Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition

Study Overview
=================
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.

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.

Official Title
-----------------
A Randomized Trial to Investigate Strategies to Reduce Mortality Among HIV-infected and HIV-exposed Children Admitted With Severe Acute Malnutrition in Mulago Hospital, Kampala, Uganda

Conditions
-----------------
HIV-1-infection, Malnutrition, Child

Intervention / Treatment
-----------------
* Drug: Ceftriaxone Sodium
* Drug: Ampicillin
* Drug: Gentamicin


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 59 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label parallel group randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftriaxone<br>Ceftriaxone will be administered intravenously at a dose of 50 - 75mg/kg once daily | Drug: Ceftriaxone Sodium<br>* 7 days of once daily dosing<br>* Other names: ZEFONE-1000;|
| Active Comparator: Ampicillin and Gentamicin<br>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<br>* 7 days of 6 hourly dosing<br>* Other names: AMPIMAX-500;Drug: Gentamicin<br>* 7 days of once daily dosing<br>* Other names: GENTAMICIN INJECTION;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In hospital mortality | Cumulative incidence | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of hospitalization | Number of days | 90 days | 
| Weight-for-height z-score | Change from baseline | 90 days | 
| Weight-for-age z-score | Change from baseline | 90 days | 
| Height-for-age z-score | Change from baseline | 90 days | 
| Pattern and antimicrobial sensitivity of pathogens | Frequency | 7 days | 
| HIV infection | Prevalence | Baseline | 
| Area under the curve (AUC 0- 12h) | Geometric means | 12hours | 
| Maximum concentration (Cmax) | Geometric means | 12hours | 
| Concentration at 12hours post dose (C12h) | Geometric means | 12hours |