Up to 26% of patients initiating ART in low and middle income countriesbdie within the first year of initiating ART, with TB being a major contributor. Strategies to reduce TB/HIV- associated mortality are urgently needed.
A5274 REMEMBER study is a multi-country randomized clinical trial comparing ART + four-drug empiric TB therapy vs. ART + isoniazid preventive therapy (IPT) in HIV-infected individuals with CD4 counts <50 cells/mm3. Participants were screened for TB prior to entry using a symptom screen, locally available diagnostics, and GeneXpert when available. Randomization was stratified by CD4 count (<25 vs. ≥25 cells/mm3) and poor prognostic factors (body mass index <18.5, hemoglobin <8 g/dl, and recent hospitalization). The primary endpoint of survival at 24 weeks post-randomization was reported elsewhere and demonstrated no effect of empiric TB treatment on mortality. To evaluate the possible effects of the intervention on longer-term outcomes, we compared the probabilities of death, death or AIDS progression, and confirmed or probable TB by week 48 between arms. Kaplan-Meier method was used to estimate the endpoint probabilities, which were compared with the z-test.
We screened 1368 individuals and enrolled 850 (62%) participants. Of 850 enrolled, 53% were male, 90% were black. The median (IQR) age was 36 (30-42) years. The median (IQR) baseline CD4 count was 18 (9, 32) cells/mm3. At week 48, there was no statistical difference in mortality between the empiric arm (7.2%; 95% CI: 5.1%, 10.1%) and the IPT arm (8.7%; 95% CI: 6.4%, 11.8%), absolute risk difference 1.6% (95% CI: -2.1%, 5.2%; p=0.41). As in the 24-week analysis, the probability of death or AIDS progression was not significantly different between arms [19.3% (95% CI: 15.8%, 23.4%) for the empiric arm vs. 15.3% (95% CI: 12.2%, 19.1%) for the IPT arm], absolute difference -4.0% (95% CI: -9.1%, 1.1%; p=0.13). At week 48, the empiric arm had more TB compared to the IPT arm (5.6% vs. 2.4%, respectively), absolute risk difference -3.2% (95% CI:-5.9%, -0.5%; p=0.02; unchanged in competing risk analysis).
In a high TB burden population of participants with advanced HIV, there was no demonstrable benefit of empiric TB therapy on mortality at 48 weeks. These data support the implementation of enhanced screening for TB prior to ART initiation and the use of IPT, even in persons with advanced HIV residing in high TB burden regions of the world.