Plasma Cytokine Predictors of Tuberculosis Recurrence in Antiretroviral-Treated Human Immunodeficiency Virus-infected Individuals from Durban, South Africa

Background. Immune correlates of tuberculosis (TB) risk in populations infected with human immunodeficiency virus (HIV) remain understudied, despite HIV being associated with a high burden of TB disease. Here we describe plasma cytokine correlates of TB recurrence in a well-characterized cohort of HIV-infected individuals on antiretroviral therapy (ART) with a history of prior TB cure. Methods. Study participants were drawn from a prospective cohort study initiated at the conclusion of a randomized clinical trial in which individuals presented with untreated HIV infection and active pulmonary TB. At baseline, ART was initiated, and TB successfully cured. Participants were screened for TB recurrence quarterly for up to 4 years. TB recurrent cases (n = 63) were matched to controls (n = 123) on sex, study arm assignment in the original trial, and month of enrollment with a subset of cases sampled longitudinally at several time-points. Results. Three cytokines were associated with increased rates of TB recurrence in univariate models: interleukin 6 (IL6) (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.34-5.28, P=.005), IP10 (OR 4.62, 95% CI 1.69-12.65, P=.003), monokine induced by IFN-gamma (MIG) (OR 3.11, 95% CI 1.10-8.82, P=.034). Conversely, interferon beta (IFN beta) was associated with decreased TB risk (OR 0.34, 95% CI 0.13-0.87, P=.025). Following multivariate analyses adjusting for covariates IL6, interleukin 1 beta (IL1 beta), and interleukin 1R alpha (IL1R alpha) were associated with increased risk and IFN beta with decreased TB risk. Longitudinal analysis showed that levels of many TB-associated markers, including IL6, IP10, sCD14, and interferon gamma (IFN gamma) are reduced following TB treatment. Conclusion. These data show that TB recurrence, in HIV-infected individuals on ART is predicted by biomarkers of systemic inflammation, many of which are implicated in more rapid HIV disease progression.