Conditions: Inflammation Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the potential effectiveness of losartan (100mg daily) for reducing inflammation and improving immune recovery.

Detailed description:
Our general goal is to evaluate the potential effectiveness of losartan (100mg daily) for reducing inflammation and improving immune recovery, given the potential for these treatment effects to reduce risk for long-term non-AIDS-defining complications among older HIV positive participants. Prior to conducting a clinical outcome trial, candidate treatments must be studied among HIV positive patients given the unique pathogenesis driving inflammation and disease risk.

The potential benefits of losartan (100mg daily) will be studied among HIV positive individuals over age 50 years whose CD4 counts remain ≤600 cells/mm3. Participants (n=110, 55 per group) will be randomized to receive losartan or matching placebo daily. After randomization, participants will start losartan (or placebo) at a dose of 50mg once daily, increasing to 100mg once daily at the 2-week study visit pending results of a week 2 toxicity lab evaluation (see 2.4 below for criteria). Following month 1, participants will return for follow-up study visit procedures at months 3, 6, 9, and 12.

Changes from baseline in measures of inflammation, immune activation, immune recovery and fibrosis within lymphatic tissues will be studied. The primary outcome will be the average of IL-6 levels over 12 months, and the main secondary outcome will be change in CD4 count in blood over 12 months.

Arms:
arm 1: Losartan 100mg daily arm 2: Matching placebo

Interventions: intervention 1: Losartan 100mg daily intervention 2: Matching placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_ICF_000.pdf: 
 __________________________________________________________________________________________________________________________________________  
i 
 
 
 
 Losartan to reduce Inflammation and Fibrosis 
Endpoints in HIV (LIFE-HIV) Trial 
 
 
ClinicalTrials.gov Identifier: NCT02049307 
 
Sponsored by:  
Minneapolis Medical Research Foundation 
 
Funding provided by:  
National Institute of Aging (NIH): R01 DA035554 
Merck Pharmaceuticals  
 
Version Number: v3.0  
 
Day Month Year 
25th January 2017 
 
 
Protocol Chair:  Jason Baker 
 
Lead Statistician: Julian Wolfson  
 
Protocol Manager:  Gary Collins 
 
Additional Protocol Team Members: Caryn Morse, Frank Rhame, Angelike Liappis, 
Stacey Rizza, Zelalem Temesgen, Jonathan Klaphake, Marie Hoover, Jennifer 
Northcott, Irini Sereti, Russell Tracy, Lewis Kuller, Timothy Schacker, Steven Deeks, 
James Neaton  
 
NOTE: This protocol was developed consistent with ‘Standard Protocol Items: 
Recommendations for Intervention Trials’ (the SPIRIT initiative).1 
 
 


 __________________________________________________________________________________________________________________________________________  
ii 
Table of Contents 
1 INTRODUCTION 
1 
1.1 
BACKGROUND AND RATIONALE 
1 
1.2 
OBJECTIVES 
4 
2 METHODOLOGY 
4 
2.1 
TRIAL DESIGN 
4 
2.2 
STUDY POPULATION 
4 
2.3 
ELIGIBILITY CRITERIA 
5 
2.4 
STUDY MEDICATION INTERVENTION 
6 
2.5 
OUTCOMES 
7 
2.6 
STUDY VISIT SCHEDULE 
8 
2.7 
SAMPLE SIZE CONSIDERATIONS 
9 
3 CLINICAL MANAGEMENT 
10 
3.1 
ADMINISTRATION OF STUDY PROCEDURES 
10 
3.2 
STUDY DRUG DOSE MODIFICATION 
10 
3.3 
ADHERENCE AND TOLERABILITY 
12 
3.4 
DATA COLLECTION 
12 
3.5 
BLOOD SPECIMEN PROCESSING 
12 
3.6 
CLINICAL LABS 
12 
3.7 
PLASMA BIOMARKERS 
12 
3.8 
IMMUNOLOGIC PHENOTYPES 
12 
3.9 
LYMPHATIC TISSUE ASSESSMENT 
13 
4 SAFETY AND ADVERSE EVENTS 
13 
4.1 
MEASURES TO REDUCE RISK FOR ADVERSE EVENTS 
13 
4.2 
ADVERSE EVENT DEFINITIONS 
14 
4.3 
DOCUMENTING ADVERSE EVENTS 
14 
4.4 
ADVERSE EVENT RELATIONSHIP TO STUDY DRUG 
15 
4.5 
REPORTING ADVERSE EVENTS 
15 
4.6 
PARTICIPANT WITHDRAWAL 
16 
5 DATA AND SAFETY MONITORING PLAN 
16 
5.1 
INTERIM ANALYSIS 
16 
5.2 
FREQUENCY AND CONTENT OF DATA AND SAFETY MONITORING 
17 
5.3 
DSMB MEMBERSHIP AND AFFILIATION 
17 
5.4 
DSMB CONFLICT OF INTEREST AND PROTECTION OF CONFIDENTIALITY 
17 
5.5 
DSMB RESPONSIBILITIES 
18 
6 ANALYSIS PLAN 
18 
REFERENCES 
20 
APPENDIX A:  BLOOD/URINE SPECIMEN COLLECTION AND STORAGE 
1 
APPENDIX B:  INFORMED CONSENT FORM (ICF) – WITH LN BIOPSY 
2 
APPENDIX C:  INFORMED CONSENT FORM (ICF) – WITHOUT BIOPSY 
11 


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List of Abbreviations 
This list should be modified to include protocol-specific terms. 
 
ACE-I 
Angiotensin Converting Enzyme Inhibitor 
AE 
Adverse Event/Adverse Experience 
AIDS 
Acquired Immune Deficiency Syndrome 
ARB 
Angiotensin Receptor Blocker 
ART 
Antiretroviral Therapy 
BMP 
Basic Metabolic Panel 
BP 
Blood Pressure 
CCC 
Clinical Coordinating Center 
CLIA 
Clinical Laboratory Improvement Amendments 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CVD 
Cardiovascular Disease 
DCC 
Data and Coordinating Center 
DM 
Diabetes Mellitus 
DSMB 
Data and Safety Monitoring Board 
ESPRIT 
Evaluation of Subcutaneous Proleukin® in a Randomized International Trial 
FDA 
Food and Drug Administration 
FRCn 
Fibroblastic Reticular Cell Network 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
IHC 
Immunohistochemistry 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LN 
Lymph Node 
LT 
Lymphatic Tissue 
N 
Number (typically refers to participants) 
NIA 
National Institute of Aging, NIH 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PBMC 
Peripheral Blood Mononuclear Cells 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QIA 
Quantitative Image Analysis 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Standard Deviation 
SILCAAT 
 
Subcutaneous, Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low 
CD4+ Counts Under Active Antiretroviral Therapy 
SMART 
Strategic Management of Anti-Retroviral Therapy 
TGF- 
Transforming growth factor-beta 
TF 
Tissue Factor 
 
 
 
 


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Protocol Summary 
Full Title 
Losartan to reduce Inflammation and Fibrosis Endpoints in HIV 
Short Title 
LIFE-HIV 
Clinical Trial Phase Phase 2 
IND Sponsor  
NA 
Conducted By 
Minneapolis Medical Research Foundation and the University 
of Minnesota 
Principal 
Investigator 
Jason Baker, MD, MS 
Lead Statistician 
Julian Wolfson, PhD 
Sample Size 
110 participants 
Study Population 
HIV positive patients ≥50 years on stable ART with HIV RNA 
level ≤200 copies/mL, CD4+ count ≤600 cells/mm3, and no 
indication for angiotensin receptor blocker (or ACE-inhibitor) 
Accrual Period 
Anticipated enrollment 1 year 
Study Design 
Randomize 110 participants 1:1 to receive losartan 100mg or 
matched placebo daily (double-blind). 
Study Duration 
12 months 
Intervention  
Losartan 100mg versus matching placebo taken daily 
Primary Objective 
 
To evaluate the effects of losartan on systemic inflammation, 
as reflected in plasma levels of IL-6   
(Main) Secondary 
Objective 
To evaluate the effects of losartan on immune recovery, as 
reflected in peripheral blood CD4+ T-cells 
Additional 
Secondary 
Objectives 
Evaluating the effects of losartan on monocyte and T-cell 
activation in blood, coagulation activation, recovery of T-cell 
subsets in blood, adherence, tolerability, durability of findings, 
and lymphatic tissue assessments (in a subset of n≥30) of 
fibrosis, cellular activation, and T-cell homeostasis 
 
 
 


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v 
Schematic of Study Design 
 
 
 
 
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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1 INTRODUCTION 
1.1 Background and Rationale 
Premise 
Contemporary antiretroviral therapy (ART)-treated HIV-infected patients are at 
increased risk for cardiovascular disease (CVD), cancer, and other HIV-associated non-
AIDS conditions. This excess risk is due to multiple factors, including a higher burden of 
traditional risk factors, persistent inflammation and sub-optimal immune recovery after 
starting ART.  Independent of HIV infection, older age increases risk for non-AIDS 
conditions and is itself associated with greater inflammation, reduced immune recovery 
after starting ART, and declining immune function (so called immune senescence). Safe 
treatments that target this pathology, beyond HIV treatment with ART, represent a major 
unmet need for older HIV positive patients. 
 
The LIFE-HIV trial is a critical step to advance this field, prior to conducting a clinical 
outcome trial, by testing the effects of losartan treatment in a translational clinical trial 
that will improve our understanding of non-AIDS disease pathogenesis. Ongoing 
inflammation contributes to excess CVD, cancer and disease in multiple organ systems.  
Specific to HIV pathogenesis, immune activation and associated inflammation also 
drives collagen deposition (i.e., fibrosis) in lymphatic tissue (LT), disrupting T-cell 
homeostasis and limiting immune recovery, which further increases non-AIDS risk. 
Losartan is a safe, inexpensive, medication with immunomodulatory and anti-fibrotic 
properties, quite apart from lowering blood pressure.  We will test the hypothesis that 
losartan will reduce inflammation and improve tissue fibrosis leading to additional 
immunologic recovery.  These treatment effects have been demonstrated in uninfected 
populations (e.g., those with renal or connective tissue diseases), but have not been 
tested among HIV positive patients where the mechanisms driving ongoing immune 
activation are somewhat unique to this disease. 
Scientific Background 
The Changing Spectrum of Morbidity and Mortality Among HIV Positive Patients: 
Antiretroviral therapy (ART) effectively and durably suppresses HIV replication, leads to 
immune recovery (increasing CD4+ T-cell counts) and prolonged life expectancy, and 
has changed the spectrum of morbidity and mortality among HIV positive persons.2-8 
Among well-treated patients with levels of HIV RNA below the level of detection, non-
AIDS-related conditions are now a more common cause of morbidity and mortality than 
AIDS.6, 9-11 The most relevant serious non-AIDS-related diseases in current clinical 
practice include atherosclerotic cardiovascular disease (CVD), cancer, liver disease, 
end-stage renal disease, bone disease and subclinical neurocognitive dysfunction. Of 
these, CVD and cancer constitute the vast majority of clinical events.5, 10-13 
 
What Contributes to Persistent Inflammation in Persons with ART-treated HIV Infection?  
HIV treatment with ART reduces activation of the immune response, including levels of 
inflammatory cytokines, though most immunologic abnormalities persist compared to 


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HIV uninfected persons.14, 15 The level of T-cell activation (e.g., CD38/HLA-DR 
expression), reflecting adaptive immunity, predicts risk for AIDS16 and has been 
associated with CVD risk in cross-sectional studies.17, 18 More recent data demonstrate 
that innate immune activation also contributes to chronic inflammation.19-21 Activated 
monocytes (e.g., CD16+) are more frequent with HIV infection.22, 23 The CD16+ 
monocyte subset may be preferentially infected by HIV, demonstrate greater production 
of cytokines, and is independently predictive of coronary artery calcium (CAC) among 
HIV+ patients.24-26  
 
The precise mechanisms driving high level immune activation are not entirely clear, but 
appear to involve both a persistent anti-HIV response (even with HIV RNA at low levels) 
and a more generalized immune activation (e.g., cytokine release).15, 27-29 Potential 
factors specific to HIV infection that may account for excess inflammation include: a) 
destruction of gut epithelium, which leads to chronic translocation of bacterial products, 
b) dysregulated inflammatory responses to co-pathogens (e.g., cytomegalovirus), and c) 
loss of key regulatory response. Given that drivers of HIV-related inflammation are 
multi-factorial and diverse, a treatment that down regulates the inflammatory response 
more broadly irrespective of the cause, like losartan, may be more likely to show 
efficacy.     
 
