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Sofosbuvir/velpatasvir shows high cure rates for all HCV genotypes, works well for patients with liver decompensation
Liz Highleyman, 2015-11-17 22:50:00
A coformulation of sofosbuvir and the pan-genotypic HCV NS5A inhibitor velpatasvir from Gilead Sciences produced sustained response in 99% of people with hepatitis C virus genotypes 1, 2, 4, 5 and 6, and 95% of those with harder-to-treat genotype 3, according to results from the phase 3 ASTRAL trials presented this week at the 2015 AASLD Liver Meeting in San Francisco.
A related late-breaking poster showed that sofosbuvir/velpatasvir with or without ribavirin cured most people with decompensated liver disease.
Interferon-free direct-acting antiviral (DAA) therapy has revolutionised treatment for chronic hepatitis C, but researchers continue to try to optimise therapy. An ideal regimen would be of short duration, not require ribavirin, and would be pan-genotypic, meaning it could be routinely prescribed without the need for genotype testing. HCV genotype 1 is most common in Europe and the US, but genotypes that are more prevalent elsewhere in the world - including 4, 5 and 6 - have not been as well studied.
ASTRAL-1
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 Meeting.
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 coformulation 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 (SVR12).
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 coformulation 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 infection."
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