Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: study protocol for a multicenter, open-label randomized controlled clinical trial

• Published in: Current controlled trials in cardiovascular medicine 2022-06, Vol.23 (1), p.531-531, Article 531
• Main Authors: Rojo, Pablo, Moraleda, Cinta, Tagarro, Alfredo, Domínguez-Rodríguez, Sara, Castillo, Lola Madrid, Tato, Luis Manuel Prieto, López, Aranzazu Sancho, Manukyan, Lilit, Marcy, Olivier, Leroy, Valeriane, Nardone, Alessandra, Burger, David, Bassat, Quique, Bates, Matthew, Moh, Raoul, Iroh Tam, Pui-Ying, Mvalo, Tisungane, Magallhaes, Justina, Buck, W Chris, Sacarlal, Jahit, Musiime, Victor, Chabala, Chishala, Mujuru, Hilda Angela
• Format: Article
• Language: English
• Subjects: Antiviral drugs; Bacterial pneumonia; Care and treatment; Child; Clinical Trials, Phase II as Topic; Complications and side effects; Cytomegalovirus; Cytomegalovirus infections; Cytomegalovirus Infections - diagnosis; Cytomegalovirus Infections - drug therapy; Demographic aspects; Empirical; Factorial; Fatalities; HIV infection; HIV Infections - complications; HIV Infections - diagnosis; HIV Infections - drug therapy; Human health and pathology; Humans; Infant; Infectious diseases; Life Sciences; Mortality; Multicenter Studies as Topic; Pediatrics; Pharmaceutical sciences; Pharmacology; Pneumonia; Pneumonia - complications; Pulmonology and respiratory tract; Randomized Controlled Trials as Topic; Risk factors; Santé publique et épidémiologie; Study Protocol; Treatment Outcome; Tuberculosis; Tuberculosis - diagnosis; Tuberculosis - drug therapy; Valganciclovir; Valganciclovir - therapeutic use
• ISSN: 1745-6215; 1745-6215
• DOI: 10.1186/s13063-022-06203-1

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. 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. 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. ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.