A 12-week triple combination of direct-acting antivirals developed by AbbVie cured at least 99% of previously untreated people with genotype 1 hepatitis C infection, Prof. Rajendar Reddy of the University of Pennsylvania Hospital told the 2014 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston on Tuesday.
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.
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.
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 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. Pruritis 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.
Ferenci P et al. PEARL III: SVR ≥99% after 12 wks of ABT-450/r/267 + ABT-333 ± RBV in treatment naïve HCV GT1b infection. 2014 Conference on Retroviruses and Opportunistic Infections, Boston, abstract 29LB, 2014.