An interferon-free regimen of daclatasvir plus sofosbuvir, with or without
ribavirin, cured all previously treated hepatitis C (HCV) patients who did not
respond to interferon-based triple therapy using the approved HCV protease
inhibitors boceprevir (Victrelis) or telaprevir (Incivo or Incivek),
according to a report on Saturday at the 48th
International Liver Congress (EASL 2013) in Amsterdam.
The advent of direct-acting antivirals has changed the treatment paradigm
for chronic hepatitis C. Yet many people with progressive liver disease are not
in a position to wait for all-oral regimens, and no options have been proven
effective for people who experience treatment failure on the latest standard-of-care
regimen consisting of pegylated interferon, ribavirin and one of the approved
HCV NS3 protease inhibitors, boceprevir or telaprevir.
Mark Sulkowski from Johns Hopkins University and colleagues conducted a
proof-of-concept study to evaluate an all-oral regimen containing Bristol-Myers
Squibb's NS5A replication complex inhibitor daclatasvir (formerly BMS-790052)
plus Gilead Sciences' nucleotide analogue HCV polymerase inhibitor sofosbuvir
(formerly GS-7977), with or without ribavirin, for people who experienced
treatment failure with boceprevir or telaprevir.
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.
As Dr Sulkowski previously
reported at The Liver Meeting in November 2012, the daclatasvir/sofosbuvir
combination was shown to be highly effective, demonstrating near complete
sustained virological response for previously untreated patients.
The current study enrolled 41 people with genotype 1 chronic hepatitis C, more
than 80% of whom had harder-to-treat subtype 1a. Nearly two-thirds were men,
90% were white and the median age was 58 years (older than the population in
most hepatitis C trials). People with known liver cirrhosis were excluded from
the study, but more than 80% had estimated Metavir scores of F2 (moderate
fibrosis) or higher according to non-invasive tests. Almost all had
unfavourable (CT or TT) IL28B gene patterns.
Most (about 80%) had previously used telaprevir, while about 20% had used
boceprevir. Participants were roughly evenly divided between prior
non-responders (continued detectable HCV RNA at the end of treatment), prior
viral breakthroughs on treatment, and prior relapsers. Those who had stopped
boceprevir or telaprevir due to adverse events were excluded. Nearly half still
had boceprevir or telaprevir resistance mutations, even though the median time
since last treatment was four years.
Study participants were randomly assigned to receive 60mg once-daily
daclatasvir plus 400mg once-daily sofosbuvir, either as a dual regimen or with
1000-1200mg/day weight-based ribavirin, for 24 weeks.
Viral decline was robust and rapid, with all participants on dual therapy
and all but one on triple therapy reaching undetectable viral load by treatment
week 4. The rate of viral decline did not differ according to pre-existing
resistance mutations. End-of-treatment response rates at the end of 24 week
were 100% for both groups. All participants had sustained virological response
(SVR) at 4 weeks post-treatment (SVR4).
At 12 weeks post-treatment, SVR12rates were 100% in the
sofosbuvir/daclatasvir arm and 95% in the sofosbuvir/daclatasvir/ribavirin arm.
Dr Sulkowski explained, however, that the one patient who did not show up for
the 12-week post-treatment visit – and was counted as a non-responder in the
intent-to-treat (missing = failure) analysis – came back for the 24-week
post-treatment visit and still had undetectable HCV. Therefore, SVR24 rates
were 100% in both arms. No virological failures or relapses occurred.
Treatment was generally safe and well tolerated in both groups. There was a
single serious adverse event in the triple-therapy arm, but no discontinuations
for this reason. Side-effects were generally similar in both groups. People
receiving ribavirin reported more fatigue and gastrointestinal symptoms, but
none developed serious anaemia.
The researchers concluded that the all-oral, once-daily combination of
daclatasvir plus sofosbuvir with or without ribavirin achieved SVR in all HCV
genotype 1 patients who had experienced prior treatment failure with boceprevir
or telaprevir and pegylated interferon/ribavirin.
"Neither baseline NS3 protease inhibitor resistance variants nor use of
ribavirin influenced response," they continued. "These data provide proof-of-concept
that the combination of two potent direct-acting antivirals with different
viral targets is effective in patients who failed [pegylated
interferon/ribavirin] plus a protease inhibitor."
"We can tell our
patients who failed triple therapy they now appear to have a path forward
toward a cure," Dr Sulkowski said.