Pathologic Consequences of Ongoing Immune Activation For Immune Recovery: 
An important pathologic consequence of persistent immune activation is fibrosis of 
lymph node (LN) structures necessary for T-cell homeostasis.30 Ongoing immune 
activation stimulates production of TGF-ß that leads to fibrotic changes in the 
parafollicular T-cell zone of lymph nodes. LN fibrosis damages the fibroblastic reticular 
cell network (FRCn) that forms the skeletal anatomy of the T-cell zone, produces IL-7, 
and directs movement of T-cells within the LN.  The loss of naïve T-cells further 
perpetuates the process through declines in lymphotoxin-β (from T-cells) that is 
essential for FRCn vitality.  The vicious cycle leads to more reductions in IL-7 and T-cell 
depletion. LN collagen is therefore not only a cause of T-cell depletion but also 
contributes to incomplete immune recovery with ART via impaired survival of naïve T-
cells. Losartan has been shown, both in vitro and in vivo, to inhibit TGF-ß and reverse 
existing fibrosis.31-35 These treatment effects may be particularly important for older HIV 
patients, given that normal aging leads to thymic involution and increased apoptosis, 
reducing circulating naïve T-cells.36, 37  
 
Study Outcomes: IL-6 and CD4 count Predict Non-AIDS Risk:  
Excess risk for non-AIDS conditions is due to multiple factors, including a higher burden 
of traditional risk factors, but persistent immune depletion and ongoing inflammation 
despite effective ART are key risk factors specific to HIV and are the focus of this trial.  
We have previously reported that CD4+ T-cell count, including changes after starting 
ART, predict risk for a composite of non-AIDS conditions (including CVD and cancer).38, 
39 Although risk for both AIDS and non-AIDS conditions decline with higher CD4+ 
counts, this is more drastic for AIDS events.39, 40  Non-AIDS conditions are therefore 
much more common than AIDS events at moderate to higher (e.g., >500 cells/mm3) 
CD4+ counts.41, 42  Mechanisms differ between distinct non-AIDS conditions, but 


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associations between CD4+ count and risk for these conditions has been reproduced in 
multiple cohorts.6, 43-47 
 
Recent data from a number of epidemiologic studies have shown that inflammatory 
biomarkers well validated in the aging and cardiovascular fields22, 48-51 are elevated with 
untreated and (to a lesser degree) treated HIV infection,14, 52, 53 and predict risk for CVD, 
cancer, and non-AIDS mortality.54-60 Our group conducted a series of nested case-
control and cohort studies, using data from 3 large HIV trials (SMART, ESPRIT, and 
SILCAAT), and determined that associations for risk of CVD, cancer, a composite of 
serious non-AIDS events, and all-cause mortality was most robust for levels of 
interleukin-6 (IL-6).61-63 These associations are not attenuated by adjusting for HIV or 
traditional CVD risk factors, are several-fold higher than reported in HIV-negative 
studies, and persist over a median of 5.5 years of follow-up, making it an ideal risk 
marker for a broad composite of non-AIDS conditions.54, 62, 64, 65 
Rationale for Losartan  
Losartan has well-established off-target, or non-blood pressure lowering, effects that 
may benefit HIV positive patients. Angiotensin-2 (AT-2), a potent vasoconstrictor, is a 
key regulator of the renin-angiotensin-aldosterone system (RAAS) that is also pro-
inflammatory (through Nuclear Factor-Kappa B [NF-B] pathways) and pro-fibrotic (via 
transforming growth factor beta [TGFβ1] induced connective tissue growth factor 
[CTGF] expression).31-35 ARBs (angiotensin receptor blockers) selectively block AT 
receptor-1, mitigating the consequences for inflammation and fibrosis, but importantly, 
have fewer side effects than ACE-I.  Tolerability to losartan (100mg) is considered 
excellent, with self-reported side effects no different than for placebo in clinical trials.66   
 
There exists a large body of evidence that ARBs (e.g., losartan) down-regulate immune 
activation.  Angiotensin-2 induces activity of NF-B,67, 68 a transcription factor that, in 
part, regulates immune activation and cytokine release (e.g., IL-6 and TNF-α).67, 69, 70 
Numerous (HIV uninfected) studies of ARBs or ACE-Is demonstrate reductions in 
inflammatory markers (e.g., IL-6, TNF-α, and CRP) via mechanisms both related to and 
independent of angiotensin receptor blockade.71-75 In hemodialysis patients, losartan 
also decreased monocyte activation (CD16+) in vivo (to levels seen in healthy controls) 
and prevented monocyte activation (or CD16 expression) in vitro.76  In animal models, 
ARBs suppress transcription and release of IL-6 and other cytokines by monocytes.77-79 
 
Independent of reducing immune activation, losartan may improve T-cell homeostasis 
and immune recovery by reversing existing tissue fibrosis through a well characterized 
mechanism of blocking TGF-ß at the level of phosphorylation of SMAD-2,3.31-35, 80-83 In 
animal models (of vascular, renal and cardiac fibrosis), losartan therapy inhibits TGF-ß 
activity and improves histologic abnormalities.84, 85 In humans, losartan reduces urinary 
levels of TGF-ß among those with transplant related kidney fibrosis,86, 87 reversed 
fibrosis and improved in cardiac function among those with myocardial fibrosis.88 
Losartan’s net effect is also to shift the balance of matrix metalloproteases and their 
inhibitors in favor of tissue remodeling, which then reduces fibrosis.89-91  
 


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Finally, the 100mg dose of losartan was chosen: a) to maximize the treatment effect on 
inflammation and fibrosis,76, 86, 92, 93 b) due to the excellent safety profile and lack of 
difference in adverse events between 50mg and 100mg doses (data from 20 clinical 
trials),66 and c) due to the predictable CVD risk reduction through BP lowering.  
 
1.2 Objectives 
Our general goal is to evaluate the potential effectiveness of losartan (100mg daily) for 
reducing inflammation and improving immune recovery, given the potential for these 
treatment effects to reduce risk for long-term non-AIDS-defining complications among 
older HIV positive participants. Prior to conducting a clinical outcome trial, candidate 
treatments must be studied among HIV positive patients given the unique pathogenesis 
driving inflammation and disease risk.  Study objectives then include: 
 
 Primary Objective: Evaluate the treatment effects of losartan on systemic 
inflammation 
 
 (Main) Secondary Objective:  Evaluate the treatment effects of losartan on T-cell 
homeostasis and immune recovery of T-cell population 
 
2 METHODOLOGY 
2.1 Trial Design 
The potential benefits of losartan (100mg daily) will be studied among HIV positive 
individuals over age 50 years whose CD4 counts remain ≤600 cells/mm3. Participants 
(n=120, 60 per group) will be randomized to receive losartan or matching placebo daily.  
After randomization, participants will start losartan (or placebo) at a dose of 50mg once 
daily, increasing to 100mg once daily at the 2-week study visit pending results of a week 
2 toxicity lab evaluation (see 2.4 below for criteria).  Following month 1, participants will 
return for follow-up study visit procedures at months 3, 6, 9, and 12.  A lymph node 
biopsy will also be performed at baseline and month 12 from a subset of participants 
(n≥30). 
 
Changes from baseline in measures of inflammation, immune activation, immune 
recovery and fibrosis within lymphatic tissues will be studied.  The primary outcome will 
be the average of IL-6 levels over 12 months, and the main secondary outcome will be 
change in CD4 count in blood over 12 months. 
  
2.2 Study Population 
The target population is HIV positive patients receiving effective treatment with ART and 
at low risk for AIDS defining complications.  For these participants, non-AIDS defining 
long-term complications (e.g., CVD and cancer) dominate the spectrum of morbidity and 
mortality.  We will also focus on participants over age 50, as advanced age is 


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5 
associated with inflammation, poor immune recovery, and also increased risk for long-
term complications such as CVD and cancer.  Any antiretroviral medications can be 
used.  Detailed inclusion and exclusion criteria are listed below. There are no 
restrictions on the use of concurrent mediations other than ARB or ACE-I, but 
participants with common diseases known to be pro-inflammatory will be excluded.   
 
2.3 Eligibility Criteria 
Inclusion Criteria 
 HIV infection (verified by previous positive antibody or detectable HIV RNA level) 
 Age ≥50 years 
 Receiving continuous ART for ≥2 years; regimen changes acceptable if >4 weeks 
prior to screening when there is an ART class change (i.e., corresponding to either a 
deletion or addition of an ART class), or at anytime for an antiretroviral change that 
is within an ART class. 
 HIV RNA level ≤200 copies/mL for ≥1 year (1 measure ≥200 allowed if also <500 
and preceded and followed by one or more undetectable values) 
 Blood CD4+ T-cell count ≤600 cells/mm3 
 Systolic blood pressure ≥110 mmHg (mean value, if ≥2 measures obtained) 
 Estimated GFR ≥30 mL/min/1.73m2 
 Do not anticipate starting (or stopping) statin or aspirin therapy during the study 
 For women of child bearing potential, agrees to use a reliable form of birth control 
Exclusion Criteria 
 Pregnancy or breast feeding 
 A contra-indication to taking an ARB (e.g., cirrhosis, prior angioedema with ACE-I, or 
use of drug with potential drug-interaction [e.g., rifaximin]) 
 A clinical indication for ARB or ACEi therapy  
 Current treatment with ARB or medication with overlapping mechanism (e.g., ACE-I 
or aldosterone antagonist)  
 Treatment with immune-modulatory drugs within the past 6 months 
 
Hepatitis C treatments (e.g., interferon, ribavirin) within the past 6 months 
 Serum potassium >5.0 mmol/L within the past 3 months  
 Grade 3/4 lab abnormality (from BMP, CBC or liver function panel)  
 Invasive cancer in the prior year or receiving cancer treatment (not including 
carcinoma-in-situ or basal cell cancer of the skin) 
 Cirrhosis or end-stage liver disease 
 Rheumatologic or chronic inflammatory disease (e.g., systemic lupus 
erythematosus, psoriasis, rheumatoid arthritis, vasculitis, sarcoidosis, Crohn’s 
disease) 
 Assessment by the clinical investigator that enrollment into the study could entail 
excess risk to the participant, beyond what is intended or expected. 
 BMI >40mg/kg2 for participants co-enrolled into the LN biopsy substudy. 
 


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NOTE:  For participants consented to co-enroll into the LN biopsy substudy, the 
following approach based on BMI at screening visit will be applied: 
i. 
BMI ≤30: participants can be co-enrolled into LN substudy. A LN assessment 
should done upon consent (by MD, NP, or RN) to determine if the participant 
has palpable LN in the inguinal region.  Findings will be documented on the 
LN Biopsy Referral Form. 
ii. 
BMI 30-40: participants must have documentation of palpable LN in the 
inguinal region at the screening visit. 
iii. 
BMI >40: participants are not eligible for LN biopsy substudy. 
 
2.4 Study Medication Intervention  
At baseline, participants will start losartan or matching placebo at 50mg daily. At 2 
weeks, side effects and blood chemistries (BMP) will be assessed. The dose of 
losartan/placebo will increase to 100mg daily at the week 2 assessment if no toxicities 
or side effects are present that are attributable to study medication (see section 3.2 
below for specific study drug dose modification criteria).  A similar repeat assessment 
will then be performed at month 1 to verify that the 100mg dose is tolerated. 
Randomization and Blinding 
Eligible participants who consent to study procedures will be randomized 1:1 to receive 
losartan or matching placebo, with stratification by clinical site and by whether the 
participant consents to undergo a LN biopsy. Treatment assignments will be generated 
using a permuted block randomization scheme. Sites will use a secure, on-line program 
to obtain treatment assignments.  The program will also verify eligibility and the 
existence of key baseline data. Treatment assignments will be verified and recorded in 
a dataset blinded to view by site staff.  
A bottle ID number (BID) unique to each bottle will be assigned to participants, and 
used by study staff to obtain the correct blinded study drug. Sites will not have access to 
the treatment assignment linked to each bottle number, and bottle numbers will not be 
assigned in sequence. 
Blinding will occur at 3 levels:  1) treatment assignment will be blinded, 2) interim data 
summaries will blinded to all but the unblinded statistician and 3) core lab staff will be 
blinded to treatment group. In the rare event that the blind must be broken, every effort 
will be made to minimize the extent of the unblinding (for staff and participants) and an 
assessment of blinding will occur at the end of the study. 
Study Drug Production and Distribution   
Active losartan 50mg tablets and matching placebo will be provided and distributed by 
Merck Pharmaceuticals. From baseline to 1-month visit, participants will take one 50mg 
tablet daily.  When/if the study drug dose is increased to 100mg, participants will take 2x 
50mg tabs once daily (for 100mg).  Study drugs will be provided in 100 count bottles.  
One bottle will be dispensed at baseline, and one additional bottle at the 1-month visit.  
Following this, 2 bottles will be dispensed at all subsequent visits (months 3, 6, and 9). 
Sites will order study drug from the DCC, which will communicate with Merck to ship 


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drug to sites. Merck will provide the DCC with the key linking the BID (unique to each 
bottle) with whether the contents are active losartan or matching placebo.  The DCC will 
then instruct sites which bottle(s) to dispense to patients based on the BID. 
Risks Associated with Study Drug 
Losartan is approved by the FDA and used to treat high blood pressure. 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, allergic reaction and kidney damage. In clinical studies, most of 
these side effects were no more common than what was experienced with placebo 
medication.  Participants will undergo a side effect assessment at each visit (see case 
report form and protocol implementation manual for ‘symptom check list’). 
Losartan should not be used during pregnancy. If a developing fetus is exposed to 
losartan, injury or even death may result. For this reason, pregnancy is an exclusion 
criterion and any pre-menopausal women of child bearing potential must be willing to 
use birth control during the study.  
 
2.5 Outcomes 
Primary Outcome 
 IL-6 plasma levels:  change from baseline over 12 months 
Main Secondary Outcome 
 CD4+ T-cell count in blood: change from baseline over 12 months 
 
Additional Secondary Outcomes 
 Adherence 
 Tolerability and side effects 
 Monocyte activation immune-phenotyping (e.g., CD14+/CD16+) 
 Systemic inflammatory biomarkers (e.g., sCD14, sCD163, TNF-α, sTNFr-1, IL-6r, 
high sensitivity C-reactive protein) 
 Coagulation activity (e.g., D-dimer levels) 
 T-cell activation and senescence phenotypes in blood 
 Recovery of CD4+ T-cell subsets (e.g., naïve) in blood  
 HIV-specific T-cell responses 
 Plasma biomarkers of fibrosis (e.g., hyaluronic acid) 
 Lymphatic Tissue fibrosis (LN biopsy substudy) 
 Lymphatic Tissue cellular immune activation (LN biopsy substudy) 
 Lymphatic Tissue T-cell homeostasis (LN biopsy substudy) 
 Frailty assessment (including 5 components: unintentional weight loss, physical 
inactivity, exhaustion, weak grip strength and slow walk) 


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2.6 Study Visit Schedule 
Participants will be screened and, if eligibility criteria are met, will be randomized at the 
baseline visit to start active study drug or matched placebo (blinded).  Randomization 
must occur within 90 days of all screening labs.  NOTE: the 90-day screening to 
randomization window applies to all participants, both those co-enrolled into the LN 
biopsy substudy and those not co-enrolled. 
 
Baseline laboratory evaluation must occur within 30 days of randomization.  For 
participants enrolled in the LN biopsy substudy, baseline labs cannot be drawn within 
the 7 days following the biopsy procedure.  A LN biopsy specimen must be obtained 
prior to randomizing the participant into the LN substudy.  If a biopsy procedure is 
attempted but a LN specimen is not obtained at baseline, the participant will still be 
eligible to be randomized into the main study (but not the LN substudy). NOTE:  the 
biopsy procedure may occur after the baseline labs are obtained but still prior to 
randomization.  
 
