Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial

Summary

Background

Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection.

Methods

The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1–3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1–3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326.

Findings

218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93–98% in mono-infected and 87–97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88–100; 43/44) and 87% (95% CI 69–96; 26/30), respectively, and with ribavirin were 93% (95% CI 85–97; 79/85) and 97% (95% CI 82–100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61–92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%).

Interpretation

Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87–98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir.

Funding

Merck & Co, Inc.

Introduction

Globally, 80–185 million people are infected with hepatitis C virus (HCV), of who an estimated 5 million are HIV/HCV co-infected.1, 2, 3 Both mono-infected and co-infected patients are at risk for progression of HCV disease, leading to cirrhosis, end-stage liver disease, hepatocellular carcinoma, liver transplantation and death. Moreover, HIV/HCV co-infected patients have higher viral loads, accelerated disease progression, and few treatment options.⁴ HCV has emerged as a leading cause of death among people living with HIV.

HCV antiviral treatment leading to virological cure has been associated with lower risk of HCV-related morbidity and mortality in both mono-infected and co-infected patients.⁵ However, HCV treatment in mono-infected and co-infected patient populations has not been very effective and, in most regions, relatively few co-infected people with chronic HCV infection have achieved sustained virological response.⁶ Although many heterogenous barriers to effective HCV treatment exist, the need for interferon alfa—the backbone of therapy since the early 1990s—has represented a major impediment.⁷ Furthermore, clinically significant adverse effects and drug interactions between first-generation HCV direct-acting antivirals and antiretroviral drugs reduce the suitability of treatment for most co-infected patients with newer approved therapies, many of which include pegylated interferon (peginterferon).⁸ Without a direct-acting antiviral, sustained virological response rates with a regimen of peginterferon plus ribavirin is low, particularly for patients with co-infection.⁹

Since 2011, additional oral HCV direct-acting antivirals with multiple mechanisms have emerged as the treatment of choice for chronic HCV infection. These drugs directly target HCV non-structural proteins (NS3/4A protease, NS5B polymerase, and the NS5A protein) that have crucial roles in the HCV lifecycle; regimens incorporating direct-acting antivirals minimise the negative effect of host factors (eg, race and ethnic origin, IFNL3 (also known as IL28B) genotype, and HIV co-infection) on the likelihood of achievement of sustained virological response. In clinical trials, interferon-free oral combinations of direct-acting antivirals have been well tolerated and highly efficacious in mono-infected patients. Although guidelines for HCV treatment are changing rapidly, current recommendations include oral direct-acting antiviral regimens with and without interferon alfa, marking the advent of interferon-free therapy for some patients.10, 11 Grazoprevir and elbasvir (Merck & Co, Inc, Whitehouse Station, NJ, USA) are once-daily, highly potent inhibitors of the HCV NS3/4A protease and NS5A protein, respectively. 12, 13 In vitro and in vivo, the combination of grazoprevir and elbasvir has a high barrier to resistance and activity against many common resistance-associated variants.¹⁴ Additionally, this direct-acting antiviral combination can be coadministered with antiretroviral regimens that contain the integrase inhibitor raltegravir and dual nucleoside-nucleotide reverse transcriptase inhibitors (eg, tenofovir or abacavir plus emtricitabine or lamivudine) without dose adjustments. As such, the combination of grazoprevir plus elbasvir has the potential to provide an all-oral, highly efficacious, simple, and well-tolerated regimen for the treatment of HCV genotype 1 infection in patients with and without HIV co-infection.

We aimed to assess the safety, tolerability, and efficacy of the oral combination of grazoprevir plus elbasvir with or without ribavirin for the treatment of HCV genotype 1 infection in previously untreated patients with no cirrhosis, with and without HIV co-infection, in a randomised phase 2 trial.