizes, standard deviations for biomarker as in Objective 1A, and Bonferroni-
adjusting the significance level to 0.0167, there will be 90% power to detect differences between 
the pre- and post-menopausal groups of 378 ng/mL for sCD14. Alternatively, if the ratio 
between female comparison groups is 1:2, sample sizes for the pre-menopausal and post-
menopausal group will be 399 and 799, respectively. Under this contingency, the minimal 
detectable differences between female comparison groups for 90% power are only slightly 
higher at 401 ng/mL.  
 
Hypothesis B) Among both pre- and post-menopausal HIV-infected women, reduced ovarian 
reserve (undetectable AMH) will relate to risk of first CVD event. As in Objective 1B: The 
primary outcome being tested in this sub-objective is the same composite clinical outcome of 
MACE occurring any time during follow-up. The secondary outcome being tested is the time 
from randomization to first MACE. Assuming 22% female enrollment in REPRIEVE and that a 
negligible proportion of the pre-menopausal women have reduced ovarian reserve such that the 
ratio of women with adequate versus reduced ovarian reserve is 1:1, then sample sizes for each 
group will be 599. As per Objective 1B, it is assumed that the overall rate of MACE among 
women will be 7%. Applying this event rate with the sample sizes above and using Fisher’s 
exact test for analysis, there will be 90% power (at 5% significance) to show a difference of 5% 
points between groups (namely, 4.5% MACE in one group and 9.4% MACE in the other.) 
Alternatively, if a significant proportion of the pre-menopausal women have reduced ovarian 
reserve such that the ratio of women with adequate versus reduced ovarian reserve is 1:4, then 
sample sizes will be 299 for the adequate ovarian reserve group and 898 for the reduced 
ovarian reserve group. In this scenario, there will be 90% power to show a difference of 5.7% 
between groups. Covariate adjusted models for this hypothesis will use multivariable logistic 
regression for the primary outcome formulation, and Cox proportional hazards modeling for the 
time-to-initial event formulation.  
 
Hypothesis C) Statins will decrease levels of immune activation markers to a greater extent in 
post-menopausal HIV-infected women versus pre-menopausal HIV-infected women. The 
outcomes being tested in this sub-objective are the changes from pre-treatment to 1 year of 
follow-up of each of the immune activation markers tested parallel to Objective 1C. Interactions 
by menopause status and treatment will be tested using linear (log transformed as indicated) 
models, which can also incorporate covariate adjustment. Assuming a 22% female enrollment 
and a 5% per year loss to follow up, the effective sample size for this analysis is 1138. 
Assuming a 1:1 ratio of female comparison groups, the sample sizes will be 569 for the pre- and 
post-menopausal groups. Using analysis assumptions from Objective 1C, and under additivity 
assuming a 375 ng/mL effect of menopause on sCD14 differences at 1 year as well as a similar 
effect of statins on sCD14 differences at 1 year, there will be 80% power to detect an additive 
interaction of menopause and statin of 390 ng/mL.  
 

 
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Hypothesis D) CVD risk-reduction will be mediated in part through statin-induced 
immunomodulation, more so in post-menopausal (vs. pre-menopausal) HIV-infected women. 
Parallel to Objective 1D, the SEM model will be used to incorporate all biomarker data into a 
single model for CVD clinical outcome, and then to test the covariate pathways, including 
directionality and temporal ordering. For this sub-objective, some of these pathways to be tested 
include the following: direct effect of menopause status on CVD, direct effect of menopause 
status on immunomodulation, direct effect of immunomodulation on CVD, menopause effect on 
CVD through immunomodulation, direct effect of statin on CVD and on immunomodulation, and 
menopause effect on CVD through statin effect. 
 
