Positive selection of core 70Q variant genotype 1b hepatitis C virus strains induced by pegylated interferon and ribavirin.
BACKGROUND
Approximately 20% of patients with hepatitis C virus (HCV) genotype 1b infection have nonresponse to the most current treatment, pegylated interferon with ribavirin. Mutations in the HCV core region were recently proposed to be associated with nonresponse. Our aim was to evaluate the viral factors associated with treatment failure.


METHODS
HCV variants were determined directly and after cloning in 66 HCV-1b-infected Japanese patients and in 5 urokinase-type plasminogen activator transgenic severe combined immunodeficiency mice with human hepatocytes (chimeric mice), at baseline, during treatment, and after treatment.


RESULTS
At baseline, glutamine at position 70 of the HCV core protein (70Q) was detected by direct sequencing in 20% of patients with virologic response and in 43.8% of patients with nonresponse. Among patients with nonresponse, who were examined during and after treatment, the prevalence of the 70Q substitution increased to 56.3%, which indicates that treatment-induced selection occurred in all patients with nonresponse who had 70Q quasispecies detectable by cloning. This observation was reinforced by the results from experimentally infected chimeric mice. Logistic regression analysis indicated that detection of 70Q quasispecies was associated with a statistically significantly increased risk of nonresponse (odds ratio, 15.1; P = .004) in the studied cohort.


CONCLUSIONS
Presence of the 70Q quasispecies at baseline was associated with an increased risk of treatment failure, as indicated by the positive selection of the 70Q clones induced by treatment with pegylated interferon with ribavirin. These results urge further investigation of the mechanisms of this association.
Kurbanov
Fuat
F
Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Nagoya, Japan.
Tanaka
Yasuhito
Y
Matsuura
Kentaro
K
Sugauchi
Fuminaka
F
Elkady
Abeer
A
Khan
Anis
A
Hasegawa
Izumi
I
Ohno
Tomoyoshi
T
Tokuda
Hiroshi
H
Mizokami
Masashi
M
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D014758:Viral Core Proteins / Q000235:genetics*
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b