Conditions: HIV Infection HIV Infections
Keywords: Infection HIV 1 HIV Losartan Fibrosis Immune Activation Immune Reconstitution
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: yes

Brief summary:
This study was designed to test the hypothesis that treatment of HIV infected subjects with losartan, an agent with specific anti-inflammatory and anti-fibrotic actions, will:

1. reverse existing lymphoid tissue fibrosis,
2. restore lymphoid tissue architecture,
3. increase the number and improve the function of peripheral and lymphatic CD4 T cells,
4. decrease levels of systemic immune activation (IA),
5. decrease size of the HIV reservoir, and
6. be safe and well tolerated.

Detailed description:
This is a randomized, double-blind, placebo-controlled trial of 50 HIV-1 infected individuals on stable ART randomized in a 1:1 ratio to losartan (50 mg orally daily titrated to 100 mg daily) vs placebo for 30 months. We plan to enroll a total of 63 HIV infected subjects to ensure that 50 complete the protocol. All HIV infected subjects will undergo biopsies of inguinal lymph node (LN) and gut associated lymphatic tissue (GALT) for primary endpoint analysis at baseline, 12 and 30 months after study enrollment. Blood will be collected at least quarterly throughout the study and an intensive blood pharmacokinetic (PK) study will be conducted at month 1. All HIV infected subjects will be vaccinated with the quadrivalent human papillomavirus (HPV) vaccine at months 23, 25 and 29.5 to measure immune function. 5 HIV uninfected control subjects will also be enrolled.

The primary endpoint is to determine the impact of losartan on lymphoid tissue fibrosis in HIV infected, ART treated adults. This will be determined by measuring the amount of collagen deposition in lymphoid tissues and the integrity of the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA).

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Losartan intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will start with 50 mg of losartan by mouth daily. The dose will be increased to 100 mg by mouth daily after 14 days. The maximal tolerable dosage (up to 100mg by mouth daily) will be continued for a total of 30 months. intervention 2: one tablet by mouth daily

Protocol document:
Prot_SAP_000.pdf: 
Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV 
Protocol Version 6.6 
March 1, 2017 
Page 1 
Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV 
Sponsored by: 
National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism:  
U01 AI105872-01 
Pharmaceutical Support Provided by: 
Merck 
IND # - not needed 
Principal Investigator/Protocol Chair: 
Timothy Schacker, MD 
NIAID Medical Monitor: 
Karin Klingman, M.D. 
DAIDS-ES Document ID: 
#11932 
Draft or Version Number: 
Version 6.6 
Day Month Year 
 01 March 2017  
This template is adapted from the ICH guidance document E6 (Good Clinical Practices), Section 6. 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, 
study staff, and applicable independent ethics committees or institutional review boards.  The contents of this document shall 
not be disclosed to others without written authorization from NIAID (or others, as applicable), unless it is necessary to obtain 
informed consent from potential study participants. 
ClinicalTrials.gov: NCT01852942


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Statement of Compliance 
 
This trial will be conducted in compliance with the protocol, International Conference on Harmonization Good 
Clinical Practice E6 (ICH-GCP), and the applicable regulatory requirements including U.S. Code of Federal 
Regulations applicable to clinical studies (45 CFR 46 and 21 CFR 50, 56 and 21 CFR 312), directive 
2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use as amended by Commission Directive 2005/28/EC and NIAID Clinical Terms of Award.  All key 
personnel (all individuals responsible for the design and conduct of this study) have completed appropriate 
Human Subjects Protection Training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Signature Page 1 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
 
________________________________________________________ 
 
________________ 
Timothy W. Schacker, MD, Professor of Medicine   
 
   
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV 
 
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Signature Page 2 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Meghan Rothenberger, MD, Assistant Professor of Medicine 
 
Signed:___________________________________________ 
Date:____________________ 
 
Gregory Beilman, MD , Professor of Surgery 
 
 
 
Signed:___________________________________________ 
Date:____________________ 
 
Jeffrey Chipman, MD, Associate Professor of Surgery 
 
 
Signed:___________________________________________ 
Date:____________________ 
 
Cavan Reilly, PhD, Associate Professor of Biostatistics 
 
 
Signed:___________________________________________ 
Date:____________________ 
 
Jason Baker, MD, Assistant Professor of Medicine  
 
 
Signed:___________________________________________ 
Date:____________________ 
 
Brian Fife, PhD, Assistant Professor of Medicine 
 
 
 
Signed:___________________________________________ 
Date:____________________ 
 
Courtney Fletcher, PharmD, Dean and Professor of Pharmacy 
 
Signed:___________________________________________ 
Date:____________________ 
 
Daniel Douek, MD, PhD, Head, Human Immunology, VRC, NIH 
 
Signed:___________________________________________ 
Date:____________________ 
 
Richard Koup, MD, Chief, Immunology Laboratory, VRC, NIH 
 
Signed:___________________________________________ 
Date:____________________ 
 
Jacob Estes, PhD, Head, Tissue Analysis Core Aids and Cancer Virus Program, NCI, NIH 
 
 
Signed:___________________________________________ 
Date:____________________ 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
Statement of Compliance .......................................................................................................................................................... 2 
Signature Page 1 ...................................................................................................................................................................... 3 
Signature Page 2 ...................................................................................................................................................................... 4 
List of Abbreviations and Acronyms .......................................................................................................................................... 8 
Protocol Summary ................................................................................................................................................................... 10 
1. 
KEY ROLES ..................................................................................................................................................................... 12 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................................................................. 14 
2.1 
Background Information ............................................................................................................................................................ 14 
2.2 
Study Hypothesis and Rationale ................................................................................................................................................ 15 
2.3 
MRI Sub-study ........................................................................................................................................................................... 16 
2.4 
Potential Risks and Benefits ...................................................................................................................................................... 16 
 
Potential Risks ................................................................................................................................................................... 16 
 
Potential Benefits ............................................................................................................................................................... 16 
3. 
STUDY OBJECTIVES ..................................................................................................................................................... 16 
3.1 
Primary Objective ...................................................................................................................................................................... 16 
3.2 
Secondary Objectives ................................................................................................................................................................. 17 
3.3 
Exploratory Objectives .............................................................................................................................................................. 17 
4. 
STUDY DESIGN .............................................................................................................................................................. 17 
4.1 
Description of the Study Design: ............................................................................................................................................... 17 
4.2 
Study Endpoints: ........................................................................................................................................................................ 17 
 
Primary Endpoint ............................................................................................................................................................... 17 
 
Secondary Endpoints .......................................................................................................................................................... 17 
 
Exploratory Endpoints ....................................................................................................................................................... 18 
5. 
STUDY POPULATION ..................................................................................................................................................... 18 
5.1 
Selection of Study Population .................................................................................................................................................... 18 
5.2 
Inclusion/Exclusion Criteria ...................................................................................................................................................... 18 
5.3 
Co-Enrollment Guidelines ......................................................................................................................................................... 20 
6. 
STUDY AGENTS ............................................................................................................................................................. 20 
6.1 
Study Agent Acquisition ............................................................................................................................................................ 20 
 
Losartan .............................................................................................................................................................................. 20 
 
Gardasil Vaccine ................................................................................................................................................................ 21 
 
Stribild................................................................................................................................................................................ 21 
 
Prezista ............................................................................................................................................................................... 21 
6.2 
Assessment of Participant Adherence with Study Product ........................................................................................................ 22 
6.3 
Permitted Medications and Procedures ...................................................................................................................................... 22 
6.4 
Prohibited Medications .............................................................................................................................................................. 22 
7. 
STUDY PROCEDURES/INTERVENTIONS .................................................................................................................... 23 
7.1 
Description and Potential Risks of Clinical Procedures ............................................................................................................. 23 
 
Medical History .................................................................................................................................................................. 23 
 
Physical Exam .................................................................................................................................................................... 23 
 
Medical Adherence Counseling ......................................................................................................................................... 23 
 
Venipuncture ...................................................................................................................................................................... 23 
 
Gardasil Vaccination .......................................................................................................................................................... 23 
 
Inguinal Lymph Node Biopsy ............................................................................................................................................ 23 
 
Colonoscopy with Ileal and Rectal Biopsies ...................................................................................................................... 24 
 
MRI .................................................................................................................................................................................... 24 
7.2 
Plan to Minimize Risks to Subjects ........................................................................................................................................... 25 
7.3 
Laboratory Evaluations and Specimen Collection ..................................................................................................................... 25 
 
Clinical and Research Laboratory Evaluations .................................................................................................................. 25 
 
Biohazard Containment ...................................................................................................................................................... 26 
 
Specimen Preparation, Handling and Shipping .................................................................................................................. 26 
8. 
STUDY SCHEDULE ........................................................................................................................................................ 26 
8.1 
Schedule for HIV infected subjects (n=50) ................................................................................................................................ 26 
 
Screening ............................................................................................................................................................................ 26 
 
Baseline Visit ..................................................................................................................................................................... 27 
 
Day 14 Visit ....................................................................................................................................................................... 27 


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Month 1 Visit ..................................................................................................................................................................... 28 
 
Months 3, 6, 9, 15, 18, 21 and 27 Visits ............................................................................................................................. 28 
 
Month 12 Visit ................................................................................................................................................................... 29 
 
Month 23 Visit ................................................................................................................................................................... 29 
 
Month 25 visit .................................................................................................................................................................... 29 
 
Month 29.5 Visit ................................................................................................................................................................ 29 
 
Month 30 Visit (Final Study Visit) .................................................................................................................................... 29 
 
Early Termination Visit...................................................................................................................................................... 29 
 
Pregnancy Visit .................................................................................................................................................................. 29 
 
Unscheduled Visits ............................................................................................................................................................ 29 
8.2 
Schedule of Events for HIV Infected Subjects ........................................................................................................................... 30 
8.3 
Schedule for Control - HIV Uninfected Subjects (n=5) ............................................................................................................. 31 
 
Screening ............................................................................................................................................................................ 31 
 
Study Visit ......................................................................................................................................................................... 31 
8.4 
Schedule for Additional 5 Control HIV Uninfected Subjects (n=5) .......................................................................................... 31 
 
Screening ............................................................................................................................................................................ 31 
 
MRI Sub-Study .................................................................................................................................................................. 31 
 
Study Visit(s) ..................................................................................................................................................................... 31 
8.5 
Schedule of Events for Additional 5 Control HIV Uninfected Subjects .................................................................................... 32 
9. 
ASSESSMENT OF SAFETY ........................................................................................................................................... 32 
9.1 
Definition of an Adverse Event (AE) ......................................................................................................................................... 32 
 
Basic Definition ................................................................................................................................................................. 32 
 
Definition of a Serious Adverse Event (SAE) .................................................................................................................... 33 
 
Definition of a Suspected Unexpected Serious Adverse Reaction (SUSAR) .................................................................... 33 
 
Preexisting Condition ......................................................................................................................................................... 33 
 
Post-study Adverse Event .................................................................................................................................................. 33 
 
Abnormal Laboratory Values ............................................................................................................................................. 33 
 
Hospitalization, Prolonged Hospitalization, or Surgery ..................................................................................................... 34 
 
Anticipated Adverse Events ............................................................................................................................................... 34 
9.2 
Unanticipated Problems ............................................................................................................................................................. 34 
9.3 
Recording and Documentation of AEs....................................................................................................................................... 35 
 
Scales Used to Grade Severity of Adverse Events ............................................................................................................. 35 
 
Scales Used to Attribute Adverse Events ........................................................................................................................... 35 
 
Analysis/Management ........................................................................................................................................................ 36 
9.4 
Reporting Procedures ................................................................................................................................................................. 36 
 
AEs to be Reported ............................................................................................................................................................ 36 
 
Expedited Adverse Event (EAE) Reporting to DAIDS ..................................................................................................... 37 
9.5 
Reporting a Pregnancy ............................................................................................................................................................... 38 
9.6 
Toxicity Management ................................................................................................................................................................ 38 
9.7 
Halting and Stopping Rules ....................................................................................................................................................... 39 
 
Halting Rules for the Protocol ............................................................................................................................................ 39 
 
Stopping Rules for an Individual Participant ..................................................................................................................... 39 
9.8 
Unblinding Procedures ............................................................................................................................................................... 40 
 
Emergency Unblinding ...................................................................................................................................................... 40 
 
Individual Unblinding ........................................................................................................................................................ 40 
 
Unmasked Analysis ............................................................................................................................................................ 40 
 
Unblinding Upon Study Completion .................................................................................................................................. 40 
10. 
CLINICAL MONITORING STRUCTURE ..................................................................................................................... 40 
10.1 
Safety Monitoring Plan .............................................................................................................................................................. 40 
 
Data and Safety Monitoring Board (DSMB) ..................................................................................................................... 41 
11. 
STATISTICAL CONSIDERATIONS ............................................................................................................................. 42 
11.1 
Overview and General Design Issues......................................................................................................................................... 42 
11.2 
Sample Size Considerations ....................................................................................................................................................... 43 
11.3 
Enrollment/Stratification/Randomization/Blinding Procedures ................................................................................................. 43 
11.4 
Maintenance of Treatment Randomization Codes ..................................................................................................................... 43 
11.5 
Final Analysis Plan .................................................................................................................................................................... 43 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................................... 44 


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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................................................................... 44 
13.1 
DAIDS Protocol Registration .................................................................................................................................................... 44 
13.2 
Institutional Review Board ........................................................................................................................................................ 44 
13.3 
Informed Consent Process ......................................................................................................................................................... 44 
13.4 
Participant Confidentiality ......................................................................................................................................................... 45 
13.5 
Study Discontinuation ................................................................................................................................................................ 45 
14. 
DATA HANDLING AND RECORD KEEPING .............................................................................................................. 45 
14.1 
Data Management Responsibilities ............................................................................................................................................ 45 
14.2 
Source documents and Access to Source Data ........................................................................................................................... 45 
14.3 
Quality Control and Quality Assurance ..................................................................................................................................... 45 
15. 
PUBLICATION POLICY ............................................................................................................................................... 46 
16. 
SCIENTIFIC REFERENCES ........................................................................................................................................ 47 
17. 
APPENDIX I ................................................................................................................................................................. 50 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations and Acronyms 
 
ACEi  
Angiotensin converting enzyme inhibitor 
ADL 
 
Activities of daily living 
AE  
 
Adverse event  
AIDS   
Acquired Immunodeficiency Syndrome 
ALT  
 
Alanine aminotransferase 
APC 
 
Antigen presenting cell 
ARB   
Angiotensin-II receptor blocker  
ART   
Antiretroviral therapy 
AST 
 
Aspartate transaminase 
cART  
Combination antiretroviral therapy 
CBC 
 
Complete blood count 
CD4 
 
Cluster of differentiation 4 
CFR    
Code of Federal Regulations 
CICP   
C-terminal propeptide of type I collagen  
CM 
 
Central memory 
CMP 
 
Comprehensive metabolic panel 
CMV 
 
Cytomegalovirus 
DNA 
 
Deoxyribonucleic acid 
DSMB  
Data and Safety Monitoring Board 
ELISA  
Enzyme-linked immunosorbent assay 
FDA   
Food and Drug Administration  
FRCn  
Fibroblastic reticular cell network 
GALT  
Gut associated lymphoid tissue 
GFR 
 
Glomerular Filtration Rate 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
HA 
 
Hyaluronic acid  
HIPAA  
Health Insurance Portability and Accountability Act 
HIV  
 
Human Immunodeficiency Virus  
HPV 
 
Human Papillomavirus  
IA 
 
Immune activation 
IHC 
 
Immunohistochemisty 
INFg 
 
Interferon gamma 
IPF 
 
Idiopathic pulmonary fibrosis 
IRB  
 
Institutional Review Board  
ISH  
 
In situ hybridization 
IL 
 
Interleukin  
IR 
 
Immune reconstitution 
LPS 
 
Lipopolysaccharide 
LT 
 
Lymphoid tissue 
MCRU  
Masonic Clinical Research Unit 
MMP  
Matrix metalloprotease 
MT 
 
Microbial translocation 
µL 
 
Microlitre 
mL  
 
Milliliter  
MRE  
Magnetic Resonance Elastography 
PB 
 
Peripheral blood 
PBMC  
Peripheral blood mononuclear cell 
PCR   
Polymerase chain reaction  
PI  
 
Principal investigator  


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po 
 
per os 
QA 
 
Quality assurance 
QIA 
 
Qualitative image analysis 
RNA 
 
Ribonucleic acid 
SAE   
Serious adverse event  
sCD14  
Soluble CD14 
SIV 
 
Simian immunodeficiency virus 
TGF-β  
Transforming growth factor beta 
TUNEL 
Terminal deoxynucleotidyl transferase dUTP nick end labeling 
TNF 
 
Tumor necrosis factor  
TZ 
 
T-cell zone 
Treg   
Regulatory T cell 
UMMC  
University of Minnesota Medical Center 
VL 
 
Viral load 


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Protocol Summary 
 
 
 
Full Title 
Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV 
 
Conducted By 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
Principal Investigator 
Timothy Schacker, MD 
Professor of Medicine 
University of Minnesota, Department of Medicine 
 
Sample Size 
50 HIV infected subjects and 10 HIV uninfected control subjects.   
 
Study Population 
HIV infected: Inclusion: Healthy, HIV-1 positive men and women 18 years of age, 
with CD4 count 200-650cells/µl, on stable antiretroviral therapy (ART). Exclusion: 
Pregnancy, use of drugs that suppress or enhance immune function, current use of 
angiotensin converting enzyme inhibitor (ACEi) or angiotensin-2 receptor blocker 
(ARB). 
HIV uninfected: Inclusion: Healthy, 18 years of age. Exclusion: Pregnancy, use of 
drugs that suppress or enhance immune function, current use ACEi or ARB. 
 
Accrual Period 
14 months  
Study Design 
This is a single-center, double-blinded, placebo-controlled study of HIV infected, 
ART treated subjects randomized 1:1 to daily losartan or placebo for 30 months. All 
HIV infected subjects will undergo biopsies of inguinal lymph node (LN) and gut 
associated lymphatic tissue (GALT) at baseline, 12 and 30 months after study 
enrollment. Blood will be collected at least quarterly throughout the study and an 
intensive blood pharmacokinetic (PK) study will be conducted at month 1. All HIV 
infected subjects will be vaccinated with the quadrivalent human papilllomavirus 
(HPV) vaccine at months 23, 25 and 29.5. HIV uninfected control subjects will not 
receive study agents or HPV vaccination and will undergo blood draw and inguinal 
LN biopsy at one time point only.  
  
Sub-study-MRI   
10 HIV+ subjects will be randomly selected to participate in the MRI sub-study 
and the 5 control subjects will be enrolled in the MRI sub-study.  We are 
collecting preliminary data to determine if there is potential for a MRI to monitor 
levels of collagen in lymph nodes.  We will image the node that will be removed in 
the losartan parent trial to have collagen levels measured.  We think it possible 
that this non-invasive procedure might someday be used as a biomarker in 
studies of anti-fibrotic therapy in HIV infection. 
 
Study Duration 
HIV infected subjects will be followed for 30 months. HIV uninfected subjects will 
have up to four study visits. We expect to complete follow up of all subjects 44 
months after the first subject is enrolled. 
Study Agent/Intervention 
Description 
Losartan 100 mg daily (starting at 50 mg and dose escalating to tolerance) vs. 
Placebo 
 
For the five additional controls: Stribild – 150 mg elvitegravir/150 mg cobicistat/200 
mg emtricitabine/300 mg tenofivir disoproxil fumarate once daily and Prezista – 
800 mg once daily 


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Primary Endpoint 
 
Impact of losartan on lymphoid tissue (LT) fibrosis as determined by the amount of 
collagen deposition in LT and integrity of the fibroblastic reticular cell network 
(FRCn).  
 
Secondary Endpoints 
1. Impact of losartan on immune reconstitution and T cell function. 
2. Impact of losartan on immune activation. 
3. Impact of losartan on HIV viral reservoir size.  
4. Determination of potential drug-drug interactions between losartan and ART.  
 
Exploratory Endpoints 
1. Assess the impact of losartan on frequency of dendritic cell and CD4 T-cell 
interactions with the FRCn using two-photon microscopy. Given that this is an 
exploratory endpoint, we will perform these assays in a subset of subjects (5 
losartan treated, 2 placebo treated, and 10 HIV uninfected controls).  
2. To develop methods to image collagen content of inguinal lymph nodes using 
MRI 
3. To measure drug levels and pharmacokinetic (PK) profile of antiretrovirals in 
lymph tissues of HIV uninfected people. 
 
 
 
 
 


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1. KEY ROLES  
Principal Investigator: 
Timothy Schacker, M.D. 
 
Professor of Medicine 
 
University of Minnesota 
 
Department of Medicine 
 
420 Delaware Street SE 
 
Minneapolis, MN 55455 
 
Phone: 612-624-9955 
 
Facsimile: 612-626-5599 
 
schac008@umn.edu 
 
Clinical 
Co-Investigators: 
University of Minnesota (UMN) 
 
Meghan Rothenberger, M.D. 
Gregory Beilman, M.D. 
 
Assistant Professor of Medicine 
Professor of Surgery 
 
 
Jeffrey Chipman, M.D. 
Alexander Khoruts, M.D. 
 
Associate Professor of Surgery 
Associate Professor of Medicine 
 
 
 
 
Hennepin County Medical Center (HCMC) 
 
Jason Baker, M.D. 
 
Assistant Professor of Medicine 
 
 
Mayo Medical School 
 
 
Andrew Badley, M.D. 
Nathan Cummins, M.D. 
 
Professor of Medicine 
Assistant Professor of Medicine 
 
Clinical Sites: 
UMN Masonic Clinical Research Unit (MCRU) 
 
Masonic 211B 
 
424 Harvard Street SE 
 
Minneapolis, MN 55455 
 
Phone: 612-624-0104 
 
 
HCMC, Positive Care Center (PCC) 
 
Blue Building, Level 1 (B1.290) 
 
900 South 8th Street 
 
Minneapolis, MN 
 
Phone: 612-873-2700 
 
Clinical Laboratories: 
UMMC-Fairview Laboratory 
 
420 Delaware Street SE 
 
Minneapolis, MN 55455 
 
 
HCMC Clinical/Anatomic Laboratories 
 
701 Park Avenue 
 
Minneapolis, MN 55415 
 
Research Laboratories: 
Timothy Schacker, M.D. 
 
2-153 MRF  
 
689 23rd Avenue SE 
 
University of Minnesota 


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Minneapolis, MN 55455 
 
 
 
Courtney Fletcher, M.D. and Yazen Alnouti, Ph.D. 
 
University of Nebraska Medical Center 
 
College of Pharmacy 
 
Antiviral Pharmacology Laboratory 
 
986045 Nebraska Medical Center, Room 4005/4007 
 
Omaha, NE 68198 
 
 
Daniel Douek, M.D., Ph.D. 
 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
Vaccine Research Center 
 
Human Immunology Section 
 
Building 40, Room 3504 
 
MSC 3022 
 
Bethesda, MD 20898 
 
 
Brian Fife, Ph.D. 
 
3-240 MMB 
 
University of Minnesota 
 
Center for Immunology 
 
2101 6th Street SE 
 
Minneapolis, MN 55455 
 
 
Richard Koup, M.D. 
 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
Vaccine Research Center 
 
Immunology Laboratory 
 
40 Convent Drive 
 
Building 40, Room 4500 
 
Bethesda, MD 20892 
 
Biostatistician: 
Cavan Reilly, Ph.D. 
 
Associate Professor of Biostatistics 
 
University of Minnesota 
 
Biostatistics, Division of SPH 
 
Mayo A460 
 
420 Delaware Street SE 
 
Minneapolis, MN 55455 
 
 


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2. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
The goal of combination antiviral therapy (cART) in HIV is to suppress viral replication and restore immune 
function.  It is possible with modern cART to suppress plasma viremia to below detectable limits in most 
people; however immune reconstitution (IR) is often incomplete, and significant immunologic abnormalities 
persist, even after years of therapy.  CD4 T cell populations in peripheral blood mononuclear cells (PBMC), 
lymph node (LN), and gut associated lymphoid tissue (GALT) do not reconstitute to normal levels [1-4], 
responses to vaccines remain abnormal [5-8], and life expectancy continues to be significantly decreased 
compared to age-matched controls [9].  The underlying mechanisms driving these persistent immune 
abnormalities are likely related to the fact that markers of immune activation (IA) do not normalize in treated 
patients [10-12]. Indeed, there is growing evidence to support a model of persistent IA during therapy driving 
disease progression, albeit at a much slower rate than in untreated patients. 
 
Causes of persistent IA before and during therapy include ongoing virus production [13], co-infections such 
as cytomegalovirus (CMV) [14], and microbial translocation (MT) of bacterial products across a persistently 
damaged gut epithelium [12, 15, 16].  IA inevitably leads to pathologic changes in lymphoid tissues (LT) that 
significantly alter their function and limit immune reconstitution (IR). The primary pathology of persistent IA 
in LT is collagen deposition in the parafollicular T-cell zone (TZ) of secondary LN and GALT that gradually 
destroys TZ structure [17, 18].  Collagen deposition is mediated by transforming growth factor beta (TGF-ß) 
that is made by regulatory T cells (Treg) recruited into LT in an attempt to control virus production [19-21].  
During chronic and treated infection, when virus production is either substantially or completely suppressed, 
co-infections and MT may play a larger role in TGF-ß production.  Irrespective of the cause, TZ collagen 
accumulates over time and leads to depletion of naive and central memory (CM) CD4 T cells and prevents 
IR when cART is begun [17, 22].  Collagen destroys the fibroblastic reticular cell network (FRCn) which is a 
mesh of hollow fibers that form the skeletal anatomy of the TZ [23].  T cells require contact with the FRCn in 
order to migrate through the TZ and initiate immune responses and gain access to IL7 (made by the FRCn) 
required for survival [24-26].  Collagen formation in the TZ is a cause of naive and CM depletion and 
prevents their full reconstitution when cART is begun.  Thus TZ collagen plays a critical role in HIV 
pathogenesis, and therapies to eliminate its presence may be an important adjunctive therapy to improve 
IR. 
 
We have used the TGF-ß inhibitor pirfenidone in a non-human primate model of LT fibrosis induced by SIV 
infection.  Pirfenidone is a drug licensed outside of the U.S. for the treatment of idiopathic pulmonary fibrosis 
(IPF) and it blocks TGF-ß at the level of phosphorylation of SMAD 2,3 in the TGF-ß signaling pathway [27-
34].  We show that animals receiving pirfenidone plus cART had significantly less TZ collagen, a more 
normal FRCn and significantly greater numbers of CD4 T cells in PBMC and LN.  Pirfenidone is not FDA 
approved and the manufacturer is unable to make it available for this study.  However, an alternative drug 
exists that may be superior to pirfenidone.  Losartan is an FDA-approved angiotensin receptor inhibitor 
(ARB) that inhibits TGF-ß at the level of phosphorylation of SMAD 2,3 [35-38] with animal and human 
studies to show it reverses existing fibrosis in lung, liver, and kidney [39-43].  It is widely used throughout 
the world in Marfan syndrome for its antifibrotic properties.  Importantly, distinct from pirfenidone, losartan 
also decreases inhibitors of matrix metalloproteases that prevent tissue remodeling and increases proteases 
that induce tissue remodeling [39, 44, 45].  Further, it has anti-inflammatory properties that may be uniquely 
beneficial in the context of HIV infection.  It inhibits LPS-induced inflammatory signaling, an important 
component of MT, and decreases levels of tumor necrosis factor (TNF), IL6, and soluble adhesion 
molecules [46, 47]. 
 
 
 


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2.2 
Study Hypothesis and Rationale 
Our hypothesis is that treatment of HIV infected subjects with losartan, which has specific anti-inflammatory 
and anti-fibrotic actions will: 1) reverse existing fibrosis, 2) restore LN architecture, 3) increase the number 
and improve the function of peripheral and lymphatic CD4 T cells, 4) decrease levels of IA, 5) decrease HIV 
reservoirs, and 5) be safe and well tolerated.  To address this hypothesis, we will enroll HIV infected 
subjects and randomize them 1:1 to losartan vs placebo, then serially sample blood and LT.  In similar 
longitudinal tissue biopsy protocols our drop-out rate has ranged from 20-25%.  Therefore, we plan to enroll 
63 HIV infected subjects in order to have 50 complete the protocol.  All HIV infected subjects randomized to 
losartan will initiate therapy at a dose of 50 mg per os (po) daily and increase the dose to 100 mg po daily if 
they have no side effects or laboratory abnormalities after 14 days.  This is standard losartan dosing for the 
treatment of hypertension and stroke reduction.  This dosing protocol was also used and was well tolerated 
by non-hypertensive subjects in a large clinical trial assessing the anti-fibrotic effect of losartan in patients 
with Marfan syndrome [48].  Given risk of teratogenicity with losartan, all female subjects of reproductive 
age who are enrolled in the protocol will be required to use a reliable and effective method of contraception 
for the duration of the study. Lymphatic tissue biopsies for primary endpoint analysis will be obtained at 
baseline and 12 and 30 months after initiation of losartan or placebo. We are following subjects for 30 
months because we felt that a long period of follow up may be required to discern a significant difference in 
the treatment groups given the persistence of LT fibrosis in subjects treated with ART alone (unpublished 
data).  HIV infected subjects will also be administered the human papillomavirus (HPV) quadrivalent vaccine 
(Gardasil) per the manufacturer’s recommended dosing schedule to assess immune response (a secondary 
endpoint).  Gardasil vaccine is FDA-approved for use in men and women ages 9 to 26 to prevent the 
complications related to infection with HPV types 6, 11, 16 and 18.  Although not approved for adults 
>26 years of age, the vaccine has been well-studied in older populations and has been found to be safe and 
well-tolerated [49-51].  It is expected that many study subjects will have been exposed to 1 or more of the 
HPV serotypes included in the vaccine; however, based on epidemiologic data, it is not expected that 
subjects will have been exposed to all 4 serotypes [52-54].  Therefore, this vaccine can be used to assess 
both neo and recall immune responses.  Vaccination will be initiated at the end of the study to maximize 
time on study drug prior to vaccination and to ensure that tissues are collected at time of maximal immune 
response.   
 
Though there are no known or anticipated drug interactions between losartan and ARVs, this has not been 
extensively studied. Therefore an intensive pharmacokinetics experiment will be conducted on all HIV infected 
subjects at month 1 of the study (when losartan is at steady state). In addition, levels of ARVs and losartan in 
plasma and PBMCs will be performed quarterly over the 30-month study period and intracellular levels of 
losartan and ARVs will be measured in LT at month 30. These analyses will be performed in semi real-time to 
ensure that subjects are not put at risk from unexpected drug-drug interactions.  
 
We will enroll 5 HIV uninfected subjects who will not be randomized to a treatment arm and will not be given 
HPV vaccination.  They will undergo a blood draw and inguinal LN biopsy at one time point only.  We will 
enroll an additional 5 HIV uninfected subject who will not be randomized to a treatment arm nor given HPV 
vaccine.  These 5 subjects will be given Stribild and Prezista for two weeks. In previous studies with HIV-
positive individuals, we have shown lymph node concentrations of all ARVs to be suboptimal. No one has 
yet measured ARV concentrations in lymph nodes of healthy volunteers; we feel this is an excellent 
opportunity to answer that question. These subjects will return to the medical center for an inguinal LN 
biopsy and colonoscopy and blood draws at baseline, hours 1, 2,3,4,6,8,12 and 24 at one time point only.  
The five control subjects who are taking Stribild and Prezista will be part of the MRI-sub-study (See 
Appendix I). This test will occur once during the two weeks while they are taking the antiretrovirals, prior to 
the biopsy.  
 
In addition, these negative controls are important to the success of the two-photon microscopy experiment, 
which is used to measure motility of lymphocytes on the LN FRCn.  The HIV negative control group will be 


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used to determine normal motility and samples obtained from HIV infected subjects on losartan and placebo 
will then be compared to these results.  We have preliminary data from similar experiments conducted in 
mice to suggest that 10 control subjects will be adequate to establish normal motility.   
 
2.3 
MRI Sub‐study  
This sub-study will involve 10 regular subjects & the 5 new HIV-negative controls. 
 
Subjects will be randomly selected to participate in the MRI sub-study.  We are collecting preliminary data to 
determine if there is potential for a MRI to monitor levels of collagen in lymph nodes.  We will image the 
node that will be removed in the losartan parent trial to have collagen levels measured.  We think it possible 
that this non-invasive procedure might someday be used as a biomarker in studies of anti-fibrotic therapy in 
HIV infection. (See Appendix I for the MRI sub-study protocol). 
 
2.4 
Potential Risks and Benefits 
 
 Potential Risks 
Potential risks of study procedures (venipuncture, inguinal LN biopsy, and colonoscopy with GALT 
biopsies) are detailed in Section 7.1 and in consent forms.  According to the Losartan package insert,  
the most severe risks of losartan use include teratogenicity in the setting of pregnancy, hypersensitivity, 
symptomatic hypotension, worsening of renal function, and electrolyte abnormalities.  The most common 
side effects of losartan include fatigue, weakness, diarrhea, chest pain, tachycardia and anemia.  
Subjects will be rigorously screened to ensure that they are at low risk for complications due to losartan 
and they will be monitored closely for side effects and signs of toxicity.  The most common side effects 
of Gardasil include headache, fever, nausea, dizziness and injection site reactions.  Severe reactions, 
including hypersensitivity, are rare.  The most common side effects of Stribild are new onset or 
worsening of renal impairment, bone effects, fat distribution and immune reconstitution syndrome. The 
most common side effects of Stribild include nausea, diarrhea, abnormal dreams, headache, rash, 
fatigue, dizziness, insomnia, flatulence, somnolence, ocular icterus and jaundice.   The most common 
side effects of Prezista are drug –induced hepatitis, skin reactions ranging from mild to severe, use with 
caution with a known sulfonamide allergy, new onset diabetes or hyperglycemia, 
redistribution/accumulation of body fat or immune reconstitution syndrome and subjects with hemophilia 
may develop increased bleeding events, The most common side effects of Prezista include diarrhea, 
nausea, rash, headache, abdominal pain and vomiting.   
 
 Potential Benefits 
All subjects (excluding control subjects) will receive results of clinical laboratory testing and HPV 
vaccination at no cost over the course of this study.  There are no other direct benefits of participation 
for the individual subjects.  However, the proposed research has the potential to significantly benefit 
people infected with HIV. 
3. STUDY OBJECTIVES 
3.1 
Primary Objective  
We will assess the impact of losartan on LT fibrosis in HIV infected, ART treated adults by measuring the 
amount of collagen deposition in LT and the integrity of the FRCn using IHC. 
 


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3.2 
 Secondary Objectives 
To determine the impact of losartan on immune reconstitution and T- cell function, immune activation, HIV viral 
reservoir size, and to determine any potential drug-drug interactions between losartan and ART. 
 
3.3 
 Exploratory Objectives 
1. Assess the impact of losartan on frequency of dendritic cell and CD4 T-cell interactions with the FRCn 
using two-photon microscopy.  
2. To develop methods to image collagen content of inguinal lymph nodes using MRI 
3. To measure drug levels and pharmacokinetic (PK) profile of antiretrovirals in lymph tissues of HIV 
uninfected people. 
 
4. STUDY DESIGN 
4.1 
Description of the Study Design: 
This is a randomized, double-blind, placebo-controlled trial of 50 HIV-1 infected individuals on stable ART 
randomized in a 1:1 ratio to losartan (50 mg orally daily titrated to 100 mg daily) vs placebo for 30 months.  
We plan to enroll a total of 63 HIV infected subjects to ensure that 50 complete the protocol.  All HIV infected 
subjects will undergo biopsies of inguinal lymph node (LN) and gut associated lymphatic tissue (GALT) for 
primary endpoint analysis at baseline, 12 and 30 months after study enrollment. Blood will be collected at least 
quarterly throughout the study and an intensive blood pharmacokinetic (PK) study will be conducted at month 1.  
All HIV infected subjects will be vaccinated with the quadrivalent human papillomavirus (HPV) vaccine at 
months 23, 25 and 29.5.  5 HIV uninfected control subjects will also be enrolled. They will not receive study 
agents or HPV vaccination and will undergo blood draw and inguinal LN biopsy at one time point only.  We 
anticipate completing subject enrollment over a 14 month period and plan to complete all subject follow up 44 
months after the first subject is enrolled. 
 
4.2 
Study Endpoints: 
 Primary Endpoint 
The primary endpoint is to determine the impact of losartan on LT fibrosis in HIV infected, ART treated 
adults.  This will be determined by measuring the amount of collagen deposition in LT and the integrity of 
the FRCn using immunohistochemistry (IHC) and quantitative image analysis (QIA). 
 
 Secondary Endpoints 
There are 4 secondary endpoints: 
 
1. We will assess the impact of losartan on immune reconstitution and T-cell function by 
measuring: 
 Frequency of CD4+ T cells, TUNEL+CD3+CD8+ T cells and cells expressing TGF-beta and 
lymphotoxin-beta in LT using IHC. 
 Serum levels of IL-7 and TGF-beta using ELISA. 
 The immune response to HPV vaccination using flow cytometry to identify cells stimulated by 
specific HPV peptides. 
 
2.  We will determine the impact of losartan on immune activation in HIV infected, treated 
individuals by determining: 


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 Frequency of activated T-cell populations (specifically CD3+CD4+CD38+, CD3+,CD8+CD38+, 
CD4+Ki67+ and CD8+Ki67+ T cells) in LT using immunofluorescence staining.  
 Percentage of activated T cells, macrophages and dendritic cells in PBMCs and LT using flow 
cytometry.  
 Intracellular levels of the inflammatory cytokines IL-17, IFNg, IL-2, TNF, IL-10, and GM-CSF in 
PBMCs and LT using cytokine staining. 
 Plasma levels of additional inflammatory markers including LPS, sCD14, I-FABP, IL-1b, IL-1RA, IL-6, 
TNF, amyloid A, CRP, and D-dimer using limulus assay (sCD14) and ELISA (all others).   
 
3.  We will assess the potential for losartan to reduce the size of the viral reservoir by 
determining the frequency of HIV RNA+ and DNA+ cells in LN and GALT using both radiolabeled 
in situ hybridization (ISH) and RNAscopeTM in situ technology.  
 
4.  To ensure that losartan is safe and well tolerated when used with ART, we will: 
 Perform an intensive pharmacokinetics experiment in all HIV infected subjects at month 1 of the study 
(when losartan is at steady state).  
 Measure levels of ARTs and losartan in plasma and PBMCs quarterly over the 30-month study period. 
 Measure intracellular levels of losartan and ARTs in LT at month 30. 
 
