This trial will evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia.
Pneumonia is the main cause of death in Human Immunodeficiency Virus (HIV)-infected children. A significant number of undiagnosed or poorly treated HIV-infected children present to health services with severe pneumonia. World Health Organization (WHO) guidelines to treat severe pneumonia in HIV-infected infants include empirical treatment against common bacteria plus Pneumocystis jirovecii. Although this approach has contributed to reducing overall case fatality rates, mortality in this particularly vulnerable group remains unacceptably high. Autopsy studies in Africa have shown that cytomegalovirus (CMV) infection and tuberculosis (TB) are important underdiagnosed and undertreated causes of deaths. Our objective is to evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia. A randomized factorial clinical trial will be conducted in six sub-Saharan African countries to evaluate the safety and efficacy of empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants aged 28 days to 365 days admitted to hospital with severe pneumonia. The primary outcome is mortality. All HIV-infected infants will receive standard of care (SoC) pneumonia treatment, including antibiotics, cotrimoxazole, and prednisolone. A group of patients will receive SoC, another group will receive valganciclovir plus SoC, another group will receive tuberculosis treatment plus SoC, and another group will receive valganciclovir, tuberculosis treatment, and SoC.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
563
Treatment for CMV
Treatment for tuberculosis
Programme PACCI. Centre Hospitalier Cocody.
Abidjan, Côte d’Ivoire
Université de Bourdeaux
Bourdeaux, France
INSERM
Toulouse, France
Mortality
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. Mortality will be calculated using all-cause mortality after the admission over all the trial time.
Time frame: 1 year
Days with oxygen therapy
1\. Duration of oxygen requirements (in days, from the first requirement until definitive withdrawal, being day 1 the first day of oxygen requirement).
Time frame: 60 days
Days of hospitalization
2\. Cumulative days of hospitalization from discharge to day +365 after enrollment
Time frame: 1 year
Serious Adverse Events
Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs.
Time frame: 1 year
Adverse Reactions
Adverse Reactions (AR)
Time frame: 1 year
Notable Adverse Events
Adverse events (AEs) requiring stop of investigational medical product (IMP), all AEs relevant for risk/benefit ratio, including infections, liver toxicity, neurological and optic toxicity, renal, hematological and any AE grade 1, 2, 3 or 4 that the investigator estimates to be relevant
Time frame: 1 year
Immune-reconstitution inflammatory syndrome
Incidence of TB-related immune-reconstitution inflammatory syndrome (IRIS)
Time frame: 6 months
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PENTA Foundation
Padua, Italy
Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine
Blantyre, Malawi
Cemtro de Investigaçao em Saúde da Manhiça
Manhiça, Mozambique
Hospital Central Maputo
Maputo, Mozambique
Stichting Katholieke Universiteit Radboudumc
Nijmegen, Netherlands
Fundación para la Investigación Biomédica del Hospital 12 de Octubre
Madrid, Spain
Makerere University - Mulago Hospital
Kampala, Uganda
...and 3 more locations
Baseline cytomegalovirus prevalence
Baseline prevalence of CMV infection and CMV-attributable pneumonia (based in a CMV viral load threshold) in recruited HIV-infected infants with severe pneumonia
Time frame: 30 days
Baseline tuberculosis prevalence
Baseline prevalence of microbiological confirmed and unconfirmed TB (according to Graham criteria, Updated Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children 2015) in recruited HIV-infected patients with severe pneumonia
Time frame: 60 days
Tuberculosis incidence
New confirmed and unconfirmed TB cases according to Graham criteria during 1-year of follow-up among patients without TB-T
Time frame: 1 year
Deaths attributable to tuberculosis
Proportion of confirmed and unconfirmed TB, according to Graham criteria, in died children
Time frame: 1 year
CMV prevalence in died participants
Proportion of CMV infection in died children
Time frame: 1 year
CMV Molecular response to treatment
Reduction of quantitative CMV viral load in blood and saliva in infants treated with valganciclovir from enrollment to day +15
Time frame: 1 year
TB-lipoarabinomannan (LAM) sensitivity and specificity
To assess the diagnostic accuracy (sensitivity and specificity) of TB-LAM for the diagnosis of confirmed TB (reference: positive Xpert Mycobacterium tuberculosis (MTB)/RIF Ultra in feces and/or NPA)
Time frame: 1 year
Quality-adjusted life expectancy
Economic evaluation for quality-adjusted life expectancy
Time frame: 1 year
Per-patient cost
Economic evaluation of the treatments (per-patient cost)
Time frame: 1 year