A 12-week triple combination of direct-acting antivirals
developed by AbbVie cured at least 99% of previously untreated people with
genotype 1b hepatitis C infection, Prof. Rajendar Reddy of the University of
Pennsylvania Hospital told the 21st Conference on Retroviruses and
Opportunistic Infections (CROI) in Boston last week.
Only one virologic failure occurred during treatment, no
patients relapsed immediately after completing treatment, and the only
other 'treatment failures' were two patients counted as virologic
failures after they
did not turn up for 12-week post-treatment monitoring visits.
The results came from the PEARL III study, one of the
largest of six phase III studies of AbbVie’s direct-acting antiviral
combination. AbbVie is one of several companies racing to develop
interferon-free combinations of oral drugs that can cure hepatitis C within 12
or 24 weeks.
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
These are the first results from AbbVie’s phase III
development programme to be presented at a scientific conference. AbbVie plans
to submit data from the phase III studies early in the second quarter of 2014
for US marketing approval and hopes to gain approval before the end of 2014.
European Union approval is likely to follow soon afterwards. The combination
will be the first to provide treatment for genotype 1b without the need for
interferon or ribavirin, a significant step forward in hepatitis C treatment.
Many of the side-effects of hepatitis C treatment are associated with
interferon and ribavirin.
Genotype 1b is the most common genotype of hepatitis C
globally, and comprises the largest proportion of infections in the European
region, Latin America, Russia, Turkey, China and Japan.
genotype 1b was traditionally considered difficult-to-treat in the era of dual
interferon and ribavirin therapy, it has been found to respond well to many new
antiviral HCV regimens with and without interferon.
The phase III studies compared various durations of
treatment with a combination of the HCV protease inhibitor ABT-450 boosted with
ritonavir co-formulated with the HCV NS5A inhibitor ABT-267, plus the HCV non-nucleoside
polymerase inhibitor ABT-333. These were tested with or without ribavirin, in untreated and
previously treated patients, including those with cirrhosis. The completed
studies did not include people with HIV and HCV co-infection.
PEARL III recruited 419 previously untreated non-cirrhotic patients with
genotype 1b infection. All participants in PEARL III received the triple
combination of direct-acting antivirals (referred to as '3D') and were randomised on a 1:1 ratio
to receive ribavirin (n=210) or placebo (n=209). Treatment in PEARL III lasted
for 12 weeks.
Approximately half of study participants in the ribavirin
arm were women, and a majority of participants in the placebo arm were women
(58.9%), an unusually high representation for a study of hepatitis C treatment.
95.2% of participants were Caucasian and 77% were recruited in the European
region. The mean age of the study population was around 49 years. The majority
of study participants had little or no evidence of liver disease: 67.8% in the
ribavirin-sparing arm and 71.4% in the ribavirin arm had F0 or F1 fibrosis.
Only 21% of the study population had an IL28B CC genotype, which confers a
better response to interferon-based treatment.
Cure rates were extremely high in both study arms. 99% of
patients in the ribavirin-sparing arm and 99.5% of patients in the ribavirin
arm achieved a sustained virologic response 12 weeks after the completion of
treatment (SVR12). One case of virologic rebound occurred at week 10 of
treatment, while two patients who achieved a virologic response at the end of
treatment were subsequently lost to follow-up. Other than these cases there
were no treatment failures. There were no significant differences by baseline
characteristics, including IL28B genotype.
Treatment was well tolerated. There were no treatment discontinuations
due to adverse events and the most common adverse events reported during the
study were headache and fatigue, which each occurred in just over one-in-five
patients. Pruritus and nausea were the only adverse events that occurred more
frequently in the ribavirin arm. Haemoglobin levels fell below the lower limit
of normal in 51.4% of patients in the ribavirin arm compared with 3.4% in the
ribavirin-sparing arm, and 9% of participants in the ribavirin arm developed anaemia compared
to none in the ribavirin-sparing arm. The ribavirin dose was reduced in 9% of
patients in the ribavirin arm. All of these patients achieved SVR12.
The study investigators concluded that in patients with
hepatitis C genotype 1b, a 12-week course of ABT-450r, ABT-333 and ABT-267 –
the so-called '3D' combination – is a highly effective and well-tolerated
treatment that can be administered without ribavirin.