Elsevier

The Lancet

Volume 385, Issue 9973, 21–27 March 2015, Pages 1075-1086
The Lancet

Articles
Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial

https://doi.org/10.1016/S0140-6736(14)61795-5Get rights and content

Summary

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 assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]).

Interpretation

Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

Funding

Merck & Co, Inc.

Introduction

Globally, 80–185 million people are infected with hepatitis C virus (HCV) according to recent estimates.1, 2, 3 In the coming decades, the number of patients with HCV needing medical care will increase, because of initiatives such as that from the US Centers for Disease Control and Prevention (which has recommended HCV screening for people born between 1945 and 1965) and the universal recognition that many people with HCV have yet to be diagnosed.4, 5, 6 Without therapy, 16% of people with chronic HCV will develop liver cirrhosis within 20 years after infection, and rising to 41% within 30 years.7 In many countries, the number of patients with advanced liver diseases (cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma) is expected to increase as the population infected with HCV ages.8 The number of people infected with HCV who have cirrhosis is projected to peak in the USA at between 626 500 and 1 million in 2015–20.9, 10 Roughly 500 000 deaths in 2010 worldwide were attributable to liver cirrhosis and hepatocellular carcinoma due to HCV.11 Effective therapy and virological cure reduce long-term complications, including hepatic decompensation and hepatocellular carcinoma.12, 13 Together, these facts point to the growing medical need of patients with chronic HCV infection for interventions that will treat and cure their infection.

Available first-line therapies for HCV infection approved for patients with chronic HCV genotype 1 (according to the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver) include sofosbuvir plus pegylated interferon (peginterferon) plus ribavirin, and simeprevir plus peginterferon plus ribavirin, yet these regimens are less effective and worse tolerated in patients with cirrhosis than in previously untreated patients without cirrhosis.14, 15, 16 The sustained virological response rates for sofosbuvir plus peginterferon plus ribavirin in previously untreated patients were 92% for those without cirrhosis and 80% for those with cirrhosis (Metavir fibrosis stage F4).14 The efficacy of simeprevir, peginterferon, and ribavirin was 83–85% in previously untreated patients with HCV genotype 1 and no cirrhosis (Metavir fibrosis stage F0–F2), but only 58–65% in previously untreated patients with cirrhosis (F4) and 53% in patients who had a null response to previous treatment with peginterferon plus ribavirin (PR-null responders).15, 16, 17 The only all-oral regimen currently approved for interferon-ineligible patients with HCV genotype 1 is sofosbuvir plus ribavirin for 24 weeks.18, 19, 20 This regimen, despite a 24-week duration, showed overall efficacy of only 68% (17 of 25 patients) in previously untreated patients without cirrhosis who were chronically infected with HCV genotype 1, but efficacy decreased to 50% (three of six patients) in patients with advanced fibrosis.18 Therapy with peginterferon plus first-line protease inhibitors plus ribavirin in patients with cirrhosis was not well tolerated, with high frequency of serious adverse events.21 Thus, there remains a high medical need for an interferon-free, all-oral, short-duration HCV therapy that is highly effective across all patient populations, including patients with cirrhosis.

Grazoprevir and elbasvir (Merck & Co, Inc, Whitehouse Station, NJ, USA) are highly potent HCV-specific inhibitors of the NS3/4A protease (grazoprevir) and the NS5A protein (elbasvir).22, 23 The combination of grazoprevir and elbasvir has a high barrier to resistance and activity against common resistance-associated variants of HCV.24

In a phase 2 efficacy and safety study, we aimed to assess an all-oral, once-daily combination regimen of grazoprevir plus elbasvir, with or without twice-daily ribavirin, in patients with chronic HCV genotype 1 infection who were previously untreated and who had well compensated cirrhosis, or were previous null responders to peginterferon plus ribavirin with or without cirrhosis. We aimed to examine the need for ribavirin and varying treatment durations, the efficacy and safety of the combination of grazoprevir and elbasvir plus ribavirin, and provide guidance for the design of future studies.

Section snippets

Study design and participants

C-WORTHY (protocol 035) was a phase 2, parallel-group, multicentre, open-label, international randomised trial enrolling diverse populations; in this report, we describe all patients enrolled in two patient cohorts: cohort 1, consisting of previously untreated patients with well compensated cirrhosis (Child-Pugh A) with HCV genotype 1 infection; and cohort 2, consisting of previously treated patients who were null responders to previous therapy with peginterferon plus ribavirin with or without

Results

Study enrolment began in Feb 27, 2013, and data collection for SVR12 concluded in July 2, 2014. A total of 471 patients were enrolled in the C-WORTHY study; here, we describe findings for 253 patients enrolled in part B of the study who were previously untreated and had cirrhosis (cohort 1, n=123, arms B4–7) or who were PR-null, with or without cirrhosis (cohort 2, n=130, arms B8–11). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin [arm B4 of the trial]

Discussion

In this open-label phase 2 study of an HCV NS3 protease inhibitor (grazoprevir) plus an HCV NS5A inhibitor (elbasvir) with or without ribavirin in HCV genotype 1-infected populations that are difficult to cure with HCV therapy (patients with well compensated cirrhosis and null responder patients with or without well compensated cirrhosis), high rates of efficacy were shown across all groups irrespective of the inclusion of ribavirin or extension of treatment duration from 12 to 18 weeks.

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