In areas of sub-Saharan Africa and Asia, most HIV-infected patients present for care after already being severely immuno-compromised. After the initiation of antiretroviral therapy (ART), the mortality within this patient population remains high with tuberculosis being a common cause of death.
Even with the availability of tests to correctly diagnose tuberculosis, many physicians initiate systemic treatment of rifampin without using these tests. As such, this study compared the benefits and risks between test-guided treatment and systemic treatment for tuberculosis in severely immuno-suppressed HIV-infected patients. The participants were randomized to receive systemic treatment or undergo screening to determine the treatment regimen.
The study by the researchers in the STATIS ANRS 12290 Trial team determined the patients in the systemic treatment group did not have a decreased rate of death or invasive bacterial disease compared to the patients in test-guided treatment group. Furthermore, the patients in the systemic treatment group experienced more severe adverse drug-related adverse events compared to the test-guided treatment group.
This randomised trial was limited by the inability to directly compare the results with current practices. The trial was designed around newer diagnostic testing, which were not readily used by physicians. Therefore, the study did not represent the actual number of physicians who opted into using the diagnostic testing prior to prescribing the tuberculosis regimen.
Further, patients assigned in the test-guided treatment group were not provided with isoniazid therapy. Though the study provided the rationale of not wanting to treat tuberculosis with isoniazid alone, the systemic treatment group received isoniazid as a part of their treatment, which created irregularities in the treatment comparison between both groups. Nonetheless, this study was strengthened by the long-term patient follow-up and matched patient characteristics between both groups.
Background: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death.
Methods: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were 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 primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization.
Results: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death 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, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment.
Conclusions: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events.
François-Xavier Blanc, Anani D Badje, Maryline Bonnet, Delphine Gabillard, Eugène Messou, Conrad Muzoora, Sovannarith Samreth, Bang D Nguyen, Laurence Borand, Anaïs Domergue, Delphine Rapoud, Naome Natukunda, Sopheak Thai, Sylvain Juchet, Serge P Eholié, Stephen D Lawn, Serge K Domoua, Xavier Anglaret, Didier Laureillard
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