scholarly journals Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days

mBio ◽  
2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Joanne Livermore ◽  
Susan J. Howard ◽  
Andrew D. Sharp ◽  
Joanne Goodwin ◽  
Lea Gregson ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Induction Therapy ◽  
Cryptococcal Meningitis ◽  
Standard Of Care ◽  
Experimental Period ◽  
Antifungal Effect ◽  
Cryptococcal Meningoencephalitis ◽  
Drug Of Choice ◽  
Days Of Therapy ◽  
Amphotericin B Deoxycholate

ABSTRACT Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log10 CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3+ CD4+ or CD3+ CD8+ cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis. IMPORTANCE Cryptococcal meningitis is a significant and neglected infection that is associated with excessive morbidity and mortality. In well-resourced health care settings, induction therapy with at least 2 weeks of amphotericin B deoxycholate (dAmB) is advocated. Multiple clinical studies suggest that dAmB is the drug of choice for cryptococcal meningitis. In many parts of the world where the burden of cryptococcal meningitis is highest, it is infeasible to administer dAmB for prolonged periods. This paper provides the experimental basis for the efficacy of abbreviated regimens of dAmB for cryptococcal meningitis. The concept was explored in two well-validated laboratory animal models of cryptococcal meningitis, and the results were bridged to humans by using a range of mathematical modeling techniques. A 3-day regimen is as effective as the standard 14-day course. An abbreviated regimen is significantly more feasible and may enable better antifungal therapy to be administered to many patients with this frequently lethal disease.

Cost-effectiveness and budget impact of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

2020 ◽  
Author(s):  
Jacqui Miot ◽  
Trudy Leong ◽  
Simbarashe Takuva ◽  
Andrew Parrish ◽  
Halima Dawood
Keyword(s):  
South Africa ◽  
Cost Effectiveness ◽  
Amphotericin B ◽  
Induction Therapy ◽  
Cryptococcal Meningitis ◽  
Budget Impact ◽  
Cost Effective ◽  
Standard Of Care ◽  
Sub Saharan Africa ◽  
Oral Regimen

Abstract Background Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135 000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. Methods A decision analytic cost-effectiveness and budget impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered four treatment arms: (a) standard of care; 2-week course of amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course of amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) and (d) oral course; 2-week oral fluconazole/flucytosine (oral). A sensitivity analysis was conducted on key variables. Results The highest total treatment costs were in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, then the 1-week AmBd/5FC with the lowest cost in the standard of care arm. Compared to standard of care the 1-week flucytosine course is most cost-effective at USD31/QALY, followed by the oral 2-week course at USD155/QALY and the 2-week flucytosine course at USD568/QALY. The budget impact analysis shows that the 1-week course has the lowest incremental cost, followed by the oral course and then the 2-week flucytosine course compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to the price of flucytosine and hospital costs, particularly length of stay. Conclusions The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective regardless of whether it is used as a 1-week, 2-week or oral regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

scholarly journals Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jacqui Miot ◽  
Trudy Leong ◽  
Simbarashe Takuva ◽  
Andrew Parrish ◽  
Halima Dawood
Keyword(s):  
South Africa ◽  
Cost Effectiveness ◽  
Amphotericin B ◽  
Induction Therapy ◽  
Cryptococcal Meningitis ◽  
Cost Effective ◽  
Standard Of Care ◽  
Sub Saharan Africa ◽  
Sensitivity Analyses ◽  
Cost Impact

Abstract Background Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135,000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. Methods A decision analytic cost-effectiveness and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables. Results The highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to the lowest cost option the 1-week flucytosine course is most cost-effective at USD119/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to life expectancy and hospital costs, particularly infusion costs and length of stay. Conclusions The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

scholarly journals Cost-effectiveness analysis of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

2020 ◽  
Author(s):  
Jacqui Miot ◽  
Trudy Leong ◽  
Simbarashe Takuva ◽  
Andrew Parrish ◽  
Halima Dawood
Keyword(s):  
South Africa ◽  
Cost Effectiveness ◽  
Amphotericin B ◽  
Induction Therapy ◽  
Cryptococcal Meningitis ◽  
Cost Effective ◽  
Standard Of Care ◽  
Cost Effectiveness Analysis ◽  
Effectiveness Analysis ◽  
Cost Impact

