Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: A systematic review and meta-analysis

Background: Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment remains challenging. Purpose: To assess evidence from randomized, controlled trials of the timing of ART initiation in HIV-infected adults with newly diagnosed pulmonary TB. Data Sources: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts, and ClinicalTrials.gov (from January 1980 to May 2015). Study Selection: Randomized, controlled trials evaluating early versus delayed ART initiation (1 to 4 weeks vs. 8 to 12 weeks after initiation of TB treatment) or deferred ART initiation (after the end of TB treatment). Data Extraction: Three reviewers independently extracted data and assessed risk of bias. The main outcome measures were all-cause mortality and the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Data Synthesis: The 8 included trials (n = 4568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I² = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4⁺ T-cell counts less than 0.050 ×10⁹ cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I² = 0%). However, a mortality benefit from early ART was not found among those with CD4⁺ T-cell counts greater than 0.050 ×10⁹ cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I² = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I² = 19%). Limitation: Few trials provided sufficient data for subgroup analysis. Conclusion: Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4⁺ T-cell counts less than 0.050 ×10⁹ cells/L, although this is associated with a 2-fold higher frequency of TB-IRIS. In patients with CD4⁺ T-cell counts greater than 0.050 ×10⁹ cells/L, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation.