Moving Toward a More Efficient Hepatitis C Treatment Regimen

Three interferon-free direct-acting antiviral (DAA) regimens approved for genotype 1 hepatitis C virus (HCV) require treating for 12 to 24 weeks, but recent trials suggest 8 weeks could be sufficient for certain patients.

Omar El-Sherif, MB, BCh (pictured), from the Hepatology Centre at St. James Hospital, Dublin, Ireland and colleagues at Beth Israel Deaconess Medical Center, Boston, MA reviewed clinical trials with dual- and triple-therapy regimens that can be effective in 8 weeks for HCV genotype 1, as well as several smaller trials that suggest circumstances in which shorter treatment periods may suffice.

"The advent of shorter duration, highly effective and well tolerated interferon-free therapy now provides an opportunity for virtually all HCV-infected individuals to be cured," the researchers wrote. "There continues to be a need to simplify therapy and shorten treatment duration while maintaining high cure rates to expand treatment access."

The prospects for 8 week regimens for HCV type 2 also appear good, albeit with the addition of ribavirin, Stephen Shafran, Professor in the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada, told MD Magazine.

"With this regimen, we had some good results with 8 weeks," Shafran said. "There's no regimen that has performed good enough (for type 2) 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."

El-Sherif and colleagues identified 2 phase 3 trials and 2 phase 2 trials assessing 8-week treatments, several phase 2 studies with 6- and 4-week treatment durations, and a couple of proof-of-concept studies that demonstrated the possibility of shortening treatment durations based on the pattern of response.

The ION-3 trial compared the efficacy of 8 weeks of sofosbuvir-ledipasvir (Harvoni) with or without ribavirin to sofosbuvir-ledipasvir alone for 12 weeks in noncirrhotic, treatment-naive genotype 1 patients.

Although SVR rates were numerically lower in those treated for 8 weeks with or without ribavirin, those with lower pre-treatment viral load achieved the same SVR rate in 8 or 12 weeks. Based on these data, the 8-week regimen was approved by the Food and Drug Administration (FDA) for patients with a pre-treatment HCV RNA of less than 6 million IU/ml.

"Despite the controversy surrounding this viral load cut-off, early data from real-world registry studies appear to support the FDA 8-week label recommendation," researchers wrote.

The OPTIMIST trial of sofosbuvir (Solvaldi) and simeprivir (Olysio) found an 83% SVR rate after 8 weeks, compared to 97% in 12 weeks. Those with a lower pre-treatment viral load (HCV RNA less than 4 million IU/ml), however, achieved a 96% SVR at 8 weeks. A lower (73%) SVR occurred in 8 weeks among those with the Q80K polymorphism.

This finding is "consistent with the reduced efficacy of simeprevir in the presence of this substitution,” researchers wrote.

A small study of sofosbuvir and velpatasvir (Epclusa) produced a 90% SVR in treatment-naÑ—ve genotype 1 patients without cirrhosis in 8 weeks. The addition of an investigational protease inhibitor (GS-9857) in patients with cirrhosis and previous interferon treatment produced a 100% SVR rate in that same treatment period.

The reviewers indicate that these 8-week regimens will be tested in phase 3 trials with a larger number of patients.

In addition to several other phase 2 studies investigating 8-, 6- and even 4-week treatments, El-Sherif and colleagues considered preliminary investigations into whether response-guided therapy could shorten treatment. Rapid virologic decline associated with combination DAA therapies has been thought to reduce usefulness of monitoring viral load during treatment, they noted.

"However, there may be a role for on-treatment HCV RNA measurements to predict duration of DAA therapy to achieve SVR, potentially allowing for shortening therapy in some patients," researchers wrote.

The review, "No one size fits all—Shortening duration of therapy with direct-acting antivirals for hepatitis C genotype 1 infection," was published online in the Journal of Viral Hepatitis this month.