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

• Published in: Journal of hepatology 1999-06, Vol.30 (6), p.1004-1013
• Main Authors: Sarrazin, Christoph, Berg, Thomas, Lee, Jung-Hun, Teuber, Gerlinde, Dietrich, Christoph F, Roth, W.Kurt, Zeuzem, Stefan
• Format: Article
• Language: English
• Subjects: Adult; Aged; Amino Acid Sequence; Antiviral Agents - therapeutic use; Biological and medical sciences; Combined Modality Therapy; Europe; Female; Hepacivirus - genetics; Hepatitis C, Chronic - therapy; Hepatitis C, Chronic - virology; Human viral diseases; Humans; Hyper-phosphorylation sites; Infectious diseases; Interferon sensitivity determining region; Interferon-alpha - therapeutic use; Male; Medical sciences; Middle Aged; Mutation; Nonstructural 5A region; Polymerase Chain Reaction; Ribavirin; Ribavirin - therapeutic use; RNA, Viral - blood; RNA-Dependent RNA Polymerase - genetics; Viral diseases; Viral hepatitis; Viral Nonstructural Proteins - genetics
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(99)80253-0

Background/Aims: Studies from Japan showed that HCV-1b isolates with at least four amino acid changes within NS5A 2209–2248 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 NS5A 2209–2248 and/or the treatment efficacy. Methods: In the present study, we therefore investigated the correlation between NS5A 2209–2248 sequences of HCV-1b isolates and sustained virological response in 72 European patients treated with 3×6 MU interferon-α 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 NS5A 2209–2248 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 NS5A 2209–2248 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-α and ribavirin, but in none of the mutant type HCV-1b infected patients treated with interferon-α alone. Quasispecies analysis of HCV in the NS5A 2209–2248 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-α 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.