After screening and baseline visits, participants will start losartan 50mg daily (or 
placebo) and return for a lab draw to assess toxicity (BMP only) at week 2.  At the week 
2 visit (after toxicity lab results return), participants will increase to losartan 100mg daily 
(or placebo) if they meet criteria based on results from the 2-week assessment (see 
section 2.4 above).  Subsequent study visit procedures will occur in the context of visits 
at months 1, 3, 6, 9, and 12.  For participants enrolled in the LN biopsy substudy, month 
12 visit labs cannot be drawn within the 7 days following the month 12 biopsy procedure 
(NOTE:  the biopsy procedure may occur after the month 12 labs are obtained).  
Participant should continue to take study medication until all study visits are completed; 
for participants enrolled in the LN biopsy substudy this includes BOTH the month 12 
biopsy as well as the month 12 labs. 
 
The target visit window for each study visit is guided by anticipated study drug quantity 
that the participant will have at the time. For week 2 and month 1, this corresponds to a 
14-day target window (or +/- 7 days).  Corresponding target windows for month 3, 6, 9, 
and 12 study visits are 32 days (or +/- 16 days).   
 
NOTE:  the ‘actual’ visit window for months 3, 6, 9, and 12 will be +/- 42 days (i.e., no 
gaps between visits where participants would not be in a visit window), but if >16days 
additional study drug should be dispensed to the participant—consistent with making 
every effort to capture study visit data while keeping participants on study drug. 
 
The visit schedule is outlined in the table below. Patients will be fasting for all blood 
draws (except screening). 
 
Toxicity labs and a clinical assessment will be ascertained as part of follow-up study 
visits.  If clinical labs (e.g., HIV RNA level, CD4 count, BMP, hepatic panel, and CBC) 
are available as part of routine clinical monitoring during the study visit window, these 
results may be used in place of repeating clinic labs at the study visit. If new symptoms 
develop that may be related to study medications, the site study investigator is to be 


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notified within 24 hours and a clinical determination is to be made whether additional 
toxicity labs and/or adherence requires assessing. 
 
 
Table 2:  Study outcomes and visit timeline 
 
 
 
Screening 
Baseline 
Week 2 
Month 1 
Month 3 
Month 6 
Month 9 
Month 12 
Informed consent and eligibility criteria 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Randomization 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
  Adherence  
-- 
-- 
-- 
X 
X 
X 
X 
X 
  Side Effects (subjective including symptom check list) 
-- 
X 
X 
X 
X 
X 
X 
X 
  Toxicity labs (BMP) 
X 
X 
X 
X 
X 
X 
X 
X 
  Toxicity labs (CBC and hepatic panel) 
X 
-- 
-- 
-- 
X 
X 
X 
X 
  HIV RNA level 
X 
-- 
-- 
-- 
X 
X 
X 
X 
  Hep Bs Ag & Hep C Ab (results within 1 year acceptable)* 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
  Lipid panel (results within 1 year acceptable) 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
  Pregnancy test (during f/u for women of childbearing potential) 
X 
X 
-- 
-- 
X 
X 
X 
X 
Blood Outcome Measures  
 
 
 
 
 
 
 
 
  IL-6 levels (plasma) 
X 
X 
-- 
X 
X 
X 
X 
X 
  CD4+ T-cell count (blood) 
X 
X 
-- 
X 
X 
X 
X 
X 
  Inflammatory, coagulation and fibrosis plasma biomarkers  
-- 
X 
-- 
-- 
X 
X 
-- 
X 
  Monocyte and T-cell Immunophenotyping 
-- 
X 
-- 
-- 
-- 
X 
-- 
X 
Functional Assessment 
 
 
 
 
 
 
 
 
Frailty criteria: unintentional weight loss, exhaustion, physical-
inactivity, weak-grip and slow-walk 
-- 
X 
-- 
-- 
-- 
X 
-- 
X 
 Tissue Outcome Measures 
 
 
 
 
 
 
 
 
  LN fibrosis 
-- 
X 
-- 
-- 
-- 
-- 
-- 
X 
  LN cellular immune activation 
-- 
X 
-- 
-- 
-- 
-- 
-- 
X 
Stored plasma 
X 
X 
-- 
X 
X 
X 
X 
X 
Stored urine 
-- 
X 
-- 
-- 
-- 
X 
-- 
X 
Stored PBMCs  
-- 
X 
-- 
-- 
-- 
X 
-- 
X 
*Prior results that do not need repeating include:  HCV Ab positive, HBsAg positive, or HBsAb positive 
along with HBsAg negative 
 
2.7 Sample Size Considerations 
Power for Reduced Inflammation (IL-6 levels) 
 The primary analysis will compare baseline-adjusted log IL-6 measurements at 1, 3, 6, 
9 and 12 months between treatment groups. 
 Standard deviation (SD) data from SMART (n=122; baseline and month 1) and 
ESPRIT (n=147; baseline and month 12) on participants who were on continuous ART 
between both time points were used to estimate a log IL-6 SD of 0.74 pg/mL.   
 We assumed a 28% reduction in IL-6 with losartan was plausible based on our pilot 
data and data from HIV negative studies in the general population.73, 74, 94  
Based on assumptions above, assuming 5% missing data, and considering the potential 


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clinical risk reduction associated with IL-6 changes of this magnitude (see epidemiologic 
data, following paragraph), a total sample size of n=110 will be enrolled.  With this 
sample we will have 80% power to detect an absolute reduction of 0.3 log(IL-6), 
corresponding to a 26% reduction in IL-6, with a two-sided Type I error of 0.05. 
Pooled data from 3,766 participants in SMART, ESPRIT and SILCAAT trials who were 
taking continuous ART with an HIV RNA level <400 copies/mL at entry—a group that 
resembles our target population—indicate that a 26% lower baseline IL-6 level is 
associated with a 34% lower risk of serious non-AIDS events or death from any cause.62  
Power for Immune Recovery (CD4+ T-cell count) 
 The primary analysis will consider average changes in log10 blood CD4 levels (total 
and naïve) over 12 months. Total CD4 count will be measured at 1, 3, 6, 9, and 12 
months, and 4 pre-treatment baseline values (2 historical within prior year, 1 
screening, 1 baseline) will be averaged to compute baseline CD4+ count for analyses. 
Averaging multiple baseline measurements will reduce variability and thereby increase 
statistical power. The log10 naïve CD4+ subset count will be measured at baseline 
and months 6 and 12. 
 Based on participants ≥ age 50 in the SMART and ESPRIT studies (n=510 total), the 
estimated SD of yearly changes in log10 total CD4+ count is 0.11. Based on 
preliminary data from Dr. Sereti’s lab, the estimated SD of yearly changes in the log10 
naïve CD4 subset is 0.24. 
With our sample size of n=110, we estimate that we will have 80% power to detect a 
9.6% (19.8%) difference in total (naïve) CD4 count. Assuming a baseline total CD4 level 
of ~300-400 cells/mm3, a 9.6% increase in CD4 count corresponds to an approximate 
average annual increase of 30-40 cells per year. From our prior epidemiologic work 
studying clinical risk based on total CD4+ count in blood after treatment with ART, a 
difference in this range would correspond to 5-8% difference in risk for a composite of 
non-AIDS events.38, 39 
 
3 CLINICAL MANAGEMENT 
3.1 Administration of Study Procedures 
Study nurses at each clinical site will be trained prior to study implementation and will 
perform all study visit procedures during the conduct of the study.  The lead physician 
investigator at each site will conduct clinical and drug toxicity assessments as indicated 
during the study.  
3.2 Study Drug Dose Modification 
At baseline, participants will start losartan or matching placebo at 50mg daily. At 2 
weeks, side effects and blood chemistries (basic metabolic panel [BMP]) will be 
assessed. The dose of losartan/placebo will increase to 100mg daily at this week 2 visit 
(i.e., once lab results return) if all of the following criteria are met:  
a) Systolic blood pressure (BP) ≥90 mmHg 


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b) Potassium ≤5.0 mmol/L 
c) eGFR ≥30 mL/min/1.73m2 
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 
 
If participants are increased to 100mg dose at the week 2 visit and continue to tolerate 
this dose at the month 1 visit, they will be contacted by phone to verify tolerability 2-4 
weeks following the month 1 visit.  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 12-month study unless new side effects or 
adverse events necessitate re-evaluation (see below criteria). 
 
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 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 


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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. 
3.3 Adherence and Tolerability 
Adherence will be assessed via participant self-report and pill count (by study nurse) 
during each follow-up visit.  Tolerability will also be assessed via self-report, with 
additional laboratory assessments performed for toxicity. 
3.4 Data Collection 
All data will be entered into web-based case report forms and transferred to servers at 
the data coordinating center (DCC) at University of Minnesota School of Public Health 
using REDCap software.  Paper source documentation will also be kept in a secure, 
locked location at each clinical site.  Study nurses and/or other qualified research 
technicians will perform all blood draws and blood specimen processing.  The blood 
specimen collection tubes and processing protocols are outlined in the study laboratory 
manual. 
 
3.5 Blood Specimen Processing 
See the LIFE-HIV study laboratory manual for details on blood specimen processing.  
Participants will be fasting for all study visit blood draws (optional for screening visit).  
Plasma and serum specimens will need to be processed from whole blood within 4 
hours of collection.   
3.6 Clinical Labs 
All clinical labs will be measured on fresh blood specimens the day of the study visit, at 
the site clinical lab using CLIA approved standards.  Plasma HIV RNA level will be 
estimated using COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0. 
 
The following clinical labs will be assessed to monitor for toxicity per Table 2 above: 
i. Complete Blood Count (CBC, with platelet count and differential) 
ii. Basic Metabolic Panel (BMP) 
iii. Hepatic panel (AST, ALT, total bilirubin, alkaline phosphatase) 
3.7 Plasma Biomarkers 
Plasma specimens will be analyzed at the Laboratory for Clinical Biochemistry 
Research (U of Vermont), under the direction of Dr. Russell Tracy. IL-6 will be 
measured with Chemiluminescent Sandwich ELISA (R&D Systems).  A high degree of 
repeatability (low analytic variability) has been reported by Dr. Tracy’s lab for assessing 
IL-6 and other plasma biomarkers.95-101  
3.8 Immunologic Phenotypes 
Immunophenotyping will be performed on cryopreserved PBMCs using multi-color ﬂow 
cytometry at an intramural NIAID/NIH laboratory under the direction of Dr. Irini Sereti. 


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Panels of fluorochrome-conjugated antibodies for cell surface markers not affected by 
cryopreservation (e.g., CD3, CD4, CD8, CD38, HLA-DR, CD14, CD16, CD142 or tissue 
factor (TF) and viability dye to exclude non-viable cells) have been validated previously 
by Dr. Sereti.102 The prevalence of classical (CD14+/CD16-), intermediate 
(CD14+/CD16+), and non-classical (CD14dim/CD16+) monocyte phenotypes and T cells 
phenotypes reflecting activation (HLA-DR+/ CD38+) with be characterized; and with 
these methods additional phenotypes may be easily characterized (e.g. TF expression 
on monocytes, T-regulatory cells, or senescent T-cells). Only live cells will be included; 
samples with low (<75%) viability will not be processed. 
3.9 Lymphatic Tissue Assessment 
Lymph node (LN) biopsy will be performed in a subset of at least 30 participants at 
baseline and month 12.  Criteria for enrollment into the LN substudy include: a) 
participant consent, b) lack of contraindications to the LN biopsy procedure, and c) 
palpable lymph nodes on exam by site investigator or research coordinator.  All 
participants at NIH will be offered participation into the LN substudy, and participants at 
HCMC and Allina/Abbott Northwestern (in Minneapolis) will be offered participation 
until/if 25 patients are enrolled. Planned analyses will be exploratory in nature focused 
on assessment of: a) collagen deposition reflecting fibrosis in T-cell zone, b) changes in 
CD4 T-cell populations, c) changes in the structure of the FRCn, and d) changes in 
cellular immune activation in lymphatic tissue. 
 
Biopsies will be performed at the University of Minnesota (for HCMC and Abbot 
Northwestern sites) and the NIH clinical center, by general surgeons using a research 
facility equipped with inpatient rooms.  Tissue specimens are placed into fresh 4% 
paraformaldehyde for 24 hours and then transferred to 80% ethanol for paraffin 
embedding.  LN tissue can also be divided at the bedside prior to processing to 
accommodate additional methods that requiring non-fixed tissue. 
 
Changes in LN T-cell zone collagen, the size of T-cell populations, and the FRCn 
structure will be measured using established methods of IHC with antibody staining and 
quantitative image analysis (QIA) developed by Dr. Schacker’s lab at the University of 
Minnesota.80, 81, 91, 103-107 A similar approach will be used to assess cellular immune 
activation within lymphatic tissue.  
 
4  SAFETY AND ADVERSE EVENTS 
4.1 Measures to reduce risk for adverse events 
Risks related to low blood pressure, or hypotension, are minimal but may increase with 
dehydration/hypovolemia.  To reduce this risk, participants will be counseled on 
maintaining good hydration and diet, and on the potential effects of orthostatic 
hypotension. 


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4.2 Adverse Event Definitions 
Adverse Event (AE): Any untoward medical occurrence in a clinical research 
participant administered an investigational product, which may or may not have a causal 
relationship with the investigational product. As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product.  
 
If a preexisting condition worsens post-enrollment (frequency increases and/or severity 
grade increases), it should be reported as an adverse event. 
 
A symptom check-list will be included in the CRF (detailed in the protocol 
implementation manual) that includes common symptoms or side effects typically 
related to losartan therapy. 
 
Appendix D provides a table of adverse events, with grading criteria, adopted from the 
DAIDS 2009 Table for Grading the Severity of Adult and Pediatric Adverse Events 
Serious Adverse Event (SAE): Any adverse event occurring at any dose that 
results in any of the following outcomes:  
i. 
Death,  
ii. 
A life-threatening condition,  
iii. 
A congenital anomaly/birth defect, 
iv. 
Inpatient hospitalization or prolongation of existing hospitalization,  
v. 
Persistent or significant disability/incapacity,  
vi. 
An important medical event that, based upon appropriate medical judgment, 
may jeopardize the patient or subject and may require intervention to prevent 
one of the outcomes listed above. 
 
