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 (ΔHCV_IFN) 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 ΔHCV_IFN at 72 hours (ΔHCV_IFN,72) increased in 15/19 (78.9%) participants by a median (interquartile range [IQR]) of 0.11 log₁₀ IU/mL (0.00-0.40; P<0.05). Increases in ΔHCV_IFN,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 ΔHCV_IFN,72 of 0.78 log₁₀ IU/mL (95% confidence interval [CI] 0.36,1.20). Pre- and post-ART ΔHCV_IFN,72 were closely associated (r=0.87; P<0.001). HCV virologic setpoint also changed after ART (ΔHCV_ART): transient median increases of 0.28 log₁₀ IU/mL were followed by eventual median decreases from baseline of 0.21 log₁₀ 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 ΔHCV_ART. 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. (Hepatology 2014;60:477-486)