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.
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
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.