High Efficacy of Sofosbuvir/Velpatasvir and Impact of Baseline Resistance–associated Substitutions in Hepatitis C Genotype 3 Infection

J. von Felden; J. Vermehren; P. Ingiliz; S. Mauss; T. Lutz; K. G. Simon; H. W. Busch; A. Baumgarten; K. Schewe; D. Hueppe; C. Boesecke; J. K. Rockstroh; M. Daeumer; N. Luebke; J. Timm; J. Schulze zur Wiesch; C. Sarrazin; S. Christensen

Disclosures

Aliment Pharmacol Ther. 2018;47(9):1288-1295. 

In This Article

Abstract and Introduction

Abstract

Background Twelve weeks of the pangenotypic direct–acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL–3 approval study. However, presence of resistance–associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.

Aim To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real–world setting.

Methods In this multicentre cohort study, GT3 patients from ten treatment centres across Germany were included. Sustained virological response was assessed 12 weeks after end–of–treatment (SVR12) in modified intention–to–treat (mITT) and per–protocol analysis (PP). NS5A RASs were tested by population–based sequencing.

Results A total of 293 GT3 patients were included. The median age was 48 years, 70% were male, 25.3% were cirrhotic, 9.2% were HCV/HIV co–infected and 21.8% were treatment–experienced, including 4.1% with DAA experience. Baseline NS5A RASs (Y93H, A30K, L31M) were detected in 11.2%. RBV was added in 5% of noncirrhotic and 58.9% of cirrhotic patients, respectively. SVR12 rates for SOF/VEL±RBV were 95.9% (mITT) and 99.5% (PP), respectively. Only 1 virological relapse occurred in a cirrhotic patient previously treated with SOF/RBV. No treatment–related major adverse events occurred.

Conclusion Twelve weeks of SOL/VEL±RBV was safe and highly efficient in HCV GT3 across a diverse patient population. Baseline NS5A RASs were rarely observed and presence did not seem to impact SVR, regardless of the use of RBV.

Introduction

Chronic hepatitis C virus (HCV) infection affects approximately 71 million patients worldwide, who are at risk of developing progressive liver disease, including cirrhosis and hepatocellular carcinoma.[1] HCV genotype 3 (GT3) is the second–most prevalent genotype, accounting for 25% of all infections, and has a particularly high prevalence among European drug users and in Southern Asia.[2,3] Moreover, recent evidence suggests that HCV GT3 infection is associated with higher rates of liver steatosis, more rapid fibrosis progression, and development of hepatocellular carcinoma compared to infection with other HCV genotypes.[4–6]

Historically, HCV GT3 infection was considered an easy–to–treat genotype with sustained virological response (SVR) rates of approximately 70% following 24–48 weeks of interferon–based therapy in noncirrhotic patients.[7,8] More recently, development of interferon–free direct–acting antiviral (DAA) drug combinations has marked a significant breakthrough in antiviral therapy for chronic HCV infection with high SVR rates.[9] However, most first–generation HCV protease inhibitors and nonstructural protein 5A (NS5A) inhibitors were less effective in GT3 infection, particularly in the presence of other negative predictive factors, including cirrhosis, prior interferon treatment failure and/or resistance–associated substitutions (RASs).[3,10] Thus, HCV GT3 infection was still regarded as one of the more "difficult–to–treat" genotypes in the era of interferon–free treatments.

Velpatasvir (VEL), a second–generation, pangenotypic HCV NS5A inhibitor in combination with the HCV NS5B polymerase inhibitor sofosbuvir (SOF) was recently introduced as an interferon–free, oral, once daily regimen for the treatment of HCV genotypes 1–6.[11,12] SOF/VEL demonstrated potent antiviral activity and a high barrier to resistance in vitro, and high SVR rates of 95%–99% were achieved across all HCV genotypes following 12 weeks of SOF/VEL therapy.[11,12] However, SVR rates were lower in HCV GT3 infection compared to other genotypes, particularly in treatment–experienced cirrhotic patients.[11,13] These observations prompted the European Medicines Agency to recommend that ribavirin (RBV) may be added in patients with HCV GT3 infection and cirrhosis although no data are available to support this recommendation.[14]

While rarely observed in the approval trials, presence of the highly resistant NS5A substitution Y93H at baseline was associated with lower SVR, and Y93H was also observed as the predominant variant in all GT3 failures at time of treatment failure.[13]

So far, no large cohort studies outside of clinical trials are available for GT3 patients, and thus, it is unclear whether equally high SVR rates reported in clinical trials are achievable under real–world conditions.

In our multicentre cohort study, we aimed to assess the efficacy and safety of 12–week therapy with SOF/VEL ± RBV in patients with HCV GT3 infection, including patients with HCV and human immunodeficiency virus–1 (HIV) co–infection, prior HCV–treatment experience and/or cirrhosis in a real–world setting. In addition, impact of baseline NS5A RASs on treatment outcome was analysed.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....