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 evaluated the activity of adjunctive sertraline, previously demonstrated to have in vitro and in vivo activity against Cryptococcus. Methods We enrolled 172 HIV-infected Ugandans with cryptococcal meningitis from August 2013 through August 2014 into an open-label dose-finding study to assess safety and microbiologic efficacy. Sertraline 100–400mg/day was added to standard therapy of amphotericin + fluconazole 800mg/day. We evaluated early fungicidal activity via Cryptococcus cerebrospinal fluid (CSF) clearance rate, sertraline pharmacokinetics, and in vitro susceptibility. Findings Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 (95%CI: −0·41, −0·33) colony forming units (CFU)/mL/day. Incidence of paradoxical immune reconstitution inflammatory syndrome (IRIS) was 5% (2/43) and relapse was 0% through 12-weeks. Sertraline reached steady state concentrations in plasma by day 7, with median steady-state concentrations of 201 ng/mL (IQR, 90–300; n=49) with 200mg/day and 399 ng/mL (IQR, 279–560; n=30) with 400mg/day. Plasma concentrations reached 83% of steady state levels by day 3. The median projected steady state brain tissue concentration at 200mg/day was 3·7 (IQR, 2·0–5·7) mcg/mL and 6·8 (IQR, 4·6–9·7) mcg/mL at 400mg/day. Minimum inhibitory concentrations were ≤2 mcg/mL for 27% (35/128), ≤4 mcg/mL for 84% (108/128), ≤6 mcg/mL for 91% (117/128), and ≤8 mcg/mL for 100% of 128 Cryptococcus isolates. Interpretation Sertraline had faster cryptococcal CSF clearance, decreased IRIS, and decreased relapse compared with historical experiences. Sertraline reaches therapeutic levels in a clinical setting. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. Funding National Institutes of Health, Grand Challenges Canada.

Sertraline demonstrates fungicidal activity in vitro for Coccidioides immitis

“…The MIC of sertraline for C. immitis is similar to the reported MIC of sertraline for Cryptococcus neoformans (Zhai et al 2012; Rhein et al 2016). Sertraline has been demonstrated to be effective in mouse models of disseminated cryptococcal infection (Zhai et al 2012).…”

“…Sertraline has been demonstrated to be effective in mouse models of disseminated cryptococcal infection (Zhai et al 2012). Initial human clinical trial results of sertraline given in addition to standard of care treatment for cryptococcal meningitis also suggest clinical utility (Rhein et al 2016), and larger-scale clinical trials are planned. If these trials demonstrate effectiveness and tolerability of sertraline for cryptococcal meningitis, the similar MIC of sertraline for C. immitis would suggest sertraline would have potential as an additional agent for the treatment of coccidioidal meningitis and possibly other forms of coccidioidal infection.…”

“…In a murine model of disseminated cryptococcosis, sertraline was as effective as fluconazole in decreasing CNS fungal burden, and worked synergistically with fluconazole to decrease fungal burden in the spleen, kidney and brain (Zhai et al 2012). Most recently, studies of the addition of sertraline to standard of care treatment for human Cryptococcal meningitis demonstrated decreased fungal burden in the CSF from the addition of sertraline (Rhein et al 2016). …”

2016, the year of Zika virus

“…• Zika virus (ZIKV) infection disrupts neurogenesis in the fetal brain, resulting in neurodevelopmental disorders, most notably microcephaly 3 • ZIKV infection has also been linked to Guillain-Barré syndrome 5 • Dexamethasone does not reduce mortality, and increases disability, among patients with HIV-associated cryptococcal meningitis 7 • Further investigation of adjunctive sertraline in cryptococcal meningitis is warranted 8 • According to new guidelines, in suspected bacterial meningitis, antibiotic therapy should be started as soon as possible, and no more than 1 h after hospitalization 10 NATURE REVIEWS | NEUROLOGY www.nature.com/nrneurol…”

“…Two large randomized clinical trials evaluated treatment options in HIV-associated cryptococccal meningitis 7,8 . Cryptococcosis is a defining opportunistic infection for AIDS, and is the second most common AIDSdefining illness in Africa.…”