Justin Beardsley1, Marcel Wolbers, Freddie M Kibengo, Abu-Baker M Ggayi, Anatoli Kamali, Ngo Thi Kim Cuc, Tran Quang Binh, Nguyen Van Vinh Chau, Jeremy Farrar, Laura Merson, Lan Phuong, Guy Thwaites, Nguyen Van Kinh, Pham Thanh Thuy, Wirongrong Chierakul, Suwatthiya Siriboon, Ekkachai Thiansukhon, Satrirat Onsanit, Watthanapong Supphamongkholchaikul, Adrienne K Chan, Robert Heyderman, Edson Mwinjiwa, Joep J van Oosterhout, Darma Imran, Hasan Basri, Mayfong Mayxay, David Dance, Prasith Phimmasone, Sayaphet Rattanavong, David G Lalloo, Jeremy N Day. 1. 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.
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.).
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: C M van der Horst; M S Saag; G A Cloud; R J Hamill; J R Graybill; J D Sobel; P C Johnson; C U Tuazon; T Kerkering; B L Moskovitz; W G Powderly; W E Dismukes Journal: N Engl J Med Date: 1997-07-03 Impact factor: 91.245
Authors: Somnuek Sungkanuparph; Scott G Filler; Ploenchan Chetchotisakd; Peter G Pappas; Tracy L Nolen; Weerawat Manosuthi; Thanomsak Anekthananon; Michele I Morris; Khuanchai Supparatpinyo; Heather Kopetskie; Amy S Kendrick; Philip C Johnson; Jack D Sobel; Robert A Larsen Journal: Clin Infect Dis Date: 2009-09-15 Impact factor: 9.079
Authors: O Lortholary; M Nicolas; S Soreda; L Improvisi; O Ronin; O Petitjean; B Dupont; M Tod; F Dromer Journal: J Antimicrob Chemother Date: 1999-06 Impact factor: 5.790
Authors: Cameron P Simmons; Guy E Thwaites; Nguyen Than Ha Quyen; Tran Thi Hong Chau; Pham Phuong Mai; Nguyen Thi Dung; Kasia Stepniewska; Nicholas J White; Tran Tinh Hien; Jeremy Farrar Journal: J Immunol Date: 2005-07-01 Impact factor: 5.422
Authors: Matthew Scarborough; Stephen B Gordon; Christopher J M Whitty; Neil French; Yasin Njalale; Alex Chitani; Timothy E A Peto; David G Lalloo; Eduard E Zijlstra Journal: N Engl J Med Date: 2007-12-13 Impact factor: 91.245
Authors: Thi Hoang Mai Nguyen; Thi Hong Chau Tran; Guy Thwaites; Van Chuong Ly; Xuan Sinh Dinh; Trung Nghia Ho Dang; Quoc Tuan Dang; Duy Phong Nguyen; Hoan Phu Nguyen; Song Diep To; van Vinh Chau Nguyen; Minh Duong Nguyen; James Campbell; Constance Schultsz; Chris Parry; M Estee Torok; Nicholas White; Tran Chinh Nguyen; Tinh Hien Tran; Kasia Stepniewska; Jeremy J Farrar Journal: N Engl J Med Date: 2007-12-13 Impact factor: 91.245
Authors: Daniel Dubinski; Elke Hattingen; Christian Senft; Volker Seifert; Kevin G Peters; Yvonne Reiss; Kavi Devraj; Karl H Plate Journal: J Cereb Blood Flow Metab Date: 2019-06-25 Impact factor: 6.200
Authors: Joseph N Jarvis; Tshepo B Leeme; Mooketsi Molefi; Awilly A Chofle; Gabriella Bidwell; Katlego Tsholo; Nametso Tlhako; Norah Mawoko; Raju K K Patel; Mark W Tenforde; Charles Muthoga; Gregory P Bisson; Jeremiah Kidola; John Changalucha; David Lawrence; Shabbar Jaffar; William Hope; Si le F Molloy; Thomas S Harrison Journal: Clin Infect Dis Date: 2019-01-18 Impact factor: 9.079
Authors: Nicole M Dischler; Lijian Xu; Yan Li; Connie B Nichols; J Andrew Alspaugh; Gerald F Bills; James B Gloer Journal: J Nat Prod Date: 2019-03-07 Impact factor: 4.050
Authors: Peter R Williamson; Joseph N Jarvis; Anil A Panackal; Matthew C Fisher; Síle F Molloy; Angela Loyse; Thomas S Harrison Journal: Nat Rev Neurol Date: 2016-11-25 Impact factor: 42.937
Authors: Anil A Panackal; Mika Komori; Peter Kosa; Omar Khan; Dima A Hammoud; Lindsey B Rosen; Sarah K Browne; Yen-Chih Lin; Elena Romm; Charu Ramaprasad; Bettina C Fries; John E Bennett; Bibiana Bielekova; Peter R Williamson Journal: Clin Infect Dis Date: 2016-11-10 Impact factor: 9.079