Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.
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.
Institute of Infection and Immunity, St. George's University of London, London, United Kingdom tbicanic@sgul.ac.uk.
Tihana
T
Bicanic
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Christian
C
Bottomley
Institute of Infection and Immunity, St. George's University of London, London, United Kingdom.
Angela
A
Loyse
Elisabeth Hospital, Tilburg, the Netherlands.
Annemarie E
AE
Brouwer
Mbarara University of Science and Technology, Mbarara, Uganda.
Conrad
C
Muzoora
Mbarara University of Science and Technology, Mbarara, Uganda.
Kabanda
K
Taseera
University of North Carolina Project, Lilongwe, Malawi.
Arthur
A
Jackson
University of North Carolina Project, Lilongwe, Malawi.
Jacob
J
Phulusa
University of North Carolina Project, Lilongwe, Malawi.
Mina C
MC
Hosseinipour
University of North Carolina Project, Lilongwe, Malawi.
Charles
C
van der Horst
Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Direk
D
Limmathurotsakul
Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Nicholas J
NJ
White
Edendale Hospital, Pietermaritzburg, South Africa.
Douglas
D
Wilson
Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Robin
R
Wood
Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Graeme
G
Meintjes
Institute of Infection and Immunity, St. George's University of London, London, United Kingdom.
Thomas S
TS
Harrison
Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom Botswana-UPenn Partnership, Gaborone, Botswana Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Joseph N
JN
Jarvis
D000328:Adult; D000666:Amphotericin B / Q000008:administration & dosage* / Q000633:toxicity; D000740:Anemia / Q000209:etiology / Q000473:pathology; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000633:toxicity; D001772:Blood Cell Count; D060085:Coinfection; D003404:Creatinine / Q000097:blood; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000254:growth & development; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000633:toxicity; D004338:Drug Combinations; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000401:mortality / Q000473:pathology / Q000821:virology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007008:Hypokalemia / Q000209:etiology / Q000473:pathology; D060828:Induction Chemotherapy / Q000379:methods*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D009503:Neutropenia / Q000517:prevention & control; D016019:Survival Analysis; D016896:Treatment Outcome
D000935:Antifungal Agents; D004338:Drug Combinations; D006454:Hemoglobins; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D003404:Creatinine; D005437:Flucytosine