Sofosbuvir/velpatasvir produces high hepatitis C cure rates and subjective improvement in ASTRAL trials

Liz Highleyman
Published:
31 May 2016

A co-formulation of Gilead Science's sofosbuvir and its investigational hepatitis C virus (HCV) NS5A inhibitor velpatasvir taken for 12 weeks produced sustained virological response in 95 to 99% of participants across HCV genotypes and led to improvements in patient-reported outcomes, according to a pair of studies presented at the 2016 Digestive Disease Week (DDW) meeting this week in San Diego.

Interferon-free therapy using direct-acting antivirals has revolutionised treatment for chronic hepatitis C, but researchers continue to try to optimise therapy, especially for difficult-to-treat patients. An ideal regimen would not require ribavirin and would be pangenotypic, or active against all HCV genotypes.

The phase 3 ASTRAL studies evaluated sofosbuvir/velpatasvir in chronic hepatitis C patients with various HCV genotypes.

ASTRAL-1 enrolled 740 patients with any genotype except 3. Just over half had genotype 1 (including a third with harder-to-treat subtype 1a), 17% had genotype 2, 19% had genotype 4 and 13% had genotype 5 or 6. About 60% were men, about 80% were white and the median age was about 54 years. A third were treatment-experienced, 19% had liver cirrhosis, and 16% had a history of depression. Participants were randomly assigned to receive sofosbuvir/velpatasvir or placebo for 12 weeks.

ASTRAL-2 enrolled 240 patients with HCV genotype 2. About 60% were men, 90% were white and the median age was 57 years; 15% were treatment-experienced and 14% had cirrhosis. Participants in this open-label study were assigned to receive sofosbuvir/velpatasvir or sofosbuvir plus ribavirin for 12 weeks.

ASTRAL-3 enrolled 552 genotype 3 patients. Just over 60% were men, most were white and the median age was 50 years. About a quarter were treatment-experienced and 30% had cirrhosis. Participants were randomised to receive either sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus ribavirin for 24 weeks.

Researchers presented efficacy results from these studies at the 2015 AASLD Liver Meeting this past November.

Overall, 99% of patients in ASTRAL-1 achieved sustained virological response, or continued undetectable viral load at 12 weeks after completion of treatment (SVR12). In ASTRAL-2 the SVR12 rates were 99% in the sofosbuvir/velpatasvir arm and 94% in the sofosbuvir plus ribavirin arm. SVR12 rates in ASTRAL-3 were 95% using sofosbuvir/velpatasvir, but only 80% using sofosbuvir plus ribavirin.

Sofosbuvir/velpatasvir cure rates were similar for previously untreated and treatment-experienced patients, and for people with and without liver cirrhosis. Sofosbuvir/velpatasvir was generally safe and well tolerated, with few serious adverse events or treatment discontinuations.

At DDW 2016 Zobair Younossi of Inova Fairfax Hospital presented additional findings on patient-reported outcomes during and after completion of treatment in these studies.

Patient-reported outcomes were assessed using four instruments: the 36-item Short Form Health Survey (SF-36), the FACIT fatigue scale (FACIT-F), the Chronic Liver Disease Questionnaire for hepatitis C (CLDQ-HCV) and the Work Productivity and Activity Impairment questionnaire (WPAI:SHP). Testing was done at baseline, during treatment and at up to 24 weeks of follow-up.

In ASTRAL-1 all patient-reported outcomes were similar at baseline across treatment arms. Patient-reported outcome scores improved shortly after starting treatment with sofosbuvir/velpatasvir.

General health, emotional wellbeing and all five CLDQ-HCV domains improved significantly by treatment week 4; improvements "became even more prominent" during the remainder of therapy, and outcomes continued to improve after completing treatment, the researchers reported.

In the placebo arm, in contrast, patient-reported outcome scores did not change – or in some cases moderately decreased – during treatment.

After adjusting for sex, history of psychiatric disorders, type 2 diabetes, cirrhosis and treatment history, using sofosbuvir/velpatasvir was independently associated with greater improvement in most patient-reported outcomes. Achieving SVR was also independently associated with improvement after treatment.

In ASTRAL-2 and ASTRAL-3 some patients were randomised to receive ribavirin, which can cause more adverse events than direct-acting antivirals and may have a detrimental effect on quality of life.

In these studies combined, patients taking sofosbuvir/velpatasvir saw significant improvements in 12 out of 23 patient-reported outcome domains by treatment week 4. Again, improvements continued with further treatment.

In the groups taking sofosbuvir plus ribavirin, about a quarter of patient-reported outcomes improved, while the rest worsened. In a multivariate analysis, using sofosbuvir/velpatasvir rather than sofosbuvir plus ribavirin was independently associated with about a 3 to 10 point advantage in outcome scores at different time points during treatment.

However, after about a month on treatment there were no remaining decrements in the sofosbuvir plus ribavirin arms, and participants showed significant patient-reported outcome improvements regardless of regimen – especially those who achieved sustained response.

"The pangenotypic regimen with a sofosbuvir/velpatasvir fixed-dose combination has not only excellent efficacy but also a significantly positive impact on patients’ experience during treatment and after achieving sustained virologic response," Dr Younossi's team concluded.

References

Younossi ZM et al. The use of sofosbuvir and velpatasvir is associated with high efficacy and improvement in patient-reported outcomes in patients with genotype 1, 2, 4, 5 and 6 chronic hepatitis C: results from the ASTRAL-1 clinical trial. Digestive Disease Week 2016, abstract 812e, 2016.

Younossi ZM et al. Ribavirin-free regimen with velpatasvir and sofosbuvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: results from ASTRAL-2 and 3 clinical trials. Digestive Disease Week 2016, abstract 499, 2016.