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Short‐duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir ( FOUR ward study)
Author(s) -
Sulkowski Mark S.,
Flamm Steve,
Kayali Zeid,
Lawitz Eric J.,
Kwo Paul,
McPhee Fiona,
Torbeyns Anne,
Hughes Eric A.,
Swenson Eugene S.,
Yin Philip D.,
Linaberry Misti
Publication year - 2017
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13335
Subject(s) - daclatasvir , sofosbuvir , medicine , hepatitis c virus , gastroenterology , clinical endpoint , hepatitis c , chronic hepatitis , virology , virus , randomized controlled trial , ribavirin
Background & Aims The phase 2, FOUR ward study ( NCT 02175966) investigated short‐duration therapy (4/6 weeks) with four direct‐acting antivirals ( DAA s) with distinct mechanisms of action in patients infected with hepatitis C virus ( HCV ) genotype‐1. Methods Non‐cirrhotic patients were randomized 1:1 to DCV ‐ TRIO (fixed‐dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice‐daily + sofosbuvir 400 mg once‐daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post‐treatment Week 12 ( SVR 12). Patients without SVR 12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV ‐ TRIO component received DCV ‐ TRIO + RBV for 12 weeks. Results Twenty‐eight patients with HCV genotype‐1 were enrolled; 79% had genotype‐1a infection and median baseline HCV ‐ RNA levels were high (9 × 10 6 IU / mL ). Most patients had undetectable HCV ‐ RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR 12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR 12 was higher in patients with lower baseline HCV ‐ RNA (<2 million IU / mL , 71% [n=5/7]; ≥2 million IU / mL , 33% [n=7/21]). None of the 16 non‐ SVR 12 patients had NS 3 or NS 5B resistance‐associated substitutions ( RAS ) detected at failure. All 15 patients retreated with DCV ‐ TRIO + RBV for 12 weeks achieved SVR 12. All regimens were well tolerated. Conclusions Short‐duration treatment with four DAA s with distinct mechanisms of action was insufficient for most patients with genotype‐1 infection and high baseline viraemia. Non‐ SVR 12 was not associated with emergence of NS 3 or NS 5B RAS and retreatment with DCV ‐ TRIO + RBV for 12 weeks led to SVR in all patients.