Jordan Feld of Toronto Western
Hospital Liver Centre presented results from the ASTRAL-1 trial (NCT02201940), which evaluated sofosbuvir/velpatasvir for patients with all
genotypes except 3, which has proven harder to treat with DAAs. Results were
published simultaneously in the November 16 online edition of the New
England Journal of Medicine. Findings from ASTRAL-2, which looked specifically at people with HCV genotype 2, and
ASTRAL-3, which enrolled genotype 3 patients, were also presented at the Liver
ASTRAL-1 enrolled 740 chronic hepatitis C patients at 81 sites in
Europe, the US, Canada and Hong Kong. Just over half had HCV genotype 1 (including
34% with harder-to-treat subtype 1a), 17% had genotype 2, 19% had genotype 4,
6% had genotype 5 and 7% had genotype 6.
About 60% of participants were men, most were white and the median age
was about 54 years. A third were treatment-experienced (prior failure of
interferon/ribavirin or a first-generation HCV protease inhibitor), two-thirds
had unfavourable IL28B non-CC gene patterns and 19% had compensated cirrhosis.
People with HIV co-infection were not included.
Participants with genotypes 1, 2, 4 or 6 were randomly assigned (5:1) to
receive either a 400mg/100mg once-daily fixed-dose co-formulation of the HCV NS5B polymerase
inhibitor sofosbuvir (marketed separately as Sovaldi) and the pan-genotypic NS5A inhibitor velpatasvir (formerly
GS-5816), or else a placebo, for 12 weeks. Because their number was small, all
genotype 5 patients received active treatment.
The primary study endpoint was sustained virological response, or
continued undetectable viral load, at 12 weeks after completion of treatment
All but two participants receiving sofosbuvir/velpatasvir completed
treatment. The overall SVR12 rate was 99%. Broken down by genotype, sustained
response rates were 98%, 99%, 100%, 100%, 97% and 100%, respectively, for
genotypes 1a, 1b, 2, 4, 5 and 6.
SVR12 rates were the same (99%) for previously untreated and
treatment-experienced patients, and for people with and without cirrhosis.
Sequencing showed that 257 participants (42%) had NS5A resistance-associated
variants (RAVs) at baseline, and this group also had a 99% cure rate.
Of the participants who did not achieve sustained response, two relapsed
(one each in the genotype 1a and 1b groups), two people were lost to follow-up,
one withdrew consent and one died from an unrelated cause.
Sofosbuvir/velpatasvir was generally safe and well-tolerated. Fifteen
people (2%) taking the co-formulation experienced serious adverse events and one
discontinued treatment due to an adverse event. Grade 3-4 laboratory
abnormalities were uncommon (7%). While more than three-quarters of patients treated
with sofosbuvir/velpatasvir reported some adverse events, this was also the
case in the placebo group. The most common side-effects were headache, fatigue,
nasopharyngitis and nausea, again reported with similar frequency in the active
treatment and placebo arms.
Based on these findings, the researchers concluded,
"[Sofosbuvir/velpatasvir] for 12 weeks provides a simple, safe and highly
effective treatment for patients with HCV genotype 1, 2, 4, 5 or 6