Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial

Area of Science:

• Infectious Diseases
• Clinical Trials
• Pharmacology

Background:

• Cryptococcal antigen screening in HIV-infected individuals with low CD4 counts can prevent cryptococcal meningitis and death.
• Standard preemptive fluconazole therapy for cryptococcal antigenemia has a failure rate of approximately 25%.
• Sertraline demonstrates in vitro and in vivo activity against Cryptococcus and synergistic effects with fluconazole in murine models.

Purpose of the Study:

• To evaluate the efficacy and safety of sertraline as an adjunctive therapy for asymptomatic cryptococcal antigenemia in HIV-infected individuals.
• To assess the impact of sertraline on meningitis-free survival in patients with cryptococcal antigenemia.

Main Methods:

• A randomized trial was conducted involving asymptomatic HIV-infected Ugandan adults with positive cryptococcal antigenemia.
• Participants received standard WHO-recommended fluconazole therapy, with randomization to either adjunctive sertraline or placebo.
• Sertraline dosage was escalated weekly up to 400 mg/day for 8 weeks, followed by tapering.

Main Results:

• The trial was halted prematurely by the data and safety monitoring board due to safety concerns after enrolling 21 subjects.
• Meningitis-free 6-month survival was observed in 9 of 11 placebo participants and 10 of 10 sertraline participants.
• Seven serious adverse events (SAEs) occurred, with four in the sertraline group, including three cases of psychosis and one serotonin syndrome.

Conclusions:

• Sertraline was associated with an excess of serious adverse events, particularly psychosis and behavioral changes.
• Early trial termination precluded the determination of sertraline's efficacy in treating cryptococcal antigenemia.
• Further research is needed to explore alternative adjunctive therapies for cryptococcal antigenemia due to safety concerns with sertraline.