Tihana Bicanic

Fungal Burden, Early Fungicidal Activity, and Outcome in Cryptococcal Meningitis in Antiretroviral-Naive or Antiretroviral-Experienced Patients Treated with Amphotericin B or Fluconazole

In a prospective observational study of 54 patients with human immunodeficiency virus-associated cryptococcal meningitis, the early fungicidal activity of amphotericin B (1 mg/kg/day) was significantly greater than that of fluconazole (400 mg/day). Compared with antiretroviral therapy-naive patients, patients developing cryptococcal meningitis while already receiving antiretroviral therapy had lower baseline fungal burdens and a longer median duration of survival, but there were no differences observed in fungal clearance, cerebrospinal fluid proinflammatory cytokines, or 10-week mortality.

High-Dose Amphotericin B with Flucytosine for the Treatment of Cryptococcal Meningitis in HIV-Infected Patients: A Randomized Trial

BACKGROUND The standard therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis of amphotericin B (AmB; 0.7 mg/kg per day) plus flucytosine frequently takes >2 weeks to sterilize the cerebral spinal fluid, and acute mortality remains high. A dosage range for AmB of 0.7-1 mg/kg per day is noted in current guidelines, but there are no data comparing 0.7 mg/kg per day with 1 mg/kg per day. METHODS Sixty-four HIV-seropositive, antiretroviral therapy-naive patients in Cape Town, South Africa, who experienced their first episode of cryptococcal meningitis during the period May 2005-June 2006 were randomized to receive either (1) AmB, 0.7 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 1; 30 patients); or (2) AmB, 1 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 2; 34 patients). Regimens were given for 2 weeks, followed by treatment with oral fluconazole. The primary outcome measure was early fungicidal activity, as determined by results of serial, quantitative cerebral spinal fluid cryptococcal cultures. Secondary outcome measures were safety and mortality. The median duration of follow-up was 1 year. RESULTS Early fungicidal activity was significantly greater for group 2 than for group 1 (mean +/- SD, -0.56 +/- 0.24 vs. -0.45 +/- 0.16 log cfu/mL of cerebral spinal fluid per day; P = .02). The incidence of renal impairment did not significantly differ between the 2 groups. Anemia was associated with female sex and, less strongly, with membership in group 2. Renal impairment and anemia reversed after the regimen was switched to fluconazole. Two- and 10-week mortality rates were 6% and 24%, respectively, with no difference between groups. CONCLUSIONS AmB, 1 mg/kg per day, plus flucytosine is more rapidly fungicidal than is standard-dose AmB plus flucytosine. Because of its size, this study provides limited data on any difference in toxicity between the regimens, but toxicities were manageable and reversible. CLINICAL TRIALS REGISTRATION NUMBER ISRCTN68133435 (http://www.controlled-trials.com).

Adjunctive interferon-γ immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial.

Background:Interferon-gamma (IFN&ggr;) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFN&ggr; to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis. Methods:Patients were randomized to amphotericin B 1 mg/kg per day and 5FC 100 mg/kg per day for 2 weeks (standard therapy), standard therapy and IFN&ggr;1b 100 &mgr;g days 1 and 3 (IFN&ggr; two doses), or standard therapy and IFN&ggr;1b 100 &mgr;g days 1, 3, 5, 8, 10 and 12 (IFN&ggr; six doses). Primary outcome was rate of clearance of cryptococcus from the cerebrospinal fluid (CSF) (early fungicidal activity, EFA) calculated from serial quantitative cultures, previously shown to be independently associated with survival. Results:Rate of fungal clearance was significantly faster in IFN&ggr; containing groups than with standard treatment. Mean EFA [log colony forming unit (CFU)/ml per day] was −0.49 with standard treatment, −0.64 with IFN&ggr; two doses, and −0.64 with IFN&ggr; six doses. Difference in EFA was −0.15 [confidence interval (95% CI) −0.02 to −0.27, P = 0.02] between standard treatment and IFN&ggr; two doses, and −0.15 (95% CI −0.05 to −0.26, P = 0.006) between standard treatment and IFN&ggr; six doses. Mortality was 16% (14/88) at 2 weeks and 31% (27/87) at 10 weeks, with no significant difference between groups. All treatments were well tolerated. Conclusion:Addition of short-course IFN&ggr; to standard treatment significantly increased the rate of clearance of cryptococcal infection from the CSF, and was not associated with any increase in adverse events. Two doses of IFN&ggr; are as effective as six doses.

Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study.

Background:Prospective data on incidence, characteristics, and risk factors for cryptococcal meningitis immune reconstitution inflammatory syndrome (CM-IRIS) are lacking. Methods:Prospective study of 65 antiretroviral therapy (ART)-naive HIV-infected cryptococcal meningitis (CM) patients, who started ART after initiation of antifungal treatment. CM-IRIS definition: (1) cerebrospinal fluid (CSF) culture-confirmed CM, (2) symptom resolution before starting ART, (3) adherence to fluconazole and ART, (4) recurrence of CM symptoms after starting ART, (5) immunologic and/or virologic response to ART, (6) no alternative diagnosis. Results:ART was started at a median of 47 days from CM diagnosis. CM-IRIS developed in 11 of 65 (17%), at a median 29 days from starting ART. No factors at first CM episode (fungal burden, rate of clearance, CSF, or HIV parameters) predicted those at risk of CM-IRIS. At 6 months on ART, IRIS patients had greater CD4 rise from baseline (220 vs. 124 × 106 cells /L in non-IRIS, P = 0.01), and 4 of 11 CM-IRIS patients died compared with 14 of 54 non-IRIS patients (P = 0.5). For those developing CM-IRIS, CSF proinflammatory cytokines interferon γ, tumour necrosis factor α, and interleukin 6, did not differ between first CM and CM-IRIS episode. Conclusions:Patients with CM-IRIS had greater immune restoration in response to ART. Although common and potentially fatal, larger prospective studies are needed to determine whether CM-IRIS, in patients treated initially with amphotericin B, is associated with any increase in overall mortality.

Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes.

Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.

Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients.

BACKGROUND Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint. METHODS We combined data from cohorts of patients with human immunodeficiency virus-associated cryptococcal meningitis from Thailand, South Africa, and Uganda, for whom the rate of clearance of infection was determined, and clinical and laboratory data prospectively collected, and explored the association between the rate of clearance of infection and mortality by Cox survival analyses. RESULTS The combined cohort comprised 262 subjects. Altered mental status at presentation, a high baseline organism load, and a slow rate of clearance of infection were independently associated with increased mortality at 2 and 10 weeks. Rate of clearance of infection was associated with antifungal drug regimen and baseline cerebrospinal fluid interferon-gamma levels. CONCLUSIONS The results support the use of the rate of clearance of infection or early fungicidal activity as a means to explore antifungal drug dosages and combinations in phase II studies. An increased understanding of how the factors determining outcome interrelate may help clarify opportunities for intervention.

Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures

Objectives:To assess impact of serial lumbar punctures on association between cerebrospinal fluid (CSF) opening pressure and prognosis in HIV-associated cryptococcal meningitis; to explore time course and relationship of opening pressure with neurological findings, CSF fungal burden, immune response, and CD4 cell count. Design:Evaluation of 163 HIV-positive ART-naive patients enrolled in three trials of amphotericin B-based therapy for cryptococcal meningitis in Thailand and South Africa. Methods:Study protocols required four lumbar punctures with measurements of opening pressure over the first 2 weeks of treatment and additional lumbar punctures if opening pressure raised. Fungal burden and clearance, CSF immune parameters, CD4 cell count, neurological symptoms and signs, and outcome at 2 and 10 weeks were compared between groups categorized by opening pressure at cryptococcal meningitis diagnosis. Results:Patients with higher baseline fungal burden had higher baseline opening pressure. High fungal burden appeared necessary but not sufficient for development of high pressure. Baseline opening pressure was not associated with CD4 cell count, CSF pro-inflammatory cytokines, or altered mental status. Day 14 opening pressure was associated with day 14 fungal burden. Overall mortality was 12% (20/162) at 2 weeks and 26% (42/160) at 10 weeks, with no significant differences between opening pressure groups. Conclusion:Studies are needed to define factors, in addition to fungal burden, associated with raised opening pressure. Aggressive management of raised opening pressure through repeated CSF drainage appeared to prevent any adverse impact of raised opening pressure on outcome in patients with cryptococcal meningitis. The results support increasing access to manometers in resource-poor settings and routine management of opening pressure in patients with cryptococcal meningitis.

Comparison of the Early Fungicidal Activity of High-Dose Fluconazole, Voriconazole, and Flucytosine as Second-Line Drugs Given in Combination With Amphotericin B for the Treatment of HIV-Associated Cryptococcal Meningitis

BACKGROUND HIV-associated cryptococcal meningitis is associated with an estimated 600 000 deaths worldwide per year. Current standard initial therapy consists of amphotericin B (AmB) plus flucytosine (5-FC), but 5-FC remains largely unavailable in Asia and Africa. Alternative, more widely available, and/or more effective antifungal combination treatment regimens are urgently needed. METHODS Eighty HIV-seropositive, antiretroviral naive patients presenting with cryptococcal meningitis were randomized to 4 treatment arms of 2 weeks duration: group 1, AmB (0.7-1 mg/kg) and 5-FC (25 mg/kg 4 times daily); group 2, AmB (0.7-1 mg/kg) and fluconazole (800 mg daily); group 3, AmB (0.7-1 mg/kg) and fluconazole (600 mg twice daily); and group 4, AmB (0.7-1 mg/kg) and voriconazole (300 mg twice daily). The primary end point was the rate of clearance of infection from the cerebrospinal fluid (CSF) or early fungicidal activity (EFA), as determined by results of serial, quantitative CSF cryptococcal cultures. RESULTS There were no statistically significant differences in the rate of clearance of cryptococcal colony-forming units (CFU) in CSF samples among the 4 treatment groups; the mean (±standard deviation) EFA for treatment groups 1, 2, 3, and 4 were -0.41 ± 0.22 log CFU/mL CSF/day, -0.38 ± 0.18 log CFU/mL CSF/day, -0.41 ± 0.35 log CFU/mL CSF/day, and -0.44 ± 0.20 log CFU/mL CSF/day, respectively. Overall mortality was 12% (9 of 78 patients died) at 2 weeks and 29% (22 of 75 patients died) at 10 weeks, with no statistically significant differences among groups. There were few laboratory abnormalities related to the second agents given; in particular, there were no statistically significant (≥grade 3) increases in alanine transaminase level or decreases in neutrophil count. CONCLUSIONS There was no statistically significant difference in EFA between AmB in combination with fluconazole and AmB plus 5-FC for the treatment of HIV-associated cryptococcal meningitis. AmB plus fluconazole (800-1200 mg/day) represents an immediately implementable alternative to AmB plus 5-FC. AmB plus voriconazole is an effective alternative combination in patients not receiving interacting medications.

Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks--eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis.

Cryptococcosis diagnosis and treatment: What do we know now

Cryptococcosis has evolved into a major invasive fungal disease over the last century. Its primary epidemiology has been focused on three major outbreaks of disease that reflects both changing environmental exposures and growth of host risk factors. The molecular understandings of yeast pathobiology have been bolstered by identification of the yeasts dynamic genomic structures and functions. It is during these new insights into epidemiology and pathobiology that we have also improved our diagnosis of this infection with a new point-of-care, simple, cheap test which utilizes a lateral flow assay for antigen detection. With methods for effective identification of Cryptococcus in the host, the principles for management of this deadly infection include both use of old drugs and new insights into treatment strategies to improve outcome. In this review there are a series of recent insights, opinions, and facts which attempt to summarize our present knowledge base for this deadly fungal central nervous system infection with a particular emphasis on its diagnosis and management.