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

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.

Time frame: 48 weeks

Population: The analysis was performed on the Full Analysis Set (FAS) which included participants who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 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.

Time frame: Baseline and Week 144

Population: Liver biopsy set consisted of 9 participants (5 MVC and 4 placebo) who had paired baseline and Week 144 liver biopsies that allowed for Ishak fibrosis scoring according to the defined secondary endpoint.

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.

Time frame: Week 144

Population: Liver biopsy set consisted of 9 participants (5 MVC and 4 placebo) who had paired baseline and Week 144 liver biopsies that allowed for Ishak fibrosis scoring according to the defined secondary endpoint.

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.

Time frame: Week 48

Population: Participants included in the statistical analysis of PK parameters were those receiving maraviroc treatment at Week 48 who had PK and liver fibrosis biomarker data available.

Plasma samples were used to determine markers of immune activation namely CD38 expression on CD4 and CD8 cells.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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.

Time frame: Week 48, 96 and 144

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 144.

Plasma samples were used to determine markers of immune activation namely CRP.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participants who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 144.

Plasma samples were used to determine markers of immune activation namely D-Dimer.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 144.

Plasma samples were used to determine markers of immune activation namely TGF beta.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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.

Time frame: 48, 96 and 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 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

Time frame: 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 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.

Time frame: 144 Weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 144.

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.

Time frame: 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 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.

Time frame: Week 96 and 144

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., 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).

Time frame: Week 48, 96 and 144

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. For calculating proportions at the analysis timepoint of interest, ie week 144, LOCF was used if the value at that timepoint was missing.

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.

Time frame: Week 48

Population: Participants included in the statistical analysis of PK parameters were those receiving maraviroc treatment at Week 48 who had PK data available.

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.

Time frame: 144 weeks

Population: 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. The median time to development was not estimable due to too few events reported under each treatment group.

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.

Time frame: 144 weeks

Population: The analysis was performed on the FAS which included participant who had received at least one dose of study drug. LOCF was used if the value at that time-point was missing, ie., week 48, 96 and 144. The median time to development was not estimable due to too few events reported under each treatment group.