Interferon γ Responses to Mycobacterial Antigens Protect against Subsequent HIV-Associated Tuberculosis

Background. The cellular immune responses that protect against tuberculosis have not been identified. Methods. We assessed baseline interferon gamma (IFN-gamma) and lymphocyte proliferation assay (LPA) responses to antigen 85 (Ag85), early secretory antigenic target 6 (ESAT-6), and Mycobacterium tuberculosis whole cell lysate (WCL) in human immunodeficiency virus (HIV)-infected and bacille Calmette-Guerin (BCG)-immunized adults with CD4 cell counts of >= 200 cells/mu L who received placebo in the DarDar tuberculosis vaccine trial in Tanzania. Subjects were followed prospectively to diagnose definite or probable tuberculosis. Results. Tuberculosis was diagnosed in 92 of 979 subjects during a mean follow-up of 3.2 years. The relative risk of tuberculosis among subjects with positive IFN-gamma responses to Ag85 was 0.51 (95% confidence interval [CI], 0.26-0.99; P = .049), to ESAT-6 was 0.44 (95% CI, 0.23-0.85; P = .004), and to WCL was 0.67 (95% CI, 0.49-0.88; P = .002). The relative risk of tuberculosis was not significantly associated with baseline LPA responses. In a multivariate Cox regression model, subjects with IFN-gamma responses to ESAT-6 and WCL had a lower hazard of developing tuberculosis, with a hazard ratio for ESAT-6 of 0.35 (95% CI, 0.16-0.77; P = .009) and a hazard ratio for WCL of 0.30 (95% CI, 0.16-0.56; P <.001). Conclusions. Baseline IFN-gamma responses to ESAT-6 and WCL were associated with protection from subsequent tuberculosis among HIV-infected subjects with childhood BCG immunization in a region of high tuberculosis prevalence.