strategies to reduce mortality among hiv-infected and hiv-exposed children admitted with severe acute malnutrition

Conditions: HIV-1-infection; Malnutrition, Child

Summary: this study to investigate whether empiric use of an antibiotic with greater antimicrobial sensitivity (ceftriaxone) than standard-of-care (ampicillin plus gentamicin) will reduce mortality among hiv-infected/heu children admitted to mwanamugimu nutrition unit, mulago hospital, kampala, uganda.

background hiv-infected and hiv-exposed-uninfected children (heu) are at increased risk of developing malnutrition. severely malnourished children have high mortality rates, but mortality is higher in those that are hiv-infected. preliminary audits at the mwanamugimu nutrition unit, mulago hospital, in 2014 showed that 43% of the severely malnourished children that died were hiv-infected/heu, despite only 30% of admissions being hiv-infected/heu, with deaths due to infections in 90% of cases. objectives this study aims to investigate whether empiric use of an antibiotic with greater antimicrobial sensitivity (ceftriaxone) than standard-of-care (ampicillin plus gentamicin) will reduce mortality among hiv-infected/heu children admitted to mwanamugimu nutrition unit. secondary objectives include: comparing length of hospitalization, weight-for-height, weight-for-age and height-for-age z-scores between ceftriaxone versus standard of care (ampicillin and gentamicin) treatment arms; ascertaining the pattern/antimicrobial sensitivity of pathogens among participants; determining the prevalence and factors associated with hiv-infection among severely malnourished children; and evaluating the pharmacokinetics (pk) of lopinavir/ritonavir (lpv/r) among severely malnourished hiv-infected children. methods this will be an open label randomized controlled trial involving 300 children; 76 hiv-infected (current mortality - 33%) and 224 heu (current mortality - 26%). the participants will be randomized to receive 1week of ceftriaxone (n= 150) or standard-of-care (ampicillin/gentamicin) (n=150), in addition to other routine care; the ratio of hiv-infected to heu (1:3) in this sample is reflective of the current proportions of the hiv-infected and heu children admitted at mwanamugimu nutrition unit. the trial's primary outcome will be in hospital mortality. 300 randomised children provides \>80% power to detect reductions in mortality from the expected 28% to 14%, allowing for 10% noncompliance/lost-to-follow-up in each group. secondary outcomes will be: length of hospitalization; weight-for-height, weight-for-age and height-for-age z-scores; and pattern/antimicrobial sensitivity of pathogens. in addition, 280 severely malnourished children of unknown serostatus will be tested for hiv at admission to determine the prevalence and factors associated with hiv-infection. 280 children provide 80% power to determine the prevalence of hiv-infection. furthermore, all the hiv-infected children on lpv/r will each provide sparse pharmacokinetic (pk) samples to evaluate the pk of lpv/r among malnourished children. in this pk sub-study, geometric means of steady-state lpv pk parameters \[area under the curve (auc) 0-12h, maximum concentration (cmax) and concentration at 12 hours after dose (c12h)\] will be determined. the pk parameters (auc 0-12h, cmax, c12) will then be put in pharmacokinetic-pharmacodynamic (pk-pd) models to determine optimal doses for the study population.

Eligibility criteria:
inclusion criteria: 1. hiv-infected children aged 1 to 59 months admitted at mwanamugimu nutrition unit with severe acute malnutrition 2. hiv exposed but uninfected children aged 1 to 59 months admitted at mwanamugimu nutrition unit with severe acute malnutrition 3. for prevalence of hiv-infection sub-study, children presenting with severe acute malnutrition on admission at mwanamugimu nutrition unit. 4. for pk sub-study, the child should have been on antiretroviral therapy for at least 2weeks and should have been in hospital for at least 2weeks. exclusion criteria: * for pk sub-study; a child with documented poor adherence to antiretroviral therapy. * for pk sub-study; a child known to have vomited the drug on the sampling day.