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Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1

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Summary

Background

Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment.

Methods

This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21.

Findings

152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93–99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred.

Interpretation

Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options.

Funding

Gilead Sciences.

Introduction

Worldwide, a small but growing population of patients with chronic hepatitis C virus (HCV) infection has been unsuccessfully treated with a direct-acting antiviral regimen; most of these patients have received regimens that include an NS5A inhibitor. NS5A inhibitors are the most potent class of direct-acting antivirals but have a relatively low barrier to resistance compared with other classes, such as non-nucleotide HCV NS5B inhibitors. Particularly when administered without an NS5B inhibitor, NS5A resistance at the time of virological failure is nearly universal in patients who do not respond to treatment with a regimen including an NS5A inhibitor. Furthermore, NS5A resistance-associated substitutions usually persist long term1 and are associated with a reduced response to treatment regimens containing NS5A inhibitors, especially in patients with advanced cirrhosis, HCV genotype 1a or 3 infection, or previous failure of interferon treatment.2, 3, 4, 5, 6

To date, the POLARIS-1 study7 has been the only phase 3 study to exclusively enrol patients who did not respond to previous treatment with an NS5A inhibitor. The study assessed 12 weeks of therapy with a combination of sofosbuvir (an NS5B inhibitor), velpatasvir (an NS5A inhibitor), and voxilaprevir (an NS3/4A protease inhibitor) versus placebo. Among 263 patients who received sofosbuvir-velpatasvir-voxilaprevir, 253 (96%) achieved sustained virological response, compared with none of the 152 patients who received placebo. On the basis of the results from POLARIS-1, sofosbuvir-velpatasvir-voxilaprevir has been approved in the USA and European Union as a pan-genotypic salvage regimen for patients previously given an NS5A inhibitor.8, 9, 10

Research in context

Evidence before this study

Before the approval of sofosbuvir–velpatasvir–voxilaprevir, no retreatment options were approved for patients with chronic hepatitis C virus infection who had been treated with a direct-acting antiviral regimen containing an NS5A inhibitor. The POLARIS-1 study was the first phase 3 registrational, randomised, placebo-controlled trial to enrol and treat such patients, as we confirmed by a review of PubMed using the search terms, “HCV”, “NS5A treatment-experienced”, “prior DAA experience”, and “salvage therapy”, for clinical trials published by Aug 21, 2015. In the primary study of POLARIS-1, 253 (96%) of 263 patients who received sofosbuvir–velpatasvir–voxilaprevir for 12 weeks achieved sustained virological response.

Added value of this study

In the current substudy of POLARIS-1, patients with genotype 1 hepatitis C virus infection assigned to the placebo group in the primary study of POLARIS-1 were subsequently treated with sofosbuvir–velpatasvir–voxilaprevir for 12 weeks to assess efficacy and safety. The large number of patients (143 [97%] of 147) treated in this deferred treatment substudy who achieved sustained virological response further supports the efficacy and safety of treatment in the primary study. Combined with the results of the primary study of POLARIS-1, 396 (97%) of 410 patients have achieved sustained virological response in clinical trials with sofosbuvir–velpatasvir–voxilaprevir.

Implications of all the available evidence

These results support the use of sofosbuvir–velpatasvir–voxilaprevir for the treatment of chronic hepatitis C virus infection in patients with NS5A inhibitor experience, regardless of which direct-acting antivirals were used in previous treatments.

Patients in POLARIS-1 who were masked to treatment and initially received placebo were eligible for a subsequent open-label substudy in which they would receive sofosbuvir-velpatasvir-voxilaprevir for 12 weeks. We report the safety and efficacy results of the deferred treatment substudy.

Section snippets

Study design and participants

This open-label deferred treatment substudy from the international phase 3, multicentre POLARIS-1 study7 was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. The initial phase of POLARIS-1 was a blinded, randomised study comparing 12 weeks of once-daily treatment with either placebo or a combination tablet containing sofosbuvir, velpatasvir, and voxilaprevir. Assignments were unblinded 4 weeks after treatment. Patients

Results

152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, 147 of whom were enrolled from March 30, 2016, to Oct 12, 2016. Five patients enrolled in the primary study were not eligible for the deferred treatment substudy; three patients had discontinued placebo in the primary study, and two patients developed new clinically significant illnesses (namely, liver decompensation and prostate cancer). The median age for the substudy

Discussion

In this open-label substudy of POLARIS-1, once daily sofosbuvir-velpatasvir-voxilaprevir was highly effective in treatment of patients with chronic HCV infection who had a history of treatment failure with an NS5A inhibitor-containing regimen. The SVR12 rate was 97% overall and 98% in patients previously treated with an NS5A inhibitor and an NS3/4A inhibitor. A substantial proportion of patients (89%) had baseline NS5A or NS3 resistance-associated substitutions detected by deep sequencing with

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