Unanticipated Problem (UP) is any event that is: 
i. Unexpected, AND  
ii. Related to study participation in this study, AND  
iii. Increase the risk of harm to the participant or others (or be an SAE) 
4.3 Documenting Adverse Events 
All new adverse events of grade ≥3 or deemed related to study drug will be ascertained 
and recorded on study visit CRFs (through the online REDCAP interface). Criteria for 
assigning a grade of severity of adverse events are summarized in Appendix D.  
NOTE:  adverse events based on laboratory criteria will only be 
ascertained/recorded if ≥ grade 3, and no adverse events will be 
ascertained/recorded based on CD4+ T-cell count criteria. 
 
There are five severity grades that can be assigned to adverse events, which are 
defined as follows:  
i. 
Grade 1 = Mild  


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ii. 
Grade 2 = Moderate  
iii. 
Grade 3 = Severe  
iv. 
Grade 4 = Potentially life-threatening  
v. 
Grade 5 = Death 
 
Additional information ascertained for each adverse event includes:  a) date of onset, b) 
relationship to study drug (see section 4.4 below), c) any action taken on study drug, 
and d) whether the adverse event qualifies as a serious adverse event (including the 
SAE criteria fulfilled). 
 
Source documentation (in addition to the CRF variables for AEs) will collected at clinical 
sites for all serious adverse events, as well as any other problems involving risks to 
participants that are unanticipated or unexpected and are reasonably believed to be 
related to research participation.   
4.4 Adverse Event Relationship to Study Drug 
For all adverse events grade ≥3 that occur after randomization, study investigator(s) will 
assess the potential relationship of the event to the study medication.  One of the 
following designations will be used:  
 
i. Related: There is a reasonable possibility that the AE may be related to the study 
agent(s). 
 
ii. Not related: There is not a reasonable possibility that the AE may be related to 
the study agent(s). Alternative etiology, diagnosis or, explanation for the AE 
should be provided. 
 
4.5 Reporting Adverse Events  
The IRB (or Human Subjects Committee) for the site where the event occurred will 
receive immediate notification of all serious adverse events (SAE) that are ALSO 
deemed protocol related, OR for any an unanticipated problem (UP; which are by 
definition protocol related).  NOTE: an adverse event (of any grade) that is unexpected, 
is reasonably believed to be related to study participation, and involves risk to the 
participant or others should be captured as a UP (per definition above 4.2).   
 
The site will enter this information into the adverse event log and SAE/UP case report 
form (via REDCap reporting).  The data coordinating center (DCC) will distribute a 
summary of each SAE/UP event to the remaining clinical sites and participating 
institutions for submission to their respective IRBs. 
 
The site will also complete FDA Form 3500 (MedWatch; see below), and submit this 
form to the FDA (via online reporting) and also to the DCC. Within 2 business days of 
learning of the event, clinical sites must: 
 
a) Inform local IRB per institutional guidelines and timelines 


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b) fill out an SAE/UP case report form, via REDCap online reporting 
c) fill out an MedWatch Form FDA 3500  
d) either submit MedWatch Form FDA 3500 to the FDA or complete voluntary 
reporting online via FDA MedWatch (see below for link)  
e) email the completed MedWatch Form FDA 3500 to:  study PI (Jason Baker; 
baker@umn.edu), DCC (Gary Collins; gary-c@ccbr.umn.edu)  
 
The DCC will submit FDA Form 3500 and any other information on the SAE/UP from 
the REDCap CRF, to a representative for Merck Pharmaceuticals.  Reporting of all 
SAE/UP events will be made to FDA and Merck Pharmaceuticals using FDA Form 
3500.   
 
FDA MedWatch reporting forms may be found at: 
http://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htm 
 
FDA MedWatch voluntary reporting can be performed at: 
https://www.accessdata.fda.gov/scripts/medwatch/ 
 
4.6 Participant Withdrawal 
Participants may withdraw from the study at any time at their request, as described in 
the consent.  All randomized participants will be encouraged to complete a final study 
visit, including all visit procedures. 
 
5 Data and Safety Monitoring Plan 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a 
daily basis. A Data and Safety Monitoring Board (DSMB) will be formed with Dr. 
Wolfson as the un-blinded statistician; other members will not be from institutions 
involved in the study and will be approved by NIA. Committee members will have 
experience with HIV/AIDS clinical research studies.  Prior to enrollment the DSMB will 
review the protocol and data analysis plan.   
The DSMB will act in an advisory capacity to the NIA Director to monitor participant 
safety, evaluate the progress of the study, and review procedures for maintaining the 
confidentiality of data, the quality of data collection, management, and analyses. During 
the study the DSMB will meet at least yearly.   
Refer to the DSMB Charter and data and safety monitoring plan for details. 
5.1 Interim Analysis 
Most of the primary blood and tissue outcomes will not be available until after visits are 
completed, as samples will be batch processed at our participating laboratory site. 
Hence, there will be no formal interim analyses for efficacy or futility related to the main 
study outcomes.  


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However, the lead study statistician will prepare and submit reports to the DSMB every 
3 months documenting study enrollment totals and adverse events. While we do not 
anticipate significant issues with safety in this short-term study, a recommendation by 
the DSMB to stop the study would likely be based on an adverse event rate that is 
deemed unacceptably high. 
Recommendations from the DSMB (e.g., continue the study as planned), and a letter 
summarizing the findings at the end of the study, will be transmitted to each site for 
submission to their IRB. 
5.2 Frequency and Content of Data and Safety Monitoring  
To ensure compliance and data are reported correctly and completely, CRF data will be 
monitored monthly for completeness and compliance with the study protocol.  Queries 
for clarification or data completion will be posted to a site-specific and password 
protected section of the LIFE-HIV website.  
 
The PI will be informed of serious adverse events as soon as they occur and will notify 
the NIA and DSMB within 24 hours of notification. During the study the DSMB will meet 
at least yearly either in-person or by teleconference call to review study progress, data 
quality, and participant safety. An initial DSMB meeting will be scheduled as soon as 
any of the following occurs: 
i. 
Six months have elapsed since enrollment of the first patient 
ii. 
50% of goal enrollment is achieved 
iii. 
30 person-years of follow-up is achieved 
  
The data and safety monitoring report will include data on: enrollment (including 
progress), visit attendance, completeness of data, completeness and quality of 
specimen collection, baseline characteristics, adherence and discontinuation of 
medication, and side effects and adverse events.   
 
5.3 DSMB Membership and Affiliation 
The following individual(s) has/have accepted position(s) as part of the DSMB. DSMB 
membership will be reviewed and approved by the NIA. Should there be any questions 
regarding the independence of the DSMB, it will be addressed and corrected if 
necessary at that time: 
 
 Biostatistician: Bryan Shepherd, PhD (bryan.shepherd@vanderbilt.edu) 
 HIV/ID medicine: Kevin High, MD (khigh@wakehealth.edu) 
 Cardiology medicine: Michael Kiernan, MD (mkiernan@tuftsmedicalcenter.org) 
 
5.4 DSMB Conflict of Interest and Protection of Confidentiality 
DSMB members should have no direct involvement with the study investigators or 
intervention. Each DSMB member will sign a Conflict of Interest Statement which 


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includes current affiliations, if any, with pharmaceutical and biotechnology companies 
(e.g., stockholder, consultant), and any other relationship that could be perceived as a 
conflict of interest related to the study and / or associated with commercial interests 
pertinent to study objectives.  
 
Data will be presented in a blinded manner during the open sessions of the DSMB. At 
DSMB meetings, data and discussion are confidential. Participant identities will not be 
known to the DSMB members. 
5.5 DSMB Responsibilities 
The DSMB Charter provides a detailed list of the DSMB responsibilities. They include: 
 Review the research protocol, informed consent documents and plans for 
data safety and monitoring; 
 Recommend subject recruitment be initiated after receipt of a satisfactory 
protocol; 
 Evaluate the progress of the trial, including periodic assessments of data 
quality and timeliness, recruitment, accrual and retention, participant risk 
versus benefit, performance of the trial sites, and other factors that can affect 
study outcome; 
 Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the trial; 
 Review study performance, make recommendations and assist in the 
resolution of problems reported by the Principal Investigator; 
 Protect the safety of the study participants; 
 Report to NIA on the safety and  progress of the trial; 
 Make recommendations to the NIA and the Principal Investigator concerning 
continuation, termination or other modifications of the trial based on the 
observed beneficial or adverse effects of the treatment under study; 
 Ensure the confidentiality of the study data and the results of monitoring; and, 
 Assist the NIA by commenting on any problems with study conduct, 
enrollment, sample size, and/or data collection. 
 
6 ANALYSIS PLAN 
The general goal of this study is to evaluate the potential treatment effects of losartan 
for reducing systemic inflammation and improving immune recovery. For the effect of 
losartan on systemic inflammation, the outcome will be the average of log IL-6 levels 
(plasma) from samples obtained at months, 1, 3, 6, 9, and 12; two pre-treatment log IL-
6 measurements will be averaged to estimate baseline log IL-6 level. The primary 


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analysis will be intention to treat using a linear model for the aforementioned outcomes 
with treatment group indicator as the main predictor, fitted using the Generalized 
Estimating Equations approach with an independence working correlation structure. The 
model will be adjusted for baseline log IL-6 and clinical center. The hypothesis of no 
treatment effect will be assessed by considering the statistical significance of the 
treatment group indicator.  Additional analyses will consider change in IL-6 at specific 
visit time points, as well as the percent of participants that achieve an IL-6 level <1.1 
pg/mL (i.e., the 25th percentile among HIV+ patients with viral suppression in the 
SMART/ESPRIT/SILCAAT trials) 
 
Immune recovery will be assessed by modeling log10 CD4+ T-cell counts in blood, using 
a linear mixed effects model that, in addition to the model components described for the 
systemic inflammation analysis above, incorporates a main effect for time (in months), a 
treatment-by-time interaction, and individual-specific intercepts and slopes (for time). 
The hypothesis of no treatment effect on rate of yearly change in log10 CD4 counts will 
be evaluated by considering the statistical significance of the treatment-by-time 
interaction term.  
 
Subgroup analyses will be performed to explore potential for differential treatment 
effects (e.g., entry CD4 count [including ≥ vs. < 350], CD4:CD8 ratio, use of statins, 
aspirin, or other drugs with potential anti-inflammatory or anti-fibrotic properties, and co-
morbidities or polymorbidities). Trends in treatment effects on the primary outcome (log 
IL-6) over time will be assessed using linear mixed effects models similar to those 
described for the modeling of log10 CD4+. 
 
The main analyses for primary and secondary outcomes will be intention to treat. As 
secondary analyses, we will perform per-protocol (‘on treatment’) and compliance-
adjusted analyses, and will also carry out analyses using all available data by multiply 
imputing missing longitudinal outcome measurements via the chained equations 
method, using linear mixed effects models incorporating baseline covariates, the 
treatment indicator, and non-missing outcome measurements.  


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REFERENCES 
1. 
Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, 
Hrobjartsson A, Mann H, Dickersin K, Berlin JA, Dore CJ, Parulekar WR, Summerskill 
WS, Groves T, Schulz KF, Sox HC, Rockhold FW, Rennie D, Moher D. Spirit 2013 
statement: Defining standard protocol items for clinical trials. Annals of internal medicine. 
2013 
2. 
Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman 
DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced 
human immunodeficiency virus infection. Hiv outpatient study investigators. N Engl J 
Med. 1998;338:853-860 
3. 
Mocroft A, Brettle R, Kirk O, Blaxhult A, Parkin JM, Antunes F, Francioli P, D'Arminio 
Monforte A, Fox Z, Lundgren JD. Changes in the cause of death among hiv positive 
subjects across europe: Results from the eurosida study. Aids. 2002;16:1663-1671 
4. 
Palella FJ, Jr., Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, Holmberg SD. 
Mortality in the highly active antiretroviral therapy era: Changing causes of death and 
disease in the hiv outpatient study. J Acquir Immune Defic Syndr. 2006;43:27-34 
5. 
Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with 
aids in the era of highly active antiretroviral therapy: New york city. Ann Intern Med. 
2006;145:397-406 
6. 
Smit C, Geskus R, Walker S, Sabin C, Coutinho R, Porter K, Prins M. Effective therapy 
has altered the spectrum of cause-specific mortality following hiv seroconversion. Aids. 
2006;20:741-749 
7. 
Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, 
Weinstein MC, Freedberg KA. The survival benefits of aids treatment in the united 
states. J Infect Dis. 2006;194:11-19 
8. 
Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, Vaeth M, Obel 
N. Survival of persons with and without hiv infection in denmark, 1995-2005. Ann Intern 
Med. 2007;146:87-95 
9. 
Lau B, Gange SJ, Moore RD. Risk of non-aids-related mortality may exceed risk of aids-
related mortality among individuals enrolling into care with cd4+ counts greater than 200 
cells/mm3. J Acquir Immune Defic Syndr. 2007;44:179-187 
10. 
The Antiretroviral Therapy Cohort Collaboration. Causes of death in hiv-1-infected 
patients treated with antiretroviral therapy, 1996-2006: Collaborative analysis of 13 hiv 
cohort studies. Clin Infect Dis. 2010;50:1387-1396 
11. 
Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, Gatell J, 
Rakhmanova A, Johnson M, Kirk O, Lundgren J. Serious fatal and nonfatal non-aids-
defining illnesses in europe. Journal of acquired immune deficiency syndromes. 
2010;55:262-270 
12. 
Crum NF, Riffenburgh RH, Wegner S, Agan BK, Tasker SA, Spooner KM, Armstrong 
AW, Fraser S, Wallace MR. Comparisons of causes of death and mortality rates among 
hiv-infected persons: Analysis of the pre-, early, and late haart (highly active 
antiretroviral therapy) eras. J Acquir Immune Defic Syndr. 2006;41:194-200 
13. 
Lewden C, May T, Rosenthal E, Burty C, Bonnet F, Costagliola D, Jougla E, Semaille C, 
Morlat P, Salmon D, Cacoub P, Chene G. Changes in causes of death among adults 
infected by hiv between 2000 and 2005: The "mortalite 2000 and 2005" surveys (anrs 
en19 and mortavic). J Acquir Immune Defic Syndr. 2008;48:590-598 
14. 
Neuhaus J, Jacobs DR, Jr., Baker JV, Calmy A, Duprez D, La Rosa A, Kuller LH, Pett 
SL, Ristola M, Ross MJ, Shlipak MG, Tracy R, Neaton JD. Markers of inflammation, 
coagulation, and renal function are elevated in adults with hiv infection. J Infect Dis. 
2010;201:1788-1795 


