Award Title: Translational Research to Reduce Mortality from CNS Infections in Africa
Funder: Department of Health and Social Care

Abstract: 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.

Lay Abstract: Meningitis and other infections of the brain (or 'central nervous system') are extremely difficult to diagnose and treat. Even in resource-rich settings, these infections cause very high rates of death and disability. In low- and middle-income settings central nervous system (CNS) infections are much more common - particularly in regions with high rates of HIV infection. Individuals infected with HIV are at risk from a very wide variety of different CNS infections, and tend to develop extremely severe illness. The highest rates of HIV infection in the world are seen in east and southern Africa, and in these regions meningitis and other brain infections are a leading cause of death. Unfortunately this has remained the case despite the widespread provision of HIV treatment, probably due to the fact that there are still many people who are not diagnosed with HIV until they have very advanced disease, and increasing numbers of people who are dropping out of HIV treatment programmes or developing resistance to the drugs. Up to 200,000 people are estimated to die from just one form of meningitis called cryptococcal meningitis (CM) every year, and overall infections of the CNS cause up to 30% of all deaths in HIV-infected individuals.To reduce this extremely high death rate several different approached are needed. It is currently not known exactly what infections cause much of the meningitis in African patients, so targeted treatment is not possible; therefore research studies to determine the specific causes of meningitis in Africa are urgently required. It is also critically important to provide doctors in Africa with the correct tools to be able to quickly and effectively diagnose CNS infections in order for the correct treatments to be given. New diagnostic tests are needed. Even with the currently available treatments for meningitis, over half of the patients with these diseases in African settings still die, thus developing new effective treatments is a priority. And finally, a better understanding of the body's response to CNS infections, and the risk factors for disease development and death, would enable the development of entirely novel treatment and prevention strategies.I aim to improve management of adult meningitis in African settings with high levels of HIV. My key goals are (1) to collect information on all patients being tested for meningitis at an African hospital, and run very detailed testing to determine the causes; (2) to evaluate new tests for meningitis capable of testing for many different infections at once and diagnosing infection at the bedside; (3) to test a new treatment for CM, the commonest cause of meningitis in this setting, based on a single very high dose of an existing drug called liposomal amphotericin; and (4) to perform a detailed examination of the patients' immune responses and genetic make up to try to find out why some patients develop CM while some do not, and what factors are associated with death from CM.This work will be based on a series of clinical studies and a large trial of new CM treatment in Botswana, South Africa, Zimbabwe, Malawi, and Uganda. The results of this work will allow treatment guidelines for meningitis to be updated based on accurate data about the causes of meningitis, leading to reductions in the high death rates. An effective new treatment for CM that is easy to administer in African hospitals would save many thousands of lives each year. And better understanding the underlying pathological processes that predispose some people to CNS infections and subsequent death could lead to new treatments and prevention strategies to further reduce the severe toll from these infections in Africa.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health Categories: INFECTION