A 12-week, once-daily regimen of the
hepatitis C (HCV) polymerase inhibitor sofosbuvir and the NS5A inhibitor daclatasvir,
without interferon or ribavirin, produced sustained virological response rates
treatment-naive people in the 90 to
100% range, and appeared effective regardless of HCV subtype, IL28B host gene
pattern or use of ribavirin, according to a late-breaker presentation this
week at The Liver Meeting 2012, the 63rd Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) in Boston.
Last year's approval of the first direct-acting hepatitis C drugs
ushered in a new era of treatment, but many patients and providers are awaiting
all-oral therapy without pegylated interferon and its difficult side-effects,
and – if possible – without ribavirin, which causes anaemia.
It has become difficult to keep track of the numerous investigational
anti-HCV drugs in the pipeline and the many different combination regimens
under study, but one that stands out is Gilead Sciences' nucleotide analogue
polymerase inhibitor sofosbuvir (formerly
GS-7977 and before that PSI-7977)
together with Bristol-Myers Squibb's
first-in-class HCV NS5A replication complex inhibitor daclatasvir (formerly BMS-790052).
Although its mechanism of action is not fully understood, NS5A appears
to play an important role in HCV replication in conjunction with
the NS5B polymerase. Based on studies to date, NS5A inhibitors plus polymerase
inhibitors may be particularly powerful combinations.
Sulkowski, from Johns Hopkins Medical School, and colleagues tested various
all-oral combinations of sofosbuvir plus daclatasvir, with or without
ribavirin, in an open-label phase 2a trial.
was one of the earlier ribavirin-free regimens to be evaluated, researchers started
with easier-to-treat patient populations and moved on to more challenging
groups as they saw promising results. All study participants to date have been
treatment-naive, a group with better prospects for a cure than non-responders
to prior interferon-based therapy.
stage of the study looked at people with easier-to-treat HCV genotypes 2 or 3,
randomising them to receive 400mg sofosbuvir plus 60mg once-daily daclatasvir – some with a seven-day sofosbuvir lead-in and some
with the addition of 800mg ribavirin – for 24 weeks.
stage enrolled people with harder-to-treat HCV genotype 1, about 75% of whom
had the most difficult subtype 1a. The first three of these arms received the
same doses of sofosbuvir plus daclatasvir, with or without ribavirin, again for
24 weeks. Then two additional arms received the sofosbuvir plus daclatasvir
combination, one group with and one without ribavirin, for 12 weeks to test if
shorter therapy is feasible.
enrolled about 170 total participants in eight study arms. The median age was
approximately 54 years. Gender distribution varied across arms, with men making
up 36 to 69%. At least 70% were white in all study arms.
of participants with the favourable IL28B CC gene variant associated with good
interferon response ranged from about 20% to nearly 60%; the figure is
typically much lower when studying prior null responders. At baseline,
approximately 40% had absent to mild fibrosis (Metavir stage F0-F1), about half
had moderate to advanced liver disease (F2-F3) and roughly 15% had cirrhosis
Looking first at the genotype 2/3 participants, 100%
achieved rapid virological response (RVR) at week 4 of treatment. This was a
modified intent-to-treat, missing = failure analysis. People who missed one
evaluation visit were considered lost to follow-up and not counted when
calculating results at that time point; however, if they returned they were
allowed to continue in the study and included in later evaluations.
After week 4, a single patient experienced viral break-though,
one relapsed after treatment, one was temporarily lost to follow-up, and one
was lost permanently. Sustained virological response rates at weeks 4, 12, and
24 post-treatment (SVR4, SVR12 and SVR24,
respectively) ranged from 88 to 100%. The addition of ribavirin – which plays a role in preventing relapse after
treatment – did not improve response rates.
Turning to the genotype 1 participants, all but one
person receiving sofosbuvir plus daclatasvir with or without ribavirin for 12
or 24 weeks achieved RVR. That individual went on to suppress HCV with further
therapy, so end-of-treatment response rates at week 12 or week 24 were 100%
across the board.
Among genotype 1 participants treated for 12 weeks, SVR4
and SVR12 rates were 100% in all three regimen arms. All
participants went on to achieve SVR24, except for one person who had
measurable HCV RNA at post-treatment week 24. Viral genetic sequencing,
however, revealed that the new virus was different from the original one,
indicating re-infection rather than relapse.
The genotype 1 participants treated for 24 weeks were
still undergoing follow-up. However, amongst the 68 participants who had reached
post-treatment week 12, all achieved SVR12.
Sofosbuvir and daclatasvir were generally safe and
well tolerated. The most common side-effects overall were fatigue, headache and
nausea, with no clear patterns across treatment arms. Moderate-to-severe
adverse events occurred somewhat more often in the 24-week lead-in arm and the
arm receiving ribavirin for 24 weeks, but numbers were too small to draw
definitive conclusions. But there was a clear association between use of ribavirin
and anaemia: six and five participants in the two triple-therapy arms developed
anaemia (haemoglobin < 9 g/dL), compared with none in the ribavirin-sparing
In summary, the researchers concluded that sofosbuvir plus daclatasvir,
with or without ribavirin, achieved SVR in more than 93% of participants with HCV
genotype 1, 2 or 3. They added that virological response "did not differ
according to IL28B genotype, viral subtype or the administration of
It remains to be seen how well sofosbuvir plus daclatasvir will work for
prior null responders to interferon. Various other direct-acting HCV drugs
under study looked good in treatment-naive patients but have not performed as
well in this more difficult-to-treat group.
As promising as the sofosbuvir plus
daclatasvir combination appears to date, its fate is uncertain. Earlier this
year Gilead indicated that it would no longer pursue development of this
particular regimen. Some have suggested that Gilead prefers to focus on
combinations including its own investigational NS5A inhibitor GS-5885, allowing
the company to produce coformulated combination pills – its speciality
in the HIV arena.
study presented at the Liver Meeting showed that sofosbuvir
plus GS-5885 plus ribavirin led to 100% SVR4 for genotype 1 treatment-naive
patients and all null responders evaluated to date. Gilead is currently testing a new coformulation of sofosbuvir/GS-5885,
without ribavirin, in treatment-naive genotype 1
Notwithstanding company decisions about which investigational agents to
test together, once individual drugs are approved and marketed, clinicians and
patients will be able to mix and match them.