ABSTRACT Central nervous system (CNS) infections are common across all ages in Africa in people with or without HIV-infection. In people with HIV, cryptococcal meningitis has historically been the second most common AIDS-defining illness in Africa and the most common cause of adult meningitis in Africa overall. The next most common cause of meningitis is likely TB meningitis, although CSF diagnostics are challenging. With the widespread availability of antiretroviral therapy (ART), long term survival in persons living with AIDS and CNS infections should be possible, but delayed or inaccurate diagnoses and limited therapeutic options contribute to poor outcomes. In the era of widespread ART access, more people are presenting with CNS infections unmasked after starting ART or with virologic failure, yet their epidemiology and outcomes are unclear. We propose to continue a prospective cohort study to enroll >1000 new persons presenting with CNS infections and HIV in Uganda. We will use point-of-care and molecular diagnostics to rapidly determine the etiologies of CNS infections, with a specific focus on optimizing and validating new diagnostic tests, such as a semi-quantitative cryptococcal antigen (CrAg-SQ) lateral flow assay and Xpert-HR Host Response gene signature for active tuberculosis. Second, we will investigate a new oral antifungal, oteseconazole, conducting a phase II randomized proof-of-concept clinical trial to investigate microbiologic activity in cryptococcosis. Oteseconazole is a tetrazole that is >100-fold more active in vitro than fluconazole. Third, we will determine the impact of oteseconazole on neurocognitive performance vs standard-of-care. Our Specific Aims include: 1. Determine the etiology of CNS infections in Africa among HIV-positive adults through use of a stepwise diagnostic algorithm, accounting for HIV therapy status. 2. Determine if adjunctive oteseconazole has greater in vivo activity than adjunctive fluconazole + flucytosine when added to single-dose IV liposomal amphotericin B in HIV-associated cryptococcal meningitis. 3. Determine if oteseconazole is associated with better quantitative neurocognitive performance Z-score (QNPZ-8) at 3-months after cryptococcal meningitis compared to standard fluconazole consolidation. Hypotheses: 1. We hypothesize that in the ART era, cryptococcal and TB meningitis will remain the two most common etiologies of meningitis in an HIV-positive population, with the majority now presenting ART-experienced. 2. We hypothesize oral oteseconazole will have a superior quantitative rate of CSF sterilization when added to IV amphotericin in comparison to adjunctive fluconazole + flucytosine. We hypothesize oteseconazole will have a lower incidence of culture-positive relapse through 1 year of follow up than standard fluconazole. 3. We hypothesize oteseconazole will have better QNPZ-8 at 3-months vs those randomized to fluconazole.