Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir

Abstract

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Trial registration: ClinicalTrials.gov NCT01672983.

Keywords: genotype 2; hepatitis C virus; ombitasvir; paritaprevir.

Figure 1

Persistence of resistance‐associated baseline polymorphisms and treatment‐emergent substitutions in GT 2a or 2b‐infected patients who experienced virologic failure. The percentage of VF patients with the designated baseline or treatment‐emergent substitution is shown for the baseline, time of VF, post‐treatment week 24, and post‐treatment week 48 time points. Columns denoted as “Any” include patients with any baseline polymorphism or treatment‐emergent substitution for NS3 or NS5A at signature resistance‐associated amino acid positions. Baseline polymorphisms L/M31 in NS5A were not included in the total “Any” count. Specific amino acid substitutions designated as “(any)” include any amino acid change from wild‐type in the total count