A Study Of Maraviroc In HIV Co-Infected Subjects With Hepatitis C And/Or Hepatitis B

A Multicenter, Randomized, Blinded, Placebo-controlled Study To Evaluate The Safety Of Maraviroc In Combination With Other Antiretroviral Agents In Hiv-1-infected Subjects Co-infected With Hepatitis C And/or Hepatitis B Virus

To describe liver enzyme elevations in patients who are coinfected with HIV and either Hepatitis C (HCV) and/or Hepatitis B (HBV) receiving maraviroc or placebo in combination with their current suppressive anti-HIV drug therapy.

Study Overview

• Status: Completed
• Conditions: HIV Coinfection
• Intervention / Treatment: Drug: Maraviroc; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno
• France
  • Lyon cedex 4, France, 69317
    • Hôpital de la Croix Rousse
  • Paris, France, 75020
    • Hopital Tenon, Service des Maladies Infectieuses
  • Paris CEDEX 14, France, 75679
    • Centre Hospitalier Cochin Saint Vincent de Paul
• Germany
  • Berlin, Germany, 12157
    • EPIMED - Gesellschaft fuer epidemiologische und klinische Forschung in der Medizin mbH
  • Bonn, Germany, 53127
    • Universitaetsklinikum Bonn, Immunologische Ambulanz HIV
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Hamburg, Germany, 20099
    • Ifi - Studien und Projekte GmbH
  • Koeln, Germany, 50937
    • Klinikum der Universitaet zu Koeln
  • Muenchen, Germany, 80336
    • Ludwig-Maximilians-Universitaet
• Hungary
  • Budapest, Hungary, 1097
    • Egyesitett Szent Istvan es Szent Laszlo Korhaz Rendelointezet
• Poland
  • Bydgoszcz, Poland, 85-030
    • Wojewodzki Szpital Obserwacyjno - Zakazny im. Tadeusza Browicza w Bydgoszczy
  • Warszawa, Poland, 01-201
    • SPZOZ Wojewodzki Szpital Zakazny
  • Dolnoslaskie
    • Wroclaw, Dolnoslaskie, Poland, 50-220
      • EMC Instytut Medyczny S.A. Przychodnia przy ul. Lowieckiej
• Puerto Rico
  • Ponce, Puerto Rico, 00717-1567
    • Ararat Research Center
  • San Juan, Puerto Rico, 00935
    • Farmacia UPR-CTU
  • San Juan, Puerto Rico, 00935
    • University of Puerto Rico - School of Medicine
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall dHebron
  • Cordoba, Spain, 14004
    • Hospital Reina Sofia Hospital Provincial
  • Madrid, Spain, 28029
    • Hospital Carlos III
  • Sevilla, Spain, 41014
    • Hospital Nuestra Senora de Valme
  • Valencia, Spain, 46014
    • Consorcio Hospital General Universitario de Valencia
• United Kingdom
  • London, United Kingdom, SW10 9NH
    • St Stephen's AIDS Trust
  • London, United Kingdom, SE1 7EH
    • Harrison Wing Research Office, Guys and St. Thomas NHS Foundation Trust
• United States
  • California
    • Bakersfield, California, United States, 93301
      • The Office of Dr. Franco Antonio Felizarta, M.D.
    • Los Angeles, California, United States, 90015
      • AIDS Research Alliance
    • Oakland, California, United States, 94602
      • Alameda Health System - Highland Hospital
    • Sacramento, California, United States, 95817
      • University of California
    • Sacramento, California, United States, 95811
      • University of California Davis Research
    • San Francisco, California, United States, 94110
      • University of California, San Francisco - Hepatitis/HIV Clinical Trials Group (HHCTG)
    • San Francisco, California, United States, 94115
      • University of California, San Francisco - Mt. Zion Hospital
  • Florida
    • Miami, Florida, United States, 33137
      • Community AIDS Resource Inc dba Care Resource
    • Tampa, Florida, United States, 33602
      • University of South Florida Health - HIV Clinical Research Unit
    • Wilton Manors, Florida, United States, 33305
      • Rowan Tree Medical, P.A.
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Regents Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Faculty Practice Associates
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Charlotte, North Carolina, United States, 28209
      • I.D. Consultants, P.A.
  • Oregon
    • Clackamas, Oregon, United States, 97015
      • Kaiser Permanente Sunnybrook Medical Office
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center at Dallas
    • Dallas, Texas, United States, 75219
      • Southwest Infectious Disease Clinical Research Inc.
    • San Antonio, Texas, United States, 78207
      • University Health Care Center Downtown

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV coinfected with HCV and/or HBV.
• Undetectable HIV-1 RNA for at least 3 months prior to the screening visit
• Treatment with current antiretroviral therapy (3-6 drugs excluding low-dose ritonavir) for at least 5 months.

