Refining Interventions to Reduce AIDS Mortality from Bacterial and Fungal Infections in Africa

Research question: How should the World Health Organization (WHO)-recommended intervention package for people with advanced HIV disease (AHD) be refined or expanded to reduce the substantial mortality caused by bacterial and fungal infections? Background: Conservatively, bacterial and fungal infections account for one-third of 650,000 global AIDS-related deaths, at least on par with tuberculosis. The WHO package already includes cotrimoxazole prophylaxis, cryptococcal antigen (CrAg) screening and pre-emptive fluconazole treatment. However, there are gaps in this package. Aims and objectives: My aim is to reduce mortality caused by serious bacterial and fungal infections among adults living with AHD in Africa. My specific objectives are to: (1) Determine the burden, aetiological causes of, and risk factors for bacterial bloodstream infections/ meningitis, relative to cryptococcosis and tuberculosis, in a South African inpatient cohort with AHD (2) Evaluate fluconazole and flucytosine treatment for cryptococcal antigenaemia in a randomised-controlled trial (EFFECT), with added-value qualitative-methods research studies guided by patient and public involvement and engagement (3) Evaluate novel quantitative molecular assays for risk stratification of subclinical cryptococcosis and early diagnosis of histoplasmosis/ emergomycosis Methods and timelines: This proposed research will be integrated into my laboratory surveillance in South Africa, my NIHR Global Health Research Group work on HIV-associated fungal infections and the multicentre EFFECT trial (and sub-studies) in Africa. A 5-year inpatient cohort with AHD will be constructed from national pathology records. The incidence of culture-confirmed bacterial infections will be calculated, stratified by pathogen, antimicrobial susceptibility and timing of infection onset. Through prospective sentinel surveillance, we will determine risk factors for bacterial infections, characterise cultured bacteria using phenotypic and genotypic methods, and test whole blood/ cerebrospinal fluid with a multi-target molecular assay to identify causes of culture-negative sepsis. Qualitative-methods research sub-studies will be embedded into the funded EFFECT trial/ sub-studies in South Africa/ Tanzania. Using purposive sampling of trial researchers/ participants and a range of external stakeholders, we will explore the acceptability of the EFFECT regimen and lumbar puncture in those without meningitis symptoms, and how to optimise the current CrAg screening approach. Whole blood from trial participants with subclinical cryptococcosis will be tested using cryptococcal-specific reverse-transcriptase quantitative PCR (RT-qPCR) assays. And whole blood from a multi-country African cohort of AHD inpatients with a clinical syndrome compatible with disseminated histoplasmosis/ emergomycosis will be screened with Histoplasma/ Emergomyces-specific RT-qPCR assays. Anticipated impact and dissemination: This research will contribute to a reduction in the considerable mortality/ economic burden that bacterial and fungal infections place on people with AHD and health services across Africa. Surveillance data will inform clinical trials for antibacterial prophylaxis, pathogen targets for diagnostic assays and empiric antibiotic treatment. EFFECT findings will have immediate and direct impact on management guidelines while qualitative-methods research findings will inform treatment scale up if this becomes standard of care. Novel molecular assays could identify patients with higher blood cryptococcal loads for intensive monitoring and potentially, enhanced antifungal treatment. Whole-blood molecular assays for disseminated histoplasmosis/ emergomycosis offer an innovative way to leverage on reflex CrAg screening platforms which use whole blood samples.