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.
Glossary
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
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".