DDW 2016: Sofosbuvir/ Velpatasvir Produces High Hepatitis C Cure Rates in ASTRAL Trials

A coformulation 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 meeting this week in San Diego.

Interferon-free therapy using direct-acting antivirals (DAAs) has revolutionized treatment for chronic hepatitis C, but researchers continue to try to optimize 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 (NCT02201940) 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 assigned to receive sofosbuvir/velpatasvir or placebo for 12 weeks.

ASTRAL-2 (NCT02220998) enrolled 266 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 randomly assigned to receive sofosbuvir/velpatasvir or sofosbuvir plus ribavirin for 12 weeks.

ASTRAL-3 (NCT02201953) 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 randomized 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/velpatasvircure rates were similar for previously untreated and treatment-experienced patients, and for people with and without cirrhosis. Sofosbuvir/velpatasvir was generally safe and well-tolerated, with few serious adverse events or treatment discontinuations.

Patient-Reported Outcomes

At DDW 2016 Zobair Younossi from 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 4 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 outcomeswere similar at baseline across treatment arms. Patient-reported outcomescores improved shortly after starting treatment with sofosbuvir/velpatasvir. General health, emotional well-being, 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.

In the placebo arm, in contrast, patient-reported outcomescores 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/velpatasvirwas 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 randomized to receive ribavirin, which can cause more adverse events than DAAs and may have a detrimental effect on quality of life.

In these studies combined, patients taking sofosbuvir/velpatasvirsaw significant improvements in 12 out of 23 patient-reported outcomedomains 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/velpatasvirrather 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 outcomeimprovements regardless of regimen -- especially those who achieved SVR12.

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

5/26/16

References

ZM Younossi, M Stepanova, JJ Feld, 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 (DDW 2016). San Diego. May 22-24, 2016. Abstract 812e.

ZM Younossi, M Stepanova, MS Sulkowski, et al. Ribavirin-Free Regimen With Velpatasvir and Sofosbuvir is Associated With High Efficiency 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 (DDW 2016). San Diego. May 22-24, 2016. Abstract 499.