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Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

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  • Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

    Volume 362:697-706 February 25, 2010 Number 8
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    Timing 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., Andrew 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., Jacqueline 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. (ClinicalTrials.gov number, NCT00398996 [ClinicalTrials.gov] .)

    -snip-
    A total of 642 patients with HIV and tuberculosis coinfection were enrolled: 429 in the combined integrated-therapy group and 213 in the sequential-therapy group (Figure 1). At baseline, patients in the two groups had similar demographic and clinical characteristics, including age, CD4+ cell counts, and HIV RNA levels (Table 1).

    Figure 1
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    Table 1:
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    Follow-up

    At the time of the data cutoff, on September 1, 2008, a total of 338 of the 642 patients (52.6%) were still in active follow-up, 52 (8.1%) had died during follow-up, 134 (20.9%) had completed follow-up, and 56 (8.7%) had withdrawn before study completion. Of the 62 patients (9.7%) who were regarded as lost to follow-up (9.6% in the integrated-therapy group and 9.9% in the sequential-therapy group), 35 were known to be alive, and the clinical status of the remaining 27 was unknown. (Patients were considered to be lost to follow-up if they went 4 months without a visit.) The median duration of follow-up in the trial was 12.1 months (interquartile range, 6.1 to 21.6).

    Initiation of Antiretroviral Therapy

    The median duration of tuberculosis therapy was similar among patients who completed such therapy: 210 days for 271 patients in the integrated-therapy group and 207 days for 137 patients in the sequential-therapy group. At the time of this analysis, 102 patients in the integrated-therapy group and 48 patients in the sequential-therapy group were still receiving tuberculosis therapy.

    Of the 350 patients in the integrated-therapy group who started antiretroviral therapy, 338 did so while they were receiving tuberculosis therapy. Patients in this group started antiretroviral therapy at a mean (?SD) of 70?72 days after the start of tuberculosis therapy. Of the 100 patients in the sequential-therapy group who started antiretroviral therapy, 7 did so while they were receiving tuberculosis therapy. In this group, antiretroviral therapy was initiated a mean of 260?71 days after the initiation of tuberculosis therapy. Thus, patients in the sequential-therapy group started antiretroviral therapy, on average, 190 days later than those in the integrated-therapy group.

    -snip-
    More charts/data here:
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