Sayoki G Mfinanga1, Bruce J Kirenga2, Duncan M Chanda3, Beatrice Mutayoba1, Thuli Mthiyane4, Getnet Yimer5, Oliver Ezechi6, Cathy Connolly4, Vincent Kapotwe7, Catherine Muwonge8, Julius Massaga1, Edford Sinkala7, Wanze Kohi1, Lucinda Lyantumba7, Grace Nyakoojo9, Henry Luwaga9, Basra Doulla10, Judith Mzyece7, Nathan Kapata11, Mahnaz Vahedi12, Peter Mwaba13, Saidi Egwaga14, Francis Adatu9, Alex Pym4, Moses Joloba15, Roxana Rustomjee4, Alimuddin Zumla16, Philip Onyebujoh17. 1. National Institute for Medical Research, Muhumbili, Tanzania. 2. Department of Medicine, Makerere University College of Health Sciences, Mulago Hospital, Kampala, Uganda. 3. Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia. Electronic address: duncanchanda@gmail.com. 4. Clinical Trials Unit, Medical Research Council, Durban, South Africa. 5. Addis Ababa University, Addis Ababa, Ethiopia. 6. Division of Clinical Sciences, Nigerian Institute of Medical Research, Lagos, Nigeria. 7. Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia. 8. WHO/TDR TB-HAART Project, Kampala, Uganda. 9. National TB/Leprosy Programme, Ministry of Health, Kampala, Uganda. 10. National TB Reference Laboratory, Muhimbili National Hospital, Dar-es-Salaam, Tanzania. 11. National TB/Leprosy Program, Ministry of Health, Lusaka, Zambia. 12. Special Programme for Research and Training in Tropical Diseases, WHO, Geneva, Switzerland. 13. Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Ministry of Health, Lusaka, Zambia. 14. National TB/Leprosy Programme, Ministry of Health and Social Welfare, Dar-es-Salaam, Tanzania. 15. Supra-National TB Laboratory, Ministry of Health, Lusaka, Zambia. 16. Institute for Medical Research & Training and UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Center for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK; NIHR Biomedical Research Centre, University College Hospitals, London, UK. 17. Inter-country Support Team for East and Southern Africa, WHO Regional Office for Africa, Harare, Zimbabwe.
Abstract
BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per μL vs ≥350 cells per μL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per μL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per μL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per μL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.
BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per μL vs ≥350 cells per μL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per μL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per μL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per μL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.
Authors: Huldrych F Günthard; Michael S Saag; Constance A Benson; Carlos del Rio; Joseph J Eron; Joel E Gallant; Jennifer F Hoy; Michael J Mugavero; Paul E Sax; Melanie A Thompson; Rajesh T Gandhi; Raphael J Landovitz; Davey M Smith; Donna M Jacobsen; Paul A Volberding Journal: JAMA Date: 2016-07-12 Impact factor: 56.272
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