Pablo Rojo1,2, Cinta Moraleda1,2, Alfredo Tagarro3,4,5, Sara Domínguez-Rodríguez2, Lola Madrid Castillo2,6, Luis Manuel Prieto Tato1,2, Aranzazu Sancho López7, Lilit Manukyan2, Olivier Marcy8, Valeriane Leroy9, Alessandra Nardone10, David Burger11, Quique Bassat12,13,14,15,16,17, Matthew Bates17, Raoul Moh18, Pui-Ying Iroh Tam19,20, Tisungane Mvalo21, Justina Magallhaes15, W Chris Buck22,23, Jahit Sacarlal24, Victor Musiime25,26, Chishala Chabala27, Hilda Angela Mujuru28. 1. Servicio de Pediatria. Hospital Universitario 12 de Octubre, Servicio Madrileño de Salud (SERMAS), Madrid, Spain. 2. Unidad Pediátrica de Investigación y Ensayos Clínicos (UPIC). Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Fundación Biomedica del Hospital Universitario 12 de Octubre (FIB-H12O), Madrid, Spain. 3. Unidad Pediátrica de Investigación y Ensayos Clínicos (UPIC). Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Fundación Biomedica del Hospital Universitario 12 de Octubre (FIB-H12O), Madrid, Spain. alfredo.tagarro@salud.madrid.org. 4. Servicio de Pediatria. Hospital Universitario Infanta Sofia, Servicio Madrileño de Salud (SERMAS), Madrid, Spain. alfredo.tagarro@salud.madrid.org. 5. Facultad de Ciencias Biomédicas, Universidad Europea de Madrid., Madrid, Spain. alfredo.tagarro@salud.madrid.org. 6. London School of Hygiene & Tropical Medicine (LMC), London, UK. 7. Pharmacology Unit, Hospital Puerta de Hierro, Servicio, Madrileño de Salud (SERMAS), Madrid, Spain. 8. Université de Bordeaux, Inserm U1219, IRD EMR271, Bordeaux Population Health, GHiGS, Bordeaux, France. 9. Institut National de la Santé et de la Recherche Médicale (Inserm), University Toulouse 3,CERPOP, Toulouse, France. 10. Penta-Onlus Foundation (PENTA), Padua, Italy. 11. Stichting Katholieke Universiteit- Radboudumc (RUMC), Nijmegen, The Netherlands. 12. ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain, Barcelona, Spain. 13. Pediatrics Department, Hospital Sant Joan de Déu, I, Universitat de Barcelona, Barcelona, Spain. 14. ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain. 15. Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique. 16. Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. 17. University of Lincoln, Lincoln, United Kingdom. 18. Unité Pédagogique de Dermatologie et Infectiologie, UFR Sciences Médicales, Programme PAC-CI, Ivory Coast, Abidjan, Côte d'Ivoire. 19. Kamuzu University Health Sciences, Blantyre, Malawi. 20. Malawi-Liverpool Wellcome Programme (MLW), Liverpool School of Tropical Medicine (LSTM), Blantyre, Malawi. 21. Lilongwe Medical Relief Trust (LMRFT), UNC Project Malawi, Lilongwe, Malawi. 22. University of California Los Angeles David Geffen School of Medicine, Los Angeles, USA. 23. Universidade Eduardo Mondlane (UEM), Maputo, Mozambique. 24. Department of Microbiology, Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique. 25. Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda. 26. Joint Clinical Research Centre, Kampala, Uganda. 27. School of Medicine, University of Zambia, Lusaka, Zambia. 28. University of Zimbabwe, Harare, Zimbabwe.
Abstract
BACKGROUND: Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia. METHODS: This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM. DISCUSSION: Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.
BACKGROUND: Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia. METHODS: This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM. DISCUSSION: Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.
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