  Exploratory Endpoints 
1. Assess the impact of losartan on frequency of dendritic cell and CD4 T-cell interactions with the FRCn using 
two-photon microscopy.  
2. To develop methods to image collagen content of inguinal lymph nodes using MRI 
3. To measure drug levels and pharmacokinetic (PK) profile of antiretrovirals in lymph tissues of HIV uninfected 
people. 
5. STUDY POPULATION 
5.1 
Selection of Study Population 
83% of persons living with HIV/AIDS in the State of Minnesota are male, 50% are white, 32% black (with 
10% being African born), 9% Hispanic/Latino, 4% American Indian, and 5% Asian or “Other” (Minnesota 
Department of Health 2010 data).  By focusing on women and minority populations in our recruitment 
efforts, we anticipate that the demographic profile of our study participants will represent this distribution.     
 
HIV infected subjects will be recruited using our well-established recruitment network in the Twin Cities that 
involves partnerships with local HIV clinics and community organizations such as the Minnesota AIDS 
Project.  We will also design study specific advertisements and flyers for use in local publications and 
clinics.  HIV uninfected subjects will be recruited through flyers placed around the University of Minnesota 
and advertisements in local magazines and newspapers. 
 
As above, based on drop-out rates in similar studies we have conducted in the past, we plan to enroll a total 
of 63 HIV infected subjects to ensure that 50 complete the protocol.  
 
5.2 
Inclusion/Exclusion Criteria 
 
HIV infected participants: 
a. Inclusion Criteria:  
Participants must meet all of the following inclusion criteria to participate in this study: 
1. HIV-1 infected. 


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2.  18 years of age. 
3. Baseline peripheral CD4+ T cell count 200-650 cells/mm3 for at least two measures and no more 
than one measure outside the range over the 6 months prior to study enrollment. 
4.  12 months of consistent use of antiretrovirals without disruption lasting ≥ 1 week in the period 
leading up to study enrollment. 
5. HIV viral load (VL) < 50 copies/mL for at least two measures over the 6 months prior to study 
enrollment. 
6. No contraindication to proposed study procedures. 
7. Women of child-bearing potential must be willing to use a form of effective contraception for the 
duration of the study. Effective contraception includes hormonal injection, implant or oral medication, 
IUD, diaphragm, or cervical cap with spermicide.  Condoms cannot be used as the sole form of 
contraception.  
 
b. Exclusion Criteria: 
Participants meeting any of the following exclusion criteria at baseline will be excluded from study 
participation: 
1. Use of any immunomodulator within the 12 months prior to study enrollment.  An immunomodulator 
for the purposes of this study is defined as a drug known to either diminish or augment a patient’s 
immune system.  Examples of these include, but are not limited to, systemic corticosteroids (use of 
topical steroids will be permitted), TNF-inhibitors, rituximab, cyclophosphamide, abatacept, 
cyclosporine, azathioprine, 6-mercaptopurine, methotrexate, sulfasalazine, cyclosporine, tacrolimus, 
sirolimus, and intravenous immune globulin. NOTE: It is considered permissible for a potential subject 
to have 1) taken a brief (≤ 2 week) course of oral corticosteroids for acute respiratory illness, 2) 
received a corticosteroid injection into a joint, and/or 3) inhaled corticosteroids for control of reactive 
airway disease. 
2. Current use of an ARB or ACEi.  
3. Current use of rifaximin, fluconazole or lithium given potential for drug interactions with losartan. 
4. Prior reaction or intolerance to an ARB or ACEi. 
5. Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence as diagnosed by 
a primary care physician or specialist.  Examples of these include, but are not limited to, systemic 
lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, mixed connective 
tissue disease, psoriasis, polymyositis, dermatomyositis, vasculitis, sarcoidosis, Wegener’s 
granulomatosis, giant cell arteritis, polyarteritis nodosa, gastrointestinal pemphigoid, eosinophilic 
colitis, Crohn’s disease, ulcerative colitis, autoimmune hepatitis. 
6. Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as 
diagnosed by a primary care physician or specialist. (Marfan’s syndrome, Ehlers-Danlos syndrome). 
7. Screening systolic blood pressure < 110. 
8. Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 within 60 days of study initiation 
or history of advanced renal disease. 
9. AST and/or ALT > 3 times the upper limit of normal within 60 days of study enrollment. 
10. Potassium > 5.0 within 60 days of study enrollment. 
11. Pregnancy. 
12. In women of childbearing age, unwillingness to use birth control for the duration of the study. 
13. Breast feeding. 
14. Prior vaccination with an HPV vaccine, including Cervarix (GlaxoSmithKline) or Gardasil (Merck). 
15. History of hypersensitivity or severe allergic reactions to yeast. 
16. At the principle investigator’s discretion if not a suitable surgical candidate. 
17. Currently undergoing treatment for hepatitis C or treatment completed within the last 3 months 
18. History of ≥ 3 previous inguinal lymph node biopsies 
 
 
HIV-uninfected: 


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      a. Inclusion Criteria 
      Participants must meet all of the following inclusion criteria to participate in this study: 
1. HIV uninfected. 
2.  18 years of age. 
3. No contraindication to proposed study procedures. 
 
 
b. Exclusion Criteria 
Participants meeting any of the following exclusion criteria at baseline will be excluded from study 
participation: 
1. Use of any immunomodulator within the 12 months prior to study enrollment (as defined above). 
2. Current use of an ARB or ACEi. 
3. Prior diagnosis of a chronic inflammatory disease with serologic or clinical evidence (as defined 
above). 
4. Prior diagnosis of a connective tissue disease with genetic, serologic or clinical evidence as 
diagnosed by a primary care physician or specialist. (Marfan’s syndrome, Ehlers-Danlos syndrome). 
5. AST and/or ALT > 1.5 times the upper limit of normal at screen 
6. At the principal investigator’s discretion if not a suitable candidate. 
7. Sulfa allergy  
8. Pregnancy. 
 
5.3 
Co‐Enrollment Guidelines 
Subjects are restricted from taking part in any other studies that involve tissue sampling or administration of 
pharmacologic agents while enrolled in this protocol.  
 
6. STUDY AGENTS 
6.1 
Study Agent Acquisition 
 Losartan 
 
 
6.1.1.1 Formulation, Packaging, and Labeling 
 
 
Losartan will be provided for this study by Merck and will be shipped directly to the  
 
 
 
Investigational Drug Services (IDS) pharmacy at the University of Minnesota.  Matched placebo  
 
 
pills will also be provided by Merck.  IDS pharmacy will maintain randomization codes and  
 
 
will provide appropriate labels for medications distributed to subjects.  
             
            6.1.1.2 Preparation, Administration, Storage, and Dosage of Study Agent(s)/Intervention(s) 
HIV infected subjects will be randomized to placebo or losartan.  Starting dose of losartan will be 
50 mg po daily.  At week 2, dose will be increased to 100 mg po daily based on tolerability, blood 
pressure, and toxicity lab results. The IDS pharmacy will be responsible for preparing pill bottles, 
distributing medications to subjects, and storing medications.  Research pharmacists and 
credentialed pharmacy technicians charged with dispensing research-related drugs will receive 
protocol-specific training and are compliant with State Board of Pharmacy requirements, FDA 
guidelines, and Good Clinical Practices.   
 
6.1.1.3 Study Agent Accountability Procedures 
Losartan or placebo will be distributed to subjects at baseline visit, week 2 visit and 
approximately every 3 months thereafter.  Pharmacy documents, including study drug 
accountability logs, study drug ordering/shipping logs, and regulatory documents are maintained 
by the pharmacy technician.  All handling of study agents (e.g., drug receipt and storage, drug 


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accountability, etc.) will be done by a pharmacist.  If subjects have study drug remaining at time 
of study completion or study withdrawal, designated study staff will collect the drug from the 
subject and return it to the UMN IDS where it will be properly disposed of. 
 
 Gardasil Vaccine 
 
 
6.1.2.1 Formulation, Packaging, and Labeling 
 
 
Standard pre-filled syringes of Gardasil will be purchased commercially through Merck for use in 
 
 
this study and will be shipped directly to the IDS pharmacy.               
             
6.1.2.2 Preparation, Administration, Storage, and Dosage of Study Agent(s)/Intervention(s) 
Gardasil will be stored in the IDS pharmacy and will be distributed by the pharmacy to 
designated study staff on the day of vaccine visits.  Research pharmacists and credentialed 
pharmacy technicians charged with dispensing research-related drugs will receive protocol-
specific training and are compliant with State Board of Pharmacy requirements, FDA guidelines, 
and Good Clinical Practices.  Trained study staff will administer 0.5mL of Gardasil (which 
contains suspension of 120 mcg L1 protein from HPV types 6, 11,16, and 18) intramuscularly in 
the thigh of HIV infected subjects at months 23, 25 and 29.5.   
 
6.1.2.3 Study Agent Accountability Procedures 
Pharmacy documents, including study drug accountability logs, study drug ordering/shipping 
logs, and regulatory documents are maintained by the pharmacy technician.  All handling of 
study agents (e.g., drug receipt and storage, drug accountability, etc.) will be done by a 
pharmacist.  IDS will properly dispose of any product that remains when the study is completed.  
 
 Stribild 
 
 
6.1.3.1 Formulation, Packaging, and Labeling 
STRIBILD is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and 
tenofovir DF for oral administration.  Stribild will be provided for this study by the research study 
and will be shipped directly to the Investigational Drug Services (IDS) pharmacy at the University 
of Minnesota. 
 
6.1.3.2 Preparation, Administration, Storage, and Dosage of Study Agent(s)/Intervention(s) 
HIV non-infected subjects will receive 150 mg elvitegravir/150 mg cobicistat/200 mg 
emtricitabine/300 mg tenofivir disoproxil fumarate to take by mouth once daily. The IDS 
pharmacy will be responsible for preparing pill bottles, distributing medications to subjects, and 
storing medications.  Research pharmacists and credentialed pharmacy technicians charged 
with dispensing research-related drugs will receive protocol-specific training and are compliant 
with State Board of Pharmacy requirements, FDA guidelines, and Good Clinical Practices 
 
6.1.3.3 Study Agent Accountability Procedures 
Pharmacy documents, including study drug accountability logs, study drug ordering/shipping 
logs, and regulatory documents are maintained by the pharmacy technician.  All handling of 
study agents (e.g., drug receipt and storage, drug accountability, etc.) will be done by a 
pharmacist.  If subjects have study drug remaining at time of study completion or study 
withdrawal, designated study staff will collect the drug from the subject and return it to the UMN 
IDS where it will be properly disposed of. 
 
 Prezista 
 
6.1.4.1 Formulation, Packaging and Labeling 


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Prezista comes in tablets or oral suspension.  Prezista will be provided for this study by the 
research study and will be shipped directly to the Investigational Drug Services (IDS) pharmacy 
at the University of Minnesota.   
 
6.1.4.2 Preparation, Administration, Storage and Dosage of Study Agent(s)/Intervention(s). 
HIV non-infected subjects will receive 800 mg of Prezista to take by mouth once daily. The IDS 
pharmacy will be responsible for preparing pill bottles, distributing medications to subjects, and 
storing medications.  Research pharmacists and credentialed pharmacy technicians charged 
with dispensing research-related drugs will receive protocol-specific training and are compliant 
with State Board of Pharmacy requirements, FDA guidelines, and Good Clinical Practices. 
 
6.1.4.3 Study Agent Accountability Procedures 
Pharmacy documents, including study drug accountability logs, study drug ordering/shipping 
logs, and regulatory documents are maintained by the pharmacy technician.  All handling of 
study agents (e.g., drug receipt and storage, drug accountability, etc.) will be done by a 
pharmacist.  If subjects have study drug remaining at time of study completion or study 
withdrawal, designated study staff will collect the drug from the subject and return it to the UMN 
IDS where it will be properly disposed of. 
 
6.2 
Assessment of Participant Adherence with Study Product 
Adherence to study drug (losartan or placebo) will be assessed by designated study staff at each study visit 
(these occur at least quarterly throughout the 30-month study).  Subjects will be asked to bring their pill 
bottle to each of these visits so that remaining pills can be counted and used as a measure of adherence.  
Gardasil will be administered at appropriate dosing intervals by designated study staff, ensuring proper 
adherence. 
 
6.3 
Permitted Medications and Procedures 
      Medications not listed under prohibited medications and the manufacturers’ package inserts are permitted 
during this study. If subjects develop a condition that requires a medical procedure while on study, we will 
determine impact of this on study participation on a case by case basis. Whenever a concomitant 
medication or study agent is initiated or a dose is changed, investigators must review the concomitant 
medications and study agents’ most recent package inserts, and Investigator’s Brochures to obtain the most 
current information on drug interactions, contraindications, and precautions.  
 
6.4 
 
Prohibited Medications  
The following drugs are not permitted for HIV subjects while on study: 
o 
Any immunomodulator (defined as a drug known to either diminish or augment a patient’s 
immune system). Examples include, but are not limited to, systemic corticosteroids (use of 
topical steroids will be permitted), TNF-inhibitors, rituximab, cyclophosphamide, abatacept, 
cyclosporine, azathioprine,  6-mercaptopurine, methotrexate, sulfasalazine, cyclosporine, 
tacrolimus, sirolimus, and intravenous immune globulin. 
o ACE inhibitors 
o ARBs other than the study drug 
o Rifampin 
o Lithium 
o Fluconazole 
 
The following drugs are not permitted for uninfected control subjects while taking Stribild and Prezista: 
o Any antiretroviral drugs 


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o Any nephrotoxic drugs 
o Any drugs that are highly dependent on CYP3A for clearance and for which elevated plasma 
concentrations are associated with serious and/or life-threatening events 
 
 
 
7. STUDY PROCEDURES/INTERVENTIONS 
7.1 
Description and Potential Risks of Clinical Procedures  
 Medical History 
At screening and baseline visits, an extensive medical history will be obtained (including prior 
diagnoses, medications, surgeries, etc.).  Interval medical histories will be obtained at each subsequent 
study visit.  Only trained designated study staff or physicians will obtain the medical history.  History will 
primarily be obtained by interviewing the subject.  If the subject is agreeable and signs a release of 
information form, medical records may also be obtained and reviewed by the study clinical team.  
Obtaining a medical history may make subjects feel uncomfortable or embarrassed.  There are no other 
potential risks.  
 
 Physical Exam  
At screening, a physical exam will be performed which will include measurement of vital signs and 
evaluation of heart, lungs, abdomen, and neurologic and lymphatic systems.  At all other time points 
indicated, a targeted physical examination including measurement of vital signs and evaluation of heart, 
lungs, abdomen, prior LN biopsy sites, and neurologic system will be performed.  Only trained study 
staff and study physicians will perform exams.  Performing a physical exam may make subjects feel 
uncomfortable or embarrassed.  There are no other potential risks.  
 
 Medical Adherence Counseling 
 
 
At each visit, designated study staff or physicians will counsel subjects about the importance of 
adherence to ART and study medications.  Women of child-bearing potential will be counseled about the 
importance of adherence to contraceptives.  There are no potential risks associated with this.  
 
 Venipuncture  
Venipuncture will be performed at each visit and will be done only in the MCRU or Positive Care Center. 
Only trained research clinic staff or physicians will be allowed to perform venipuncture.  The risks of 
venipuncture are transient pain, bleeding, lightheadedness, bruising, possible vasovagal reaction, and 
infection. 
 
 Gardasil Vaccination 
Gardasil vaccine will be administered to HIV infected subjects at months 23, 25 and 29.5.  Only study 
staff well trained in vaccine administration will be allowed to administer Gardasil.  The vaccine will be 
administered intramuscularly in the thigh at the month 29.5 visit so that local response to the vaccine in 
the draining inguinal lymph node can be assessed.  The most common side effects of this vaccination 
are headache, fever, nausea, dizziness and injection site reactions.  Severe reactions, including 
hypersensitivity, are rare. 
 
 Inguinal Lymph Node Biopsy 
Inguinal lymph node biopsies will be performed by Dr. Gregory Bielman or Dr. Jeffrey Chipman, 
members of the Department of Surgery at the University of Minnesota.  HIV infected subjects will have 


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biopsies performed at baseline and months 12 and 30.  HIV uninfected control subjects will have 
biopsies performed at one time point only.  Procedures will be done in the MCRU under local 
anesthesia.  The surgeon will first clean and sterilize the inguinal area, inject a local anesthetic and 
make a small (5 cm) incision over the lymph node.  It will be removed and the incision closed.  This 
technique has been successfully used in over 200 lymph node biopsies at the University of Minnesota in 
the past 5 years without any significant complications. 
 
The risks of the lymph node biopsy are bleeding, infection, seroma, and scarring.  Any participant who 
develops a seroma will have it drained with a syringe in the clinic.  These complications are rare.  All 
post-operative and post-biopsy care will be provided by designated study staff. If complications occur, 
the subject will be seen immediately by the appropriate study physician(s).  
 
 
  
 
 Colonoscopy with Ileal and Rectal Biopsies 
Colonoscopies with ileal biopsies will be completed by Dr. Alex Khoruts, a member of the Division of 
Gastroenterology in the Department of Medicine at the University of Minnesota.  HIV infected subjects 
will have biopsies performed at baseline and months 12 and 30. Procedures will be done in the UMMC 
Endoscopy Center under conscious sedation.  Subjects will complete the required bowel regimen the 
night prior to their scheduled procedure.  For the procedure, the participant will lie on their left side and 
the colonoscope will be inserted and guided through the colon.  After 20 small tissue biopsies of the 
ileum and rectum are obtained, the colonoscope will be removed.    
 
The risks of colonoscopy are abdominal cramping, bleeding, anxiety, and dizziness from the sedation. A 
very rare complication of colonoscopy is perforation of the intestine.  All post-procedure and post-biopsy 
care will be given by designated study staff who are specially trained to do this. 
 
 MRI  
MRI will be performed by Greg Metger, PhD, a faculty member of the Department of Radiology at the 
University of Minnesota. MRI sub-study participants will undergo MRI one to three weeks prior to the 
baseline, Month 12 or Month 30 visit. MRI will be performed at the Center for Magnetic Resonance 
Research (CMRR) without use of contrast dye. Sub-study participants will be screened and consented 
prior to undergoing MRI by trained CMRR staff. Subjects will be asked to avoid eating or drinking 
anything for four hours prior to the procedure. The subject will be positioned on their back on the 
scanner table, will enter the magnet tunnel feet first, and will have a surface coil consisting of a flexible 
plastic sheet placed around their body and secured with Velcro. A series of scans that in total will last 
between 60 – 180 minutes will be performed. These scans are intended to develop new methods for 
acquiring and analyzing MRI data to characterize structural and functional changes of the lymphatic 
tissue between the normal and disease state.  
Risks of moving in/near the scanner and during the MR scanning include dizziness, warming, and 
muscle twitching. Some metallic objects are attracted to the magnet and cannot be brought into the 
room. Some participants may experience claustrophobia. The MR scanner makes loud noses. Some 
people report mild nausea, headache, a metallic taste in their mouth, or sensations of flashing lights that 
if present, subside shortly after leaving the magnet. There is a risk of unknown effects related to 
participation in MRI research. There are no benefits to participation. Incidental findings are not expected, 
but if found, a Radiologist associated with CMRR will review the MR images and will recommend the 
subject follow-up with their primary medical provider as needed. 
See Appendix I for additional information about MRI 
 


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7.2 
Plan to Minimize Risks to Subjects 
All investigators and study staff have completed required training regarding human subject protections.  
Study staff will comply with all related regulations and laws, included, but not limited to 45 CFR 46 and 21 
CFR 50, 56 (FDA version), and HIPAA Privacy Regulations.  Study will be conducted in accordance with US 
and international standards for good clinical practices, applicable regulations, and institutional research 
policies and procedures. 
 