 
 

 
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REFERENCES 
 
Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and 
immune activation in HIV-infected women. J Infect Dis 2013;208(11):1737-46. 
Freiberg MS, Chang CCH, Kuller LH, et al. HIV infection and the risk of acute myocardial 
infarction. JAMA Intern Med 2013;173(8):614-22. 
Hatleberg CI, Ryom L, El-Sadr W, et al. Gender differences in HIV-positive persons in use of 
cardiovascular disease-related interventions: D:A:D study. J Int AIDS Soc 2014;17(4 Suppl 
3):19516. 
Looby SE, Fitch KV, Srinivasa S, et al. Reduced ovarian reserve relates to monocyte 
activation and subclinical coronary atherosclerotic plaque in women with HIV. AIDS 2015 
Published ahead of print. doi: 10.1097/QAD.0000000000000902. 
Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the 
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a 
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Triant VA, Hang Lee, Hadigan C, Grinspoon SK, et al. Increased acute myocardial infarction 
rates and cardiovascular risk factors among patients with human immunodeficiency virus 
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VanderWeele TJ. Sample size and power calculations for additive interactions. Epidemiol 
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Willig JH, Jackson DA, Westfall AO, et al. Clinical inertia in the management of low-density 
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APPENDIX V: REPRIEVE ANCILLARY STUDY: EFFECT OF PITAVASTATIN ON KIDNEY 
FUNCTION IN HIV-INFECTED PERSONS 
 
BACKGROUND 
 
With advances in HIV therapy, the incidence of HIV-associated nephropathy and subsequent 
end-stage renal disease (ESRD) have declined substantially [Lucas 2014; Lucas 2008; SMART 
2006]. Still, 30-40% of HIV-infected persons are estimated to have Stage 1 or greater chronic 
kidney disease (CKD) [Gupta 2004; Overton 2012; Szczech 2004], and HIV infection remains 
an established risk factor for CKD, even after adjusting for traditional risk factors [Althoff 2015; 
Coresh 2003]. Black race, diabetes mellitus (DM) and hypertension (HTN) are common among 
HIV-infected persons and associated with an increased risk for CKD [Gathogo 2014; Jotwani 
2012]. In fact, the effect of HIV may be additive to traditional risk factors like diabetes [Medapalli 
2012].  
 
This increased risk of CKD among HIV-infected individuals is likely mediated by inflammation 
[Mallipattu 2013]. HIV infection induces a paradoxical state of both immune suppression (low 
CD4+ T-cell count with increased risk of opportunistic pathogens) and immune activation 
[Deeks 2011]. The depletion of CD4+ T cells in the gut-associated lymphoid tissue facilitates 
excess microbial translocation and ensuing activation of both the innate and adaptive arms of 
the immune system [Brenchley 2006]. Such chronic immune activation translates into a well-
characterized exhausted T-cell phenotype and a persistent pro-inflammatory milieu with 
elevated inflammatory cytokines and cellular immune activation markers, as well as markers of 
oxidative stress [Dolan 2005; Ross 2008]. Identifying adjunctive therapies that target these 
inflammatory pathways has the potential to prevent CKD in HIV-infected individuals. 
 
In certain risk groups in the general population (DM, HTN, and pre-existing CVD), post-hoc 
analyses of randomized controlled trials (RCTs) have suggested that HMG-CoA reductase 
inhibitors (ie, statins) have a beneficial effect on the kidney. For example, in an RCT of 
atorvastatin for secondary prevention of strokes, eGFR improved with atorvastatin but not 
placebo, independent of baseline kidney function [Amarenco 2014]. These findings corroborate 
an analysis from the Collaborative Atorvastatin Diabetes Study, in which persons with diabetes 
and normal LDL-cholesterol were randomized to atorvastatin or placebo. Participants assigned 
to statin therapy demonstrated statistically significant improvement in eGFR that was most 
pronounced among persons with pre-existing microalbuminuria [Colhoun 2009]. These 
beneficial effects of statins have been shown to be most robust in persons with higher 
inflammatory biomarkers at baseline [Tonelli 2005]. These data suggest that the kidney 
protective effect of statins may be mediated through anti-inflammatory pathways, highly relevant 
in the setting of HIV infection. A recent Cochrane review of statins administered in the setting of 
CKD concluded that statins have uncertain effects on progressive CKD and additional 
prospective trials are warranted, particularly among persons with diabetes and other high-risk 
populations [Palmer 2014]. These post-hoc analyses from HIV negative individuals indicate that 
equipoise exists as to whether statins protect kidney function, particularly in populations with 
increased systemic inflammation, such as seen with HIV infection. Given the established 
association of CKD with CVD endpoints [Chronic Kidney Disease Prognosis Consortium 2010], 

 
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interventions that prevent eGFR decline and albuminuria may also have important implications 
for CVD and all-cause mortality. 
OBJECTIVES  
 
OBJECTIVE 1: To evaluate the effects of pitavastatin on clinically relevant parameters of kidney 
function among HIV-infected individuals on ART.  
 
