BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.
Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.
The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.
Triple Therapy With Only New Agents
A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.
"SVR4 [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.
In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.
The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.
In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR4 rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.
In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR4 and SVR12 rates were each 94% in this cohort.
The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.
In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.
They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.