Telaprevir twice-daily works as well as every eight hours, safe for hepatitis C patients with cirrhosis

Published: 23 November 2012

The hepatitis C protease inhibitor telaprevir (Incivo or Incivek) taken twice daily with pegylated interferon plus ribavirin is as likely to produce sustained virological suppression as the approved three-times-daily schedule, with similar safety and tolerability even for people with advanced liver fibrosis, according to study findings presented last week at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

The pivotal trials that supported approval of telaprevir – one of the first direct-acting antiviral agents for hepatitis C treatment – administered the drug every eight hours. But this dosing regimen is inconvenient for people taking the drug, which may result in missed doses and reduced effectiveness.

Maria Buti from Hospital Vall d'Hebron in Barcelona and colleagues conducted the phase 3 open-label OPTIMIZE trial comparing telaprevir twice-daily versus every eight hours, to see if less frequent dosing is non-inferior to the approved regimen.

OPTIMIZE enrolled 740 previously untreated patients with genotype 1 chronic hepatitis C virus (HCV), mostly in Europe and North America. About 60% were men, more than 90% were white and the mean age was 48 years. Nearly 60% had harder-to-treat HCV subtype 1a and about 70% had non-favourable IL28B gene variants. About 30% had advanced liver disease (stage F3-F4), including 14% with cirrhosis.

Participants were randomly assigned to receive telaprevir at doses of either 750mg every eight hours or 1125mg every twelve hours, both in combination with pegylated interferon alfa-2a (Pegasys) and 1000-1200mg/day weight-adjusted ribavirin.

In an intent-to-treat analysis, similar proportions of participants in both arms – 73% taking telaprevir every eight hours and 74% taking it twice daily – achieved sustained virological response twelve weeks after completing treatment (SVR12). In a per-protocol or as-treated analysis, response rates remained similar, 75% and 76%, respectively. On-treatment viral breakthrough rates were the same in both arms.

Proportions of study participants with rapid virological response at week 4 who went on to achieve SVR12 were also similar: 85% and 86%, respectively. Response rates did not differ significantly between three-times-daily and twice-daily dosing for any patient subgroup based on IL28B status or fibrosis stage. For people with cirrhosis, SVR12 rates were 49% and 54%, respectively.

Rates of serious adverse events (9% and 8%, respectively) and adverse events leading to telaprevir discontinuation (19% vs 15%, respectively) were similar in both dose schedule arms. About half of participants in both groups developed a rash. The rate of grade 3 or higher anaemia was somewhat higher in the twice-daily arm (19% vs 26%), but the difference was not statistically significant.

"In this study, with a high proportion of patients with bridging fibrosis or compensated cirrhosis, the efficacy of 1125mg [twice-daily] telaprevir was non-inferior to 750mg [every eight hours], offering the potential of simplified dosing to genotype 1 HCV-infected patients", the researchers concluded. "Safety and tolerability were generally similar between regimens and consistent with the known profile of telaprevir".

Reference

Buti M et al. OPTIMIZE trial: Non-inferiority of twice-daily telaprevir versus administration every 8 hours in treatment-naïve, genotype 1 HCV infected patients. 63rd Annual Meeting of the American Association for the Study of Liver Disease. Boston, abstract LB-8, 2012.

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