Abstract and Introduction
Abstract
Background & Aims: The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection—the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients.
Methods: We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin.
Results: Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%–100%; and group 2: 100%; 95% confidence interval, 95.9%–100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL.
Conclusions: The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events.
Introduction
Untreated chronic hepatitis C virus (HCV) infection is a leading cause of liver damage, cirrhosis, and hepatocellular carcinoma.[1] The prevalence of HCV infection is estimated to be 3% worldwide and results in approximately 350, 000 deaths annually.[2,3] Genotype 1 accounts for approximately 70% of all HCV infections and subgenotype 1b is most predominant in Europe and Eastern Asia. Approved direct-acting antiviral agents (DAAs), telaprevir, boceprevir, sofosbuvir, and simeprevir, given with peginterferon (pegIFN) and ribavirin (RBV), have reported sustained virologic response (SVR) rates of 67%–89% in HCV genotype 1–infected patients. Response rates with DAA regimens are generally lower in patients who have failed previous pegIFN-containing treatment regimens than in treatment-naive patients, and are noticeably lower among prior null responders.[4–8] In addition, the toxicity of pegIFN and long duration of therapy (up to 48 weeks with some regimens) are a hardship for patients.[9] Notably, pegIFN-based treatment regimens have well-documented adverse event (AE) profiles including influenza-like symptoms and depression, which have led to unfavorable discontinuation rates in clinical trials,[6,9–12] and RBV also has associated side effects including teratogenicity, hemolytic anemia, and rash.[13,14]
All-oral and interferon-free HCV treatment regimens with DAAs provide wider treatment access to patients in need with chronic liver disease. ABT-450 is an NS3/4A protease inhibitor with in vitro nanomolar antiviral activity and is co-dosed with the CYP3A4 inhibitor, ritonavir, which significantly increases peak and trough drug concentrations, enabling once-daily dosing.[15] The multitargeted, all-oral combination of the 3 DAAs of ABT-450/ritonavir, ombitasvir (formerly ABT-267), an HCV NS5A inhibitor with pangenotypic picomolar antiviral activity,[16] and dasabuvir (formerly ABT-333), an HCV NS5B RNA non-nucleoside polymerase inhibitor, with RBV was shown in a phase 2b trial to achieve high rates of SVR 12 weeks post-treatment (SVR12) in treatment-naive and treatment-experienced genotype 1–infected patients. With this regimen, a 93% SVR12 rate was achieved in genotype 1–infected noncirrhotic patients with prior null response to pegIFN/RBV, and a 100% SVR12 rate was achieved in the genotype 1b patient subset.[17] These high response rates in prior null responders, considered difficult to cure, are promising and require confirmation in a large phase 3 trial. Although ABT-450/ritonavir/ombitasvir and dasabuvir with RBV may achieve high SVR12 rates, determining the benefit gained by including RBV in the regimen has not been assessed in these patients. This phase 3 study (PEARL-II) evaluated the efficacy and safety of 12 weeks of treatment with coformulated ABT-450/ritonavir/ombitasvir and dasabuvir with or without RBV exclusively in noncirrhotic pegIFN/RBV treatment-experienced HCV genotype 1b–infected patients.
Gastroenterology. 2014;147(2):359-365. © 2014 AGA Institute
