Three-drug regimens taken for 8 weeks demonstrate high hepatitis C cure rate

Liz Highleyman
13 January 2016
Edward Gane, presenting at AASLD 2015. Photo by Liz Highleyman,

An interferon-free regimen containing Merck's grazoprevir, the NS5A inhibitors elbasvir or MK8404, and the experimental nucleotide polymerase inhibitor MK-3682, taken for 8 weeks, cured more than 90% of hepatitis C patients without cirrhosis with genotypes 1, 2 or 3, according to late-breaking research from the phase 2 C-CREST trial presented at the 2015 AASLD Liver Meeting in November.

The advent of direct-acting antiviral agents used in interferon-free regimens has revolutionised hepatitis C treatment, with most studies showing cure rates of 90% or better for combination therapy taken for 12 or 24 weeks. But there remains room for more effective drugs for difficult-to-treat patients, including people with hepatitis C virus (HCV) genotype 3, and shorter therapy would be less expensive and improve convenience and potentially adherence.

Dr Edward Gane from Auckland Clinical Studies in New Zealand and colleagues conducted the C-CREST study to evaluate the safety and efficacy of all-oral regimens consisting of three direct-acting antivirals: the NS3/4A HCV protease inhibitor grazoprevir (formerly MK-5172), the HCV NS5B polymerase inhibitor MK-3682, and an NS5A inhibitor – either elbasvir (formerly MK-8742) or MK8404.

Grazoprevir plus elbasvir taken for 12 weeks has demonstrated good efficacy in Phase 3 trials for previously untreated people (C-EDGE Treatment-naive) and prior non-responders to interferon-based therapy (C-EDGE Treatment-experienced). A co-formulation of these drugs, to be marketed as Zepatier, is currently being evaluated for approval in the US and Europe.

Dr Gane's team assessed whether adding a third antiviral that targets a different step in the HCV lifecycle might allow treatment to be shortened to 8 weeks without reducing effectiveness.

C-CREST 1 and 2 Part A included a total of 240 previously untreated chronic hepatitis C patients without cirrhosis. C-CREST 1 enrolled 93 people with HCV genotype 1 (46 with harder-to-treat subtype 1a and 47 with 1b) and 61 with genotype 2, while C-CREST 2 enrolled 86 patients with genotype 3 – now considered the most challenging type.

About half of participants were men, more than 90% were white and the median age was approximately 48 years. Most had absent to moderate liver fibrosis (stage F0-F2), but about 7% had advanced fibrosis (stage F3). People with HIV or hepatitis B co-infection, significant laboratory abnormalities or liver cancer were excluded.

Participants in this open-label study were randomly allocated to four once-daily 8-week regimens containing 100mg grazoprevir, 300 or 450mg MK-3682, and either 50mg elbasvir or 60mg MK-8408. None of the regimens included ribavirin.

The primary endpoint was sustained virological response, or continued undetectable HCV viral load at 12 weeks after completing treatment (SVR12).

Among participants with HCV genotype 1, the SVR12 rate was 98% for both subtype 1a and 1b, with two relapses in the arm assigned to grazoprevir, 450mg MK-3682 and MK-8408.

Among people with HCV genotype 2, the regimen containing grazoprevir, 450mg MK-3682 and MK-8408 was highly effective, with an SVR12 rate of 94%. However, regimens containing 300mg MK-3682 or elbasvir were less effective, with SVR12 rates ranging from 60 to 71%.

Among people with HCV genotype 3, the overall SVR12 rate was 91%, with no significant differences across treatment arms (86 to 95%)

No treatment-emergent NS5A resistance-associated variants (RAVs) were detected in the two relapsers with genotype 1. Genotype 3 patients with NS5A RAVs at baseline had a lower response rate (85%), and one of the three relapsers had a treatment-emergent Y93H variant.

All regimens were generally well tolerated and all study participants completed the full 8 weeks of treatment. There were no drug-related serious adverse events, and no participants discontinued therapy due to adverse events. The most common drug-related adverse events were headache (23%), fatigue (20%) and nausea (13%). There were no consistent treatment-related differences in laboratory tests, vital signs, ECG (cardiac) or kidney safety parameters.

"An 8-week regimen of grazoprevir/MK-8408/MK-3682 (450mg) was highly effective, with SVR12 >90% in treatment-naive, non-cirrhotic patients with HCV genotype 1, 2 or 3 infection," the researchers concluded. "[Treatment] was generally safe and well tolerated, with no discontinuations due to adverse events and no cardiac or renal signals."

They added that the results of Part A "support further evaluation of this pan genotypic three-drug combination among a diverse population of HCV-infected patients, including those with additional HCV genotypes, cirrhosis, prior treatment and HIV/HCV co-infection."

Based on the results from this initial trial, Merck indicated in a press release that it has initiated a further study of grazoprevir (100mg), MK-3682 (450mg), and MK-8408 (60mg) in Part B of the C-CREST phase 2 clinical development programme.


Gane EJ et al. Phase 2, randomized, open-label clinical trials of the efficacy and safety of grazoprevir and MK-3682 (NS5B polymerase inhibitor) with either elbasvir or MK-8408 (NS5A inhibitor) in patients with chronic HCV GT1, 2 or 3 infection (Part A of C-CREST-1 & 2). AASLD Liver Meeting, abstract LB-15, 2015.