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 (ΔHCVIFN ) 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 ΔHCVIFN at 72 hours (ΔHCVIFN,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 ΔHCVIFN,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 ΔHCVIFN,72 of 0.78 log10 IU/mL (95% confidence interval [CI] 0.36,1.20). Pre- and post-ART ΔHCVIFN,72 were closely associated (r = 0.87; P < 0.001). HCV virologic setpoint also changed after ART (ΔHCVART ): 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 ΔHCVART .


CONCLUSIONS
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.
Department of Medicine, Johns Hopkins University Baltimore, MD.
Ashwin
A
Balagopal
Abraham J
AJ
Kandathil
Yvonne H
YH
Higgins
Jonathan
J
Wood
Justin
J
Richer
Jeffrey
J
Quinn
Lois
L
Eldred
Zhiping
Z
Li
Stuart C
SC
Ray
Mark S
MS
Sulkowski
David L
DL
Thomas
D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D060085:Coinfection / Q000188:drug therapy*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008099:Liver / Q000821:virology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
D044966:Anti-Retroviral Agents; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins