Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Abstract

ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10 IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥ 40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.).

Copyright © 2016 Lawitz et al.

Figures

FIG 1

Study design. The study consisted of a 3-day monotherapy period, a 12-week combination treatment period, and a 48-week posttreatment period. Data reported here are from the 3-day monotherapy period. During the 3-day monotherapy period, doses administered in the treatment arms for patients without cirrhosis were 100, 200, 300, 400, and 700 mg (ABT-493) and 15, 40, 120, and 400 mg (ABT-530). The treatment regimen administered during the 12-week combination treatment period consisted of ombitasvir, paritaprevir, and ritonavir (25, 150, and 100 mg, respectively) administered once daily, dasabuvir (250 mg) administered twice daily, and weight-based ribavirin (total daily dose of 1,000 or 1,200 mg, divided in two).

FIG 2

Mean changes in HCV RNA levels from baseline during monotherapy with ABT-493 or ABT-530. Data are presented as the mean changes in HCV RNA levels from baseline 0 to 72 h after the first dose for each ABT-493 (A) or ABT-530 (B) dose studied. Standard deviations are shown as error bars.

FIG 3

Changes in HCV RNA levels from baseline in patients with baseline NS3 RAVs who received ABT-493. Data are presented as the changes in HCV RNA levels from baseline 0 to 72 h after the first dose for each patient with baseline NS3 RAVs, compared to the mean decline curves for all patients in the corresponding ABT-493 dose groups. (A) 100 mg. (B) 200 mg. (C) 300 mg. (D) 400 mg. (E) 700 mg. Standard deviations within each dose group are shown as error bars. RAVs are listed in parentheses, and a mixture of amino acids detected at a position is denoted by a slash. One patient who had a baseline NS3 Q80K variant was not included in the HCV RNA analysis due to noncompliance.

FIG 4

Changes in HCV RNA levels from baseline in patients with baseline NS5A RAVs who received ABT-530. Data are presented as the changes in HCV RNA levels from baseline 0 to 72 h after the first dose for each patient with baseline NS5A RAVs, compared to the mean decline curves for all patients in the corresponding ABT-530 dose groups. (A) 15 mg. (B) 40 mg. (C) 120 mg. (D) 400 mg. (E) 120 mg (with cirrhosis). Standard deviations within each dose group are shown as error bars. RAVs are listed in parentheses, and a mixture of amino acids detected at a position is denoted by a slash.