Retreatment With Elbasvir, Grazoprevir, Sofosbuvir ± Ribavirin Is Effective for GT3 and GT1/4/6 HCV Infection After Relapse

Timothy Papaluca; Marie Sinclair; Paul Gow; Stephen Pianko; William Sievert; Niranjan Arachchi; Karla Cameron; Scott Bowden; Jacinta O'Keefe; Joseph Doyle; Mark Stoove; Margaret Hellard; David Iser; Alexander Thompson

Disclosures

Liver International. 2019;39(12):2285-2290. 

In This Article

Abstract and Introduction

Abstract

Introduction: Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) ±ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (±RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients.

Methods: We evaluated the efficacy and safety of SOF/ELB/GZR ± RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis.

Results: There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated.

Discussion: The combination of SOF/ELB/GZR ± RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.

Introduction

The introduction of highly effective and well-tolerated direct-acting antiviral (DAA) therapy has revolutionised hepatitis C virus (HCV) treatment. Despite excellent cure rates which exceed 95%, some patients experience virological relapse after treatment. Virological relapse is associated with the selection of HCV resistance-associated substitutions (RAS), which reduce viral susceptibility to currently available DAAs.[1] NS5A inhibitors are the backbone of most DAA regimens and selection of NS5A RAS is the most common reason for DAA failure. NS5A variants can persist for many years post-relapse.[2] Variants in the NS5B region and/or NS3/4a region may also be selected with sofosbuvir (SOF) or protease inhibitor therapy respectively. The ideal salvage regimen should involve combination therapy with at least two agents that are active against all the prevalent HCV quasispecies. Triple combination therapy involving sofosbuvir (SOF), a protease inhibitor and an NS5A inhibitor is therefore attractive as a salvage strategy.

Elbasvir (ELB) plus grazoprevir (GZR) is licensed for treatment of HCV genotype (GT)1 and 4 infection.[3] Recent data have demonstrated that ELB/GZR in combination with SOF (±ribavirin (RBV)) is also an effective salvage treatment for cirrhotic DAA-experienced GT1/4 patients, those genotypes for which ELB/GZR has the greatest in vitro and in vivo activity.[4] ELB and GZR alone have reduced effectiveness against HCV GT3 infection, with a significantly higher EC50 than for GT1 HCV in vitro and suboptimal SVR12 rates in clinical trials.[3,5] Despite this, ELB/GZR in combination with SOF plus RBV was highly effective for the treatment of DAA-naive GT3 patients; in a large prospective study SVR12 rates exceeded 94% in those treated for 12 to 16 weeks, including participants with cirrhosis.[6]

In this context, we hypothesised that SOF plus ELB/GZR ± RBV (ELB/GZR/SOF ± RBV) would be an effective salvage regimen for DAA-experienced patients, irrespective of GT or underlying cirrhosis.

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