Wayne Greaves

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial.

BACKGROUND Rates of sustained virological response (SVR) to peginterferon-ribavirin are low in patients with hepatitis C virus (HCV) genotype 1 and HIV. We aimed to assess efficacy and safety of triple therapy with boceprevir plus pegylated interferon alfa-2b (peginterferon) and ribavirin, which increases rates of SVR in patients with HCV alone. METHODS In our double-blind, randomised controlled phase 2 trial, we enrolled adults (18-65 years) with untreated HCV genotype 1 infection and controlled HIV (HIV RNA <50 copies per mL) at 30 academic and non-academic study sites. We randomly allocated patients (1:2) according to a computer generated sequence, stratified by Metavir score and baseline HCV RNA level, to receive peginterferon 1·5 μg/kg per week with weight-based ribavirin (600-1400 mg per day) for 4 weeks, followed by peginterferon-ribavirin plus either placebo (control group) or 800 mg boceprevir three times per day (boceprevir group) for 44 weeks. Non-nucleoside reverse-transcriptase inhibitors, zidovudine, and didanosine were not permitted. The primary efficacy endpoint was SVR (defined as undetectable plasma HCV RNA) at follow-up week 24 after end of treatment. We assessed efficacy and safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00959699. FINDINGS From Jan 15, 2010, to Dec 29, 2010, we enrolled 99 patients, 98 of whom received at least one treatment dose. 40 (63%) of 64 patients in the boceprevir group had an SVR at follow-up week 24, compared with ten (29%) of 34 control patients (difference 33·1%, 95% CI 13·7-52·5; p=0·0008). Adverse events were more common in patients who received boceprevir than in control patients: 26 (41%) versus nine (26%) had anaemia, 23 (36%) versus seven (21%) pyrexia, 22 (34%) versus six (18%) decreased appetite, 18 (28%) versus five (15%) dysgeusia, 18 (28%) versus five (15%) vomiting, and 12 (19%) versus two (6%) neutropenia. Three patients who received boceprevir plus peginterferon-ribavirin and four controls had HIV virological breakthrough. INTERPRETATION Boceprevir in combination with peginterferon-ribavirin could be an important therapeutic option for patients with HCV and HIV. FUNDING Merck.

Characterization of Emergent HIV Resistance in Treatment-Naive Subjects Enrolled in a Vicriviroc Phase 2 Trial

BACKGROUND Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus. METHOD HIV-1 RNA from treatment-naive subjects who experienced virological failure in a phase 2 dose-finding trial was evaluated for coreceptor usage and susceptibility. For viruses that exhibited reduced susceptibility to vicriviroc, envelope clones were phenotypically and genotypically characterized. RESULTS Twenty-six vicriviroc-treated subjects experienced virological failure; for 24 the virus remained CCR5-tropic, and 2 had dual/X4 virus. Reduced susceptibility to vicriviroc, manifested as decreases in the maximum percent inhibition value (no increase in median inhibitory concentration), was detected in 4 of the 26 subjects who experienced virological failure. Clonal analysis of envelopes in samples from these 4 subjects revealed multiple sequence changes in gp160, principally within the variable domain 1/variable domain 2, variable domain 3, and variable domain 4 loops. However, no consistent pattern of mutations was observed across subjects. CONCLUSIONS In this study, only a small proportion of treatment failures were associated with tropism changes or reduced susceptibility to vicriviroc. Genotypic analysis of cloned env sequences revealed no specific mutational pattern associated with reduced susceptibility to vicriviroc, although numerous changes were observed in the variable domain 3 loop and in other regions of gp160.

Vicriviroc plus optimized background therapy for treatment-experienced subjects with CCR5 HIV-1 infection: Final results of two randomized phase III trials

BACKGROUND Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/μL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).

Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4–5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. METHODS In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. FINDINGS Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. INTERPRETATION These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme.

50 BOCEPREVIR PLUS PEGINTERFERON/RIBAVIRIN FOR THE TREATMENT OF HCV/HIV CO-INFECTED PATIENTS: END OF TREATMENT (WEEK 48) INTERIM RESULTS

366 International Liver Congress 2012 47th Annual Meeting of the European Association for the Study of the Liver Barcelona, Spain April 20, 2012

Elbasvir/grazoprevir does not worsen renal function in patients with hepatitis C virus infection and pre-existing renal disease

Treatment options have been limited for patients with hepatitis C virus (HCV) infection and chronic kidney disease stage 4/5 (CKD 4/5). The aim of this analysis was to evaluate the impact of elbasvir/grazoprevir (EBR/GZR) on estimated glomerular filtration rate (eGFR) in patients with CKD stage 3 enrolled in phase II/III clinical trials.

Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist—Vicriviroc

BACKGROUND Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIVs entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop. OBJECTIVES To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials. STUDY DESIGN Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff. RESULTS 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed. CONCLUSIONS In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.