An all-oral combination of daclatasvir (Daklinza) plus sofosbuvir (Sovaldi),
taken for 12 weeks, produced sustained virological response rates of 90% for
previously untreated patients and 86% for prior non-responders with hepatitis C
virus genotype 3 in the phase 3 ALLY-3 trial, researchers reported last month at
the American Association for the Study of Liver Diseases (AASLD) Liver Meeting
in Boston, United States. This regimen did not work as well, however, for
people with liver cirrhosis.
The advent of interferon-free therapy using direct-acting antiviral
agents that target different steps of the hepatitis C virus (HCV) lifecycle has
brought about a revolution in chronic hepatitis C treatment.
Gilead Sciences' nucleotide HCV polymerase inhibitor sofosbuvir is among
the most effective of these new drugs. A dual combination of sofosbuvir plus
Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir appeared
promising in phase 2 studies, but Gilead elected to halt development of this
regimen in favour of its own experimental NS5A inhibitor, ledipasvir. Unlike
ledipasvir – which primarily works against HCV genotype 1 – daclatasvir is
'pan-genotypic', or active against multiple genotypes.
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.
A sofosbuvir/ledipasvir co-formulation (Harvoni) was recently approved in the US and Europe, while daclatasvir
has been approved in Europe and is awaiting US approval. Once sofosbuvir went
on the market, Bristol-Myers Squibb was able to resume phase 3 trials without
Gilead's co-operation.
David Nelson from the University of Florida presented final results from
the phase 3 ALLY-3 trial, which tested daclatasvir plus sofosbuvir in people
with HCV genotype 3, including treatment-naive and treatment-experienced
patients with and without liver cirrhosis.
In the era of interferon-based therapy, genotype 3 – the second most
common type worldwide – was classified with genotype 2 as 'easier-to-treat'.
But it is now recognised that genotype 3 is more prone to resistance and does
not respond as well to interferon-free therapy, requiring longer treatment
duration or addition of ribavirin and/or other direct-acting antivirals.
ALLY-3 included 152 participants, of whom 101 were previously untreated
for hepatitis C and 51 were treatment-experienced. More than half were men,
most were white and the median age was approximately 55 years. Three-quarters
had high baseline HCV viral load (>800,000 IU/ml) and 60% had unfavourable
IL28B gene variants; 19% of treatment-naive and 25% of treatment-experienced patients
had cirrhosis
The previously treated participants included prior relapsers (61%),
partial responders (4%), null responders (14%) and people who experienced
on-treatment viral breakthrough or could not tolerate interferon-based therapy
(22%). A small number had previously used sofosbuvir or the investigational
cyclophilin inhibitor alisporivir, but prior
use of NS5A inhibitors was not permitted.
All participants in this open-label study were treated with 60mg
daclatasvir plus 400mg sofosbuvir, both once-daily, for 12 weeks without
ribavirin. Patients were followed for 12 weeks after completing therapy to
determine sustained virological response (SVR12), or continued undetectable HCV
viral load – considered to be a cure.
Overall, at 12 weeks post-treatment, 90% of the previously untreated
patients and 86% of the treatment-experienced group achieved SVR12.
People with liver cirrhosis were less likely to be cured. In the
treatment-naive group SVR12 rates were 97% for people without cirrhosis versus
58% for people with cirrhosis. In the treatment-experienced group, the
corresponding rates were 94% and 69%, respectively.
SVR12 rates were similar, however, for people with low and high baseline
viral load (91% and 88%, respectively) and for those with favourable and
unfavourable IL28B variants (92% and 87%, respectively).
Most treatment failures were attributable to post-treatment relapse:
nine (9%) in the treatment-naive group and seven (14%) in the
treatment-experienced group. Eleven of the 16 relapsers had cirrhosis. There
were no cases of viral breakthrough during therapy, but one treatment-naive
patient with cirrhosis still had detectable HCV RNA at the end of treatment.
Nine relapsers had evidence of treatment-emergent resistance-associated viral
variants.
Treatment with daclatasvir plus sofosbuvir was generally safe and
well-tolerated. There was just one serious adverse event and no treatment
discontinuations for this reason. The most common side-effects were headache
(20%), fatigue (19%) and nausea (12%). No one taking this ribavirin-free
regimen developed anaemia.
"Daclatasvir + sofosbuvir for a shorter 12-week duration achieved
high SVR12 rates in patients with genotype 3 infection," the researchers
concluded. "High SVR rates of 96% were achieved in patients without
cirrhosis."
These results support the currently approved European indication of daclatasvir
plus sofosbuvir for 12 weeks for previously untreated genotype 3 patients
without cirrhosis, but suggest that 12 instead of 24 weeks may also be adequate
for treatment-experienced people who do not have cirrhosis.
When asked what to do for people with cirrhosis, Nelson replied that
longer treatment duration – he suggested 16 rather than 24 weeks – or adding
ribavirin could help.
The daclatasvir plus sofosbuvir regimen is also being tested in two
other phase 3 trials: ALLY-1 for patients with cirrhosis and liver transplant
recipients with HCV genotypes 1-6, and ALLY-2 for people with HIV and HCV co-infection
who have genotypes 1-6.