The Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS): recent advances in clinical and pathogenesis research

Purpose of the review: Anti-retroviral therapy (ART) is an essential, life-saving intervention for HIV infection. However, ART initiation is frequently complicated by the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in TB endemic settings. Here, we summarise current understanding highlighting the recent evidence. Recent findings: The incidence of paradoxical TB-IRIS is estimated at 18% (95% CI 16-21%), higher than previously reported and may be over 50% in high-risk groups. Early ART initiation in TB patients increases TB-IRIS risk by greater than two-fold, but is critical in TB patients with CD4 counts <50 cells/µl because it improves survival. There remains no validated diagnostic test for TB-IRIS, and biomarkers recently proposed are not routinely used. Prednisone initiated alongside ART in selected patients with CD4 ≤100 cells/µl reduced the risk of paradoxical TB-IRIS by 30% in a recent randomised-controlled trial and were not associated with significant adverse effects. Effective also for treating paradoxical TB-IRIS, corticosteroids remain the only therapeutic intervention for TB-IRIS supported by randomised-controlled trial data. TB-IRIS pathogenesis studies implicate high antigen burden, innate immune cell cytotoxicity, inflammasome activation and dysregulated matrix metalloproteinases in the development of the condition. Summary: Specific biomarkers would aid in identifying high-risk patients for interventions and a diagnostic test is needed. Clinicians should consider prednisone for TB-IRIS prevention in selected patients. Future research should focus on improving diagnosis and investigating novel therapeutic interventions, especially for patients in whom corticosteroid therapy is contraindicated. Two meta-analyses of randomised-controlled trials (RCTs) on the optimal time to initiate ART following commencement of TB treatment in HIV-associated TB have reported combined relative risks of TB-IRIS of 2.19 (95% CI 1.77-2.70) and 2.31 (95% CI 1.87-2.86) for early (up to four weeks) vs late (8-12 weeks) ART initiation 6]. In patients with a CD4 count below 50 cells/mm 3 a mortality benefit was apparent with early ART, favouring ART initiation within 2 weeks following TB treatment in such patients. However, a relatively high incidence of TB-IRIS can be expected in these patients who commence ART at 2 weeks of anti-tuberculous therapy – the risk was elevated over two-fold with early ART.

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