Abstract:
Background—Mortality within the first 6 months after initiating antiretroviral therapy (ART)
is common in resource-limited settings and is often due to tuberculosis (TB) among patients with
advanced HIV disease. Isoniazid preventive therapy (IPT) is recommended in HIV-infected adults,
but sub-clinical TB can be difficult to diagnose. We hypothesized that empiric TB treatment would
reduce early mortality compared to IPT in high-burden settings.
Methods—We conducted a multi-country randomized clinical trial comparing empiric TB
therapy (Empiric) vs. isoniazid preventive therapy (IPT) in HIV-infected outpatients initiating
ART with CD4 counts <50 cells/mm 3 . Individuals were screened for TB using a symptom screen,
locally available diagnostics, and the GeneXpert MTB/RIF assay when available. The primary
endpoint was survival (death or unknown status) at 24 weeks post randomization. Kaplan Meier
estimates of the endpoint rates across arms were compared by the z-test. Registered at
ClinicalTrials.gov (NCT01380080).
Findings—From October 31, 2011 until June 9, 2014, we randomized 850 participants (424 in
Empiric arm and 426 in IPT arm); the median CD4 count at baseline was 18 cells/mm 3 (IQR: 9,
32). At week 24, each arm had 22 primary endpoints, for rates of 5.2% in each arm (95% CI: 3.5%
to 7.8% for Empiric and 3.4% to 7.8% for IPT; absolute risk difference of -0.06% (95% CI:
−3.05% to 2.94%). Grade 3 or 4 signs or symptoms occurred in 50 (12%) in the Empiric arm and
46 (11%) in the IPT arm. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) in the
Empiric arm and 97 (23%) in the IPT arm. Incident TB was more common in the Empiric arm (31
vs. 18 events, p=0.01).Interpretation—Empiric TB therapy did not reduce mortality at 24 weeks in outpatient adults
initiating ART with advanced HIV disease. The low mortality rate of the trial supports
implementation of systematic TB screening and IPT in outpatients with advanced HIV disease.
