An all-oral regimen of daclatasvir plus simeprevir,
without interferon or ribavirin, led to sustained response in 85 to 95% of people
with hepatitis C genotype 1b, but this combination did not work well against
genotype 1a, researchers reported last week at the 21st Conference on
Retroviruses and Opportunistic Infections (CROI) in Boston.
The advent of direct-acting antivirals that target different steps of
the hepatitis C virus (HCV) lifecycle has begun to bring about a revolution in
treatment, curing more people in a shorter time without the side-effects of
interferon. As new medications emerge from the development pipeline, people
with hepatitis C and their doctors are eager for more data about which drugs
work best in which combinations and for which patients.
Christophe Hézode from Hôpital Henri Mondor in Paris presented findings from LEAGUE-1, a
multi-centre European trial evaluating the safety and efficacy of a dual oral
regimen of daclatasvir plus simeprevir for treatment-naive people and prior
null responders with genotype 1 chronic hepatitis C.
Bristol-Myers Squibb's NS5A inhibitor daclatasvir has shown promising
outcomes in all-oral combinations with drugs including the HCV
protease inhibitor asunaprevir and Gilead Sciences' recently approved HCV
polymerase inhibitor sofosbuvir (Sovaldi).
The daclatasvir/asunaprevir combination has been
submitted for approval in Japan, and the US FDA has designated it as a
'breakthrough therapy' for expedited review. Daclatasvir is pending
European Union approval for use with other direct-acting agents.
The main part of the LEAGUE-1 trial (AI444-062) included 147
participants with HCV genotype 1b, including 104 previously untreated patients
and 43 prior null responders. Null responders had little or no response to a
prior attempt at interferon-based therapy and are considered the most difficult
group to treat. An exploratory part of the study looked at 21 people with harder-to-treat
HCV genotype 1a.
Just over half of the study participants with HCV genotype 1b were
women, more than 90% were white and the median age was approximately 55 years.
The participants with genotype 1a were mostly white men. In both genotype
groups more than one-quarter of treatment-naive patients – but no more than 5%
of null responders – had the favourable IL28B gene variant associated with good
interferon responsiveness. About 15% of untreated patients had liver cirrhosis,
as assessed by biopsy or FibroScan, rising
to 40% of null responders. (The overall proportion of participants with
advanced fibrosis or cirrhosis was capped at 35% in the trial protocol.)
Participants with genotype 1b were randomly assigned to receive 30mg
once-daily daclatasvir plus 150mg once-daily simeprevir, either with or without
weight-based ribavirin. After 12 weeks of treatment they were re-randomised to
either stop all treatment or continue their assigned regimen for an additional
12 weeks. In the exploratory part, all participants with genotype 1a received
daclatasvir, simeprevir and ribavirin for 24 weeks.
Simeprevir is processed by the CYP450 enzyme system and can interact
with other drugs including daclatasvir. Previous pharmacokinetic studies in
healthy volunteers without hepatitis C showed that daclatasvir levels doubled
when combined with simeprevir. The 30mg dose used in LEAGUE-1 was based on these
findings, but the researchers noted that daclatasvir exposure was "less
than anticipated" in this study.
Among genotype 1b treatment-naive participants, sustained virological
response rates at 12 weeks after completing treatment (SVR12) were 85% with the
dual daclatasvir and simeprevir regimen, and 75% with the triple daclatasvir,
simeprevir, and ribavirin regimen in an intent-to-treat analysis. In an
observed analysis excluding people with missing data at week 12, the SVR12
rates were 90 and 83%, respectively.
Looking at the effect of treatment duration, 81% of treatment-naive
patients using the dual regimen for 12 weeks and 89% treated for 24 weeks
achieved SVR12. Among those receiving the triple regimen, SVR12 rates were 75%
for 12 weeks and 74% for 24 weeks, not a significant difference.
Turning to the genotype 1b prior null responders, SVR12 rates were 65%
with the dual regimen and 95% with the triple regimen in an intent-to-treat
analysis. In an observed analysis, the corresponding rates were 79 and 95%,
Looking again at treatment duration, 83% of null responders taking the
dual regimen for 12 weeks and 50% treated for 24 weeks achieved SVR12. Among
those taking the triple regimen, SVR12 rates were 100% for 12 weeks and 89% for
Overall, participants with liver cirrhosis did about as well as those
without. SVR12 rates were 56-100% for people with cirrhosis compared with
71-94% for those without cirrhosis, but the number of people with cirrhosis in
each treatment arm was small.
Of the 15 cases of observed viral breakthrough during therapy, 11
occurred at or before treatment week 8. Of the six people who experienced
post-treatment relapse, two were treated for 12 weeks, three for 24 weeks, and
one stopped treatment prematurely after two weeks.
In the exploratory genotype 1a analysis, 67% of treatment-naive
participants achieved SVR12 – including both patients with cirrhosis – while
four of the 12 (33%) experienced viral breakthrough. Seven of the nine genotype
1a null responders experienced viral breakthrough, and they were given the
option to add pegylated interferon to their regimen.
Daclatasvir and simeprevir were generally safe and well tolerated. Nine
per cent of people taking the dual regimen and 4% who used ribavirin
experienced serious adverse events; 3% and 2%, respectively, discontinued
treatment due to adverse events. Eight people developed elevated bilirubin, all
but one of them in the ribavirin arms. No one in either arm reported serious anaemia,
a potential side-effect of ribavirin.
Based on these findings, the researchers concluded that the all-oral
combination of low-dose 30mg daclatasvir plus 150mg simeprevir, both once daily,
with or without ribavirin "achieved SVR12 rates of 75-85% in
treatment-naive patients and 65-95% in prior null responders with genotype 1b
infection," while there was a "high rate of virologic breakthrough in
genotype 1a null responders."
Hézode said response rates were similar in ribavirin-containing and
ribavirin-sparing arms, "suggesting it’s possible to treat these patients without
ribavirin." Likewise, SVR rates "seem similar" in people with
and without cirrhosis. Finally, the results suggest that 12 weeks of therapy is
"optimal," and there was not a significant difference with longer
Further studies of daclatasvir in direct-acting antiviral studies –
including those with simeprevir – will use the recommended 60mg dose of
daclatasvir, the researchers noted.