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AASLD 2015: 3-Drug Combos for 8 Weeks Demonstrate High Hepatitis C Cure Rate


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 non-cirrhotic hepatitis C patients with HCV genotypes 1, 2, or 3, according to late-breaking research presented at the AASLD Liver Meeting in November.

The advent of direct-acting antiviral agents used in interferon-free regimens has revolutionized hepatitis C treatment, with most studies showing cure rates of 90% or higher 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.

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 3 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 coformulation of these 2 drugs, to be marketed as Zepatier, is currently being evaluated for approval in the U.S. and Europe.

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 coinfection, significant laboratory abnormalities, or liver cancer were excluded.

Participants in this open-label study were randomly allocated to 4 once-daily 8-week regimens containing 100 mg grazoprevir, 300 mg or 450 mg MK-3682, and either 50 mg elbasvir or 60 mg 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 2 relapses in the arm assigned to grazoprevir, 450 mg MK-3682, and MK-8408.
  • Among people with HCV genotype 2, the regimen containing grazoprevir, 450 mg MK-3682, and MK-8408 was highly effective, with an SVR12 rate of 94%.
  • However, regimens containing 300 mg 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 2 relapsers with genotype 1.
  • Genotype 3 patients with NS5A RAVs at baseline had a lower response rate (85%), and 1 of the 3 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 (450 mg) 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 pangenotypic 3-drug combination among a diverse population of HCV-infected patients, including those with additional HCV genotypes, cirrhosis, prior treatment, and HIV/HCV coinfection."

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



EJ Gane, S Pianko, SK Roberts, 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 2015. San Francisco, November 13-17, 2015. Abstract LB-15.

Other Source

Merck. Merck Announces Presentation of Results from Two Phase 2 Studies of Investigational Triple-Combination Chronic Hepatitis C Therapy at The Liver Meeting. Press release. November 16, 2015.