Drug Quartet Cocktail Proves Effective for HCV Genotype 3

A triple combination of hepatitis C agents administered with another manufacturer's direct acting antiviral overcomes most difficult-to-cure Genotype 3.

A triple, fixed-dose anti-HCV product given with another manufacturer's direct acting antiviral (DAA) was efficacious in treating the most difficult-to-cure genotype 3, and shortened the duration of treatment for genotype 2, in a recently published Phase II multi-center international study.

The investigators targeted genotype 3 for its persistence against DAA treatments which have produced virtual cures in other genotypes, remaining associated with rapid disease progression and increased risks of cirrhosis and hepatocellular carcinoma.

Stephen Shafran (pictured), MD, Professor, Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta Canada and colleagues explained the rationale for a study that required obtaining products from different manufacturers to configure a potentially effective treatment regimen.

"Combining multiple DAAs with different viral targets and non-overlapping resistance profiles may enhance antiviral activity, which might achieve higher response rates for difficult-to-cure populations and allow for shorter durations of treatment," the researchers wrote in the study.

Shafran told MD Magazine that there is precedent for employing multiple manufacturer brand products in infectious disease regimens, in the treatment of HIV.

"I'm not a health economist, but I think, realistically, that companies need to price regimens out, not pills," Shafran said.

The fixed-dose combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (Technivie, AbbVie), which is approved to treat HCV genotype 4, was combined with the pangenotypic DAA, sofosbuvir (SOF) (Sovaldi, Gilead), in addition to ribavirin for 12 weeks in patients having genotype 3 with cirrhosis, and with or without ribavirin in type 3 patients without cirrhosis. In addition, the regimen with ribavirin was administered for either 6 or 8 weeks to genotype 2 patients without cirrhosis.

If the regimen without ribavirin proves efficacious, Shafran explained, it would offer a treatment option for many patients unable to tolerate it.

"I can tell you I don't like ribavirin, and I try to avoid it wherever possible," Shafran said. "The biggest problem with ribavirin is that you need to do extra monitoring of the patients. When you have a regimen that is both interferon- and ribavirin-free, you actually don't need to do any on-therapy monitoring."

The "quartet" drug regimen of OBV/PTV/r plus SOF did produce an effective cure in genotype 3 patients without cirrhosis, whether or not ribavirin was added to the regimen. The regimen with ribavirin was comparably effective in type 3 patients with cirrhosis — with an overall 98% sustained virologic response (SVR) at 12 weeks across genotype 3 groups.

The findings suggest to Shafran that ribavirin can be omitted from the regimen in treating genotype 3 without cirrhosis, but he cautioned against reaching that conclusion from just this study, "with the limitation that this is not a large number of subjects.

"The problem is when you do pilot studies, there's relatively wide confidence intervals so its hard to say that for sure," Shafran said.

The study also found that 8 weeks of treatment with the regimen containing ribavirin produced SVR in 90% of type 2 patients without cirrhosis, but in only 44% in the 6 week trial. It was noted that the failure to respond in the shorter trial was due to relapse, rather than emergence of viral resistance.

"With this regimen, we had some good results with 8 weeks," Shafran observed. "There's no regimen that has performed good enough with 6 weeks. There's been several regimens that have been tested in small, proof-of-concept studies, and there isn't one yet where 6 weeks had a low enough relapse rate to say that that's good enough."

The study, "Efficacy and Safety Results of Patients with HCV Genotype 2 or 3 Infection Treated with Ombitasvir/Paritaprevir/ritonavir and Sofosbuvir with or without Ribavirin (QUARTZ II-III)," was published online in the Journal of Viral Hepatology last month.

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