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AASLD 2013: MK-5172 + Ribavirin Works Well for People with Hepatitis C Genotype 1b

An interferon-free regimen consisting of Merck's next-generation hepatitis C virus (HCV) protease inhibitor MK-5172 plus ribavirin led to high rates of viral suppression and promising early cure rates for patients with HCV subtype 1b, according to a poster presented at the 64thAASLD Liver Meeting last month in Washington, DC.

The advent of direct-acting antiviral agents has brought about a revolution in hepatitis C treatment. Adding first-generation HCV protease inhibitors -- boceprevir (Victrelis) or telaprevir (Incivek) -- to pegylated interferon/ribavirin improves cure rates, but many patients and providers are waiting for interferon-free therapy.

Edward Gane from Auckland Clinical Studies and colleagues evaluated a dual oral regimen of MK-5172 -- a pan-genotypic NS3/4A protease inhibitor with a high genetic barrier to resistance -- plus ribavirin in easier-to-treat genotype 1 patients with no prior treatment experience, no liver cirrhosis, and the favorable IL28B CC gene pattern associated with good interferon responsiveness.

This proof-of-concept study included 26 participants (1 of whom left the study on the first day and 1 of whom was later determined to have IL28B CT instead of CC). Two-thirds were men, most were white, and the average age was 43 years. 12 had HCV subtypes 1a and 14 had 1b. People with hepatitis B or HIV coinfection were excluded.

Participants in this open-label study were randomly assigned to receive 100 mg once-daily MK-5172 plus 800-1400 mg/day weight-based ribavirin for either 12 or 24 weeks. Patients in the 12-week arm who still had detectable HCV RNA at week 4 had their treatment duration extended to 24 weeks.

Results

• 8 of 13 patients randomized to 12 weeks of therapy had unquantifiable HCV RNA (<25 IU/mL) at week 4 and qualified to stop at 12 weeks.
• 88% of participants treated for 12 weeks had unquantifiable viral load at 4 weeks post-treatment (SVR4).
• Some patients relapsed after this point, however, resulting in an SVR12 rate of 68%:

o   Of the 3 genotype 1a patients, 2 relapsed and 1 achieved SVR12.

o   Of the 5 genotype 1b patients, 1 relapsed and 4 achieved SVR12.

• Among the 4 patients assigned to the 12-week arm who had detectable HCV RNA at week 4 and continued therapy through week 24, 1 experienced viral breakthrough and 3 (75%) achieved SVR4 (SVR12 follow-up ongoing).
• Among patients initially randomized to 24-week treatment, 73% achieved SVR4 (SVR12 follow-up ongoing):

o   Of the 6 genotype 1a patients, 1 had viral breakthrough, 1 withdrew with unquantifiable HCV RNA, and 4 achieved SVR4.

o   Of the 7 genotype 1b patients, 1 had viral breakthrough (later determined to have IL28B CT), 1 withdrew with unquantifiable viral load at the end of treatment, and 5 achieved SVR4.

• MK-5172 plus ribavirin was generally safe and well-tolerated, with a tolerability profile "similar to that of ribavirin alone."
• There were no serious adverse events or treatment discontinuations for this reason.
• The most common adverse events were headache, weakness, anemia, gastrointestinal upset or nausea, and insomnia.
• Alanine aminotransferase (ALT) normalized in all patients with elevated levels at baseline.
• 9 people experienced mild, transient bilirubin elevations.

"Patients with HCV genotype 1a or genotype 1b infection receiving MK-5172 + ribavirin achieved rapid and sustained HCV RNA suppression," the researchers concluded. "After 12 weeks of treatment, SVR12 was achieved in 4 of 5 (80%) patients infected with genotype 1b, but only 1 of 3 (33%) patients infected with genotype 1a."

Strategies to improve SVR rates will include longer treatment duration and addition of a second direct-acting antiviral, the NS5A inhibitor MK-8742, as described in another presentation at the conference.

12/4/13

Reference

EJ Gane, Z Ben Ari, L Mollison, et al. Efficacy and Safety of an Interferon-Free Regimen of MK-5172 + Ribavirin for 12 Weeks or 24 Weeks in Treatment-Naive, Noncirrhotic Subjects With HCV GT1 Infection: The C-SPIRIT Study. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract1110.