Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

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New England Journal of Medicine Volume 362:697-706February 25, 2010Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

Salim S. Abdool Karim, M.B., Ch.B., Ph.D., Kogieleum Naidoo, M.B.,

Ch.B., Anneke Grobler, M.Sc., Nesri Padayatchi, M.B., Ch.B., Cheryl

Baxter, M.Sc., Gray, M.Sc. (Pharm.), Tanuja Gengiah,

M.Clin.Pharm., M.S. (Epi.), Gonasagrie Nair, M.B., Ch.B., Sheila

Bamber, M.B., Ch.B., Aarthi Singh, M.B., Ch.B., Munira Khan, M.B.,

Ch.B., Pienaar, M.Sc., Wafaa El-Sadr, M.D., M.P.H., Gerald

Friedland, M.D., and Quarraisha Abdool Karim, Ph.D. ABSTRACT Background The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial.

Methods In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim–sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause.

Results This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P=0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups.

Conclusions The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services.