register interest

Professor Jeremy Day

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health
Keywords: CNS, Infections, Cryptococcus, meningitis, HIV, opportunistic infections and randomized controlled trials

In the CNS-HIV infections research group we run a programme of science driven by randomized controlled trials powered to relevant and easily understandable clinical endpoints. The main areas of interest are opportunistic infections including cryptococcosis and penicilliosis, TB meningitis, acute bacterial meningitis, encephalitis and HIV drug resistance. In addition to improving patient outcomes, we are interested in innovative approaches to clinical trial design, health economics,  ecology, epidemiology and determinants of pathogenicity of the organisms we study.

Name Department Institution Country
Professor Stephen Baker Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Professor Guy Thwaites Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Emeritus Professor Nick Hunt University of Sydney Australia
Professor John Perfect Duke University United States
Henrik Antii University of Umea Sweden
Professor Joel Tarning Tropical Medicine Oxford University, Bangkok Thailand
Professor David Lalloo Liverpool School of Tropical Medicine United Kingdom
Professor William Hope Liverpool University United Kingdom
Professor Sir Nicholas J White FRS Tropical Medicine Oxford University, Bangkok Thailand
Professor Gordon Dougan FRS Microbial Pathogenesis Wellcome Trust Sanger Institute United Kingdom
Dr Simon Harris Sanger Institute United Kingdom
Professor Paul Newton Tropical Medicine Oxford University, Vientiane Laos
Wirongrong Cheirakul Tropical Medicine Oxford University, Bangkok Thailand
Anatoli Kamali MRC/UVRI Uganda Uganda
Freddie Kibengo MRC/UVRI Entebbe Uganda
Associate Professor Dee Carter University of Sydney Australia
Professor Damian Krysan University of Rochester United States
Professor Nicholas PJ Day FMedSci FRCP Tropical Medicine Oxford University, Bangkok Thailand
Professor Tran T Hien Tropical Medicine Oxford University, Ho Chi Minh City Vietnam
Le T, Kinh NV, Cuc NTK, Tung NLN, Lam NT, Thuy PTT, Cuong DD, Phuc PTH, Vinh VH, Hanh DTH et al. 2017. A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis. N Engl J Med, 376 (24), pp. 2329-2340. | Show Abstract | Read more

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 .).

Day JN, Qihui S, Thanh LT, Trieu PH, Van AD, Thu NH, Chau TTH, Lan NPH, Chau NVV, Ashton PM et al. 2017. Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam. PLoS Negl Trop Dis, 11 (6), pp. e0005628. | Show Abstract | Read more

The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher's exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109 cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

Heemskerk AD, Nguyen MTH, Dang HTM, Vinh Nguyen CV, Nguyen LH, Do TDA, Nguyen TTT, Wolbers M, Day J, Le TTP et al. 2017. Clinical Outcomes of Patients With Drug-Resistant Tuberculous Meningitis Treated With an Intensified Antituberculosis Regimen. Clin Infect Dis, 65 (1), pp. 20-28. | Show Abstract | Read more

Background: Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment. Methods: We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression. Results: Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM. Conclusions: Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored. Clinical Trials Registration: ISRCTN61649292.

Berto A, Day J, Van Vinh Chau N, Thwaites GE, My NN, Baker S, Darton TC. 2017. Current challenges and possible solutions to improve access to care and treatment for hepatitis C infection in Vietnam: a systematic review. BMC Infect Dis, 17 (1), pp. 260. | Show Abstract | Read more

BACKGROUND: Hepatitis C infection is a major public health concern in low- and middle-income countries where an estimated 71.1 million individuals are living with chronic infection. The World Health Organization (WHO) has recently released new guidance for hepatitis C virus (HCV) treatment programs, which include improving the access to new direct-acting antiviral agents. In Vietnam, a highly populated middle-income country, the seroprevalence of HCV infection is approximately 4% and multiple genotypes co-circulate in the general population. Here we review what is currently known regarding the epidemiology of HCV in Vietnam and outline options for reducing the significant burden of morbidity and mortality in our setting. METHODS: We performed a systematic review of the currently available literature to evaluate what has been achieved to date with efforts to control HCV infection in Vietnam. RESULTS: This search retrieved few publications specific to Vietnam indicating a significant gap in baseline epidemiological and public health data. Key knowledge gaps identified included an understanding of the prevalence in specific high-risk groups, characterization of circulating HCV genotypes in the population and likely response to treatment, and the extent to which HCV treatment is available, accessed and utilized. CONCLUSIONS: We conclude that there is an urgent need to perform up to date assessments of HCV disease burden in Vietnam, especially in high-risk groups, in whom incidence is high and cross infection with multiple genotypes is likely to be frequent. Coordinating renewed surveillance measures with forthcoming HCV treatment studies should initiate the traction required to achieve the WHO goal of eliminating HCV as a public health threat by 2030, at least in this region.

