New DAA for Hepatitis C Effective in Large Majority of Patients with Resistance-Associated Substitutions

AUGUST 27, 2018
Jared Kaltwasser
People with hepatitis C virus infection whose previous treatment with direct-acting antivirals (DAAs) failed are having success with a fixed-dose combination therapy of sofosbuvir, velpatasvir, and voxilaprevir (Vosevi, Gilead), according to the results a new study.

The 3 drugs included in the therapy target the NS5B polymerase (sofosbuvir), the NS5A protein (velpatasvir), and the NS3/4A protease (voxilaprevir). For the study, investigators set out to determine whether the presence of resistance-associated substitutions (RASs) in DAA-experienced patients would inhibit the efficacy of the SOF/VEL/VOX therapy.

Of the 248 people enrolled in the study with NS5A experience, 82.7% had baseline NS5A or NS3 RASs. The majority (79%) had NS5A RASs. Study results revealed, however, that sustained virologic response after 12 weeks on SOF/VEL/VOX occurred regardless of the presence of NS5A or NS3 RASs, and regardless of the presence of RASs related to velpatasvir or voxilaprevir.

“The results show that daily treatment with the single-tablet regimen of SOF/VEL/VOX for 12 weeks is highly effective for a broad range of DAA-experienced patients infected with [hepatitis C virus] of any genotype regardless of the presence of RASs,” wrote Hadas Dvory-Sobol, MSc, PhD, a senior research scientist at Gilead Sciences Inc, and the study’s corresponding author.

Notably, of the 7 patients in the study who relapsed, treatment-selected resistance was observed in just 1 patient.

“Vosevi provides a treatment option for some patients who were not successfully treated with other [hepatitis C virus] drugs in the past,” said Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, in a press release.

Viral resistance has become a significant issue in the treatment of patients with hepatitis C virus, and has been the subject of a number of studies. In a 2017 study, David L. Wyles, MD, and Anne F. Luetkemeyer, MD, explained that the problem involves the mechanisms behind the virus.

“The replication dynamics of [hepatitis C virus] in chronically-infected humans combines a high rate of viral production with an error-prone RNA polymerase, providing a favorable setting for the emergence and enrichment of viral nucleotide substitutions that confer resistance to specific drugs or drug classes, particularly under drug selection pressure,” they wrote.

Dvory-Sobol’s study is the latest in a series of papers looking at retreatment options for patients with RASs.

“In contrast to the prior studies of regimens targeting 2 distinct [hepatitis C virus] proteins, the presence of NS3, NS5A and/or NS5B NI RASs did not affect treatment outcome in DAA-experienced patients including those who were previously treated with NS5A inhibitors upon treatment with SOF/VEL/VOX for 12 weeks in phase 3 trials,” Dvory-Sobol and colleagues wrote. They added that SOF/VEL/VOX showed it had a high barrier to resistance, making it a strong option for patients with prior unsuccessful treatment.

The SOF/VEL/VOX combination was approved by the US Food and Drug Administration (FDA) last year.

The study, “No Impact of Resistance Associated Substitutions on the Efficacy of Sofosbuvir, Velpatasvir, and Voxilaprevir for 12 Weeks in HCV DAA-experienced Patients,” was published in the Journal of Hepatology.

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