 Protocol Version 3.0 
JAN 2017 
 
21
15. 
Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, Hsue P, Emu 
B, Krone M, Lampiris H, Douek D, Martin JN, Deeks SG. Relationship between t cell 
activation and cd4+ t cell count in hiv-seropositive individuals with undetectable plasma 
hiv rna levels in the absence of therapy. J Infect Dis. 2008;197:126-133 
16. 
Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated cd38 
antigen expression on cd8+ t cells is a stronger marker for the risk of chronic hiv disease 
progression to aids and death in the multicenter aids cohort study than cd4+ cell count, 
soluble immune activation markers, or combinations of hla-dr and cd38 expression. J 
Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:83-92 
17. 
Kaplan RC, Sinclair E, Landay AL, Lurain N, Gange SJ, Sharrett AR, Xue X, Hunt P, 
Hodis H, Deeks SG. T-cell senescence and t-cell activation predict carotid atheroslerosis 
in hiv-infected women. 17th Conference on Retroviruses and Opportunistic Infections. 
2010;Abstract #709 
18. 
Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Parrinello 
CM, Hunt P, Deeks SG, Hodis HN. T cell activation predicts carotid artery stiffness 
among hiv-infected women. Atherosclerosis. 2011;217:207-213 
19. 
Crowe SM, Westhorpe CL, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M. 
The macrophage: The intersection between hiv infection and atherosclerosis. J Leukoc 
Biol. 2010;87:589-598 
20. 
Sandler N, Wand H, Nixon D, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Deeks 
SG, Sereti I, Douek D. Plasma levels of soluble cd14 predict mortality in hiv infection. 
17th Conference of Retroviruses and Opportunistic Infections. 2010;Abstract #303 
21. 
Scherberich JE, Nockher WA. Cd14++ monocytes, cd14+/cd16+ subset and soluble 
cd14 as biological markers of inflammatory systemic diseases and monitoring 
immunosuppressive therapy. Clin Chem Lab Med. 1999;37:209-213 
22. 
Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH, Gottdiener J, Fried 
LP. Frailty and activation of the inflammation and coagulation systems with and without 
clinical comorbidities: Results from the cardiovascular health study. Arch Intern Med. 
2002;162:2333-2341 
23. 
Hearps AC, Maisa A, Cheng WJ, Angelovich TA, Lichtfuss GF, Palmer CS, Landay AL, 
Jaworowski A, Crowe SM. Hiv infection induces age-related changes to monocytes and 
innate immune activation in young men that persist despite combination antiretroviral 
therapy. Aids. 2012;26:843-853 
24. 
Ellery PJ, Tippett E, Chiu YL, Paukovics G, Cameron PU, Solomon A, Lewin SR, Gorry 
PR, Jaworowski A, Greene WC, Sonza S, Crowe SM. The cd16+ monocyte subset is 
more permissive to infection and preferentially harbors hiv-1 in vivo. J Immunol. 
2007;178:6581-6589 
25. 
Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B, Espevik 
T, Ziegler-Heitbrock L. The proinflammatory cd14+cd16+dr++ monocytes are a major 
source of tnf. J Immunol. 2002;168:3536-3542 
26. 
Baker JV. The role of biomarkers for predicting outcomes in hiv-infection. 51st Annual 
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). 2011 
27. 
Sodora DL, Silvestri G. Immune activation and aids pathogenesis. Aids. 2008;22:439-
446 
28. 
Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, Dong T, Chesney G, 
Waters A, Easterbrook P, Dunbar PR, Shepherd D, Cerundolo V, Emery V, Griffiths P, 
Conlon C, McMichael AJ, Richman DD, Rowland-Jones SL, Appay V. Immune activation 
and cd8(+) t-cell differentiation towards senescence in hiv-1 infection. PLoS Biol. 
2004;2:E20 


 Protocol Version 3.0 
JAN 2017 
 
22
29. 
Weissman D, Barker TD, Fauci AS. The efficiency of acute infection of cd4+ t cells is 
markedly enhanced in the setting of antigen-specific immune activation. J Exp Med. 
1996;183:687-692 
30. 
Schacker T. The role of secondary lymphatic tissue in immune deficiency of hiv infection. 
Aids. 2008;22 Suppl 3:S13-18 
31. 
Kranzhofer R, Browatzki M, Schmidt J, Kubler W. Angiotensin ii activates the 
proinflammatory transcription factor nuclear factor-kappab in human monocytes. 
Biochem Biophys Res Commun. 1999;257:826-828 
32. 
Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin ii 
stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappab 
activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 
2000;20:645-651 
33. 
Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J. Angiotensin ii 
activates nuclear transcription factor kappab through at(1) and at(2) in vascular smooth 
muscle cells: Molecular mechanisms. Circ Res. 2000;86:1266-1272 
34. 
Ruperez M, Lorenzo O, Blanco-Colio LM, Esteban V, Egido J, Ruiz-Ortega M. 
Connective tissue growth factor is a mediator of angiotensin ii-induced fibrosis. 
Circulation. 2003;108:1499-1505 
35. 
Yoshiji H, Kuriyama S, Fukui H. Blockade of renin-angiotensin system in antifibrotic 
therapy. J Gastroenterol Hepatol. 2007;22 Suppl 1:S93-95 
36. 
Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, 
Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to aging. Clin Immunol. 
2008;127:107-118 
37. 
Aggarwal S, Gupta S. Increased apoptosis of t cell subsets in aging humans: Altered 
expression of fas (cd95), fas ligand, bcl-2, and bax. Journal of immunology. 
1998;160:1627-1637 
38. 
Baker JV, Peng G, Rabkin J, Krason D, Reilly C, Cavert WP, Abrams D, MacArthur RD, 
Henry WK, Neaton JD. Poor initial cd4+ recovery with antiretroviral therapy prolongs 
immune depletion and increases risk for aids and non-aids diseases. JAIDS. 2008;In 
Press 
39. 
Baker JV, Peng G, Rapkin J, Abrams D, Silverberg MJ, MacArthur RD, Cavert WP, 
Henry WK. Cd4+ count and risk of non-aids diseases following initial treatment for hiv 
infection. Aids. 2008;22:841-848 
40. 
Opportunistic Infections Project Team of the Collaboration of Observational HIVERiEiE, 
Young J, Psichogiou M, Meyer L, Ayayi S, Grabar S, Raffi F, Reiss P, Gazzard B, 
Sharland M, Gutierrez F, Obel N, Kirk O, Miro JM, Furrer H, Castagna A, De Wit S, 
Munoz J, Kjaer J, Grarup J, Chene G, Bucher H. Cd4 cell count and the risk of aids or 
death in hiv-infected adults on combination antiretroviral therapy with a suppressed viral 
load: A longitudinal cohort study from cohere. PLoS Med. 2012;9:e1001194 
41. 
Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, Gatell J, 
Rakhmanova A, Johnson M, Kirk O, Lundgren J, Euro SSG. Serious fatal and nonfatal 
non-aids-defining illnesses in europe. J Acquir Immune Defic Syndr. 2010;55:262-270 
42. 
Neuhaus J, Angus B, Kowalska JD, La Rosa A, Sampson J, Wentworth D, Mocroft A. 
Risk of all-cause mortality associated with nonfatal aids and serious non-aids events 
among adults infected with hiv. Aids. 2010;24:697-706 
43. 
Achhra AC, Amin J, Law MG, Emery S, Gerstoft J, Gordin FM, Vjecha MJ, Neaton JD, 
Cooper DA. Immunodeficiency and the risk of serious clinical endpoints in a well studied 
cohort of treated hiv-infected patients. Aids. 2010;24:1877-1886 
44. 
Phillips AN, Neaton J, Lundgren JD. The role of hiv in serious diseases other than aids. 
Aids. 2008;22:2409-2418 


 Protocol Version 3.0 
JAN 2017 
 
23
45. 
Weber R, Friis-Moller N, Sabin C, Reiss P, d'Arminio Monforte A, Dabis F, El-Sadr WM, 
de Wit S, Morfeldt L, Law MG, Pradier C, Calvo G, Holkmann-Olsen C, Phillips A, 
Lundgren JD. Hiv and non-hiv related deaths and their relationship to immunodeficiency:  
The d:A:D study. 12th Conference on Retrovirusews and Opportunistic Infections. 2005 
46. 
Barton OG, Neumann B, Stammler HG, Mattay J. Intramolecular direct arylation in an 
a,c-functionalized calix[4]arene. Org Biomol Chem. 2008;6:104-111 
47. 
Rommel D, Abarca-Quinones J, De Saeger C, Peeters F, Leclercq I, Duprez T. 
Enhanced choline metabolism in a rodent rhabdomyosarcoma model: Correlation 
between rt-pcr and translational 3 t h-mrs. Magn Reson Imaging. 2012;30:1010-1016 
48. 
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of c-reactive protein and 
low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. 
N Engl J Med. 2002;347:1557-1565 
49. 
Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins 
JP, Lennon L, Eiriksdottir G, Rumley A, Whincup PH, Lowe GD, Gudnason V. Long-term 
interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective 
studies and a systematic review. PLoS Med. 2008;5:e78 
50. 
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of 
inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 
2000;342:836-843 
51. 
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentrations of interleukin-
6 and the risk fo future myocardial infarction among apparently healthy men. Circulation. 
2000;101:1767-1772 
52. 
Armah KA, McGinnis K, Baker J, Gibert C, Butt AA, Bryant KJ, Goetz M, Tracy R, 
Oursler KA, Rimland D, Crothers K, Rodriguez-Barradas M, Crystal S, Gordon A, 
Kraemer K, Brown S, Gerschenson M, Leaf DA, Deeks SG, Rinaldo C, Kuller LH, 
Justice A, Freiberg M. Hiv status, burden of comorbid disease and biomarkers of 
inflammation, altered coagulation and monocyte activation. Clin Infect Dis. 2012;55:126-
136 
53. 
Neuhaus J, Jacobs DR, Baker JV, Calmy A, Duprez D, La Rosa A, Kuller LH, Pett S, 
Ristola M, Ross MJ, Shlipak MG, Tracy R, Neaton JD, for the INSIGHT SMART 
MaCRG. Markers of inflammation, coagulation, and renal function in hiv-infected adults 
in smart and in two large population-based cohorts. Journal of Infectious Diseases. 
2010;in press 
54. 
Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, 
Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD. Inflammatory and coagulation 
biomarkers and mortality in patients with hiv infection. PLoS Med. 2008;5:e203 
55. 
Tien PC, A.I. C, A.R. Z, C. B, Scherzer R, Bacchetti P, Shlipak M, Grunfeld C. 
Inflammation and mortality in hiv-infected adults:  Analysis of the fram study cohort. 17th 
Conference on Retroviruses and Opportunistic Infections (CROI). 2010;Abstract #725 
56. 
Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, 
Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I, 
Douek DC. Plasma levels of soluble cd14 independently predict mortality in hiv infection. 
J Infect Dis. 2011;203:780-790 
57. 
Triant VA, Meigs JB, Grinspoon SK. Association of c-reactive protein and hiv infection 
with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268-273 
58. 
Kaplan RC, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Hunt P, 
Karim R, Kern DM, Hodis HN, Deeks SG. T cell activation and senescence predict 
subclinical carotid artery disease in hiv-infected women. J Infect Dis. 2011;203:452-463 
59. 
Duprez D, Neuhaus J, Kuller L, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, 
Ledergerber B, Lundgren J, Nixon D, Paton NI, Prineas R, Neaton JD. Inflammation, 


 Protocol Version 3.0 
JAN 2017 
 
24
coagulation and cardiovascular disease in hiv-infected individuals PLoS One. 2012;in 
press 
60. 
Borges A, Silverberg MJ, Wentworth D, Grulich AE, Fatkenheuer G, Mitsuyasu R, 
Tambussi G, Sabin C, Neaton J, Lundgren J, Group ftISESS. Predicting risk of cancer 
during hiv infection: The role of inflammation and coagulation biomarkers. 14th 
International Workship on Co-morbidities and Adverse Drug Reactions in HIV. 2012 
61. 
Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane 
HC, Ledergerber B, Lundgren J, Nixon D, Paton NI, Prineas RJ, Neaton JD, Group ISS. 
Inflammation, coagulation and cardiovascular disease in hiv-infected individuals. PLoS 
One. 2012;7:e44454 
62. 
Grund B, Baker J, Deeks SG, Wolfson J, Wentworth D, Cozzi-Lepri A, Cohen C, Phillips 
A, Lundgren J, Neaton J, INSIGHT SMART/ESPRIT/SILCAAT Study Groups. Combined 
effect of interleukin-6 and d-dimer on the risk of serious non-aids conditions:  Data from 
3 prospective cohorts. 20th Conference on Retroviruses and Opportunistic Infections. 
2013;#60 
63. 
Borges AH, Silverberg MJ, Wentworth D, Grulich AE, Fatkenheuer G, Mitsuyasu R, 
Tambussi G, Sabin CA, Neaton JD, Lundgren JD, for the Insight Smart ESSG. 
Predicting risk of cancer during hiv infection: The role of inflammatory and coagulation 
biomarkers. Aids. 2013;27:1433-1441 
64. 
Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WHJ, Heimovitz H, 
Cohen HJ, Wallace R. Associations of elevated interleukin-6, c-reative protein levels with 
mortality in the elderly. American Journal of Medicine. 1999;106:506-512 
65. 
Folsom AR, Delaney JA, Lutsey PL, Zakai NA, Jenny NS, Polak JF, Cushman M. 
Associations of factor viiic, d-dimer, and plasmin-antiplasmin with incident cardiovascular 
disease and all-cause mortality. Am J Hematol. 2009;84:349-353 
66. 
Weber M. Clinical safety and tolerability of losartan. Clin Ther. 1997;19:604-616; 
discussion 603 
67. 
Han Y, Runge MS, Brasier AR. Angiotensin ii induces interleukin-6 transcription in 
vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa b 
transcription factors. Circ Res. 1999;84:695-703 
68. 
Brasier AR, Jamaluddin M, Han Y, Patterson C, Runge MS. Angiotensin ii induces gene 
transcription through cell-type-dependent effects on the nuclear factor-kappab (nf-
kappab) transcription factor. Mol Cell Biochem. 2000;212:155-169 
69. 
Bourcier T, Sukhova G, Libby P. The nuclear factor kappa-b signaling pathway 
participates in dysregulation of vascular smooth muscle cells in vitro and in human 
atherosclerosis. J Biol Chem. 1997;272:15817-15824 
70. 
Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of nf-kappa b. 
Annu Rev Cell Biol. 1994;10:405-455 
71. 
Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, Kluft C, Blann A, 
Cokkinos D, Ferrari R. Ace inhibition with perindopril and endothelial function. Results of 
a substudy of the europa study: Pertinent. Cardiovasc Res. 2007;73:237-246 
72. 
Ceconi C, Fox KM, Remme WJ, Simoons ML, Deckers JW, Bertrand M, Parrinello G, 
Kluft C, Blann A, Cokkinos D, Ferrari R. Ace inhibition with perindopril and biomarkers of 
atherosclerosis and thrombosis: Results from the pertinent study. Atherosclerosis. 
2009;204:273-275 
73. 
Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin ii and inflammation: The 
effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockade. J 
Hum Hypertens. 2007;21:20-27 
74. 
Garcia F, Vidal C, Gatell JM, Miro JM, Soriano A, Pumarola T. Viral load in 
asymptomatic patients with cd4+ lymphocyte counts above 500 x 10(6)/l. AIDS. 
1997;11:53-57 


