Elsevier

The Lancet HIV

Volume 2, Issue 8, August 2015, Pages e319-e327
The Lancet HIV

Articles
Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

https://doi.org/10.1016/S2352-3018(15)00114-9Get rights and content

Summary

Background

Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection.

Methods

In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662.

Findings

Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9–98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia.

Interpretation

This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.

Funding

Merck Sharp & Dohme Corp.

Introduction

HIV co-infection is common in patients with hepatitis C virus (HCV) infection.1, 2, 3, 4 HIV co-infection accelerates the progression of HCV-related liver disease, making HCV a leading cause of morbidity and mortality in patients with HIV-1.5, 6, 7 Compared with patients with HCV monoinfection, patients with HIV and HCV co-infection have higher baseline HCV viral loads, more rapid progression of liver disease,8 and an increased risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.9 Co-infected patients are also more susceptible to anaemia and more rapid progression to AIDS and AIDS-related death.5, 6, 10 Direct-acting antiviral agents have revolutionised treatment of HCV infection;11, 12, 13, 14, 15 however, many regimens for patients with HIV and HCV co-infection are restricted by their requirement for co-administration with peginterferon or ribavirin, particularly in patients infected with HCV genotype 1a and in those with cirrhosis.16 Grazoprevir, an NS3/4A protease inhibitor (MK-5172), and elbasvir, an NS5A inhibitor (MK-8742; Merck & Co, Inc, Kenilworth, NJ, USA), are being assessed as a once-daily, fixed-dose combination tablet. The phase 2 C-WORTHY study showed a good safety profile and high efficacy of grazoprevir plus elbasvir with or without ribavirin for 12 weeks in monoinfected and co-infected patients with HCV genotype 1 infection, with or without cirrhosis.13, 17 The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of a fixed-dose combination of grazoprevir plus elbasvir in patients with HIV and HCV co-infection.

Section snippets

Study design and participants

The C-EDGE CO-INFECTION study was an uncontrolled, non-randomised, open-label, single-arm, multicentre study. Treatment-naive patients older than 18 years with chronic HCV genotype 1, 4, or 6 infection and baseline HCV RNA of at least 10 000 IU/mL were enrolled. All patients were co-infected with HIV-1 and either naive to antiretroviral therapy (ART) or on stable ART with tenofovir or abacavir, and either emtricitabine or lamivudine plus raltegravir, dolutegravir, or rilpivirine for at least 8

Results

Patients were enrolled between June 11, 2014, and Aug 29, 2014, at 37 centres in nine countries across Europe, the USA, and Australia. 261 patients were screened; 218 were enrolled and received grazoprevir plus elbasvir for 12 weeks (figure 1; table 1).

In the overall population, 210 (96%) achieved SVR12 (95% CI 92·9–98·4), exceeding the historical reference rate of 70% (table 2). Five patients relapsed after having undetectable HCV RNA concentrations at the end of treatment (table 3). All

Discussion

This single-arm, open-label trial showed the efficacy of 12 weeks of treatment with a fixed-dose combination of grazoprevir plus elbasvir in patients with HIV infection and HCV genotype 1, 4, or 6 co-infection. The overall SVR12 rate was 95% in the primary analysis and 97% in the per-protocol analysis. In the C-EDGE Treatment-Naive trial19 in patients with HCV monoinfection, SVR12 was achieved in 95% of patients, thus supporting the growing body of data suggesting that patients with HCV and HIV

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