Olalekan A. Uthman, MBBS, MPH, PhD; Charles Okwundu, MBBS, MPH; Kayode Gbenga, MBBS, MPH; Jimmy Volmink, MBChB, MPH, PhD; David Dowdy, MD, PhD; Alimuddin Zumla, BSc, MBChB, MSc, PhD; Jean B. Nachega, MD, MPH, PhD, DTM&H
Note: The results of this review were accepted for presentation at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Vancouver, Canada, 18–22 July 2015. Abstract MOPEB165.
Acknowledgment: The authors thank John L. Johnson, MD (Professor of Medicine at Case Western Reserve University), for critical review of the manuscript.
Grant Support: Dr. Uthman acknowledges support from the Swedish Council for Working Life and Social Research Marie Curie International Postdoctoral fellowship (2012-0064). Dr. Nachega receives research grant support from the National Institute for Allergy and Infectious Disease of the National Institutes of Health, the AIDS Clinical Trial Group, and Stellenbosch University Clinical Trial Unit (2UM1AI069521-08); the Medical Education Partnership Initiative through the U.S. President Emergency Plan for AIDS Relief (T84HA21652-01-00); the European Developing Countries Clinical Trial Partnership Senior Fellowship Award (TA-08-40200-021); and the Wellcome Trust Southern Africa Consortium for Research Excellence (WT087537MA). Dr. Zumla receives support from the European Commission Seventh Framework Programme (Rapid Identification of Respiratory Tract Infections Project) and the National Institutes of Health Research Biomedical Research Centre. Dr. Volmink receives support from Stellenbosch University and the South African Medical Research Council.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2979.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Olalekan A. Uthman, MBBS, MPH, PhD, Warwick Centre for Applied Health Research and Delivery, Division of Health Sciences, Warwick Medical School, Medical Teaching Centre, Warwick University, Coventry CV4 7AL, United Kingdom; e-mail, email@example.com.
Current Author Addresses: Dr. Uthman: Warwick Centre for Applied Health Research and Delivery, Division of Health Sciences, Warwick Medical School, Medical Teaching Centre, Coventry CV4 7AL, United Kingdom.
Mr. Okwundu and Dr. Volmink: Centre for Evidence-Based Health Care, Stellenbosch University, Tygerberg 7505, South Africa.
Mr. Gbenga: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht 3584 CG, The Netherlands.
Dr. Dowdy: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Baltimore, MD 21205.
Dr. Zumla: Division of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, University College London Hospital, London WC1E 6BT, United Kingdom.
Dr. Nachega: Pittsburgh Graduate School of Public Health, Department of Epidemiology. 130, DeSoto Street, Parran Hall 503, Pittsburgh, PA 15261.
Authors Contributions: Conception and design: O.A. Uthman, A. Zumla, J.B. Nachega.
Analysis and interpretation of the data: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.
Drafting of the article: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, A. Zumla, J.B. Nachega.
Critical revision of the article for important intellectual content: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.
Final approval of the article: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.
Provision of study materials or patients: O.A. Uthman.
Statistical expertise: O.A. Uthman.
Administrative, technical, or logistic support: O.A. Uthman, J.B. Nachega.
Collection and assembly of data: O.A. Uthman, C. Okwundu, K. Gbenga, A. Zumla.
Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment remains challenging.
To assess evidence from randomized, controlled trials of the timing of ART initiation in HIV-infected adults with newly diagnosed pulmonary TB.
PubMed, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts, and ClinicalTrials.gov (from January 1980 to May 2015).
Randomized, controlled trials evaluating early versus delayed ART initiation (1 to 4 weeks vs. 8 to 12 weeks after initiation of TB treatment) or deferred ART initiation (after the end of TB treatment).
Three reviewers independently extracted data and assessed risk of bias. The main outcome measures were all-cause mortality and the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS).
The 8 included trials (n = 4568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I2 = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4+ T-cell counts less than 0.050 × 109 cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I2 = 0%). However, a mortality benefit from early ART was not found among those with CD4+ T-cell counts greater than 0.050 × 109 cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I2 = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I2 = 19%).
Few trials provided sufficient data for subgroup analysis.
Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4+ T-cell counts less than 0.050 × 109 cells/L, although this is associated with a 2-fold higher frequency of TB-IRIS. In patients with CD4+ T-cell counts greater than 0.050 × 109 cells/L, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation.
None. (PROSPERO registration: CRD42012001884)
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Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163:32-39. doi: 10.7326/M14-2979
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Published: Ann Intern Med. 2015;163(1):32-39.
HIV, Infectious Disease, Mycobacterial Infections, Pulmonary Tuberculosis, Pulmonary/Critical Care.
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