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

Journal of Hepatology
Volume 60, Issue 3 , Pages 490-499, March 2014

Anna S. Lok, David F. Gardiner, Christophe Hézode, Eric J. Lawitz, Marc Bourlière, Gregory T. Everson, Patrick Marcellin, Maribel Rodriguez-Torres, Stanislas Pol, Lawrence Serfaty, Timothy Eley, Shu-Pang Huang, Jianling Li, Megan Wind-Rotolo, Fei Yu, Fiona McPhee, Dennis M. Grasela, Claudio Pasquinelli

Received 8 August 2013; received in revised form 24 September 2013; accepted 14 October 2013. published online 28 October 2013.

See Focus, pages 471–472

Abstract

Background & Aims

Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after greater than or equal to12weeks 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 (60mg) 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 12weeks post-treatment (sustained virologic response, SVR12).

Results

Across all groups, mean HCV RNA was greater than or equal to 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.

Abbreviations: HCV, hepatitis C virus, PegIFNα, pegylated interferon alfa-2a, RBV, ribavirin, SVR, sustained virologic response, QUAD,quadruple, DAA, direct-acting antiviral, SVR24, sustained virologic response at 24weeks post-treatment, LLOQ, lower limit of quantification,LOD, limit of detection, SNP, single nucleotide polymorphism, SVR12, sustained virologic response at 12weeks post-treatment, SVR4,sustained virologic response at 4weeks post-treatment, ALT, alanine aminotransferase, AST, aspartate aminotransferase

Keywords: Direct-acting antiviral agents, Sustained virologic response, Hepatitis C treatment, Protease inhibitor, HCV NS5A inhibitor, Non-responders

Source