December 2, 2016
Eric Lawitz, M.D., presenting study results (Credit: Warren Tong)
MK3, a fixed-dose combination of three direct-acting antivirals (DAAs) with different mechanisms of action, provided sustained virologic response (SVR) rates usually exceeding 95% in patients with hepatitis C (HCV) genotype (GT) 1, 2 or 3, with or without cirrhosis, in the randomized, open-label C-CREST trial. Adding ribavirin for GT2 or GT3 infection did not improve SVRs in this 664-person study.
MK3 combines MK-3682, an NS5B inhibitor; grazoprevir (MK-5172), an NS3/4A protease inhibitor; and ruzasvir (MK-8408), an NS5A inhibitor, in a single tablet (225/50/30 mg) taken as two tablets once daily without regard to food. C-CREST evaluated the three DAAs as the fixed-dose tablet or individual components in GT1, 2 and 3 patients with or without compensated cirrhosis and with or without HIV infection.
C-CREST has six arms: (1) MK3 for eight weeks in GT1, GT2 and GT3 patients; (2) MK3 plus ribavirin (Rebetol) for eight weeks in GT2 and GT3 patients; (3) MK3 for 12 weeks in GT1, GT2 and GT3 patients; (4) MK3 plus ribavirin for 12 weeks in GT2 and GT3 patients; (5) MK3 for 16 weeks in GT2 and GT3 patients; and (6) MK3 plus ribavirin for 16 weeks in GT3 patients. GT1 and GT2 participants were HCV treatment-naive; GT3 patients could be naive or have a record of failure with pegylated interferon plus ribavirin. Participants could have compensated cirrhosis or HIV infection. The trial excluded anyone with hepatitis B, decompensated liver disease, evidence or suspicion of hepatocellular carcinoma or significant lab abnormalities. The primary endpoint was SVR 12 weeks after treatment ended (SVR12).
In the overall 664-person study group, 59% of participants were men, 90% white, 5% black and 13% Hispanic. Median age stood at 54 years (range 19 to 85). While 22% of participants had treatment experience, 4% had HIV infection. North America contributed 45% of participants, Europe 39%, the Asian/Pacific region 8% and the Middle East 8%.
In an analysis including all participants who received at least one dose, SVR12s for GT1a were 93% with eight weeks of MK3 and 98% for 12 weeks; for GT1b 98% with eight weeks of MK3 and 100% with 12 weeks; for GT2 86% with eight weeks of MK3, 97% with 12 weeks and 100% with 16 weeks; for GT3 95% with eight weeks of MK3, 97% with 12 weeks and 96% with 16 weeks.
In a per-protocol analysis excluding failures for administrative reasons but including failures due to adverse events, SVR12s for GT1a were 95% with eight weeks of MK3 and 100% with 12 weeks; for GT1b 98% with eight weeks of MK3 and 100% with 12 weeks; for GT2 87% with eight weeks of MK3, 100% with 12 weeks and 100% with 16 weeks; for GT3 96% with eight weeks of MK3, 98% with 12 weeks and 97% with 16 weeks.
In per-protocol analyses, cirrhosis had no impact on SVR12, regardless of HCV genotype or treatment duration. In per-protocol analyses of GT2 and GT3 patients, ribavirin did not improve SVR12, regardless of treatment duration. In a per-protocol analysis of GT3 patients, treatment experience did not affect SVR12, regardless of treatment duration.
A resistance analysis excluded patients who stopped treatment for nonvirologic failure and those without baseline sequencing data. Baseline resistance-associated variants (RAVs) at positions 28, 30, 31 or 93 had no impact on SVR12 in GT1a or GT1b patients regardless of treatment duration. In GT2 patients treated for eight weeks, SVR12 was 80% in those with a baseline L31M RAV and 94% in those without L31M. L31M did not affect SVR12 rate in GT2 patients with 12 weeks of treatment. Among GT3 patients treated for eight weeks, SVR12 was 50% (two of four patients) in those with the Y93H RAV at baseline and 98% in those without baseline Y93H. In GT3 patients treated for 12 weeks, SVR12 was 71% (five of seven patients) in those with the Y93H RAV at baseline and 99% in those without baseline Y93H.
Drug-related adverse events proved less frequent when MK3 was taken without ribavirin than with ribavirin (36% versus 67%), as did discontinuations for adverse events (0.6% versus 3%). Low hemoglobin and elevations in total bilirubin, aminotransferases and creatinine affected 1% or fewer taking MK3 without ribavirin. The most common adverse events without ribavirin were headache (19%), fatigue (15%) and nausea (11%).
Mark Mascolini writes about HIV and hepatitis virus infection.
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