Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens

Abstract

Background: The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy.

Methods: In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology.

Results: Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed.

Conclusions: In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants.

Clinical trials registration: NCT01805882.

Keywords: direct-acting antiviral agents; hepatitis C; ledipasvir; retreatment; sofosbuvir.

Figure 1.

Study flow diagram.

Figure 2.

Patients with hepatitis C virus (HCV) RNA lower than the level of quantification (LLOQ). Treatment response, as measured by HCV RNA LLOQ at all subsequent visits. One patient missed the week 12, end-of-treatment (EOT), visit. Because that patient's HCV viral load was detectable at the preceding visit, the HCV viral load was counted as detectable at week 12. This participant did go on to achieve sustained virological response (SVR) 12. Abbreviations: LDV, ledipasvir; SOF, sofosbuvir.