TY - JOUR
T1 - Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders
AU - Lok, Anna S.
AU - Gardiner, David F.
AU - Hézode, Christophe
AU - Lawitz, Eric J.
AU - Bourlière, Marc
AU - Everson, Gregory T.
AU - Marcellin, Patrick
AU - Rodriguez-Torres, Maribel
AU - Pol, Stanislas
AU - Serfaty, Lawrence
AU - Eley, Timothy
AU - Huang, Shu Pang
AU - Li, Jianling
AU - Wind-Rotolo, Megan
AU - Yu, Fei
AU - McPhee, Fiona
AU - Grasela, Dennis M.
AU - Pasquinelli, Claudio
N1 - Funding Information:
AS Lok is supported in part by the NIH/NCRR Clinical and Translational Science Award to the University of Michigan, UL1RR024986.
Funding Information:
AS Lok has served on advisory panels for Achillion, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis and Roche, and has received research grants from Abbott, Bristol-Myers Squibb, Gilead, Idenix and Merck. E Lawitz has served on advisory panels for Abbott, Achillion, Anadys, Biolex, BioCryst, Biotica, Enanta, GlobeImmune, Idenix, Inhibitex, Janssen, Merck, Novartis, Pharmasset, Santaris, Tibotec, Theravance, and Vertex; has served as a speaker for Gilead, Kadmon, Merck, and Vertex; and has received research grants from Abbott, Achillion, Anadys, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix, Idera, Inhibitex, Intercept, Janssen, Medarex, Medtronic, Merck, Novartis, Pharmasset, Presidio, Roche, Schering-Plough, Santaris, Scynexis, Vertex, ViroChem, and Zymogenetics. M Bourlière has served on advisory panels for MSD, Gilead, Janssen, Boehringer Ingelheim, Vertex, and Bristol-Myers Squibb. G Everson has served on advisory panels for Bristol-Myers Squibb and Gilead, and has received research grants from Bristol-Myers Squibb and Gilead. P Marcellin has served as a speaker or expert for Abbott, Bristol-Myers Squibb, Gilead, Janssen, MSD, Novartis, and Vertex, and has received research grants from Alios, Bristol-Myers Squibb, Gilead, Janssen, MSD, Novartis, and Roche. M Rodriguez-Torres has served as a consultant to Akros, Bristol-Myers Squibb, Genentech, Hoffman-LaRoche, Inhibitex, Janssen, MSD, Pharmasset, Santaris, and Vertex, and has received research grants from Abbott, Akros, Anadys, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, Hoffman-LaRoche, Human Genome Sciences, Idenix, Idera, Inhibitex, Johnson and Johnson, MSD, Mochida, Novartis, Pfizer, Pharmasset, Santaris, Scynexis, Siemens Healthcare Diagnostics, Vertex, and Zymogenetics. S Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec, Vertex, Gilead, Roche, Schering-Plough/Merck, Novartis, Abbott/Abbvie, Sanofi, and GlaxoSmithKline, and has received grants from Bristol-Myers Squibb, Gilead, Roche, and Merck/Schering-Plough. DF Gardiner, T Eley, S-P Huang, J-L Li, M Wind-Rotolo, F Yu, F McPhee, DM Grasela, and C Pasquinelli are employees of Bristol-Myers Squibb. All other authors have no conflicts of interest to report.
PY - 2014/3
Y1 - 2014/3
N2 - 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. SVR 12 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.
AB - 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. SVR 12 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.
KW - Direct-acting antiviral agents
KW - HCV NS5A inhibitor
KW - Hepatitis C treatment
KW - Non-responders
KW - Protease inhibitor
KW - Sustained virologic response
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U2 - 10.1016/j.jhep.2013.10.019
DO - 10.1016/j.jhep.2013.10.019
M3 - Article
C2 - 24444658
AN - SCOPUS:84894099866
VL - 60
SP - 490
EP - 499
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 3
ER -