Nguyen Thi Hoang M, Nguyen Hoan P, Le Van T, McBride A, Ho Dang Trung N, Tran Tan T, Nguyen Thi Thu H, Heemskerk D, Day J, Vincent A et al. 2017. First reported cases of anti-NMDA receptor encephalitis in Vietnamese adolescents and adults. J Neurol Sci, 373 pp. 250-253. | Show Abstract | Read more

INTRODUCTION: Anti-NMDA receptor encephalitis is increasingly recognised as an important differential diagnosis in patients with encephalitis of unknown aetiology. We report the first case series of patients diagnosed in Vietnam. METHODS: Samples of CSF from patients with presumed encephalitis but negative microbiological investigations, who exhibited dyskinesia, autonomic instability or psychosis were tested for antibodies against the NR1 subunit of the glutamate (type-NMDA) receptor using an indirect immunofluorescence assay. RESULTS: Of 99 patients admitted with all-cause encephalitis over an 18month period, 9.1% (n=9 patients, 5 female, median age 28years) had confirmed NMDAR encephalitis. All patients were admitted from one mental health hospital, and the incidence may therefore be an underestimate. Common features included reduction in speech (n=9), catatonia (n=9), convulsions (n=7), dyskinesia (n=9), rigidity (n=9) and autonomic dysfunction (n=7). Aside from a modest lymphocytic pleocytosis, routine CSF analysis was usually normal. No female patient had ovarian teratoma detected by abdominal ultrasound. Most patients were treated with high dose corticosteroids, and one patient received intravenous immunoglobulin. The median duration of hospitalization was 75days and no patient died during admission. CONCLUSIONS: Anti-NMDA receptor encephalitis is an important differential diagnosis to consider for patients presenting with acute onset psychiatric symptoms, who develop ensuing seizures, movement or autonomic disorder in Vietnam. A stronger evidence base for management and access to second line immunotherapy agents may help to reduce morbidity from this disease.

McBride A, Chau TTH, Hong NTT, Mai NTH, Anh NT, Thanh TT, Van TTH, Xuan LT, Sieu TPM, Thai LH et al. 2017. Angiostrongylus cantonensis Is an Important Cause of Eosinophilic Meningitis in Southern Vietnam. Clin Infect Dis, 64 (12), pp. 1784-1787. | Show Abstract | Read more

We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity.

Bang ND, Caws M, Truc TT, Duong TN, Dung NH, Ha DT, Thwaites GE, Heemskerk D, Tarning J, Merson L et al. 2016. Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: a prospective descriptive study. BMC Infect Dis, 16 (1), pp. 573. | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome. METHODS: A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion. RESULTS: The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19-10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01-174.3, p < 0.001), focal neurological deficits (HR 15.7, 95CI 1.67-2075, p = 0.01), Blantyre Coma Score (HR 3.75, 95CI 0.99-14.2, p < 0.001) and CSF protein, lactate and glucose levels. Neck stiffness, MRC grade (children aged >5 years) and hydrocephalus were also associated with the combined endpoint of death or disability. CONCLUSIONS: Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes.

Veringa A, van der Elst KC, Day JN, Thwaites GE, Alffenaar JW. 2016. Sertraline for HIV-associated cryptococcal meningitis. Lancet Infect Dis, 16 (10), pp. 1111. | Read more

Beardsley J, Wolbers M, Day JN, CryptoDex Investigators. 2016. Dexamethasone in Cryptococcal Meningitis. N Engl J Med, 375 (2), pp. 189-190. | Read more

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L et al. 2016. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med, 374 (6), pp. 542-554. | Show Abstract | Read more

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.).

Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT et al. 2016. Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engl J Med, 374 (2), pp. 124-134. | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). CONCLUSIONS: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).

Oude Munnink BB, Phan MVT, van der Hoek L, Kellam P, Cotten M. 2016. Genome Sequences of a Novel Vietnamese Bat Bunyavirus Genome Announcements, 4 (6), pp. e01366-16-e01366-16. | Show Abstract | Read more

© 2016 Oude Munnink et al. To document the viral zoonotic risks in Vietnam, fecal samples were systematically collected from a number of mammals in southern Vietnam and subjected to agnostic deep sequencing. We describe here novel Vietnamese bunyavirus sequences detected in bat feces. The complete L and S segments from 14 viruses were determined.

Pouplin T, Bang ND, Toi PV, Phuong PN, Dung NH, Duong TN, Caws M, Thwaites GE, Tarning J, Day JN. 2016. Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infect Dis, 16 (1), pp. 144. | Show Abstract | Read more

BACKGROUND: Among the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30% mortality and 50% of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen. METHODS: We performed a prospective observational study of 100 consecutively treated children (≤ 15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled non-compartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age. RESULTS: Younger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with -14%, -22% and -16% for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children. CONCLUSIONS: There is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.

