IAS 2013: AbbVie Interferon-Free Hepatitis C Combo Works Well with Reduced Ribavirin Dose

Hepatitis C patients who reduced their dose of ribavirin due to side effects nevertheless had a high likelihood of achieving sustained response when treated with an all-oral regimen containing 3 direct-acting antiviral agents, researchers reported at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this week in Kuala Lumpur.

The advent of direct-acting antivirals has brought about a new paradigm in hepatitis C treatment, and the pending availability of interferon-free regimens will introduce even greater changes. While omitting pegylated interferon eliminates many adverse events, including ribavirin in a regimen can lead to anemia and other side effects.

AbbVie's Phase 2 AVIATOR study compared various interferon-free 3- and 4-drug combinations containing the HCV protease inhibitor ABT-450 boosted with ritonavir, the HCV NS5A inhibitor ABT-267, the HCV non-nucleoside polymerase inhibitor ABT-333, and ribavirin, for durations of 8, 12, or 24 weeks.

As reported at this year's EASL International Liver Congress, 96% of treatment-naive patients and 93% of prior null responders who received all 4 drugs for 12 weeks achieved sustained virological response, or continued undetectable HCV RNA, at 24 weeks post-treatment (SVR24). The sustained response rate was lower -- 87% -- for patients treated with the 3 direct-acting antivirals without ribavirin for 12 weeks (this regimen was not tested in null responders).

In the analysis presented at the IAS meeting, Barry Bernstein and colleagues from AbbVie looked at outcomes among patients who reduced their ribavirin dose levels due to adverse events, in particular anemia.

The analysis included 247 genotype 1 chronic hepatitis C patients (159 treatment-naive and 88 prior null responders) who received 100 or 150 mg once-daily ABT-450 boosted with 100 mg ritonavir plus 25 mg once-daily ABT-267 plus 400 mg twice-daily ABT-333 and 1000-1200mg/day weight-based ribavirin for 12 or 24 weeks. AbbVie has selected the 12-week 4-drug regimen for Phase 3 development.

About half of treatment-naive participants and two-thirds of null responders were men, 86% were white, and the mean age was about 51 years. People with HIV or hepatitis B coinfection were not included. With regard to liver disease severity, 28% of naive patients and 53% of null responders had moderate-to-severe fibrosis (stage F2-F3), but people with cirrhosis (stage F4) were excluded. About two-thirds had harder-to-treat HCV subtype 1a; 25% of naives but only 3% of null responders had the favorable IL28B CC gene variant.

Results

• Treatment was generally safe and well tolerated.
• More than 90% of both treatment-naive participants and null responders took at least 90% of their ribavirin doses.
• 4 people (1.6%) discontinued treatment due to adverse events.
• Although 16 patients (6.5%) saw their hemoglobin level fall below 10 g/dL, indicating moderate anemia, only 1 person (0.4%) developed severe anemia with hemoglobin below 8.5 g/dL.
• Ribavirin dose reductions due to toxicity were uncommon overall.
• 24 participants, or 10%, reduced their doses for this reason, with similar rates in the groups treated for 12 or 24 weeks.
• Treatment-naive patients reduced their doses more often and earlier (about half within the first 4 weeks) than prior null responders (mostly between weeks 8 and 12).
• Anemia was the most common cause of toxicity-related dose reduction (14 patients).
• Other side effects causing people to lower their ribavirin levels included fatigue, elevated creatinine, diarrhea, dizziness, shortness of breath, and itching (2-3 patients each).
• Ribavirin dose reduction did not negatively affect the likelihood of sustained response.
• SVR24 rates were 100% for both treatment-naive patients and null responders who lowered their doses, compared with 92% and 94%, respectively, or those who maintained full doses.

"Ribavirin dose reduction did not adversely impact SVR rate with this interferon-free regimen," the researchers concluded. As used in this combination, dose reduction occurred less often than previously seen in studies of interferon-based regimens, usually around 30%, they noted.

Although this study did not include people with HIV, Bernstein said that AbbVie is now completing drug-drug interaction studies necessary to support trials for HIV/HCV coinfected patients, which the company hopes to start within the next several months.

7/3/13

Reference

D Cohen, W Xie, L Larsen, B Bernstein, et al. Safety of ribavirin-containing regimens of ABT- 450/r, ABT-333 and ABT-267 for the treatment of HCV genotype 1 infection and efficacy in subjects with ribavirin dose reductions. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Kuala Lumpur, June 30-July 3, 2013. Abstract TUAB0103.