OBJECTIVE 1A: To determine whether pitavastatin is associated with a lower incidence of 
clinically relevant eGFR decline in HIV-infected persons.  
 
OBJECTIVE 1B: To determine whether pitavastatin is associated with a lower prevalence of 
albuminuria.  
 
HYPOTHESES: 1. We hypothesize that randomization to pitavastatin versus placebo will be 
associated with a lower incidence of clinically relevant eGFR decline, defined as ≥30% decline 
from baseline, a Food and Drug Administration/National Kidney Foundation (FDA/NKA) 
recommended surrogate endpoint for CKD [Inker 2014]. 2. We hypothesize that randomization 
to pitavastatin versus placebo will be associated with a lower prevalence of albuminuria, defined 
as urine albumin/creatinine ratio (ACR) >30 mg/g. 
 
OBJECTIVE 2: To assess whether the effect of pitavastatin 4 mg/daily on eGFR and 
albuminuria is stronger in high-risk groups defined by older age, black race, hypertension, lower 
CD4 cell counts, or the use of tenofovir disoproxil fumarate (TDF)-containing regimens.  
 
HYPOTHESIS: We hypothesize the kidney protective effect of pitavastatin will be stronger in 
high-risk groups.  
 
OBJECTIVE 3: To determine whether the effect of pitavastatin on kidney function is mediated 
through anti-inflammatory effects.  
 
HYPOTHESIS: We hypothesize that effects of pitavastatin on eGFR and albuminuria will be 
mediated by systemic and vascular inflammation and oxidative stress, as measured by 
circulating levels of key inflammatory biomarkers. 
 
 
SIGNIFICANCE 
 
By adding collection of urine and blood longitudinally in at least 2500 participants, this ancillary 
study will definitively assess whether pitavastatin therapy will prevent significant decline in 
kidney function and the development of albuminuria (ACR >30 mg/g). This sample will further 
provide the opportunity to evaluate the effect of pitavastatin in sub-groups of HIV-infected 
participants for whom the risk of CKD has been demonstrated to be higher, including persons of 
older age, black race, hypertension, lower CD4 T-cell counts, and on tenofovir-containing 
regimens. Finally, the mechanisms of action will be assessed to determine whether the 
protective effect of pitavastatin is mediated through pathways involving inflammation and 
oxidative stress. Ultimately, the findings of this study will provide longitudinal data on the 

 
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epidemiology of CKD in the setting of HIV infection, provide mechanistic insights into whether 
statins prevent CKD by modulating inflammation and oxidative stress, and potentially change 
guidelines for the prevention of CKD in this at-risk population. 
INTEGRATION OF OBJECTIVES INTO A5332  
 
This ancillary study requires only modest changes to the procedures of the parent study as it will 
leverage the existing study infrastructure, data collection, and trial visits to allow for additional 
stored blood and urine collection for a longitudinal assessment of relevant kidney function 
parameters. As CKD and albuminuria are independent risk factors for ASCVD, this ancillary 
study will provide additional insight into the primary focus of the parent trial. Furthermore, only 
modest changes to the parent protocol and informed consent are required to facilitate these 
evaluations, including collection of stored blood and urine at entry and years 1, 2, and 4 of study 
follow up. 
 
STATISTICAL CONSIDERATIONS  
 
Overview Considerations  
 
Overall sample size assumptions: This ancillary study is projected to include at least 2500 
persons, or approximately 38% of the total REPRIEVE study sample. The ancillary study will 
only recruit participants from the ACTG study sites. 
 
