Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

ABSTRACTAmphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3;P= 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11;P= 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

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Short-Course Induction Treatment with Intrathecal Amphotericin B Lipid Emulsion for HIV Infected Patients with Cryptococcal Meningitis

Journal of Tropical Medicine ◽

10.1155/2015/864271 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Gerardo Alvarez-Uria ◽

Manoranjan Midde ◽

Raghavakalyan Pakam ◽

Pradeep Sukumar Yalla ◽

Praveen Kumar Naik ◽

...

Keyword(s):

Confidence Interval ◽

Risk Reduction ◽

Amphotericin B ◽

Cryptococcal Meningitis ◽

Lipid Emulsion ◽

Absolute Risk ◽

White Blood Cells ◽

Sub Saharan Africa ◽

Induction Treatment ◽

Short Course

Cryptococcal meningitis (CM) is a common cause of death among HIV infected patients in developing countries, especially in sub-Saharan Africa. In this observational HIV cohort study in a resource-limited setting in India, we compared the standard two-week intravenous amphotericin B deoxycholate (AmBd) (Regimen I) with one week of intravenous AmBd along with daily therapeutic lumbar punctures and intrathecal AmB lipid emulsion (Regimen II) during the intensive phase of CM treatment. 78 patients received Regimen I and 45 patients received Regimen II. After adjustment for baseline characteristics (gender, age, altered mental status or seizures at presentation, CD4 cell count, white blood cells, cerebrospinal fluid white cells, and haemoglobin), the use of Regimen II was associated with a significant relative risk reduction in mortality (adjusted hazard ratio 0.4, 95% confidence interval, 0.22–0.76) and 26.7% absolute risk reduction (95% confidence interval, 9.9–43.5) at 12 weeks. The use of Regimen II resulted in lower costs of drugs and hospital admission days. Since the study is observational in nature, we should be cautious about our results. However, the good tolerability of intrathecal administration of AmB lipid emulsion and the clinically important mortality reduction observed with the short-course induction treatment warrant further research, ideally through a randomized clinical trial.

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HIV-associated Cryptococcal Meningitis: a Review of Novel Short-Course and Oral Therapies

Current Treatment Options in Infectious Diseases ◽

10.1007/s40506-020-00239-0 ◽

2020 ◽

Vol 12 (4) ◽

pp. 422-437

Author(s):

Letumile R. Moeng ◽

James Milburn ◽

Joseph N. Jarvis ◽

David S. Lawrence

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Liposomal Amphotericin ◽

Phase Iii ◽

Induction Treatment ◽

High Dose ◽

Ongoing Research ◽

Short Course ◽

Incidence And Mortality ◽

The Impact

Abstract Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

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

BMC Infectious Diseases ◽

10.1186/s12879-021-06049-z ◽

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02526-17 ◽

2018 ◽

Vol 62 (7) ◽

Cited By ~ 4

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.

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Randomized Comparison of Amphotericin B Deoxycholate Dissolved in Dextrose or Intralipid for the Treatment of AIDS-Associated Cryptococcal Meningitis

Clinical Infectious Diseases ◽

10.1093/clinids/23.3.556 ◽

1996 ◽

Vol 23 (3) ◽

pp. 556-562 ◽

Cited By ~ 32

Author(s):

V. Joly ◽

P. Aubry ◽

A. Ndayiragide ◽

I. Carriere ◽

E. Kawa ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Amphotericin B Deoxycholate

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy267 ◽

2018 ◽

Vol 5 (11) ◽

Cited By ~ 10

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.

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

Southern African Journal of HIV Medicine ◽

10.4102/sajhivmed.v14i2.82 ◽

2013 ◽

Vol 14 (2) ◽

pp. 76-86 ◽

Cited By ~ 17

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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