Award Title: Multimorbidity in children with HIV and severe acute malnutrition in sub-Saharan Africa
Funder: Department of Health and Social Care

Abstract: Background  One-third of children hospitalised with severe acute malnutrition (SAM) in sub-Saharan Africa have HIV infection (HIV-SAM). Children with HIV-SAM have 3-fold higher mortality, slower nutritional recovery and a higher risk of relapse compared to children with SAM alone, despite current interventions. Mortality following hospital discharge is predominantly driven by infections, compounded by poor nutritional convalescence. Moreover, children are discharged to homes characterised by poverty and multiple caregiver vulnerabilities. Addressing this complex multimorbidity requires a deeper understanding of the underlying biological and social pathways to inform new intervention approaches.  Aims and Objectives  Our aim is to define causal pathways underlying multimorbidity in HIV-SAM, and to develop and test multimodal interventions addressing the biological and social factors preventing convalescence.  Our objectives are:    Characterise the multimorbidity of HIV-SAM to identify tractable pathways for intervention.  Develop multimodal packages of interventions for children with HIV-SAM.  Test the effects of single and combined biomedical and psychosocial interventions on morbidity and mortality, and determine the cost-effectiveness and mechanism of action of the intervention packages.      Methods  Our interdisciplinary programme unites two networks of researchers in southern and east Africa and will be conducted in three stages. In Stage 1, we will leverage existing samples and data from each network to characterise HIV-SAM multimorbidity. We will use targeted and exploratory omics-based techniques to undertake molecular characterisation of HIV-SAM to identify tractable biological pathways for intervention. We will define the social and environmental determinants of HIV-SAM through in-depth qualitative research to understand the contexts in which child convalescence occurs. In Stage 2, we will develop and optimise intervention packages aimed at (i) preventing infections; (ii) improving nutrient bioavailability; and (iii) enhancing psychosocial support for caregiver-child pairs. In Stage 3, interventions will be tested in an adaptive clinical trial in Kenya, Zimbabwe and Zambia. We will recruit 732 children with HIV-SAM at the time of hospital discharge and randomise them to: (i) a double-sized control arm, (ii) anti-infection arm, (iii) nutrition arm, (iv) psychosocial arm, and (v) a combination of all intervention packages for 12 weeks. The primary composite outcome will be morality or hospitalisation by 24 weeks, with secondary outcomes of morbidity, growth, neurodevelopment, HIV viral load, CD4 count, and adverse events. Mechanistic sub-studies will define mechanisms of action for each intervention. Process evaluation and health economics evaluations will inform feasibility and cost-effectiveness of interventions.  Timelines for delivery  Stage 1 and Stage 2 will last 18 months. In Stage 3, trial enrolment will take 2 years, with 6 months of follow-up.  Anticipated Impact and Dissemination   Malnutrition and HIV impair child survival and human capital in high-burden countries. An effective package of care for children with HIV-SAM would reduce mortality, decrease hospital re-admissions and promote healthy growth and neurodevelopment. We will disseminate findings to participants through community advisory boards and caregiver meetings; to researchers through academic papers, policy briefs and media channels; and to policymakers through our partnerships with Ministries of Health and UNICEF, which will help to sustainably scale-up effective approaches.

Lay Abstract: Malnutrition in its most life-threatening form, severe acute malnutrition (SAM), can require hospital admission in children under 5 years of age to treat medical complications and regain weight. Up to one-in-five children die in hospital, despite the best available treatment, and one-in-ten die in the year after discharge. If children have both SAM and HIV infection (HIV-SAM), the risk of dying is three times higher, and there are long-term effects on learning, growth and risk of heart disease as adults. SAM and HIV affect multiple body systems, including metabolism, immune defence, hormone pathways, and gut function. Children leave hospital before all these systems are fully restored, meaning there is an ongoing risk of dying after discharge. Children also return to the same home environment, which is often complicated by poverty, caregiver depression, and poor engagement with medical care. We believe there is an urgent need to improve recovery in children with HIV-SAM after they leave hospital, by tackling underlying medical and social causes of ill-health.     In this project, we bring together two networks of researchers from southern and east Africa with experience in HIV and SAM, to better understand how these two conditions interact in children. We will use stored blood and urine samples from children with HIV-SAM to pinpoint underlying problems in the body s immune and metabolic functions, to help us find “targets” for new medical treatments. We will also interview caregivers of children with HIV-SAM to understand the challenges they face once children leave hospital, including their own mental health, social support and ability to access care. We will then develop several new treatments for HIV-SAM. First, we will redesign the therapeutic food that children receive so that it is more easily digested; second, we will select antibiotics to give to children as they leave hospital to prevent infections, which are the leading cause of death; and third, we will provide social and mental health support for caregivers of children with HIV-SAM. Finally, we will do a clinical trial, which compares the new treatments (either alone or combined together) against the best current treatment, which is therapeutic food, anti-HIV drugs and an antibiotic called cotrimoxazole. We will compare how many childen die or get readmitted to hospital, and how children grow and develop, between the treatment groups. We will explore how well the interventions are taken up, and how cost-effective they are. At the end of this project, we hope to better understand how HIV and SAM interact to prevent children from thriving, and to have several promising new treatments for HIV-SAM. We will tell the communities involved in the research about our findings, as well as policymakers who make decisions about new treatments for HIV and SAM.

Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS;6.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION