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.
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
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.
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
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
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