Browsing by Author "Day, Jeremy N"

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Open Access
A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.
(N Engl J Med, 2018-03-16) Le, Thuy; Kinh, Nguyen Van; Cuc, Ngo TK; Tung, Nguyen LN; Lam, Nguyen T; Thuy, Pham TT; Cuong, Do D; Phuc, Pham TH; Vinh, Vu H; Hanh, Doan TH; Tam, Vu Van; Thanh, Nguyen T; Thuy, Tran P; Hang, Nguyen T; Long, Hoang B; Nhan, Ho T; Wertheim, Heiman FL; Merson, Laura; Shikuma, Cecilia; Day, Jeremy N; Chau, Nguyen VV; Farrar, Jeremy; Thwaites, Guy; Wolbers, Marcel; IVAP Investigators
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 .).
Open Access
Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis
(New England Journal of Medicine, 2016-02-11) Beardsley, Justin; Wolbers, Marcel; Kibengo, Freddie M; Ggayi, Abu-Baker M; Kamali, Anatoli; Cuc, Ngo Thi Kim; Binh, Tran Quang; Chau, Nguyen Van Vinh; Farrar, Jeremy; Merson, Laura; Phuong, Lan; Thwaites, Guy; Van Kinh, Nguyen; Thuy, Pham Thanh; Chierakul, Wirongrong; Siriboon, Suwatthiya; Thiansukhon, Ekkachai; Onsanit, Satrirat; Supphamongkholchaikul, Watthanapong; Chan, Adrienne K; Heyderman, Robert; Mwinjiwa, Edson; van Oosterhout, Joep J; Imran, Darma; Basri, Hasan; Mayxay, Mayfong; Dance, David; Phimmasone, Prasith; Rattanavong, Sayaphet; Lalloo, David G; Day, Jeremy N
Open Access
AIDS-associated Penicillium marneffei infection of the central nervous system.
(Clin Infect Dis, 2010-12-15) Le, Thuy; Huu Chi, Nguyen; Kim Cuc, Ngo T; Manh Sieu, Tran Phu; Shikuma, Cecilia M; Farrar, Jeremy; Day, Jeremy N
Penicillium marneffei is an important human immunodeficiency virus-associated opportunistic infection endemic in Southeast Asia. Central nervous system infection has not been described. We report the first case series of 21 human immunodeficiency virus-infected patients who presented with a syndrome consistent with acute central nervous system infection and who had Penicillium marneffei isolated from cerebrospinal fluid.
Open Access
AIDS‐associated Cryptococcus neoformans and Penicillium marneffei coinfection: a therapeutic dilemma in resource‐limited settings.
(Clin Infect Dis, 2010-11-01) Le, Thuy; Hong Chau, Tran Thi; Kim Cuc, Ngo Thi; Si Lam, Pham; Manh Sieu, Tran Phu; Shikuma, Cecilia M; Day, Jeremy N
AIDS‐associated Cryptococcus neoformans and Penicillium marneffei coinfection has not been adequately studied and poses unique therapeutic challenges in resource‐limited settings. Itraconazole poorly penetrates the central nervous system, whereas fluconazole has poor activity against P. marneffei. We prospectively report management of 1 patient and retrospectively review 7 coinfection cases from Vietnam.
Open Access
Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam.
(Clin Infect Dis, 2011-04-01) Le, Thuy; Wolbers, Marcel; Chi, Nguyen Huu; Quang, Vo Minh; Chinh, Nguyen Tran; Lan, Nguyen Phu Huong; Lam, Pham Si; Kozal, Michael J; Shikuma, Cecilia M; Day, Jeremy N; Farrar, Jeremy
BACKGROUND: Penicillium marneffei is an important human immunodeficiency virus (HIV)-associated opportunistic pathogen in Southeast Asia. The epidemiology and the predictors of penicilliosis outcome are poorly understood. METHODS: We performed a retrospective study of culture-confirmed incident penicilliosis admissions during 1996-2009 at the Hospital for Tropical Diseases in Ho Chi Minh City, Viet Nam. Seasonality of penicilliosis was assessed using cosinor models. Logistic regression was used to assess predictors of death or worsening disease based on 10 predefined covariates, and Cox regression was performed to model time-to-antifungal initiation. RESULTS: A total of 795 patients were identified; hospital charts were obtainable for 513 patients (65%). Cases increased exponentially and peaked in 2007 (156 cases), mirroring the trends in AIDS admissions during the study period. A highly significant seasonality for penicilliosis (P<.001) but not for cryptococcosis (P=.63) or AIDS admissions (P=.83) was observed, with a 27% (95% confidence interval, 14%-41%) increase in incidence during rainy months. All patients were HIV infected; the median CD4 cell count (62 patients) was 7 cells/μL (interquartile range, 4-24 cells/μL). Hospital outcome was an improvement in 347 (68%), death in 101 (20%), worsening in 42 (8%), and nonassessable in 23 (5%) cases. Injection drug use, shorter history, absence of fever or skin lesions, elevated respiratory rates, higher lymphocyte count, and lower platelet count independently predicted poor outcome in both complete-case and multiple-imputation analyses. Time-to-treatment initiation was shorter for patients with skin lesions (hazard ratio, 3.78; 95% confidence interval, 2.96-4.84; P<.001). CONCLUSIONS: Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome.
Open Access
High prevalence of PI resistance in patients failing second-line ART in Vietnam.
