12-week all-oral combination of simeprevir plus sofosbuvir led to sustained
virological response in 93% of genotype 1 prior null responders with
mild-to-moderate liver fibrosis, working as well as a longer course of
treatment or triple therapy including ribavirin, according to late-breaking
findings from the COSMOS trial presented yesterday at 'The Liver Meeting 2013', the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD) in
also showed that 100% of treatment-naive patients and null responders with
advanced fibrosis or cirrhosis achieved early sustained response at 4 weeks
post-treatment using the same dual regimen.
The advent of
next-generation direct-acting antivirals (DAAs) has been described as a
revolution in the treatment of chronic hepatitis C virus (HCV) infection. While
the first of these new agents will initially be approved as add-ons to
interferon-based therapy, people with hepatitis C and their clinicians are
eagerly awaiting interferon-free regimens.
Multiple DAAs developed
by several major drug companies have performed well in all-oral regimens in
trials to date, but their effectiveness varies based on a bewildering array of
factors including HCV subtype (1b vs 1a), host IL28B gene pattern ('CC' vs
non-'CC'), prior treatment status (untreated, relapser, prior partial or null
responder) and extent of liver damage (absent, mild or moderate fibrosis vs
advanced fibrosis or cirrhosis).
Ira Jacobson of Weill Cornell Medical College presented
findings from the phase 2a COSMOS trial, evaluating oral regimens containing
Janssen/Medivir's HCV protease
inhibitor simeprevir (formerly TMC435) and Gilead Science’s nucleotide
polymerase inhibitor sofosbuvir (formerly GS-7977), taken with or without
This open-label study
enrolled two cohorts of patients with genotype 1 chronic hepatitis C:
- Cohort 1: 80 prior
interferon null responders with absent-to-moderate fibrosis (Metavir stage
- Cohort 2: 87 treatment-naive
individuals and prior null responders with advanced fibrosis or compensated
About 60% of
participants in Cohort 1 were men, 29% were black and the median age was 56
years. Just over three-quarters had harder-to-treat HCV subtype 1a, and half of
these had the Q80K resistance mutation at baseline. Only 6% had the favourable
IL28B 'CC' gene variant associated with good interferon responsiveness –
typical of null responders. About 40% had stage F0-F1 fibrosis while 60% had F2.
In Cohort 2,
two-thirds were men, 9% were black and the median age was 58 years. Again 78%
had subtype 1a, 40% with the Q80K mutation. Participants were about evenly
divided between treatment-naives and null responders, and 21% had the
favourable 'CC' variant. Just over half had advanced fibrosis, the rest
randomly assigned to receive a dual regimen of 150mg once-daily simeprevir plus
400mg once-daily sofosbuvir, or else a triple regimen of these two drugs plus
1000-1200mg weight-based ribavirin taken twice-daily. In addition, they were
randomised to receive these regimens for either 12 or 24 weeks.
results from a planned interim analysis. Cohort 1 started earlier and had long
enough follow-up to determine sustained virological response at 12 weeks after
completing treatment (SVR12), which is considered a cure. Cohort 2 started
later and had 4-week post-treatment follow-up results (SVR4), which is too soon
to declare them cured as relapses could still occur.
participants treated for 12 weeks completed therapy in both cohorts. In Cohort
1, about 87% treated for 24 weeks finished therapy. Two people in the dual
therapy arm and three in the triple therapy arm stopped early, one in each arm
due to adverse events. More than 90% of Cohort 2 participants treated for 24
weeks were still in treatment or follow-up; again one in each arm discontinued
due to adverse events.
All Cohort 1
participants who completed therapy had undetectable HCV RNA at the end of
treatment and no viral breakthroughs occurred. Amongst those treated for 12
weeks, 93% taking simeprevir/sofosbuvir and 96% taking
simeprevir/sofosbuvir/ribavirin achieved SVR12. There was one relapse in each
regimen arm. Amongst those treated for 24 weeks, SVR12 rates were 93% and 79%,
respectively. There was one relapser and four people with 'non-virological
failure' in the ribavirin arm.
In Cohort 2,
all 14 participants who completed therapy had undetectable end-of-treatment
viral load with no breakthroughs. One hundred per cent of both treatment-naive patients and
null responders taking simeprevir/sofosbuvir who had adequate follow-up (seven
of each) achieved SVR4, as did 100% of naive participants and 93% of null
responders (all but one) treated with simeprevir/sofosbuvir/ribavirin.
cohorts, 100% of people with HCV subtype 1b or with subtype 1a but lacking the
Q80K mutation achieved SVR12 or SVR4. Three relapsers in Cohort 1 and one in
Cohort 2 had subtype 1a with the mutation (SVR12 of 89% and SVR4 of 91%,
looked at the effect of adding ribavirin to the 12-week course of therapy for
difficult-to-treat subgroups in both cohorts combined. Amongst people with
unfavourable IL28B status, 96% taking either the ribavirin-sparing or
the ribavirin-containing regimen achieved SVR4. Amongst prior null responders the
SVR4 rate was 95% using either regimen. Amongst people with cirrhosis, SVR4
rates were 100% without and 91% with ribavirin.
generally safe and well tolerated. Amongst people treated for 12 weeks in both
cohorts combined, there were no serious adverse events, grade 3-4 laboratory
abnormalities or discontinuations due to adverse events with either regimen.
Amongst people treated for 24 weeks, serious adverse events were rare (3 to 4%)
and there were two discontinuations due to adverse events in both regimen arms.
The most common
side-effects were fatigue, headache, nausea and insomnia, which occurred with
similar frequency in both the ribavirin-sparing and ribavirin-containing arms.
Anaemia and elevated bilirubin, however, were more common amongst ribavirin
Based on these
findings the researchers concluded that treatment with simeprevir plus
sofosbuvir, with or without ribavirin, resulted in high SVR12 rates (79 to 96%) in
HCV genotype 1 null responders with stage F0-F2 fibrosis, as well as high SVR4
rates (96 to 100%) in treatment-naive and null responder patients with stage F3 fibrosis or
ribavirin to simeprevir and sofosbuvir "may not be needed to achieve high
rates of SVR in this patient population," they added. "12 weeks of
treatment may confer similar SVR rates compared with 24 weeks of
Given last month's recommendation for approval of both simeprevir and
sofosbuvir by a US Food and Drug Administration advisory committee, Jacobson
was asked about the prospect of using these drugs together off-label as an
interferon-free regimen, especially for patients with advanced disease who need
treatment now but cannot tolerate ribavirin.
"It's difficult to provide definitive
guidance," Jacobson replied. "But all of us want to help our
patients, and it's not difficult to imagine extrapolating from these