Background Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa. Based on phase-II data, we performed a phase-III randomized controlled non-inferiority trial to determine the efficacy of a single high-dose liposomal amphotericin B based treatment regimen. Methods HIV-positive adults with cryptococcal meningitis in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomized 1:1 to induction therapy of either (i) single, high-dose liposomal amphotericin B 10mg/kg given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome group), or (ii) the current WHO recommended treatment of 7 daily doses of amphotericin B deoxycholate (1mg/kg/day) plus flucytosine (100mg/kg/day), followed by 7 days of fluconazole 1200mg/day (control group). The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority at a 10% margin. Results We randomized 844 participants. None were lost-to-follow-up. In intention-to-treat analysis, 10-week mortality was 24.8% (101 of 407; 95% confidence interval [CI] 20.7-29.3%) in the AmBisome group and 28.7% (117 of 407; 95% CI 24.4-33.4%) in controls. The absolute difference in mortality was -3.9%, with an upper 1-sided 95% confidence interval of 1.2%. Fungal clearance from cerebrospinal fluid was -0.40 log 10 CFU/ml/day in the AmBisome group and -0.42 log 10 CFU/ml/day in the control group. Fewer participants experienced grade 3 or 4 adverse events in the AmBisome group than the control group (50.0% vs. 62.3%). Conclusions Single dose liposomal amphotericin B (10mg/kg) on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis and associated with fewer adverse events. (Trial registration number: ISRCTN72509687.)

Background: Identifying new antifungals for cryptococcal meningitis remains a priority given the inadequacy of current therapy. Sertraline has previously demonstrated in vitro and in vivo activity against Cryptococcus. We evaluated the efficacy of adjunctive sertraline for cryptococcal meningitis in a double-blind, randomised, placebo-controlled clinical trial. Methods: We assessed 18-week survival among HIV-infected Ugandan adults with cryptococcal meningitis enrolled from 09 March 2015 to 29 May 2017. Participants were randomly assigned to receive standard therapy with 7-14 days of amphotericin (0•7-1•0 mg/kg/day) + fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. Randomisation in a 1:1 ratio was performed with variable block sizes of 2 and 4, with stratification by site (Kampala or Mbarara) and antiretroviral status (experienced or naïve). Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number .

The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.