(J Antimicrob Chemother, 2016-03) Thao, Vu Phuong; Quang, Vo Minh; Day, Jeremy N; Chinh, Nguyen Tran; Shikuma, Cecilia M; Farrar, Jeremy; Van Vinh Chau, Nguyen; Thwaites, Guy E; Dunstan, Sarah J; Le, Thuy
BACKGROUND: There are limited data from resource-limited settings on antiretroviral resistance mutations that develop in patients failing second-line PI ART. METHODS: We performed a cross-sectional virological assessment of adults on second-line ART for ≥6 months between November 2006 and December 2011, followed by a prospective follow-up over 2 years of patients with virological failure (VF) at the Hospital for Tropical Diseases, Vietnam. VF was defined as HIV RNA concentrations ≥1000 copies/mL. Resistance mutations were identified by population sequencing of the pol gene and interpreted using the 2014 IAS-USA mutation list and the Stanford algorithm. Logistic regression modelling was performed to identify predictors of VF. RESULTS: Two hundred and thirty-one patients were enrolled in the study. The median age was 32 years; 81.0% were male, 95.7% were on a lopinavir/ritonavir-containing regimen and 22 (9.5%) patients had VF. Of the patients with VF, 14 (64%) carried at least one major protease mutation [median: 2 (IQR: 1-3)]; 13 (59%) had multiple protease mutations conferring intermediate- to high-level resistance to lopinavir/ritonavir. Mutations conferring cross-resistance to etravirine, rilpivirine, tipranavir and darunavir were identified in 55%, 55%, 45% and 27% of patients, respectively. Higher viral load, adherence <95% and previous indinavir use were independent predictors of VF. The 2 year outcomes of the patients maintained on lopinavir/ritonavir included: death, 7 (35%); worsening virological/immunological control, 6 (30%); and virological re-suppression, 5 (25%). Two patients were switched to raltegravir and darunavir/ritonavir with good HIV control. CONCLUSIONS: High-prevalence PI resistance was associated with previous indinavir exposure. Darunavir plus an integrase inhibitor and lamivudine might be a promising third-line regimen in Vietnam.
Open Access
Occult Talaromyces marneffei Infection Unveiled by the Novel Mp1p Antigen Detection Assay.
(Open forum infectious diseases, 2020-11) Ly, Vo Trieu; Thanh, Nguyen Tat; Thu, Nguyen Thi Mai; Chan, Jasper; Day, Jeremy N; Perfect, John; Nga, Cao Ngoc; Vinh Chau, Nguyen Van; Le, Thuy
Talaromyces marneffei causes fatal invasive mycosis in Southeast Asia. Diagnosis by culture has limited sensitivity and can result in treatment delay. We describe the use of a novel Mp1p enzyme immunoassay (EIA) to identify blood culture-negative talaromycosis, subsequently confirmed by bone marrow cultures. This EIA has the potential to speed diagnosis, enabling early therapy initiation.
Open Access
Superiority of a novel Mp1p antigen detection enzyme immunoassay compared to standard BACTEC blood culture in the diagnosis of talaromycosis.
(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-06-21) Thu, Nguyen TM; Chan, Jasper FW; Ly, Vo Trieu; Ngo, Hoa T; Hien, Ha TA; Lan, Nguyen PH; Chau, Nguyen VV; Cai, Jian-Piao; Woo, Patrick CY; Day, Jeremy N; van Doorn, Rogier; Thwaites, Guy; Perfect, John; Yuen, Kwok; Le, Thuy
BACKGROUND:Talaromycosis is an invasive mycosis endemic in Southeast Asia and causes substantial morbidity and mortality in individuals with advanced HIV disease. Current diagnosis relies on isolating Talaromyces marneffei in cultures, which takes up to 14 days and is detectable only during late-stage infection, leading to high mortality. METHODS:In this retrospective case-control study, we assessed the accuracy of a novel Mp1p antigen-detecting enzyme immunoassay (EIA) in stored plasma samples of 372 patients who had culture-proven talaromycosis from blood or sterile body fluids(reference standard) and of 517 individuals without talaromycosis (338 healthy volunteers; 179 with other infections). All participants were recruited between 2011-2017 in Vietnam. RESULTS:66.1% and 75.4% of cases and controls were male; the median age was 33 and 37, respectively. All cases were HIV-infected; median CD4 count was 10 cells/mm3. At an optical density cut-off of 0.5, the specificity was 98.1% (95% CI: 96.3%-99.0%); the sensitivity was superior to blood culture, 86.3% (95% CI: 82.3%-89.5%) versus 72.8% (95% CI: 68.0%-77.2%), P<0.001, McNemar test. The time-to-diagnosis was 6 hours versus 6.6 ± 3.0 days for blood culture. Paired plasma and urine testing in the same patients (N=269) significantly increased sensitivity compared to testing plasma alone P<0.001, or testing urine alone P=0.02, McNemar tests. CONCLUSIONS:The Mp1p EIA is highly specific and is superior in sensitivity and time-to-diagnosis compared to blood culture for the diagnosis of talaromycosis. Paired plasma and urine testing further increases sensitivity, introducing a new tool for rapid diagnosis, enabling early treatment and potentially reducing mortality.
Open Access
The decline of typhoid and the rise of non-typhoid salmonellae and fungal infections in a changing HIV landscape: bloodstream infection trends over 15 years in southern Vietnam
(Transactions of the Royal Society of Tropical Medicine and Hygiene, 2012-01) Nga, Tran Vu Thieu; Parry, Christopher M; Le, Thuy; Lan, Nguyen Phu Huong; Diep, To Song; Campbell, James I; Hoang, Nguyen Van Minh; Dung, Le Thi; Wain, John; Dolecek, Christiane; Farrar, Jeremy J; Chau, Nguyen Van Vinh; Hien, Tran Tinh; Day, Jeremy N; Baker, Stephen