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 drugspecific 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-naı ¨ve 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 < 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. (HEPATOLOGY 2009;49:1069-1082.)
H epatitis C treatment has been transformed over the last decade by the use of improved therapy regimens, including pegylated interferon-alfa, as either monotherapy or combined with the nucleoside analog ribavirin. 1,2 Combination therapy is effective in obtaining a sustained virological response in most treated individuals. 1,2 However, response rates to pegylated interferon-alfa/ribavirin therapy are lower in individuals with the prevalent genotype 1 strain compared with those with genotypes 2 and 3. Also, current therapies are often poorly tolerated because of a plethora of treatment-associated side effects. 1 Currently, there is no available effective alternative therapy in individuals who fail to achieve a sustained virological response to current treatment regimens.
Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins integral to the hepatitis C virus (HCV) life cycle. These drugs, collectively termed spe-