REDMOTHIV: Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Ceftriaxone Ceftriaxone will be administered intravenously at a dose of 50 - 75mg/kg once daily |
Drug: Ceftriaxone Sodium
7 days of once daily dosing
Other Names:
|
| Active Comparator: Ampicillin and Gentamicin Ampicillin will be administered intravenously at a dose of 50mg/kg 6hourly Gentamicin will be administered intravenously at a dose 5mg/kg once daily |
Drug: Ampicillin
7 days of 6 hourly dosing
Other Names:
Drug: Gentamicin
7 days of once daily dosing
Other Names:
|
Outcome Measures
Primary Outcome Measures
- In hospital mortality [4 weeks]
Cumulative incidence
Secondary Outcome Measures
- Length of hospitalization [90 days]
Number of days
- Weight-for-height z-score [90 days]
Change from baseline
- Weight-for-age z-score [90 days]
Change from baseline
- Height-for-age z-score [90 days]
Change from baseline
- Pattern and antimicrobial sensitivity of pathogens [7 days]
Frequency
- HIV infection [Baseline]
Prevalence
- Area under the curve (AUC 0- 12h) [12hours]
Geometric means
- Maximum concentration (Cmax) [12hours]
Geometric means
- Concentration at 12hours post dose (C12h) [12hours]
Geometric means
Eligibility Criteria
Criteria
Inclusion Criteria:
-
HIV-infected children aged 1 to 59 months admitted at Mwanamugimu Nutrition Unit with severe acute malnutrition
-
HIV exposed but uninfected children aged 1 to 59 months admitted at Mwanamugimu Nutrition Unit with severe acute malnutrition
-
For prevalence of HIV-infection sub-study, children presenting with severe acute malnutrition on admission at Mwanamugimu Nutrition Unit.
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Makerere University College of Health Sciences | Kampala | Central | Uganda | 7072 |
Sponsors and Collaborators
- Makerere University
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- REC.REF.2020-165
- HS1277ES