A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1.

BACKGROUND & AIMS: ABT-450 (combined with low-dose ritonavir, ABT-450/r) is a potent HCV NS3 protease inhibitor, and ABT-072 is a non-nucleoside NS5B polymerase inhibitor. The goal of this study was to evaluate the safety, tolerability, and efficacy of the peginterferon-free combination of ABT-450/r and ABT-072 with ribavirin in treatment-naïve patients with IL28B CC genotype, infected with HCV genotype 1. METHODS: This was a phase 2a, multicenter, open-label, single-arm study in 11 treatment-naïve, non-cirrhotic HCV GT1-infected patients with IL28B rs12979860 genotype CC. Patients received ABT-450/r 150/100 mg once daily and ABT-072 400 mg once daily with weight-based ribavirin 1000-1200 mg/day dosed twice daily for 12 weeks. RESULTS: Eight (73%) patients were male, 9 (82%) were Caucasian (including 3 who self-identified as Hispanic); mean baseline HCV RNA was 6.9 log10 IU/ml (range 6.5-7.3 log10 IU/ml). All 11 patients completed 12 weeks of treatment and maintained HCV RNA <25 IU/ml from weeks 4 through 12 of treatment. Ten patients (91%) achieved sustained virologic response 24 weeks post-treatment, with a second patient relapsing 36 weeks post-treatment. There were no deaths, serious or severe adverse events, or premature discontinuations. Adverse events were mostly mild and the most frequent were headache, fatigue, nausea, and dry skin. CONCLUSIONS: A 12-week regimen of ABT-450/r and ABT-072 with ribavirin was well tolerated with 9/11 patients achieving sustained virologic response through 36 weeks of post-treatment observation. These findings suggest that peginterferon-free regimens may have the potential to cure a high proportion of HCV genotype 1-infected patients.

Exploratory study of oral combination antiviral therapy for hepatitis C.

BACKGROUND: There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection. METHODS: We conducted a 12-week, phase 2a, open-label study involving patients who had HCV genotype 1 infection without cirrhosis. All patients received ABT-333 (400 mg twice daily) and ribavirin (1000 to 1200 mg per day) and one of two daily doses of ABT-450/r. Groups 1 and 2 included previously untreated patients; group 1 received 250 mg of ABT-450 and 100 mg of ritonavir, and group 2 received 150 mg and 100 mg, respectively. Group 3, which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin, received daily doses of 150 mg of ABT-450 and 100 mg of ritonavir. The primary end point was an undetectable level of HCV RNA from week 4 through week 12 (extended rapid virologic response). RESULTS: A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting. CONCLUSIONS: This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor, a nonnucleoside polymerase inhibitor, and ribavirin may be effective for treatment of HCV genotype 1 infection. (Funded by Abbott; ClinicalTrials.gov number, NCT01306617.).