A dual oral regimen of daclatasvir plus sofosbuvir cured more than 90%
of chronic hepatitis C patients without interferon or ribavirin,
according to a report in the January 16, 2014, New England Journal of Medicine.
A series of new studies of this combination in difficult-to-treat
groups including people with HIV/HCV coinfection and liver transplant
recipients is underway.
The advent of direct-acting antiviral agents has started a revolution
in hepatitis C treatment, but many people with hepatitis C and their
care providers are awaiting all-oral regimens that avoid the notorious side-effects of interferon.
Mark Sulkowski from Johns Hopkins and fellow investigators with the AI444040 Study Group evaluated interferon-free therapy consisting of Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (formerly BMS-790052) and Gilead Science's recently approved HCV polymerase inhibitor sofosbuvir (formerly GS-7977 and PSI-7977), with or without ribavirin.
Glossary
- 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.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
This combination was initially studied before Gilead purchased
Pharmasset – the company that discovered daclatasvir – and
discontinued the research in favour of focusing on its own NS5A inhibitor, ledipasvir (GS-5885). Data from this study were previously presented in part at the 2012 AASLD Liver Meeting and the 2013 EASL International Liver Congress.
This open-label Phase 2 trial included a total of 211 participants at
18 centres in the US between June 2011 and November 2012. The study
initially enrolled 44 previously untreated participants with HCV
genotype 1 and 44 patients with HCV genotypes 2 or 3. It was then
expanded to include an additional 82 treatment-naive genotype 1 patients
and 41 who were prior non-responders to triple therapy with pegylated
interferon, ribavirin, and either boceprevir (Victrelis) or telaprevir
(Incivek).
Overall, just over half of participants (52%) were men, most (about
80%) were white, and the mean age was 52 years. A majority (63%) had
harder-to-treat HCV subtype 1a, 17% had 1b, 12% had genotype 2, and 9%
had genotype 3. The proportion with the favorable IL28B CC gene variant
ranged from about 20% to nearly 60% in the various treatment arms, being
lower for prior non-responders. About two-thirds had
moderate-to-advanced liver fibrosis or cirrhosis (stage F2-F4).
In the first stage of the study, participants received 60mg
daclatasvir once-daily plus 400mg sofosbuvir once-daily, with or
without ribavirin, for 24 weeks (some received a 7-day sofosbuvir
lead-in before adding daclatasvir). In the second stage, patients were
randomly assigned to receive the same doses of daclatasvir and
sofosbuvir, with or without ribavirin, for 12 weeks (if treatment naive)
or 24 weeks (if treatment experienced). The primary endpoint was
sustained virological response (SVR), or continued undetectable HCV RNA
(<25 IU/mL), at 12 weeks post-treatment (SVR12).