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

Published:October 28, 2013DOI:https://doi.org/10.1016/j.jhep.2013.10.019

      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 (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 ⩾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

      Linked Article

      • “There are decades where nothing happens; and there are weeks where decades happen” – Vladimir Ilyich Lenin
        Journal of HepatologyVol. 60Issue 3
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          Lenin could have hardly imagined that his words describing the Bolshevik revolution almost 100 years ago could be applied to the breathtaking approvals in HCV therapies in the past few weeks. Yet, if one defines ‘revolution’ (from the Latin revolutio, “a turnaround”) as “a significant change that usually occurs in a short period of time”, there is little doubt that we are experiencing a revolutionary epoch in hepatology, and practitioners would be wise to mark this watershed in their collective memories.
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