A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis

Thuy Le, Nguyen Van Kinh, Ngo T K Cuc, Nguyen L N Tung, Nguyen T Lam, Pham T T Thuy, Do D Cuong, Pham T H Phuc, Vu H Vinh, Doan T H Hanh, Vu Van Tam, Nguyen T Thanh, Tran P Thuy, Nguyen T Hang, Hoang B Long, Ho T Nhan, Heiman F L Wertheim, Laura Merson, Cecilia Shikuma, Jeremy N Day, Nguyen V V Chau, Jeremy Farrar, Guy Thwaites, Marcel Wolbers, IVAP Investigators, Nguyen Huu Chi, Vo Minh Quang, Nguyen Tran Chinh, Nguyen Quoc Hung, Le Duc Vinh, Nguyen Thanh Liem, Ly Quoc Cong, Vo Trieu Ly, Nguyen Phu Huong Lan, Dinh Nguyen Huy Man, Nguyen Thi Quynh Nga, Ta Thi Dieu Ngan, Nguyen Thi Hoai Dung, Nguyen Kim Thu, Pham Thi Khuong, Dang Thi Bich, Nguyen Van Long, Do Minh Hoang, Hoang Thi Thanh Tu, Le Xuan Luat, Nguyen Thi Dung, Nguyen Thi Lan, Tran Bang Huyen, Nguyen Quang Tuan, Doan Thu Tra, Le Thi Hoa, Tran Minh Hanh, Nguyen Thi Phuong, Tran Thi Lien, Dao Trong Hoang, Vu Thi Sinh, Chu Thi Nga, Lai Thi Quynh, Tran Viet Tiep, Ha Van Hien, Trinh Thu Hoan, Nguyen Thi Thu Ha, Le Quang Dong, Nguyen Thi Kim Anh, Tran Tinh Hien, Nguyen Thi Mai Thu, Ha Thuc Ai Hien, Ashley Nguyen, Vu Phuong Thao, Phan Thi Hong Dao, Hoang Suong Nguyet Anh, Duong Van Anh, James Campbell, Nguyen Thi Thanh Thuy, Nguyen Thi Phuong Dung, Ho Van Hien, Nguyen Thanh Tien, Nguyen Thu Van, Hoang Dieu Linh, Tran Thi Kieu Huong, Ngo Thanh Bao, Nguyen Bao Tran, Behzah Nadjim, Rogier van Doorn, Alastair Gray, William Hope, Mattias Larsson, Thomas Pouplin, Thuy Le, Nguyen Van Kinh, Ngo T K Cuc, Nguyen L N Tung, Nguyen T Lam, Pham T T Thuy, Do D Cuong, Pham T H Phuc, Vu H Vinh, Doan T H Hanh, Vu Van Tam, Nguyen T Thanh, Tran P Thuy, Nguyen T Hang, Hoang B Long, Ho T Nhan, Heiman F L Wertheim, Laura Merson, Cecilia Shikuma, Jeremy N Day, Nguyen V V Chau, Jeremy Farrar, Guy Thwaites, Marcel Wolbers, IVAP Investigators, Nguyen Huu Chi, Vo Minh Quang, Nguyen Tran Chinh, Nguyen Quoc Hung, Le Duc Vinh, Nguyen Thanh Liem, Ly Quoc Cong, Vo Trieu Ly, Nguyen Phu Huong Lan, Dinh Nguyen Huy Man, Nguyen Thi Quynh Nga, Ta Thi Dieu Ngan, Nguyen Thi Hoai Dung, Nguyen Kim Thu, Pham Thi Khuong, Dang Thi Bich, Nguyen Van Long, Do Minh Hoang, Hoang Thi Thanh Tu, Le Xuan Luat, Nguyen Thi Dung, Nguyen Thi Lan, Tran Bang Huyen, Nguyen Quang Tuan, Doan Thu Tra, Le Thi Hoa, Tran Minh Hanh, Nguyen Thi Phuong, Tran Thi Lien, Dao Trong Hoang, Vu Thi Sinh, Chu Thi Nga, Lai Thi Quynh, Tran Viet Tiep, Ha Van Hien, Trinh Thu Hoan, Nguyen Thi Thu Ha, Le Quang Dong, Nguyen Thi Kim Anh, Tran Tinh Hien, Nguyen Thi Mai Thu, Ha Thuc Ai Hien, Ashley Nguyen, Vu Phuong Thao, Phan Thi Hong Dao, Hoang Suong Nguyet Anh, Duong Van Anh, James Campbell, Nguyen Thi Thanh Thuy, Nguyen Thi Phuong Dung, Ho Van Hien, Nguyen Thanh Tien, Nguyen Thu Van, Hoang Dieu Linh, Tran Thi Kieu Huong, Ngo Thanh Bao, Nguyen Bao Tran, Behzah Nadjim, Rogier van Doorn, Alastair Gray, William Hope, Mattias Larsson, Thomas Pouplin

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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 .).

Source: PubMed

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