Antiretroviral Therapy, Interferon Sensitivity, and Virologic Setpoint in Human Immunodeficiency Virus/Hepatitis C Virus Coinfected Patients

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause substantial mortality, especially in persons chronically infected with both viruses. HIV infection raises plasma HCV RNA levels and diminishes the response to exogenous alpha interferon (IFN). The degree to which antiretroviral therapy (ART) control of infection overcomes these HIV effects is unknown. Participants with HIV-HCV coinfection were enrolled in a trial to measure HCV viral kinetics after IFN administration (Delta HCVIFN) twice: initially before (pre-ART) and then after (post-ART) HIV RNA suppression. Liver tissue was obtained 2-4 hours before each IFN injection to measure interferon stimulated genes (ISGs). Following ART, the Delta HCVIFN at 72 hours (Delta HCVIFN,72) increased in 15/19 (78.9%) participants by a median (interquartile range [IQR]) of 0.11 log(10) IU/mL (0.00-0.40; P < 0.05). Increases in Delta HCVIFN,(72) post-ART were associated with decreased hepatic expression of several ISGs (r=-0.68; P=0.001); a 2-fold reduction in a four-gene ISG signature predicted an increase in Delta HCVIFN,(72) of 0.78 log(10) IU/mL (95% confidence interval [CI] 0.36,1.20). Pre- and post-ART Delta HCVIFN,72 were closely associated (r=0.87; P < 0.001). HCV virologic setpoint also changed after ART (Delta HCVART): transient median increases of 0.28 log(10) IU/mL were followed by eventual median decreases from baseline of 0.21 log(10) IU/mL (P=0.002). A bivariate model of HIV RNA control (P < 0.05) and increased expression of a nine-gene ISG signature (P < 0.001) predicted the eventual decreased DHCVART. Conclusion: ART is associated with lower post-IFN HCV RNA levels and that change is linked to reduced hepatic ISG expression. These data support recommendations to provide ART prior to IFN-based treatment of HCV and may provide insights into the pathogenesis of HIV-HCV coinfection.