Conditions: Hepatitis C Human Immunodeficiency Virus
Keywords: hepatitis C virus (HCV) Maraviroc Human immunodeficiency virus (HCV)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: no

Brief summary:
This is a single-site, longitudinal, open-label, interventional study for evaluating the effect of maraviroc on hepatitis C viral levels in patients infected with both hepatitis C and human immunodeficiency virus (HIV) and taking antiretroviral therapy for HIV.

Detailed description:
Recently, in-vitro studies (experiments performed in a laboratory, not on a person) have demonstrated that maraviroc, a medication that is used in human immunodeficiency (HIV) therapy, appears to have significant hepatitis C antiviral effect, comparable to sofosbuvir-a potent anti-hepatitis C medication. In this study, the investigators will evaluate the antiviral effect of maraviroc on hepatitis C virus in people infected with both hepatitis C and HIV, and whom have never been treated for hepatitis with direct antiviral agents. Participants will take maraviroc for 4 weeks in addition to their regular HIV antiretrovirals (ART). The investigators will measure the hepatitis C viral load before, during, and after the 4-week maraviroc time.

Arms:
arm 1: To start maraviroc immediately after randomization. arm 2: To start maraviroc 8 weeks after enrollment.

Interventions: intervention 1: Maraviroc
Intervention descriptions: intervention 1: Participants will receive 4 weeks of maraviroc (dosing based on concomitant HIV antiretroviral regimen). Serial measurements of HCV viral load will be obtained before, during, and after maraviroc exposure. Study duration will be approximately 12 to 16 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Clinical Study Protocol 
 
A Pilot Study to Evaluate Anti-HCV Effect of Maraviroc in HIV/HCV Co-infected 
Patients   
 
MAraViroc Efficacy foR HepatItis C (MAVERIC) 
 
Principal Investigator:  Lydia Tang, MBChB 
 
NCT02881762 
 
 
 
 
Version Number: 1.2 
 
 
May 18, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information contained herein is the property of IHV and may not be reproduced, 
published or disclosed to others without written authorization. 
 


 MAVERIC  
Jan, 2017 
 
Page 2 of 30 
Study Staff Roster   
 
Lydia Tang, MBChB 
 
Principal Investigator:    
Institute of Human Virology (IHV) 
 
 
 
 
 
725 West Lombard Street 
 
 
 
 
 
Baltimore, MD 21201 
 
 
 
 
 
Tel: 410-706-6567 
 
 
 
 
 
Fax: 410-706-3243 
 
Associate Investigators:  
Shyam Kottilil, MD, PhD 
Benjamin Emmanuel, MPH 
Gregory Brogden, BS 
Jennifer Hoffmann, RN, MSN, MPH 
Angie Price, ARNP 
Amy Nelson, RN 
 
 
 
 
 
David Riedel, MD 
Eleanor Wilson, MHS, MD 
Joel Chua, MD 
Jennifer Husson, MD 
Haley Ward, BS 
Emily Covert, BS 
Manasa Bhatta, BS 
 
Collaborating Investigators 
Kenneth Sherman MD, Ph.D 
 
 
 
 
 
Jason Blackard Ph.D 
 
Study Site:   
 
 
Institute of Human Virology 
 
 
 
 
 
725 West Lombard Street 
 
 
 
 
 
Baltimore, MD 21201 
 
Collaborating Sites 
University of Cincinnati College of Medicine 
Division of Digestive Diseases 
231 Albert Sabin Way 
Cincinnati, OH  45267-0595 
 
 
 


TABLE OF CONTENTS 
 
Page 3 of 30 
 
 
Protocol Summary ................................................................................................ 6 
Précis .................................................................................................................... 7 
1 
Background Information and Scientific Rationale .......................................... 8 
 
Epidemiology .......................................................................................... 8 
 
Baltimore and Washington DC ............................................................... 8 
 
Treatment ............................................................................................... 8 
 
Rationale ................................................................................................ 9 
 
Institutional Background ....................................................................... 10 
2 
Study Objectives .......................................................................................... 10 
 
Primary Objective ................................................................................. 10 
 
Secondary Objectives ........................................................................... 11 
 
Exploratory Objectives .......................................................................... 11 
3 
Study Design ............................................................................................... 11 
 
Study Drug ............................................................................................ 11 
 
Research Strategy ................................................................................ 12 
 
Primary Hypothesis .............................................................................. 12 
4 
Study Population .......................................................................................... 13 
 
Rationale for Subject Selection ............................................................. 13 
 
Subject Inclusion Criteria ...................................................................... 13 
 
Subject Exclusion Criteria ..................................................................... 14 
 
Justification for Exclusion: Children and Pregnant Women .................. 14 
5 
Study Schedule ............................................................................................ 15 
 
Screening /Enrollment .......................................................................... 15 
5.1.1 
Procedures to be performed at Screening/Enrollment ...................... 15 
 
Randomization ...................................................................................... 15 
 
Day 0 to Day 7 ...................................................................................... 15 
5.3.1 
Study visit, all subjects: Baseline Visit – Day 0 ................................. 15 
5.3.2 
Study Visits, immediate start group only: Days 2, 3, 5 and 7 ............ 15 
 
Study visit, immediate start group only: Day 14 (Week 2 visit) ............. 16 
 
Study visits, immediate start group only: Day 21/week 3 ...................... 16 
 
Study visit, both groups: Day 28/week 4 ............................................... 16 
 
Washout period, week 4 through to week 8 .......................................... 16 
 
Study visit, both groups: Day 56/week 8 ............................................... 16 
 
Study visits, delayed start group only: Day 58, 59, 61, 63, 70 (week 10), 
77 (week 11).................................................................................................... 16 
 
Study visit, both groups: Day 84/Week 12 ............................................ 16 
 
Study Visit, delayed start group only: Day 112/week 16 ....................... 17 
6 
Study Procedures/Evaluations ..................................................................... 17 
 
Clinical Evaluations .............................................................................. 17 
 
Laboratory Evaluations ......................................................................... 17 
 
HCV and HIV Virologic Studies ............................................................ 18 
7 
Potential Risks and Benefits ........................................................................ 19 
 
Potential Risks ...................................................................................... 19 
 
Potential Benefits .................................................................................. 20 


TABLE OF CONTENTS 
 
Page 4 of 30 
8 
Stored Samples and Future Research ......................................................... 20 
9 
Assessment of Safety & Monitoring ............................................................. 21 
 
Recording/Documentation .................................................................... 22 
 
Definitions ............................................................................................. 22 
9.2.1 
Reporting Protocol Deviations, AEs and Deaths ........................... 22 
9.2.2 
Annual Reporting to the IRB .......................................................... 22 
 
Type and Duration of the Follow-up of Subjects after Adverse Events . 23 
 
Withdrawal of a Subject ........................................................................ 23 
 
Return of Withdrawn/Removed Subjects .............................................. 23 
10 
Remuneration Plan for Subjects ............................................................... 24 
11 
Statistical Considerations ......................................................................... 24 
 
Sample size .......................................................................................... 24 
 
Description of the Analyses .................................................................. 24 
12 
Ethics/Protection of Human Subjects ....................................................... 24 
 
