A regimen of sofosbuvir and the pan-genotypic HCV NS5A inhibitor
ravidasvir, with or without ribavirin, demonstrated sustained response
ranging from 86% to 100% in the largest phase 3 trial to date of
interferon-free treatment for people with hepatitis C virus genotype 4,
according to study findings presented Monday at the 2015 AASLD Liver Meeting in San Francisco.
While interferon-free therapy using oral direct-acting antiviral agents has
revolutionised treatment for chronic hepatitis C, there is room to optimise
therapy for harder-to-treat patients. An ideal regimen would be pan-genotypic,
meaning it is active against all types of HCV and could be routinely prescribed
without the need for genotype testing.
Gamal Esmat of Cairo
University reported results from a phase 3 study of genotype 4 hepatitis C
patients evaluating Gilead Sciences' HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi) and the NS5A inhibitor
ravidasvir (formerly PPI-668), being developed by Pharco Pharmaceuticals in Alexandria, Egypt, and Presidio Pharmaceuticals in
HCV genotype 4 – which is predominant in the Middle East and parts of
Africa – accounts for 15% of all chronic hepatitis C worldwide, the researchers
noted as background. Egypt has one of the highest hepatitis C prevalence rates
in the world, 90% of which is genotype 4. So far this genotype has not been as
extensively studied as genotype 1, which is the most common type in Europe and
the US. Approved regimens include sofosbuvir/ledipasvir (Harvoni), paritaprevir/ritonavir/ombitasvir (Viekirax), and sofosbuvir plus ribavirin, but cure rates are lower
than those for genotype 1.
This study enrolled 300 participants in Egypt. About 70% were men and
the mean age was 48 years. Half were previously untreated and half had
previously received interferon-based therapy. More than 40% had liver cirrhosis
at baseline but no history of decompensation. People with hepatitis B virus or
HIV co-infection were excluded. The study had a complex design that stratified
participants by prior treatment and cirrhosis status:
- Group 1a (n = 90): treatment-naive without cirrhosis
- Group 1b (n = 60): treatment-naive with cirrhosis
- Group 2 (n = 80): treatment-experienced without
- Group 3 (n = 70): treatment-experienced with cirrhosis
Participants in groups 1a, 1b and 2 were randomly assigned to receive 400mg
sofosbuvir plus 200mg ravidasvir once-daily either with or without ribavirin
for 12 week. People in group 3 were randomised to receive sofosbuvir plus
ravidasvir with ribavirin for either 12 or 16 weeks.
The primary study endpoint was sustained virological response, or continued
undetectable viral load at 12 weeks after completion of treatment (SVR12). At
the time of data analysis 266 of the 300 participants had either reached the SVR12
time point or discontinued treatment prematurely. Four patients without cirrhosis and 30 patients with cirrhosis were still in the post-treatment waiting period.
Looking first at treatment-naive participants without cirrhosis, SVR12
rates were 100% for those treated with sofosbuvir and ravidasvir alone, and 98%
for those who added ribavirin. Among treatment-experienced
participants without cirrhosis the response rates were 95% and 100%, respectively.
Turning to participants with cirrhosis, SVR12 rates were 93% for
treatment-naive patients treated with sofosbuvir and ravidasvir alone, and 92%
for those who added ribavirin. Among treatment-experienced patients
with cirrhosis response rates were 86% and 100%, respectively, for those treated for 12 and 16
There were no on-treatment viral breakthroughs and none of the participants without cirrhosis relapsed after finishing treatment. Among
patients with cirrhosis there were six post-treatment relapses, including one person who
discontinued due to an adverse event after only 8 weeks of treatment. Four of
the relapsers were taking ribavirin. Half of the relapses occurred by week 4
and half by week 8 post-treatment. No one treated with the triple regimen for
16 weeks relapsed.
In a per-protocol or as-treated analysis, sustained response rates were
100% for participants without cirrhosis, 94% for participants with cirrhosis and 98% overall.
Treatment was generally safe and well-tolerated. There was one serious
adverse event considered possibly related to study drugs, transient symptomatic
bradycardia (slow heartbeat), which Esmat noted is a rare side-effect
Overall adverse events rates were low and similar across patient groups.
The most common side-effects were headache (13%), abdominal discomfort (6%),
fatigue (5%), itching (4%) and diarrhoea (2%). Three people taking ribavirin
developed anaemia and two lowered their ribavirin dose.
"Ravidasvir + sofosbuvir is a promising new once-daily oral
treatment that was well-tolerated and achieved high SVR rates in HCV genotype 4
patients," the researchers concluded.
Asked why the study did not include a ribavirin-free arm for
treatment-experienced patients with cirrhosis, Esmat said the researchers had thought
ribavirin would be necessary, but
after seeing these results they want to study this. He was asked whether 8
weeks might be enough for easier-to-treat non-cirrhotic people and said this
also deserves further study.