 Protocol Version 3.0 
JAN 2017 
 
25
75. 
Boston: Important trial of treatment vaccine, cd4 over 500. AIDS Treat News. 1995:4-5 
76. 
Merino A, Alvarez-Lara MA, Ramirez R, Carracedo J, Martin-Malo A, Aljama P. Losartan 
prevents the development of the pro-inflammatory monocytes cd14+cd16+ in 
haemodialysis patients. Nephrol Dial Transplant. 2012 
77. 
Miyoshi M, Miyano K, Moriyama N, Taniguchi M, Watanabe T. Angiotensin type 1 
receptor antagonist inhibits lipopolysaccharide-induced stimulation of rat microglial cells 
by suppressing nuclear factor kappab and activator protein-1 activation. Eur J Neurosci. 
2008;27:343-351 
78. 
Chapman LE, Green TA, Ahmed F, Parekh BS, Rimland D, Kaplan JE, Thompson MA, 
Folks TM. Effect of clinical events on plasma hiv-1 rna levels in persons with cd4+ t-
lymphocyte counts of more than 500 x 10(6) cells/l. AIDS. 2000;14:1135-1146 
79. 
Larrayoz IM, Pang T, Benicky J, Pavel J, Sanchez-Lemus E, Saavedra JM. Candesartan 
reduces the innate immune response to lipopolysaccharide in human monocytes. J 
Hypertens. 2009;27:2365-2376 
80. 
Schacker TW, Nguyen PL, Beilman GJ, Wolinsky S, Larson M, Reilly C, Haase AT. 
Collagen deposition in hiv-1 infected lymphatic tissues and t cell homeostasis. The 
Journal of clinical investigation. 2002;110:1133-1139 
81. 
Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, Larson M, Haase 
AT. Amount of lymphatic tissue fibrosis in hiv infection predicts magnitude of haart-
associated change in peripheral cd4 cell count. AIDS. 2005;19:2169-2171 
82. 
Piconi S, Parisotto S, Rizzardini G, Passerini S, Meraviglia P, Schiavini M, Niero F, 
Biasin M, Bonfanti P, Ricci ED, Trabattoni D, Clerici M. Atherosclerosis is associated 
with multiple pathogenic mechanisms in hiv-infected antiretroviral-naive or treated 
individuals. AIDS. 2013;27:381-389 
83. 
Healy CM, Baker CJ. Infant pertussis: What to do next? Clinical infectious diseases : an 
official publication of the Infectious Diseases Society of America. 2012;54:328-330 
84. 
Boffa JJ, Lu Y, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C. Regression of 
renal vascular and glomerular fibrosis: Role of angiotensin ii receptor antagonism and 
matrix metalloproteinases. J Am Soc Nephrol. 2003;14:1132-1144 
85. 
Lim DS, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian 
AJ. Angiotensin ii blockade reverses myocardial fibrosis in a transgenic mouse model of 
human hypertrophic cardiomyopathy. Circulation. 2001;103:789-791 
86. 
el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O, Ghoneim MA. 
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;23:300-306 
87. 
Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis. Hypertension. 
2001;38:635-638 
88. 
Young J, Psichogiou M, Meyer L, Ayayi S, Grabar S, Raffi F, Reiss P, Gazzard B, 
Sharland M, Gutierrez F, Obel N, Kirk O, Miro JM, Furrer H, Castagna A, De Wit S, 
Munoz J, Kjaer J, Grarup J, Chene G, Bucher H. Cd4 cell count and the risk of aids or 
death in hiv-infected adults on combination antiretroviral therapy with a suppressed viral 
load: A longitudinal cohort study from cohere. PLoS medicine. 2012;9:e1001194 
89. 
Boffa JJ, Lu Y, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C. Regression of 
renal vascular and glomerular fibrosis: Role of angiotensin ii receptor antagonism and 
matrix metalloproteinases. Journal of the American Society of Nephrology : JASN. 
2003;14:1132-1144 
90. 
Molina-Molina M, Serrano-Mollar A, Bulbena O, Fernandez-Zabalegui L, Closa D, Marin-
Arguedas A, Torrego A, Mullol J, Picado C, Xaubet A. Losartan attenuates bleomycin 
induced lung fibrosis by increasing prostaglandin e2 synthesis. Thorax. 2006;61:604-610 


 Protocol Version 3.0 
JAN 2017 
 
26
91. 
Masutomo K, Makino N, Fushiki MS. Effects of losartan on the collagen degradative 
enzymes in hypertrophic and congestive types of cardiomyopathic hamsters. Mol Cell 
Biochem. 2001;224:19-27 
92. 
Koh KK, Chung WJ, Ahn JY, Han SH, Kang WC, Seo YH, Ahn TH, Choi IS, Shin EK. 
Angiotensin ii type 1 receptor blockers reduce tissue factor activity and plasminogen 
activator inhibitor type-1 antigen in hypertensive patients: A randomized, double-blind, 
placebo-controlled study. Atherosclerosis. 2004;177:155-160 
93. 
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC, 3rd. Angiotensin ii 
blockade and aortic-root dilation in marfan's syndrome. The New England journal of 
medicine. 2008;358:2787-2795 
94. 
Baker JV, Huppler Hullsiek K, Prosser R, Duprez D, Grimm R, Tracy RP, Rhame F, 
Henry K, Neaton JD. Angiotensin converting enzyme inhibitor and hmg-coa reductase 
inhibitor as adjunct treatment for persons with hiv infection: A feasibility randomized trial. 
PLoS One. 2012;7:e46894 
95. 
Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am 
J Hypertens. 2001;14:44S-54S 
96. 
Sakkinen PA, Macy EM, Callas PW, Cornell ES, Hayes TE, Kuller LH, Tracy RP. 
Analytical and biologic variability in measures of hemostasis, fibrinolysis, and 
inflammation: Assessment and implications for epidemiology. Am J Epidemiol. 
1999;149:261-267 
97. 
Cushman M, Cornell ES, Howard PR, Bovill EG, Tracy RP. Laboratory methods and 
quality assurance in the cardiovascular health study. Clin Chem. 1995;41:264-270 
98. 
Jenny NS, Arnold AM, Kuller LH, Sharrett AR, Fried LP, Psaty BM, Tracy RP. Soluble 
intracellular adhesion molecule-1 is associated with cardiovascular disease risk and 
mortality in older adults. J Thromb Haemost. 2006;4:107-113 
99. 
Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma 
concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial 
infarction in apparently healthy men. Lancet. 1998;351:88-92 
100. 
Hwang PM, Ballantyne CM, Sharrett AR, al. e. Circulating adhesion molecules vcam-1, 
icam-1, and e-selectin in carotid atherosclerosis and incident coronary heart disease 
cases:  The atherosclerosis risk in communities (aric) study. Circulation. 1997;96:4219-
4225 
101. 
Tracy RP. Epidemiological evidence for inflammation in cardiovascular disease. 
Thrombosis and Haemostasis. 1999;82:826-831 
102. 
Ford ES, Greenwald JH, Richterman AG, Rupert A, Dutcher L, Badralmaa Y, Natarajan 
V, Rehm C, Hadigan C, Sereti I. Traditional risk factors and d-dimer predict incident 
cardiovascular disease events in chronic hiv infection. Aids. 2010;24:1509-1517 
103. 
Schacker TW, Brenchley JM, Beilman GJ, Reilly C, Pambuccian SE, Taylor J, Skarda D, 
Larson M, Douek DC, Haase AT. Lymphatic tissue fibrosis is associated with reduced 
numbers of naive cd4+ t cells in human immunodeficiency virus type 1 infection. Clin 
Vaccine Immunol. 2006;13:556-560 
104. 
Estes J, Baker JV, Brenchley JM, Khoruts A, Barthold JL, Bantle A, Reilly CS, Beilman 
GJ, George ME, Douek DC, Haase AT, Schacker TW. Collagen deposition limits 
immune reconstitution in the gut. J Infect Dis. 2008;198:456-464 
105. 
Martin GE, Gouillou M, Hearps AC, Angelovich TA, Cheng AC, Lynch F, Cheng WJ, 
Paukovics G, Palmer CS, Novak RM, Jaworowski A, Landay AL, Crowe SM. Age-
associated changes in monocyte and innate immune activation markers occur more 
rapidly in hiv infected women. PLoS One. 2013;8:e55279 
106. 
Sullivan AK, Raben D, Reekie J, Rayment M, Mocroft A, Esser S, Leon A, Begovac J, 
Brinkman K, Zangerle R, Grzeszczuk A, Vassilenko A, Hadziosmanovic V, Krasnov M, 
Sonnerborg A, Clumeck N, Gatell J, Gazzard B, Monforte A, Rockstroh J, Lundgren JD. 


 Protocol Version 3.0 
JAN 2017 
 
27
Feasibility and effectiveness of indicator condition-guided testing for hiv: Results from 
hides i (hiv indicator diseases across europe study). PLoS One. 2013;8:e52845 
107. 
Ebell MH, Lundgren J, Youngpairoj S. How long does a cough last? Comparing patients' 
expectations with data from a systematic review of the literature. Ann Fam Med. 
2013;11:5-13 
 
 


 Protocol Version 3.0 
JAN 2017 
 
1 
APPENDIX A:  BLOOD/URINE SPECIMEN COLLECTION AND STORAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated: August 2014 
 
 
Screening  
Baseline 
Follow-up*   
Month (M) of Study 
 
 
M 0 
M 1 
M 3 
M 6 
M 9 
M 12 
Clinical 
Tube Type (for draw) 
mL (#tubes) 
mL (#tubes) 
mL (#tubes) 
mL (#tubes) 
mL (#tubes) 
mL (#tubes) 
mL (#tubes) 
CD4 count +/- CBC 
4mL (EDTA) lavender 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
BMP, hepatic panel, 
and/or lipid panel 
5mL green  
5 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
4 (1) 
Pregnancy, urine/serum 
 
X 
X 
-- 
X 
X 
X 
X 
HBsAg, HCV Ab  
4mL (serum) red  
-- 
2 (1) 
-- 
-- 
-- 
-- 
-- 
HIV RNA level 
10mL (EDTA) lavender  
5 (1) 
-- 
-- 
5 (1) 
5 (1) 
5 (1) 
5 (1) 
Blood for Storage 
Tube Type (for draw) 
 
 
 
 
 
 
 
PBMC  
8-10mL ACD tube 
-- 
40-50 (5) 
-- 
-- 
40-50 (5) 
-- 
40-50 
(5) 
Serum 
4.5mL SST 
-- 
4 (1) 
-- 
4 (1) 
-- 
4 (1) 
-- 
Platelet Poor Plasma 
10mL (EDTA) lavender 
8-10 (1) 
24 (3) 
24 (3) 
24 (3) 
24 (3) 
24 (3) 
24 (3) 
Platelet Poor Plasma 
4.5mL (NaCitrate) blue  
-- 
8 (2) 
8 (2) 
-- 
8 (2) 
-- 
8 (2) 
Whole Blood Storage 
[take from NaCitrate 
tube prior to 
processing] 
-- 
 
 
-- 
 
-- 
 
Daily Blood Volume (mL) 
 
≤25 
≤100 
≤40 
≤50 
≤110 
≤40 
≤110 
Cryovials for Storage 
(Tube Type for Draw) 
# vials 
# vials 
# vials 
# vials 
# vials 
# vials 
# vials 
  Serum 
SST 
 
2 
 
2 
 
2 
 
  PP Plasma 
EDTA 
4 
8 
8 
8 
8 
8 
8 
  PP Plasma 
NaCitrate 
 
2 
2 
 
2 
 
2 
  Whole blood 
NaCitrate 
 
2 
1 
 
1 
 
1 
  Urine 
Urine Collection  
 
1 
 
 
1 
 
1 
Cryovials Totals (74) 
 
4 
15 
11 
10 
12 
10 
12 
  
*NOTE:  week 2 visit will collect BMP (5mL green tube) for clinical toxicity assessment, but no additional blood collection for processing or storage 
 


 
 
 
 
 
 
 
 
 
 
APPENDIX B:  INFORMED CONSENT FORM (ICF) – WITH LN BIOPSY 
 
Protocol Name: Losartan to reduce Inflammation and Fibrosis Endpoints in HIV 
 
Short Title: 
LIFE-HIV 
 
Funding: 
National Institute of Aging / National Institutes of Health 
 
Merck Pharmaceuticals (study drug) 
 
Site: 
[SITE] 
 
Investigators:   
[SITE INVESTIGATOR(S)] 
 
CONSENT FOR PARTICIPATING IN AN NIA/NIH-FUNDED RESEARCH TRIAL 
 
INTRODUCTION AND PURPOSE: WHY IS THIS STUDY BEING DONE? 
You are invited to be in a research study that looks at the use of a medication that may 
improve the health of HIV positive people who are already on HIV medicines. The 
medication (losartan, or COZAAR) is approved by the Food and Drug Administration (FDA), 
but not for treatment of HIV infection; it is commonly used to treat high blood pressure.  
However, this medication may help address some of the damage that HIV causes in the 
body.  One hundred HIV positive patients will be enrolled in this study, at 5 clinical sites in 
the U.S.  
 