Informed Consent Process ................................................................... 24 
12.1.1 
Illiteracy and Consenting ............................................................ 25 
 
Subject Confidentiality .......................................................................... 25 
Appendix A: Scientific References ...................................................................... 25 
Appendix B: Schedule of Procedures/Evaluations .............................................. 28 


MAVERIC  
Jan, 2017 
 
Page 5 of 30 
List of Abbreviations 
 
AE 
 
Adverse Event/Adverse Experience 
Coinfection Identifier for those with both HIV and hepatitis B or C  
DAA  
Directly Acting Antiviral 
ART  
Highly Active Anti-retroviral Therapy 
HBV  
Hepatitis B Infection 
HCV  
Hepatitis C Infection 
HIPAA 
Health Insurance Portability and Accountability Act 
MAVERIC 
Study short name 
IHV 
 
Institute of Human Virology 
IRB 
 
Institutional Review Board 
N 
 
Number (typically refers to number of subjects/sample size) 
PI 
 
Principal Investigator 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAE  
Serious Adverse Event/Serious Adverse Experience 
SVR  
Sustained Virologic Response 12 weeks following therapy 
VL 
 
Viral Load 
WHO  
World Health Organization 


MAVERIC  
Jan, 2017 
 
Page 6 of 30 
Protocol Summary 
Full Title: 
A Pilot Study to Evaluate Anti-HCV Effect of 
Maraviroc in HIV/HCV Co-infected Patients   
Short Title: 
MAVERIC 
Conducted by: 
Institute of Human Virology, University of Maryland 
Principal Investigator: 
Lydia Tang, MBChB 
Sample Size: 
N= 10 
Accrual Ceiling: 
 
15 
Study Population: 
Adults infected with viral hepatitis C and being treated 
for HIV infection 
Study Design: 
Single-site, longitudinal, open-label, interventional 
pilot study for evaluation of the effectiveness of 
Maraviroc on HCV viral levels in patients with HCV 
and HIV undergoing antiretroviral therapy. 
Participants will be seen at a IHV Clinic, Baltimore MD 
21201.  
Study Duration: 
Start Date:  August 1, 2016 
 
 
End Date:  August 1, 2017.   
Primary Objective:  
1. Determine the in-vivo antiviral efficacy of Maraviroc 
in HIV/HCV coinfected patients 
Secondary Objectives: 
1. Determine the viral kinetics of HCV in HIV/HCV 
infected subjects initiated with maraviroc.   
 
 
2. Assess the safety and tolerability of adding 
maraviroc to ART in HIV/HCV coinfected subjects.  
Exploratory Objectives: Virologic and Immunologic assays to evaluate 
changes associated with CCR5 antagonism. 
 
Endpoints: 
 
Primary Endpoint: 1. Change in HCV VL from 
baseline to day 7. 
Secondary Endpoints: 1. Changes in HCV slope/log 
change in HCV VL between each patient  
2. Changes in HCV slope between the two groups 
3. Changes in HCV VL from baseline to day 2, day 3, 
day 5, week 1, week 2, 3, 4 
4. Changes in CD4 and HIV viral load 
5. Patient reports of adverse events 
6. Percentage of patient with breakthrough of HIV 
 


MAVERIC  
Jan, 2017 
 
Page 7 of 30 
Précis 
 
Hepatitis C virus (HCV) chronically infects over 170 million people worldwide.1-3  
Hepatitis C virus (HCV) is a leading cause of chronic liver disease and the leading 
indication for liver transplantation in the United States (US) with estimates of more 
than 5 million individuals infected in the US.4 Standard therapy for HCV is 
undergoing significant change, moving away from interferon injections and 
ribavirin toward all oral directly acting antivirals (DAAs).  It is expected that 
treatment rates will increase and success of treatment will continue to improve.5  
 
HCV infection occurs more commonly in patients infected with HIV due to shared 
routes of transmission. HIV infection modifies the natural history of HCV infection 
considerably by increasing persistence, accelerating liver fibrosgenesis and 
historically is associated with poorer rates of responses. Although recent studies 
using DAA agents have been promising with high sustained virologic response 
(SVR, considered functional cure), widespread uptake of DAA agents in HIV/HCV 
coinfected patients is restricted due to unrecognized drug–drug interactions 
between HIV antiretroviral therapy (ART) and DAA agent. In this regard, treatment 
of HCV in HIV/HCV coinfected patients remains a complex issue.  
 
Recently, in-vitro studies have demonstrated that maraviroc, and HIV ART that 
exerts anti-HIV effects through CCR5 antagonism, appears to have significant anti-
viral effect on HCV replication comparable to sofosbuvir–a potent HCV NS5B 
inhibitor and the back bone to several combination anti-HCV DAA therapy currently 
approved. In this study, we propose to characterize the antiviral effect of Maraviroc 
in HIV/HCV coinfected patents naïve to anti-HCV DAA therapy. We intend to 
evaluate HCV viral kinetics after adding maraviroc to existing ART in 10 HIV/HCV 
coinfected patients by performing serial HCV RNA measurements. This study will 
provide the in-vivo evidence that CCR5 antagonists can be used to treat HCV and 
may offer prolonged effect in the HIV/HCV coinfection by assisting with modulation 
of hepatic regeneration pathways.  
 
 
 
 


MAVERIC  
Jan, 2017 
 
Page 8 of 30 
1 Background Information and Scientific Rationale  
 
Epidemiology  
Hepatitis C virus (HCV) is a major cause of chronic liver disease and is the leading 
indication for liver transplantation in the US. Approximately 4.1 million individuals 
(1.6%) in the US population have been infected with HCV.6 Approximately 50% of 
HCV infected persons have been tested, with the remainder unaware of their 
diagnosis. Of those that reach care, 16% have been treated, and 9% have been 
cured of HCV.7 8 Among HIV-positive individuals, coinfection with HCV is relatively 
high, ranging from 15% to 30%.9,10 Liver disease in HIV patients has become a 
major source of morbidity and mortality in the US and worldwide.11 HIV/HCV 
coinfection is especially problematic in the US now that HIV patients are living 
longer on highly active antiretroviral therapy (ART), and are often dying of 
complications from liver disease primarily related to HCV. In addition, more than 
75% of adults in the US infected with HCV were born between 1945 through 1965. 
As a result, the prevalence of liver disease resulting from HCV is likely to increase 
over time, adding a significant burden to the medical system. It is expected to 
continue to rise as more and more people get screened. The impact of chronic 
HCV on liver failure, HCC and mortality is enormous and continues to increase at 
an alarming rate. Recent advances in effective pill-only treatment regimens to treat 
and cure HCV is promising making it feasible to test, link and treat this population 
effectively.  
 
Baltimore and Washington DC 
Baltimore has been cited as a leading city in terms of injection drug use, ranking 
second in the nation for intravenous drug use (IVU) per capita in 200412. A more 
recent study looking at patterns of drug use and infectious disease in Baltimore 
drug users found that 45% of recent users of cocaine or heroin were infected with 
hepatitis C and with nearly 8% co-infected with HIV13.  
 
Treatment 
 
Until recently, a major limiting factor in expansion of treatment for HCV has been 
standard of care therapy with pegylated interferon, ribavirin, and more recently for 
genotype 1 disease, boceprevir and telaprevir. These medications have significant 
side effect profiles, response-based dosing regimens of over 6 months, and 
decreased efficacy in key groups including: those with genotype 1 disease, HIV 
coinfection, and cirrhosis. In particular the response rates observed in HIV/HV 
coinfected patients were much lower than those without HIV infection.14,15 
However, with new therapeutics becoming available, the picture is quite hopeful.  
There has been dramatic improvement using all oral DAA regimens with sustained 
virologic response (SVR) rates over 90%, short-duration therapies and well-
tolerated, simple regimens including among those with HIV coinfection. Although 
the rates of SVR has been relatively high in limited studies that have evaluated 
these novel DAA regimens in HIV/HCV coinfected patients, it is unclear whether 


MAVERIC  
Jan, 2017 
 
Page 9 of 30 
achieving an SVR will result in  regression of liver fibrosis. It is also not understood, 
at what rate the regression of fibrosis may occur and whether it would occur in all 
patients regardless of HIV status. In this regard, HIV/HCV coinfected patients have 
demonstrated a much more rapid progression of liver fibrosis over time. Hence, 
management of HIV/HCV coinfected patients offer several challenges that need to 
be addressed. 
 
Rationale 
CCR5 is a chemokine co-receptor best known for its central role in HIV binding to 
T-cells. However, CCR5 is expressed in hepatocytes, stellate cells and Kupffer 
cells within the liver16 and may mediate liver fibrosis.17-19 Interaction between HIV 
(or gp120) and CCR5 has been shown to upregulate HCV replication as well.20 A 
recent study hypothesized that CCR5 blockade might modulate HCV 
replication.21 They examined the effect of CCR5 blockade using two potent 
receptor antagonists, cenicriviroc (dual CCR2/5 antagonist) and maraviroc 
(CCR5 antagonist), on HCV replication in-vitro. Both agents  are known to inhibit 
HIV  replication and cenicriviroc is being evaluated  in  a  Phase 2b trial in adults 
with NASH and  hepatic fibrosis. Briefly, 100,000 Huh7.5JFH1 human hepatocyte 
cells, which constitutively produce a cell-line adapted strain of HCV genotype 2 
and express CCR5 were seeded in 24-well format plates. The next day, cells 
were incubated with 25 ug/ml, 0.25 ug/ml, or 0.0025 ug/ml of the antiviral drugs 
under investigation. These included maraviroc or cenicriviroc, sofosbuvir (an 
HCV polymerase inhibitor positive control) or raltegravir (an HIV integrase 
inhibitor negative control). The culture supernatants were collected after 24 hours 
of incubation with the drug. Cell number was evaluated to determine if cell 
viability affected HCV viral load production. HCV replication was monitored using 
a commercial HCV Core Antigen ELISA assay (Cell BioLabs, San Diego, CA). 
Negative strand HCV RNA was detected by a qualitative strand-specific RT-PCR 
assay as a measure of actively replicating virus . Positive strand HCV RNA was 
measured by qRT-PCR in the cell culture supernatant. 
 
Collectively, CCR5 blockade with cenicriviroc & maraviroc decreased HCV core 
production, HCV negative strand production and HCV RNA released to 
supernatant to extents comparable with sofosbuvir, a known HCV NS5B inhibitor 
with extremely potent anti-HCV activity in-vitro and in-vivo.22 The results were 
specific to R5 antagonism since Raltegravir (an HIV integrase inhibitor) did not 
lead to a similar effect on HCV replication. These results led us to believe that 
CCR5 blockade appears to modulate HCV replication in an in-vitro Huh7.5JFH1 
human hepatocyte cell system. This potent inhibition suggests that CCR5 may 
represent a new target for multidrug HCV therapy and warrants evaluation in 
HIV/HCV coinfected patients. In this regard, we intend to study a small group pf 
HIV/HCV infected patients. 
 


MAVERIC  
Jan, 2017 
 
Page 10 of 30 
 
Figure 1A – Change in HCV Core Antigen concentrations 
A dose-dependent response was observed for maraviroc, cenicriviroc, and sofosbuvir at 
the 0.25 ug/ml and 25 ug/ml concentrations but not at 0.0025 ug/ml. Raltegravir had no 
effect on HCV  core antigen production, nor did DMSO buffer controls. Cell viability was 
not affected by any drug or by the DMSO buffer solution.  
Figure 1B – Change in HCV Negative Strand RNA quantity 
RNA from cell lysates was extracted using the mirVana miRNA Isolation Kit (Ambion) 
and resuspended in 50 uL of elution buffer.  HCV RNA was detected by reverse 
transcription PCR and primers HCV-II sense (5'-CAC TCC CCT GTG AGG AAC T-3', 
nucleotides [nt] 38–56 of the 5'UTR) and HCV-I antisense (5'-TGG ATG CAC GGT CTA 
CGA GAC CTC-3', nt 342–320). Thirty cycles of PCR (94C for 30 sec, 58C for 1 min, 
and 72C for 2 min) were performed, and PCR products (295 base pairs in length) were 
visualized by gel electrophoresis. GAPDH (400 bp) was amplified as a control. 
Figure 1C – Change in HCV Positive Strand RNA  
HCV RNA was measured in the cell culture supernatants after 24 hours of drug 
incubation. Data shown is the fold change of RNA detected normalized and compared to 
HCV RNA at baseline.  
 
Institutional Background 
The Institute of Human Virology (IHV) is a world renowned institution dedicated to 
the study of natural history, pathogenesis, and therapeutics for human viral 
infection. The IHV has led the field in HIV and HCV pathogenesis and therapeutics 
for over the past two decades. IHV has spearheaded HIV therapeutics and as a 
single institution has initiated ART in over 1 million HIV-infected subjects globally. 
In this study, IHV is partnered with University of Cincinnati with Dr. Kenneth E 
Sherman, who is a leading hepatologist in the world and a pioneer in studies 
involving HIV and HCV coinfection. The preliminary data supporting this trial was 
performed in Dr. Sherman’s laboratory.  
 
2 Study Objectives 
 
Primary Objective 
Determine the in-vivo anti-HCV efficacy of Maraviroc in HIV/HCV coinfected 
patients. 


MAVERIC  
Jan, 2017 
 
Page 11 of 30 
 
Secondary Objectives  
1. Determine the viral kinetics of HCV in HIV/HCV infected subjects initiated with 
maraviroc.   
2. Assess the safety and tolerability of adding maraviroc to ART in HIV/HCV 
coinfected subject 
 
Exploratory Objectives   
Virologic and Immunologic assays to evaluate changes associated with CCR5 
antagonism. 
3 Study Design 
This is a single-site, open-label, randomized, prospective, cross-over pilot 
interventional study for evaluating the anti-HCV effect if CCR5 antagonism in 
HIV/HCV coinfected patients receiving ART.  
 
