Virological escape in HCV genotype-1-infected patients receiving daclatasvir plus ribavirin and peginterferon alfa-2a or alfa-2b.
BACKGROUND
Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of HCV non-structural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV.


METHODS
In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10 mg or 60 mg) plus peginterferon alfa-2b or alfa-2a and ribavirin. Virological failure occurred in 14% (5/36) of treatment-naive patients and 54% (19/35) of prior alfa/ribavirin non-responders. Resistance testing was performed on baseline samples and samples with HCV RNA≥1,000 IU/ml at week 1 through post-treatment week 24.


RESULTS
Baseline NS5A resistance-associated polymorphisms had less impact on virological response rates than IL28B genotype. All patients with virological failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) of treatment-naive patients and 74% (14/19) of non-responders with failure. Emergent resistance variants in prior non-responders (four viral breakthroughs, one relapse) were more varied with novel combinations such as L31F-ΔP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥ two resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study.


CONCLUSIONS
Virological failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior non-responders, emergent variants associated with failure also included NS5A-A92K or NS5A-ΔP32. As with L31-Y93 variants, these variants persisted.
Bristol-Myers Squibb, Wallingford, CT, USA. fiona.mcphee@bms.com.
Fiona
F
McPhee
Dennis
D
Hernandez
Nannan
N
Zhou
Fei
F
Yu
Joseph
J
Ueland
Aaron
A
Monikowski
Kazuaki
K
Chayama
Joji
J
Toyota
Namiki
N
Izumi
Osamu
O
Yokosuka
Norifumi
N
Kawada
Yukio
Y
Osaki
Eric A
EA
Hughes
Hideaki
H
Watanabe
Hiroki
H
Ishikawa
Hiromitsu
H
Kumada
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load; D055815:Young Adult; D000095022:Interferon Lambda
D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011759:Pyrrolidines; D011994:Recombinant Proteins; D012254:Ribavirin; D014633:Valine; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C417083:peginterferon alfa-2b; C549273:daclatasvir