Subjects will be rigorously screened against inclusion/exclusion criteria to ensure that their participation is 
safe.  All staff members responsible for taking a medical history that could potentially make the participant 
uncomfortable have been specifically trained for how to do this in a sensitive manner. Only qualified study or 
clinic staff or physicians will draw blood to minimize risks. Pregnancy testing will be performed at screening, 
baseline, every 3 months, and anytime during follow up when the woman or investigator suspects 
pregnancy.  In addition, study staff will stress the importance of adherence to contraceptives in order to 
minimize risks related to unintended fetal exposure. Subjects will be closely observed for systemic adverse 
events and toxicity related to the study drug on a routine basis through interviews, clinical assessment 
(including measuring vital signs and physical exam), and monitoring of renal function, liver function, and 
hematologic panel.  All lymph node biopsies will be performed by either Dr. Gregory Beilman, Dr. Jeffrey 
Chipman, or Dr. Torfi Hoskuldsson who have performed >400 LN biopsies in the research setting without 
significant complications. All colonoscopies will be performed by Dr. Alexander Khoruts who has performed 
>300 colonoscopies and biopsies in related HIV studies in the past without any complications.  Subjects will 
be monitored after biopsy procedures for at least 4 hours by study staff trained in managing postoperative 
patients.  They will be monitored for at least 30 minutes after HPV vaccine administration to ensure that they 
tolerate the vaccine without difficulty.   
 
Samples obtained for pharmacokinetic analysis will be immediately sent to Dr. Fletcher’s laboratory and will 
be analyzed in semi real-time. Levels of losartan and all ARVs that an individual subject is taking will be 
monitored to ensure that subjects are not exposed to supratherapeutic levels of any drug, that losartan does 
not decrease levels of any ARVs, and that the active metabolite of losartan is within the expected range.     
Results of these analyses will be communicated to the PI as soon as they are available.  If losartan is found 
to either increase or decrease levels of a particular ARV, the IRB will be notified and all enrolled subjects 
taking that ARV will be contacted and the finding explained.  Depending on the type of drug-drug interaction, 
toxicity labs and/or HIV VL will be obtained within 3 days of obtaining the drug level results.  If dose 
adjustments can be used to overcome these interactions, they will be made if the subject is willing.  If dose 
adjustments are not possible, subjects taking the ARV will be withdrawn from the study and the protocol will 
be amended so that no additional subjects taking that ARV will be enrolled.  If losartan metabolite levels are 
found to be lower than the expected range, the losartan dose will be increased.  If losartan metabolite levels 
are higher than expected, toxicity labs will be obtained and the dose will be decreased.  After any dose 
adjustments of losartan or ARVs, follow up drug levels will be monitored closely to ensure that target levels 
have been achieved.  
 
7.3 
Laboratory Evaluations and Specimen Collection 
 
 Clinical and Research Laboratory Evaluations  
Comprehensive list of clinical laboratory evaluations are detailed in the Protocol Analyte List and a 
comprehensive list of non-FDA approved endpoint assays are detailed in the Non-FDA Approved End 
Point Test List.  As a reference, both lists are included in the grant application appendix, located in the 
study files. 
  


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 Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions will be 
employed by all personnel in the drawing of blood and shipping and handling of all specimens for this 
study, as currently recommended by the Centers for Disease Control and Prevention and the National 
Institutes of Health (NIH). 
 
 
 Specimen Preparation, Handling and Shipping  
Please refer to the Specimen Management Plan included in the appendix of this grant for further details 
pertaining to specimen preparation, handling and shipping.   
 
7.3.3.1 Blood 
All blood samples taken in the MCRU and Positive Care Clinic will be immediately transferred to 
the appropriate site. Research study staff will order clinical labs (e.g. CD4 T cell count, HIV VL, 
CMP, and CBC) and ensure that the appropriate blood collection tubes are sent to the 
appropriate clinical laboratory.  Samples drawn for research purposes will be transported by a 
scientist in the Schacker lab from the MCRU to the laboratory for isolation of plasma, serum and 
PBMCs.  Research samples obtained in the Positive Care Clinic will be transported to the 
Schacker lab by courier and immediately processed.  Please refer to the Specimen Management 
Plan in the study files for details regarding the distribution of serum, plasma and PBMCs to 
specialized laboratories for analysis.  
 
 
 
7.3.3.2 Inguinal Lymph Node Biopsies 
Lymph nodes will be harvested in the MCRU and immediately sectioned at the bedside by a 
study physician.  For HIV infected subjects, one portion will be placed into freshly made 4% 
paraformaldehyde (PFA) for 24 hours (and then transferred to 80% ethanol prior to paraffin 
embedding) and the other is placed into RPMI and immediately transported to the Schacker 
laboratory for preparation of cell suspension.  Distribution of isolated cells is detailed in the 
Specimen Management Plan. For subjects enrolled in the two-photon microscopy study, a small 
section of the LN intended for histology will be immediately transferred fresh to the Fife 
laboratory.  For HIV uninfected control subjects, half of the LN will be placed into fresh PFA and 
managed as above.  The other half will be transferred fresh to the Fife laboratory.   
 
7.3.3.3 Colonoscopy with Ileal and Rectal Biopsies 
Approximately 20 snip biopsies of ileum and rectum will be obtained. Half of these samples will 
be placed in 4% PFA followed by 80% ethanol. They will then be paraffin embedded and used in 
IHC and ISH studies.  The remaining samples will be immediately placed into RPMI and 
transferred to the Schacker lab for preparation of cell suspensions. Distribution of isolated cells is 
detailed in the Specimen Management Plan in the study files. 
 
8. STUDY SCHEDULE      
8.1 
Schedule for HIV infected subjects (n=50) 
 Screening  
At this visit, consents will be reviewed in detail and the subject will have the opportunity to ask any 
questions they may have.  Subjects will be asked if they would like to participate in the additional two-


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photon microscopy sub-study which entails additional blood draws at several scheduled study visits.  
Designated study staff or physician will interview the participant and a physical exam (which includes 
vital signs and exam of heart, lungs, abdomen, neurologic and lymphatic systems) will be performed.  
Blood will be obtained for CD4 T cell count, HIV VL, HIV antibody, liver function tests, electrolyte panel 
including creatinine, and complete hematology count (CBC - white blood cell count with differential, 
hemoglobin and platelets).  Screening for hepatitis C will also be performed.  Women of childbearing 
age will have a urine pregnancy test. Once lab results are available (within 3 days), they will reviewed by 
designated study staff to ensure that laboratory inclusion/exclusion criteria are met. If the subject has 
met all entry criteria, they will be contacted by the designated study staff.  The study protocol will again 
be reviewed and if they are still interested in enrolling, they will be scheduled for the day 0 visit.  
Subjects who have not met the criteria will also be contacted by the designated study staff and told that 
they do not qualify to participate in the study. At this visit, an “enroll by date” will be designated that is no 
more than 60 days from the screen date to ensure screening labs are no more than 60 days old at the 
time of randomization. If more than 60 days passes between “Screen” and randomization, a 
comprehensive chemistry panel will be redrawn with the results known to be within study-required 
parameters prior to randomization.  
 
 Baseline Visit 
 
Designated study staff will review medical history with the participant and perform a targeted physical 
exam (vitals, heart, lung, abdomen, neurologic system). The subject will not be randomized until lab 
results have been reviewed and found to be within limits designated in the protocol. The designated 
study staff or principal investigator will sign off on lab results and eligibility criteria on the day of 
randomization to ensure labs are no more than 60 days old and the subject still meets all eligibility 
criteria. Blood will then be drawn for CBC, comprehensive metabolic panel (CMP – includes electrolytes, 
creatinine, and liver function tests), CD4 and VL as well as plasma, serum and PBMCs for study 
endpoints.  Subjects in the two-photon microscopy sub-study will also have an additional 90cc of blood 
drawn.  Inguinal LN biopsy and colonoscopy with ileal and rectal biopsies will be performed (described in 
detail in section 7.1 above). They will remain in the MCRU for 4 hours after procedures for monitoring. 
 
Following procedures, subjects will be randomized to receive either losartan or placebo.  The drug will 
be dispensed to the participant to begin administration on that day.  At this baseline visit, participants will 
start losartan or matching placebo at 50mg daily. Prior to the first dose, the subject will be counseled 
regarding dosing schedule, potential side effects, and the importance of adherence.  A member of the 
study team will contact the subject by telephone at day 7 to check for tolerability. 
  
 Day 14 Visit 
Subjects will be seen at day 14 for clinical assessment (interval history and targeted exam), assessment 
of drug adherence and to obtain toxicity labs (CBC and CMP).  If the subject meets the following criteria: 
lack of dizziness, lightheadedness, or faintness upon rising, confusion, palpitations, and cough; GFR 
greater than or equal to 30 ml/min/1.73 m2 and potassium level less than or equal to 5.0, the dose of 
losartan/placebo will be increased to 100 mg po daily.  The maximal tolerable dosage (up to 100 mg a 
day) will be continued for a total of 30 months.   
 
At Day 14, side effects and blood chemistries (comprehensive chemistry panel) will be assessed. The 
dose of losartan/placebo will increase to 100mg daily at this Day 14 visit (i.e., once lab results return) if 
all of the following criteria are met:  
a) Systolic blood pressure (BP) ≥90 mmHg 
b) Potassium ≤5.0 mmol/L 
c) eGFR ≥30 mL/min/1.73m2 


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d) Lack of a grade ≥3 side effect since the last evaluation deemed possibly/probably related to 
the study drug.  
e) Lack of significant side effects deemed related to study drug (e.g., lightheaded upon 
standing) 
f) Lack of other concerns to increase study drug dosing, as determined by site investigator 
Participants may be evaluated by clinical labs and/or have side effects assessed at any point during the 
study, per the discretion of the site investigator.  If participants are increased to 100mg daily (or 
matching placebo) they will maintain this dose for the duration of the 30-month study unless new side 
effects or adverse events necessitate re-evaluation (see below criteria for dose reduction or stopping 
study medication). 
 
If participants do not increase dose to 100mg daily at the week 2 visit (e.g., if symptomatic or if systolic 
BP is not ≥90 mmHg), the criteria for dose escalation may be reassessed at the 1-month visit. If 
participants do not meet criteria for dose increase (from 50mg to 100mg daily) after the 1-month visit, 
they will be maintained on 50mg dose until the month 3 visit, at which time the dose may be increased to 
100mg daily if the first five criteria above are met (a-e).  At any point when participants have dose 
increased from 50mg to 100mg, they will be contacted by phone within 2 weeks to assess sides effects 
and have clinical labs drawn to assess toxicity; a full study visit for side effect and adverse event 
documentation can occur at any point, per the discretion of the site investigator.  
 
Dose Reduction: Tolerability, side effects, and clinical laboratory monitoring will be assessed at each 
study visit (via participant report and clinical labs), and at any other time point at the discretion of the 
clinical site investigator.  Adverse events that are assessed as related to study drug will prompt re-
evaluation via phone or as an adverse event visit, per clinical discretion of the site investigator. If this 
event worsens or does not resolve after re-evaluation, then study medication dose should be decreased 
(i.e., from 100mg to 50mg) or stopped (if taking 50mg daily).  If signs and symptoms resolve after 2 
weeks, then the participant may resume or increase dose (i.e., back to 100mg if previously reduced to 
50mg daily), per the clinical discretion of the site investigator. 
 
Stopping Study Medication:  If an adverse event of grade ≥3 is assessed as related to study drug, study 
medication should be stopped and the participant should be re-evaluated in 2 weeks.  If a grade 2 rash 
is persistent, study medication may also be stopped at the discretion of the site investigator and the 
participant should be re-evaluated in 2 weeks. If signs and symptoms resolve after 2 weeks, then the 
participant may be re-challenged at a lower dose (i.e., at 50mg if previously taking 100mg daily) per the 
clinical discretion of the site investigator.  If study medication is stopped for an adverse event that is later 
determined NOT to be related to study medication, then the medication may be resumed at 50mg and 
increased to 100mg per initial criteria for dose escalation and at the discretion of the clinical site 
investigator.  
 
 Month 1 Visit 
Subjects will be seen at month 1 for clinical assessment (interval history and targeted exam) and review 
of drug adherence.  Blood will be drawn.  They will then take their daily ART and study drug and will 
remain in the MCRU for additional blood draws at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration 
in order to intensively study the pharmacokinetics of ARTs and losartan.  They will then return to the 
MCRU the following morning for one additional blood draw at 24 hours after drug administration.  
 
 Months 3, 6, 9, 15, 18, 21 and 27 Visits 
 
Subjects will be seen for clinical assessment (interval history and targeted exam), review of drug 
adherence, refill of study drug, and blood draw for CBC, CMP, CD4, VL, plasma, serum and PBMCs. 
 


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 Month 12 Visit 
Subjects will be seen at month 12 for clinical assessment (interval history and targeted exam), review of 
drug adherence, refill of study drug, and blood draw for CBC, CMP, CD4, VL, plasma, serum and 
PBMCs.  Subjects in the two-photon microscopy sub-study will also have an additional 90cc of blood 
drawn.  Subjects will then undergo repeat inguinal LN biopsy and colonoscopy with rectal and ileal 
biopsies.  They will remain in the MCRU for 4 hours after procedures for clinical monitoring. 
 
 Month 23 Visit 
Subjects will be seen for clinical assessment (interval history and targeted exam), review of drug 
adherence, refill of study drug, and blood draw for CBC, CMP, CD4, VL, plasma, serum and PBMCs.  In 
addition, the first dose of Gardasil (human papillomavirus recombinant vaccine) will be administered.  
Subjects will remain in the MCRU for 30 minutes after administration for monitoring. 
 
 Month 25 visit 
Subjects will return for clinical assessment (interval history and targeted exam), review of drug 
adherence, refill of study drug and blood draw for plasma, serum and PBMCs.  The second dose of 
Gardasil will then be administered. Subjects will remain in the MCRU for 30 minutes after administration 
for monitoring. 
 
 Month 29.5 Visit 
Subjects will be seen for clinical assessment (interval history and targeted exam), review of drug 
adherence and blood draw for CBC, CMP, CD4, VL, plasma, serum and PBMCs.  In addition, the third 
and final dose of Gardasil will be administered. Subjects will remain in the MCRU for 30 minutes after 
administration for monitoring. 
 
 Month 30 Visit (Final Study Visit) 
Subjects will be seen at the end of month 30 for the final scheduled study visit. Clinical assessment 
(interval history and targeted exam) and review of drug adherence will be performed and any remaining 
study drug will be collected by the designated study staff.  Blood will be drawn for CMP, CBC, HIV VL, 
CD4 T cell count, serum, plasma, and PBMCs.  Subjects in the two-photon microscopy sub-study will 
also have an additional 90cc of blood drawn. Subjects will undergo final biopsy procedures (ileal, rectal, 
and lymph node). They will remain in the MCRU for 4 hours after procedures for clinical monitoring. 
They will complete the off-study form prior to discharge from the MRCU.  Subjects will be instructed to 
report any subsequent event(s) within 3 months of study completion that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.   
 
 Early Termination Visit 
Participants may withdraw voluntarily from the study at any time.  If a subject opts to discontinue, 
attempts will be made to schedule and conduct an early termination visit for medical assessment and 
return of any unused study drug for proper disposal.  If a subject withdraws after an adverse event (AE), 
they will be followed until resolution of the issue or until their condition is stable.   
 
 Pregnancy Visit 
In the event that a study subject becomes pregnant, termination, reporting, and follow-up procedures 
outlined in Section 9.9 will be followed. 
 
 Unscheduled Visits 
Additional visits will be scheduled as needed to follow up AEs, evaluate biopsy sites, address subject 
concerns, etc.  


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8.2 
Schedule of Events for HIV Infected Subjects 
 
 
Table 1. Protocol summary for HIV infected subjects: 
 
  
Screen 
Day 
0 
Day 
14 
Month 
1 
Months  
3, 6, 9, 
15, 18, 
21, 27  
Month 
12 
Month 
23 
Month 
25 
Month 
29.5 
Month 
30 
Medical history 
X 
X  
  
  
  
  
 
  
 
  
Interval medical 
history 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment and 
counseling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test2 
X 
X  
  
X  
X  
 X 
 
X  
X 
  
HCV Ab 
X 
  
  
  
  
  
 
  
 
  
CMP 
X 
X  
X 
X 
X 
X 
X 
  
X 
X 
CBC w diff 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
CD4 count 
X 
X 
  
X 
X 
X 
X 
  
X 
X 
HIV viral load 
X 
X  
  
X 
X 
X 
X 
  
X 
X 
Serum3 
  
X 
  
X 
X 
X 
X 
X  
X 
X 
Plasma /PBMCs4 
  
X 
  
X 
X 
X 
X 
X  
X 
X 
Additional PBMCs5 
 
X 
 
 
 
X 
 
 
 
X 
Biopsies6 
  
X 
  
  
  
X 
 
  
 
X 
HPV vaccine7 
  
  
  
  
  
  
X 
X 
X 
  
PK assessment 
  
  
  
X8 
X9 
X9 
 
X9 
 
 X10 
 
1. At screening, a full physical exam will be performed (described above).  At subsequent visits, a targeted 
exam will be performed.  
2. Women of childbearing age must have a negative pregnancy test prior to enrollment.  Pregnancy testing 
will also occur roughly every 3 months during follow up and additionally if the subject or investigator 
suspects pregnancy. 
3. Serum will be used to determine levels of IL-7 and TGF-beta. 
4. Plasma will be used to determine levels of cytokines and markers of inflammation.  PBMCs will be used 
in flow cytometry and intracellular cytokine staining. 
5. Additional blood will be obtained from subjects enrolled in the two-photon microscopy sub-study. 
6. Inguinal LN biopsy and colonoscopy with sampling of ileal and rectal tissues. 
7. Human papillomavirus quadrivalent vaccine (Gardasil) will be administered at 3 time points per 
recommended vaccine schedule and immune response will be assessed at month 30. 
8. Intensive 24-hour PK assessment will be performed at month 1 visit.  
9. Plasma and intracellular PBMC concentration of losartan and ARVs will be determined approximately 
every quarter. 
10. Plasma and intracellular PBMC concentration of losartan and ARVs PLUS concentrations in LN and 
GALT will be determined at month 30. 
 


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8.3 
Schedule for Control ‐ HIV Uninfected Subjects (n=5) 
 Screening  
At this visit, consents will be reviewed in detail and the subject will have the opportunity to ask any 
questions they may have. The designated study staff or physician will interview the participant and a 
physical exam will be performed.  Blood will be obtained for HIV antibody, liver function tests, electrolyte 
panel including creatinine, and CBC.  Screening for hepatitis C will also be performed.  Women of 
childbearing age will have a urine pregnancy test. Once lab results are available (within 3 days), they will 
reviewed by designated study staff to ensure that laboratory inclusion/exclusion criteria are met. If the 
subject has met all entry criteria, they will be contacted by the designated study staff.  The study 
protocol will again be reviewed and if the subject is still interested in enrolling, they will be scheduled for 
the study visit.  Subjects who have not met the criteria will also be contacted by the designated study 
staff and told that they do not qualify to participate in the study. 
 
 Study Visit 
Designated study staff will review medical history with the participant and perform a targeted physical 
exam.  Blood will then be drawn for CD4, plasma, serum and PBMCs.  Inguinal LN biopsy will be 
performed. The subject will remain in the MCRU for 4 hours after procedures for monitoring. They will 
complete the off-study form prior to discharge from the MRCU. Subjects will be instructed to report any 
subsequent event(s) within 3 months of study completion that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.   
 
