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Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

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  • 1 Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
  • | 2 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • | 3 Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • | 4 Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands.
  • | 5 Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
  • | 6 Centre de Récherches Medicales en Lambaréné (CERMEL), Albert Schweitzer Hospital, Lambaréné, Gabon.
  • | 7 Department of Microbiology, University of Venda, Thohoyandou, South Africa.
  • | 8 Catholic University of Mozambique, Beira, Mozambique.
  • | 9 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
  • | 10 Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands.
  • | 11 Institute of Tropical Medicine, Antwerp, Belgium.
  • | 12 Global Health Institute, University of Antwerp, Belgium.
  • | 13 KNCV Tuberculosis Foundation, The Hague, The Netherlands.

Abstract

Early mortality after initiation of antiretroviral therapy (ART) occurs in 9–39% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count < 50 cells/μL and BMI < 18 kg/m2 were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART (N = 23) (ART + TB) or ART only (N = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9–35) cells/μL and a median BMI of 17.5 (IQR: 16.6–18.0) kg/m2. The mortality was 14% (95% confidence interval [CI]: 5.3–27.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30–8.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions.

Author Notes

* Address correspondence to Yukari C. Manabe, Infectious Diseases Institute, Makerere University College of Health Sciences, P.O. Box 22418, Mulago Hospital Complex, Kampala, Uganda. E-mail: ymanabe@jhmi.edu† These authors contributed equally to this work.

Financial support: This clinical trial was funded by European Developing Countries Trials Program (EDCTP) (grant no. IP.2009.33011.007). Funding was withdrawn when EDCTP decided against trial continuation. Additional support for Yukari C. Manabe and William Worodria was provided from the National Institutes of Health Fogarty International Center (D43TW009771).

Authors' addresses: Yukari C. Manabe, Johns Hopkins University, Medicine, Baltimore, MD, E-mail: ymanabe@jhmi.edu. William Worodria, Department of Medicine, Mulago Hospital, Kampala, Uganda, E-mail: worodria@yahoo.com. Frank van Leth, Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, E-mail: f.vanleth@aighd.org. Harriet Mayanja-Kizza, Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda, E-mail: hmk@chs.mak.ac.ug. Afsatou Ndama Traore, Department of Microbiology, University of Venda, Thohoyandou, South Africa, E-mail: afsatou.traore@univen.ac.za. Josefo Ferro, Department of Medicine, Catholic University of Mozambique, Beira, Mozambique, E-mail: josefoferro@yahoo.com.br. Nadine Pakker, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands, E-mail: n.pakker@aighd.org. Matthias Frank, Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany, E-mail: matthias.frank@uni-tuebingen.de. Martin P. Grobusch, Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, University of Amsterdam, Amsterdam, The Netherlands, E-mail: m.p.grobusch@amc.uva.nl. Robert Colebunders, Clinical Sciences, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium, E-mail: bcoleb@itg.be. Frank Cobelens, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands, and Department of Global Health, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, E-mail: f.cobelens@aighd.org.

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