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

Gaudieri, Silvana; Rauch, Andri; Pfafferott, Katja; Barnes, Eleanor; Cheng, Wendy; McCaughan, Geoff; Shackel, Nick; Jeffrey, Gary P; Mollison, Lindsay; Baker, Ross; Furrer, Hansjakob; Günthard, Huldrych F; Freitas, Elizabeth; Humphreys, Isla; Klenerman, Paul; Mallal, Simon; James, Ian; Roberts, Stuart; Nolan, David and Lucas, Michaela (2009). Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology, 49(4), pp. 1069-82. Hoboken, N.J.: Wiley Interscience 10.1002/hep.22773

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

UniBE Contributor:

Rauch, Andri and Furrer, Hansjakob

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:14

Last Modified:

04 May 2014 23:23

Publisher DOI:

10.1002/hep.22773

PubMed ID:

19263475

Web of Science ID:

000264862100004

URI:

https://boris.unibe.ch/id/eprint/32455 (FactScience: 197663)

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