Empiric systemic tuberculosis treatment not superior to test-guided treatment for HIV patients

1. Empiric systemic treatment for tuberculosis was shown not to be better than test-guided treatment among severely immunosuppressed adults with human immunodeficiency virus (HIV) infection.

2. Systemic treatment for tuberculosis was associated with more grade 3 and 4 drug-related adverse events compared to test-guided treatment.

Evidence Rating Level: 1 (Excellent)

Study Rundown: In areas of sub-Saharan Africa and Asia, most HIV-infected patients present for care after already being severely immunocompromised. 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 immunosuppressed HIV-infected patients. The participants were randomized to receive systemic treatment or undergo screening to determine the treatment regimen. The study 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 randomized 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.

Click to read the study, published today in NEJM

Relevant Reading: The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

In-Depth [randomized controlled trial]: This randomized control trial enrolled 1050 patients in a multicenter study from 6 sites in four countries. Inclusion criteria included HIV-infected adults who were 18 years of age or older with no evidence of tuberculosis and CD4+ T-cell count less than 100 cells per cubic millimeter. The exclusion criteria for the study included prior or ongoing use of ART, CD4+ T-cell count greater than 100 cells per cubic millimeter and known or suspected tuberculosis. The patients were randomized to the systemic treatment or test-guided treatment group in a 1:1 ratio. Systemic treatment consisted of rifampin, isoniazid, ethambutol, and pyrazinamide. The diagnostic testing for the test-guided treatment group consisted of urinary lipoarabinomannan (LAM) an Xpert MTB/RIF, which was a rapid nucleic acid amplification test to detect Mycobacterium tuberculosis and rifampin resistance.  The primary outcome was a composite of death from any cause or invasive bacterial disease within 24 and 48 weeks. Invasive bacterial disease was defined as bacteremia or clinical, biologic, or radiographic findings compatible with a bacterial infection. The composite value was calculated as the number of first events per 100,000 patient-years. Additionally, adverse drug-related outcomes within both treatment groups were recorded. At week 24, the rate of death from any cause or invasive bacterial disease was 19.4 in the systemic treatment group and 20.3 in the test-guided treatment group (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). The most common causes of death were tuberculosis, invasive bacterial disease, and AIDS-defining illnesses. The cumulative probability of an incident or prevalent tuberculosis diagnosis was 3.0% in the systemic treatment group and 17.9% in the test-guided treatment group (adjusted hazard ration, 0.15; 95% CI, 0.09 to 0.26) at week 24. At week 48, the rate of death from any cause or invasive bacterial disease was 12.8 in the systemic treatment group and 13.3 in the test-guided treatment group (adjusted hazard ratio, 0.97; 95% CI, 0.67 to 1.40). Additionally, the cumulative probability of an incident or prevalent tuberculosis diagnosis was 3.6% in the systemic treatment group and 19.2% in the test-guided treatment group (adjusted hazard ration, 0.17; 95% CI, 0.10 to 0.28). Overall, tuberculosis occurred in 18 patients in the systemic treatment group and 99 patients in the test-guided treatment group. The most common grade 3 or 4 drug-related adverse events were noninfectious transaminitis and pruritis. At week 24, the cumulative probability of a grade 3 or 4 adverse drug-related event was 17.4% in the systemic treatment group and 7.2% in the test-guided treatment (adjusted hazard ratio, 2.57; 95% CI, 1.75 to 3.78). Taken together, systemic treatment caused more grade 3 and 4 adverse drug-related events and was not a better treatment for tuberculosis in severely immunocompromised HIV patients when compared to test-guided treatment.

Image: PD

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