People taking hepatitis C treatment who reduced their dose of ribavirin due to side-effects nevertheless had a high likelihood of achieving sustained virological response when treated with an all-oral regimen containing three direct-acting antiviral agents, researchers reported on Tuesday at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) in Kuala Lumpur.
The advent of direct-acting antivirals has brought about a new paradigm in treatment for hepatitis C virus (HCV), 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 anaemia and other side-effects.
SVR24 rates were 100% for both treatment-naive participants and null responders who lowered their doses.
AbbVie's phase 2 AVIATOR study compared various interferon-free three- and four-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 International Liver Congress (EASL 2013), 96% of treatment-naive patients and 93% of prior null-responders who received all four 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 people taking the three 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 people who reduced their ribavirin dose levels due to adverse events, in particular anaemia.
The analysis included 247 people with genotype 1 chronic hepatitis C (159 treatment-naive and 88 prior null responders) who received 100 or 150mg once-daily ABT-450 boosted with 100mg ritonavir, 25mg once-daily ABT-267, 400mg twice-daily ABT-333 and 1000-1200mg/day weight-based ribavirin for 12 or 24 weeks. AbbVie has selected the 12-week four-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 co-infection were not included. With regard to liver disease severity, 28% of treatment-naive participants 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 treatment-naive people but only 3% of null responders had the favourable IL28B CC gene variant.
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. Four people (1.6%) discontinued treatment due to adverse events. Although 16 people (6.5%) saw their haemoglobin level fall below 10g/dL, indicating moderate anaemia, only one person (0.4%) developed severe anaemia with haemoglobin below 8.5g/dL.
Ribavirin dose reductions due to toxicity were uncommon overall. A total of 24 participants, or 10%, reduced their doses for this reason, with similar rates in the groups treated for 12 or 24 weeks. Treatment-naive participants reduced their doses more often and earlier (about half within the first four weeks) than prior null responders (mostly between weeks 8 and 12).
Anaemia was the most common cause of toxicity-related dose reduction (14 people). Other side-effects causing people to lower their drug levels included fatigue, elevated creatinine, diarrhoea, 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 participants and null responders who lowered their doses, compared with 92 and 94%, respectively, or those who maintained full doses.
As used in this interferon-free combination, dose reduction occurred less often than previously seen in studies of interferon-based regimens, usually around 30%, the researchers 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 people with HIV and HCV co-infection, which the company hopes to start within the next several months.
Cohen D 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 IAS Conference on HIV Pathogenesis, Treatment and Prevention, Kuala Lumpur, abstract TUAB0103, July 2013. View the abstract on the IAS conference website.