Exclusion Criteria:

• Currently receiving maraviroc.
• Active opportunistic infections.
• ALT and/or AST >5x upper limit of normal.
• Direct bilirubin >1.5x upper limit of normal.
• Severe or decompensated liver disease.
• Liver disease unrelated to viral hepatitis infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 2	Drug: Placebo; 150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy
Experimental: 1.0	Drug: Maraviroc; 150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy; Other Names: Selzentry, Celsentri

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Grade 3 and Grade 4 Alanine Aminotransferase (ALT) Abnormalities at Week 48	Percentage of participants with Grade 3 or Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, up to and including Week 48 in the maraviroc arm versus the placebo arm. The baseline was defined as the last measurement prior to Day 1 dosing.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Through Week 144	Percentage of participants with Grade 3 or Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, up to and including Week 96 and Week 144 in the maraviroc arm versus the placebo arm. The baseline was defined as the last measurement prior to Day 1 dosing.	Week 96 and 144
Time to Development of Grade 3 and Grade 4 ALT Abnormalities	Time taken in days to development of Grade 3 and Grade 4 ALT abnormalities defined as >5x ULN for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, at Week 144.	144 weeks
Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Associated With a Change From Baseline ALT >100 IU/L	Percentage of participants who had Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >100 IU/L during the 144-week period. Baseline will be defined as the last measurement prior to Day 1 dosing.	144 weeks
Time to Development of Grade 3 and Grade 4 ALT Abnormalities at Week 144 Associated With a Change From Baseline ALT >100 IU/L	Time to development of Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >100 IU/L during the 144-week period. Baseline will be defined as the last measurement prior to Day 1 dosing.	144 weeks
Number of Participants With Hy's Law Abnormalities Through Week 144	Hy's law was defined as a total bilirubin >2x ULN with a simultaneous ALT or aspartate transaminase (AST)>3x ULN, excluding participants with an alkaline phosphatase>3x ULN	144 weeks
Percentage of Participants With Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Concentration <40 Copies/mL at Week 48, 96 and 144	The Food and Drug Administration (FDA's) snapshot algorithm was used to derive the efficacy endpoint of the proportion of participants with HIV-1 RNA <40 copies/mL at Week 48. This algorithm included the missing data imputation method and used the plasma HIV-1 RNA concentration in the visit window only, followed the "virology-first principle" and considered a participant who had a missing plasma HIV-1 RNA concentration, or switched to a prohibited background anti-retroviral regimen or discontinues from the study or study drug as a failure (MSDF).	Week 48, 96 and 144
Mean Change From Baseline in CD4+ and CD8+ Cell Counts at Week 48, 96 and 144	Immunologic response (magnitude of change in CD4+ and CD8+ cell counts from baseline) was measured. Baseline value for CD4 and CD8 is defined as the pre-dose measurement taken at Day 1 visit.	Week 48, 96 and 144
Mean Change From Baseline in CD38 Expression on CD4 and CD8 Cells at Weeks 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely CD38 expression on CD4 and CD8 cells.	48, 96 and 144 weeks
Mean Change From Baseline in Markers of Immune Activation: C-reactive Protein (CRP) - Week 48, 96 and 144.	Plasma samples were used to determine markers of immune activation namely CRP.	48, 96 and 144 weeks
Mean Change From Baseline in Markers of Immune Activation: D Dimer - Week 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely D-Dimer.	48, 96 and 144 weeks
Mean Change From Baseline in Markers of Immune Activation: Transforming Growth Factor-beta (TGF Beta) - Week 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely TGF beta.	48, 96 and 144 weeks
Mean Change From Baseline in Log10 Plasma Hepatitis C Virus (HCV) RNA at Week 48, 96 and 144	Plasma samples were used to determine HCV RNA using the Roche COBAS Ampliprep/COBAS HCV Taqman assay, RUO version (LOD=15 IU/mL).Baseline value for HCV RNA/HBV DNA is defined as the pre-dose measurement taken at Day 1 visit.	48, 96 and 144 weeks
Mean Change From Baseline in Plasma Hepatitis B Virus (HBV) DNA at Week 48, 96 and 144	Plasma samples were used to determine HBV DNA using the Roche COBAS Taqman HBV assay. Baseline value for HCV RNA/HBV DNA is defined as the pre-dose measurement taken at Day 1 visit.	48, 96 and 144 weeks
Mean Change From Baseline in Enhanced Liver Fibrosis (ELF) Test at Week 48, 96 and 144	The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on an ADVIA Centaur XP and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1). ELF score < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis.	48, 96 and 144 weeks
Mean Change From Baseline in the Hepatic Elastography (FibroscanTM) at Week 48, 96 and 144	Participants had transient hepatic elastography using FibroScan technology. It rapidly and non invasively measures hepatic tissue stiffness. Through a probe, a low frequency vibration of low amplitude is transmitted to the liver. The velocity of the wave that is generated during the procedure correlates directly with tissue stiffness as it passes through the liver; the harder or stiffer the liver, the faster the shear wave propagates. Results are reported in kilopascals (kPa). A negative change in the fibroscan values (i.e. decrease in liver stiffness) correlates with a decrease in fibrosis and thus improved outcome.	48, 96 and 144 weeks
Absolute Fibrosis Score (Ishak) in Liver Biopsy Samples at Baseline and at Week 144	Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and α smooth muscle actin staining for activated stellate cells. Samples were collected, processed, stored and shipped in accordance with the procedure documented in a separate handling document. The Ishak fibrosis scoring system was used to score the fibrosis observed, with a minimum score of 0 and maximum score of 6 (where 0 = no fibrosis, 1 = expansion of some portal areas with or without septa, 2 = expansion of most portal areas with or without septa, 3 = expansion of most portal areas with occasional portal or portal bridging, 4 = expansion of portal areas with marked bridging [portal-portal and/or portal-central], 5 = marked bridging with occasional nodules [incomplete cirrhosis], 6 = cirrhosis, probable or definitive). The scores for liver biopsies were summarized based upon the availability of liver biopsy results.	Baseline and Week 144
Change From Baseline in Fibrosis Score (Ishak) in Liver Biopsy Samples at Week 144	Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and α smooth muscle actin staining for activated stellate cells. Samples were collected, processed, stored and shipped in accordance with the procedure documented in a separate handling document. The Ishak fibrosis scoring system was used to score the fibrosis observed, with a minimum score of 0 and maximum score of 6 (where 0 = no fibrosis, 1 = expansion of some portal areas with or without septa, 2 = expansion of most portal areas with or without septa, 3 = expansion of most portal areas with occasional portal or portal bridging, 4 = expansion of portal areas with marked bridging [portal-portal and/or portal-central], 5 = marked bridging with occasional nodules [incomplete cirrhosis], 6 = cirrhosis, probable or definitive). The scores for liver biopsies were summarized based upon the availability of liver biopsy results.	Week 144
Percentage of Participants Who Were Hospitalized Due to Hepatic Disease Through Week 144	Healthcare resource utilization data was collected using the Healthcare Resource Utilization Questionnaire at all study visits except Screening and Baseline. Other components of healthcare resource utilization, including length of hospital stay, type of ward, associated investigative and therapeutic procedures and concomitant medications were captured from primary and secondary data sources.	144 Weeks
Summary of Estimated Maraviroc PK Parameters	Week 4 and Week 48 clinic visits were scheduled such that a trough sample may be taken within a time window of 8-16 hours after the previous dose (Ctrough). Blood samples (4mL) were collected from all participants at the Week 4 and 48 visits.	Week 48
Exposure-response Relationship Between Change From Baseline in Liver Fibrosis Biomarkers Versus MVC Cavg at Week 48	The relationship between change from baseline in liver fibrosis biomarkers (AST, ALT, ALK, BIL, ELF and FSCN) versus MVC Cavg was analyzed using Bayesian methods. P-values were assessed for significance in the relationship between liver fibrosis biomarkers and MVC Cavg. P-value <0.05 was regarded as significantly related.	Week 48

