Mortality within the first 6 months after initiating ART is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy (IPT) is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. The aim was to assess whether empirical tuberculosis treatment (ETT) would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.
A multicountry open-label randomised clinical trial compared ETT with IPT in HIV-positive outpatients initiating ART with CD4 cell counts < 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests ≤ 2-5 times the upper limit of normal, a creatinine clearance > 30 mL/min, and a Karnofsky score > 30. Participants were randomly assigned (1:1) to either ART and ETT or ART and IPT. The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of ART and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.
Between Oct 31, 2011, and June 9, 2014, were enrolled 850 participants: 424 were randomised to receive ETT and 426 to the IPT group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9–32). At week 24, 22 (5.2%) participants from each group died or were of unknown status (95% CI 3·5–7·8 for ETT group and 3·4–7·8 for IPT ; absolute risk difference of –0·06% (95% CI –3·05 to 2·94). All primary endpoints were deaths except for 2 unknown vital status events in the ETT. The time to the primary event did not differ between groups. Causes of death included HIV-associated infections (17 in ETT group, 11 in IPT group), non-HIV diagnoses (5 in IPT group), renal toxicity attributed to tenofovir (1 in IPT group), unknown in 6 cases (2 in ETT group, 4 in IPT group), and motor vehicle accident (1 in IPT group). The most common HIV-associated causes of death were cryptococcal meningitis (n=4), Kaposi's sarcoma (n=3), and extrapulmonary tuberculosis (n=3). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the ETT group and 46 (11%) participants in the IPT group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the ETT group and 97 (23%) participants in the IPT group. By week 24, the ETT group had a higher rate of death or AIDS progression than the IPT group (72 [17%] vs 53 [13%]; p=0·06) and the time to death or AIDS progression was more rapid in the ETT group. This result was mainly due to an increased incidence of tuberculosis (31 participants in the ETT group and 18 participants in the IPT group; p=0·01), including both pulmonary and extrapulmonary disease. The time to confirmed or probable tuberculosis in the ETT group was also more rapid. The ETT group also had more premature discontinuations of tuberculosis drugs by week 24 (47 vs 18). A viral load < 400 copies per mL was achieved by 84% of participants in the ETT group and 85% participants in the IPT group. The median CD4 change at 24 weeks was 96 (IQR 55–147) in the ETT group and 102 (60–159) in the IPT group (p=0·25 by Wilcoxon test). Tuberculosis-immune reconstitution inflammatory syndrome cases were reported in 19 (2%) participants (9 in the ETT group and 10 in the IPT group).
In conclusion, empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating ART. In patients with advanced HIV disease in settings where tuberculosis incidence is high, the low mortality rate of the trial supports urgent implementation of systematic tuberculosis screening and isoniazid preventive therapy before ART initiation.
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