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

Abstract

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-γ (MIG) (OR 3.11, 95% CI 1.10-8.82, P = .034). Conversely, interferon β (IFNβ) 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 1β (IL1β), and interleukin 1Rα (IL1Rα) were associated with increased risk and IFNβ with decreased TB risk. Longitudinal analysis showed that levels of many TB-associated markers, including IL6, IP10, sCD14, and interferon γ (IFNγ) 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.

Clinical trials registration: NCT 01539005.

Keywords: ART; HIV; Tuberculosis; chemokine; cytokine.

Figure 1.

Cytokines/chemokines differentially expressed between controls (n = 123) and cases (n = 63) by univariate conditional logistic regression. Five cytokines were associated with increased rates of TB recurrence, including IL6 (OR 2.66, 95% CI 1.34–5.27, P = .005), IP10 (OR 4.62, 95% CI 1.69–12.65, P = .003), MIG (OR 3.11, 95% CI 1.10–8.82, P = .034) and IL1β (OR 1.89, 95% CI 0.97–3.68, P = .064) and IL1Rα (OR 1.52, 95% CI 0.95–2.45, P = .084, whereas IFNβ was associated with decreased risk (OR 0.34, 95% CI 0.13–0.87, P = .025). Cytokines were plotted on log scale (Log 10), Box and Whiskers (5–95%). P-values indicated in the figures are result of a univariate conditional logistic regression (Table 1). Abbreviations: CI, confidence interval; IL, interleukin; IFN, interferon; IP, interferon gamma induced protein; MIG, monokine induced by IFN-γ; OR, odds ratio; TB, tuberculosis.

Figure 2.

Effect of treatment completion on cytokine/chemokine expression following active TB (n = 15). A, Effect of treatment following the first TB episode, during early ART. Expression of 2 analytes was decreased IP10 (mean difference (MD) 0.271, 95% CI 0.0618 to 0.4803, P = .0148), sCD14 (MD = 0.0847, 95% CI 0.0186–0.1508, P = .0157), whereas IL6 (MD = 0.222, 95% CI −0.0461 to 0.4909, P = .097) and IFNγ (MD = 0.4687, 95% CI −0.2097 to 1.1472. P = .159) expression was not significantly affected. B, Effect of treatment following the recurrent TB episode. Expression of 4 analytes was decreased following TB treatment completion, including IP10 (MD = 0.281, 95% CI −0.0167 to 0.5788 P = .0625), sCD14 (MD = 0.1289, 95% CI 0.0249–0.2328, P = .0187), IL6 (MD = 0.5352, 95% CI 0.1913–0.8791, P = .0049), IFNγ (MD = 0.6821, 95% CI 0.1313–1.233, P = .0188). Paired t-test was used to evaluate changes in analyte expression between different time points. (Cytokines significantly affected at either of the time-points are shown here. Information for the rest of the measured cytokines can be found in Sup. Table 1). Abbreviations: ART, antiretroviral therapy; CI, confidence interval; IL, interleukin; IFN, interferon; IP, interferon gamma induced protein; sCD, soluble CD; TB, tuberculosis.