Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy

Publisher DOI
PubMed ID
19263475
Abstract
The efficacy of specifically targeted anti-viral therapy for hepatitis C virus (HCV) (STAT-C), including HCV protease and polymerase inhibitors, is limited by the presence of drug-specific viral resistance mutations within the targeted proteins. Genetic diversity within these viral proteins also evolves under selective pressures provided by host human leukocyte antigen (HLA)-restricted immune responses, which may therefore influence STAT-C treatment response. Here, the prevalence of drug resistance mutations relevant to 27 developmental STAT-C drugs, and the potential for drug and immune selective pressures to intersect at sites along the HCV genome, is explored. HCV nonstructural (NS) 3 protease or NS5B polymerase sequences and HLA assignment were obtained from study populations from Australia, Switzerland, and the United Kingdom. Four hundred five treatment-naïve individuals with chronic HCV infection were considered (259 genotype 1, 146 genotype 3), of which 38.5% were coinfected with human immunodeficiency virus (HIV). We identified preexisting STAT-C drug resistance mutations in sequences from this large cohort. The frequency of the variations varied according to individual STAT-C drug and HCV genotype/subtype. Of individuals infected with subtype 1a, 21.5% exhibited genetic variation at a known drug resistance site. Furthermore, we identified areas in HCV protease and polymerase that are under both potential HLA-driven pressure and therapy selection and identified six HLA-associated polymorphisms (P <or= 0.05) at known drug resistance sites. CONCLUSION: Drug and host immune responses are likely to provide powerful selection forces that shape HCV genetic diversity and replication dynamics. Consideration of HCV viral adaptation in terms of drug resistance as well as host "immune resistance" in the STAT-C treatment era could provide important information toward an optimized and individualized therapy for chronic hepatitis C.
Date Issued
2009
Publication Type
Article
Language(s)
en
Author(s)
Gaudieri, Silvana
Pfafferott, Katja
Barnes, Eleanor
Cheng, Wendy
McCaughan, Geoff
Shackel, Nick
Jeffrey, Gary P
Mollison, Lindsay
Baker, Ross
Günthard, Huldrych F
Freitas, Elizabeth
Humphreys, Isla
Klenerman, Paul
Mallal, Simon
James, Ian
Roberts, Stuart
Nolan, David
Lucas, Michaela
Additional Credits
Journal
Hepatology
Publisher
Wiley Interscience
ISSN
0270-9139
Access(Rights)
metadata.only
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