Project Lead(s): David Meya
Cryptococcal meningitis has become the most common cause of adult meningitis in many parts of Africa, where Cryptococcosis now rivals tuberculosis in all-cause mortality in HIV-infected adults.
In many settings, standard induction therapy for Cryptococcus includes amphotericin B for up to 14 days, combined with high-dose fluconazole, alongside aggressive in-patient management of raised pressure around the brain.
Adhering to accepted guidelines for treating Cryptococcal meningitis in resource-limited areas remains a challenge with several barriers. These include costs and availability of drugs, intravenous (IV) drug administration (which requires hospitalization), co-administration of IV fluids and supplemental electrolytes, and the severe and potentially life-threatening renal toxicity from amphotericin, which necessitates rapid and reliable laboratory monitoring.
Identifying more effective and less toxic adjunctive antifungal therapy is required to allow for faster fungal clearance during the induction phase, which could lead to less dependence on completing a full 14-day course of amphotericin.
An open-label study was conducted to evaluate the rate of cerebrospinal fluid (CSF) clearance of Cryptococcus yeasts when sertraline (Zoloft) was added to standard amphotericin-based therapy for Cryptococcal meningitis.
In addition to standard induction therapy for Cryptococcal meningitis, subjects received increasing doses of sertraline in a dose-escalation study design.
The first subjects enrolled received 100 mg/day of sertraline. This dose was then sequentially increased by 100 mg/day up to a maximum of 400 mg daily for two weeks; then patients received 200mg/day, the normal maximal sertraline daily dose given for depression.
The study enrolled 173 HIV-infected patients diagnosed with Cryptococcal meningitis in Kampala, Uganda, who received standard therapy plus adjunctive sertraline.
Participants received increasing doses (100–400mg/day) of sertraline for 14 days, followed by 200mg/day of sertraline for 10 weeks.
Standard therapy included amphotericin B (0.7-1 mg/kg/day for 7–14 days) plus fluconazole (800–1200mg/day induction, followed by 400mg/day consolidation).
CSF samples from serial therapeutic lumbar punctures were used to calculate the rate of CSF clearance.
The rate of clearance was measured in 128 participants who had a culture-positive, first episode of Cryptococcal meningitis with at least two quantitative cultures.
The results showed that sertraline has an antifungal effect in HIV-infected humans with Cryptococcal meningitis, resulting in a faster rate of clearance of the fungus from cerebrospinal fluid.
Patients who received standard therapy plus adjunctive sertraline at any dose had a 23% faster rate of CSF clearance than historical controls treated with amphotericin and fluconazole alone.
The incidence of culture-positive relapse disease decreased from 5% in the historical cohort to <1% in this study.
The incidence of paradoxical immune reconstitution inflammatory syndrome (IRIS) decreased from ~15% to ~3%.
The project team has applied for Phase II Transition To Scale funding to investigate whether sertraline improves survival after Cryptococcal meningitis.