This is a phase III randomized trial to evaluate whether sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, will lead to improved survival . Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study. Phase III Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at 400mg/day. We will use a permutated block randomization in a 1:1 allocation (n=275 per arm). Total anticipated enrollment: 550 subjects.
Inclusion Criteria: - Cryptococcal meningitis diagnosed by CSF cryptococcal antigen (CRAG) - HIV-1 infection - Ability and willingness of the participant or legal guardian/representative to provide informed consent - Willing to receive protocol-specified lumbar punctures Exclusion Criteria: - Age < 18 years - Receipt of >=3 doses of amphotericin therapy - Cannot or unlikely to attend regular clinic visits - History of known liver cirrhosis - Presence of jaundice - Pregnancy - Current breastfeeding