Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection.
BACKGROUND
A region associated with sensitivity to interferon has been identified in the nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) genotype 1b. The region spans amino acid residues 2209 to 2248 (NS5A2209-2248) of HCV-J, a strain of HCV-1b whose complete genomic sequence has been identified. We examined whether the NS5A2209-2248 sequence present before therapy could be used as a predictor of the response to interferon therapy in patients with chronic HCV-1b infection.


METHODS
We retrospectively analyzed 84 patients with chronic HCV-1b infection who had received interferon alfa (total dose, 516 million to 880 million units) for six months. Pretreatment serum samples were analyzed. The amino acid sequence of NS5A2209-2248 was determined by direct sequencing of the HCV genome amplified by the polymerase chain reaction (PCR) and was compared with the established sequence for HCV-J.


RESULTS
A complete response, as evidenced by the absence of HCV RNA in serum on nested reverse-transcription PCR for six months after therapy, did not occur in any of the 30 patients whose NS5A2209-2248 sequences were identical to that of HCV-J (wild type). Five of 38 patients (13 percent) with 1 to 3 changes in NS5A2209-2248 (intermediate type) had complete responses, as did all 16 patients with 4 to 11 amino acid substitutions (mutant type), indicating that the mutant type was significantly associated with a complete response (P < 0.001). Although baseline serum HCV RNA levels, as measured by a branched-chain DNA assay, were lower in patients with the mutant type of NS5A2209-2248 than in those with the other types (P < 0.001), multivariate analyses revealed that the number of amino acid substitutions in NS5A2209-2248 was the only variable associated with an independent effect on the outcome of interferon therapy (odds ratio, 5.3; 95 percent confidence interval, 1.6 to 18; P = 0.007).


CONCLUSIONS
In patients with chronic HCV-1b infection, there is a substantial correlation between responses to interferon and mutations in the NS5A gene.
Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
N
N
Enomoto
I
I
Sakuma
Y
Y
Asahina
M
M
Kurosaki
T
T
Murakami
C
C
Yamamoto
Y
Y
Ogura
N
N
Izumi
F
F
Marumo
C
C
Sato
D000595:Amino Acid Sequence; D001483:Base Sequence; D002908:Chronic Disease; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000628:therapy / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D012189:Retrospective Studies; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics*
D016898:Interferon-alpha; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins