Relationships between cellular immune responses and treatment outcomes with interferon and ribavirin in HIV/hepatitis C virus co-infection

Abstract

Objective: To test the hypothesis that hepatitis C virus (HCV)-specific interferon (IFN)gamma immune responses are correlated with HCV virological response following treatment in subjects with HIV-1 and HCV co-infection.

Design: Immune responses were studied in a treatment trial comparing standard interferon alfa (IFN) to pegylated interferon alfa (PEG-IFN), each with ribavirin (R).

Methods: Using HCV antigens core, NS3 and NS5, and Candida, enzyme-linked immunosorbent spots on peripheral blood mononuclear cells measured IFNgamma and interleukin (IL)-10 production. Immunologic, virologic and clinical variables were modeled using recursive partitioning (CART) to identify factors associated with HCV virological response at week 24 (VR) and week 72 (SVR) in 108 patients.

Results: There were no significant differences in baseline IFNgamma immune responses and higher IL-10 to NS3 in subjects with VR versus non-responders. Subjects who had significant decreases in IL-10 responses at week 24 compared to baseline for NS3, NS5, or summed HCV responses were more likely to be VR. Using baseline immunological responses and clinical data in CART models, patients who were randomized to PEG-IFN/R and had high IL-10 responses to summed HCV proteins were more likely to be VR (73%), whereas those on IFN/R who had low IFNgamma responses to Candida were less likely to be VR (5%). The main correlate of SVR for genotype-1 subjects was maintenance of HCV-specific IFNgamma responses from baseline to week 72.

Conclusions: In this cohort of subjects with HIV and HCV, a decrease in HCV-specific IL-10 responses and maintenance of IFNgamma responses during treatment with IFN were associated with week 24 or 72 virological response.

Figures

Fig. 1. Classification and regression tree (CART) for predicting the outcome of week 24 virological response (VR)

Thirty percent of the overall cohort had week 24 VR. CART identified useful baseline predictors for subgroups with higher or lower frequencies of week 24 VR. All percentages indicate classified subjects with week 24 VR compared to the total subjects in that classified group. IL-10 Sum-HCV = sum of interleukin (IL)-10 responses to hepatitis C virus (HCV) proteins core, NS3 and NS5. Numbers associated with immune response data represent spot-forming cells (SFC)/106 peripheral blood mononuclear cells. IDU, injection drug users; IFN, interferon alfa-2a; PEG-IFN, pegylated interferon alfa-2a; RBV, ribavirin.

Fig. 2. Classification and regression tree (CART) for predicting the outcome of week 24 virological response (VR) in 93 subjects who had immune response data for baseline and week 24 time points

CART identified useful predictors for subgroups with higher or lower frequencies of week 24 VR. IL-10 Sum-HCV = sum of interleukin (IL)-10 responses to hepatitis C virus (HCV) proteins core, NS3 and NS5. Numbers associated with immune response data represent spot-forming cells (SFC)/106 peripheral blood mononuclear cells. IFN, interferon alfa-2a.

Fig. 3. Classification and regression tree (CART) for predicting the outcome of sustained virological response (SVR) in 54 subjects who had immune response data for baseline, week 24 and week 72 time points

IFNγ Sum-HCV = sum of interferon (IFN)γ responses to hepatitis C virus (HCV) proteins core, NS3 and NS5. Numbers associated with immune response data represent spot-forming cells (SFC)/106 peripheral blood mononuclear cells.