Thao VP, Quang VM, Day JN, Chinh NT, Shikuma CM, Farrar J, Van Vinh Chau N, Thwaites GE, Dunstan SJ, Le T. 2016. High prevalence of PI resistance in patients failing second-line ART in Vietnam. J Antimicrob Chemother, 71 (3), pp. 762-774. | Show Abstract | Read more

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.

Wolbers M, Day JN. 2015. Limitation of the Benefit of Amphotericin-Flucytosine Combination Therapy in Patients With Lower Conscious Level: An Ecological Fallacy? Open Forum Infect Dis, 2 (2), pp. ofv069. | Read more

Beardsley J, Denning DW, Chau NV, Yen NT, Crump JA, Day JN. 2015. Estimating the burden of fungal disease in Vietnam. Mycoses, 58 Suppl 5 pp. 101-106. | Show Abstract | Read more

Data regarding the prevalence of fungal infections in Vietnam are limited yet they are likely to occur more frequently as increasingly sophisticated healthcare creates more iatrogenic risk factors. In this study, we sought to estimate baseline incidence and prevalence of selected serious fungal infections for the year 2012. We made estimates with a previously described actuarial method, using reports on the incidence and prevalence of various established risk factors for fungal infections from Vietnam, or similar environments, supplemented by personal communications. Global data were used if local data were unavailable. We estimated 2,352,748 episodes of serious fungal infection occurred in Vietnam in 2012. Frequent conditions included recurrent vaginal candidiasis (3893/100,000 women annually), tinea capitis (457/100,000 annually) and chronic pulmonary aspergillosis (61/100,000/5 year period). We estimated 140 cases of cryptococcal meningitis, 206 of penicilliosis and 608 of Pneumocystis jirovecii pneumonia. This is the first summary of Vietnamese fungal infections. The majority of severe disease is due to Aspergillus species, driven by the high prevalence of pulmonary tuberculosis. The AIDS epidemic highlights opportunistic infections, such as penicilliosis and cryptococcosis, which may complicate immunosuppressive treatments. These estimates provide a useful indication of disease prevalence to inform future research and resource allocation but should be verified by further epidemiological approaches.

Day J, Imran D, Ganiem AR, Tjahjani N, Wahyuningsih R, Adawiyah R, Dance D, Mayxay M, Newton P, Phetsouvanh R et al. 2014. CryptoDex: a randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial. Trials, 15 (1), pp. 441. | Show Abstract | Read more

BACKGROUND: Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa.No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested.The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention. METHOD: A double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University's Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012.

Tan LEV, Thai LEH, Phu NH, Nghia HD, Chuong LV, Sinh DX, Phong ND, Mai NT, Man DN, Hien VM et al. 2014. Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years. PLoS Negl Trop Dis, 8 (8), pp. e3127. | Show Abstract | Read more

BACKGROUND: Central nervous system (CNS) infections are important diseases in both children and adults worldwide. The spectrum of infections is broad, encompassing bacterial/aseptic meningitis and encephalitis. Viruses are regarded as the most common causes of encephalitis and aseptic meningitis. Better understanding of the viral causes of the diseases is of public health importance, in order to better inform immunization policy, and may influence clinical management. METHODOLOGY/PRINCIPAL FINDINGS: Study was conducted at the Hospital for Tropical Diseases in Ho Chi Minh City, a primary, secondary, and tertiary referral hospital for all southern provinces of Vietnam. Between December 1996 and May 2008, patients with CNS infections of presumed viral origin were enrolled. Laboratory diagnostics consisted of molecular and serological tests targeted at 14 meningitis/encephalitis-associated viruses. Of 291 enrolled patients, fatal outcome and neurological sequelae were recorded in 10% (28/291) and 27% (78/291), respectively. Mortality was especially high (9/19, 47%) amongst those with confirmed herpes simplex encephalitis which is attributed to the limited availability of intravenous acyclovir/valacyclovir. Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses were the most common viruses detected, responsible for 36 (12%), 19 (6.5%), 19 (6.5%) and 8 (2.7%) respectively, followed by rubella virus (6, 2%), varicella zoster virus (5, 1.7%), mumps virus (2, 0.7%), cytomegalovirus (1, 0.3%), and rabies virus (1, 0.3%). CONCLUSIONS/SIGNIFICANCE: Viral infections of the CNS in adults in Vietnam are associated with high morbidity and mortality. Despite extensive laboratory testing, 68% of the patients remain undiagnosed. Together with our previous reports, the data confirm that Japanese encephalitis virus, dengue virus, herpes simplex virus, and enteroviruses are the leading identified causes of CNS viral infections in Vietnam, suggest that the majority of morbidity/mortality amongst patients with a confirmed/probable diagnosis is preventable by adequate vaccination/treatment, and are therefore of public health significance.

Day JN. 2014. Open access clinical trials in cryptococcal meningitis MYCOSES, 57 pp. 28-28.

Day JN, Duong VA, Chau TTH, Hoang TN, Wolbers M. 2014. Relationship of susceptibility testing of Cryptococcus neoformans to survival and mycological clearance in HIV associated cryptococcal meningitis MYCOSES, 57 pp. 106-107.

Nhu NT, Heemskerk D, Thu DODA, Chau TT, Mai NT, Nghia HD, Loc PP, Ha DT, Merson L, Thinh TT et al. 2014. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol, 52 (1), pp. 226-233. | Show Abstract | Read more

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Microbiological confirmation is rare, and treatment is often delayed, increasing mortality and morbidity. The GeneXpert MTB/RIF test was evaluated in a large cohort of patients with suspected tuberculous meningitis. Three hundred seventy-nine patients presenting with suspected tuberculous meningitis to the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, between 17 April 2011 and 31 December 2012 were included in the study. Cerebrospinal fluid samples were tested by Ziehl-Neelsen smear, mycobacterial growth indicator tube (MGIT) culture, and Xpert MTB/RIF. Rifampin (RIF) resistance results by Xpert were confirmed by an MTBDR-Plus line probe assay and all positive cultures were tested by phenotypic MGIT drug susceptibility testing. Overall, 182/379 included patients (48.0%) were diagnosed with tuberculous meningitis. Sensitivities of Xpert, smear, and MGIT culture among patients diagnosed with TBM were 59.3% (108/182 [95% confidence interval {CI}, 51.8 to 66.5%]), 78.6% (143/182 [95% CI, 71.9 to 84.3%]) and 66.5% (121/182 [95% CI, 59.1 to 73.3%]), respectively. There was one false-positive Xpert MTB/RIF test (99.5% specificity). Four cases of RIF resistance (4/109; 3.7%) were identified by Xpert, of which 3 were confirmed to be multidrug-resistant (MDR) TBM and one was culture negative. Xpert MTB/RIF is a rapid and specific test for the diagnosis of tuberculous meningitis. The addition of a vortexing step to sample processing increased sensitivity for confirmed TBM by 20% (P = 0.04). Meticulous examination of a smear from a large volume of cerebrospinal fluid (CSF) remains the most sensitive technique but is not practical in most laboratories. The Xpert MTB/RIF represents a significant advance in the early diagnosis of this devastating condition.

Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. 2013. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother, 68 (11), pp. 2435-2444. | Show Abstract | Read more

Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.

Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ et al. 2013. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med, 368 (14), pp. 1291-1302. | Show Abstract | Read more

BACKGROUND: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

Day JN, Chau TT, Lalloo DG. 2013. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med, 368 (26), pp. 2522-2523. | Read more

Henk DA, Shahar-Golan R, Devi KR, Boyce KJ, Zhan N, Fedorova ND, Nierman WC, Hsueh PR, Yuen KY, Sieu TP et al. 2012. Clonality despite sex: the evolution of host-associated sexual neighborhoods in the pathogenic fungus Penicillium marneffei. PLoS Pathog, 8 (10), pp. e1002851. | Show Abstract | Read more

Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei.

Tho DQ, Török ME, Yen NT, Bang ND, Lan NT, Kiet VS, van Vinh Chau N, Dung NH, Day J, Farrar J et al. 2012. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis. Antimicrob Agents Chemother, 56 (6), pp. 3074-3079. | Show Abstract | Read more

HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.

Ho Dang Trung N, Le Thi Phuong T, Wolbers M, Nguyen Van Minh H, Nguyen Thanh V, Van MP, Thieu NT, Van TL, Song DT, Thi PL et al. 2012. Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study. PLoS One, 7 (5), pp. e37825. | Show Abstract | Read more

BACKGROUND: Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen. METHODS: We conducted a prospective Provincial Hospital-based descriptive surveillance study in adults and children at thirteen hospitals in central and southern Viet Nam between August 2007-April 2010. The pathogens of CNS infection were confirmed in CSF and blood samples by using classical microbiology, molecular diagnostics and serology. RESULTS: We recruited 1241 patients with clinically suspected infection of the CNS. An aetiological agent was identified in 640/1241 (52%) of the patients. The most common pathogens were Streptococcus suis serotype 2 in patients older than 14 years of age (147/617, 24%) and Japanese encephalitis virus in patients less than 14 years old (142/624, 23%). Mycobacterium tuberculosis was confirmed in 34/617 (6%) adult patients and 11/624 (2%) paediatric patients. The acute case fatality rate (CFR) during hospital admission was 73/617 (12%) in adults and to 42/624 (7%) in children. CONCLUSIONS: Zoonotic bacterial and viral pathogens are the most common causes of CNS infection in adults and children in Viet Nam.

