PMID- 36041016 OWN - NLM STAT- MEDLINE DCOM- 20230210 LR - 20240427 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 76 IP - 3 DP - 2023 Feb 8 TI - Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349). PG - e580-e589 LID - 10.1093/cid/ciac707 [doi] AB - BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts >/=100 cells/muL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and >/= grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/muL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts >/=100 cells/muL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Pettit, April C AU - Pettit AC AUID- ORCID: 0000-0001-8832-0866 AD - Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. FAU - Phillips, Patrick P J AU - Phillips PPJ AD - UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA. FAU - Kurbatova, Ekaterina AU - Kurbatova E AD - Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Vernon, Andrew AU - Vernon A AD - Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Nahid, Payam AU - Nahid P AD - UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA. FAU - Dawson, Rodney AU - Dawson R AD - Center for TB Research Innovation, University of Cape Town Lung Institute, Cape Town, South Africa. FAU - Dooley, Kelly E AU - Dooley KE AD - Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Sanne, Ian AU - Sanne I AD - Clinical HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa. FAU - Waja, Ziyaad AU - Waja Z AD - Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa. FAU - Mohapi, Lerato AU - Mohapi L AD - Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa. FAU - Podany, Anthony T AU - Podany AT AD - Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, USA. FAU - Samaneka, Wadzanai AU - Samaneka W AD - Department of Medicine, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. FAU - Savic, Rada M AU - Savic RM AD - UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA. FAU - Johnson, John L AU - Johnson JL AD - Tuberculosis Research Unit, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. AD - Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda. FAU - Muzanyi, Grace AU - Muzanyi G AD - Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda. FAU - Lalloo, Umesh G AU - Lalloo UG AD - Enhancing Care Foundation, Durban University of Technology, Durban, South Africa. FAU - Bryant, Kia AU - Bryant K AD - Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Sizemore, Erin AU - Sizemore E AD - Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Scott, Nigel AU - Scott N AD - Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. FAU - Dorman, Susan E AU - Dorman SE AD - Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Chaisson, Richard E AU - Chaisson RE AD - Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Swindells, Susan AU - Swindells S AD - Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. CN - Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) A5349 study team LA - eng SI - ClinicalTrials.gov/NCT02410772 GR - UM1 AI069423/AI/NIAID NIH HHS/United States GR - UM1 AI069432/AI/NIAID NIH HHS/United States GR - UM1 AI068634/AI/NIAID NIH HHS/United States GR - U01 AI069432/AI/NIAID NIH HHS/United States GR - U01 AI068636/AI/NIAID NIH HHS/United States GR - UM1 AI069453/AI/NIAID NIH HHS/United States GR - UM1 AI069463/AI/NIAID NIH HHS/United States GR - P30 AI110527/AI/NIAID NIH HHS/United States GR - UM1 AI106701/AI/NIAID NIH HHS/United States GR - UM1 AI069436/AI/NIAID NIH HHS/United States GR - U01 AI069436/AI/NIAID NIH HHS/United States GR - UM1 AI068636/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - XJM390A33U (rifapentine) RN - VJT6J7R4TR (Rifampin) RN - JE6H2O27P8 (efavirenz) RN - U188XYD42P (Moxifloxacin) RN - 0 (Antitubercular Agents) RN - V83O1VOZ8L (Isoniazid) SB - IM MH - Humans MH - Rifampin/adverse effects MH - Moxifloxacin/adverse effects MH - Antitubercular Agents/adverse effects MH - HIV MH - Isoniazid/therapeutic use MH - Drug Therapy, Combination MH - *Tuberculosis, Pulmonary/complications/drug therapy/microbiology MH - *Tuberculosis/drug therapy MH - *HIV Infections/complications/drug therapy PMC - PMC10169427 OTO - NOTNLM OT - human immunodeficiency virus OT - moxifloxacin OT - phase 3 clinical trial OT - rifapentine OT - tuberculosis COIS- Potential conflicts of interest. The authorship team members have declared any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi's commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. A. V. reports unpaid participation on 2 advisory boards for a TB trial of high-dose rifampin (InterTB; St George's Hospital, London), and for a trial of shortened treatment for latent TB (McGill University, Montreal) and other financial or nonfinancial interests as part of this trial, Sanofi (Paris, France, and Bridgewater, NJ, USA) donated rifapentine and all other study drugs, supported shipping of study drugs to all sites, and provided funding support for pharmacokinetic testing. From 2007 until 2016, Sanofi donated a total of $2.9 million to the CDC Foundation to supplement CDC funding for rifapentine research; these funds supported prior TBTC studies of rifapentine but were not part of the support for this trial. This information was included in the main study publication (New England Journal of Medicine, 2021). L. M. reports grants or contracts from Merck Sharpe & Dohme Corp (institution received clinical trial fees), Viiv Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), Sanofi-Aventis (pharmaceutical support on protocol), and Adagio Therapeutics, Inc (institution received clinical trial fees). R. M. S. reports grants or contracts from TB Alliance: Drug regimen optimization for new and existing TB drugs, NIH/NIAID: Novel Biomarkers to Shorten TB Treatment, BMGF: TB Drug Lesion Penetration and Translational Modeling, NIH/NIAID/Rutgers: Impact of Pregnancy on Tuberculosis, BMGF/C-Path: In silico assessment of Adaptive Trial Designs, BMGF/DRI: Accelerating evaluation and development of new combination TB drug treatments, UNITAID/SU: Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids), NIH/NIAID: Identifying Optimal Treatment Strategies for Tuberculosis, NIH/NIAID/SU: Optimizing and operationalizing pediatric drug-resistant tuberculosis treatment, and BMGF/C-Path: Model-based meta-analysis of endpoints analyzed in Phase III Quinolones clinical trials; including leadership or fiduciary role in other board, society, committee or advocacy group for Leadership and Operations Center (LOC), AIDS Clinical Trials Group (ACTG), WHO working group: Reaching UNGA HLM on TB targets for ending TB in children and adolescents, and Working Group on New TB Drugs (WGND), Core Member. S. S. reports Research contracts with ViiV Healthcare (paid to institution) and participates for NIH DMSB (unpaid participation). R. E. C. reports contract to institution from Unitaid, grant to institution from National Institutes of Health and Novartis, consultant from Johnson & Johnson and spouse is stockholder for Merck. S. E. D. reports support for attending meetings and/or travel from US CDC contract (provided reimbursement of travel expenses to attend the twice-yearly scientific meetings of the CDC TB Trials Consortium.). I. M. S. is the Vice-Chair for ACTG International. P. N. reports a contract from the CDC TB Trials Consortium. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. EDAT- 2022/08/31 06:00 MHDA- 2023/02/11 06:00 PMCR- 2023/08/30 CRDT- 2022/08/30 14:05 PHST- 2022/04/20 00:00 [received] PHST- 2022/08/31 06:00 [pubmed] PHST- 2023/02/11 06:00 [medline] PHST- 2022/08/30 14:05 [entrez] PHST- 2023/08/30 00:00 [pmc-release] AID - 6679254 [pii] AID - ciac707 [pii] AID - 10.1093/cid/ciac707 [doi] PST - ppublish SO - Clin Infect Dis. 2023 Feb 8;76(3):e580-e589. doi: 10.1093/cid/ciac707.