Sofosbuvir-velpatasvir combo has potential to fight all forms of HCV

Last Updated: 2015-11-10

By Reuters Staff

NEW YORK (Reuters Health) - A combination of two direct-acting antivirals from Gilead Sciences - sofosbuvir and velpatasvir - has strong potential to be a pangenotypic regimen for all forms of hepatitis C virus (HCV) infection, according to findings from two randomized phase 2 open-label trials.

"The clinical potential of the combination of sofosbuvir and velpatasvir is suggested by their nonoverlapping viral targets, the proven success of sofosbuvir in combination with other NS5A inhibitors, and the in vitro potency of velpatasvir," Dr. Gregory T. Everson of University of Colorado Denver School of Medicine in Aurora and colleagues note in their paper online November 9 in Annals of Internal Medicine.

They assessed safety and efficacy of 12 weeks of velpatasvir (25 or 100 mg) coadministered with sofosbuvir (400 mg) in 377 treatment-naive noncirrhotic U.S. patients with HCV genotypes 1 to 6 and of adding ribavirin for patients receiving eight weeks of treatment.

They report "high" rates of sustained virologic response at 12 weeks (SVR12) with the sofosbuvir/velpatasvir combination across all HCV genotypes. For genotype 1, SVR12 rates were 96% with velpatasvir 25 mg and 100% with velpatasvir 100 mg; 93% in both groups for genotype 3; and 96% and 95% with velpatasvir 25 mg and 100 mg for genotypes 2, 4, 5, and 6.

The SVR rates in this study of treatment-naive noncirrhotic patients are on par with those observed with standard-of-care regimens, Dr. Everson and colleagues note.

Ribavirin didn't boost efficacy; the high SVR rates were achieved without ribavirin suggesting that it would not be needed for optimal efficacy, "further reducing the complexity of treatment," they report.

Virologic failure was "rare" in patients treated for 12 weeks, occurring in one of 55 patients with HCV genotype 1 infection, three of 54 with genotype 3 infection, and none of 45 with genotype 2, 4, 5, or 6 infection. One patient with HCV genotype 3 infection had no response and one with genotype 1 had a relapse - both were receiving 25 mg of velpatasvir, suggesting that the 100-mg dose might be better when given with sofosbuvir.

Overall, the sofosbuvir-velpatasvir combination with or without ribavirin was well-tolerated, with "low rates" of serious adverse events and only one discontinuation due to adverse events. Patients taking ribavirin had higher incidence of ribavirin-associated toxicities.

Limitations of the study include the open-label design and small sample sizes, particularly for genotype 4, 5, and 6.

"This is, to our knowledge, the first demonstration of a DAA combination with pangenotypic activity against HCV genotypes 1 to 6," the authors write.

A companion study in Annals of Internal Medicine reports that the sofosbuvir 400 mg and velpatasvir 100 mg regimen is "highly effective" in treatment-experienced patients with HCV genotype 1 or 3 with or without compensated cirrhosis, with SVR12 rates ranging from 88% to 100%, which compare "favorably" to other regimens.

This trial included a total of 321 patients from Australia, New Zealand and the U.S. It also suggests "no benefit" of adding ribavirin to the sofosbuvir plus velpatasir 100 mg regimen, note Dr. Stephen Pianko of Monash University, Victoria, Australia, and colleagues.

"The presence of pretreatment NS5A RAVs (resistance-associated variants) did not seem to affect SVR12 rates in patients with genotype 1 or 3 HCV infection, except for the patients with genotype 3a HCV infection receiving 25 mg of velpatasvir. The high SVR12 achieved by patients treated with sofosbuvir and 100 mg of velpatasvir with and without ribavirin suggests that this velpatasvir dose effectively suppressed both wild-type virus and virus with RAVs," the authors report.

"These results support the formulation of a fixed-dose combination tablet of sofosbuvir and 100 mg of velpatasvir for evaluation in phase 3 studies with the goal of developing a simple, all-oral, highly effective, and well-tolerated regimen with broad genotypic coverage," they conclude.

Gilead Sciences funded both studies and had a role in design, collection, analysis, interpretation of the data and writing the report. Several authors have disclosed financial relationships with the company.

SOURCE: http://bit.ly/1L7hj61 and http://bit.ly/1WJFUK7

Ann Intern Med 2015.