Interferon-free simeprevir + sofosbuvir suppresses hepatitis C with or without ribavirin

An all-oral regimen consisting of simeprevir (formerly TMC435) plus sofosbuvir, (formerly GS-7977), with or without ribavirin, produced an 8-week post-treatment sustained response 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 month 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 virus (HCV), but many people living with hepatitis C and their care 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 analogue polymerase inhibitor sofosbuvir.

COSMOS was designed to enrol two 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 people 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-log decline in HCV RNA with prior interferon/ribavirin therapy. Almost all had unfavourable 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 150mg once-daily simeprevir plus 400mg once-daily sofosbuvir either in a dual combination or with 1000-1200mg/day weight-adjusted ribavirin, with each regimen taken for either 12 or 24 weeks.

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

• 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 people had a relapse 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.
• Anaemia 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 people with cirrhosis, is currently underway.