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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV Coinfection

Intervention / Treatment
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* Drug: Maraviroc
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV coinfection, maraviroc, CCR5 blocker, entry inhibitor, liver disease, viral hepatitis