Mutations in the NS5B region of the hepatitis C virus genome correlate with clinical outcomes of interferon-alpha plus ribavirin combination therapy.
OBJECTIVE
Combination treatments of interferon-alpha (IFN) and ribavirin (RBV) are more effective than those of IFN alone in hepatitis C virus (HCV) infection. However, mechanisms of the action of the combination regimen are not well understood. To elucidate the viral genetic basis of IFN plus RBV combination therapy, genetic variabilities of HCV-1b were analyzed.


METHODS
We performed pair-wise comparisons of full-length HCV genomic sequences in three patients' sera before and after initiation of IFN plus RBV treatment. Subsequently, we analyzed amino acid sequences of the NS5B region, which codes for the viral RNA-dependent RNA polymerase, and compared these with the outcomes of the therapy in 81 patients.


RESULTS
Analysis of the entire HCV sequence in patients who received IFN plus RBV therapy did not show consistent amino acid changes between before and after the initiation of the therapy. NS5B sequence analyses revealed that mutations at positions 300-358 of NS5B, including polymerase motif B to E, occurred more frequently in a group of patients exhibiting a sustained viral response (SVR) or an end-of-treatment response (ETR) compared with a group of patients exhibiting a non-response (NR). Closer examination revealed that mutations at aa 309, 333, 338 and 355 of NS5B occurred significantly more frequently in the SVR plus ETR group than in the NR group (P = 0.0004). Multivariate analysis showed that the number of mutations at these four sites was an independent predictor of SVR plus ETR versus NR.


CONCLUSIONS
Particular amino acid changes in the NS5B region of HCV may correlate with outcomes of IFN plus RBV combination therapy.
Hamano
Kosei
K
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan.
Sakamoto
Naoya
N
Enomoto
Nobuyuki
N
Izumi
Namiki
N
Asahina
Yasuhiro
Y
Kurosaki
Masayuki
M
Ueda
Eri
E
Tanabe
Yoko
Y
Maekawa
Shinya
S
Itakura
Jun
J
Watanabe
Hideki
H
Kakinuma
Sei
S
Watanabe
Mamoru
M
D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016679:Genome, Viral / Q000235:genetics*; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012254:Ribavirin / Q000627:therapeutic use; D020539:Sequence Analysis, Protein; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase