Clinic-based Screening to Prevent HIV-associated Cryptococcal Mortality

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DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of AIDS-related mortality worldwide. Circulating cryptococcal antigens can be detected weeks before the onset of neurological symptoms, and pre-emptive anti-fungal therapy can prevent cryptococcal meningitis and death. Unfortunately, most clinics in cryptococcal endemic regions do not have access to laboratory-based testing for cryptococcal antigens. A newly-approved, rapid cryptococcal antigen test can facilitate implementing a clinic-based screening strategy in any resource-limited setting, which, when coupled with oral anti-fungal therapy, could save thousands of lives each year worldwide. However, evidence on the feasibility and impact of conducting point-of-care testing for cryptococcal antigens in a clinic-based setting is needed. My career goal is to become an independent investigator in clinical research with a focus on implementation science to improve clinical diagnosis and treatment of cryptococcal infections and prevention of cryptococcal meningitis in resource-limited settings. I will draw upon the methodological training of the K23 award and leverage the existing research infrastructure of my co-mentors and collaborators in Durban, South Africa to accomplish my scientific objective: to better understand the value of point-of-care testing, clinic-based screening, and implementation science for cryptococcal disease among HIV-infected adults in resource-limited settings. My hypothesis is that clinic-based, nurse-driven, point-of-care screening for cryptococcal antigens at the time of initial HIV diagnosis will be feasible and will improve patient outcomes. I will tes this hypothesis through the following four specific aims: (1) To estimate CD4-specific prevalence of cryptococcal antigenemia and cumulative incidence of cryptococcal meningitis and mortality for those with and without cryptococcal antigenemia within 12 months of HIV diagnosis in a standard-of-care, lab-based serum CrAg screening program, (2) To evaluate a rapid point-of-care LFA CrAg test by measuring test characteristics of whole blood and urine samples, compared with gold-standard serum-based tests, (3) To estimate cumulative incidence of cryptococcal meningitis and mortality within 12 months of HIV diagnosis when implementing an active, clinic-based screening program for CrAg in urine and/or whole blood among newly- diagnosed HIV-infected adults, and to compare cumulative incidence of cryptococcal meningitis and mortality to the standard-of-care, lab-based serum CrAg screening program (measured in Aim #1), and (4) To assess the long-term clinical outcomes, cost, and cost-effectiveness of intensified CrAg screening, compared to lab- based CrAg screening, among newly-diagnosed HIV-infected adults in South Africa. I am well positioned to accomplish these aims, based on my educational and mentorship plans, as well as my experience conducting a clinic-based, nurse-driven evaluation of a point-of-care diagnostic test for tuberculosis. I will draw upon the guidance of my renowned mentors and collaborators, who have extensive experience in HIV care, cryptococcal disease, clinical research, evaluating screening strategies, and cost-effectiveness analysis, while also developing my own distinct research trajectory. My approach is innovative by: (1) validating a point-of-care test in a clinical setting by nurses, (2) evaluatig the impact of clinic-based screening on patient outcomes, and (3) use of a novel, rapid cryptococcal antigen testing platform. The proposed research is significant because it will provide the tools to implement clinic-based screening for cryptococcus, a common and fatal disease in resource-limited settings, and provide a platform to launch my career as an independent investigator.