Study Drug   
Maraviroc (trade name: Selzentry) is an antiretroviral drug in the CCR5 receptor 
antagonist class used in the treatment of HIV infection. It is also classed as an 
entry inhibitor. Maraviroc was approved for the treatment of HIV infection by the 
Food and Drug Administration in 2007. Specifically, maraviroc is a negative 
allosteric modulator of the chemokine CCR5 receptor, found on the surface of T 
lymphocytes. The chemokine receptor CCR5 is an essential co-receptor for most 
HIV strains and necessary for HIV to infect lymphocytes. The drug binds to CCR5 
at a non-competitive site and alters gp120 binding site of CCR5, thereby blocking 
the HIV entry into the target cell.23 Maraviroc is very safe and Phase III clinical 
trials did not show any difference in the incidence of adverse events in the placebo 
or maraviroc treated groups. 
Dosing 
Available as 150 or 300 mg tablets. As per labeling based on concomitant ART 
(see table 1 below). 
Table 1. Maraviroc dosing for participants based on concomitant ART 
Background Antiretroviral Therapy 
Regimen 
Maraviroc dose 
With NRTI’s, tipranavir/ritonavir, 
nevirapine, raltegravir, and other drugs 
that are not potent CYP3A inducers nor 
inhibitors 
300mg tablet twice a day 
With potent CYP3A inducers including 
efavirenz (without a potent CYP3A 
inhibitor) 
600mg (two 300mg tablets) twice a day 
Boosted protease inhibitor-containing 
regimen 
150mg tablet twice a day 


MAVERIC  
Jan, 2017 
 
Page 12 of 30 
 
 
Research Strategy   
Study subjects will be selected and enrolled at a single site at IHV. HIV infected 
participants (coinfected with HCV and DAA-treatment naïve for HCV) who are 
well controlled on ART will receive Maraviroc for one month and serial 
measurements of viral and immune parameters will be performed. Rationale for 
not recruiting treatment naïve HIV/HCV coinfected participants is based on 
previous studies that have demonstrated an increase in HCV VL in HIV/HCV 
coinfected patients who initiated ART.24 We believe this will interfere from 
characterizing the anti-viral effect, if any, of CCR5 antagonism. Hence, we plan 
to do an interventional study with frequent in-vivo viral kinetic analysis to evaluate 
anti-HCV effect of CCR5 antagonism. 
Patients with HIV/HCV coinfection with HIV viral suppression and active HCV 
infection will be included. Patients will be randomized to one of 2 cohorts: immediate 
start of maraviroc (cohort 1), and delayed start (cohort 2). All patients will receive 4 
weeks of Maraviroc (dose adjusted according to intake of concurrent CYP 3A 
inducers, see table 1) in addition to their regular ART. The immediate start group will 
receive maraviroc in addition to their HIV antiretroviral regimen from week 0 to 4. 
This will be followed by a wash out period of 4 weeks after cessation of Maraviroc. 
After the 4-week wash out period, patients will be crossed over the no-maraviroc 
arm. The delayed start group will receive no maraviroc from weeks 0 to 4, followed 
by a 4 week wash out period, before crossing over to the on-maraviroc arm. Figure 2 
below illustrates the study scheme. 
 
 
 
Figure 2: Study scheme 
 
Primary Hypothesis   
The primary hypothesis is that CCR5 antagonism will lead to lower HCV viral 
load. In addition, we hypothesize that CCR5 antagonism using maraviroc will 
demonstrate significantly lower HCV viral kinetics in the first 7 days of initiation of 
therapy. 


MAVERIC  
Jan, 2017 
 
Page 13 of 30 
   
4 Study Population 
Patients will have HCV and HIV and receiving HIV therapy using ART as 
recommended by HIV treatment guidelines. These patients will be selected to 
receive one month of maraviroc and have serial measurements of viral, safety 
and immune parameters to evaluate the anti-HCV efficacy of CCR5 antagonism. 
 
Rationale for Subject Selection  
Subjects of both genders will be considered for inclusion in this study. There will 
be no racial, ethnic, or gender discrimination. Persons in jail or prison are not 
eligible for this study. Women will not have research procedures while pregnant. 
 
Subject Inclusion Criteria 
To be eligible for participation on this protocol, a participant must satisfy all of 
the following conditions: 
 
1. Be ≥18 years old 
2. HCV-infected without plans to undergo HCV treatment for duration of 
study   
3. HIV infected 
4. Currently receiving ART with HIV VL <50 IU/ml for ≥ 12 months 
a. One virologic blip ≤ 400 copies/ml permissible within the 12 
months 
5. CD4 T cell counts > 100 cells/mm3 
6. Non-cirrhotics and cirrhotics can be included 
7. Willing to sign informed consent 
 
An HCV infected individual is defined as any individual with documentation of the 
following in the past:  
• Positive HCV antibody and/or positive HCV RNA test  (HCV RNA of 2,000 
IU/mL or greater). 
 
Anti-HCV DAA treatment naïve is defined as: 
• No previous treatment for HCV with any DAA. Previous exposure to 
interferon and ribavirin are allowed. 
 
An HIV infected individual is defined as any individual with documentation of the 
following: 
• Positive Enzyme Linked Immunosorbent Assay followed by a positive 
Western Blot or detectable HIV viral load, or HIV viral <50 copies/mL with 
documentation this individual is currently on an active HIV ART. 
 


MAVERIC  
Jan, 2017 
 
Page 14 of 30 
Cirrhosis is defined as 
• FibroTest score >0.75 OR APRI (AST to Platelet Ratio Index) >2 AND 
FIB-4 (Fibrosis-4) >3.25 OR FibroScan with a result of >12.5kPa OR 
liver biopsy showing cirrhosis at any time 
 
Absence of cirrhosis is defined as 
• FibroTest score <0.48 OR APRI <1 AND FIB-4 <1.45 performed within 
1 year of screening OR FibroScan with result of <12.5kPa within 1 year 
of screening OR liver biopsy within 3 years of screening showing 
absence of cirrhosis. 
  
 
 Subject Exclusion Criteria 
A participant will be ineligible to participate on this study if any of the following 
criteria are met: 
 
1. Age < 18  
2. Unable to comply with study visits, research study visits, or is planning 
to relocate during the study. 
3. Have any condition that the investigator considers a contraindication 
to study participation 
4. Pregnancy of breast feeding 
5. Decompensated liver disease (Child-Pugh C) 
6. Imminent treatment for HCV 
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>2.5 times the upper limits of normal 
8. Concomitant use of drugs known to impact or be impacted in terms of 
pharmacokinetics or drug-drug interactions with either raltegravir, 
dolutegravir, or maraviroc. This includes: 
• Inducers of UGT1A1 (such as rifampin, phenytoin, phenobarbital 
rifabutin, St. John’s wort)  
• CYP3A 
inhibitors 
(such 
as 
ketoconazole, 
itraconazole, 
clarithromycin, nefazodone, and telithromycin) 
• CYP3A inducers (such as rifampin, carbamazepine, phenobarbital 
and phenytoin) 
 
 
Justification for Exclusion: Children and Pregnant Women 
The study will be limited to adults ≥ 18 years of age as HCV is predominately a 
disease in adults. Children and pregnant or breast-feeding women will not be 
enrolled because of the lack of immediate benefit for the patient with the added 
risk of blood draws associated with the study.  
  


