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
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References
World Health Organization. Global Alert and Response (GAR) – Hepatitis C 2012; 2012. (Accessed 2/2013 at http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index4.html).
- The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J Hepatol. 2006; 45: 529-538
- The global health burden of hepatitis C virus infection.Liver Int. 2011; 31: 1-3
- American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update.Hepatology. 2009; 49: 1335-1374
- Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428
- Sustained virologic response (SVR) in prior PegIFN/RBV (PR) treatment failures after retreatment with boceprevir (BOC) + PR: the PROVIDE study interim results.J Hepatol. 2012; 56: S6
- Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB) and ribavirin (R) +/− peginterferon alfa-2a (40KD) (P) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study.Hepatology. 2012; 56: 231A-232A
- A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection.Hepatology. 2012; 56 ([Abstract LB-1])
- Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416
- Factors that predict response of patients with hepatitis C virus infection to boceprevir.Gastroenterology. 2012; 143: 608-618
- Preliminary study of two antiviral agents for hepatitis C genotype 1.N Engl J Med. 2012; 366: 216-224
- High sustained virologic response rate in treatment-naive HCV genotype 1a and 1b patients treated for 12 weeks with an interferon-free all-oral QUAD regimen: interim results.J Hepatol. 2012; 56: S560
- Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response.Hepatology. 2012; 56: 308A-309A
- Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.Nature. 2010; 465: 96-100
- Effect on hepatitis C virus replication of combinations of direct-acting antivirals, including NS5A inhibitor daclatasvir.Antimicrob Agents Chemother. 2012; 56: 5230-5239
- Combinations of lambda interferon with direct-acting antiviral agents are highly efficient in suppressing hepatitis C virus replication.Antimicrob Agents Chemother. 2013; 57: 1312-1322
- Multiple ascending dose study of BMS-790052, an NS5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1.Hepatology. 2011; 54: 1956-1965
- Daclatasvir for previously untreated chronic hepatitis C genotype 1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.Lancet Infect Dis. 2012; 12: 671-677
- Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study.J Hepatol. 2013; 58: S570-S571
- High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3.Hepatology. 2012; 56 ([Abstract LB-02])
- Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032).Antimicrob Agents Chemother. 2012; 56: 5387-5396
- Single and multiple ascending dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.Antimicrob Agents Chemother. 2012; 56: 1838-1844
- Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients.J Hepatol. 2013; 58: S573
- Randomized study of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 chronic hepatitis C.Antivir Ther. 2013;
- Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir.Antimicrob Agents Chemother. 2012; 56: 3670-3681
- Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders.Hepatology. 2012; 55: 742-748
- Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options.J Hepatol. 2013; 58: 655-662
- Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.N Engl J Med. 2013; 368: 34-44
- Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir.Hepatology. 2013; ([Epub ahead of print])https://doi.org/10.1002/hep.26388
- Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.Nature. 2009; 461: 399-401
Article info
Publication history
Published online: October 28, 2013
Accepted:
October 14,
2013
Received in revised form:
September 24,
2013
Received:
August 8,
2013
See Focus, pages 471–472Identification
Copyright
© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
