839 The Association of Hepatitis C Virus-specific Immune Responses with Liver Histology and Treatment Outcomes in Subjects with HIV/HCV Co-infection C. Graham*1, A. Wells1, T. Liu2, K. Sherman3, M. Peters4, R. Chung5, J. Andersen2, M. Koziel1, the ACTG 5071 Study Team6 1Beth Israel Deaconess Med Ctr and Harvard Med Sch, Boston, MA; 2Harvard Sch of Public Hlth, Boston, MA; 3Univ of Cincinnati, OH; 4Univ of California at San Francisco; 5Massachusetts Gen Hosp and Harvard Med Sch, Boston; and 6The AIDS Clin Trial Group
Background: The relationship of HCV-specific immune responses to liver injury and treatment outcome is poorly understood, but is important to understanding the pathogenesis of liver damage and improving treatment outcomes. We tested the hypotheses that 1) vigorous HCV-specific Th1-like immune responses are correlated with milder liver disease, and 2) HCV-specific Th1 responses are associated with a higher probability of HCV virological response during treatment. This is the largest cohort characterized to date with respect to HCV-specific immune responses and clinical outcomes.
Methods: A representative subset of the subjects enrolled in ACTG 5071 (n = 102/133 eligible) was studied. This trial compared 2 forms of interferon plus ribavirin for the treatment of HCV, with the primary endpoint being HCV clearance at 24 wks. Subjects had liver biopsies prior to entry. PBMCs were isolated at baseline and 24 wks. ELISpot assays were performed for IFNgamma and IL-10 using HCV antigens (Ag) Core, NS3 and NS5, recall Ag candida (Can), and PHA. Data were analyzed using nonparametric methods, including Spearman rank correlation and recursive partitioning (CART).
Results: There were significant negative correlations between the inflammatory score (IS) and IFNgamma production at baseline in response to the HCV proteins core (p = 0.02) and NS5 (p = 0.002). Fibrosis scores (FS) were negatively correlated with IFNgamma production at baseline in response to NS5 (p = 0.03). There were also strong negative correlations between IFNgamma production at baseline in response to Can and the IS (p = 0.001) and FS (p < 0.001). There was no correlation for IL-10 production in response to Ag or Can with either FS or IS at baseline. CART suggested important joint associations of IFNgamma core and Can responses, and IL-10 Can and NS3 responses with IS. There was no association of HCV-specific response and CD4 count in this cohort (median CD4 count 486, range 177-1,001). In contrast, only IL-10 production in response to NS3 at baseline was associated with being a treatment responder at 24 wks (p = 0.02). There was no association between changes in Th1 HCV-specific responses from baseline to 24 wks and treatment outcome.
Conclusions: In this large cohort of subjects co-infected with HIV and HCV, HCV-specific Th1 responses in PBMC are correlated with milder inflammation and fibrosis but are not associated with treatment outcome.