Nga TV, Parry CM, Le T, Lan NP, Diep TS, Campbell JI, Hoang NV, Dung LET, Wain J, Dolecek C et al. 2012. 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. Trans R Soc Trop Med Hyg, 106 (1), pp. 26-34. | Show Abstract | Read more

The etiological spectrum of bloodstream infections is variable between industrialized and developing countries and even within a defined location over time. We investigated trends in bloodstream infections at an infectious disease hospital in Ho Chi Minh City, Vietnam, from 1994-2008. Amongst 66,111 blood cultures performed, a clinically relevant pathogen was isolated in 7645 episodes (positivity rate; 116/1000 cultures). Salmonella Typhi was the predominant pathogen until 2002; however, a considerable annual decline in the proportion of S. Typhi was observed (OR 0.6993, 95% CI [0.6885, 0.7103], p<0.0001). Conversely, there was a significant increase in the proportions of non-typhoidal Salmonella (NTS), Cryptococcus neoformans and Penicillium marneffei, concurrent with increasing HIV prevalence. These data document a substantial longitudinal shift in bloodstream infection etiology in southern Vietnam. We propose such changes are related to increasing economic prosperity and HIV prevalence, and this pattern marks a substantial change in the epidemiology of invasive salmonellosis in Southeast Asia.

Le T, Wolbers M, Chi NH, Quang VM, Chinh NT, Lan NP, Lam PS, Kozal MJ, Shikuma CM, Day JN, Farrar J. 2011. Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis, 52 (7), pp. 945-952. | Show Abstract | Read more

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.

Heemskerk D, Day J, Chau TT, Dung NH, Yen NT, Bang ND, Merson L, Olliaro P, Pouplin T, Caws M et al. 2011. Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. Trials, 12 (1), pp. 25. | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. METHODS/DESIGN: A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. DISCUSSION: Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN61649292.

Wolbers M, Heemskerk D, Chau TT, Yen NT, Caws M, Farrar J, Day J. 2011. Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis. Trials, 12 (1), pp. 26. | Show Abstract | Read more

BACKGROUND: In certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design. METHODS: We compared the two approaches using the design of a new trial in tuberculous meningitis as an example. In that trial the combination of 2 drugs added to standard treatment is assumed to reduce the hazard of death by 30% and the sample size of the combination trial to achieve 80% power is 750 patients. We calculated the power of corresponding factorial designs with one- to sixteen-fold the sample size of the combination trial depending on the contribution of each individual drug to the combination treatment effect and the strength of an interaction between the two. RESULTS: In the absence of an interaction, an eight-fold increase in sample size for the factorial design as compared to the combination trial is required to get 80% power to jointly detect effects of both drugs if the contribution of the less potent treatment to the total effect is at least 35%. An eight-fold sample size increase also provides a power of 76% to detect a qualitative interaction at the one-sided 10% significance level if the individual effects of both drugs are equal. Factorial designs with a lower sample size have a high chance to be underpowered, to show significance of only one drug even if both are equally effective, and to miss important interactions. CONCLUSIONS: Pragmatic combination trials of multiple interventions versus standard therapy are valuable in diseases with a limited patient pool if all interventions test the same treatment concept, it is considered likely that either both or none of the individual interventions are effective, and only moderate drug interactions are suspected. An adequately powered 2 x 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61649292.

Vinh H, Anh VT, Anh ND, Campbell JI, Hoang NV, Nga TV, Nhu NT, Minh PV, Thuy CT, Duy PT et al. 2011. A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children. PLoS Negl Trop Dis, 5 (8), pp. e1264. | Show Abstract | Read more

BACKGROUND: The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the current recommendation of the World Health Organization. Resistance to nalidixic acid is a marker of reduced susceptibility to older generation fluoroquinolones, such as ciprofloxacin. We aimed to assess the efficacy of gatifloxacin versus ciprofloxacin in the treatment of uncomplicated shigellosis in children. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a randomized, open-label, controlled trial with two parallel arms at two hospitals in southern Vietnam. The study was designed as a superiority trial and children with dysentery meeting the inclusion criteria were invited to participate. Participants received either gatifloxacin (10 mg/kg/day) in a single daily dose for 3 days or ciprofloxacin (30 mg/kg/day) in two divided doses for 3 days. The primary outcome measure was treatment failure; secondary outcome measures were time to the cessation of individual symptoms. Four hundred and ninety four patients were randomized to receive either gatifloxacin (n=249) or ciprofloxacin (n=245), of which 107 had a positive Shigella stool culture. We could not demonstrate superiority of gatifloxacin and observed similar clinical failure rate in both groups (gatifloxacin; 12.0% and ciprofloxacin; 11.0%, p=0.72). The median (inter-quartile range) time from illness onset to cessation of all symptoms was 95 (66-126) hours for gatifloxacin recipients and 93 (68-120) hours for the ciprofloxacin recipients (Hazard Ratio [95%CI]=0.98 [0.82-1.17], p=0.83). CONCLUSIONS: We conclude that in Vietnam, where nalidixic acid resistant Shigellae are highly prevalent, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute shigellosis.

Day JN, Hoang TN, Duong AV, Hong CT, Diep PT, Campbell JI, Sieu TP, Hien TT, Bui T, Boni MF et al. 2011. Most cases of cryptococcal meningitis in HIV-uninfected patients in Vietnam are due to a distinct amplified fragment length polymorphism-defined cluster of Cryptococcus neoformans var. grubii VN1. J Clin Microbiol, 49 (2), pp. 658-664. | Show Abstract | Read more

Cryptococcal disease most commonly occurs in patients with an underlying immune deficit, most commonly HIV infection, and is due to Cryptococcus neoformans var. grubii. Occasionally disease due to this variety occurs in apparently immunocompetent patients. The relationship between strains infecting immunosuppressed and immunocompetent patients is not clear. Amplified fragment length polymorphism (AFLP) analysis was used to characterize the relationship between strains infecting HIV-infected and uninfected patients. Isolates from 51 HIV-uninfected patients and 100 HIV-infected patients with cryptococcal meningitis were compared. C. neoformans var. grubii VNI was responsible for infections in 73% of HIV-uninfected and 100% of HIV-infected patients. AFLP analysis defined two distinct clusters, VNIγ and VNIδ. The majority (84%) of isolates from HIV-uninfected patients were VNIγ, compared with only 38% of isolates from HIV-infected patients (odds ratio, 8.30; 95% confidence interval [CI], 3.04 to 26.6; P < 0.0001). In HIV-uninfected patients, underlying disease was less frequent in those with VNIγ infections. Two clusters of C. neoformans var. grubii VN1 are responsible for the majority of cases of cryptococcal meningitis in Vietnam. The distribution of these clusters differs according to the immune status of the host.

Le T, Huu Chi N, Kim Cuc NT, Manh Sieu TP, Shikuma CM, Farrar J, Day JN. 2010. AIDS-associated Penicillium marneffei infection of the central nervous system. Clin Infect Dis, 51 (12), pp. 1458-1462. | Show Abstract | Read more

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.

Ha DT, Lan NT, Kiet VS, Wolbers M, Hang HT, Day J, Hien NQ, Tien NA, An PT, Anh TT et al. 2010. Diagnosis of pulmonary tuberculosis in HIV-positive patients by microscopic observation drug susceptibility assay. J Clin Microbiol, 48 (12), pp. 4573-4579. | Show Abstract | Read more

The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P<0.001; MODS versus MGIT, P=0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P=0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings.

Chau TT, Mai NH, Phu NH, Nghia HD, Chuong LV, Sinh DX, Duong VA, Diep PT, Campbell JI, Baker S et al. 2010. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis, 10 (1), pp. 199. | Show Abstract | Read more

BACKGROUND: Most cases of cryptococcal meningitis occur in patients with HIV infection: the course and outcome of disease in the apparently immunocompetent is much more poorly understood. We describe a cohort of HIV uninfected Vietnamese patients with cryptococcal meningitis in whom underlying disease is uncommon, and relate presenting features of patients and the characteristics of the infecting species to outcome. METHODS: A prospective descriptive study of HIV negative patients with cryptococcal meningitis based at the Hospital for Tropical Diseases, Ho Chi Minh City. All patients had comprehensive clinical assessment at baseline, were cared for by a dedicated study team, and were followed up for 2 years. Clinical presentation was compared by infecting isolate and outcome. RESULTS: 57 patients were studied. Cryptococcus neoformans var grubii molecular type VN1 caused 70% of infections; C. gattii accounted for the rest. Most patients did not have underlying disease (81%), and the rate of underlying disease did not differ by infecting species. 11 patients died while in-patients (19.3%). Independent predictors of death were age > or = 60 years and a history of convulsions (odds ratios and 95% confidence intervals 8.7 (1 - 76), and 16.1 (1.6 - 161) respectively). Residual visual impairment was common, affecting 25 of 46 survivors (54.3%). Infecting species did not influence clinical phenotype or outcome. The minimum inhibitory concentrations of flucytosine and amphotericin B were significantly higher for C. neoformans var grubii compared with C. gattii (p < 0.001 and p = 0.01 respectively). CONCLUSION: In HIV uninfected individuals in Vietnam, cryptococcal meningitis occurs predominantly in people with no clear predisposing factor and is most commonly due to C. neoformans var grubii. The rates of mortality and visual loss are high and independent of infecting species. There are detectable differences in susceptibility to commonly used antifungal drugs between species, but the clinical significance of this is not clear.

