Central nervous system (CNS) infections are common across all ages in Sub-Saharan Africa in people with or without HIV-infection. In persons with HIV, cryptococcal meningitis is particularly common, being the second most common AIDS defining illness in Africa and the most common cause of meningitis in adults in Sub-Saharan Africa overall. With the widespread availability of HIV antiretroviral therapy (ART), long term survival in AIDS patients with CNS infections should be possible, but delayed or inaccurate diagnoses contributes to poor acute outcomes, including high acute mortality. We propose a prospective cohort study of 1000 HIV-infected persons presenting with suspected CNS infection in Kampala, Uganda. We will use point-of-care and molecular diagnostics to rapidly determine the etiologies of CNS infections, with a specific focus on new diagnostic tests for Tuberculosis (TB) meningitis. Among persons with cryptococcal meningitis, we will prospectively assess neurological, functional, and neurocognitive status in a randomized clinical trial to determine if adjunctive sertraline has antifungal activity and neurocognitive benefit. In his trial, we will also assess for risk factors for adverse neurocognitive outcomes in persons with cryptococcosis. Hypotheses: 1. We hypothesize that implementation of a new meningitis diagnostic algorithm will improve the rapidity and accuracy of diagnoses and lower costs compared to a standard CSF analysis. 2. We hypothesize that sertraline has an antifungal activity in HIV-infected persons with cryptococcal meningitis, and adjunctive sertraline therapy will improve the rate of CSF sterilization and improve neurologic outcomes. 3. We hypothesize that worse neurocognitive outcomes can be predicted based on early parameters, including: i) decreased CSF IFN-y;ii) increased CSF IL-7;iii) higher CSF amphotericin levels;iv) development of immune reconstitution inflammatory syndrome (IRIS).
Specific Aims 1) By implementing a novel diagnostic algorithm to determine the etiology of CNS infections in Sub- Saharan Africa among HIV-infected adults, we will decrease costs and improve outcomes. 2) We will determine if adjunctive sertraline improves anti-fungal and neurocognitive outcomes among HIV-infected persons with cryptococcal meningitis. 3) We will determine risk factors for poor neurocognitive outcomes in persons with cryptococcosis.

Public Health Relevance

Cryptococcal meningitis, a fungal meningitis, is the second most common AIDS defining illness in Sub-Saharan Africa causing approx. 25% of the AIDS-attributable mortality in Africa. Overall Cryptococcus is the most common cause of meningitis in Sub-Saharan Africa;however, a significant number of brain infections are of unknown etiology. This project seeks to test new diagnostics and new therapies for meningitis in order to improve neurologic outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS086312-01
Application #
8651643
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (55))
Program Officer
Wong, May
Project Start
2013-09-01
Project End
2018-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$649,235
Indirect Cost
$128,412
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Rhein, Joshua; Bahr, Nathan C; Hemmert, Andrew C et al. (2016) Diagnostic performance of a multiplex PCR assay for meningitis in an HIV-infected population in Uganda. Diagn Microbiol Infect Dis 84:268-73
Rhein, Joshua; Morawski, Bozena M; Hullsiek, Kathy Huppler et al. (2016) Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis 16:809-18

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