DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of death among persons living with AIDS in resource-limited settings. In 2014, cryptococcal meningitis was responsible for approximately 15% of deaths in HIV treatment programs in Africa. Many of these deaths are preventable. Furthermore, the aggressive roll-out of ART in Sub-Saharan Africa has resulted in only slight decreases in cryptococcal meningitis incidence, e.g. 10-15% per South African national surveillance. In Uganda among hospitalized patients with suspected meningitis in 2014, Cryptococcus still remains more common than all other causes of meningitis combined. One strategy to prevent the early mortality in ART programs is to screen for sub-clinical cryptococcal infection among asymptomatic persons living with AIDS using a simple blood test (cryptococcal antigen or CrAg). The prevalence of this detectable sub-clinical cryptococcal infection averages 7.2% (95%CI: 6.8-7.6%) among 36 African cohorts with CD4<100 not receiving ART. If identified, these asymptomatic CrAg+ persons can be given "preemptive" fluconazole antifungal therapy to prevent the development of meningitis or death. Our stepped- wedge randomized "ORCAS" trial demonstrated that pre-ART CrAg screening among HIV- infected persons with CD4<100 cells/mcL led to a 30% relative reduction in overall 6-month mortality within 18 clinics in Uganda. A similar ~30% benefit was seen in a separate randomized clinical trial in Tanzania and Zambia. However, while the CrAg screening intervention was successful, the survival of CrAg+ persons was 2-fold worse than CrAg-negative persons in both trials. Based on our team's prior research, Uganda and multiple other countries have incorporated pre-ART CrAg screening of persons with CD4<100 into National HIV Guidelines. Therefore, further improvements in CrAg screening and preemptive therapy regimens are needed in order to reduce early ART mortality. First, we will evaluate in a randomized comparative effectiveness trial if 6-month cryptococcal-free survival of CrAg+ persons can be improved with enhanced preemptive antifungal therapy using adjunctive sertraline compared with the current WHO recommended preemptive CrAg+ therapy. Second, we will identify risk factors for failure of preemptive CrAg+ therapy with respect to 6-month cryptococcal-free survival. Overall we seek to innovate the delivery of HIV care to reduce early mortality on ART through implementation of an improved package of care for late presenters to care.