8.4 
Schedule for Additional 5 Control HIV Uninfected Subjects (n=5) 
Our first experiments with human tissue demonstrated that we need to change procedures for handling and 
imaging the tissue.  The first few controls were not fully interpretable because of this.  In addition the data 
we are generating suggests that increasing the number of controls by 5 subjects will significantly increase 
our power to detect changes in the FRCn attributable to the intervention. 
 
 Screening 
At this visit, consents will be reviewed in detail and the subject will have the opportunity to ask any 
questions they may have. The designated study staff or physician will interview the participant and a 
physical exam will be performed.  Blood will be obtained for HIV antibody, liver function tests, electrolyte 
panel including creatinine, and CBC.  Screening for hepatitis C will also be performed.  Women of 
childbearing age will have a urine pregnancy test. Once lab results are available (within 3 days), they will 
reviewed by designated study staff to ensure that laboratory inclusion/exclusion criteria are met. If the 
subject has met all entry criteria, they will be contacted by the designated study staff.  The study 
protocol will again be reviewed and if the subject is still interested in enrolling, they will be scheduled for 
the study visit.  Subjects who have not met the criteria will also be contacted by the designated study 
staff and told that they do not qualify to participate in the study 
 
 MRI Sub-Study 
Within two weeks of the biopsy a MRI will be scheduled, see Appendix I for MRI sub-study protocol. 
 
 Study Visit(s) 
If subject agrees to participate in the trial they will return to the MCRU to receive Stribild and Prezista.  
The subjects will take these medications for two weeks and return to be seen by the designated study 
staff.  At this time a review of the medical history with the participant and a targeted physical exam will 
be performed.  Blood will then be drawn for CD4, plasma, serum and PBMCs.  Inguinal LN biopsy with 
colonoscopy with ileal and rectal biopsies will be performed.  During this time blood draws will be taken 
at baseline and hours 1,2,3,4,6,8,12, and 24 post-drug administration.  The subject will remain at the 


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MCRU for 12 hours for monitoring.  They will then return to the MCRU the following morning for one 
additional blood draw at 24 hours after drug administration. They will complete the off-study form prior to 
discharge from the MRCU. Subjects will be instructed to report any subsequent event(s) within 3 months 
of study completion that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study.   
8.5 
Schedule of Events for Additional 5 Control HIV Uninfected Subjects 
 
Table 2. Protocol summary for HIV uninfected (control) subjects: 
 
 
Screen Study Drug 
 Pick-Up 
MRI Week 2 
Medical history 
X 
 
 
 
Interval medical history  
 
 
X 
Physical Exam1 
X 
 
 
X 
Safety screening 
 
 
X 
 
MRI 
 
 
X 
 
Adherence counseling 
 
X 
 
 
Pregnancy test2 
X 
 
 
 
HIV & HCV Ab 
X 
 
 
 
CMP 
X 
 
 
X 
CBC w diff 
X 
 
 
X 
CD4 count 
X 
 
 
X 
Serum3 
 
 
 
X 
Plasma /PBMCs4 
 
 
 
X 
Biopsies5 
 
 
 
X 
PK assessment6 
 
 
 
X 
 
1. At screening, a full physical exam will be performed.  At the Week 2 visit, a targeted exam will be 
performed.  
2. Women of childbearing age must have a negative pregnancy test prior to enrollment.   
3. Serum will be used to determine levels of IL-7 and TGF-beta. 
4. Plasma will be used to determine levels of cytokines and markers of inflammation.  PBMCs will be used 
in flow cytometry and intracellular cytokine staining. Additional blood will be obtained for two-photon 
microscopy. 
5. Inguinal LN biopsy and colonoscopy with sampling of ileal and rectal tissues. 
6. Intensive 24-hour PK assessment  
 
9. ASSESSMENT OF SAFETY 
9.1 
Definition of an Adverse Event (AE) 
 Basic Definition 
An AE is any symptom, sign, illness, or experience that develops or worsens in severity during the 
course of the study but does not necessarily have a causal relationship with a study agent/intervention 
or procedure.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study 
agent/intervention or procedures whether or not it is related to the study agent/intervention.  Intercurrent 


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illnesses or injuries will be regarded as AEs.  Abnormal results of diagnostic procedures are considered 
to be AEs if the abnormality: 
 
results in study withdrawal, 
 
is associated with a serious adverse event (SAE), 
 
is associated with clinical signs or symptoms, 
 
leads to additional treatment or to further diagnostic tests, or 
 
is considered by the Investigator to be of clinical significance. 
 
 Definition of a Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  An SAE is any AE that is:  
 
Fatal, 
 
life-threatening, 
 
requires or prolongs a hospital stay, 
 
results in persistent or significant disability or incapacity, 
 
a congenital anomaly or birth defect, or 
 
an important medical event. 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.  They may jeopardize the subject, and may require intervention to prevent one of 
the other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not 
result in inpatient hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. All AEs that do not meet any of the criteria for serious should be 
regarded as non-serious AEs. 
 
 Definition of a Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An AE that is: 
• Serious (i.e., an SAE), 
• Related (i.e., there is a reasonable possibility that the AE may be related to the study product), and 
• Unexpected (i.e., an AE whose nature or severity [intensity] is not consistent with the applicable  
product information found in an investigator’s brochure, a package insert or a summary of agent 
characteristics). 
 
 
 Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition will be 
recorded as an AE if the frequency, intensity, or character of the condition worsens during the study 
period. 
 
 Post-study Adverse Event 
All unresolved AEs will be followed by the Investigator until the events are resolved, the subject is lost to 
follow-up, or the AE is otherwise explained.  At the last scheduled visit, the Investigator will instruct each 
subject to report any subsequent event(s) within 3 months of study completion that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.   
 
 Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an AE if any 1 of the following conditions is 
met:  
 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality, 


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 
The abnormality suggests a disease and/or organ toxicity, or 
 
The abnormality is of a degree that requires active management; e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
 Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization will be documented and reported as a 
SAE unless specifically instructed otherwise in this protocol.  Any condition responsible for surgery 
should be documented as an AE if the condition meets the criteria for an AE.  
Neither the condition, nor hospitalization, nor prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances: 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an AE if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical Investigator. 
 
 Anticipated Adverse Events  
AEs are not anticipated, but there are AEs associated with the use of both study agents and with the 
procedures being performed in the study. Possible AEs are described above in section 7.1 above and in 
consent forms. Plans to minimize the occurrence of these AEs are described in section 7.2 above. We do 
not expect any serious adverse events due to losartan, Stribild, Prezista, or Gardasil use or from any of 
the study procedures.  
 
9.2 
Unanticipated Problems 
Unanticipated problems (UP), as defined by the OHRP include any incident, experience, or outcome that 
meets all of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance document, “possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
Upon becoming aware of any AE, the PI will assess whether the AE represents an unanticipated problem by 
applying the criteria described above.  If the PI determines that the AE represents an unanticipated problem, 
the PI will report it promptly to the University of Minnesota IRB and DSMB within their reporting timelines.  In 
addition, incidents, experiences and outcomes that occur during the conduct of this study that represent 
unanticipated problems but are not considered AEs may require reporting under the HHS regulations at 45 


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CFR 46.103(a) and 46.103(b)(5).  Further details and examples of such scenarios are described in the 
OHRP policy (http://www.hhs.gov/ohrp/policy/advevntguid.html#Q1).  Unanticipated problems involving risks 
to participants or others will be reported as detailed in the DAIDS Critical Event Policy 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Safety.aspx).   
 
9.3 
Recording and Documentation of AEs 
At each contact with the subject, designated study staff must seek information as to discomforts or adverse 
experiences by specific questioning and, as appropriate, by examination. At study visits, safety laboratory 
evaluations will also be performed to identify any laboratory AEs.  All side effects will be reported to the PI 
and/or physician co-investigators on a daily basis and toxicity laboratory results will be reviewed in real time.  
Information about AEs to be recorded includes event description, time of onset, investigator assessment of 
severity, relationship to study agent(s)/Intervention(s), and time of resolution/stabilization of the event.  All 
AEs occurring during the study period (from time of consent signing to 3 months after the last study visit) 
must be documented appropriately regardless of relationship to study products or procedures.  Information 
on all AEs will be promptly recorded in the source document and also in the appropriate AE module of the 
case report form (CRF).   
 
Any medical condition that is present at the time that the participant is screened should be considered as 
baseline and not recorded as an AE.  However, if the condition deteriorates at any time during the study it 
should be recorded and reported as an AE.  Changes in the severity of an AE should be documented to 
allow an assessment of the duration of the event at each level of intensity to be performed.  Adverse events 
characterized as intermittent require documentation of the onset and duration of each episode.  Changes in 
the assessment of relationship to the study agent(s)/interventions should also be clearly documented. 
 
 Scales Used to Grade Severity of Adverse Events 
The grading system for severity of AEs is located in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification August 2009), which can be found on 
the DAIDS RSC Web Site:  http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
 Scales Used to Attribute Adverse Events 
The Principal Investigator will assess the relationship of all AEs to any drug or study procedure according to 
the following criteria: 
1. 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study agent/intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the study 
agent/intervention (de-challenge) should be clinically plausible. The event must be pharmacologically 
or phenomenologically definitive, with use of a satisfactory re-challenge procedure if necessary. 
2. 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable 
time sequence to administration of the study agent/intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition.  
3. 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, the influence of other 
factors may have contributed to the event (e.g., the subject’s clinical condition or other concomitant 
events). Although an adverse drug event may rate only as “possible” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probable” or “certain” as appropriate. 
4. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal relationship to 
study agent/intervention administration makes a causal relationship improbable (e.g., the event did 


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not occur within a reasonable time after administration of the trial medication) and in which other drugs 
or chemicals or underlying disease provides plausible explanations (e.g., the subject’s clinical 
condition or other concomitant treatments). 
5. 
Not Related: The AE is completely independent of study agent/intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative 
and definitive etiology documented by the clinician.  
 
 Analysis/Management 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Any measures taken or follow-up 
results are to be recorded in the study file.  In addition, any clinically meaningful incidental findings from 
colonoscopies or lymph node biopsies will be promptly communicated to the study participant’s primary care 
provider by fax, e-mail, letter, and/or telephone call.  Documentation of appropriate follow up and reporting 
of all AEs will consist of written telephone contact reports, faxes, e-mail messages, and/or letters, which will 
be kept in the study files.  SAEs that are still ongoing at the end of the study period must be followed to 
determine the final outcome. Study physicians will be responsible for evaluating subjects in the case of AEs.  
Study physicians and study staff are responsible for communicating to subjects information arising from the 
study (on harm or benefit, for example), or from other research on the same topic that could affect subjects’ 
willingness to continue in the study.   
 
9.4 
Reporting Procedures 
 AEs to be Reported 
The following AEs will be promptly reported within three reporting days to the DSMB and the DAIDS 
medical monitor:  
 
  
 
all cancers, all autoimmune diseases, all fetal losses associated with an AE,  
 
all overdoses associated with an AE, and  
 
any definitely related, unexpected, and serious adverse events (SUSARS).  
 
Other AEs or unanticipated problems will be reported to the IRB and DSMB within their reporting 
timelines (such as annual review or if prompt reporting is required, within the urgent reporting timeline 
requirements).  
 
At the time of the initial report, the following information should be provided: 
 
Study identifier, 
 
Subject number, 
 
A description of the event, 
 
Date of onset, 
 
Current status, 
 
Whether study treatment was discontinued, 
 
The reason why the event is classified as serious, and 
 
Investigator assessment of the association between the event and study treatment. 
 
Copies of each report and documentation of applicable IRB notification and receipt will be kept in the 
Clinical Investigator’s binder. All reportable AEs will be followed until satisfactory resolution or until the 
PI or Sub-investigator deems the event to be chronic or the participant to be stable. If a previous SAE 
that was not initially deemed reportable under expedited reporting criteria is later found to fit the criteria 


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for reporting, the PI will submit the SAE in a written report as soon as possible.  The full list of adverse 
events and complications will be reviewed by the IRB and DSMB on an annual basis.  
 
Table: Expedited Reporting to IRB, DSMB and DAIDS 
 
Expedited Reporting 
to Whom 
 
Criteria for 
Reporting 
Timeframe 
Submission Format  
IRB  
Unanticipated death 
of a locally enrolled 
subject(s);  
New or increased risk; 
Any adverse event 
that requires a change 
to the protocol or 
consent form; 
Unanticipated 
problems; 
Refer to the IRB 
website for complete 
details on required 
reporting criteria. 
5 working days 
Local IRB’s standard 
reporting form 
DSMB  
1) SUSARS 
2) all cancers, all 
autoimmune 
diseases, all fetal 
losses associated with 
an AE, and all 
overdoses associated 
with an AE 
3) Unanticipated 
death of locally 
enrolled subject(s) 
3 reporting days 
(defined as M-F, 
including holidays) 
Submit AE/SAE CRF, and 
IRB Report form, if 
available. 
DAIDS  
 
1) SUSARS 
2) all cancers, all 
autoimmune 
diseases, all fetal 
losses associated with 
an AE, and all 
overdoses associated 
with an AE 
3) Grade 3 and 4 AEs 
that are attributed to 
study procedures 
(graded as per section 
9.3.1 above) 
3 reporting days 
(defined as M-F, 
including holidays) 
Submit SAE/AE CRF to 
DAIDS medical officer. 
 
 Expedited Adverse Event (EAE) Reporting to DAIDS 
EAE Reporting to DAIDS 
The definitions of AEs requiring expedited reporting are outlined in Version 2.0 of the DAIDS EAE 
Manual, which is available on the DAIDS RSC website at  http://rsc.tech-
res.com/safetyandpharmacovigilance/.   
 


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      EAE Reporting Requirements for the Study 
The events for which expedited reporting is required include Suspected, Unexpected Serious 
Adverse reactions (SUSARs). In addition to the EAE Reporting Category identified above, other AEs 
that will be reported in an expedited manner include all cancers, all autoimmune diseases, all fetal 
losses associated with an AE, all overdoses associated with an AE and all Grade 3 and 4 AEs that 
are attributed to study procedures (graded as per section 9.3.1 above).  
 
The timeline for reporting of expedited events to the DAIDS medical officer is as defined in the DAIDS 
EAE manual.  
 
The study agents for which expedited reporting is required are losartan, placebo for losartan, 
Gardasil, darunavir, and elvitegravir/cobicistat/emtricitabine/tenofovir.  
Grading Severity of EAEs 
The grading table used for this study is the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification August 2009), which can be 
found on the DAIDS RSC Web Site:  http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
Expedited AE Reporting Period 
The reporting period will be from the time the subject starts the study drug until the end of the study 
follow up for that participant. After the protocol-defined AE reporting period, only SUSARs as defined 
in Version 2.0 of the EAE Manual will be reported to the IRB and DSMB if the study staff become 
aware of the events on a passive basis (from publicly available information). A copy of these reports 
will also be sent to the DAIDS Medical Officer. 
9.5 
Reporting a Pregnancy 
Pregnant women are not eligible to participate in the study. Women are counseled regarding prevention of 
pregnancy and encouraged to make every effort to avoid pregnancy during study participation.  In addition 
to the screening and baseline visits, pregnancy testing will occur every 3 months and anytime during follow 
up when the woman or investigator suspects pregnancy.  If a study participant becomes pregnant during 
study participation, no further doses of losartan or Gardasil will be given and no additional study procedures 
will be performed.  Basic information about the pregnancy will be recorded on the “Pregnancy” CRF and 
permission to record survival data for her until the end of the pregnancy and of the baby at birth will be 
requested.  If there are complications during the pregnancy, the complications are recorded as AEs in the 
usual way. The participant is asked to report outcome of the pregnancy. If there is a congenital anomaly in 
the infant, this is recorded as a serious adverse event (SAE) in the data forms for the mother (i.e., the study 
participant).   
 
9.6 
Toxicity Management 
The grading system for drug toxicities is located in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification August 2009), which can be found on 
the DAIDS RSC Web Site:  http://rsc.tech-res.com/safetyandpharmacovigilance/. Participants experiencing 
side effects related to losartan, will be evaluated immediately by a study physician and may be referred to 
their primary HIV provider for evaluation and treatment if indicated.  Subjects who develop drug-related 
toxicity of Grade 1 or 2 may continue study participation.  If a participant experiences any drug-related 
toxicity >Grade 2 and it is judged to be due to losartan, losartan will be discontinued.  If a participant 
experiences any drug-related toxicity >Grade 2 and it is judged to be due to Gardasil, further doses of 
Gardasil will not be administered.   
 
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9.7 
Halting and Stopping Rules 
 
 Halting Rules for the Protocol 
At the initial meeting, which will take place during the administrative start-up period of this project and 
prior to the enrollment of any subjects, the DSMB will develop the DSMB charter, which includes triggers 
set for stopping the study for safety concerns and for efficacy.  Subsequent review of serious, 
unexpected and related adverse events by the Medical Monitor, DSMB, ethics review committee or IRB, 
the sponsor(s), and other regulatory authorities may also result in suspension of further trial 
interventions/administration of study agent at a site.  The study sponsor(s) and other regulatory 
agencies retain the authority to suspend additional enrollment and study agent(s)/intervention(s) 
administration for the entire study as applicable. 
 
 Stopping Rules for an Individual Participant 
Subjects may withdraw from the study (and all follow-up procedures) for any reason and at any time. 
Participants may also choose to discontinue study medication and continue all follow-up procedures.  
This is most likely in the event of a toxicity that, in the opinion of the investigators, is related to the study 
agents.   
 
If a subject withdraws, attempts will be made to schedule and conduct an early termination visit as 
described in section 8.1.11.  The reason and date of withdrawal will be documented on the subject’s 
CRF.  Date of withdrawal will be documented as the date of last study drug treatment, not the date that 
the decision to withdraw was made.  Participants will be followed after withdrawal from the study for 3 
months after discontinuation.  All AEs during that period will be reported.   
 
The PIs may withdraw participants to protect their safety or if participants are unable or unwilling to 
comply with visits, study procedures, or study medication.  Participants will be removed from the study if 
they experience any drug-associated toxicity > grade 2 and it is judged to be due to losartan (e.g., a 
complication of the biopsy procedure may not necessitate removal from the study).  Subjects will not be 
withdrawn if they experience toxicity > grade 2 that is deemed due to Gardasil but will not continue to be 
given Gardasil.  Subjects will also be removed in the event of pregnancy. Healthy controls will be 
removed from the study if they experience rash, moderate GI symptoms and/or symptoms consistent 
with clinical hepatitis with no other medically reasonable cause. Other exit criteria include: 
 
completion of the study,  
 
withdrawal of consent,  
 
moving to an area that would prohibit the subject from returning for visits, and  
 
death. 
 
Even though subjects may be withdrawn prematurely from the study, we will continue to collect survival 
data on such subjects throughout duration of the 30 months. If a subject withdraws consent to 
participate in the study, attempts will be made to obtain permission to record survival data up to the 30-
month end point.  Methods used for follow up will include at least 5 phone calls and 3 letters to the 
participant. 
 
Any subject withdrawn from the study prior to Month 1 will be replaced by another enrolled participant to 
meet study objectives.  
 


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9.8 
Unblinding Procedures 
The Investigational Drug Service (IDS) Pharmacy is responsible for the administration of the blinded study 
agent as the intervention. This pharmacy holds the record of randomization for this study. The study 
participant, investigators, study coordinator, other study staff, statistician, and DSMB are blinded. The 
following conditions or events in which unblinding may occur are: 
 
 Emergency Unblinding  
Please see Fairview IDS Pharmacy Emergency Blind SOP for detailed description of the unblinding 
process that will occur in the case of an emergency.  
 