Damage caused by HIV infection results in problems with the immune system.  These 
problems cannot be fully corrected, even with effective treatment using antiretroviral 
medications.  One of these problems is inflammation. ‘Inflammation’ occurs when the 
body’s immune system is responding to injury or infection.  Inflammation can be helpful in 
the short term, but when it is persistent it can also cause more damage to the body over 
time.  HIV also damages the immune system by causing scarring in tissues such as lymph 
nodes.  This scarring limits recovery of the immune system after treatment with 
antiretroviral therapy is started.   
 
Ongoing inflammation and damage to the immune system is thought to contribute to risk for 
heart disease and cancer among HIV positive persons.  This study will determine if 
losartan, a commonly used medication for blood pressure, reduces inflammation and 
improves immune recovery (possibly by reducing scarring in lymph nodes).   
 
YOUR PARTICIPATION IS VOLUNTARY  
This consent form gives you information about the clinical research study that will be 
discussed with you.  Once you understand the study, and if you agree to take part, you will 
be asked to sign this consent form. You will be given a copy to keep.  
 
Before you learn about the study, it is important that you know the following: 
Your participation is entirely voluntary.  
 


 
 
 
 
 
 
 
 
 
 
You may decide not to take part or to withdraw from the study at any time without losing the 
benefits of your routine medical care. 
 
Eligibility:  Who is being asked to be part of this research study? 
You may be eligible for this study if you are over age 50, you have HIV infection, you are 
doing well with taking your antiretroviral medications, and you do not have contraindications 
to study procedures.  Your HIV ‘viral load’ must be undetectable.  If your doctor or the study 
investigators feel that it would not be safe to take the study medication then you will not be 
eligible to participate. Some factors that could make you ineligible for this study include low 
blood pressure, chronic inflammatory disease, and liver or kidney disease. 
 
HOW LONG WILL YOU BE IN THE STUDY? 
The study will last approximately 12 months.  After the screening visit, if you qualify, you 
will come in for a ‘baseline’ study visit, receive a blood draw after 2 weeks and then a 
follow-up visit at 1, 3, 6, 9, and 12 months. 
 
HOW WILL THE STUDY WORK? 
If you agree to participate in this study, you will be randomly assigned (like flipping a coin) 
to start either losartan or a placebo (inactive pill) for 12 months. Neither you, nor the study 
investigators, will know which study medication you will take.  You will start out taking 50mg 
of losartan or matching placebo.  If you are not having any problems after 2 weeks, the 
dose will be increased to 100mg of losartan or matching placebo for the duration of the 
study.  
 
PROCEDURES:  WHAT DO YOU HAVE TO DO IF YOU ARE IN THIS STUDY? 
 
Screening visit: 
You will be asked to come in for a screening visit, where your study investigators will review 
the study procedures and this consent form.  If you agree to participate, you will have your 
blood drawn (approximately 2 tablespoons) and medical history reviewed (similar to a 
routine clinic visit) to determine if you are eligible to participate.  If you meet study criteria, 
you will then return within 2 months to begin the study. 
 
Baseline and follow-up (month 1, 3, 6, 9, 12) clinic study visits: 
The baseline and follow-up clinical visit will last approximately 1-2 hours, and will consist of: 
 
Medical History: You will be interviewed to review your medical history and assess your risk 
for developing heart disease.  We will also access your medical chart to obtain the results 
of recent lab tests and medications you are taking.  
 
Blood Draw:  We will obtain a blood sample (up to 8 tablespoons) from a vein in your arm.  
The total blood draw volumes per visit will be less than 100 mL.  You must be fasting for at 
least 6 hours prior to having your blood drawn at study visits. Blood samples will be used to 
measure markers in the blood related to inflammation and other markers that may 
contribute to heart disease and other complications of HIV infection.  These samples may 
be stored for up to 20 years. 


 
 
 
 
 
 
 
 
 
 
 
At the baseline visit, you will start taking losartan (or placebo). You will take 1 tablet (50 
mg) every day, until a member of the study team tells you to stop or changes your dose. 
The nurses will give you the study medicine during your clinic visits. At follow-up visits you 
will be asked to bring in all of your study medication, and adherence and tolerability to the 
treatment will be assessed. 
 
Blood draw at week 2: 
Two weeks after you start taking study medication (at baseline), you will be asked to have 
your blood drawn to make sure you are not having significant toxicity from the study 
medication.  You will also be asked several questions to determine if you are experiencing 
any side effects.  If the study investigators determine that you are not having any toxicity or 
side effects, the dose of the study medication will be increased from 50mg to 100mg at (or 
immediately after) this visit. 
 
Biopsy procedure visits (baseline and month 12): 
If you agree to a lymph node biopsy and study investigators can palpate a candidate lymph 
node to biopsy, a surgeon will collect a lymph node from your groin twice during the study.  
This procedure will occur after or very close to the baseline and month 12 study visits.  The 
purpose of this biopsy is to see if losartan reduces scarring in immune system tissue, that 
in-turn improves recovery of immune cells (such as T-cells). 
 
Lymph node biopsies of your groin will be done at [the University of Minnesota or NIH 
Clinical Center]. The actual surgery will only take 30-40 minutes but the visit will take 
approximately 6 hours. You should not eat or drink anything for at least 6 hours before 
surgery. You will be given one dose of an oral antibiotic 30 minutes prior to the biopsy. 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 about 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 approximately 6 hours. 
 
Three days after the procedure you will 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.  The surgeon will advise you 
as to the best way to manage stitches that are in place.  
 
Physical function test (baseline, month 6 and month 12): 


 
 
 
 
 
 
 
 
 
 
We will also ask you to perform a short physical function test at three times during the 
study.  The first test is grip strength.  You will be asked to squeeze a hand held device for a 
few seconds that measures the force you can generate. The second test involves having 
you walk a short distance of four meters at your usual pace.  This will be done twice.  
These physical functions tests will take 5 minutes. 
 
STORED SAMPLES 
During your participation in this study, blood will be collected by standard blood drawing 
techniques.  Lymph node tissue will be collected by biopsy.  
 
Samples will be used to evaluate the potential benefits of losartan. Additional samples will 
be stored up to 20 years for future research.  These samples can help us learn more about 
HIV, AIDS, immune function, inflammation, fibrosis (scarring), or other related diseases.  In 
general, the research tests we perform are not like routine medical tests and may not relate 
directly to your medical care.  For this reason, we may not put future test results in your 
medical record or share these test results with your medical provider 
 
Genetic Testing 
Future research on stored samples might involve genetic testing.  Genetic testing may tell 
researchers something about how health or illness is passed on to you by your parents or 
from you to your children. Some genetic information, such as the ability to make certain 
proteins in the body, has been associated with an increased risk of certain diseases like 
arthritis.  
 
Any genetic information collected or discovered about you or your family will be 
confidential. Genetic information about you will not be revealed to others, including your 
relatives, without your permission. We will not release any information about you or your 
family to any insurance company or employer unless you sign a document allowing release 
of information.  
 
HOW WILL YOU GET MEDICINES FOR THE STUDY? 
Study medications will be provided to you by the study and will be distributed by study 
nurses during study visits.   You will be provided with sufficient supply to last the duration of 
the study.  You will be asked to return any unused study medication, including empty 
containers. 
 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF THIS STUDY? 
 
You will be monitored for side effects at each visit, and your lab tests will include an 
evaluation for signs of medication toxicity. 
 
Risks of Study Procedures 
You will have your blood drawn at each study visit. This is identical to having your blood 
drawn at a medical clinic, and can involve discomfort, light-headedness and/or minor 
bruising. 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. We do not expect that losartan will interact with any of your HIV medicines.  In 
clinical studies, most of these side effects were no more common than what was 
experienced with placebo medication. 
 
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 woman of 
childbearing potential, 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 for the duration of the study period, such as a barrier method or spermicide. 
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 site investigator or a 
study nurse immediately. We will ask that you return any study medication. We will ask 
permission to contact you at the end of the pregnancy to check on the health of you and the 
baby. 
 
Lymph Node Biopsies 
If you have agreed to a lymph node biopsy, the 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 1-2 percent. There is the 
possibility you might develop a seroma, which is a collection of fluid under the skin and 
around the wound.  This is also very rare. 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 does happen on 
occasion. 
 
Physical Function Tests 
You may fall during the short 4-meter walk.  If you feel unable to perform any of the walk 
test or grip strength test, you will not need to perform them. We will not ask you to perform 
any activities that put you at more than a minimal risk of falling or injuring yourself. 
 
WHAT ABOUT PREGNANCY AND BREASTFEEDING? 
If you are pregnant, breastfeeding or planning to become pregnant, you will not be eligible 
for this study.  If you become pregnant during the study, you will be asked to stop study 
medications and withdraw.  Therefore, if it is possible that you could become pregnant, we 
ask that you use a reliable form of birth control for the duration of the study (listed above in 
‘Study Medication’). 
 


 
 
 
 
 
 
 
 
 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
If you take part in this study, there are no anticipated benefits to your health.  The research 
has the potential to benefit people with HIV infection, after the study is completed and the 
findings are analyzed.   
  
COMPENSATION 
You will be paid $XX for each study visit you attend after the screening visit.  You will 
receive $XXX for each biopsy of a groin lymph node you complete. If you complete two 
study-related lymph node biopsies, you may receive a total of $XXX for participating in the 
study.  Study investigators may ask for your social security number as part of the 
monitoring process for this compensation. 
 
WHAT IF THERE ARE NEW FINDINGS? 
We will not be analyzing data during the study.  However, 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.  You may 
request your own results after the study by contacting the research investigators.  
 
WHAT IF YOU DON’T WANT TO BE IN THE STUDY ANY LONGER?  
If you enroll in this study, you may decide to stop participating at any time.  Withdrawing 
from this study will not affect the benefits of your regular medical care.   
 
CAN YOUR STUDY PARTICIPATION BE STOPPED WITHOUT YOUR CONSENT?  
You may be taken off of study medicines before the end of the study if investigators or your 
doctor recommend this.  You may be taken off the entire study without your consent if: 
 Your study doctor decides that continuing in the study would harm you; 
 Your lab results indicate that you are experiencing toxicity from study medications; 
 
WHAT OTHER CHOICES DO YOU HAVE BESIDES THIS STUDY?  
You may discuss other strategies for improving your health with your doctor.  
 
WHAT ARE THE COSTS TO YOU? 
The medications that are part of this study will be provided free-of-cost to you, and will be 
distributed during study visits.   During the study, you, your insurance company, or some 
other third-party payer must pay for all other medicines, including HIV medicines not paid 
by the study and medicines needed to prevent or treat other illnesses.  We will provide all 
clinical and professional services, lab work, and other tests that are part of this study and 
not part of your regular care at no cost to you.   
 
HOW IS YOUR PRIVACY PROTECTED?  
Any information that could be used to identify you will be treated in strict confidence to the 
extent allowed by law.  Nevertheless, some uses and disclosures of your information are 
necessary to conduct the study.  If you agree to be part of this study, you will also be 
allowing the uses and disclosures of your private health information as needed for the 
purposes of this study as described in this consent.  
 


 
 
 
 
 
 
 
 
 
 
“Private health information” means information that identifies you and is collected: 
 during this study; 
 from your past and current medical records maintained by your regular health care 
providers, to the extent the information is relevant to this study or to your eligibility for 
this study; or 
 from any payment records relating to items or services furnished to you during this 
study. 
 
By signing this consent, you are agreeing that your private health information may be 
disclosed to and used by: 
 the doctors and other health care providers involved in this study; 
 their staff;  
 the research center; 
 members of this institution’s Human Subjects Research Committee/Institutional Review 
Board; 
 Merck Pharmaceuticals; 
 the sponsor of this study and its agents; and 
 monitors from the United States Government and/or Food and Drug Administration 
(FDA). 
 
The findings of this study may be used for scientific meetings, written reports, and 
publications, but no information that could be used to identify you will be disclosed for these 
purposes. 
 
Once your private health information has been disclosed to a third party, federal privacy 
laws may no longer protect it from re-disclosure.  However, anyone obtaining access to 
your private health information under this consent must agree to protect your information as 
required by this consent.   
 
This consent to use your private health information as described above does not expire. 
However, if you later change your mind, you can revoke this consent by writing to [SITE 
INVESTIGATOR] saying that you no longer wish to allow your private health information to 
be used for this study.  If you revoke your consent, you may no longer be able to participate 
in the study.  Moreover, we cannot undo uses or disclosures of your private health 
information that have already taken place in reliance on your prior consent. 
 
PLEASE NOTE: 
In the event of a positive result for Hepatitis B or C, reporting of the results to the 
local state Department of Health may be required. 
 
WHAT IF YOU ARE INJURED?  
If you are injured as a result of being in this study, you will be given immediate treatment.  
The cost for treatment will be charged to you or your insurance company.  There is no 
program through this institution to compensate participants who have research related 
injuries. You will not be giving up any of your legal rights by signing this consent. 
 


 
 
 
 
 
 
 
 
 
 
WHAT IF YOU HAVE PROBLEMS OR QUESTIONS?  
If you ever have questions or in the case of research-related injuries, you should contact:  
 
[LIST STUDY INVESTIGATORS] 
 
If you have questions about research subject’s rights you can contact: 
 
[SITE IRB CONTACT INCLUDING PHONE NUMBER] 
 
RESEARCH STUDY REGISTRY 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Website will not include information that can identify you.  At 
most, the Website will include a summary of the results.  You can search this Website at 
anytime. 


 
 
 
 
 
 
 
 
 
 
SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE LIFE-HIV STUDY  
 
If tissue samples are not fully used for this study, do you consent to allow further study of 
these specimens beyond this study: 
 
☐ YES ☐ NO 
 
I have read this consent form, had the opportunity to ask questions and have received 
answers to any questions I have asked.  I willingly give my consent to participate in this 
study, and authorize the use and disclosure of my health information as described in this 
form.  By signing this consent form I do not give up any of my legal rights.  Upon signing 
this form I will be given a signed copy of the form for my records. 
 