Abstract Background: Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135 000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. Methods: A decision analytic cost-effectiveness analysis and cost impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered five treatment arms: (a) standard of care; 2-week course of amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course of amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) (d) oral course; 2-week oral fluconazole/flucytosine (oral) and e) 1-week course amphotericin B/fluconazole (1wk AmBd/Flu). A sensitivity analysis was conducted on key variables. Results: The highest total treatment costs are in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, the 1-week AmBd/5FC, then standard of care with the lowest cost in the 1-week AmBd/Flu arm. Compared to standard of care the 1-week flucytosine course is most cost-effective at USD106/QALY. The cost impact analysis shows that the 1-week flucytosine course has an incremental cost of just over USD293 per patient per year compared to what is currently spent on standard of care Sensitivity analyses suggest that the model is most sensitive to the probability of survival at 12 months and hospital costs, particularly length of stay. Conclusions: The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective when it is used as a 1-week AmBd/5FC regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

scholarly journals Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Katharine E. Stott ◽  
Justin Beardsley ◽  
Sarah Whalley ◽  
Freddie Mukasa Kibengo ◽  
Nguyen Thi Hoang Mai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Rate Constant ◽  
Cryptococcal Meningitis ◽  
Drug Exposure ◽  
Meta Analysis ◽  
Central Compartment ◽  
Order Rate Constant ◽  
Peripheral Compartment ◽  
First Order ◽  
Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

scholarly journals Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Jodi Lestner ◽  
Laura McEntee ◽  
Adam Johnson ◽  
Joanne Livermore ◽  
Sarah Whalley ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Induction Therapy ◽  
Liposomal Amphotericin ◽  
Experimental Models ◽  
Liposomal Amphotericin B ◽  
Perivascular Spaces ◽  
Histopathological Changes ◽  
Time Curve ◽  
Cryptococcal Meningoencephalitis ◽  
The Brain

ABSTRACT Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg · h/liter). Amphotericin B was visible in the intra- and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.

scholarly journals High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Raju K K Patel ◽  
Tshepo Leeme ◽  
Caitlin Azzo ◽  
Nametso Tlhako ◽  
Katlego Tsholo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Routine Care ◽  
Outcome Data ◽  
High Dose ◽  
Recommended Treatment ◽  
Amphotericin B Deoxycholate ◽  
Intravenous Amphotericin

Abstract Background Cryptococcal meningitis (CM) causes 10%–20% of HIV-related deaths in Africa. Due to limited access to liposomal amphotericin and flucytosine, most African treatment guidelines recommend amphotericin B deoxycholate (AmB-d) plus high-dose fluconazole; outcomes with this treatment regimen in routine care settings have not been well described. Methods Electronic national death registry data and computerized medical records were used to retrospectively collect demographic, laboratory, and 1-year outcome data from all patients with CM between 2012 and 2014 at Botswana’s main referral hospital, when recommended treatment for CM was AmB-d 1 mg/kg/d plus fluconazole 800 mg/d for 14 days. Cumulative survival was estimated at 2 weeks, 10 weeks, and 1 year. Results There were 283 episodes of CM among 236 individuals; 69% (163/236) were male, and the median age was 36 years. All patients were HIV-infected, with a median CD4 count of 39 cells/mm3. Two hundred fifteen person-years of follow-up data were captured for the 236 CM patients. Complete outcome data were available for 233 patients (99%) at 2 weeks, 224 patients (95%) at 10 weeks, and 219 patients (93%) at 1 year. Cumulative mortality was 26% (95% confidence interval [CI], 20%–32%) at 2 weeks, 50% (95% CI, 43%–57%) at 10 weeks, and 65% (95% CI, 58%–71%) at 1 year. Conclusions Mortality rates following HIV-associated CM treated with AmB-d and fluconazole in a routine health care setting in Botswana were very high. The findings highlight the inadequacies of current antifungal treatments for HIV-associated CM and underscore the difficulties of administering and monitoring intravenous amphotericin B deoxycholate therapy in resource-poor settings.

