All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: A multinational, phase 3, multicohort study
Journal
The Lancet
Journal Volume
384
Journal Issue
9954
Pages
1597-1605
Date Issued
2014
Author(s)
Manns M.
Pol S.
Jacobson I.M.
Marcellin P.
Gordon S.C.
Peng C.-Y.
Chang T.-T.
Everson G.T.
Heo J.
Gerken G.
Yoffe B.
Towner W.J.
Bourliere M.
Metivier S.
Chu C.-J.
Sievert W.
Bronowicki J.-P.
Thabut D.
Lee Y.-J.
McPhee F.
Kopit J.
Mendez P.
Linaberry M.
Hughes E.
Noviello S.
Abstract
Background: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Methods: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Findings: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (?2% each). Interpretation: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferonfree and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. Funding: Bristol-Myers Squibb.
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; asunaprevir; daclatasvir; hemoglobin; liver enzyme; peginterferon alpha; placebo; ribavirin; virus RNA; antivirus agent; asunaprevir; BMS-790052; imidazole derivative; isoquinoline derivative; sulfonamide; virus RNA; abnormal laboratory result; adult; aged; alanine aminotransferase blood level; anemia; Article; Asia; aspartate aminotransferase blood level; asthenia; chronic hepatitis; clinical assessment; cohort analysis; confidence interval; controlled study; diarrhea; double blind procedure; drug efficacy; drug response; drug safety; drug tolerability; drug withdrawal; Europe; fatigue; female; headache; heart atrium fibrillation; hematologic disease; hemoglobin blood level; hepatitis C; Hepatitis C virus; Hepatitis C virus genotype 1b; human; liver cirrhosis; major clinical study; male; multicenter study; nausea; North America; phase 3 clinical trial; priority journal; randomized controlled trial; rash; side effect; South America; sustained virological response; thrombocyte count; treatment outcome; treatment response; virus load; blood; classification; clinical trial; drug combination; genetics; genotype; Hepacivirus; Hepatitis C, Chronic; isolation and purification; middle aged; oral drug administration; very elderly; virology; young adult; Administration, Oral; Adult; Aged; Aged, 80 and over; Antiviral Agents; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Isoquinolines; Male; Middle Aged; RNA, Viral; Sulfonamides; Treatment Outcome; Young Adult
Publisher
Lancet Publishing Group
Type
journal article