General analysis plans: A baseline assessment of kidney function will be performed to assess 
baseline measures of kidney function and to assess clinical parameters associated with lower 
eGFR and albuminuria at baseline. For Objective 1, an intention-to-treat approach will be used 
based on randomization to pitavastatin or placebo for pitavastatin in the parent trial. For 
Objective 2, the effect of pitavastatin will be assessed in high-risk subgroups (HTN, age, race, 
tenofovir use) as outlined below. Objective 3 will utilize a case-control design to determine 
relevant mechanistic pathways through which the effects of pitavastatin are mediated.  
 
General monitoring considerations: Safety of human participants participating in the kidney 
ancillary study will be monitored by the REPRIEVE DSMB as part of the REPRIEVE trial study 
monitoring plan. 
 
OBJECTIVE 1: To evaluate the effects of pitavastatin on clinically relevant parameters of kidney 
function among HIV-infected individuals on ART. 
 
Endpoints 
For the primary analysis, we will use accepted measures of decreased eGFR. We have 
selected 30% decline in eGFR or ESRD for our primary outcome based on recommendations 
from a joint NKF-FDA workshop, which concluded that this should be considered as an 
alternative CKD endpoint for clinical trials [Inker 2014]. Specifically, in a pooled cohort of 
850,096 individuals with eGFR ≥60 mL/min/1.73 m2, a decline in eGFR ≥30% over 3 years of 
follow-up was associated with a hazard ratio of 7.0 for developing ESRD over the following 
decade. In secondary analysis, we will consider the more stringent endpoints of 40% decline in 
eGFR and development of eGFR <60 mL/min/1.73m2. We will use the CKD Epidemiology 

 
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Collaboration (CKD-EPI) creatinine equation to estimate GFR, as it has been demonstrated to 
be more accurate than other creatinine-based formulas in both the general population and in  
HIV-infected cohorts [Matsushita 2010; Levey 2015; Inker 2012; Gagneux-Brunon 2012; Bhasin 
2013]. The CKD-EPI creatinine equation had statistically significantly higher accuracy and less 
bias than the cystatin C equation in HIV-infected persons [Inker 2012].  
 
Albuminuria will be quantified by ACR calculated as urinary albumin in mg/dL divided by urinary 
creatinine in g/dL. Albuminuria is an easily assessed marker of kidney damage, which may 
precede eGFR decline, and is strongly linked to adverse clinical outcomes [Gerstein 2001]. 
Even at levels of albuminuria >30 mg/g, persons are at increased risk for CVD events and all-
cause mortality [Gerstein 2001; Wyatt 2010; Wyatt 2011]. We will use the ACR as a measure of 
albuminuria, as it is widely available in clinical practice and recommended by the IDSA Clinical 
Practice Guideline for CKD in HIV-Infected persons [Lucas 2014]. The ACR from a random 
urine sample is simple to obtain, correlates well with data from 24-hour urine collections, but is 
more practical and less prone to error than a 24-hour collection [Eknoyan 2003].  
 
Data Analysis Plan  
Aim 1A: Determine whether pitavastatin 4mg daily is associated with a lower incidence of >30% 
eGFR decline in HIV-infected persons. We will use an intention-to-treat approach for Aim 1. 
Descriptive statistics for participant characteristics will be presented by randomization 
assignment. The percent change in eGFR from baseline at study visits at 1, 2, and 4 years post-
randomization, separately, will be calculated as follow-up eGFR minus baseline eGFR divided 
by baseline eGFR. For our primary analysis, the CKD endpoint will be a decline in eGFR ≥30% 
from the baseline visit or incident ESRD. The percentage of participants randomized to 
pitavastatin and, separately, placebo having a decline in eGFR ≥30% will be calculated at each 
follow-up visit. Additionally, the cumulative proportion of participants with ≥30% decline in eGFR 
throughout follow-up will be calculated by randomization arm and differences in these 
percentages of participants reaching the endpoint during follow-up will be compared using a chi-
square test. We will assess these differences using logistic regression adjusted for key risk 
covariates as a confirmatory analysis. Additionally, we will evaluate time-to-event using interval 
censored regression models. Interval censored regression models are proposed as we do not 
know the exact date an individual reaches the CKD endpoint - only that it occurred between two 
visits. 
 
