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HIV controllers demonstrate high rates of spontaneous clearance of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the role of human leukocyte antigen (HLA) B*57 and other genetic polymorphisms on HCV clearance in HIV controllers.This is a prospective cohort study.Patients in the Study of the Consequences of Protease Inhibitor Era (SCOPE) were tested for anti-HCV using enzyme immunoassay (EIA3) and HCV RNA using discriminatory HCV transcription-mediated amplification assay (Norvatis). We compared the proportion of HIV controllers and noncontrollers demonstrating HCV clearance and fitted multivariable Poisson regression models with robust standard errors to estimate adjusted prevalence ratios (APRs) and assessed genetic and immunologic predictors of HCV clearance.Of 279 HIV/HCV seropositive individuals, 48 were HIV controllers. HIV controllers compared to HIV noncontrollers, were significantly more likely to have HLA B*57 (33 vs. 10%, P < 0.01). In multivariate analyses, adjusting for HLAB57, IL28B genotype, age, sex and race/ethnicity, HCV clearance was significantly more likely in HIV controllers than HIV noncontrollers [APR 1.78; 95% confidence interval (CI) 1.06–3.0; P = 0.03]. HLA B*57 did not explain the increased proportion of HCV clearance in HIV controllers, but IL28B CC genotype was independently associated with spontaneous HCV clearance (APR 2.76; 95% CI 1.85–4.11; P < 0.001).Although enriched in HIV controllers, HLA B*57 does not explain the increased HCV clearance. Further identification of host immunologic or genetic factors that contribute to control of HIV and HCV may support the development of novel treatments for and effective vaccines against both viruses.