 Individual Unblinding 
For individual unblinding, the PI should assess the need for unblinding where a SAE has occurred and 
the treatment or allocation code is required in order to enable clinical treatments to be planned. In the 
event that this occurs, the IDS pharmacy will be contacted by a member of the study staff and given the 
following details: caller name and position, study site, site investigator, name of participant, study 
protocol number, and subject identification number. Upon unblinding, the study staff member will record 
the participant withdrawal and allocation in the person’s clinical and trial notes along with appropriate 
clinical notations. The study staff member will log the unblinded reports and the PI will report unblind 
rates to the local IRBs, DSMB, OHRP, and DAIDS. 
 
 Unmasked Analysis 
The DSMB will determine that an unmasked analysis is required. The decision will be documented in the 
committee meeting minutes.  A DSBM designee will make a written request to the PI for study 
unblinding. The PI will request the IDS pharmacy to provide randomization schedules to the DSMB 
designee. The IDS pharmacy will check the allocation log for completions to date, sign and date the last 
entry with a note to indicate point of request, and provide the DSMB designee with the register of all 
study allocations. The lead statistician will merge the study data with the table of allocation codes as per 
the data transfer instructions within the data management plan and undertake unmasked analysis as 
determined by the DSMB. 
 
 Unblinding Upon Study Completion 
The PI will determine that study recruitment is complete and unblinding is required for analysis. A study 
staff member will contact the IDS pharmacy for the schedules and a request for return all unblinded 
study agent. The IDS pharmacy will check the allocation log for completion, sign and dater the last entry, 
provide the study staff member with the schedule of all study allocations, and ensure all invoicing has 
been completed. The study staff member will enter all identification numbers and allocations into a file 
and send the file to the statistician as outlined in the Data Management Plan. The statistician will confirm 
receipt of the file containing the ID numbers and allocations, and merge the study data with the new file 
in preparation for analysis.  
 
10. 
CLINICAL MONITORING STRUCTURE 
10.1 Safety Monitoring Plan 
The PI will oversee safety of study, including careful assessment and appropriate reporting of AEs, 
regardless of their clinical significance or their relationship to the study.  Subjects will be routinely 
questioned about adverse events at all study visits.  Study related monitoring, audits, inspections by the 
IRB, DSMB, regulatory bodies and University compliance and QA groups will be conducted. Information 
about subjects will be kept confidential and managed in accordance with HIPAA.  Study data will be 


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recorded in study progress notes.  Explanations will be mandated for any missing data.  Study records will 
be retained according to federal regulations. Subjects will be instructed to seek necessary medical attention 
and to notify the investigator immediately if they experience any AEs.   
 
 Data and Safety Monitoring Board (DSMB) 
A DSMB will be assembled by the University of Minnesota’s Clinical and Translational Science Institute 
(CTSI). This DSMB will have at least 3 members, including a statistician, at least one member with 
previous DSMB experience, and at least one member with relevant clinical expertise and/or experience.   
 
It is the role of the DSMB to protect trial subjects and to provide impartial advice and assistance to the PI 
regarding the conduct and continuation of the study, so as to protect the validity and credibility of the 
trial.  The DSMB will have access to the clinical protocol, interim data, adverse event reports, clinical 
monitoring reports, annual and/or progress reports submitted to the IRB and/or regulatory agency, and 
correspondence between the PI and either the IRB or any Regulatory Agency of competent jurisdiction. 
 
 
The relationship between the DSMB and the PI shall be an advisory role. The specific roles of this 
DSMB will be to: 
 
Assess data quality, including completeness.  
 
Monitor compliance with the protocol by participants and investigators. 
 
Monitor recruitment progress and losses to follow up.   
 
Monitor evidence for treatment differences in the main efficacy outcome measures. 
 
Monitor evidence for treatment harm (SAEs). 
 
Advise on protocol modifications suggested by investigators or sponsors. 
 
Develop and/or monitor clinical trial stopping rules. 
 
Recommend and/or decide whether trial termination is appropriate. 
 
DSMB members shall disclose potential competing interests, both financial and intellectual.  Members 
shall not use interim trial results to inform trading in pharmaceutical or device company shares or stock 
in competing companies. 
 
The initial DSMB meeting will occur within the first two months of the study period, prior to enrollment of 
subjects.  At this meeting the DSMB will discuss the protocol and the DSMB charter which includes 
triggers set for data review or analyses, definition of a quorum, and guidelines for monitoring the study. 
Guidelines will also address stopping the study for safety concerns and for efficacy based on plans 
specified in the protocol. At this meeting, the DSMB will also develop procedures for conducting 
business (e.g., voting rules, attendance, etc.).  
 
The DSMB will then meet at least once annually to examine the accumulated safety and enrollment 
data, review study progress, and discuss other factors (internal or external to the study) that might 
impact continuation of the study as designed. The frequency of meetings may be increased if 
unanticipated adverse events (AEs) or safety issues are observed or enrollment rate exceeds 
expectations. A DSMB meeting may be requested by DSMB members, study sponsor, industrial 
collaborator, IRB, or study PI at any time to discuss safety concerns. Decisions to hold ad hoc meetings 
will be made by the DSMB Chair. Meetings may be held by conference calls or videoconferences or as 
face-to-face meetings. In the event a DSMB member cannot attend a meeting, he/she may receive a 
copy of the closed session DSMB report and either participate by conference call or provide written 
comments to the DSMB Chair for consideration at the meeting.  
 
DSMB meetings will be held in two parts. First, an open section will be held in which demographic data 
and trial progress will be discussed. Quality assurance and compliance issues may be discussed in this 


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session, and this session is open to investigators, sponsors, funder, patient advocates, and others as 
appropriate. Open sessions will be followed by closed sections in which only the DSMB members and 
specifically invited guests will attend. In closed sessions, the outcomes data will be assessed and 
recommendations formulated. Closed session meetings may be conducted by teleconference at the 
discretion of the DSMB Chair.  
 
Meeting notes will be prepared from both the open and closed sessions within 2 weeks of the meetings. 
The DSMB will not share confidential information, particularly trial interim data with anyone, including the 
PI. The recommendations of the DSMB will be communicated in writing to the Trial Sponsor, PI, IRB, 
and/or appropriate regulatory agency. The recommendations open to the DSMB will include the 
following: 
• No action required; continue trial as planned. 
• Early termination due to a clear benefit or harm in the interventional group. 
• Early termination due to futility. 
• Termination of recruitment and/or treatment within a subgroup or single arm of a multi-arm trial. 
• Extending recruitment or follow up for all or individual arms of the protocol. 
 
If immediate action is required, the DSMB Chair will personally notify the DAIDS program officer of any 
findings of a serious and immediate nature or recommendations to discontinue all or part of the trial. In 
addition to verbal communications, recommendations to discontinue or substantially modify the design 
or conduct of a study must be conveyed to DAIDS in writing by e-mail, fax, or courier on the day of the 
DSMB meeting. This written, confidential report may contain unmasked supporting data and include the 
DSMB member's rationale for his/her recommendations.  
 
11. 
STATISTICAL CONSIDERATIONS 
11.1 Overview and General Design Issues 
From the perspective of statistical analysis, the aims of the proposed study are all quite similar: to determine 
if a randomized intervention has an impact on a longitudinally observed outcome. Despite this similarity, 
there are differences in the frequency with which some outcomes of interest will be observed and this will 
impact the details of how the analysis will be conducted. In particular, some variables will be measured 
quarterly (those that are assessed in peripheral blood, such as LPS, IL-6, TNF and ICAM-1) while those 
variables assessed via biopsy (such as the number of Ki67+ cells and the magnitude of the FDC pool) will 
only be available at baseline, and 12 and 30 months after initiating treatment with losartan. The approach 
that will be used to test for treatment effects in both scenarios will involve fitting mixed models with 
treatment group indicators, time effects and interactions between time and treatment group to allow for 
testing for differences in rates of change between the 2 groups. What will differ between the 2 scenarios will 
be the modeling strategy, as the data that is more frequently observed will permit more sophisticated 
modeling strategies. These strategies include allowing for nonlinear trajectories via cubic splines and more 
flexible covariance structures. These models will be fit via restricted maximum likelihood and tests for 
differences between the treatment groups will be conducted using Wald tests. Standard diagnostics will be 
employed to assess the adequacy of the fit and remedial measures (e.g. transforming the outcome variable) 
will be employed as appropriate. The most current version of the statistical software R and the lme package 
will be used to fit models and examine the data.  With 25 subjects per group the study should have 
adequate power to find strong effects; however losartan has not previously been used in the proposed 
context.  
 
Analysis of data from the MRI substudy will be descriptive in nature. We are seeking to identify MRI 
methods that will render an image of the inguinal lymph node that is about to be excised. We will compare 


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collagen signal by MRI with collagen content measured by trichome stain. Analysis of PK data will include a 
comparison to previous data collected from HIV infected persons using a similar protocol. We will determine 
if blood and tissue levels of drug are similar or if they are statistically greater, or smaller than those historical 
controls.  
 
 
11.2 Sample Size Considerations 
A previous study of collagen deposition in humans conducted in the Schacker lab found a standard 
deviation for collagen deposition of 0.81 (log scale). We can use this estimate to examine the power of a 2 
sample t-test to find differences between 2 groups of 25 subjects as this power depends on the magnitude 
of the difference between the 2 groups. 
Difference in average 
of collagen 
0.5 
0.6 
0.7 
0.8 
Power 
0.59 
0.75 
0.86 
0.94 
 
11.3 Enrollment/Stratification/Randomization/Blinding Procedures 
HIV infected subjects will be randomized to receive losartan or placebo in a 1:1 manner using ordinary 
methods for generating random deviates. Study staff (other than those in the IDS pharmacy) and 
participants will be blinded to the random assignments of all HIV infected study participants. All study drug 
will be supplied in identical containers. 
 
The two-photon microscopy sub-study of the HIV infected subjects requires 5 participants on losartan and 5 
on placebo.  Investigators are blinded to treatment assignment.  To be able to ensure we have the 5 on 
losartan and 5 on placebo we will give the list of all subjects who agree to the sub-study to the investigation 
pharmacist who maintains the blind.  They will identify the ten participants we should use for the sub-study. 
 
Blinding will be maintained until all data are entered into the study database, all study endpoint data and 
other data included in the final analysis have been verified and the data are ready for final analysis. This will 
be explained to participants as part of the study. Unblinding will occur according to standard operating 
procedures as per section 9.13.  
 
11.4 Maintenance of Treatment Randomization Codes 
The investigational pharmacy at the University of Minnesota Medical Center will make randomization 
assignments and will maintain the treatment randomization codes.  They will be responsible for informing 
the DSMB of these codes for any interim analysis that is planned. 
11.5 Final Analysis Plan 
As detailed in section 11.1, once all of the data is available, mixed effects models will be used to test for 
differences between treatment groups using standard methods for the analysis of longitudinal data. 
Conventional significance levels will be used and the fit of the models will be assessed using standard tools 
(e.g. residual plots).   
 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Please refer to detailed Site Quality Management Plan and Manual of Procedures in the grant application 
appendix, which is maintained in the study records, for quality control and assurance protocols.  
 
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 DAIDS Protocol Registration 
Prior to implementation of this protocol, and any subsequent full version amendments, each site must have 
the protocol and the protocol informed consent form(s) approved, as appropriate, by their local institutional 
review board (IRB)/ethics committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the DAIDS Protocol 
Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  The DAIDS PRO will review the 
submitted protocol registration packet to ensure that all of the required documents have been received.   
 
Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved by the DAIDS PRO, and 
sites will receive an Initial Registration Notification when the DAIDS PRO receives a complete registration 
packet.  Receipt of an Initial Registration Notification indicates successful completion of the protocol 
registration process. Sites will not receive any additional notifications from the DAIDS PRO for the initial 
protocol registration.  A copy of the Initial Registration Notification should be retained in the site's regulatory 
files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites should 
implement the amendment immediately.  Sites are required to submit an amendment registration packet to 
the DAIDS PRO at the RSC.  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) WILL NOT be reviewed and 
approved by the DAIDS PRO and sites will receive an Amendment Registration Notification when the 
DAIDS PRO receives a complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required for initial and 
amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual. 
 
13.2 Institutional Review Board 
The investigator will ensure that this study is conducted in full conformity with the current revision of the 
Declaration of Helsinki, or with the International Conference for Harmonization Good Clinical Practice (ICH-
GCP) regulations and guidelines, whichever affords the greater protection to the subject. This protocol and 
associated informed consent documents must be reviewed and approved by the University of Minnesota 
Institutional Review Board prior to protocol implementation.  
 
13.3  Informed Consent Process 
All participants participating in this study will be required to sign an IRB approved informed consent form.  
Participants who enroll in any of the sub-studies will also sign an additional consent form specific to each 
applicable sub-study. Prior to signing the consent form(s), the participants will meet with designated study 
staff who has been specially trained in obtaining informed consent.  The participant will review the consent 
form in detail with the designated study staff and have the chance to ask questions.  The study coordinator 
will then ask the participant questions to ensure that they understand the information presented in the 
consent form.  The rights and welfare of the participants will be protected by emphasizing to them that the 


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quality of their medical care will not be adversely affected if they decline to participate in this study.  
Participants will be given time to consider the risks and benefits of participating.  A copy of the informed 
consent document will be given to the participants for their records.  The participants may withdraw consent 
at any time throughout the course of the trial.  Consent forms for HIV infected and HIV uninfected (control) 
participants are included in this application.  
13.4 Participant Confidentiality 
A Certificate of Confidentiality will be obtained and all information that identifies study subjects will be 
handled in accordance with regulatory bodies including HIPAA regulations and the University of Minnesota’s 
IRB.  Information will be made available to the PI and designated study staff who directly participate in the 
research visits.  In addition, information may be reviewed by the NIH, the Office For Human Research 
Protections and the IRB.  Prior to screening, participants in this study will sign an authorization to use or 
disclose protected health information for research purposes.  All staff will have been trained in the use of 
protected health information.  Subjects will be assigned to a subject ID number and a link between 
identifiers will be maintained in a log.  This log will be kept in a locked cabinet in a secure office.  Only the PI 
and designated study staff will have access to this link.   
 
13.5 Study Discontinuation  
After study completion or in the event that the study is discontinued, subjects will stop taking study agents 
(for the HIV group: losartan or placebo; for controls: Stribild and Prezista).  
 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 Data Management Responsibilities 
Data collection is the responsibility of the clinical research staff under the supervision of the PI, Dr. 
Schacker. Study data will be recorded in study progress notes.  Explanations will be mandated for any 
missing data.  Study records will be retained according to federal regulations. For further detailed 
description of data management please refer to the Manual of Procedures and Data Management Plan 
maintained in the study files.  
 
14.2 Source documents and Access to Source Data 
In accordance with NIH policy we will make any source data accumulated as a result of this program 
available to others in a timely and reasonable fashion.  We will make data available at the time it is accepted 
for publication.  Written requests for access to data before publication can be made to the administrative 
core and, if reasonable, data will be forwarded to the individual(s) requesting access. 
 
14.3 Quality Control and Quality Assurance 
We have designed a multi-step process to ensure data quality and accuracy.  Clinical data will be collected 
into a standardized CRF that includes collection of source documents from the clinical laboratory performing 
the assays. Designated study staff will enter this data in real-time into our database. Data generated from 
Dr. Schacker’s laboratory, Dr. Fife’s laboratory, Dr. Douek’s laboratory, Dr. Fletcher’s laboratory, and Dr. 
Estes’ laboratory will be entered into the database by the research staff in the laboratory. In addition, a 
written report of the data with a full accounting of how the data was generated, how much sample was used, 
and any unusual circumstances surrounding the generation of data (need for repeated experiments, reason 
for rejecting data from a data set, specimen handling problems, etc.) will be sent on a monthly basis to 
designated study staff. They will place a copy of the written report into the study chart of each individual 


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participant with data in the report and will scan it into the database, which will contain links back to the 
subject and the laboratory. Designated study staff will conduct monthly audits of a randomly selected series 
of 10 subject study charts to compare source documentation with data entered locally and at remote 
laboratories. Discrepancies will be resolved immediately. If an error rate of data entry of more than 3% is 
discovered for an individual or a laboratory, we will conduct a full audit of data from that person or that site.  
We prefer to have data entered by the investigator performing the research (as opposed to a data entry 
person working off faxed records) because we have found that data is available for discussion more rapidly 
and this fosters better collaboration and a more interactive research environment.  
 
 
15. 
PUBLICATION POLICY 
Publication of the results of this trial will be governed by NIAID publication policies.  Any presentation, abstract, 
or manuscript will be made available for review by the NIAID supporters prior to submission. 
 


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16. 
SCIENTIFIC REFERENCES  
1. 
Estes, J., et al., Collagen deposition limits immune reconstitution in the gut. J Infect Dis, 2008. 198(4): p. 
456-64. 
2. 
Mehandru, S., et al., Primary HIV-1 infection is associated with preferential depletion of CD4+ T 
lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004. 200(6): p. 761-70. 
3. 
Talal, A.H., et al., Virologic and immunologic effect of antiretroviral therapy on HIV-1 in gut-associated 
lymphoid tissue. J Acquir Immune Defic Syndr, 2001. 26(1): p. 1-7. 
4. 
Guadalupe, M., et al., Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human 
immunodeficiency virus type 1 infection and substantial delay in restoration following highly active 
antiretroviral therapy. J Virol, 2003. 77(21): p. 11708-17. 
5. 
Lange, C.G., et al., Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional 
responses to immunizations in chronic HIV-1 infection. Aids, 2003. 17(14): p. 2015-23. 
6. 
Lange, C.G., et al., CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on 
phenotypic and functional immune restoration in HIV-1 infection. Clin Immunol, 2002. 102(2): p. 154-61. 
7. 
Rigaud, M., et al., Impaired immunity to recall antigens and neoantigens in severely immunocompromised 
children and adolescents during the first year of effective highly active antiretroviral therapy. J Infect Dis, 
2008. 198(8): p. 1123-30. 
8. 
Vigano, A., et al., Humoral and cellular response to influenza vaccine in HIV-infected children with full 
viroimmunologic response to antiretroviral therapy. J Acquir Immune Defic Syndr, 2008. 48(3): p. 289-
96. 
9. 
Lohse, N., et al., Survival of persons with and without HIV infection in Denmark, 1995-2005. Annals of 
internal medicine, 2007. 146(2): p. 87-95. 
10. 
Deeks, S.G., E. Verdin, and J.M. McCune, Immunosenescence and HIV. Curr Opin Immunol, 2012. 
11. 
Hunt, P.W., et al., T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency 
virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis, 2003. 
187(10): p. 1534-43. 
12. 
Jiang, W., et al., Plasma levels of bacterial DNA correlate with immune activation and the magnitude of 
immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis, 2009. 199(8): p. 
1177-85. 
13. 
Plaeger, S.F., et al., Immune activation in the pathogenesis of treated chronic HIV disease: a workshop 
summary. AIDS Res Hum Retroviruses, 2012. 28(5): p. 469-77. 
14. 
Hunt, P.W., et al., Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete 
CD4+ T cell recovery on antiretroviral therapy. J Infect Dis, 2011. 203(10): p. 1474-83. 
15. 
Brenchley, J.M., et al., Microbial translocation is a cause of systemic immune activation in chronic HIV 
infection. Nat Med, 2006. 12(12): p. 1365-71. 
16. 
Sandler, N.G., et al., Plasma levels of soluble CD14 independently predict mortality in HIV infection. J 
Infect Dis, 2011. 203(6): p. 780-90. 
17. 
Schacker, T.W., et al., Lymphatic tissue fibrosis is associated with reduced numbers of naive CD4+ T 
cells in human immunodeficiency virus type 1 infection. Clin Vaccine Immunol, 2006. 13(5): p. 556-60. 
18. 
Schacker, T.W., et al., Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J 
Clin Invest, 2002. 110(8): p. 1133-9. 
19. 
Zeng, M., et al., Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV 
infections. J Clin Invest, 2011. 121(3): p. 998-1008. 
20. 
Estes, J.D., et al., Premature induction of an immunosuppressive regulatory T cell response during acute 
simian immunodeficiency virus infection. J Infect Dis, 2006. 193(5): p. 703-12. 
21. 
Estes, J.D., et al., Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by 
transforming growth factor beta 1-positive regulatory T cells and begins in early infection. J Infect Dis, 
2007. 195(4): p. 551-61. 


