all-oral combination of daclatasvir, sofosbuvir and ribavirin taken for 12 or
16 weeks led to high sustained virological response rates for people with
hard-to-treat hepatitis C virus (HCV) genotype 3 and advanced liver fibrosis or
cirrhosis, according to findings from the ALLY-3+ study presented at the 2015
AASLD Liver Meeting this week in San Francisco, USA.
direct-acting antiviral therapy has revolutionised treatment for chronic hepatitis
C, but better options are still needed for people with genotype 3, which is the
most difficult type to cure in the post-interferon era. Genotype 3 – which
accounts for an estimated 30% of all hepatitis C cases worldwide – is
associated with faster liver disease progression and is more likely to lead to
cirrhosis and liver cancer than other genotypes.
Vincent Leroy of Centre Hospitalier Universitaire de Grenoble presented
late-breaking results from the ALLY-3+ trial, a phase 3b study evaluating
Bristol-Myers Squibb’s pan-genotypic HCV NS5A replication complex inhibitor daclatasvir (Daklinza), Gilead Sciences’ HCV
polymerase inhibitor sofosbuvir (Sovaldi)
and ribavirin for people with genotype 3 who had advanced liver disease.
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
In the previous ALLY-3 study daclatasvir plus sofosbuvir taken for 12 weeks
led to a sustained virological response rate of 96% for people without
cirrhosis, but only 63% for those with cirrhosis. ALLY-3+ assessed whether
adding ribavirin to this combination for 12 or 16 weeks could improve outcomes
for people with advanced fibrosis or cirrhosis.
ALLY-3+ enrolled 50 people with genotype 3 chronic
hepatitis C. Most (80%) were men, almost all were white and the mean age was 54
years. About three-quarters had prior treatment experience, including 12% who
relapsed after taking sofosbuvir plus ribavirin (with or without interferon);
people who had previously used NS5A inhibitors were excluded. Over a quarter
(28%) had advanced fibrosis (stage F3) while 72% had compensated cirrhosis
(stage F4). About half had high HCV viral load at baseline (> 6
Participants in this open-label trial were randomly
assigned to take 60mg daclatasvir and 400mg sofosbuvir once daily plus
1000-1200 mg/day weight-based ribavirin for either 12 or 16 weeks.
Overall, sustained virological response rates at 12
weeks post-treatment (SVR12) were 88% in the 12-week treatment arm and 92% in
the 16-week arm in an intention-to-treat analysis – not a significant
Everyone with advanced fibrosis achieved SVR12 in both
the 12-week and 16-week treatment arms. Among people with cirrhosis, SVR12 rates
were 83% and 89%, respectively. Looking
at treatment history, SVR12 rates were 92% for treatment-naive people (88% for people
with cirrhosis who were treatment-naive) and 89% for treatment-experienced
patients (86% for people with cirrhosis who were treatment-experienced).
There were no viral breakthroughs during treatment,
but four people relapsed after finishing therapy (2 in each study arm).
Eight participants had NS5A resistance-associated
variants (RAVs) at baseline, and among these 88% achieved SVR12. Two of the
relapsers had also previously relapsed on sofosbuvir plus ribavirin; however,
no sofosbuvir-associated NS5A RAVs were detected at either baseline or relapse.
Treatment was generally safe and well-tolerated, with
no treatment-related serious adverse events or discontinuations due to adverse
events; there was 1 treatment-unrelated death. The most common adverse events
were insomnia (30%), fatigue (26%) and headache (24%). One person in the
16-week arm developed grade 3 anaemia. All
six people who reduced their ribavirin doses went on to achieve SVR12, while
the four relapsers had no dose reductions.
Based on these findings the researchers concluded,
"Daclatasvir + sofosbuvir + ribavirin for 12 or 16 weeks is a highly
efficacious therapy for genotype 3-infected patients with advanced fibrosis or
compensated cirrhosis, a population in urgent need of treatment."
Dr Leroy said that 12 and
16 weeks of treatment "probably perform the same," and it is not yet
known whether extending therapy to 24 weeks would further reduce relapses.
A pair of
real-world studies presented at the Liver Meeting also showed good results for
people with advanced liver disease treated with daclatasvir plus sofosbuvir,
with or without ribavirin, in compassionate use programmes.