Evaluation of CRAG screening with enhanced antifungal therapy for asymptomatic CRAG-positive persons

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Dr. Rajasingham is an Assistant Professor in the Division of Infectious Diseases & International Medicine at the University of Minnesota. Her long-term goal is to become an independent investigator with expertise in evaluating the effectiveness and cost-effectiveness of innovative diagnostics and therapeutics related to the prevention and management of AIDS-related opportunistic infections. She is particularly interested in using cost-effectiveness analysis alongside clinical trials, in order to translate effective interventions into policy. Training: This K23 award will provide the mentored clinical research experience and didactic training in decision analysis and simulation modeling necessary to establish her independent research career. With the mentorship of an interdisciplinary team with expertise in decision analysis, biostatistics, and HIV international clinical trials, she will: 1) acquire advanced training in decision analysis and simulation modeling, 2) acquire expertise in HIV international clinical research methodology, and 3) develop multidisciplinary collaborative and networking skills. Research: Cryptococcus is a leading cause of AIDS-related morbidity and mortality worldwide. Cryptococcal antigen (CRAG) can be detected in the blood weeks to months prior to the onset of meningitis and is an independent predictor of mortality. A public health strategy to reduce mortality is to screen for CRAG in the plasma of people entering HIV care with a CD4 count <100 cells/mcL. Those who are asymptomatic CRAG+ can be treated preemptively with fluconazole antifungal therapy to prevent meningitis or death while receiving HIV therapy. Despite the survival benefit associated with this WHO-recommended CRAG screening and treatment strategy, ~30% of asymptomatic CRAG+ persons die despite standard of care treatment with fluconazole. Those with high CRAG titers (>1:160) are 3 times more likely to die than are those with low CRAG titers (<1:80) in blood. I hypothesize that customized antifungal therapy based on CRAG titers will improve survival, whereby patients with high titers (>1:160) require more aggressive antifungal therapy. The overall objective of this proposal is to identify a more clinically effective yet economically feasible treatment strategy for asymptomatic CRAG+ persons. The aims of this proposal are to: 1) determine if enhanced antifungal therapy improves 6-month survival for asymptomatic persons with high CRAG titers; 2) determine the cost-effectiveness of enhanced antifungal therapy for HIV-infected CRAG+ persons, stratified by CRAG titer; and 3) validate a novel semi-quantitative CRAG lateral flow assay to rapidly detect high CRAG titers (>1:160). The proposed study seeks to improve the international standard of clinical care for HIV-infected persons with advanced disease, and to generate evidence that will inform international HIV care guidelines. The findings and the training in decision analysis that Dr. Rajasingham will obtain will inform future proposals to evaluate cost-effective strategies to reduce AIDS-related deaths across sub-Saharan Africa.