Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study

Abstract

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.

Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385.

Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0·37 colony forming units per mL per day (95% CI -0·41 to -0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1·27, 95% CI 0·69-2·32; p=0·45).

Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy.

Funding: National Institutes of Health, Grand Challenges Canada.

Figure 1. Flowchart of study participation

A total of 172 individuals with HIV-associated cryptococcal meningitis were enrolled in the study. This reflects N=60 participants being evaluated for safety and tolerability of adjunctive sertraline and additional N=112 participants that either underwent a ‘mock’ randomization of open-labeled sertraline (N=96; participants with first-episode of cryptococcal meningitis) or received 200mg daily of adjunctive sertraline for second episode of cryptococcal meningitis (N=16).

Figure 2. Rate of CSF Clearance of Cryptococcus

The figure displays the rate of CSF clearance by sertraline dose. There was no statistical difference in the early fungicidal activity (EFA) between doses of sertraline. Due to the relatively small sample sizes of the dose groups and inherent differences in statistical methods of estimating EFA (i.e. linear regression vs. mixed-model using longitudinal repeated measures), the 95% CI of each sertraline dose groups overlap, and the 95% CI should be appreciated instead of any exact point estimate. Supplemental Figure 2 provides EFA plots by sertraline dose.

Figure 3. Kaplan-Meier plot of 12 week survival during consolidation therapy, stratified by 2 week CSF quantitative culture sterility

Participants received 200mg/day sertraline with fluconazole for the duration of consolidation therapy. Fluconazole was dosed at 800mg for approximately 4 weeks until 2 week cultures were known to be sterile and ART was initiated. Unlike traditional consolidation therapy using only 400mg/day fluconazole,^– we did not observe that 2 week CSF culture positivity was associated with excess mortality while receiving sertraline at 200mg/day in combination with fluconazole (P=.78).

Figure 4. Probability of Achieving Therapeutic Sertraline brain tissue levels based on Cryptococcus Susceptibility and Sertraline Dose in a Population

Based on the steady state levels achieved between day 7 and 14 as well as the distribution of MICs, in Monte Carlo simulation 81% of a population would likely achieve therapeutic sertraline levels in the brain with 400mg/day, 65% of those ART-naïve receiving 200mg/day, and 35% of those receiving ART with 200mg/day. In the presence of 2-fold additive/synergistic effects of fluconazole, 97% at 400mg/day, 90% at 200mg/day without ART, and 62% at 200mg/day on ART would achieve therapeutic sertraline activity in brain. Overall, 91% (117/128) of Cryptococcus isolates exhibited a MIC of ≤6 µg/mL, 84% (108/128) with ≤4 µg/mL, and 27% (35/128) with MIC ≤2 µg/mL.