Sample Size 
We will enroll a sample size of at least 2500 participants. This sample size will provide adequate 
statistical power to achieve our aims. We anticipate an annual event rate of 2.5% based on 
previous reported results [Lucas 2007; Lucas 2008]. Therefore, over 4 years, we anticipate 10% 
of participants will meet our primary outcome of eGFR decline. As we do not know the exact 
incidence of eGFR decline, we provide the minimal detectable difference based on this event 
rate and also for 8% and 15% incidence of eGFR decline (ie, annual event rates of 2% and 
3.75%, respectively). Based on sample size of 2500 participants (50% randomized to 
pitavastatin and 50% placebo), a two-tailed alpha error of 5% and assuming 5% of participants 
will be lost during follow-up, we will have 90% statistical power to detect clinically relevant 
differences in the cumulative incidence of eGFR decline across randomization arms. For 
example, if 10% of participants randomized to placebo develop our primary endpoint over the 4-

 
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year follow-up period, we will have 90% power to detect an absolute reduction in incidence of 
3.6% associated with pitavastatin (10% in placebo vs. 6.4% in pitavastatin arm; Table 1). Given 
that albuminuria is anticipated to be a more frequent endpoint than ≥30% eGFR decline, we will 
have 90% power to detect clinically relevant differences in the percentage of participants 
developing this outcome measure. Previous RCTs of pitavastatin in individuals with diabetes 
and persons with hyperlipidemia demonstrated a 52% and 67% reduction in measures of 
albuminuria, respectively [Nakamura 2005; Yagi 2011]. Although we expect to see at least a 
50% reduction in albuminuria in the pitavastatin group (from 15% to 7.5%) and a modest 
increase in prevalence of albuminuria in the placebo group [Szczech 2010], we will be powered 
to detect smaller differences. 
 
Table 1. Minimal detectable difference in incidence of CKD 
endpoint in REPRIEVE participants randomized to pitavastatin vs 
placebo. 
 
Proportion of control population 
developing CKD 
Aim 1A eGFR decline 
8% 
10% 
15% 
90% statistical power 
3.2% 
3.6% 
4.3% 
80% statistical power 
2.6% 
3.2% 
3.5% 
 
Proportion of control population with 
albuminuria 
Aim 1B % with 
albuminuria 
15% 
20% 
25% 
90% statistical power 
4.3% 
4.9% 
5.4% 
80% statistical power 
3.8% 
4.3% 
4.7% 
 
OBJECTIVE 2: Assess whether the effect of pitavastatin on CKD is stronger in high-risk groups 
defined by older age, black race, hypertension, lower CD4 cell counts, or the use of TDF-
containing regimens. We will divide the cohort based on the median age to evaluate differences 
between the groups above and below the median age. Similar dichotomous approaches will be 
taken for black race, hypertension (systolic blood pressure ≥140 mmHg, diastolic blood 
pressure ≥90 mmHg or antihypertensive medication use), and TDF-containing regimens. Within 
each sub-group studied, participant characteristics will be calculated by randomization 
assignment (pitavastatin or placebo). The percentage of participants developing ≥30% eGFR 
decline and separately, with ACR >30 mg/g during follow-up will be calculated for participants 
randomized to pitavastatin and, separately, their counterparts randomized to placebo. The 
statistical significance of differences within sub-groups will be calculated using interval censored 
regression models and chi-square tests as described in Aim 1 above. We will use multiplicative 
interaction terms (eg, black race * pitavastatin) to assess differences in the effect of pitavastatin 
on CKD across sub-groups. We will evaluate CD4 count as a continuous variable to determine if 
there is a threshold below which statin therapy has greater benefit for kidney function. We will 
model the interaction between pitavastatin versus placebo and CD4 count as a continuous 
variable with interval censored regression models and logistic regression for the cumulative 
incidence [Howard 2011].   
 

