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Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial

https://doi.org/10.1016/S1473-3099(17)30496-6Get rights and content

Summary

Background

The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis.

Methods

We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432.

Findings

Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98–100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events.

Interpretation

Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden.

Funding

AbbVie.

Introduction

Hepatitis C virus (HCV) infection affects 72–185 million individuals worldwide1, 2, 3 and, when left untreated, chronic infection can lead to liver cirrhosis. In the absence of therapy, the number of HCV-infected patients with cirrhosis is projected to rise over the next decade.4 Patients with cirrhosis are at increased risk for development of hepatocellular carcinoma, and those with hepatocellular carcinoma who do not undergo liver transplantation have a 5 year survival rate of 50%.5, 6 The incidence of HCV infection continues to increase worldwide, and every year an estimated 500 000 people die of HCV-related diseases.7 Six major genotypes and 67 subtypes of HCV have been identified.8 Genotype 1 is the most prevalent in the USA (78%) and has an estimated worldwide prevalence of 46%. Genotypes 2, 3, 4, 5, and 6 have global prevalence rates of roughly 9%, 30%, 8%, 0·8%, and 5%, respectively.2, 9

Combinations of direct-acting antiviral drugs for targeting multiple components of the HCV viral replication process, including HCV non-structural (NS) proteins 3/4A, 5A, and 5B, have shown high rates of sustained virological response and favourable tolerability.10 However, most guideline-recommended treatment options are not equally effective across all genotypes, and some can require addition of ribavirin or extension of the treatment duration up to 24 weeks to increase efficacy for patients with compensated cirrhosis.11, 12 Because longer treatment durations often require additional on-treatment monitoring, and use of ribavirin is contraindicated for several medical conditions, a regimen that overcomes these requirements could make treatment available to a broader population of patients and physicians. A pangenotypic, direct-acting antiviral HCV treatment for patients with compensated cirrhosis that maintains high efficacy across all major HCV genotypes without the need for baseline genotyping, viral load, or resistance testing is desirable and might further simplify treatment algorithms.13

Research in context

Evidence before this study

We searched PubMed and meeting abstracts from the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) from Nov 1, 2015, to April 1, 2017 for late-stage clinical trials done in patients with hepatitis C virus (HCV) genotype 1–6 infection and cirrhosis treated with pegylated interferon-free direct-acting antiviral drugs. We used the search terms “HCV or hepatits C virus” and “cirrho” and “clinical study or trial”. We excluded studies that included pegylated interferon in combination with a direct-acting antiviral. At the time of study design, a pangenotypic treatment for patients with cirrhosis was unavailable. Direct-acting antiviral treatment options approved for patients with HCV infection and cirrhosis include 12 weeks of sofosbuvir plus velpatasvir for HCV genotypes 1–6, and 12–16 weeks of grazoprevir plus elbasvir for patients with genotype 1 or 4 infection. Sofosbuvir plus ledipasvir, sofosbuvir plus simeprevir, and ombitasvir, paritaprevir, and ritonavir plus dasabuvir, and are only approved in patients with HCV genotype 1 infection. The SURVEYOR-I and SURVEYOR-II phase 2 studies in patients with HCV genotype 1 or 3 infection and compensated cirrhosis showed that treatment with glecaprevir and pibrentasvir for 12 weeks without ribavirin resulted in a sustained virological response rate of 96% and a favourable safety profile.

Added value of this study

Our findings show that treatment with co-formulated glecaprevir plus pibrentasvir once daily for 12 weeks achieved a sustained virological response rate of 99% in 145 of 146 patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis (patients with genotype 3 infection and cirrhosis were enrolled in a separate study). Notably, there were no elevations in alanine aminotransferase and no treatment discontinuations due to adverse events, which is indicative of the regimen's favourable safety and tolerability profile.

Implications of all the available evidence

The incidence of HCV infection continues to increase worldwide, and estimates place the number of HCV-related deaths at 500 000 per year. When left untreated, chronic HCV infection can lead to liver cirrhosis; patients with cirrhosis are at increased risk for development of hepatocellular carcinoma, and those with hepatocellular carcinoma who do not undergo liver transplantation have a 5 year survival rate of 50%. An interferon-free and ribavirin-free treatment for most patients with HCV infection and compensated cirrhosis might help simplify treatment algorithms and reduce treatment burden.

Glecaprevir (formerly ABT-493)—an NS3/4A protease inhibitor coformulated with pibrentasvir (formerly ABT-530), an NS5A inhibitor—is currently being evaluated as a pangenotypic regimen and has shown a high barrier to resistance and potency against common NS3 and NS5A polymorphisms.14, 15 Phase 2 studies in patients with HCV genotype 1 or 3 infection and compensated cirrhosis treated with glecaprevir and pibrentasvir for 12 weeks without ribavirin resulted in a sustained virological response rate of 96% at 12 weeks after treatment and a favourable safety profile.16

We did the EXPEDITION-1 study to assess the efficacy and safety of 12 weeks of coformulated glecaprevir plus pibrentasvir in adults with chronic HCV genotype 1, 2, 4, 5 or 6 infection and compensated cirrhosis. Patients with compensated cirrhosis and genotype 3 HCV infection were enrolled in a separate study.17

Section snippets

Study design and participants

We did this single-arm, open-label, phase 3 study at 40 study sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older (no upper limit) if they had chronic HCV infection, defined as a positive anti-HCV antibody status or HCV RNA at least 6 months before screening, a liver biopsy consistent with chronic HCV infection or abnormal alanine aminotransferase (ALT) for at least 6 months before screening. A plasma HCV RNA concentration of 1000

Results

Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis (figure 1), of whom 48 (33%) patients had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection (table 1). Most patients were white, male, and treatment-naive (table 1). Of the 36 treatment-experienced patients, 25 (69%) had failure of previous treatment

Discussion

12 weeks of treatment with once-daily glecaprevir coformulated with pibrentasvir yielded a sustained virological response rate of 99% in patients with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis, with no clinically significant safety events or laboratory abnormalities. These results confirm those from phase 2 studies, in which treatment with glecaprevir and pibrentasvir yielded high rates of sustained virological response and had a favourable safety profile in patients

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