Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy.
OBJECTIVE
Studies from Japan showed that HCV-1b isolates with at least four amino acid changes within NS5A2209-2248 compared with the prototype sequence HCV-J are more sensitive to interferon than isolates with a prototype sequence. However, the data were not unequivocally confirmed in studies from other geographical areas. These discrepancies may be explained by differences in the prevalence of multiple mutations within the NS5A2209-2248 and/or the treatment efficacy.


METHODS
In the present study, we therefore investigated the correlation between NS5A2209-2248 sequences of HCV-1b isolates and sustained virological response in 72 European patients treated with 3x6 MU interferon-a per week with (n = 26) and without (n = 46) ribavirin (1000-1200 mg/day). Serum HCV RNA was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the NS5A2209-2248 region was analyzed by sequencing of PCR products or individual clones.


RESULTS
Compared with HCV-1b prototype sequences, 19 patients (26%) had no amino acid changes (prototype), 47 patients (65%) had 1-3 mutations (intermediate type) and six patients (8%) had at least 4 mutations in the NS5A2209-2248 region (mutant type). Nine of the 12 patients with sustained virological response were infected with an intermediate type HCV-1b, the remaining three patients revealed a mutant type HCV-1b. A sustained virological response was achieved in three of four patients with a mutant type HCV-1b treated with interferon-alpha and ribavirin, but in none of the mutant type HCV-1b infected patients treated with interferon-a alone. Quasispecies analysis of HCV in the NS5A2209-2248 region showed only minor heterogeneity of the amino acid sequence.


CONCLUSIONS
The prevalence of mutant type HCV-1b isolates in European patients is low. In patients treated with combination therapy interferon-a and ribavirin, a correlation between mutant type HCV-1b isolates and sustained virological response was observed. The discrepancies between previous studies appear to be related to the efficacy of antiviral treatment and to the low prevalence of mutant type HCV-1b isolates in Western countries.
Medizinische Klinik II, J.W. Goethe-University, Frankfurt am Main, Germany.
C
C
Sarrazin
T
T
Berg
J H
JH
Lee
G
G
Teuber
C F
CF
Dietrich
W K
WK
Roth
S
S
Zeuzem
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005060:Europe; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000628:therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics*; D012254:Ribavirin / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000235:genetics*
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D012254:Ribavirin; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase