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Globally, cryptococcal meningitis is a leading cause of mortality among people with AIDS, despite the availability of effective amphotericin B–based therapy. In this trial in sub-Saharan Africa, the efficacy of two simpler treatment regimens was assessed.

Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening. We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age ≥18 years, CD4 count of <200 cells per μL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6–8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413. Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10–43) lower in the clinic plus community support group than in standard care group (p=0·004). Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa. European and Developing Countries Clinical Trials Partnership.

Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. National Institutes of Health and Medical Research Council, Wellcome Trust.

The role of glucocorticoids in the treatment of bacterial or fungal meningitis is controversial. In this trial, adjunctive dexamethasone therapy in patients with HIV-associated cryptococcal meningitis did not confer a benefit and was associated with increased adverse events. Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection is estimated to cause more than 600,000 deaths each year, the vast majority in sub-Saharan Africa and in South and Southeast Asia. 1 Among patients receiving combination antifungal therapy with amphotericin B and either flucytosine or fluconazole, mortality remains more than 30% at 10 weeks, and survivors often have substantial disability. 2 , 3 There is a pressing need to improve outcomes. However, no new anticryptococcal agents are currently close to approval for clinical use, so innovative strategies are needed. Adjunctive treatments, such as glucocorticoids, have shown some benefit in central nervous system (CNS) . . .

Introduction. Cryptococcal meningitis is the most common cause of adult meningitis in sub-Saharan Africa. Raised intracranial pressure (ICP) is common in cryptococcosis. Prior studies suggest elevated ICP is associated with mortality, and guidelines recommend frequent lumbar punctures (LPs) to control ICP. However, the magnitude of the impact of LPs on cryptococcal-related mortality is unknown. Methods. In sum, 248 individuals with human immunodeficiency virus (HIV)-associated cryptococcal meningitis, screened for the Cryptococcal Optimal ART Timing (COAT) trial in Uganda and South Africa, were observed. Individuals received an LP to diagnose meningitis, and subsequent therapeutic LPs were recommended for elevated ICP (>250 mmH2O) or new symptoms. We compared survival, through 11 days, between individuals receiving at least 1 therapeutic LP with individuals not receiving therapeutic LPs. The COAT trial randomized subjects at 7–11 days; thus, follow-up stopped at time of death, randomization, or 11 days. Results. Seventy-five (30%) individuals had at least 1 therapeutic LP. Individuals receiving therapeutic LPs had higher cerebrospinal fluid (CSF) opening pressures, higher CSF fungal burdens, and were more likely to have altered mental status at baseline than those with no therapeutic LPs. Thirty-one deaths (18%) occurred among 173 individuals without a therapeutic LP and 5 deaths (7%) among 75 with at least 1 therapeutic LP. The adjusted relative risk of mortality was 0.31 (95% confidence interval: .12–.82). The association was observed regardless of opening pressure at baseline. Conclusions. Therapeutic LPs were associated with a 69% relative improvement in survival, regardless of initial intracranial pressure. The role of therapeutic LPs should be reevaluated.

Data continue to emerge that suggest treating HIV infection as early as possible is beneficial. In this trial assessing the timing of antiretroviral therapy initiation in patients with acute cryptococcal meningitis and newly diagnosed HIV infection, early initiation was associated with increased mortality. Cryptococcus neoformans is the most common cause of meningitis in adults in sub-Saharan Africa, 1 – 5 and meningitis caused by C. neoformans accounts for approximately 20 to 25% of deaths from the acquired immunodeficiency syndrome (AIDS) in Africa. 6 – 9 Determining when antiretroviral therapy (ART) should be initiated after a diagnosis of cryptococcal meningitis involves balancing the survival benefit conferred by ART against the risk of the immune reconstitution inflammatory syndrome (IRIS), a paradoxical reaction that occurs during immunologic recovery with ART despite effective therapy for the opportunistic infection. Since 2009, the international standard of care has shifted toward earlier ART . . .

Determining the best therapy for HIV-associated cryptococcal meningitis in resource-poor settings is controversial. In this trial in Vietnam, initial therapy with amphotericin B with flucytosine had better outcomes than amphotericin B alone or with fluconazole. There are approximately 1 million cases of cryptococcal meningitis annually and 625,000 deaths. 1 Treatment guidelines recommend induction therapy with amphotericin B deoxycholate (0.7 to 1 mg per kilogram of body weight per day) and flucytosine (100 mg per kilogram per day). 2 However, this treatment has not been shown to reduce mortality, as compared with amphotericin B monotherapy. 2 , 3 Flucytosine is frequently unavailable where the disease burden is greatest, and concerns about cost and side effects have limited its use in resource-poor settings. 4 Fluconazole is readily available, is associated with low rates of adverse events, and has good penetration into cerebrospinal . . .

Background. Correlates of immune protection in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis are poorly defined. A clearer understanding of these immune responses is essential to inform rational development of immunotherapies. Methods. Cryptococcal-specific peripheral CD4 + T-cell responses were measured in 44 patients with HIV-associated cryptococcal meningitis at baseline and during follow-up. Responses were assessed following ex vivo cryptococcal mannoprotein stimulation, using 13-color flow-cytometry. The relationships between cryptococcal-specific CD4 + T-cell responses, clinical parameters at presentation, and outcome were investigated. Results. Cryptococcal-specific CD4 + T-cell responses were characterized by the production of macrophage inflammatory protein 1α, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α). Conversely, minimal interleukin 4 and interleukin 17 production was detected. Patients surviving to 2 weeks had significantly different functional CD4 + T-cell responses as compared to those who died. Patients with a response predominantly consisting of IFN-γ or TNF-α production had a 2-week mortality of 0% (0/20), compared with 25% (6/24) in those without this response (P=.025). Such patients also had lower fungal burdens (10 400 vs 390 000 colony-forming units/mL; P < .001), higher cerebrospinal fluid lymphocyte counts (122 vs 8 cells/μL; P < .001), and a trend toward faster rates of clearance of infection. Conclusions. The phenotype of the peripheral CD4 + T-cell response to Cryptococcus was associated with disease severity and outcome in HIV-associated cryptococcal meningitis. IFN-γ/TNF-α—predomiant responses were associated with survival.

Background. Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)–associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. Methods. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Results. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4+ cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity ± standard deviation, −0.28±0.17 log colony-forming units [CFU]/mL per day vs −0.11±0.09 log CFU/mL per day; P<.001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P=.20), but there was no increase in infection-related adverse events. Conclusions. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.

Background. Cryptococcal meningitis (CM) remains a leading cause of acquired immunodeficiency syndrome-related death in sub-Saharan Africa. The timing of the initiation of antiretroviral therapy (ART) for human immunodeficiency virus (HIV)-associated CM remains uncertain. The study aimed to determine the optimal timing for initiation of ART in HIV-positive individuals with CM. Methods. A prospective, open-label, randomized clinical trial was conducted at a tertiary teaching hospital in Zimbabwe. Participants were aged ⩾18 years, were ART naive, had received a first CM diagnosis, and were randomized to receive early ART (within 72 h after CM diagnosis) or delayed ART (after 10 weeks of treatment with fluconazole alone). Participants received 800 mg of fluconazole per day. The ART regimen used was stavudine, lamivudine, and nevirapine given twice daily. The duration of follow-up was up to 3 years. The primary end point was all-cause mortality. Results. Fifty-four participants were enrolled in the study (28 in the early ART arm and 26 in the delayed ART arm). The median CD4 cell count at enrollment was 37 cells/mm3 (interquartile range, 17–69 cells/mm3). The 3-year mortality rate differed significantly between the early and delayed ART groups (88% vs 54%; P < .006); the overall 3-year mortality rate was 73%. The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P = .031, by log-rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1–7.23). The study was terminated early by the data safety monitoring committee. Conclusions. In resource-limited settings where CM management may be suboptimal, when compared with a delay of 10 weeks after a CM diagnosis, early initiation of ART results in increased mortality. Trial registration. ClinicalTrials.gov identifier: NCT00830856.