Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis. Cryptococcal meningitis (CM) is a major causative agent of fungal meningitis worldwide.   In sub-Saharan Africa, cryptococcal meningitis is the most common cause of meningitis in adults and causes 20-25% of AIDS-related mortality.  The excessive early mortality from cryptococcosis is in large part due to the high cost, toxicity, and relatively limited repertoire of available anti-fungals, which have changed little in the last 30 years.  For these reasons, the identification of new anti-fungals effective for the treatment of fungal meningitis must be a high priority.  One problem with many current anti-fungal drugs is that they penetrate poorly into the brain.  This is a particularly difficult problem in treating fungal meningitis, which is an infection around the brain.   New research suggests that sertraline, one of the most widely prescribed antidepressants in the world, has anti-fungal activity against Cryptococcus.  The findings are the result of investigations testing sertraline against Cryptococcus neoformans in culture, in a mouse model of infection, and in studies of it's mechanism of action which appear to be inhibiting protein synthesis in the Cryptococcus yeast.  Sertraline is known to be well-tolerated and is effective as an antidepressant.  Preliminary investigations of sertraline in a mouse model of systemic cryptococcal infection revealed that it combats infection with efficacy similar to fluconazole, an oral anti-fungal drug used commonly for fungal disease since 1990.  Most importantly, the combination of sertraline and fluconazole was found to work better than either drug alone.  Sertraline is concentrated in the brain (average of 22-fold over blood levels), and thus may be an ideal oral medicine to add to standard therapy for cryptococcal meningitis.   Despite these promising initial studies, no studies have been conducted in actual humans. This study seeks to help answer these questions.  The research team, based in Uganda, plans to determine whether the addition of sertraline to standard therapy for CM will result in more rapid clearance of the fungal infection. An This project will have two phases.  An initial pharmacokinetic dose finding and safety study was conducted Aug 2013-Feb 2014 which has informed the sertraline dosing choices, confirmed the general tolerability, and provided preliminary data that the rate of clearance of yeasts from the cerebrospinal fluid (termed early fungicidal activity) is approximately 25% faster over the first two weeks than current standard therapy.    This proposal is for support of a multisite, Phase III study to determine whether sertraline improves survival in comparison to placebo.  All research participants will receive standard anti-fungal therapy of amphotericin + fluconazole as induction therapy.   The implications of this research are clear.  Since strong safety data already exists, investigation into the use of sertraline as anti-fungal is greatly accelerated.  If sertraline proves to be effective in treatment of Cryptococcus in humans, it would be immediately available for use, essentially creating a shortcut from bench to bedside.  This would result in huge cost savings compared to bringing an entirely new drug to the market.  Sertraline could have the potential to revolutionize cryptococcal care in Sub-Saharan Africa as it is an existing low cost, generic medicine made by >=25 manufacturers worldwide. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.