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Background & Aims Telaprevir plus pegylated interferon/ribavirin (TPV + PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) and TPV + PegIFN/RBV. Methods Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r + DSV + weight-based RBV, OBV/PTV/r + DSV (treatment-naïve, GT1b-infected patients only), or 12 weeks of TPV + PegIFN + weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. Results Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r + DSV + RBV, OBV/PTV/r + DSV, and TPV + PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r + DSV + RBV and TPV + PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p <0.05) and rates of hemoglobin decline to <10 g/dl (0-4% and 34-47%, respectively, p <0.05) were lower for OBV/PTV/r + DSV ± RBV than TPV + PegIFN/RBV. Conclusions Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12 week, multi-targeted OBV/PTV/r + DSV ± RBV regimens and 66-82% with 24-48 total weeks of TPV + PegIF

Background: A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). Methods: This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. Results: In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated disease

Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assign

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebocontrolled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferonalfa: 2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCVRNA< lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa: 2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1

IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. OBJECTIVE: All-oral therapy with daclatasvir (nonstructural protein 5A [NS5A] inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. INTERVENTIONS: All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR12). RESULTS: One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5%CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.

Background & Aims Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. Methods Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). Results Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those exp

Purpose: The purpose of this study was to assess the efficacy, safety and effective treatment duration of MK-5172 (hepatitis C virus [HCV] NS3/4A protease inhibitor) in combination with MK-8742 (an HCV NS5A replication complex inhibitor) +/- ribavirin in patients with HCV genotype (GT)1 infection with baseline characteristics of poor response, including either cirrhosis or prior null response to peginterferon /ribavirin (PR null). Method(s): Patients with a prior PR null response +/- cirrhosis or treatment-naive patients with cirrhosis were randomized to receive MK-5172 (100 mg QD) and MK-8742 (50 mg QD) +/- ribavirin (weight-based) for 12 or 18 weeks. Primary endpoint was the proportion of patients achieving HCV RNA<25 IU/mL 12 weeks after end of treatment (SVR12) assessed by COBAS TaqMan v2.0 (lower limit of quantitation <25 IU/mL). The study is ongoing, and all patients will have received 24 weeks of follow-up by November 2014. Result(s):253 patients were enrolled (male, 58%; African American, 6%; GT1a, 65%). Among patients treated for 12 weeks with MK-5172 + MK-8742 without RBV, 94% (28/29) of treatment-naive patients with cirrhosis and 91% (30/33) of prior PR null responders achieved SVR12 (Table). High SVR12 rates were achieved regardless of the use of ribavirin or extending the treatment duration from 12 to 18 weeks (results as of May 1, 2014). Among prior PR null patients with cirrhosis treated for 12 or 18 weeks with MK-5172 + MK-8742 +/- RBV, 95% (41/43) achieved SVR12. Final SVR12 and SVR24 results will be presented. Adverse events reported in >10% of patients were fatigue (25%), headache (24%) and asthenia (14%). Conclusion(s): Treatment with MK-5172 + MK-8742 +/- RBV demonstrated high rates of efficacy in treatment-naive patients with cirrhosis and prior PR null responders. Neither RBV nor extension of treatment duration from 12 to 18 weeks was needed to achieve SVR12 in a high proportion of patients. These results support the ongoing Phase 3 developmen

BACKGROUND: BMS-790052 is a 1st-in-class, highly selective NS5A Replication Complex Inhibitor (NS5A RCI) with pM potency and broad genotypic coverage in vitro. Treatmentnaive patients with genotype (GT)-1 chronic HCV (CHC) achieved high rates of SVR after 48 weeks of BMS-790052 + pegIFNalpha-2alpha/ribavirin (P/R) in a Phase 2a study. Phase 2b Week 12 interim results for GT-1 and 4 CHC are reported here. METHOD(S): AI444010 is a randomized, double-blind study in which patients with CHC GT-1 (n=365) or GT-4 (n=30) receive placebo, 20 mg, or 60 mg BMS-790052 + P/R for 24 or 48 weeks. Patients on BMS-790052 with HCV RNA Week 4 < LOQ (25 IU/mL) and Week 10 undetectable [Roche COBAS TaqMan High Pure v2.0] will receive 24 weeks triple therapy or 12 weeks triple therapy then 12 wks P/R. RESULT(S): For GT-1 both BMS doses had higher response rates compared to PBO. Virologic breakthrough (HCV RNA: > 1 log10 increase over nadir or >= LOQ after undetectable) occurred in 4% and 8% in the 20 mg or 60 mg arms, respectively. All GT-4 (19/19) with available Week 12 data treated with BMS 20 or 60 mg were HCV RNA undetectable compared to 50% for PBO (3/6). SAE (6-8%) and D/C to AE (4-5%) were consistent across the 20 mg, 60 mg or PBO groups. There was one death (unrelated per investigator; cause unknown) in the BMS 20 mg arm. AE were those commonly reported for P/R. Grade 3-4 laboratory abnormalities, mean levels of hemoglobin, absolute lymphocytes, absolute neutrophils, ALT, and total bilirubin at Week 12 were consistent across treatment groups, as were the use of erythropoietin (4-6%) and filgrastim (0-3%. Rash (Grade 1-4) was reported in 24%, 22%, and 28%, and led to D/C in 1, 1, and 0 patients for 20 mg, 60 mg or PBO respectively. CONCLUSION(S): Once daily BMS-790052 NS5A RCI + P/R resulted in higher rates of early virologic suppression compared to placebo in both GT-1 and 4 CHC. The majority of BMS- 790052-treated patients were eligible for 24 weeks of therapy. The AE profile of