MAVERIC  
Jan, 2017 
 
Page 15 of 30 
5 Study Schedule 
 
Screening /Enrollment 
Screening will occur at the IHV.  Subjects who consent to the study will be 
enrolled.  A health history will be reviewed and a physical exam will occur prior to 
the baseline research lab draw.  Outside labs performed within the last six 
months may be used to determine eligibility. 
5.1.1 
Procedures to be performed at Screening/Enrollment 
• Complete Medical History  
• Complete Physical Examination - including body weight, height, and vital 
signs (temperature, pulse, respiratory rate, and blood pressure) must be 
obtained. 
• Complete Medication History – A complete review of all medications and 
supplements the patient is currently taking. 
• Urine Pregnancy test for women of child bearing potential 
o Female subjects of childbearing potential will have a urine 
pregnancy test (HCG) performed prior to the study start date. 
Women who are found to be pregnant will be excluded from the 
study. 
• Blood for Screening Labs obtained within 6 months of study entry  –  
o CBC with differential 
o Serum Chemistry  
o LFT’s (including AST, ALT, Total bilirubin) 
o Hepatitis C Quantitative RNA  
o HIV-1 RNA PCR 
o CD4 Cell Count 
 
Randomization 
Enrolled participants will be randomized to the immediate start or delayed start 
group in a 1:1 fashion at time of enrollment. 
 
Day 0 to Day 7 
5.3.1 
Study visit, all subjects: Baseline Visit – Day 0 
Once eligibility is known, all subjects will have baseline research sample 
collection of HCV VL, and PBMC, plasma,  serum and Paxgene RNA and DNA 
for storage. Maraviroc will be initiated for participants randomized to the 
immediate start group. 
5.3.2 
Study Visits, immediate start group only: Days 1, 2, 4 
and 7 


MAVERIC  
Jan, 2017 
 
Page 16 of 30 
HCV VL will be obtained at days 1, 2, 4 and 7. Day 7 labs can be completed up 
to 1 day later. 
 
Study visit, immediate start group only: Day 14 (Week 2 visit) 
HCV VL will be obtained. Safety assessment will be performed (CBC with 
differential and CD4 and HIV viral loads. Patient reports of adverse effects). Labs 
can be completed up to 2 days later.  
 
Study visits, immediate start group only: Day 21/week 3 
HCV VL will be obtained. Labs can be completed 2 days later. 
 
Study visit, both groups: Day 28/week 4 
HCV VL and PBMC, plasma, serum and Paxgene RNA for storage will be 
obtained. Labs can be completed 2 days later. 
Immediate start group: Maraviroc will be discontinued at day 28/week 4. 
 Washout period, week 4 through to week 8 
 Study visit, both groups: Day 56/week 8  
HCV VL and PBMC, plasma, serum and Paxgene RNA for storage will be 
obtained.  
Delayed start group: A review of medical history and medication history will be 
performed to evaluate for any interim changes from screening visit. Physical 
exam will be performed. HCV VL and PBMC, plasma, serum, and Paxgene RNA 
for storage will be obtained. Maraviroc will be started.  
 Study visits, delayed start group only: Day 57, 58, 60, 63, 70 (week 10), 
77 (week 11)  
HCV VL will be obtained  
Safety assessment at day 70/week 10 (on week 2 after initiating maraviroc).  
Weeks 10 and 11 labs can be completed up to 2 days later. 
 Study visit, both groups: Day 84/Week 12 
HCV VL and PBMC, plasma, serum. and Paxgene RNA for storage will be 
obtained. Visits can be completed up to 2 days later. 
Delayed start group: Maraviroc will be discontinued. Safety assessment. 
Immediate start group: End of study participation. Safety assessment. 


MAVERIC  
Jan, 2017 
 
Page 17 of 30 
 Study Visit, delayed start group only: Day 112/week 16  
HCV VL and PBMC, plasma, serum, and Paxgene RNA for storage will be 
obtained. Safety assessment. End of study participation. Visit can be 
completed up to 2 days later. 
 
6 Study Procedures/Evaluations 
 Clinical Evaluations 
Participants will be seen by a study team member at screening, and maraviroc 
start dates (day 0 for immediate start group, and day 56/week 8 for the delayed 
start group) for a review of health history.   
Participants will also be seen by a study team member every weeks while taking 
maraviroc (day 0, week 1, week 2, week 3 week 4 for the immediate start group, 
and Day 56/week8, week 9, week 10, week 11, week 12 for the delayed start 
group) and every 4 weeks prior to starting, and after completing maraviroc (week 
8 and week 12 for the immediate start group, and day 0, week 4, and week 16 for 
the delayed start group) for adverse event monitoring.  
 Laboratory Evaluations 
Blood will be collected by standard blood drawing techniques. All laboratory 
assays will be done at University of Maryland Medical Center or at the IHV 
research lab facilities depending upon the assay. Stored samples will be 
processed and stored at the IHV research laboratories. 
Screening:  CBC with differential; creatinine and hepatic function tests including; 
albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) will be collected or outside records showing eligibility will 
be used.  Hepatitis serologies and viral loads will be completed if medically 
indicated. 
Research Visits:  
At the first study visit the following tests will be done: 
• Baseline HCV VL  
• Serum storage (10 ml) 
• Plasma storage (6ml) 
• DNA paxgene will be collected (8.5ml) 
• RNA paxgene will be collected (2.5ml) 
• Peripheral blood mononuclear cell (50 ml)  
 
 


MAVERIC  
Jan, 2017 
 
Page 18 of 30 
At all study visit including the first study visit the following clinical laboratory 
tests will be done: 
• Hepatitis C viral load  
 
After the first 2 weeks while on maraviroc (day 14/week 2 for the immediate start 
group; and day 70/week 10 for the delayed start group) the following safety 
assessment will be done: 
• HIV VL, CBC with differential, and CD4 count (24.5 ml) 
• Patient reports of adverse effects 
 
Every week while taking maraviroc, and once every 4 weeks prior to starting, and 
after completing maraviroc, the following clinical assessments will be done: 
• Adverse event monitoring (patient reports of adverse effects)  
• Medication review 
 
At study visits every 4 weeks including the first study visit the following blood 
specimens may be collected for research laboratory storage and tests (total 
68.5 ml research, or about 4.6 tablespoons):  
• RNA paxgene (2.5ml) 
• Peripheral blood mononuclear cell (50 ml)  
• Serum storage (10 ml) 
• Plasma storage (6ml) 
 
Outside Tests:  Tissue may be requested from liver biopsies done for clinical 
purposes; imaging, FibroScan or other liver evaluation results may also be 
requested from outside providers with subject consent. 
 HCV and HIV Virologic Studies 
We will study the viral and host immunity to HCV and HIV in all patients. The 
results will be used to characterize each individual with regards to immune status 
and chronicity of disease.  
A] Full length HCV genome sequencing will be performed on plasma using the 
protocol as described and compared for variability of sequences. 
B] Genome-wide transcriptional profiling Sequencing will be performed using 
RNAseq approach. This will provide the most comprehensive coverage of the 
genome, including empirically supported and predicted transcribed sequences, 


MAVERIC  
Jan, 2017 
 
Page 19 of 30 
enabling the discovery of previously unidentified novel events. We will analyze 
array data from samples from whole blood pax genes and will design a low-
density PCR array of 20-30 genes of most interest that are highly representative 
of the analysis group for validation.  
 
