Reem Ghalib

Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection

BACKGROUND Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection

BACKGROUND Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

BACKGROUND High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus

BACKGROUND & AIMS We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphisms clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study

BACKGROUND Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. METHODS We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. FINDINGS 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. INTERPRETATION Combined simeprevir and sofosbuvir was efficacious and well tolerated. FUNDING Janssen.

Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1

BACKGROUND Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen. METHODS This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period. RESULTS A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range. CONCLUSIONS This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

All‐oral 12‐week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY‐3 phase III study

Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all‐oral regimens requiring 24‐week treatment and the addition of ribavirin (RBV). This phase III study (ALLY‐3; ClinicalTrials.gov: NCT02032901) evaluated the 12‐week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once‐daily for 12 weeks. Coprimary endpoints were the proportions of treatment‐naïve and treatment‐experienced patients achieving a sustained virological response (SVR) at post‐treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment‐naïve and treatment‐experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF‐containing regimen and 2 of 2 who previously failed treatment with an alisporivir‐containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV‐RNA levels, and interleukin‐28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on‐treatment, which was unrelated to study medications. The few treatment‐emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12‐week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (Hepatology 2015;61:1127–1135)

Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial

Context Various oral interferon- and ribavirin-free regimens are becoming available to treat chronic hepatitis C virus (HCV) infection. A grazoprevirelbasvir combination regimen has shown promise in phase 2 trials. Contribution This phase 3 trial found a once-daily grazoprevirelbasvir regimen to be effective and well-tolerated in patients with HCV genotype 1, 4, or 6 infection. Outcomes were similar in patients with and without cirrhosis. Caution The study did not include an active comparator, so how this regimen compares with others is unknown. Implication Grazoprevirelbasvir represents a new therapeutic option for chronic HCV infection. Chronic hepatitis C virus (HCV) infection remains a growing cause of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver transplantation (1). Effective therapy for HCV infection diminishes long-term liver-related complications and mortality (2). Convenient, oral, direct-acting antiviral regimens are being investigated for chronic HCV infection (3). Grazoprevir is an NS3/4A protease inhibitor that has high potency in vitro against HCV genotype (GT) 1, GT2, GT4, GT5, and GT6 but is less active against GT3 (4). Grazoprevir retains substantial activity against resistance-associated variants (RAVs) commonly detected after failed therapy with first-generation protease inhibitors (4, 5). Elbasvir is an NS5A inhibitor active against GT1, GT2a, GT3, GT4, GT5, and GT6, even in the presence of RAVs associated with failure of other NS5A inhibitors, such as daclatasvir and ledipasvir (6, 7). Grazoprevirelbasvir has been evaluated in an extensive phase 2 clinical development program (5, 810). The C-WORTHY study indicated that grazoprevirelbasvir with or without ribavirin for 12 weeks provided efficacious and well-tolerated therapy for monoinfected and HIVco-infected patients, treatment-naive and treatment-experienced patients, and noncirrhotic and cirrhotic patients (9, 10). The objective of the phase 3 C-EDGE Treatment-Naive trial was to evaluate the efficacy and safety profile of a once-daily, fixed-dose, oral, 12-week regimen of grazoprevirelbasvir without interferon or ribavirin in treatment-naive monoinfected patients with and without cirrhosis and with GT1, GT4, or GT6 infection. Methods Study Design The C-EDGE Treatment-Naive study was an international, randomized, blinded, placebo-controlled, parallel-group trial of a fixed-dose combination of grazoprevir 100 mg/elbasvir 50 mg for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV GT1, GT4, or GT6 infections. A historical SVR12 rate was used as the comparator for efficacy. A deferred-treatment group was included as a concurrent placebo group to assess safety; after the follow-up period, placebo recipients received open-label grazoprevirelbasvir so that all participants would receive therapy during the study. Recruitment of Study Participants Patients were recruited from general medical clinics at 60 trial centers: 4 in Australia, 4 in the Czech Republic, 5 in France, 5 in Germany, 5 in Israel, 3 in Puerto Rico, 3 in South Korea, 4 in Sweden, 3 in Taiwan, and 24 in the United States. Patients who fulfilled inclusion criteria were asked to participate in the trial. Selected clinical sites were experienced in the management and care of HCV-infected patients, with a history of successful study conduct and the capability for rapid enrollment. Sites were chosen to allow a wide geographic distribution and to ensure that requirements for minority representation, enrollment of patients with cirrhosis, and genotype distribution were met. Eligibility Criteria Adults (aged >18 years) with HCV RNA levels greater than 104 IU/mL were eligible. Hepatic fibrosis was staged by biopsy or noninvasive assessment (Appendix 1) (11). Exclusion criteria were decompensated liver disease, hepatocellular carcinoma, HIV or hepatitis B virus co-infection, uncontrolled diabetes mellitus (hemoglobin A1c level >10%), elevated prothrombin time unrelated to anticoagulation, creatinine clearance less than 50 mL/min, hemoglobin level less than 95 g/L, thrombocytopenia (platelet count <50109 cells/L), aminotransferase levels more than 10 times the upper limit of normal, or hypoalbuminemia (albumin level <30 g/L). Enrollment was constrained to meet the following targets: 20% of the participants having cirrhosis and 15% having GT4 or GT6 infection. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent ethics committees reviewed and approved the protocol and applicable amendments for each institution. Randomization and Masking After stratification by presence or absence of cirrhosis and GT1, GT4, or GT6, patients were randomly assigned in a 3:1 ratio to receive immediate or deferred therapy with grazoprevirelbasvir through a central interactive voice-response system according to a computer-generated random allocation schedule. Patients took 1 fixed-dose combination tablet of grazoprevirelbasvir (immediate-treatment group) or matching placebo (deferred-treatment group) once daily at approximately the same time, without regard to food, for 12 weeks. Patients, clinical site, and sponsor personnel were blinded to treatment assignment (except for a separate unblinded medical team that monitored virologic failures and serious adverse events). Four weeks after completion of therapy, treatment allocation was unblinded, and patients in the deferred-treatment group then received open-label grazoprevirelbasvir for 12 weeks. All patients were to be followed for 24 weeks after cessation of active study therapy (Figure 1). Figure 1. Diagram of study design. DFW = deferred follow-up week; DTW = deferred-treatment week; FU = follow-up; FW = follow-up week; GZREBR = grazoprevirelbasvir; TW = treatment week. Outcome Measures This report describes the efficacy among patients enrolled in the immediate-treatment group through 12 weeks after treatment and the safety findings among patients enrolled in both groups through 14 days after the end of therapy in the initial treatment period. Efficacy and safety results for both groups through follow-up week 24 are still being collected and will be presented in a future report. The primary efficacy outcome variable was the proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after the end of study treatment (SVR12). Virologic failures encompassed breakthrough viremia (confirmed HCV RNA level at or above the lower limit of quantification [LLOQ] during treatment after previously being below the LLOQ) and relapse (confirmed HCV RNA level at or above the LLOQ subsequent to cessation of study therapy after becoming undetectable at the end of treatment). Viral and Resistance Assays Plasma HCV RNA levels were measured by the COBAS AmpliPrep/COBAS TaqMan HCV test, version 2.0 (Roche Molecular Diagnostics, Branchburg, NJ), with an LLOQ of 15 IU/mL. Specimens for viral load measurements were collected at screening; baseline; treatment weeks 4, 8, and 12; and follow-up weeks 4, 12, and 24. Circulating viral quasi-species at baseline or at the time of virologic failure underwent population sequencing with a detection limit for variants of approximately 25% prevalence (12). The complete NS3 and NS5A genes were amplified from samples with RNA levels of 1000 IU/mL or greater by using reverse transcription polymerase chain reaction (5, 12, 13). Resultant amino acid sequences were compared with wild-type GT1a (H77; accession number NC004102), GT1b (Con1; AJ238799), GT4a (ED43; GU814265), or GT6a (EUHK2; Y12083) reference sequences. To assess the effect of baseline NS3 variants, specific amino acid loci prone to selection by early-generation NS3/4A protease inhibitors (positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175) were studied in replicon cell lines encoding mutations in a GT1a backbone (5, 14). These substitutions were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to grazoprevir. Likewise, to assess the effect of baseline NS5A variants, amino acid loci selected by NS5A inhibitors (positions 28, 30, 31, 58, and 93) were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to elbasvir in the replicon assay. Statistical Analysis The C-EDGE Treatment-Naive study was designed to randomly assign approximately 400 patients, with 300 patients in the immediate-treatment group and 100 patients in the deferred-treatment group (which served as the placebo control group for the first 12 weeks). After a 4-week follow-up period, placebo recipients were unblinded at study week 16 and received open-label grazoprevirelbasvir. The primary efficacy hypothesis exclusively applied to patients in the immediate-treatment group. Assuming a response rate of 85% or greater, the study had more than 99% power to demonstrate an SVR12 rate superior to the reference rate of 73% at an overall 1-sided value of 0.025. The historical reference rate of 73% was derived from phase 3 trials of simeprevir/peginterferon + ribavirin in treatment-naive monoinfected patients, after adjustment for the expected proportion of cirrhotic patients and the anticipated improved tolerability with an interferon-free regimen (Appendix 1) (15, 16). The primary efficacy and safety analyses were performed on the full data set, which included all patients receiving at least 1 dose of the study treatment. The primary efficacy end point was prespecified as the proportion of patients with an HCV RNA level below the LLOQ 12 weeks after the end of treatment (SVR12) (17). Missing outcome data were imputed as failures unless the values immediately before and after the missing result were both successes, in which case the absent value was imputed as a success. The 95% CIs were computed by the conservative ClopperPear

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial

BACKGROUND Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING Bristol-Myers Squibb.

Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2).

Hepatitis C virus (HCV)–infected patients with cirrhosis are historically a difficult‐to‐treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1–infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open‐label, single‐arm study (OPTIMIST‐2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1–infected treatment‐naive or treatment‐experienced patients with cirrhosis. Patients (aged 18‐70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient‐reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%‐91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment‐naive and treatment‐experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient‐reported outcomes improved from baseline to follow‐up week 12. Conclusion: Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment‐naive and treatment‐experienced HCV GT1‐infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360‐369)