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

Abstract

<p id="d7536547e217">Significantly higher plasma levels of IL6, IL1β, and sIL1Rα were associated with increased risk, whereas plasma IFNβ levels were associated with a decreased risk of TB recurrence in TB Recurrence upon Treatment with HAART (TRuTH) cohort, based in Durban, South Africa. </p><div class="section"> <a class="named-anchor" id="s01"> <!-- named anchor --> </a> <h5 class="section-title" id="d7536547e223">Background</h5> <p id="d7536547e225">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. </p> </div><div class="section"> <a class="named-anchor" id="s02"> <!-- named anchor --> </a> <h5 class="section-title" id="d7536547e228">Methods</h5> <p id="d7536547e230">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. </p> </div><div class="section"> <a class="named-anchor" id="s03"> <!-- named anchor --> </a> <h5 class="section-title" id="d7536547e233">Results</h5> <p id="d7536547e235">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, <i>P</i> = .005), IP10 (OR 4.62, 95% CI 1.69–12.65, <i>P</i> = .003), monokine induced by IFN-γ (MIG) (OR 3.11, 95% CI 1.10–8.82, <i>P</i> = .034). Conversely, interferon β (IFNβ) was associated with decreased TB risk (OR 0.34, 95% CI 0.13–0.87, <i>P</i> = .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. </p> </div><div class="section"> <a class="named-anchor" id="s04"> <!-- named anchor --> </a> <h5 class="section-title" id="d7536547e250">Conclusion</h5> <p id="d7536547e252">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. </p> </div><div class="section"> <a class="named-anchor" id="s05"> <!-- named anchor --> </a> <h5 class="section-title" id="d7536547e255">Clinical Trials Registration</h5> <p id="d7536547e257">NCT 01539005.</p> </div>