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22. 
Schacker, T.W., et al., Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-
associated change in peripheral CD4 cell count. Aids, 2005. 19(18): p. 2169-71. 
23. 
Zeng, M., et al., Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell 
reconstitution after antiretroviral therapy. PLoS pathogens, 2012. 8(1): p. e1002437. 
24. 
Dummer, W., et al., Autologous regulation of naive T cell homeostasis within the T cell compartment. J 
Immunol, 2001. 166(4): p. 2460-8. 
25. 
Tan, J.T., et al., IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad 
Sci U S A, 2001. 98(15): p. 8732-7. 
26. 
Rathmell, J.C., et al., IL-7 enhances the survival and maintains the size of naive T cells. J Immunol, 2001. 
167(12): p. 6869-76. 
27. 
Shihab, F.S., et al., Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins 
and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant, 2002. 2(2): p. 111-9. 
28. 
Iyer, S.N., D.M. Hyde, and S.N. Giri, Anti-inflammatory effect of pirfenidone in the bleomycin-hamster 
model of lung inflammation. Inflammation, 2000. 24(5): p. 477-91. 
29. 
Miric, G., et al., Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-
diabetic rats. Br J Pharmacol, 2001. 133(5): p. 687-94. 
30. 
Azuma, A., et al., Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary 
fibrosis. Am J Respir Crit Care Med, 2005. 171(9): p. 1040-7. 
31. 
Brook, N.R., et al., The experimental agent pirfenidone reduces pro-fibrotic gene expression in a model of 
tacrolimus-induced nephrotoxicity. J Surg Res, 2005. 125(2): p. 137-43. 
32. 
Card, J.W., et al., Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the 
hamster model of amiodarone-induced pulmonary toxicity. Toxicol Sci, 2003. 75(1): p. 169-80. 
33. 
Di Sario, A., et al., The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation 
of procollagen alpha1(I), TIMP-1 and MMP-2. Dig Liver Dis, 2004. 36(11): p. 744-51. 
34. 
Garcia, L., et al., Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol, 2002. 37(6): p. 
797-805. 
 
35. 
Elbaz, M., et al., Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy(2J) 
/dy(2J) mouse. Ann Neurol, 2012. 71(5): p. 699-708. 
36. 
Campistol, J.M., et al., Losartan decreases plasma levels of TGF-beta1 in transplant patients with chronic 
allograft nephropathy. Kidney Int, 1999. 56(2): p. 714-9. 
37. 
Volpini, R.A., et al., Effect of enalapril and losartan on the events that precede diabetic nephropathy in 
rats. Diabetes Metab Res Rev, 2003. 19(1): p. 43-51. 
38. 
Arnold, S.A., et al., Losartan slows pancreatic tumor progression and extends survival of SPARC-null 
mice by abrogating aberrant TGFbeta activation. PLoS ONE, 2012. 7(2): p. e31384. 
39. 
Boffa, J.J., et al., Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor 
antagonism and matrix metalloproteinases. J Am Soc Nephrol, 2003. 14(5): p. 1132-44. 
40. 
el-Agroudy, A.E., et al., Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and 
interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol, 2003. 23(5): p. 300-6. 
41. 
Mezzano, S.A., M. Ruiz-Ortega, and J. Egido, Angiotensin II and renal fibrosis. Hypertension, 2001. 38(3 
Pt 2): p. 635-8. 
42. 
Lim, D.S., et al., Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of 
human hypertrophic cardiomyopathy. Circulation, 2001. 103(6): p. 789-91. 
43. 
Diez, J., et al., Losartan-dependent regression of myocardial fibrosis is associated with reduction of left 
ventricular chamber stiffness in hypertensive patients. Circulation, 2002. 105(21): p. 2512-7. 
44. 
Molina-Molina, M., et al., Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin 
E2 synthesis. Thorax, 2006. 61(7): p. 604-10. 
45. 
Masutomo, K., N. Makino, and M.S. Fushiki, Effects of losartan on the collagen degradative enzymes in 
hypertrophic and congestive types of cardiomyopathic hamsters. Mol Cell Biochem, 2001. 224(1-2): p. 
19-27. 
46. 
Guo, L., et al., Angiotensin II induces interleukin-6 synthesis in osteoblasts through ERK1/2 pathway via 
AT1 receptor. Arch Oral Biol, 2011. 56(3): p. 205-11. 


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47. 
Han, C., et al., Angiotensin II induces C-reactive protein expression through ERK1/2 and JNK signaling in 
human aortic endothelial cells. Atherosclerosis, 2010. 212(1): p. 206-12. 
48. 
Radonic, T., et al., Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center   
randomized controlled COMPARE trial. Trials. 11: p. 3. 
49. 
Einstein, M.H., et al., Comparison of the immunogenicity and safety of Cervarix and Gardasil human 
papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin, 2009. 
5(10): p. 705-19. 
50. 
Einstein, M.H., et al., Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 
vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of 
healthy women aged 18-45 years. Hum Vaccin. 7(12): p. 1343-58. 
51. 
Einstein, M.H., et al., Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 
vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in 
healthy women aged 18-45 years. Hum Vaccin. 7(12): p. 1359-73. 
52. 
Hariri, S., et al., Prevalence of genital human papillomavirus among females in the United States, the 
National Health And Nutrition Examination Survey, 2003-2006. J Infect Dis. 204(4): p. 566-73. 
53. 
Dunne, E.F., et al., Human papillomavirus (HPV) 6, 11, 16, and 18 prevalence among females in the 
United States--National Health And Nutrition Examination Survey, 2003-2006: opportunity to measure 
HPV vaccine impact? J Infect Dis. 204(4): p. 562-5. 
54. 
Markowitz, L.E., et al., Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United 
States: National Health and Nutrition Examination Survey 2003-2004. J Infect Dis, 2009. 200(7): p. 1059-
67. 
 
 
 
 
 
 


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17. 
APPENDIX I 
MRI Sub-study 
 
The purpose of the study is to develop new ways to acquire and analyze MRI data to characterize the structural 
and functional changes of the body between the normal and disease state.  This information would be valuable 
if and when the developed methods are incorporated into future clinical studies to help guide and monitor 
therapeutic interventions. The methods being developed will be experimental and will only be used for research 
purposes. We think it possible that this non-invasive procedure might someday be used as a biomarker in 
studies of anti-fibrotic therapy in HIV infection.  
 
We will explore several standard and novel contrasts and their parametric maps to assess lymph flow and 
collagen amounts in LT. MRI studies will be performed on a 3 Tesla and/or 7T imaging systems (Siemens 
Medical Solutions, Erlangen, Germany). To acquire data, surface or surface array coils will be used for signal 
reception.  
 
Protocol: 
1) 
Scout imaging to localize target anatomy. (1 minute) 
2) 
Maps of B1+ by the 3D AFI technique (4 minutes) 
3) 
T2 weighted imaging (turbo spin echo, 0.5x0.5x3.0 mm3 resolution in the three planes) (10 minutes) 
4) 
T2 mapping with the methods by Liney et al. (5 minutes) 
5) 
T1 mapping with DESPOT (72) (5 minutes) 
6) 
Diffusion weighted imaging (DWI), using a standard single shot approach in three orthogonal directions 
with multiple diffusion encoding b-values (e.g. 0, 50, 400 and 800 s/mm2) allowing the calculation of ADC– how 
long? (5 minutes) 
7) 
Magnetization transfer (MT) using GRE readout, with T1sat mapping (10 minutes) 
8) 
T1ρ mapping, using GRE readout (not clear, the application mention them, but then does not give 
details)  (5 minutes) 
9) 
T2ρ mapping, using GRE readout (not clear, the application mentions them, but then does not give 
details) (5 minutes) 
10) 
RAFFn mapping using GRE readout (10 minutes)  
 
Inclusion Criteria:   (See Section 5.2) 
Same as parent losartan study. 
 
Exclusion Criteria: 
 
Exclusion criteria will be assessed during a safety screening interview and during final consent.  A questionnaire 
will be provided regarding general health and exclusion/inclusion criteria.  The investigator doing the interview 
will determine if any of the exclusion criteria apply.  Subjects will be asked: 
1) 
To describe any previous surgeries to help subjects and study staff open a dialogue as to any possible 
contraindications listed in the yes/no section below. 
2) 
If they are claustrophobic and to rate the severity. 
3) 
If they wear hearing aids and if they can be removed for the scan. 
4) 
If they have a transdermal delivery system, and if yes where is it located and if it can be removed for the 
study. 
5) 
If they wear colored contact lenses and, if yes, can they be removed for the study. 
6) 
To provide a list of medications, dosages and time of last dose for medicines taken regularly. 


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7) 
To identify if they have any pre-existing medical conditions including Hypertension, Hypotension, 
Diabetes, Cardiovascular Disease and Fever. 
8) 
To identify if they ever had an operation. 
9) 
To indicate if they have ever been injured by a metallic foreign body which was never removed. 
10) 
If they wear braces and/or if they have removable bridgework, false teetch or a permanent retainer. 
11) 
If they have any tattoos, non-removable body piercings or hair extensions. 
12) 
If they are currently using/wearing an IUD or diaphragm. 
13) 
If they have any reason to believe they are pregnant.  (If the subjects are unsure about their pregnancy 
status, test kits will be available to subjects). 
 
In addition, a set of yes/no questions will be asked in the screening form for the participant to confirm or deny 
the presence of items that may be hazardous to their safety and/or some interfere with the MRI examination, 
including: 
 
 Yes  No Cardiac pacemaker 
 Yes  No Implanted cardiac defibrillator 
 Yes  No Carotid artery vascular clamp 
 Yes  No Intravascular stents, filters, or coils 
 Yes  No Aortic clip 
 Yes  No Internal pacing wires 
 Yes  No Vascular access port and/or catheter 
 Yes  No Swan-Ganz catheter 
 Yes  No Shunt (spinal or intraventricular) 
 Yes  No Aneurysm clip(s) 
 Yes  No Neurostimulator 
 Yes  No Electrodes (on body, head, or brain) 
 Yes  No Heart valve prosthesis 
 Yes  No Any type of prosthesis (eye, penile, etc.) 
 Yes  No Artificial limb or joint replacement 
 Yes  No Bone growth/fusion stimulator 
 Yes  No Bone/joint pin, screw, nail, wire, plate 
 Yes  No Metal rods in bones 
 Yes  No Harrington rods (spine) 
 Yes  No Metal or wire mesh implants 
 Yes  No Wire sutures or surgical staples 
 Yes  No Insulin pump or infusion device 
 Yes  No Any metal fragments (i.e. metal shop) 
 Yes  No Any implant held in place by a magnet 
 Yes  No Cochlear, otologic, or ear implant 
 
 
  
RISKS AND BENEFITS:   
 
NOTE: Appendix F’s for both 3T and 7T systems are on file at the IRB and will not need to be submitted with 
this addendum. 
 
Other Potential Risks. 
 
1) 
Magnetic Field in the MRI (subject environment) 
2) 
Metallic objects carried into the MRI room 
3) 
Other energies, such as radiofrequency pulses, or rapid changes in the field strength 


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4) 
Displacement of Implanted metallic devices 
5) 
Acoustic noise  
 
Any risks from high magnetic field strength that has been identified as a concern by the FDA's office of device 
evaluation, has been addressed by our researchers, who performed numerous animal experiments. The results 
indicate non-significant risks (either short term or long term) at these magnetic field strengths (3T/7T). 
 
Data over the last 10+ years indicate that the 7 Tesla magnetic field does not pose a significant risk to human 
volunteers. Metallic objects that are entered into the magnetic field can accelerate into the magnet potentially 
causing damage to the magnet or persons in the magnet room.  
 
In addition, implanted metallic objects can be displaced. The acoustic noise generated by the scanner without 
ear protection could possibly impose damage to a person's hearing.  
 
Finally, radiofrequency pulses impart small amounts of energy into the subject, and needs to be monitored by 
both hardware and software monitor to prevent inadvertent application of significant energies which may result 
in heating.  
 
Most people experience no ill effects from the strong magnetic field, but some people report dizziness, mild 
nausea, headache, a metallic taste in their mouth, or sensations of flashing lights. These symptoms, if present, 
subside shortly after leaving the magnet. No serious ill effects have been reported to date at any site operating 
at 7T. If any sensations experienced cause discomfort or pain, informing the researcher will terminate the 
ongoing study and the subject will be taken out of the magnetic field. 
 
The risk of metallic objects being carried into the magnet room by subjects has been addressed by having 
volunteers remove all jewelry and valuables (keys, hair pins, coins, glasses, watches, etc. ) for secure storage 
in a locker provided to them, prior to entering the magnet room.  
 
All risk of other energies involved in MRI imaging are controlled such that they are not a significant risk and are 
substantially equivalent to clinical MRI systems, such as the Philips and Siemens devices currently in use at the 
University of Minnesota Medical Center, Fairview. These factors are in compliance with FDA guidelines. 
 
 
In addition, there are safety monitors in the MRI instrument that will prevent the machine from running if these 
energies exceed the FDA levels. Risks posed to persons with implanted devices are avoided by exclusion of 
such persons from the study. Any unknown risks posed to fetuses are avoided by exclusion of pregnant women.  
Acoustic noise is reduced to FDA acceptable levels by having the subjects wear ear plugs, providing padding 
around the subject ears, and by additional noise reduction foam place inside the magnet itself. The acoustic 
noise has been carefully measured using a special probe inside the magnet.   
 
MRI scans have become a routine diagnostic tool widely used in medicine. Based on more than two decades of 
experience with this technique, appropriate guidelines exist for its use to minimize the risks of the study. 
Although there is no direct benefit to the research subjects, the parameters and research data garnered from 
the studies will lead to being able to make much improved clinical and diagnostic decisions. With minimal risk to 
the subjects, this research and the MRI instruments will allow us to obtain improved anatomic and functional 
throughout the human body. Twenty years of research at 4 tesla and 15 years at 7 Tesla has established this 
type of research as extremely safe, as well as extremely beneficial to the scientific and clinical communities. 
 
There are no direct benefits to the individuals participating in this study as subjects.  However, the new methods 
under development may provide novel biomarkers for monitoring disease progression and treatment response, 
aid in the development and evaluation of novel interventions, and/or provide unique tools to aid in the diagnosis 
and prognosis of disease. 


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INFORMED CONSENT PROCESS: 
 
Upon arrival at the CMRR, the subject will be greeted by research staff, provided the consent and MRI safety 
screening forms and given a brief description of the study that will be conducted that day.  Specific details of the 
study which will be reviewed including:  
- 
the field strength of the study (3T or 7T) 
- 
the region of the body that will be studied 
- 
the RF coils that will be used 
- 
any additional hardware such as ECG leads or respiratory monitoring equipment that will be necessary 
- 
any particular tasks that they may be asked to perform such as breath holding during the MRI 
procedure. 
 
After this introduction the subject will then be given an opportunity to read the consent form and ask questions.  
The researcher will provide the participant ample time to decide whether or not to participate. The researcher 
will also assess whether the participant understands the study’s procedures and will stress the voluntary nature 
of the experiment. In addition, the subject will be reminded that this is purely a research study and that the data 
acquired cannot be used in place of standard imaging obtained through their physician. 
 
 
Volunteers will be given the study specific consent form upon arriving at the CMRR at which time the 
investigator will detail the specific goals for the study that day and provide any study specific instructions.   
 
The investigator will give the participant ample time to review the informed consent document. This may entail 
waiting with the subject while they review the material or leaving the room if they need more time to consider 
the study. When the participant has finished reading the document and signs (or chooses not to sign) it, they 
will notify the researcher. Participant questions will be answered prior to their consenting. 
 
One of the investigators listed on the protocol will obtain informed consent. Usually it will be the individual who 
will be performing the MRI scan.  
Gregory J. Metzger – Associate Professor – already trained and running similar studies 
Silivia Mangia – Associate Professor – already trained and running similar studies  
Shalom Michaeli – Associate Professor – already trained and running similar studies 
Diane Hutter – Research Nurse – already trained and consenting on similar protocols 
 
The subject will always provide the informed consent or the study will not be performed. 
 
As described above, the investigator(s) will give the participant ample time to review the informed consent 
document. This may entail leaving the room if they need more time to consider the study reducing any pressure 
to sign it. Subjects are also instructed that they may terminate participation at any time without prejudice.  
 

