Elsevier

Journal of Hepatology

Volume 62, Issue 5, May 2015, Pages 1047-1055
Journal of Hepatology

Research Article
Efficacy and safety of simeprevir with PegIFN/ribavirin in naïve or experienced patients infected with chronic HCV genotype 4

https://doi.org/10.1016/j.jhep.2014.12.031Get rights and content

Background & Aims

Simeprevir (SMV) is a once-daily (QD), oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of genotype (GT) 1 and GT4 infection. This Phase III, open-label, single-arm study (RESTORE; NCT01567735) evaluated efficacy/safety of SMV with peginterferon-α-2a/ribavirin (PR) in patients with chronic HCV GT4 infection.

Methods

107 patients were included. Treatment-naïve (n = 35) and prior relapse patients (n = 22) received SMV 150 mg QD + PR (12 weeks), followed by PR alone (12 or 36 weeks, response-guided [HCV RNA <25 IU/ml detectable/undetectable at week 4 and <25 IU/ml undetectable at week 12]). Prior non-responders (partial, n = 10; null, n = 40) received SMV/PR (12 weeks), followed by PR for 36 weeks. The primary endpoint was sustained virologic response 12 weeks after end of treatment (SVR12).

Results

Median age: 49.0 years; 28.0% Black/African; 7.5% IL28B CC; 28.8% METAVIR F4. Overall, 65.4% (70/107) of patients achieved SVR12 (82.9% [29/35] treatment-naïve; 86.4% [19/22] prior relapsers; 60.0% [6/10] prior partial responders; 40.0% [16/40] prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% [31/35] and 90.9% [20/22]), SVR12 rates were high: 93.5% [29/31] and 95.0% [19/20], respectively. Overall on-treatment failure and relapse rates were 23.4% (25/107) and 14.6% (12/82), respectively. Adverse events (AEs) were mainly grade 1/2; serious AEs were infrequent (4.7%) and considered unrelated to SMV.

Conclusions

Efficacy and safety of SMV 150 mg QD for 12 weeks with PR in treatment-naïve or -experienced patients with chronic HCV GT4 infection were in line with previous reports for HCV GT1 infection.

Introduction

Hepatitis C virus (HCV) genotype (GT) 4 infection is common in the Middle East and sub-Saharan Africa, and accounts for ∼90% of HCV infections in Egypt [1]. Its prevalence has increased in several European countries [2], [3], which is considered to be largely a consequence of immigration and intravenous drug use [4], [5].

Triple therapy with a direct-acting antiviral agent (DAA) in combination with peginterferon plus ribavirin (PR) is the current standard-of-care for chronic HCV GT4 infection. In the USA, sofosbuvir plus PR is the recommended regimen, with simeprevir (SMV) plus PR listed as an alternative option, while in Europe both of these regimens are recommended for GT4 infection [6], [7]. SMV is a once-daily (QD), oral HCV NS3/4A protease inhibitor, approved in the European Union (EU), United States and other countries for the treatment of HCV GT1 infection. In the EU, SMV is also approved for the treatment of HCV GT4 infection. In addition to triple therapy, SMV is approved as part of IFN-free combinations.

In vitro, SMV is fully active against HCV GT4, displaying activity similar to that observed against HCV GT1 [8]. The multi-genotypic activity of SMV was confirmed in vivo in a Phase IIa study in treatment-naïve, non-GT1-infected patients in which SMV monotherapy (200 mg QD for 1 week) demonstrated antiviral activity in all HCV genotypes except GT3, with the highest activity observed against GT4 and GT6, followed by GT2 and GT5 [9]. In particular, high antiviral activity against GT4 was observed with a consistent and substantial decline in HCV RNA, which was comparable to that previously observed in studies in HCV GT1-infected patients [10], [11]. No difference in efficacy was observed between GT4 subtypes 4a, 4c, and 4d, while there was variability in antiviral activity in GT2-infected patients, possibly caused by the different subtypes included [9]. In the Phase III QUEST-1 and QUEST-2 trials in treatment-naïve patients with HCV GT1 infection, significantly improved sustained virologic response (SVR) rates were observed following the addition of SMV to PR (SVR 12 weeks after planned end of treatment [EOT] [SVR12] rates of 80% and 81% [210/264 and 209/257 patients], respectively), allowing a shorter 24-week overall treatment duration in 85% and 91% of patients (224/264 and 235/257 patients), respectively [12], [13]. In treatment-experienced patients, SMV 150 mg QD in combination with PR led to overall SVR12 rates of 61–80% in a Phase IIb study that included prior null responders [14]. In the Phase III ATTAIN study, 70% (101/145) of prior partial responders and 44% (102/234) of prior null responders achieved SVR12 [15], while in the Phase III PROMISE study, 79% (206/260) of SMV/PR-treated prior relapsers achieved SVR12, and 93% (241/260) were eligible to complete treatment at week 24 [16].

Here we report the final results of RESTORE, a Phase III, multicentre, open-label, single-arm study exploring the efficacy and safety of SMV in combination with PR in treatment-naïve and -experienced patients with chronic HCV GT4 infection.

Section snippets

Patients

Treatment-naïve and -experienced adults aged 18–70 years with chronic HCV GT4 infection and plasma HCV RNA >10,000 IU/ml at screening were considered. Treatment-experienced patients included well-characterised patients with prior relapse or a prior partial or null response to PR treatment.

For all patients, a liver biopsy within 3 years prior to screening, unless contraindicated, was required. In patients with a clinical contraindication for biopsy, non-invasive methods were used (for example,

Patient disposition

The study was conducted between 16 February 2012 and 20 March 2014. A total of 136 patients from 8 centres in France and Belgium were screened. Of these, 107 received treatment and were included in the ITT population (35 treatment-naïve, 22 prior relapsers, 10 prior partial responders and 40 prior null responders) (Fig. 2). At the time of the final analysis, 103 patients (96.3%) had completed the study and 4 (3.7%) had discontinued early (3 lost to follow-up and 1 withdrew consent).

Most

Discussion

Limited data are available to guide clinical decision-making in patients with chronic HCV GT4 infection. HCV GT4 is considered difficult to cure compared to GT2 and GT3; however, GT4 has not been extensively studied. Previously, sofosbuvir plus PR led to a cure rate of 96% in patients with GT4 in the NEUTRINO study; however, the patient numbers with GT4 in that study were small (n = 28) and treatment-experienced patients were not included [17]. In this open-label, Phase III study, the overall

Financial support

The trial was funded by Janssen Research & Development.

Conflict of interest

CM has been paid as a speaker or adviser for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen and MSD, and has received research grants from Gilead Sciences, Janssen, MSD, Novartis and Roche. CH has acted as a speaker and/or adviser for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, MSD and Roche. PM has acted as an investigator, speaker or consultant and has received grants from Alios BioPharma, Bristol-Myers Squibb, Gilead Sciences, Janssen, MSD, Novartis and Roche; has been an

Authors’ contributions

CM, CH, PM, SB, SF, DS, FZ, and JDG were investigators in the trial and were involved in data acquisition, analysis and interpretation, as well as in critical revision of the manuscript for important intellectual content. US was responsible for the supervision of study conduct, and acquisition and interpretation of data. OL performed the virology analysis, and contributed to the writing of the manuscript. SOM and BF provided scientific input in the clinical study and contributed to the writing

Acknowledgements

The authors thank all the patients and their families for participating in this trial. Medical writing support was provided by Chrissie Kouremenou of Complete Medical Communications, funded by Janssen Research & Development.

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    Clinical Trials.gov identifier: NCT01567735.

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