High antiviral activity of NS5A inhibitor ABT-530 with paritaprevir/ritonavir and ribavirin against hepatitis C virus genotype 3 infection

Abstract

Background & aims: ABT-530 is a next-generation hepatitis C virus (HCV) NS5A inhibitor with potent pangenotypic antiviral activity in vitro. Paritaprevir is an NS3/4A protease inhibitor codosed with ritonavir that displays in vitro activity against HCV genotypes 1-4 and 6.

Methods: Efficacy, pharmacokinetics and safety of ABT-530 with paritaprevir/ritonavir and ribavirin were evaluated in this phase 2, open-label, multicentre study in treatment-naïve non-cirrhotic patients with genotype 3 infection. Ten patients, all genotype 3a, received 120 mg ABT-530 and 150/100 mg paritaprevir/ritonavir once daily with ribavirin for 12 weeks.

Results: Nine (90%) patients achieved a sustained virological response at post-treatment weeks 12 and 24. One patient experienced virological failure at treatment week 6. Sequence analyses for HCV variants in samples from this patient identified A166S in NS3 at baseline and after breakthrough, as well as A30K at baseline and linked S24F+M28K+A30K variants in NS5A after breakthrough. Neither genotype 3 NS3 A166S nor NS5A A30K variant confers any resistance to paritaprevir or ABT-530 respectively. However, genotype 3 NS5A S24F+M28K+A30K-linked variant confers a >5000-fold increase in ABT-530 EC50 relative to that of the wild-type replicon. This patient's ABT-530 exposure was comparable to the cohort, while paritaprevir and ritonavir exposures were the lowest of all patients. No serious or severe adverse events and adverse events leading to early discontinuation were reported.

Conclusions: Results from this study show that ABT-530 holds promise as part of a direct-acting antiviral treatment regimen for HCV genotype 3 infection.

Trial registration: ClinicalTrials.gov NCT02068222.

Keywords: direct-acting antiviral; next generation; pharmacokinetics; resistant variant; sustained virological response.

© 2016 AbbVie Inc. Liver International Published by John Wiley & Sons Ltd.

Figures

Figure 1

Study design. This study consisted of a 12‐week treatment period followed by a 24‐week post‐treatment period. PTV/r, paritaprevir/ritonavir; RBV, ribavirin; SVR12, sustained virological response at post‐treatment week 12 (primary endpoint); SVR24, sustained virological response at post‐treatment week 24.

Figure 2

Mean hepatitis C virus (HCV) RNA levels for patients who received ABT‐530 in combination with paritaprevir/ritonavir and ribavirin for 12 weeks. Presented are the mean HCV RNA levels (log10 IU/ml) evaluated during the M14‐213 study for each of the 10 patients who received ABT‐530 in combination with paritaprevir/ritonavir and ribavirin. The genotype 3 subtype and IL28B genotype are described for each patient in parentheses. Dotted line at y‐axis 0 indicates HCV RNA below the lower limit of detection (15 IU/ml). * indicates the one patient with on‐treatment breakthrough at treatment week 6; this patient did not have assessments following post‐treatment week 2. BL, baseline; W, treatment week; PTW, post‐treatment week.

Figure 3

Distribution of trough plasma concentrations measured for patients who received ABT‐530 in combination with paritaprevir/ritonavir and ribavirin for 12 weeks. Presented is the distribution of trough plasma concentrations for the 10 patients who received ABT‐530 in combination with paritaprevir/ritonavir and ribavirin for 12 weeks. The middle line indicates the mean value, and top and bottom lines show the maximum and minimum values, respectively, for each compound. Data for the patient who experienced virological failure at treatment week 6 are indicated in red. Ctrough, trough plasma concentrations, is estimated based on concentrations measured at 22–26 h post dosing for ABT‐530, paritaprevir and ritonavir and at 10–14 h post dosing for ribavirin.