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J Hepatol. 2014 Mar;60(3):490-9. doi: 10.1016/j.jhep.2013.10.019. Epub 2013 Oct 26.

Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders.

Author information

1
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. Electronic address: aslok@med.umich.edu.
2
Bristol-Myers Squibb, Hopewell, NJ, USA.
3
Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France.
4
The Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX, USA.
5
Hôpital Saint-Joseph, Marseille, France.
6
University of Colorado Denver, Aurora, CO, USA.
7
Hôpital Beaujon, Clichy, France.
8
Fundación de Investigación, San Juan, PR, USA.
9
Hôpital Cochin, Paris, France.
10
Hôpital Saint-Antoine, Paris, France.
11
Bristol-Myers Squibb, Princeton, NJ, USA.
12
Bristol-Myers Squibb, Wallingford, CT, USA.

Abstract

BACKGROUND & AIMS:

Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after ⩾ 12 weeks of PegIFN/RBV) have limited options. We evaluated daclatasvir plus once- or twice-daily asunaprevir in non-cirrhotic genotype 1 null responders.

METHODS:

In this randomized, phase 2a, open-label, 24-week treatment study, 101 patients received daclatasvir (60 mg) once-daily. In addition, 38 genotype 1b patients received asunaprevir (200mg) twice- (DUAL A1) or once-daily (DUAL A2); 36 genotype 1a and 5 genotype 1b patients received asunaprevir twice- (QUAD B1) or once-daily (QUAD B2) plus PegIFN/RBV; and 18 genotype 1a and 4 genotype 1b patients received asunaprevir twice-daily plus ribavirin (TRIPLE B3). The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (sustained virologic response, SVR12).

RESULTS:

Across all groups, mean HCV RNA was ⩾ 6 log IU/ml, and 99% of patients had a non-CC IL28B genotype. SVR12 rates were 78% (A1), 65% (A2), 95% (B1), and 95% (B2). In B3, most genotype 1a patients experienced virologic breakthrough. The most common adverse events were headache, diarrhea, and asthenia. Grade 3-4 aminotransferase elevations were infrequent and not treatment-limiting.

CONCLUSIONS:

In genotype 1 null responders, daclatasvir plus twice-daily asunaprevir DUAL therapy is effective for most genotype 1b patients, and daclatasvir, asunaprevir, and PegIFN/RBV QUAD therapy is effective for nearly all genotype 1a and 1b patients; but neither DUAL nor TRIPLE therapy is effective for genotype 1a patients. Interferon-free regimens including daclatasvir and twice-daily asunaprevir for genotype 1 null responders should be tailored to subtype.

KEYWORDS:

ALT; AST; DAA; Direct-acting antiviral agents; HCV; HCV NS5A inhibitor; Hepatitis C treatment; LLOQ; LOD; Non-responders; PegIFNα; Protease inhibitor; QUAD; RBV; SNP; SVR; SVR(12); SVR(24); SVR(4); Sustained virologic response; alanine aminotransferase; aspartate aminotransferase; direct-acting antiviral; hepatitis C virus; limit of detection; lower limit of quantification; pegylated interferon alfa-2a; quadruple; ribavirin; single nucleotide polymorphism; sustained virologic response; sustained virologic response at 12weeks post-treatment; sustained virologic response at 24weeks post-treatment; sustained virologic response at 4weeks post-treatment

PMID:
24444658
DOI:
10.1016/j.jhep.2013.10.019
[Indexed for MEDLINE]
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