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

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• 作者：Anna S. Lok ; David F. Gardiner ; Christophe H茅zode ; Eric J. Lawitz ; Marc Bourli猫re ; 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
• 关键词：HCV ; hepatitis C virus ; PegIFN伪 ; pegylated interferon alfa-2a ; RBV ; ribavirin ; SVR ; sustained virologic response ; QUAD ; quadruple ; DAA ; direct-acting antiviral ; SVR24 ; sustained virologic response at 24  ; weeks post-treatment ; LLOQ ; lower limit of quantification ; LOD ; limit of detection ; SNP ; single nucleotide polymorphism ; SVR12 ; sustained virologic response at 12  ; weeks post-treatment ; SVR4 ; sustained virologic response at 4  ; weeks post-treatment ; ALT ; alanine aminotransferase ; AST
• 刊名：Journal of Hepatology
• 出版年：March, 2014
• 年：2014
• 卷：60
• 期：3
• 页码：490-499
• 全文大小：984 K

文摘

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Background & Aims

Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after 猢?2 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 (200 mg) 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 猢? 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.