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

Discussion

The results of this pooled analysis demonstrate the overall rates of efficacy of treatment with EBR/GZR ± RBV for 12 or 16 weeks in HCV GT4-infected treatment-naïve participants (SVR12 = 96.4% [95% CI = 91.0, 99.0]; 107/111) and in treatment-experienced participants (SVR12 = 88.6% [95%CI = 75.4, 96.2]; 39/44). This study included a relatively large population of 155 participants including GT4 diversity with 11 subtypes represented.

There was no impact of the 11 subtypes of GT4 on the high rate of efficacy. This result reflects the potent in vitro inhibition of EBR or GZR against most HCV GT4 subtypes. There were also no significant differences in the SVR12 rates with 12 weeks of EBR/GZR in the subgroups of cirrhosis status, sex, race, age, baseline HCV RNA levels or HIV/HCV co-infection (Figure 3). There was no impact of GT4 baseline NS5A or NS3 RASs on efficacy (Figure 4). This suggests that baseline testing for RASs is not necessary in the treatment of GT4-infected individuals with EBR/GZR, especially in treatment-naïve individuals who are likely to comprise the majority of infections in the resource-limited settings where HCV genotype 4 is endemic. Furthermore, there were no consistent RASs observed after virologic failure (Table 2).

The approved regimen for EBR/GZR for the treatment of adult individuals with chronic HCV genotype 4 infection depends on the previous treatment experience and/or baseline HCV RNA levels. For example, treatment-naïve and treatment-experienced GT4 individuals (with or without cirrhosis) with HCV RNA ≤800 000 IU/mL are recommended by the EMA and the EASL Guidelines to be treated with 12 weeks of EBR/GZR without RBV. For treatment-naïve and treatment-experienced GT4 individuals (with or without cirrhosis) with HCV RNA >800 000 IU/mL, 16 weeks of EBR/GZR with RBV should be considered.[33,34] The results in this pooled analysis showed SVR12 rates in individuals with HCV RNA >800 000 IU/mL of 95% (60/63; 95% CI = 87, 99) who were treated with 12 weeks of EBR/GZR without RBV and 100% (5/5; 95% CI = 48, 100) in those who were treated with 16 weeks of EBR/GZR plus RBV (Table S5). The recommendations from the U.S. FDA, Australia TGA and Health Canada are 12 weeks of EBR/GZR in treatment-naïve GT4 individuals (with or without cirrhosis) and 16 weeks of EBR/GZR with RBV in treatment-experienced GT4 individuals (with or without cirrhosis).[32,35,36] The results in this pooled analysis showed SVR12 rates in treatment-experienced individuals of 88% (14/16; 95% CI = 62, 98) treated with 12 weeks of EBR/GZR without RBV and 100% (8/8; 95% CI = 63, 100) in individuals treated with 16 weeks of EBR/GZR plus RBV (Table S5). Currently, approved regimens have durations of 12 weeks (ledipasvir/sofosbuvir; sofosbuvir/velpatasvir; ombitasvir/paritaprevir/ritonavir/RBV; glecaprevir/pibrentasvir in individuals with cirrhosis) or 8 weeks (glecaprevir/pibrentasvir in individuals without cirrhosis), and similar efficacy vs genotype 4 as EBR/GZR.[34,37,38]

A low virologic failure rate (2%) was observed among treatment-naïve GT4 participants treated with 12 weeks of EBR/GZR, suggesting that certain patient subtypes may benefit from even shorter durations of therapy. Preclinical studies demonstrated that the in vitro activity of both EBR and GZR against GT4 was similar to GT1b when assessed in HCV replicon cell-based assays. Furthermore, the response rate noted in treatment-naïve GT4 participants treated with 12 weeks of EBR/GZR was similar to that observed in a pooled analysis of HCV GT1b participants wherein 828/851 (97%) treatment-naïve HCV GT1b participants achieved SVR12 after 12 weeks of EBR/GZR.[39] As HCV GT4 and GT1b demonstrated comparable in vitro profiles and similar clinical outcomes when treated with 12 weeks of EBR/GZR, HCV GT4-infected individuals may respond similar to HCV GT1b-infected individuals treated with shorter durations. An 8-week regimen of EBR and GZR in non-cirrhotic HCV treatment-naïve participants with GT1b infection demonstrated that 28/29 (97%) treatment-naïve GT1b participants with F0-F2 fibrosis achieved SVR12.[40] Accordingly, a forthcoming clinical study will evaluate an 8-week regimen of EBR/GZR in 50 treatment-naïve HCV GT4 participants with stage 0–2 liver fibrosis (NCT03111108).

This analysis had several limitations. Firstly, it was retrospective and included data pooled from several studies, none of which were designed to specifically assess efficacy of EBR/GZR regimens in HCV GT4 infection. Secondly, while data were pooled from 8 different studies, the majority of study participants were managed at well-resourced centres, which may limit the generalisability of these results to other settings.

In this integrated analysis, a 12-week regimen of EBR/GZR, which is administered as a one-pill, once-a-day fixed-dose tablet, was highly effective in HCV GT4 participants, especially those who were naïve to HCV treatment and thus offers the prospect of expanded treatment access across all regions impacted by HCV GT4 infection, especially those without extensive healthcare resources such as comprehensive laboratory testing capabilities.

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