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Rockstroh JK, Plonski F, Bansal M, Fatkenheuer G, Small CB, Asmuth DM, Pialoux G, Zhang-Roper R, Wang R, Pineda JA, Heera J. Hepatic safety of maraviroc in patients with HIV-1 and hepatitis C and/or B virus: 144-week results from a randomized, placebo-controlled trial. Antivir Ther. 2017;22(3):263-269. doi: 10.3851/IMP3116. Epub 2016 Dec 7.
• Rockstroh JK, Soriano V, Plonski F, Bansal M, Fatkenheuer G, Small CB, Asmuth DM, Pialoux G, Mukwaya G, Jagannatha S, Heera J, Pineda JA. Hepatic safety in subjects with HIV-1 and hepatitis C and/or B virus: a randomized, double-blind study of maraviroc versus placebo in combination with antiretroviral agents. HIV Clin Trials. 2015 Mar-Apr;16(2):72-80. doi: 10.1179/1528433614Z.0000000011. Erratum In: HIV Clin Trials. 2015 Nov;16(6):236-8.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2011
• Primary Completion (Actual): April 23, 2013
• Study Completion (Actual): March 24, 2015

Study Registration Dates

• First Submitted: March 22, 2011
• First Submitted That Met QC Criteria: March 31, 2011
• First Posted (Estimate): April 1, 2011

Study Record Updates

• Last Update Posted (Actual): December 6, 2017
• Last Update Submitted That Met QC Criteria: November 2, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: liver disease; maraviroc; HIV coinfection; viral hepatitis; CCR5 blocker; entry inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; HIV Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis C; Coinfection; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Maraviroc
• Other Study ID Numbers: A4001098; 2010-021994-35 (EudraCT Number)