If you have read the consent (or if you have had it explained to you) and understand the 
information, and you voluntarily agree to join this study, please sign your name below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
______________________ 
 
___________ 
Participant’s name  
 
Participant’s signature 
 
 
Date 
(typed or printed) 
 
 
 
_________________________________ 
 
 
_______________  
 
Person obtaining consent  
 
 
 
 
Date 


 
 
 
 
 
 
 
 
 
 
APPENDIX C:  INFORMED CONSENT FORM (ICF) – WITHOUT BIOPSY 
 
Protocol Name: Losartan to reduce Inflammation and Fibrosis Endpoints in HIV 
 
Short Title: 
LIFE-HIV 
 
Funding: 
National Institute of Aging / National Institutes of Health 
 
Merck Pharmaceuticals (study drug) 
 
Site: 
[SITE] 
 
Investigators:   
[SITE INVESTIGATOR(S)] 
 
CONSENT FOR PARTICIPATING IN AN NIA/NIH-FUNDED RESEARCH TRIAL 
 
INTRODUCTION AND PURPOSE: WHY IS THIS STUDY BEING DONE? 
You are invited to be in a research study that looks at the use of a medication that may 
improve the health of HIV positive people who are already on HIV medicines. The 
medication (losartan, or COZAAR) is approved by the Food and Drug Administration (FDA), 
but not for treatment of HIV infection; it is commonly used to treat high blood pressure.  
However, this medication may help address some of the damage that HIV causes in the 
body.  One hundred HIV positive patients will be enrolled in this study, at 5 clinical sites in 
the U.S.  
 
Damage caused by HIV infection results in problems with the immune system.  These 
problems cannot be fully corrected, even with effective treatment using antiretroviral 
medications.  One of these problems is inflammation. ‘Inflammation’ occurs when the 
body’s immune system is responding to injury or infection.  Inflammation can be helpful in 
the short term, but when it is persistent it can also cause more damage to the body over 
time.  HIV also damages the immune system by causing scarring in tissues such as lymph 
nodes.  This scarring limits recovery of the immune system after treatment with 
antiretroviral therapy is started.   
 
Ongoing inflammation and damage to the immune system is thought to contribute to risk for 
heart disease and cancer among HIV positive persons.  This study will determine if 
losartan, a commonly used medication for blood pressure, reduces inflammation and 
improves immune recovery (possibly by reducing scarring in lymph nodes).   
 
YOUR PARTICIPATION IS VOLUNTARY  
This consent form gives you information about the clinical research study that will be 
discussed with you.  Once you understand the study, and if you agree to take part, you will 
be asked to sign this consent form. You will be given a copy to keep.  
 
Before you learn about the study, it is important that you know the following: 
Your participation is entirely voluntary.  
 


 
 
 
 
 
 
 
 
 
 
You may decide not to take part or to withdraw from the study at any time without losing the 
benefits of your routine medical care. 
 
Eligibility:  Who is being asked to be part of this research study? 
You may be eligible for this study if you are over age 50, you have HIV infection, you are 
doing well with taking your antiretroviral medications, and you do not have contraindications 
to study procedures.  Your HIV ‘viral load’ must be undetectable.  If your doctor or the study 
investigators feel that it would not be safe to take the study medication then you will not be 
eligible to participate. Some factors that could make you ineligible for this study include low 
blood pressure, chronic inflammatory disease, and liver or kidney disease. 
 
HOW LONG WILL YOU BE IN THE STUDY? 
The study will then last approximately 12 months. After the screening visit, if you qualify, 
you will come in for a ‘baseline’ study visit, receive a blood draw after 2 weeks and then a 
follow-up visit at 1, 3, 6, 9, and 12 months. 
 
HOW WILL THE STUDY WORK? 
If you agree to participate in this study, you will be randomly assigned (like flipping a coin) 
to start either losartan or a placebo (inactive pill) for 12 months. Neither you, nor the study 
investigators, will know which study medication you will take.  You will start out taking 50mg 
of losartan or matching placebo. If you are not having any problems after 2 weeks, your 
dose will be increased to 100mg of losartan or matching placebo for the duration of the 
study.  
 
PROCEDURES:  WHAT DO YOU HAVE TO DO IF YOU ARE IN THIS STUDY? 
 
Screening visit: 
You will be asked to come in for a screening visit, where your study investigators will review 
the study procedures and this consent form.  If you agree to participate, you will have your 
blood drawn (approximately 2 tablespoons) and medical history reviewed (similar to a 
routine clinic visit) to determine if you are eligible to participate.  If you meet study criteria, 
you will then return within 2 months to begin the study. 
 
Baseline and follow-up (month 1, 3, 6, 9, 12) clinic study visits: 
The baseline and follow-up clinical visit will last approximately 1-2 hours, and will consist of: 
 
Medical History: You will be interviewed to review your medical history and assess your risk 
for developing heart disease.  We will also access your medical chart to obtain the results 
of recent lab tests and medications you are taking.  
 
Blood Draw:  We will obtain a blood sample (up to 7-8 tablespoons) from a vein in your 
arm.  The total blood draw volumes per visit will be less than 100 mL.  You must be fasting 
for at least 6 hours prior to having your blood drawn at study visits. Blood samples will be 
used to measure markers in the blood related to inflammation and other markers that may 
contribute to heart disease and other complications of HIV infection.  These samples may 
be stored for up to 20 years. 


 
 
 
 
 
 
 
 
 
 
 
At the baseline visit, you will start taking losartan (or placebo). You will take 1 tablet (50 
mg) every day, until a member of the study team tells you to stop or changes your dose. 
The nurses will give you the study medicine during your clinic visits. At follow-up visits you 
will be asked to bring in all of your study medication, and adherence and tolerability to the 
treatment will be assessed. 
 
Blood draw at week 2: 
Two weeks after you start taking study medication (at baseline), you will be asked to have 
your blood drawn to make sure you are not having significant toxicity from the study 
medication.  You will also be asked several questions to determine if you are experiencing 
any side effects.  If the study investigators determine that you are not having any toxicity or 
side effects, the dose of the study medication will be increased from 50mg to 100mg at (or 
immediately after) this visit. 
 
Physical function assessments (baseline, month 6 and month 12): 
We will also ask you to perform a short physical function test at three times during the 
study.  The first test is grip strength.  You will be asked to squeeze a hand held device for a 
few seconds that measures the force you can generate. The second test involves having 
you walk a short distance of four meters at your usual pace.  This will be done twice.  
These physical functions tests will take 5 minutes. 
 
STORED SAMPLES 
During your participation in this study, blood will be collected by standard blood drawing 
techniques.  
 
Samples will be used to evaluate the potential benefits of losartan. Additional samples will 
be stored up to 20 years for future research.  These samples can help us learn more about 
HIV, AIDS, immune function, inflammation, fibrosis (scarring), or other related diseases.  In 
general, the research tests we perform are not like routine medical tests and may not relate 
directly to your medical care.  For this reason, we may not put future test results in your 
medical record or share these test results with your medical provider 
 
Genetic Testing 
Future research on stored samples might involve genetic testing.  Genetic testing may tell 
researchers something about how health or illness is passed on to you by your parents or 
from you to your children. Some genetic information, such as the ability to make certain 
proteins in the body, has been associated with an increased risk of certain diseases like 
arthritis.  
 
Any genetic information collected or discovered about you or your family will be 
confidential. Genetic information about you will not be revealed to others, including your 
relatives, without your permission. We will not release any information about you or your 
family to any insurance company or employer unless you sign a document allowing release 
of information.  
 


 
 
 
 
 
 
 
 
 
 
HOW WILL YOU GET MEDICINES FOR THE STUDY? 
Study medications will be provided to you by the study and will be distributed by study 
nurses during study visits.   You will be provided with sufficient supply to last the duration of 
the study.  You will be asked to return any unused study medication, including empty 
containers. 
 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF THIS STUDY? 
 
You will be monitored for side effects at each visit, and your lab tests will include an 
evaluation for signs of medication toxicity. 
 
Risks of Study Procedures 
You will have your blood drawn at each study visit. This is identical to having your blood 
drawn at a medical clinic, and can involve discomfort, light headedness and/or minor 
bruising. 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. We do not expect that losartan will interact with any of your HIV medicines.  In 
clinical studies, most of these side effects were no more common than what was 
experienced with placebo medication. 
 
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 woman of 
childbearing potential, 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 for the duration of the study period, such as a barrier method or spermicide. 
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 site investigator or a 
study nurse immediately. We will ask that you return any study medication. We will ask 
permission to contact you at the end of the pregnancy to check on the health of you and the 
baby. 
 
Physical Function Tests 
You may fall during the short 4-meter walk.  If you feel unable to perform any of the walk 
test or grip strength test, you will not need to perform them. We will not ask you to perform 
any activities that put you at more than a minimal risk of falling or injuring yourself. 
 
WHAT ABOUT PREGNANCY AND BREASTFEEDING? 
If you are pregnant, breastfeeding or planning to become pregnant, you will not be eligible 
for this study.  If you become pregnant during the study, you will be asked to stop study 


 
 
 
 
 
 
 
 
 
 
medications and withdraw.  Therefore, if it is possible that you could become pregnant, we 
ask that you use a reliable form of birth control for the duration of the study (listed above in 
‘Study Medication’). 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
If you take part in this study, there are no anticipated benefits to your health.  The research 
has the potential to benefit people with HIV infection, after the study is completed and the 
findings are analyzed.   
  
COMPENSATION 
You will be paid $XX for each study visit you attend after the screening visit. You may 
receive a total of $XXX for participating in the study.  Study investigators may ask for your 
social security number as part of the monitoring process for this compensation. 
 
WHAT IF THERE ARE NEW FINDINGS? 
We will not be analyzing data during the study.  However, 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.  You may 
request your own results after the study by contacting the research investigators.  
 
WHAT IF YOU DON’T WANT TO BE IN THE STUDY ANY LONGER?  
If you enroll in this study, you may decide to stop participating at any time.  Withdrawing 
from this study will not affect the benefits of your regular medical care.   
 
CAN YOUR STUDY PARTICIPATION BE STOPPED WITHOUT YOUR CONSENT?  
You may be taken off of study medicines before the end of the study if investigators or your 
doctor recommend this.  You may be taken off the entire study without your consent if: 
 Your study doctor decides that continuing in the study would harm you; 
 Your lab results indicate that you are experiencing toxicity from study medications; 
 
WHAT OTHER CHOICES DO YOU HAVE BESIDES THIS STUDY?  
You may discuss other strategies for improving your health with your doctor.  
 
WHAT ARE THE COSTS TO YOU? 
The medications that are part of this study will be provided free-of-cost to you, and will be 
distributed during study visits.   During the study, you, your insurance company, or some 
other third-party payer must pay for all other medicines, including HIV medicines not paid 
by the study and medicines needed to prevent or treat other illnesses.  We will provide all 
clinical and professional services, lab work, and other tests that are part of this study and 
not part of your regular care at no cost to you.   
 
HOW IS YOUR PRIVACY PROTECTED?  
Any information that could be used to identify you will be treated in strict confidence to the 
extent allowed by law.  Nevertheless, some uses and disclosures of your information are 
necessary to conduct the study.  If you agree to be part of this study, you will also be 


 
 
 
 
 
 
 
 
 
 
allowing the uses and disclosures of your private health information as needed for the 
purposes of this study as described in this consent.  
 
“Private health information” means information that identifies you and is collected: 
 during this study; 
 from your past and current medical records maintained by your regular health care 
providers, to the extent the information is relevant to this study or to your eligibility for 
this study; or 
 from any payment records relating to items or services furnished to you during this 
study. 
 
By signing this consent, you are agreeing that your private health information may be 
disclosed to and used by: 
 the doctors and other health care providers involved in this study; 
 their staff;  
 the research center; 
 members of the clinical site Human Subjects Institutional Review Board; 
 Merck Pharmaceuticals; 
 the sponsor of this study and its agents; and 
 monitors from the United States Government and/or Food and Drug Administration 
(FDA). 
 
The findings of this study may be used for scientific meetings, written reports, and 
publications, but no information that could be used to identify you will be disclosed for these 
purposes. 
 
Once your private health information has been disclosed to a third party, federal privacy 
laws may no longer protect it from re-disclosure.  However, anyone obtaining access to 
your private health information under this consent must agree to protect your information as 
required by this consent.   
 
This consent to use your private health information as described above does not expire. 
However, if you later change your mind, you can revoke this consent by writing to [SITE 
INVESTIGATOR] saying that you no longer wish to allow your private health information to 
be used for this study.  If you revoke your consent, you may no longer be able to participate 
in the study.  Moreover, we cannot undo uses or disclosures of your private health 
information that have already taken place in reliance on your prior consent. 
 
PLEASE NOTE: 
In the event of a positive result for Hepatitis B or C, reporting of the results to the 
local state Department of Health may be required. 
 
WHAT IF YOU ARE INJURED?  
If you are injured as a result of being in this study, you will be given immediate treatment.  
The cost for treatment will be charged to you or your insurance company.  There is no 


 
 
 
 
 
 
 
 
 
 
program through this institution to compensate participants who have research related 
injuries. You will not be giving up any of your legal rights by signing this consent. 
 
WHAT IF YOU HAVE PROBLEMS OR QUESTIONS?  
If you ever have questions or in the case of research-related injuries, you should contact:  
 
[LIST STUDY INVESTIGATORS] 
 
If you have questions about research subject’s rights you can contact: 
 
[SITE IRB CONTACT INCLUDING PHONE NUMBER] 
 
RESEARCH STUDY REGISTRY 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Website will not include information that can identify you.  At 
most, the Website will include a summary of the results.  You can search this Website at 
anytime. 


 
 
 
 
 
 
 
 
 
 
SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE LIFE-HIV STUDY  
 
I have read this consent form, had the opportunity to ask questions and have received 
answers to any questions I have asked.  I willingly give my consent to participate in this 
study, and authorize the use and disclosure of my health information as described in this 
form.  By signing this consent form I do not give up any of my legal rights.  Upon signing 
this form I will be given a signed copy of the form for my records. 
 
If you have read the consent (or if you have had it explained to you) and understand the 
information, and you voluntarily agree to join this study, please sign your name below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
______________________ 
 
___________ 
Participant’s name  
 
Participant’s signature 
 
 
Date 
(typed or printed) 
 
 
 
_________________________________ 
 
 
_______________  
 
Person obtaining consent  
 
 
 
 
Date