Alvarez-Uria G, Day JN, Nasir AJ, Russell SK, Vilar FJ. 2010. Reduction in neutrophil count during hepatitis C treatment: drug toxicity or predictor of good response? Dig Dis Sci, 55 (7), pp. 2058-2062. | Show Abstract | Read more

BACKGROUND: Bone marrow suppression is a well-recognized toxicity of the treatment of hepatitis C virus (HCV). Reduction of the peginterferon dose because of neutropenia is common in clinical practice. However, reduction of peginterferon dose during the first weeks of HCV treatment is associated with failure to achieve sustained virological response. AIMS: The objective of this study is to investigate whether the fall of neutrophil count during hepatitis C treatment is associated with achieving sustained virological response. METHODS: We performed an observational study of patients who completed peginterferon and ribavirin treatment in an Infectious Diseases Department in Manchester, UK. RESULTS: Of the 74 patients included in the analysis, 78% had genotype 2 or 3 hepatitis C and 15% had liver cirrhosis. Sustained virological response was achieved in 78% of patients. On univariate analysis, factors related to achieving sustained virological response were younger age, genotype 2 or 3, baseline neutrophil count, and fall of neutrophil count during treatment. Multivariate analysis showed baseline neutrophil count >3.5 x 10(3) cells/mm(3) [odds ratio (OR) 5.7; 95% confidence interval (CI) 1.24-26.3] and a reduction of neutrophil count >60% (OR 4.5; 95% CI 1.03-19.9) to be independently associated with achieving sustained virological response. Neutropenia was not associated with an increased risk of infections. CONCLUSIONS: In this observational study, higher baseline neutrophil count and fall of neutrophil count during the treatment of hepatitis C was associated with achieving sustained virological response. These findings could have important implications for the monitoring and management of HCV treatment with peginterferon if they are confirmed in other studies.

Le T, Hong Chau TT, Kim Cuc NT, Si Lam P, Manh Sieu TP, Shikuma CM, Day JN. 2010. AIDS‐associated Cryptococcus neoformans and Penicillium marneffei coinfection: a therapeutic dilemma in resource‐limited settings. Clin Infect Dis, 51 (9), pp. e65-e68. | Show Abstract | Read more

AIDS&#x2010;associated Cryptococcus neoformans and Penicillium marneffei coinfection has not been adequately studied and poses unique therapeutic challenges in resource&#x2010;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.

Karkey A, Arjyal A, Anders KL, Boni MF, Dongol S, Koirala S, My PV, Nga TV, Clements AC, Holt KE et al. 2010. The burden and characteristics of enteric fever at a healthcare facility in a densely populated area of Kathmandu. PLoS One, 5 (11), pp. e13988. | Show Abstract | Read more

Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A (S. Typhi and S. Paratyphi A) remains a major public health problem in many settings. The disease is limited to locations with poor sanitation which facilitates the transmission of the infecting organisms. Efficacious and inexpensive vaccines are available for S. Typhi, yet are not commonly deployed to control the disease. Lack of vaccination is due partly to uncertainty of the disease burden arising from a paucity of epidemiological information in key locations. We have collected and analyzed data from 3,898 cases of blood culture-confirmed enteric fever from Patan Hospital in Lalitpur Sub-Metropolitan City (LSMC), between June 2005 and May 2009. Demographic data was available for a subset of these patients (n = 527) that were resident in LSMC and who were enrolled in trials. We show a considerable burden of enteric fever caused by S. Typhi (2,672; 68.5%) and S. Paratyphi A (1,226; 31.5%) at this Hospital over a four year period, which correlate with seasonal fluctuations in rainfall. We found that local population density was not related to incidence and we identified a focus of infections in the east of LSMC. With data from patients resident in LSMC we found that the median age of those with S. Typhi (16 years) was significantly less than S. Paratyphi A (20 years) and that males aged 15 to 25 were disproportionately infected. Our findings provide a snapshot into the epidemiological patterns of enteric fever in Kathmandu. The uneven distribution of enteric fever patients within the population suggests local variation in risk factors, such as contaminated drinking water. These findings are important for initiating a vaccination scheme and improvements in sanitation. We suggest any such intervention should be implemented throughout the LSMC area.

Ha DT, Lan NT, Wolbers M, Duong TN, Quang ND, Thi Van Thinh T, Thi Hong Ngoc L, Thi Ngoc Anh N, Van Quyet T, Thi Bich Tuyen N et al. 2009. Microscopic observation drug susceptibility assay (MODS) for early diagnosis of tuberculosis in children. PLoS One, 4 (12), pp. e8341. | Show Abstract | Read more

