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

doi:10.1016/S0168-8278(99)80253-0

Journal of Hepatology

Volume 30, Issue 6, June 1999, Pages 1004-1013

https://doi.org/10.1016/S0168-8278(99)80253-0 Get rights and content

Abstract

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.

Section snippets

Patients

The study group consisted of the 72 unselected patients (43 men, 29 women, mean age 48 (range 20–72) years) chronically infected with HCV genotype 1b who were treated at the University Hospitals of Frankfurt a.M. and Berlin. Forty-six of these patients received 6 MU recombinant IFN-α three times per week subcutaneously for the initial 3 (n=23) or 6 (n=23) months, followed by 3 MU IFN-α thrice weekly for a total of 12 months (total dose 585 and 702 MU, respectively). The remaining 26 patients

Results

In the present study, treatment of 72 patients chronically infected with HCV subtype 1b was initiated with 6 MU recombinant IFN-α thrice weekly. Twenty-six patients received combination treatment with ribavirin (1000–1200 mg/d according to body weight). The clinical, biochemical, serological, and histological characteristics of the patients are summarized in Table 1.

Seventeen of the 72 patients (24%) had a complete virological response at the end of therapy (ETR). However, only 12 patients

Discussion

Comparative analysis of the full-length HCV genome suggested that a small region of NS5A (codons 2209–2248) of HCV-1b is associated with sensitivity to interferon-α (6). In the IFN-α resistant strains, the NS5A_2209–2248 sequence was the same as that of the prototypical HCV-1b strains HCV-J (9) and HC-J4 (22), whereas IFN-α sensitive strains had multiple amino acid substitutions in this region (6). In vitro, NS5A interacts with and inhibits the function of protein kinase RNA, a cellular

Acknowledgements

This work was supported in part by a “Stipendium für Nachwuchsforscher der J. W. Goethe-Universität” to C.S. and the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (BMBF).

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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

Abstract

Section snippets

Patients

Results

Discussion

Acknowledgements

Gastroenterology

Virology

Gastroenterology

J Hepatol

Anal Biochem

Virology

The natural history of community-acquired hepatitis C in the United States

N Engl J Med

Clinical outcomes after transfusion-associated hepatitis C

N Engl J Med

Hepatitis C virus infection is associated with the development of hepatocellular carcinoma

Proc Natl Acad Sci USA

Hepatitis C serotype and response to interferon therapy

N Engl J Med

Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b

J Clin Invest

Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection

N Engl J Med

Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis

Proc Natl Acad Sci USA

Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-β therapy

Hepatology

Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection

Hepatology