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Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking.In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile.The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

Original publication

DOI

10.1056/nejmoa1613306

Type

Journal article

Journal

The New England journal of medicine

Publication Date

06/2017

Volume

376

Pages

2329 - 2340

Addresses

From Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit (T.L., N.T.T., T.P.T., N.T.H., H.B.L., H.T.N., H.F.L.W., J.N.D., J.F., G.T., M.W.), and the Hospital for Tropical Diseases (N.T.K.C., N.L.N.T., N.V.V.C.), Ho Chi Minh City, the National Hospital for Tropical Diseases (N.V.K., N.T.L.) and Bach Mai Hospital (P.T.T.T., D.D.C.), Hanoi, Viet Tiep Hospital, Hai Phong (P.T.H.P., V.H.V.), and Vietnam-Sweden Uong Bi Hospital, Quang Ninh (D.T.H.H., V.V.T.) - all in Vietnam; the Centre for Tropical Medicine and Global Health (T.L., J.N.D., G.T., M.W.), and the Worldwide Antimalarial Resistance Network (L.M.), University of Oxford, Oxford, United Kingdom; the Department of Medical Microbiology, Radboudumc, Nijmegen, the Netherlands (H.F.L.W.); and the Hawaii Center for AIDS, University of Hawaii at Manoa, Honolulu (T.L., C.S.).

Keywords

IVAP Investigators, Humans, Talaromyces, AIDS-Related Opportunistic Infections, Mycoses, Amphotericin B, Itraconazole, Creatinine, Deoxycholic Acid, Drug Combinations, Antifungal Agents, Administration, Oral, Infusions, Intravenous, Adult, Female, Male, Induction Chemotherapy