 
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OBJECTIVE 3: To determine whether the effect of pitavastatin on kidney function is mediated 
through anti-inflammatory effects. This analysis will follow the traditional case-cohort design. 
The case-cohort design combines the advantages of cohort studies and case-control analyses. 
In a case-cohort design, the comparison group is not defined on the basis of the “absence” of 
the outcome (≥30% eGFR decline or ACR >30 mg/g; as in a traditional “case-control” study 
design). This is advantageous for the following reasons: 1) the strategy allows for studying 
multiple endpoints using the same "control" group (ie, the sub-cohort); 2) it bypasses a certain 
degree of arbitrariness unavoidable when attempting to define the comparison group intended 
to include only “non-cases” (ie, the inclusion of “false negatives”); 3) the strategy allows a 
random sample of the cohort for valid cross-sectional comparisons (eg, the association between 
baseline ACR and biomarkers of CKD and systemic and vascular inflammation and oxidative 
stress in the cohort random sample); and 4) it allows calculation of hazard ratios using survival 
models rather than relying on logistic regression and calculation of odds ratios. 
 
The distribution of biomarkers at baseline and during follow-up will be graphed. For biomarkers 
that are not normally distributed, an appropriate transformation will be performed (eg, log 
transformation). Mean baseline and change in the levels of these biomarkers will be calculated 
for participants who experience a ≥30% decline in eGFR and the sub-cohort. Differences will be 
calculated using ANOVA with weighting to account for the probability of selection into the sub-
cohort. Next, we will calculate the association between biomarkers of CKD, systemic and 
vascular inflammation and oxidative stress with CKD progression using a pseudo-likelihood, 
weighted Cox regression model. Using the approach of Barlow and Prentice for case-cohort 
analysis, we will calculate the hazard ratio for a ≥30% decline in eGFR associated with each 
biomarker separately. Initial models will control for age, race, and sex. Subsequent models will 
include further adjustment for systolic blood pressure, total and HDL-cholesterol, cigarette 
smoking, waist circumference, and baseline eGFR and ACR. A final model will include further 
adjustment for log10 HIV RNA load and CD4+ T-cell counts.  
 
Next, we will conduct a mediation analysis to test whether pitavastatin lowers the incidence of 
≥30% eGFR decline by reductions in biomarkers assessed. To address mediation that 
pitavastatin will reduce the incidence of eGFR decline through improvements in systemic and 
vascular inflammation and oxidative stress, we will apply the regression technique described by 
Judd and Kenny and elaborated by MacKinnon [Judd 1981; MacKinnon 1994]. The technique, 
will account for each biomarker separately and for all biomarkers simultaneously (mediators) 
using two regression equations (Table 2). Y is the outcome result (eg, eGFR decline ≥30%), Xp 
is randomization to pitavastatin versus placebo and Xi represents the k biomarkers, our 
purported mediators. The total effect of pitavastatin on the outcome (measured by the 
coefficient, ) is the sum of direct effect () of treatment and the mediated, or indirect, effects. 
The assessment of the amount of change in these biomarkers mediating the effect of 
pitavastatin on eGFR decline will be addressed by considering two multivariable regression 
models (see Table 2). First, a regression model that estimates the decreased risk of a ≥30% 
eGFR decline with pitavastatin without mediating risk factors but considering other risk factors 
(eg, age, race, sex, hypertension) and a second Cox regression model that further makes 
adjustment for the mediating risk factor (ie, biomarkers of inflammation and oxidative stress). 
For these analyses, the parameter of interest (ie, log hazard ratio) is not the impact of 
pitavastatin on outcomes, but rather the difference in the estimated impact of pitavastatin 

 
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between the two models ( - ), which serves as a direct measure of the degree to which the 
effect of pitavastatin is due to improvements in these biomarkers. Whether the biomarkers 
“significantly” mediate the benefits of pitavastatin can be addressed by creating empirical 
confidence intervals around the change in its coefficient. Confidence interval of the change in 
the coefficient associated with the disparity will be calculated using bootstrap methods. 
 
 
 
 
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