 
 
We will screen patient samples for miRNA panel that comprises of over 400 
known, well-characterized miRNAs. The TaqMan Array Human MicroRNA Panel 
(Applied Biosystems, Inc.) is a fixed-set microfluidic card that simplifies the 
profiling of 400plus human miRNAs. After extracting RNA and making cDNA we 
will use the Multiplex RT and TaqMan MicroRNA Reverse Transcription Kit 
loaded on the micro-fluidic card, and run on the Applied Biosystems7900HT Fast 
Real-Time PCR System. 
C] We will screen sera from all patients for differential expression of protein 
peaks that may be associated with liver fibrosis and HCC with the aid of a high-
throughput approach using multiplex cytokine arrays, which has the capability of 
detecting several different cytokines and other biologically relevant proteins. 
D] We will perform detailed phenotypic and functional evaluation of immune cell 
types in the periphery and liver (as available). This will help us in determining the 
nature of immune responses in patients who are chronically infected. 
Determination of specific immune defects in these individuals are important 
milestones in deciding future therapeutics. Exhaustion and activation markers on 
T, B and NK cells will be quantified. Specific immune responses against pooled 
HBV and HCV peptides will be performed using an ELISPOT assay and flow 
cytometry as previously described.    
 
7 Potential Risks and Benefits 
 Potential Risks  
The potential risks includes risks of phlebotomy which include: pain, bruising, 
fainting and very rarely, infection. These risks will be minimized by having trained 
staff perform the procedure.  
 
There is potential for loss of confidentiality, which will be minimized by providing 
privacy during study visits. In addition, all laboratory specimens, and research 
records will be coded by a number to maintain subject confidentiality. All paper 
records will be kept locked with limited access. Electronic data will be password 
protected and will not include participant names or contact details. 
 
Risks with Use of Maraviroc (MVC, Selzentry™) 
 
Common side effects reported with maraviroc that may or may not be causally 
related include: cough, fever, colds/upper respiratory tract infections, rash, 


MAVERIC  
Jan, 2017 
 
Page 20 of 30 
muscle and joint aches, stomach pain, diarrhea, edema, sleeping problems, and 
dizziness.25,26  
 
Serious side effects may include serious skin rash and allergic reactions, and 
elevations in liver function tests. People who are co-infected with hepatitis B or C 
might be at higher risk of having liver problems, although data from trials showed 
similar rates of liver function test abnormalities in patients on maraviroc 
compared to placebo groups.  
 
Postural hypotension was reported in patients taking higher doses (than currently 
approved) of maraviroc in clinical studies.25  
 
Post-marketing experience has reported skin and subcutaneous tissue disorders 
including Stevens-Johnson syndrome (a severe and sometimes fatal form of skin 
rash). 
 
Maraviroc contains soya lecithin. Therefore if you have a medical history of 
allergy to soya or peanuts, you may develop an allergy reaction to maraviroc. 
 Potential Benefits 
Participants will derive no direct clinical benefit from participation in this protocol. 
It is hoped that this research will be of benefit to society by aiding the 
understanding of immunological and virological aspects associated with the 
disease.   
 
8 Stored Samples and Future Research 
Future use of the specimens will be based on the scientific merit of the 
investigation and would be decided by the Principal Investigator. They would be 
related to the study of HCV and/or HIV. Other investigators may wish to study 
these samples and/or data.  In that case, IRB approval must be sought prior to 
any sharing of samples and/or data.  Any clinical information shared about the 
sample would similarly require prior IRB approval. If approved, and once a 
Material Transfer Agreement (MTA) has been established, the study team may 
send de-identified samples to the collaborators. Investigators will use stored 
samples only for research.  
• Intended Use: Some tissue and blood samples may be stored for future 
analysis in this research study. These samples will be stored by the IHV 
researchers and may be used in future research to learn more about HCV 
and HIV, the immune system and/or other related medical conditions. The 
blood and tissue will be used over time to gain a better understanding of 
the pathogenesis of HCV and HIV, and especially the degree of liver 
disease progression.  Genetic testing will be performed. Different 
analytical and laboratory methods will be employed including but not 
limited to: PCR, ELISA, ELISPOT and immunohistochemistry; RNA/DNA, 


MAVERIC  
Jan, 2017 
 
Page 21 of 30 
cytokine and antibody quantitation; viral particle detection and 
identification of genetic markers. The consent will include language for 
specimen storage. 
• Storage:  Samples will be kept in secure facilities with limited access. 
Samples and data will be stored using a unique identifier.  Only 
investigators and study staff will have access to the samples and data.  
• Tracking:  Extra blood and tissue samples will be stored using a unique 
identifier that only the study team can trace back to the participants. These 
stored samples as well as a linkage file will be maintained in a database 
that will be managed by the Investigators and/or Study Coordinators and 
will be maintained on the IHV server. This database will also be stored on 
the password-protected computer of the Lead-Investigator/Study 
Coordinator in an encrypted and/or password-coded file. 
• Disposition at the Completion of the Protocol: At the completion of the 
protocol (termination), samples and data will either be destroyed, or after 
IRB approval, transferred to another existing protocol. Final disposition of 
any samples cannot be done without written permission from the PI. 
 
• Reporting the Loss or Destruction of Samples/Specimens/Data to the 
IRB: 
o Any loss or unanticipated destruction of samples or data resulting in 
a violation that compromises the scientific integrity of the data 
collected for the study will be reported to the IRB.  
o Participants may request at any point not to have their samples 
stored. In this case, the Principal Investigator will destroy all known 
remaining samples and report what was done to both the 
participant and to the IRB. This decision will not affect the subject’s 
participation in any other protocols.  
 
Generally, the results from the research stored samples will not be given to the 
participant's primary care provider or appear in the medical record. This is 
because the test results, unlike routine medical testing, may be experimental or 
preliminary. The relevance of these tests to direct patient care may be unknown. 
At the participant's request, the results of any research tests will be discussed 
with the primary care physician by the Investigators. 
 
9 Assessment of Safety & Monitoring 
As this is an observational study with intervention limited to blood collection, 
safety issues are not expected. Only those reportable Adverse Events (AEs) 
related to the research procedures will be reported. The PI will review the safety 
data and report any unexpected events to the IRB along with annual continuing 
review.  
 


MAVERIC  
Jan, 2017 
 
Page 22 of 30 
 Recording/Documentation 
At each contact with the patient (once a week while taking maraviroc, and then 
every 4 months prior to and after completing maraviroc), information regarding 
adverse events related to research procedures will be elicited by appropriate 
questioning and examinations and will be immediately recorded on a source 
document.  Source documents will include: progress notes, laboratory reports 
and data collection tools. Source documents will be reviewed in a timely manner 
by the research team. 
 Definitions 
Adverse Event: Any untoward medical occurrence in a human subject, including 
any abnormal sign, symptom, or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.   
 
