Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial.

Abstract

BACKGROUND:

Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.

OBJECTIVE:

To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.

DESIGN:

Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467).

SETTING:

60 centers in the United States, Europe, Australia, Scandinavia, and Asia.

PATIENTS:

Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.

INTERVENTION:

Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.

MEASUREMENTS:

Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.

RESULTS:

Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).

LIMITATION:

The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.

CONCLUSION:

Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.

PRIMARY FUNDING SOURCE:

Merck & Co.

• Authors: Stefan Zeuzem, Reem Ghalib, K Rajender Reddy, Paul J Pockros, Ziv Ben Ari, Yue Zhao, Deborah D Brown, Shuyan Wan, Mark J DiNubile, Bach-Yen Nguyen, Michael N Robertson, Janice Wahl, Eliav Barr, Joan R Butterton
• Journal: Annals of internal medicine (Ann Intern Med) Vol. 163 Issue 1 Pg. 1-13 (Jul 07 2015) ISSN: 1539-3704 [Electronic] United States
• PMID: 25909356 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Antiviral Agents
• Benzofurans
• Carbamates
• Cyclopropanes
• Imidazoles
• Quinoxalines
• Sulfonamides
• grazoprevir
• elbasvir

Topics

• Administration, Oral
• Adult
• Aged
• Amides
• Antiviral Agents (adverse effects, therapeutic use)
• Benzofurans (adverse effects, therapeutic use)
• Carbamates
• Cyclopropanes
• Drug Administration Schedule
• Drug Therapy, Combination
• Fatigue (chemically induced)
• Female
• Genotype
• Headache (chemically induced)
• Hepacivirus (genetics)
• Hepatitis C, Chronic (complications, drug therapy, virology)
• Humans
• Imidazoles (adverse effects, therapeutic use)
• Liver Cirrhosis (complications)
• Male
• Middle Aged
• Nausea (chemically induced)
• Quinoxalines (adverse effects, therapeutic use)
• Sulfonamides
• Treatment Outcome
• Viral Load
• Young Adult