ICF_001.pdf: 
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Reversing Tissue Fibrosis to Improve Immune Reconstitution in HIV
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Page 1 of 12
IRB Code #:  1111M06585
  CONSENT FORM
Protocol Name:
Reversing Tissue Fibrosis to Improve Immune 
Reconstitution in HIV 
Site:
University of Minnesota
Investigators:
Timothy Schacker, M.D.  
(612) 624-9996
Gregory Beilman, M.D.
(612) 625-7911
Jeffrey Chipman, M.D.
(612) 625-7911
Alexander Khoruts, M.D.
(612) 625-8999
Jason Baker, M.D.
(612) 873-2700 
You are invited to be in a research study that looks at the use of a medication that 
may slow down HIV infection in the body. The study’s purpose is to find out if the 
medication makes HIV infected people who are already on HIV medicines 
healthier.  
This medication is called losartan and is approved by the Food and Drug 
Administration (FDA), but not for treatment of HIV infection. Losartan is commonly 
used to treat high blood pressure.  However, this medication may help to limit the 
damage that HIV causes in the body.
You were selected as a possible participant because you have an HIV infection 
that is relatively well controlled. Some factors that could make you ineligible for this 
study include low blood pressure, chronic inflammatory disease, and liver or kidney 
disease. We ask that you read this form and ask any questions you may have 
before agreeing to be in the study.
This study is being conducted at the University of Minnesota by Dr. Timothy 
Schacker from the department of infectious diseases, and is being sponsored by 
the National Institutes of Health. The pharmaceutical company, Merck, will be 
supplying the study drug.  Fifty HIV infected subjects will be enrolled in this study. 
Background Information:
Research has shown that HIV copies itself mostly in lymphatic tissue.  These 
tissues are sometimes referred to as nodes and are found throughout the body. 
For example, tonsils are part of the lymph system.  
The lymph cells in which HIV copies itself most are called CD4 cells. HIV can infect 
CD4 cells that are either resting or “active,” but copies itself well only when it 
enters an “active” CD4 cell. When HIV copies itself in them, it destroys these cells.  
When CD4 cells are destroyed, it makes people infected with HIV at risk of getting 
infections and cancers.  This process is also related to inflammation and scarring 


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of healthy tissues.  There seems to be a connection between presence of scarring 
and a smaller number of healthy immune cells to fight infection.
The purpose of this study is to find out if losartan, a non-HIV medication, can lower 
the amount of scarring and the number of “active” CD4 cells in the body of a 
person with HIV infection. Lowering the number of “active” CD4 cells means that 
fewer CD4 cells are “targets” for infection by HIV. The main questions we hope the 
study might answer are: 
Does the use of a commonly-used high blood pressure medication lower the 
amount of scarring in the lymph nodes (where CD4 cells live and work)?
How do the CD4 cell death and growth rates change with the use of this 
medication during HIV infection?
Does the use of a commonly-used high blood pressure medication lower the 
number of “active” CD4 cells that HIV can infect? 
Does the use of this medication boost your immune system to respond to 
vaccines?
None of the tests, vaccines, or procedures in this study is experimental.  However, 
our testing of an FDA-approved non-HIV medication in the setting of HIV infection 
is experimental.  
Procedures:
The study will last for 30 months. If you agree to be in this study, we would ask you 
to do the following things. 
You will be asked to provide some information about your current health 
conditions, medications you are currently taking, and data such as your age, date 
of birth and ethnic origin.
You will be randomized (like flipping a coin) to receive either losartan or a placebo 
(sugar pill). The study will supply both. The study will be double-blinded, which 
means that neither you nor the research investigators and staff will know if you will 
receive the study drug or the placebo.  
For the 30 months of the study, you will take 1 pill of the study drug, once each 
day. If you are tolerating the drug, we will increase the dose after the first 14 days. 
At 30 months, you will stop taking the drug. We ask that you bring your pill 
container and any unused medication to each clinic visit so we can keep track of 
how many doses of the medication you have taken. At each visit after screening, 


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IRB Code #:  1111M06585
you will also be counseled about the importance of taking the study drug as 
prescribed.  
After taking losartan for about two years, you will come for three visits for Gardasil 
vaccine injections to see if losartan boosts your immune system’s ability to respond 
to vaccines.
Screening Visit:  You will be asked to come to the University of Minnesota Health 
Clinical Research Unit where you will be asked to go through a screening process 
to make sure you are able to take part in the study. At the screening visit, you will 
undergo a health history and full physical exam. If study doctors are unable to 
obtain your original HIV antibody results, blood will be drawn to verify you have 
HIV antibodies. Blood will be drawn (about 2 tablespoons) to check your CD4 cell 
count and HIV viral load and to make sure your kidney, liver, and blood cells are 
healthy prior to starting one of the two study medications. Hepatitis C (HCV) testing 
will also be performed. Prior to this, study staff will talk with you about HCV, 
including how it is spread, how to protect yourself, and the testing process. Results 
will be available within 72 hours. If any tests are abnormal, you will be referred to 
an appropriate medical provider. Positive HCV test results will be reported to the 
Minnesota Department of Health. All women of childbearing age will have a 
pregnancy test, as a negative test is required prior to starting the study 
medications.  
Day 0:  You will be asked to come to the research unit where a medical history and 
targeted physical exam will be performed and blood samples will be collected 
(about 6 tablespoons). A biopsy (a sample of tissue) of a lymph node in your groin 
will be collected by a surgeon. A colonoscopy with biopsy will also be done by a 
doctor who specializes in this test. After these procedures you will be asked to rest 
in the research unit for at least 4 hours. While in the research unit, you will be 
given a supply of the study drug and will start taking it right away. 
Day 7: We will call you to check on how you are feeling since starting the study 
drug. 
Day 14: You will come to the research unit for a brief check up and to have blood 
drawn (about 1 ½ teaspoons).
Optional MRI Sub-study Visit: Within two weeks after the screening visit, an MRI 
visit will be scheduled. This MRI will occur at the Center for Magnetic Research 
(CMRR), this visit will last about 3 hours. During this visit, before your MRI, a 
portable ultrasound machine will be used to identify your lymph nodes that will be 
scanned and biopsied at a future visit. It is expected that you will only have one 
MRI visit. However, you may be asked to return for another MRI visit at a different 
magnet strength.


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You will sign a separate consent form for this sub-study that will discuss the study 
procedures and risks associated with an MRI. The goal of the sub-study is to 
develop new ways to acquire and analyze MRI data to look at changes in the body 
between the normal and disease state. The MRI sub-study may involve imaging 
any part of the body from head to toe. If you do not want to participate in the MRI 
sub-study, you may choose not to sign the sub-study consent form. You may still 
participate in the main study if you wish.
Month 1: You will come to the research unit for a check up (which includes 
medical history and targeted exam) and will then be asked to stay for 12 hours and 
return the next day for a blood draw.  Blood will be collected at 1, 2, 3, 4, 6, 8, 12, 
and 24 hours after you take a dose of your study drug and HIV medications to 
monitor medication levels in blood.  About 15 tablespoons of blood will be drawn 
over the course of this visit.
 
Months 3, 6, 9, 15, 18, 21 and 27:  Come to the research unit for a brief check up 
(which includes medical history and targeted exam) and to have blood drawn 
(about 6 tablespoons).  
Month 12:  Come to the research unit for a check up (which includes medical 
history and targeted exam) and blood sample collection (about 6 tablespoons). A 
biopsy (a sample of tissue) of a lymph node in your groin will again be collected 
and a colonoscopy with biopsy will also be repeated at this visit. After these 
procedures you will be asked to rest in the research unit for at least 4 hours.
Month 23: Come to the research unit for a check up (which includes medical 
history and targeted exam) and to have blood drawn (about 6 tablespoons). You 
will be given the 1st dose of the human papillomavirus (HPV) vaccine. This vaccine 
is also known as Gardasil. This is a shot that will be given into the muscle of your 
thigh. You will be monitored in the research unit for 30 minutes after the vaccine is 
given to make sure you don’t have a reaction. 
Month 25: Come to the research unit for check up (which includes medical history 
and targeted exam) and to have blood drawn (about 3 ½ tablespoons). You will be 
given the 2nd dose of the HPV vaccine in your thigh. You will be monitored in the 
research unit for 30 minutes after the vaccine is given to make sure you don’t have 
a reaction. 
Month 29.5: Come to the research unit for a check up (which includes medical 
history and targeted exam) and to have blood drawn (about 6 tablespoons). You 
will be given the 3rd dose of the HPV vaccine in your thigh. You will be monitored in 
the research unit for 30 minutes after the vaccine is given to make sure you don’t 
have a reaction. 


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Months 30: This is the last scheduled study visit. You will come to the research 
unit for a check up (which includes medical history and targeted exam) and blood 
sample collection (about 6 tablespoons). A biopsy (a sample of tissue) of a lymph 
node in your groin will again be collected. A portable ultrasound machine will be 
used to identify this lymph node before the biopsy. You will also have a 
colonoscopy with biopsy. After these procedures are complete, you will be advised 
to stop the study drug. After these procedures you will be asked to rest in the 
research unit for at least 4 hours. 
A total of about 81 tablespoons of blood will be collected over the 30 month 
duration of the study. At all visits except month 25, blood will be obtained to  
monitor the health of your blood cells, kidneys and liver. At all visits except Day 14 
and Month 25, blood will also be obtained to monitor your HIV viral load and CD4 
count.  
For women of childbearing age, pregnancy testing will be performed at screening, 
baseline, every 3 months and anytime during follow up when the woman or 
investigator suspects a pregnancy. 
 
You may choose to end your participation before the end of the 30 month study 
period. If you chose to end your participation early, we will ask that you return any 
study medication and for permission to contact you at the end of the 30 month 
period to check on your health status.
After all subjects have completed this study, you will receive information about 
which study drug you were receiving (either losartan or the placebo drug).  
Explanation of Risks of Being in the Study:
The study has several risks. Questions about recent sexual activity may cause 
embarrassment.  Anticipation of a medical procedure may cause stress or anxiety.  
Physical examination of the groin may be uncomfortable and cause 
embarrassment. Discussion of past medical history or risk factors for HIV infection 
may be stressful and cause anxiety. You may decline to answer any questions that 
you do not feel comfortable answering.
Study Medication: Losartan
This medication is approved by the FDA. Losartan is used to treat high blood 
pressure. The possible side effects of Losartan include dizziness, lightheadedness, 
headache, fatigue, cough, upset stomach, vomiting, diarrhea, sore throat, fever, 
sweating, fast heart rate, chest pain, weakness, anemia (low red blood cell count), 
allergic reaction and kidney damage.
This medication should not be used during pregnancy. If a developing fetus is 
exposed to losartan, injury or even death may result. For this reason, if you are a 


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woman of childbearing age, you will be asked whether or not you are sexually 
active and if you are, what type of birth control you use. You must be willing to use 
a reliable form of birth control such as birth control pills, intrauterine device (IUD), 
depo-provera, diaphragm, cervical cap with spermicide, or implant medication for 
the 30 month study period. Condoms cannot be the only form of birth control you 
use. If you become pregnant during the study or think you may be pregnant, you 
should inform either the Principal Investigator, Dr. Timothy Schacker, or a study 
nurse immediately. We will ask that you return any study medication and stop your 
participation in the study. We will ask permission to contact you at the end of the 
pregnancy to check on the health of you and the baby.
Although we do not expect that losartan will interact with any of your HIV 
medicines, this has not been well studied. For this reason, we will be measuring 
levels of losartan and your HIV medicines in your body regularly throughout this 
study. You will be informed if there are any interactions between these medicines. 
Blood Sample Collection
The most common risks of blood sample collection are pain and infection at the 
puncture site, bruising, bleeding, a feeling of lightheadedness and possible 
fainting.
Human Papillomavirus 9-valent Vaccine, Recombinant (Gardasil), Merck & Co., 
Inc.
This vaccine is approved for use in men and women ages 9 to 26 to prevent 
disease related to certain strains of human papillomavirus (HPV). HPV is the virus 
that causes genital warts and cervical cancer. It is not approved for use in older 
individuals because it is not clear how well it would work in this group of people 
since many of them have already been exposed to HPV. However, there is no 
evidence to suggest that this vaccine is not safe for use in older people. 
This vaccine will be injected into the muscle of your thigh. 
The vaccine 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 
these drugs. 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.
The following serious side effects have been associated with the use of Gardasil:

Hypersensitivity (allergic) reactions, such as rash, fever, flu-like feeling, 
blisters, facial swelling, or even problems breathing. These reactions, in 
severe form, may be life threatening.

Guillain-Barré Syndrome (a form of paralysis)


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In addition to the serious side effects listed above, additional side effects include:

Soreness, tenderness, itching, redness, bruising, or swelling at the injection 
site

Headache

Fever

Nausea and vomiting

Dizziness

Fainting may occur after receiving the injection, which may result in falling 
with injury. Shaking, stiffening and other seizure-like activity have also been 
reported. 

Tiredness

Chills
If after being injected with the vaccine, you become pregnant or think you may be 
pregnant, you should inform either the Principal Investigator, Dr. Timothy 
Schacker, or a study nurse immediately, so the study team can inform the 
company who makes the vaccine.
Lymph Node Biopsies
Lymph node biopsies of your groin will be done at the research unit. The actual 
surgery will only take 30-40 minutes but you will need to be there 6 hours. You 
should not eat or drink anything for at least 6 hours before surgery. The groin area 
will be scrubbed with an antiseptic solution. Local anesthetics (similar to Novocain) 
will be injected to numb the area. An incision between 1 and 3 inches will be made.  
The lymph node will be uncovered and removed. A lymph node is about the size of 
a peanut.  The surgeon will close the wound with stitches, and then a bandage will 
be put over the wound.
After a period of at least 4 hours you will be allowed to leave the biopsy 
appointment. You will be asked to remain inactive until the next morning. You and 
the surgeon will discuss the use of a drug to relieve any pain. The entire procedure 
from the time you enter the hospital until you are discharged should be no longer 
than 8 hours.
Three days after the procedure you may be examined in the clinic. The wound will 
be examined and you will be asked questions about pain, drainage from the 
wound, or discomfort. If there is any sign of infection you will be referred back to 
the surgeon for another examination and a prescription of antibiotics or another 
appropriate treatment. The exact antibiotic will be chosen by the surgeon or 
investigator.


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The surgeon will advise you as to the best way to manage stitches that are in 
place. He may ask you to come back to clinic 5-7 days after the procedure to have 
the stitches removed, or the stitches may be the dissolving type. You will be fully 
informed of which type you have.
The lymph node biopsy procedure may cause pain, even though you have been 
given an anesthetic. There may be bleeding associated with the procedure. There 
is the risk of infection, however it is less than 2 percent. There is the possibility you 
might develop a seroma, which is a collection of fluid under the skin and around 
the wound. There is the possibility that you may develop a scar at the site of your 
lymph node biopsy. You will most likely have pain after the lymph node biopsy. 
Occasionally, when we do a lymph node biopsy we cannot find the lymph node 
that was felt prior to the procedure. This is unlikely; however, it has happened.
Colonoscopies
A colonoscopy is a visual exam of the lining of the rectum and colon (large 
intestine) using a flexible tube with a tiny camera on the end. This instrument 
allows the doctor to view the inside of your rectum and colon and take a small 
piece of tissue from the small bowel. The bowel must first be cleared of all residue 
before the test. To do this, you will be asked to stop eating solid foods at 3pm the 
day before your procedure. It is okay to drink clear liquids such as Gatorade, broth, 
etc. At 5pm you will start to drink a gallon of a solution that will make you have 
bowel movements until your bowel is emptied. You should complete this by 10pm.  
You can continue to drink clear liquids until 6 hours before your appointment. 
The colonoscopy will be performed at the University of Minnesota Medical Center, 
Fairview on the same day as your lymph node biopsy. You will lie on your left side 
or on your back during the exam. The doctor will insert the colonoscope into your 
rectum. The tube is about the size of an adult's forefinger. The colonoscope will be 
gently guided through your colon. The doctor will put air into your colon to see it 
better. This may make you feel full and crampy. Some of the air will be removed at 
the end of the exam. You may pass any remaining air. Twenty small tissue 
samples will be collected from your small bowel and large bowel during the 
procedure. These biopsies will not hurt.
The entire procedure usually takes less than an hour. There is little pain. However,
mild sedation is given to relieve anxiety and discomfort. After the colonoscopy,
there may be slight discomfort, which quickly improves with the expelling of gas.
Most people can resume their regular diet later that day.
The most common risks associated with colonoscopy are: abdominal cramping,
bleeding, anxiety, and a feeling of dizziness from the medications used to help you
relax. A very rare complication of colonoscopy is perforation, or small hole, of the 
intestine.


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Because you will be given sedating medications for the procedure, you will not be
allowed to drive home at the end of the study day. We will arrange for
transportation for you if needed.
If any abnormalities that may impact your health are found on physical exam, 
during the colonoscopy procedure or on analysis of tissue or blood samples, the 
research team will discuss this with you, provide you with a copy of the results, 
and, if you have signed a release of information, will discuss results with your 
primary doctor.
Benefits:
This research has the potential to benefit people infected with HIV but no direct 
benefit is assured by participating in this study. However, you will be provided with 
results of all clinical lab tests obtained during this study as well reports from your 
colonoscopies. If there are any abnormalities found on pathology review of your 
biopsy samples you will be notified of these results as well. 
Compensation:
For your time and inconvenience related to your participating in this study, you will 
be paid the following amounts for each of the study visits you complete:

Quarterly Blood Draw: 12 visits, $20 paid via Target gift cards, $240 total

Inguinal Lymph Node Biopsy: 3 visits, $300 paid via check, $900 total

Colonoscopy with Ileal and Rectal Biopsy: 3 visits, $300 paid via check, 
$900 total

Month 1 visit: 1 visit, $130 paid via check, $130 total

MRI Sub-study: 1-2 visits, $85 paid via check, $170 total if you are asked to 
come in for a second MRI. 
All checks will be mailed to you 2-3 weeks after each visit, and Target gift cards will 
be given during the visit. The maximum amount you could receive by completing 
all of the scheduled study visits in the study is $2170, or if you also participate in 
the MRI sub-study, the maximum amount is $2255 ($2340 if you are asked to 
come in for a second MRI). You may be asked to come in for additional 
unscheduled blood draw visits. 


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If you receive more than $600 in a calendar year you may be required to report the 
compensation to the Internal Revenue Service (IRS). 
Research-Related Injury:
In the event that this research activity results in an injury, treatment will be 
available, including first aid, emergency treatment and follow-up care as needed.  
Care for such injuries will be billed in the ordinary manner, to you or your insurance 
company. The National Institutes of Health does not have a mechanism to provide 
compensation for research related injury. If you think that you have suffered a 
research related injury let the study physicians know right away. You are not giving 
up your legal rights by signing this consent form. 
Confidentiality:
A Certificate of Confidentiality will be obtained for this study and records of this 
study will be kept private. In publications or presentations, we will not include any 
information that will make it possible to identify you as a subject. Your record for 
the study may; however, be reviewed by the National Institutes of Health, the 
Office for Human Research Protections, the Institutional Review Board, by 
departments at the University of Minnesota, and other local, US, and international 
regulatory entities with appropriate regulatory oversight.  To these extents, 
confidentiality is not absolute. Study data will be encrypted according to current 
University policy for protection of confidentiality. 
Your insurance information may be collected at the time of check in for your 
research visits. If you have questions about what will or will not be billed to you, 
please ask your study team.
Information collected about you for research may be recorded in your medical 
record. If you do not have a medical record in the Fairview system, one will be 
created for you.
A description of this clinical trial will be available on ClinicalTrials.gov, as required 
by U.S. law. This website will not include information that can identify you. At most, 
the web site will include a summary of the results. You can search this website at 
any time.
Any samples donated by you will be kept for up to 5 years for possible use in future 
studies. This is a requirement for study participation. The sample will be labeled 
with a tracking number that will allow the investigators to know who donated the 
specimen and when; however the specimen will not have any other information on 
it that might identify you.


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Protected Health Information (PHI):
Your PHI created or received for the purposes of this study is protected under the 
federal regulation known as HIPAA. Refer to the attached HIPAA authorization for 
details concerning the use of this information.
Voluntary Nature of the Study:
Your decision whether or not to participate will not affect your current or future 
relations with the University. If you decide to participate, you are free to withdraw at 
any time without affecting those relationships. You may be terminated from the 
study by the Principal Investigator to protect your safety or if you are unable or 
unwilling to comply with visits, study procedures, study medication or your HIV 
medicines. You will also be withdrawn if the study is stopped. In some situations, 
participants may be discontinued from the study medication but will continue follow 
up procedures. If you discontinue the study, you will be asked to return for an Early 
Termination visit at which time a medical assessment will take place and you will 
return any unused study drug. If you terminate the study you will be followed for 3 
months to ensure that no complications of study participation develop and we may 
also contact you to check in at the end of the 30 month study period. 
Alternatives to participating in this study:
The alternative to participating in this study is to decide not to be in it. Treatment 
can be obtained as a part of standard care from your physician.
New Information:
If during the course of this research study, there are significant new findings 
discovered which might influence your willingness to continue, the researchers will 
inform you of those developments.
Contacts and Questions:
The principal researcher conducting this study is Timothy Schacker, M.D. If you 
have further questions at any time regarding the trial or your rights as a trial subject, 
or if you have a trial related injury, you should contact him at (612) 624-9996.
To share feedback privately about your research experience, including any 
concerns about the study, call the Research Participants Advocate Line: 612-625-
1650 or give feedback online at www.irb.umn.edu/report.html. You may also 
contact the Human Research Protection Program in writing at D528 Mayo, 420 
Delaware St. Southeast, Minneapolis, Minnesota 55455.
You will be given a copy of this form to keep for your records.


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Statement of Consent:
I have read the above information. I have asked questions and have received 
answers. I consent to participate in the study. 
Signature of Subject
Date
Printed Name of Subject
Date
Signature of Person Obtaining Consent
Date