Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis
Antimicrobial Agents and Chemotherapy December 2015 V.59 N.12 P.7224-7231
Tihana Bicanic, Christian Bottomley, Angela Loyse, Annemarie E. Brouwer, Conrad Muzoora, Kabanda Taseera, Arthur Jackson, Jacob Phulusa, Mina C. Hosseinipour, Charles van der Horst, Direk Limmathurotsakul, Nicholas J. White, Douglas Wilson, Robin Wood, Graeme Meintjes, Thomas S. Harrison, and Joseph N. Jarvis
aInstitute of Infection and Immunity, St. George’s University of London, London, United Kingdom
bFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
cElisabeth Hospital, Tilburg, the Netherlands
dMbarara University of Science and Technology, Mbarara, Uganda
eUniversity of North Carolina Project, Lilongwe, Malawi
fMahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
gCentre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
hEdendale Hospital, Pietermaritzburg, South Africa
iDesmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
jDivision of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa
kInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
lDepartment of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
mBotswana-UPenn Partnership, Gaborone, Botswana
nDivision of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Amphotericin 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.