For severely immunosuppressed adults with HIV infection who had not previously undergone treatment with antiretroviral therapy (ART), systematic treatment for tuberculosis was not found to be superior to test-guided treatment in terms of reducing the rate of death or invasive bacterial disease over 24 or 48 weeks; according to the results of a study published in The New England Journal of Medicine. Furthermore, systematic treatment for tuberculosis was associated with more grade 3 or 4 adverse events.
In regions with overlapping, high burdens of tuberculosis and HIV, many HIV-infected adults begin ART when already severely immunocompromised. Following ART initiation, mortality is high among these patients, with tuberculosis and invasive bacterial disease contributing to these outcomes. To investigate this, a 48-week trial of empirical treatment for tuberculosis compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts <100 cells/mm3 was conducted (ClinicalTrials.gov Identifier: NCT02057796).
Patients from Ivory Coast, Uganda, Cambodia, and Vietnam were enrolled: 522 patients in the systematic group and 525 in the guided-treatment group. Patients were initially randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months.
The rate of deaths at week 24 from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio [HR] 0.95; 95% CI 0.63-1.44); corresponding rates at week 48 were 12.8 and 13.3 (adjusted HR 0.97; 95% CI 0.67-1.40). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs 17.9%; adjusted HR 0.15; 95% CI 0.09-0.26). However, the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs 7.2%; adjusted HR 2.57; 95% CI 1.75-3.78) and serious adverse events were more common.
The investigators noted several study limitations including the fact that neither of the assigned strategies can be directly compared with those used in current practice. When the trial was designed, most clinicians used only sputum smear for tuberculosis screening prior to ART, but the investigators “anticipated that the development of the Xpert MTB/RIF and urinary LAM tests would lead to their use in future care.” Also, at the time of randomization, isoniazid preventive therapy was deliberately not given to the patients who were assigned to the guided-treatment group, despite the fact that it was known to decrease the rate of and mortality from tuberculosis among HIV-infected adults in areas with a high burden of tuberculosis. This was done to avoid the potential risk of treating undiagnosed tuberculosis with isoniazid alone and was deemed acceptable because patients were screened for tuberculosis at each trial visit. In addition, despite systematic review, cause of death was undocumented for 21 patients.
The investigators conclude that “systematic empirical treatment for tuberculosis and treatment guided by specific testing had similar effects on the rate of death or invasive bacterial disease in a population of HIV-infected adults with CD4+ T-cell counts below 100 cells per cubic millimeter.”
Blanc FX, Badje AD, Bonnet M, et al; for the STATIS ANRS 12290 Trial Team. Systematic or test-guided treatment for tuberculosis in HIV-infected adults. N Engl J Med. 2020;382(25):2397-2410.