scholarly journals Comparative Effectiveness of Induction Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: A Network Meta-Analysis

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Jeffrey I. Campbell ◽  
Steve Kanters ◽  
John E. Bennett ◽  
Kristian Thorlund ◽  
Alexander C. Tsai ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amphotericin B ◽  
Induction Therapy ◽  
Cryptococcal Meningitis ◽  
Comparative Effectiveness ◽  
Treatment Guidelines ◽  
Meta Analysis ◽  
High Dose ◽  
Mortality Benefit ◽  
Immunodeficiency Virus

Abstract Background.  Multiple international treatment guidelines recommend amphotericin-based combination regimens for induction therapy of cryptococcal meningitis. Yet, only 1 trial has reported a mortality benefit for combination amphotericin-flucytosine, and none have reported a mortality benefit for combination amphotericin-fluconazole. Methods.  We conducted a Bayesian network meta-analysis to estimate the comparative effectiveness of recommended induction therapies for HIV-associated cryptococcal meningitis. We searched PubMed and Cochrane CENTRAL for clinical reports of induction therapy for HIV-associated cryptococcal meningitis. We extracted or calculated early (two-week) and late (six to 12-week) mortality by treatment arm for the following induction regimens: amphotericin B alone, amphotericin B + flucytosine, amphotericin B + triazoles, amphotericin B + flucytosine +triazoles, triazoles alone, triazoles + flucytosine, liposomal amphotericin B, and amphotericin B + other medicines. Results.  In the overall sample (35 studies, n = 2483), we found no evidence of decreased mortality from addition of flucytosine or triazoles to amphotericin B, compared with amphotericin B alone. Although we did find a nonsignificant benefit for addition of flucytosine to amphotericin B in studies including participants with altered levels of consciousness, we did not ide.jpegy a benefit for combination therapy in restricted analyses in either resource-rich or resource-limited settings, studies conducted before or after 2004, and studies restricted to a high dose of amphotericin B and fluconazole. Conclusions.  Given considerations of drug availability and toxicity, there is an important need for additional data to clarify which populations are most likely to benefit from combination therapies for human immunodeficiency virus-associated cryptococcal meningitis.

scholarly journals Ambulatory induction phase treatment of cryptococcal meningitis in HIV integrated primary care clinics, Yangon, Myanmar

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Clare E. Warrell ◽  
Catriona Macrae ◽  
Alistair R. D. McLean ◽  
Edmund Wilkins ◽  
Elizabeth A. Ashley ◽  
...  
Keyword(s):  
Primary Care ◽  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Integrated Primary Care ◽  
Induction Treatment ◽  
Induction Phase ◽  
Retrospective Case ◽  
Primary Care Clinics ◽  
Amphotericin B Deoxycholate ◽  
One Year

Abstract Background Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. Method This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7–1.0 mg/kg) and oral fluconazole (800 mg orally/day). Results Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. Conclusion Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.

scholarly journals Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update

2013 ◽  
Vol 14 (2) ◽  
pp. 76-86 ◽  
Author(s):  
The Southern African HIV Clinicians Society
Keyword(s):  
South Africa ◽  
Antiretroviral Therapy ◽  
Intracranial Pressure ◽  
Amphotericin B ◽  
Opportunistic Infection ◽  
Cryptococcal Meningitis ◽  
Laboratory Diagnosis ◽  
First Episode ◽  
Raised Intracranial Pressure ◽  
Amphotericin B Deoxycholate

Six years after the first Society guidelines were published, cryptococcal meningitis (CM) remains an important cause of morbidity and mortality among HIV-infected adults in South Africa. Several important developments have spurred the  publication of updated guidelines to manage this common fungal opportunistic infection. Recommendations described here include: (1) screening and pre-emptive treatment; (2) laboratory diagnosis and monitoring; (3) management of a first episode of CM; (4) amphotericin B deoxycholate toxicity prevention, monitoring and management; (5) timing of antiretroviral therapy among patients with CM; (6) management of raised intracranial pressure; (7) management of relapse episodes of CM.

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