Protocol Deviation: Any change, divergence, or departure from the IRB approved 
study procedures in a research protocol. Protocol deviations are designated as 
serious or non-serious and further characterized as: 
• Those that occur because a member of the research team deviates from the 
protocol. 
• Those that are identified before they occur, but cannot be prevented. 
• Those that are discovered after they occur 
9.2.1 
Reporting Protocol Deviations, AEs and Deaths   
Anticipated deviations in the conduct of the protocol will not be reported to the 
IRB unless they occur at a rate greater than anticipated by the study team. 
Expected adverse events will not be reported to the IRB unless they occur at a 
rate greater than that known to occur in those having phlebotomy procedures 
normally. If the rate of these events exceeds the rate expected by the study 
team, the events will be classified and reported. Deaths related to the natural 
history of hepatitis or co-infection will be reported at the time of continuing 
review.  
9.2.2 
Annual Reporting to the IRB 
The following items will be reported to the University of Maryland IRB in summary 
at the time of Continuing Review: 
• Serious adverse events or deaths that are not related to the research 
• All adverse events associated with research including expected AEs Protocol 
deviations.  This includes AEs related to phlebotomy within 48 hours of 
procedure. 
• Serious, continuing, and minor non-compliance 
• Any trends or events which in the opinion of the investigator should be 
reported 
 


MAVERIC  
Jan, 2017 
 
Page 23 of 30 
 Type and Duration of the Follow-up of Subjects after Adverse Events 
All SAEs and non-serious AEs identified in this study will be followed until 
resolution or until the PI judges the AE/SAE has stabilized and no more follow-up 
is required.  This requirement indicates that the follow-up may be required for 
some events after the participant discontinues participation from the study.  
These events will be reported to the IRB annually. 
 Withdrawal of a Subject 
A participant may withdraw from the study at any time.  As part of their duties to 
ensure that research participants are protected, the IRB, IHV, or other 
government agencies may discontinue the study at any time.  Voluntary 
withdrawal from the protocol may occur at any time at the request of either the 
participant or the PI.  If a request is made to withdraw from the protocol, all 
further planned study procedures will be immediately cancelled and further 
follow-up will be terminated. Samples and data collected prior to this request will 
be stored and used as outlined in the protocol unless a specific request is made 
by the participant to remove all of their samples from the study. Data already 
obtained from the participant’s samples will not be discarded. In addition, 
participants with poor compliance and/or failure to present for follow-up visits 
may be withdrawn from the study at the discretion of the PI.  
 
If a patient becomes pregnant during the course of the study, the investigator, in 
consultation with the patient, should consider whether the potential benefit 
justifies the potential risk to the fetus of continuing the study therapy. If it is 
determined that the potential benefit does not outweigh the potential risk to the 
fetus, the patient should be discontinued from the study.  
 
Should a subject develop evidence of HIV virologic breakthrough, or decline in 
CD4 to less than 200 (if above 200 at baseline) during the study they will be 
evaluated by their primary HIV provider and may be withdrawn from the study at 
the discretion of the PI. 
 
Discontinuation of maraviroc will be considered in any patient with signs or 
symptoms of acute hepatitis, in particular if drug-related hypersensitivity is 
suspected or with increased liver transaminases combined with rash or other 
systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophila or 
elevated IgE).  
 
Should a subject be started on anti-HCV therapy while in the study, maraviroc 
will be discontinued and the subject will be withdrawn from the study.  
 Return of Withdrawn/Removed Subjects 
A participant who has withdrawn may not return to the study. 
 


MAVERIC  
Jan, 2017 
 
Page 24 of 30 
10 Remuneration Plan for Subjects  
Participants will be remunerated with cash for each study visit time point completed 
to help cover the cost of travel and expenses.   
 
Lab only study visits: participants will be renumerated $20 cash per visit 
Study visits with physical exams: participants will be renumerated $50 cash per 
visit. 
Viral Kinetics during initial addition of maraviroc: During the first week of maraviroc 
initiation, lab visits will occur more frequently, but will be very short. Participants 
will be renumerated on (and including) day 7 pro-rated per visit completed and will 
be renumerated an additional $50 cash on day 7 upon completion of the all lab 
visits during that time period. 
Virologic and immunologic studies: participants will be renumerated an additional 
$100 cash for completing all lab study visits for sample collection for storage (not 
including maraviroc initiation visit). 
 
11 Statistical Considerations 
 Sample size 
Primary end point is change in week 7 HCV viral load from baseline.   
 Description of the Analyses 
We estimate a 1 log drop in HCV VL in seven days is true. 
The primary efficacy analysis will be intention-to-treat and include all patients who 
were enrolled into the study and received at least one dose of the study medication. 
Demographic and baseline characteristics will be summarized using standard 
descriptive statistics. Association of adverse events with treatment duration, HIV 
coinfection, fibrosis stage, and presence of cirrhosis will be explored. A 2-sided, 
exact, 1-sample binomial test will be used to test the statistical hypothesis 
described above at a significant level of 0.05. All analyses will be performed on 
SAS, version 9.3 (Cary, NC) or STATA version 13.0. 
 
12 Ethics/Protection of Human Subjects 
 Informed Consent Process 
Informed consent is a process where information is presented to enable persons 
to voluntarily decide whether or not to participate as a research subject. It is an 
on-going conversation between the human research subject and the researchers 
which begins before consent is given and continues until the end of the subject's 
involvement in the research. Discussions about the research will provide 


MAVERIC  
Jan, 2017 
 
Page 25 of 30 
essential information about the study and include: purpose, duration, procedures, 
alternatives, risks and benefits.  Subjects will be given the opportunity to ask 
questions and have them answered.  
The subjects will personally sign and date the informed consent document prior 
to undergoing any research procedures. The subjects may withdraw consent at 
any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the subjects for their records. Consenting process will 
be documented in the record. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study.  
 
12.1.1 
Illiteracy and Consenting 
As the majority of the patient populations from which the study participants are 
drawn are literate, written consent will be obtained. Oral short form consent will 
be obtained in the case of illiterate participants with the written consent being 
presented orally by the person obtaining consent and witnessed by an impartial 
third party who will also sign the consent. The participant will be asked to sign the 
form or thumb-print the form if unable to sign 
 Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and 
local law. The study monitors and other authorized representatives of the 
Sponsor may inspect all documents and records required to be maintained by the 
Investigator, including but not limited to, medical records. Records will be kept 
locked and all computer entry and networking programs will be done with coded 
numbers only.  Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by IRB, FDA, the Joint 
Commission or the HHRP. 
 
Appendix A: Scientific References 
 
1. 
The Silent Pandemic, Tackling Hepatitis C With Policy Innovation. 2012; 
Available from: http://www.janssen-emea.com/the-silent-pandemic. 
2. 
Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet 
2008;372:321-32. 
3. 
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global 
epidemiology of hepatitis C virus infection: New estimates of age-specific 
antibody to HCV seroprevalence. Hepatology 2013;57:1333-42. 
4. 
Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus 
infection in USA: an estimate of true prevalence. Liver international : official 
journal of the International Association for the Study of the Liver 2011;31:1090-
101. 


