title: Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.
abstract: BACKGROUND
  Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis.
  
  
  METHODS
  In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole.
  
  
  RESULTS
  The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.
  
  
  CONCLUSIONS
  Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167.).
authors: From the Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Vietnam (J.B., M.W., J.F., L.M., G.T., J.N.D.), Hospital for Tropical Diseases (N.T.K.C., N.V.V.C.), Cho Ray Hospital (T.Q.B., L.P.), Ho Chi Minh City, and the National Hospital for Tropical Diseases (N.V.K.) and Bach Mai Hospital (P.T.T.), Hanoi - all in Vietnam; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford (J.B., M.W., J.F., L.M., G.T., M.M., D.D., J.N.D.), University College London, London (R.H.), and Liverpool School of Tropical Medicine, Liverpool (D.G.L.) - all in the United Kingdom; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda (F.M.K., A.-B.M.G., A.K.); Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok (W.C.), Ubon Sappasithiprasong Hospital, Ubon (S.S., W.S.), and Udon Thani Hospital, Udon Thani (E.T., S.O.) - all in Thailand; Dignitas International, Zomba (A.K.C., E.M., J.J.O.), and Malawi-Liverpool-Wellcome Trust, Clinical Research Programme (R.H., D.G.L.), and University of Malawi College of Medicine (R.H., J.J.O.), Blantyre - all in Malawi; Sunnybrook Health Sciences Centre, University of Toronto, Toronto (A.K.C.); Cipto Mangunkusumo Hospital (D.I.) and Eijkman Oxford Clinical Research Unit (H.B.) - both in Jakarta, Indonesia; and Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital (M.M., D.D., P.P., S.R.), and University of Health Sciences (M.M.) - both in Vientiane, Laos.
authors: Justin
authors: J
authors: Beardsley
authors: Marcel
authors: M
authors: Wolbers
authors: Freddie M
authors: FM
authors: Kibengo
authors: Abu-Baker M
authors: AB
authors: Ggayi
authors: Anatoli
authors: A
authors: Kamali
authors: Ngo Thi Kim
authors: NT
authors: Cuc
authors: Tran Quang
authors: TQ
authors: Binh
authors: Nguyen Van Vinh
authors: NV
authors: Chau
authors: Jeremy
authors: J
authors: Farrar
authors: Laura
authors: L
authors: Merson
authors: Lan
authors: L
authors: Phuong
authors: Guy
authors: G
authors: Thwaites
authors: Nguyen
authors: N
authors: Van Kinh
authors: Pham Thanh
authors: PT
authors: Thuy
authors: Wirongrong
authors: W
authors: Chierakul
authors: Suwatthiya
authors: S
authors: Siriboon
authors: Ekkachai
authors: E
authors: Thiansukhon
authors: Satrirat
authors: S
authors: Onsanit
authors: Watthanapong
authors: W
authors: Supphamongkholchaikul
authors: Adrienne K
authors: AK
authors: Chan
authors: Robert
authors: R
authors: Heyderman
authors: Edson
authors: E
authors: Mwinjiwa
authors: Joep J
authors: JJ
authors: van Oosterhout
authors: Darma
authors: D
authors: Imran
authors: Hasan
authors: H
authors: Basri
authors: Mayfong
authors: M
authors: Mayxay
authors: David
authors: D
authors: Dance
authors: Prasith
authors: P
authors: Phimmasone
authors: Sayaphet
authors: S
authors: Rattanavong
authors: David G
authors: DG
authors: Lalloo
authors: Jeremy N
authors: JN
authors: Day
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D002555:Cerebrospinal Fluid / Q000382:microbiology; D015170:Cerebrospinal Fluid Pressure; D015169:Colony Count, Microbial; D003455:Cryptococcus neoformans / Q000302:isolation & purification*; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016919:Meningitis, Cryptococcal / Q000188:drug therapy* / Q000401:mortality; D017211:Treatment Failure
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone