Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders.
OBJECTIVE
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 (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 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.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. Electronic address: aslok@med.umich.edu.
Anna S
AS
Lok
Bristol-Myers Squibb, Hopewell, NJ, USA.
David F
DF
Gardiner
Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France.
Christophe
C
Hézode
The Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, TX, USA.
Eric J
EJ
Lawitz
Hôpital Saint-Joseph, Marseille, France.
Marc
M
Bourlière
University of Colorado Denver, Aurora, CO, USA.
Gregory T
GT
Everson
Hôpital Beaujon, Clichy, France.
Patrick
P
Marcellin
Fundación de Investigación, San Juan, PR, USA.
Maribel
M
Rodriguez-Torres
Hôpital Cochin, Paris, France.
Stanislas
S
Pol
Hôpital Saint-Antoine, Paris, France.
Lawrence
L
Serfaty
Bristol-Myers Squibb, Hopewell, NJ, USA.
Timothy
T
Eley
Bristol-Myers Squibb, Princeton, NJ, USA.
Shu-Pang
SP
Huang
Bristol-Myers Squibb, Princeton, NJ, USA.
Jianling
J
Li
Bristol-Myers Squibb, Princeton, NJ, USA.
Megan
M
Wind-Rotolo
Bristol-Myers Squibb, Wallingford, CT, USA.
Fei
F
Yu
Bristol-Myers Squibb, Wallingford, CT, USA.
Fiona
F
McPhee
Bristol-Myers Squibb, Hopewell, NJ, USA.
Dennis M
DM
Grasela
Bristol-Myers Squibb, Hopewell, NJ, USA.
Claudio
C
Pasquinelli
D000998:Antiviral Agents / Q000008:administration & dosage*; D002219:Carbamates; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000008:administration & dosage; D012254:Ribavirin / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage*; D014633:Valine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007546:Isoquinolines; D011759:Pyrrolidines; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
ALT; AST; DAA; Direct-acting antiviral agents; HCV; HCV NS5A inhibitor; Hepatitis C treatment; LLOQ; LOD; Non-responders; PegIFNα; Protease inhibitor; QUAD; RBV; SNP; SVR; SVR(12); SVR(24); SVR(4); Sustained virologic response; alanine aminotransferase; aspartate aminotransferase; direct-acting antiviral; hepatitis C virus; limit of detection; lower limit of quantification; pegylated interferon alfa-2a; quadruple; ribavirin; single nucleotide polymorphism; sustained virologic response; sustained virologic response at 12weeks post-treatment; sustained virologic response at 24weeks post-treatment; sustained virologic response at 4weeks post-treatment