Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

Timothy Papaluca,Siddharth Sood,Miriam Levy,Jacob George,William Sievert,Edmund Tse,Kate New,Simon Hazeldine,Bruce Mcgarity,Martin Weltman,Gerry Macquillan,Ivan Valiozis,Jacinta O’Keefe,Zina Valaydon,Alan Wigg,Golo Ahlenstiel,Scott Bowden,Joseph Doyle,Marie Sinclair,Margaret Hellard,James O’Beirne,Rohit Sawhney,Mazhar Haque,Leslie R Fisher ,Stuart K Roberts ,Simone I Strasser ,Mark L Wilson ,Katherine Stuart ,Aidan J Woodward ,Mark W Douglas ,Gregory J Dore ,James A Thomas ,E J Prewett ,Geoffrey C Farrell ,Amanda Wade ,Mark Stoové ,Alexander Thompson

doi:10.1093/cid/ciaa1318

Abstract

In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Highlights

Hepatitis C virus (HCV) infection affects approximately 71 million people worldwide, and contributes significantly to liver related morbidity and mortality [1,2]
Virological failure is associated with the selection t of HCV resistance associated substitutions (RAS) and ideal retreatment regimens should target the ip NS5A, NS5B and NS3 proteins [8,9]. cr The efficacy of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for relapsed HCV infection s following treatment with an NS5A-inhibitor (NS5Ai) containing Direct acting antiviral (DAA) regimen has been investigated in nu multiple clinical trials [10]
We have evaluated the efficacy and safety of SOF/VEL/VOX in a difficult to cure population with advanced liver disease or prior-liver transplantation (LT)

Summary

Introduction

Hepatitis C virus (HCV) infection affects approximately 71 million people worldwide, and contributes significantly to liver related morbidity and mortality [1,2]. Anuscript Discussion: M This is the first Australian real-world study to investigate the efficacy and safety of SOF/VEL/VOX d amongst participants with relapsed HCV infection following treatment with an NS5Ai-containing DAA te regimen, and advanced liver disease or LT. As expected, where virological testing was available, there was a high prevalence of HCV NS5A RAS at baseline (90%, n=49/54), and 15% had previously failed multiple NS5Ai-containing DAA regimens, in some cases up to four Despite these difficult-to-cure characteristics, we show that 12 weeks SOF/VEL/VOX can achieve high rates of cure in clinical practice. Ep Baseline RAS testing was available for 54 participants and the presence of NS5A RAS was not c associated with treatment failure This is in keeping with results of a post-hoc analysis of Ac SOF/VEL/VOX registration data demonstrating that multitargeted combination therapy can overcome baseline resistance quasispecies [20].

Accepted Manuscript

Findings

Treatment related