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DDW 2013: Interferon-free Simeprevir + Sofosbuvir Suppresses Hepatitis C with or without Ribavirin

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An all-oral regimen consisting of simeprevir (formerly TMC435) plus sofosbuvir, (formerly GS-7977), with or without ribavirin, produced an 8-week post-treatment cure for most prior null responders with genotype 1 hepatitis C in the COSMOS trial, according to a poster presented at the Digestive Disease Week meeting (DDW 2013) last week in Orlando.

The addition of direct-acting antiviral agents (DAAs) to pegylated interferon and ribavirin is a paradigm shift in the treatment of chronic hepatitis C, but many patients and providers are awaiting oral regimens that omit interferon -- and possibly ribavirin as well. While several DAAs in the pipeline work well for easier-to-treat patients, the challenge now is to find regimens that are effective and tolerable for more difficult sub-groups including prior null responders and those with advanced liver disease.

Eric Lawitz from the Texas Liver Institute presented interim findings from an open-label study evaluating interferon-free combinations containing Janssen/Medivir's NS3/4A protease inhibitor simeprevir and Gilead Sciences' NS5B nucleotide analog polymerase inhibitor sofosbuvir.

COSMOS was designed to enroll 2 cohorts of prior null responders with genotype 1 HCV, stratified by IL28B gene pattern and HCV subtype (1a vs 1b). Cohort 1 included people with absent-to-moderate fibrosis (Metavir stage F0 to F2) to evaluate initial safety, followed by Cohort 2, which included patients with advanced fibrosis or cirrhosis (stage F3-F4).

The 80 participants in Cohort 1 were treatment-experienced null responders who had less than a 2-logdecline in HCV RNA with prior interferon/ribavirin therapy. Almost all had unfavorable IL28B gene variants associated with poor interferon response, and 80% had more difficult-to-treat HCV subtype 1a. About 40% had absent-to-mild fibrosis (stage F0-F1) and about 60% had moderate fibrosis (stage F2).

Participants were randomly assigned to receive 150 mg once-daily simeprevir plus 400 mg once-daily sofosbuvir either in a dual combination or with 1000-1200 mg/day weight-adjusted ribavirin, with each regimen taken for either 12 or 24 weeks.

The DDW poster focused on an interim analysis of patients in Cohort 1 who were randomized to the 12-week arm and had 8 weeks of follow-up after finishing therapy, allowing researchers to report rates of sustained virological response, or continued undetectable HCV RNA, at post-treatment week 8 (SVR8). While SVR4 is too soon to determine whether hepatitis C is cured, U.S. and European regulatory agencies consider SVR12 to be a valid measure of treatment success.

Results

  • HCV viral load declined steeply soon after starting therapy in all treatment arms.
  • No viral breakthroughs occurred during treatment.
  • At the end of treatment, all evaluable participants had undetectable HCV RNA.
  • A few patients relapsed after completing treatment, resulting in SVR8 rates of 93% in the simeprevir/sofosbuvir arm and 96% in the simeprevir/sofosbuvir/ribavirin arm.
  • The small proportion of participants who reached post-treatment week 12 maintained viral suppression.
  • There was no significant difference in efficacy between dual and triple therapy.
  • Both oral regimens were generally safe and well-tolerated.
  • Most side effects were mild-to-moderate, and there were no serious adverse events attributed to study drugs.
  • 1 patient discontinued treatment due to an adverse event.
  • Anemia was less common among people taking simeprevir/sofosbuvir without ribavirin.

The researchers concluded that simeprevir plus sofosbuvir for 12 weeks, with or without ribavirin, was effective and well-tolerated. Based on these findings, Cohort 2, looking at more difficult-to-treat cirrhotic patients, is currently underway.

5/30/13

Reference

E Lawitz, R Ghalib, M Rodriguez-Torres. SVR4 Results of a Once Daily Regimen of Simeprevir (TMC435) Plus Sofosbuvir (GSs-7977) with or without Ribavirin (RBV) in HCV GT 1 Null Responders. Digestive Disease Week. Orlando, May 18-21, 2013. Abstract Sa2073.