Sequences in the NS5A protein of hepatitis C virus and the serum alanine aminotransferase response to interferon therapy in Japanese patients.
OBJECTIVE
Chronic hepatitis C is a slowly progressive disease and eventually causes hepatocellular carcinoma in many patients. Although interferon (IFN) therapy has been used for viral eradication, its success rate is only about 30%. In patients in whom it has failed (non-responders), there are several patterns of serum alanine aminotransferase (ALT) values, and detection of serum HCV-RNA during and after IFN therapy and improved long term prognosis were reported in patients whose serum ALT values were normalised by IFN therapy even if HCV viraemia persisted. The present study sought to clarify the virological characteristics contributing to these differences.


METHODS
Complete or partial length dominant sequences of hepatitis C virus genotype 1b (HCV-1b) were determined by direct sequencing. Firstly, the complete sequences of HCV-1b genomes were determined in six non-responders; three showed normalisation of serum ALT values during IFN-alpha therapy and the other three did not. Subsequently, the amino acid residues that were different in the two groups were further analysed retrospectively in another 82 patients.


RESULTS
Comparison of the sequences suggested an association between amino acids 2154-2172 of HCV-1b and serum ALT normalisation. A retrospective analysis of 82 patients revealed that the number of amino acid substitutions in this region was the only statistically significant variable associated with ALT normalisation (odds ratio 31.0; 95% confidence interval 5.0-286) in multivariate analyses.


CONCLUSIONS
A HCV genomic region that correlates with the ALT response to IFN therapy appears to be present in virologically IFN ineffective patients.
Nagayama
K
K
Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan, 113-8519.
Enomoto
N
N
Izumi
N
N
Kurosaki
M
M
Miyasaka
Y
Y
Watanabe
H
H
Itakura
J
J
Chen
C H
CH
Tazawa
J
J
Hoshino
Y
Y
Ikeda
T
T
Marumo
F
F
Sato
C
C
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood* / Q000187:drug effects; D019943:Amino Acid Substitution / Q000235:genetics; D015415:Biomarkers; D005260:Female; D016679:Genome, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012367:RNA, Viral / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D000410:Alanine Transaminase; D015415:Biomarkers; D007372:Interferons; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase