Browsing by Author "Douglas Wilson"

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    Determinants of mortality in a combined cohort of 501 patients with HIV-associated cryptococcal meningitis: Implications for improving outcomes
    (2014-03-01) Joseph N. Jarvis; Tihana Bicanic; Angela Loyse; Daniel Namarika; Arthur Jackson; Jesse C. Nussbaum; Nicky Longley; Conrad Muzoora; Jacob Phulusa; Kabanda Taseera; Creto Kanyembe; Douglas Wilson; Mina C. Hosseinipour; Annemarie E. Brouwer; Direk Limmathurotsakul; Nicholas White; Charles Van Der Horst; Robin Wood; Graeme Meintjes; John Bradley; Shabbar Jaffar; Thomas Harrison; St George's University of London; University of Cape Town; London School of Hygiene & Tropical Medicine; University of North Carolina Project; University of California, San Francisco; Mbarara University of Science and Technology; Edendale Hospital; Radboud University Nijmegen Medical Centre; Mahidol University; Nuffield Department of Clinical Medicine; Imperial College London
    Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes.Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality.Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 109cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age.In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P =. 007), but not with time to initiation of antiretroviral therapy (ART).Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes. © 2013 The Author.
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    Toxicity of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated cryptococcal meningitis
    (2015-12-01) 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; Joseph N. Jarvis; St George's University of London; London School of Hygiene & Tropical Medicine; St. Elisabeth Ziekenhuis; Mbarara University of Science and Technology; University of North Carolina Project; Mahidol University; Nuffield Department of Clinical Medicine; Edendale Hospital; University of Cape Town; Botswana-UPenn Partnership; University of Pennsylvania
    Copyright © 2015 Bicanic et al. 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; = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; = 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.