MAVERIC  
Jan, 2017 
 
Page 26 of 30 
5. 
Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a 
systematic review. Jama 2014;312:631-40. 
6. 
Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, 
and treatment of hepatitis C: An update. Hepatology 2009;49:1335-74. 
7. 
Yehia BR, Schranz AJ, Umscheid CA, Lo Re V, 3rd. The treatment 
cascade for chronic hepatitis C virus infection in the United States: a systematic 
review and meta-analysis. PloS one 2014;9:e101554. 
8. 
Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in 
the United States. The New England journal of medicine 2013;368:1859-61. 
9. 
Sulkowski MS. Hepatitis C virus infection in HIV-infected patients. Current 
HIV/AIDS reports 2004;1:128-35. 
10. 
Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or 
hepatitis B virus coinfection. Seminars in liver disease 2004;24 Suppl 2:61-8. 
11. 
Pineda JA, Garcia-Garcia JA, Aguilar-Guisado M, et al. Clinical 
progression of hepatitis C virus-related chronic liver disease in human 
immunodeficiency virus-infected patients undergoing highly active antiretroviral 
therapy. Hepatology 2007;46:622-30. 
12. 
Friedman SR, Tempalski B, Cooper H, et al. Estimating numbers of 
injecting drug users in metropolitan areas for structural analyses of community 
vulnerability and for assessing relative degrees of service provision for injecting 
drug users. J Urban Health 2004;81:377-400. 
13. 
Harrell PT, Mancha BE, Petras H, Trenz RC, Latimer WW. Latent classes 
of heroin and cocaine users predict unique HIV/HCV risk factors. Drug Alcohol 
Depend 2012;122:220-7. 
14. 
Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus 
ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-
coinfected persons. The New England journal of medicine 2004;351:451-9. 
15. 
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-
2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. 
The New England journal of medicine 2004;351:438-50. 
16. 
Nomiyama H, Hieshima K, Nakayama T, et al. Human CC chemokine 
liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and 
CCR5, and constitutively expressed by hepatocytes. Int Immunol 2001;13:1021-
9. 
17. 
Seki E, De Minicis S, Gwak GY, et al. CCR1 and CCR5 promote hepatic 
fibrosis in mice. J Clin Invest 2009;119:1858-70. 
18. 
Larrubia JR, Benito-Martinez S, Calvino M, Sanz-de-Villalobos E, Parra-
Cid T. Role of chemokines and their receptors in viral persistence and liver 
damage during chronic hepatitis C virus infection. World J Gastroenterol 
2008;14:7149-59. 
19. 
Abdel-Hameed E, Rouster S, D, Sherman KE. Assessment of Hepatitic 
Antifibrotic Effect of Cenicriviroc in patients with HIV.  The Annual Conference on 
Retroviruses and Opportunistic Infections. Boston, USA2016. 
20. 
Lin W, Weinberg EM, Chung RT. Pathogenesis of accelerated fibrosis in 
HIV/HCV co-infection. J Infect Dis 2013;207 Suppl 1:S13-8. 


MAVERIC  
Jan, 2017 
 
Page 27 of 30 
21. 
Sherman KE, Kong L, Blackard JT. Inhibition of Hcv Replication by Ccr5 
Blockade with Cenicriviroc and Maraviroc. J Hepatol 2015;62:S684-S. 
22. 
Kattakuzhy S, Levy R, Kottilil S. Sofosbuvir for treatment of chronic 
hepatitis C. Hepatol Int 2015;9:161-73. 
23. 
Gilliam BL, Riedel DJ, Redfield RR. Clinical use of CCR5 inhibitors in HIV 
and beyond. J Transl Med 2011;9 Suppl 1:S9. 
24. 
Bower WA, Culver DH, Castor D, et al. Changes in hepatitis C virus (HCV) 
viral load and interferon-alpha levels in HIV/HCV-coinfected patients treated with 
highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2006;42:293-7. 
25. 
Wasmuth JC, Rockstroh JK, Hardy WD. Drug safety evaluation of 
maraviroc for the treatment of HIV infection. Expert Opin Drug Saf 2012;11:161-
74. 
26. 
Boesecke C, Pett SL. Clinical studies with chemokine receptor-5 (CCR5)-
inhibitors. Curr Opin HIV AIDS 2012;7:456-62. 
 
 


APPENDICES 
MAVERIC  
 
 
 
 
 
 
          July, 2016 
 
Page 28 of 30 
Appendix B: Schedule of Procedures/Evaluations  
Study 
Day/Week 
Screena 
D0  
D1 
D2  
 
D4 
D7 
W1 
D14 
W2 
D21 
W3 
D28 
W4 
D35 
W5 
D42 
W6 
D49 
W7 
D56 
W8 
 
D59 
 
 
D63 
W9 
D70 
W10 
D77 
W11 
D84 
W12 
D91 
W13 
D98 
W14 
D105 
W15 
D112 
W16 
IMMEDIATE START GROUP 
Study Visit 
 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
Administrative 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Medical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Procedures/ 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted 
Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals and 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Monitoring  
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Laboratory 
Proceures/ 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C VL  
Ⓧ 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
HIV VL  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
CD4  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
CBC with Diff  
Ⓧ 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Creatinine 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic panel 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


APPENDICES 
MAVERIC  
July, 2016 
 
Page 29 of 30 
FibroTest or 
FibroScan 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testing (if 
applicable) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research and 
Storage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pax RNA 
(2.5ml red 
paxgene) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Pax DNA 
(8.5ml blue 
paxgene) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
storage (6ml 
purple top) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Serum storage 
(10ml SST) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
PBMC storage 
(50ml green 
top) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
DELAYED START GROUP 
Study 
Day/Week 
Screena 
D0  
D2 
D3  
 
D5 
D7 
W1 
D14 
W2 
D21 
W3 
D28 
W4 
D35 
W5 
D42 
W6 
D49 
W7 
D56 
W8 
D57 
D58 
 
D60 
D63 
W9 
D70 
W10 
D77 
W11 
D84 
W12 
D91 
W13 
D98 
W14 
D105 
W15 
D112 
W16 
Study Visit 
 
1 
 
 
 
 
 
 
2 
 
 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
11 
Administrative 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Medical 
History 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Procedures/ 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitals and 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Monitoring  
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
X 


APPENDICES 
MAVERIC  
July, 2016 
 
Page 30 of 30 
Laboratory 
Proceures/ 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C VL  
Ⓧ 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
HIV VL  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
CD4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
CBC with Diff  
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Creatinine 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic panel 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FibroTest or 
FibroScan 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Testing (if 
applicable) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research and 
Storage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pax RNA 
(2.5ml red 
paxgene) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Pax DNA 
(8.5ml blue 
paxgene) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
storage (6ml 
purple top) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Serum storage 
(10ml SST) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
PBMC storage 
(50ml green 
top) 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
a Screening and day 0 visit  can occur on the same day.  
ⓍLabs from outside records from the last 6 months can be used. HCV VL at screening will only be done if no HCV VL available from outside 
records from the last 12 months. FibroTest at screening will only be done if no fibrosis staging available from outside records (see section 4.2 
Subject inclusion criteria, definitions of cirrhosis and absence of cirrhosis) 
Period of Maraviroc exposure for immediate start group 
Period of Maraviroc exporsure for delayed start group