In sub-Saharan Africa, central nervous system infections kill up to 30% of HIV-infected adults starting antiretroviral therapy, yet doctors often do not know which pathogen is causing the meningitis. This research aims to close that diagnostic and treatment gap. The team will build a meningitis surveillance network across five African countries, using advanced molecular tests and metagenomic sequencing to identify the full range of pathogens—including previously unrecognised ones—in patients with suspected meningitis. They will also validate two new diagnostic tools: a multiplex PCR test that detects multiple pathogens at once, and a rapid, affordable point-of-care test for cryptococcal antigen. If successful, the project could transform how meningitis is diagnosed and treated in resource-limited settings. A phase-III trial will test whether a single-dose liposomal amphotericin B treatment is as effective as the current standard therapy for HIV-associated cryptococcal meningitis. A simpler, shorter treatment regimen could prevent thousands of deaths. Additionally, genetic and immune studies may reveal why some patients develop cryptococcal meningitis while others do not, pointing toward future prevention strategies.
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Background: Infections of the central nervous system (CNS) are major causes of mortality in low- and middle-income countries. In sub-Saharan Africa CNS infections are a leading cause of death in HIV-infected adults, accounting for up to 30% of early mortality in ART programmes. Detailed understanding of the aetiology of adult meningitis in this setting is of critical importance to inform diagnostic pathways and treatment strategies. Novel affordable point-of-care diagnostic tests for meningitis, with the ability to detect multiple pathogens simultaneously, are urgently needed to facilitate diagnosis, screening and prevention strategies. And effective treatments are required to improve patient outcomes. Aims and objectives: I aim to improve outcomes of adult meningitis in high HIV-prevalence African settings. My specific objectives are to: (1) Develop a meningitis surveillance network using enhanced molecular diagnostics and metagenomic assays to describe meningitis aetiology, and determine the clinical impact of concurrent CNS pathogens; (2) Validate novel multiplex and rapid meningitis diagnostic technologies community and inpatient settings; (3) Evaluate novel short-course liposomal amphotericin B based treatment for HIV-associated CM in a multi-centre phase-III randomized controlled trial; (4) Perform HLA genotyping, KIR genotyping, and a genome wide association study (GWAS) with linked immune phenotyping in a cohort of HIV-infected individuals with CM and controls. Methods: The proposed research builds on my current meningitis surveillance and diagnostic studies, and an ongoing cryptococcal meningitis treatment trial in Botswana, South Africa, Zimbabwe, Malawi, and Uganda. To determine meningitis aetiology a panel of sequential molecular diagnostic assays will be performed in a cohort of patients with suspected meningitis. CSF samples will be bio-banked for subsequent metagenomic analysis and deep-sequencing to identify previously unrecognized or novel pathogens in meningitis cases without confirmed diagnoses. This prospective meningitis surveillance study will serve as a platform to validate a multiplex PCR-based meningo-encephalitis diagnostic and evaluate the performance of the Biosynex® CryptoPS, a novel point of care semi-quantitative cryptococcal antigen detection assay. A multi-centre phase-III randomised non-inferiority trial to determine whether a novel single-dose liposomal amphotericin B treatment is as effective as standard therapy in averting all-cause mortality in HIV-associated CM will be performed. This trial is already funded through the the EDCTP and Joint Global Health Trials Scheme, and will recruit 850 patients at 6 African partner-sites. Within the clinical trial we will investigate host genetic susceptibility to cryptococcal meningitis in a large cohort of patients. A GWAS and HLA and KIR genotyping will be performed to identify modifiable risk factors for CM development and poor outcomes that would be amenable to future clinical intervention trials. Anticipated impact and dissemination: The research findings will enable diagnostic and treatment strategies across Africa to be updated, leading to significant improvements in outcomes from meningitis.The results of the treatment trial have the potential to provide a highly effective treatment option for cryptococcal meningitis that is practical and accessible in Africa with the potential to prevent many thousands of deaths. And advances in understanding of the pathophysiology of cryptococcal infection will inform future patient-targeted immune modulation therapy.
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