Efficacy of Elbasvir and Grazoprevir in Participants With Hepatitis C Virus Genotype 4 Infection

A Pooled Analysis

Tarik Asselah; Hendrik Reesink; Jan Gerstoft; Victor de Ledinghen; Paul J. Pockros; Michael Robertson; Peggy Hwang; Ernest Asante-Appiah; Janice Wahl; Bach-Yen Nguyen; Eliav Barr; Rohit Talwani; Lawrence Serfaty

Disclosures

Liver International. 2018;38(9):1583-1591. 

In This Article

Abstract and Introduction

Abstract

Background & Aims: The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir.

Methods: Treatment-naïve and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy).

Results: Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype.

Conclusions: The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naïve and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4-infected participants.

Introduction

Hepatitis C virus (HCV) is genetically diverse and is classified into 7 genotypes (GTs) and multiple subtypes which currently number around 70.[1] This classification is based on viral genome sequence homology, which differs from 30% to 35% between genotypes, while within each subtype there is <15% sequence variability. Adult migrants originating from Asia, Sub-Saharan Africa and Eastern Europe are at increased risk for HCV infection and may benefit from targeted HCV screening.[2] Migration from endemic regions is changing the distribution of GT4 infection worldwide. HCV GT4 accounts for approximately 20% of the 170 million HCV infections worldwide, and about 85% of these infections are located in the Middle East and northern and central Africa. In Egypt, which has the highest prevalence of HCV infection in the world (12%–15%), over 90% of infections are with HCV GT4.[3,4] Distribution of the remaining HCV GT4 infections mirror migration patterns from these regions, notably to western and southern Europe, where the prevalence of GT4 infection is increasing. Across this region, there are over 1.5 million cases of HCV GT4 infection. The majority of individuals with HCV GT4 infection are undiagnosed (and therefore belong to the treatment-naïve population). While there is regional variability in the prevalence of GT4 infection, several local surveys performed in France and southern Europe demonstrated that 12%–26% of all HCV infections are GT4.[5–8]

There is considerable genetic diversity in clinical isolates of GT4, with 17 subtypes confirmed to date.[9] The prevalence of these subtypes varies geographically, even within the endemic region. While GT4a predominates in Egypt, non-4a and non-4d subtypes are the most common strains found in Sub-Saharan Africa. The distribution of GT4 subtypes in Europe is more heterogeneous, perhaps reflecting the country of origin of the infected individual.[10] A phylogenetic analysis that combined participant-derived GT4 specimens from daclatasvir late-stage clinical trials with GT4 sequences from the European HCV database demonstrated that of 128 GT4 sequences from Europe, 54 (42%) were GT4a, and 46 (36%) were GT4d, while the remaining 28 (22%) were distributed across 11 GT4 subtypes.[9] Sequence analyses also suggest that subtype-specific clustering of infections occurs in Europe, for example, HCV GT4d in southern Italy.[6]

Historically, HCV GT4 has been considered difficult to treat.[11,12] The use of combinations of DAAs increased the SVR rates in HCV GT4-infected individuals.[13–15] Accordingly, standard of care of treatment for chronic HCV infection is rapidly evolving to all oral IFN-sparing DAA regimens. However, availability of DAA-based therapy may be limited in certain regions. Given that the disease burden of HCV GT4 infection primarily impacts resource-constrained regions, and that data on the efficacy of DAA regimens in this population are limited to pilot or single arm studies with small sample sizes, studies in larger pooled data sets are of value to help inform local and regional treatment practices. In general, DAA-based treatment responses in GT4 infection have been similar to those observed in genotype 1 infection; however, the impact of GT4 subtype and baseline polymorphisms on treatment response is not well characterized nor is the in vitro activity of DAA against a majority of GT4 subtypes.

EBR/GZR is a fixed-dose combination DAA-based treatment recently approved in the USA, Canada, Europe, and other countries for the treatment of HCV GT1 and GT4 infection. EBR, an NS5A inhibitor, and GZR, an NS3/4A protease inhibitor, have demonstrated high in vitro potency against most HCV genotypes, including HCV GT4 replicons as well as resistance-associated substitutions (RASs) that confer resistance to first-generation protease inhibitors and RASs related to treatment failures on daclatasvir and ledipasvir.[16–20] Among treatment-naïve and treatment-experienced participants with HCV GT1 or GT4 mono-infection or HIV-HCV co-infection, a once-daily, oral, 12-week regimen of EBR/GZR has been shown to be generally well tolerated with consistently high-virologic response rates.[21–25] EBR/GZR is approved as slightly different regimens for the treatment of HCV GT4-infected individuals in different countries. The aim of this integrated analysis was to assess the efficacy of the once-daily combination of 12 or 16 weeks of EBR (50 mg/d) and GZR (100 mg/d) with or without ribavirin in GT4-infected participants enrolled in the Phase 2/3 clinical programme with EBR/GZR.

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