TB is a major cause of morbidity and mortality in low- and middle-income countries despite the use of antiretroviral therapy (ART). The A5274/REMEMBER trial team previously reported that a strategy of Empiric 4-drug TB therapy +ART provided no additional benefit in reducing mortality within 24 weeks after ART initiation compared to INH preventive therapy (IPT)+ART. We now present the 96 weeks results.
In this multi-country randomized clinical trial, HIV-infected individuals with CD4<50 cells/mm3 were screened using a TB symptom screen, locally available diagnostics, and GeneXpert when available. Randomization was stratified by CD4 (<25 vs. ≥25 cells/mm3) and poor prognostic factors (BMI<18.5, HGB<8 g/dL, and recent hospitalization). To evaluate the effects of the intervention on longer-term outcomes, Kaplan-Meier estimates of the probabilities of death and confirmed/probable TB by week 96 were compared using a Z-test. In addition, Cox proportional hazards models were used to evaluate the association between TB medication adherence through week 24 (assessed via ACTG adherence questionnaire) and death or TB by week 96.TB adherence was defined as the number of visits with 100% adherence divided by the number of visits with available adherence assessments over all visit weeks up to week 24.
Of 850 enrolled, 53% were male, 90% black, median age 36 years, and median baseline CD4 18 cells/mm3. At week 96, there was no statistical difference in mortality between the Empiric and IPT arms (10.1% vs. 10.5%, respectively); absolute risk difference 0.4% (95% CI: -3.8%, 4.6%; p=0.86). At week 96, the Empiric arm had more TB compared to the IPT arm (6.1% vs. 2.7%, respectively); absolute risk difference -3.4% (95% CI:-6.2%, -0.6%; p=0.02; unchanged in competing risk analysis). The hazard of death was 23% and 20% lower per 10% increase in the proportion of 100% adherence in the Empiric and IPT arms, respectively (p<0.01). Adherence had no effect on TB in the Empiric arm (p=0.44). However, hazard of TB was 17% lower per 10% increase in the proportion of 100% IPT adherence (p=0.03).
In this population of participants with advanced HIV, adherence to both empiric TB therapy and IPT was associated with improved survival. Adherence to IPT was associated with reduced risk of developing TB, but adherence to empiric TB therapy was not. Supporting IPT+ART initiation and adherence are critical to preventing the high TB incidence and mortality observed in those with advanced HIV.