MODS is a novel liquid culture based technique that has been shown to be effective and rapid for early diagnosis of tuberculosis (TB). We evaluated the MODS assay for diagnosis of TB in children in Viet Nam. 217 consecutive samples including sputum (n = 132), gastric fluid (n = 50), CSF (n = 32) and pleural fluid (n = 3) collected from 96 children with suspected TB, were tested by smear, MODS and MGIT. When test results were aggregated by patient, the sensitivity and specificity of smear, MGIT and MODS against "clinical diagnosis" (confirmed and probable groups) as the gold standard were 28.2% and 100%, 42.3% and 100%, 39.7% and 94.4%, respectively. The sensitivity of MGIT and MODS was not significantly different in this analysis (P = 0.5), but MGIT was more sensitive than MODS when analysed on the sample level using a marginal model (P = 0.03). The median time to detection of MODS and MGIT were 8 days and 13 days, respectively, and the time to detection was significantly shorter for MODS in samples where both tests were positive (P<0.001). An analysis of time-dependent sensitivity showed that the detection rates were significantly higher for MODS than for MGIT by day 7 or day 14 (P<0.001 and P = 0.04), respectively. MODS is a rapid and sensitive alternative method for the isolation of M.tuberculosis from children.

Khatri NS, Maskey P, Poudel S, Jaiswal VK, Karkey A, Koirala S, Shakya N, Agrawal K, Arjyal A, Basnyat B et al. 2009. Gallbladder carriage of Salmonella paratyphi A may be an important factor in the increasing incidence of this infection in South Asia. Ann Intern Med, 150 (8), pp. 567-568. | Read more

Alvarez-Uria G, Day JN, Nasir AJ, Russell SK, Vilar FJ. 2009. Reduction in Neutrophil Count During Hepatitis C Treatment: Drug Toxicity or Predictor of Good Response? Digestive Diseases and Sciences, pp. 1-5.

Alvarez-Uria G, Day JN, Nasir AJ, Russell SK, Vilar FJ. 2009. Factors associated with treatment failure of patients with psychiatric diseases and injecting drug users in the treatment of genotype 2 or 3 hepatitis C chronic infection. Liver Int, 29 (7), pp. 1051-1055. | Show Abstract | Read more

BACKGROUND: Genotype 2/3 hepatitis C virus (HCV) has a good response to treatment with peginterferon and ribavirin. Patients with psychiatric disorders and injecting drug users (IDUs) are considered 'difficult to treat' and are often excluded from treatment despite the lack of evidence supporting this decision. AIMS: To investigate the outcome and factors associated with treatment failure in these groups. METHODS: This is an observational study of a cohort of patients infected by genotype 2/3 HCV. IDUs and patients with psychiatric diseases were not excluded from treatment. We performed an intention-to-treat analysis to evaluate factors related to treatment failure. RESULTS: A sustained virological response (SVR) was achieved in 91 of the 125 patients treated (72.8%). Patients with chronic psychotic disorders or former IDUs had SVR rates similar to other groups. After multivariate analysis, independent factors associated with treatment failure were liver cirrhosis [odds ratio (OR) 3.4, 95% confidence interval (CI) 1.1-10.4], a history of depression and not being on antidepressants at the commencement of HCV treatment (OR 4.4, 95% CI 1.2-16) and active IDUs (OR 7.3, 95% CI 1.77-30.4). CONCLUSIONS: Patients with a history of depression who were not receiving antidepressants and active IDUs are more likely to fail treatment for genotype 2/3 HCV and will need additional support.

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Ha DTM, Lan NTN, Wolbers M, Duong TN, Quang ND, van Thinh TT, Ngoc LTH, Anh NTN, van Quyet T, Tuyen NTB et al. 2009. Microscopic observation drug susceptibility assay (MODS) for early diagnosis of tuberculosis in children PLoS ONE, 4 (12), | Show Abstract | Read more

MODS is a novel liquid culture based technique that has been shown to be effective and rapid for early diagnosis of tuberculosis (TB). We evaluated the MODS assay for diagnosis of TB in children in Viet Nam. 217 consecutive samples including sputum (n=132), gastric fluid (n=50), CSF (n= 32) and pleural fluid (n=3) collected from 96 children with suspected TB, were tested by smear, MODS and MGIT. When test results were aggregated by patient, the sensitivity and specificity of smear, MGIT and MODS against ''clinical diagnosis'' (confirmed and probable groups) as the gold standard were 28.2% and 100%, 42.3% and 100%, 39.7% and 94.4%, respectively. The sensitivity of MGIT and MODS was not significantly different in this analysis (P= 0.5), but MGIT was more sensitive than MODS when analysed on the sample level using a marginal model (P =0.03). The median time to detection of MODS and MGIT were 8 days and 13 days, respectively, and the time to detection was significantly shorter for MODS in samples where both tests were positive (P,0.001). An analysis of time-dependent sensitivity showed that the detection rates were significantly higher for MODS than for MGIT by day 7 or day 14 (P,0.001 and P =0.04), respectively. MODS is a rapid and sensitive alternative method for the isolation of M.tuberculosis from children. © 2009 Ha et al.

Ustianowski AP, Sieu TP, Day JN. 2008. Penicillium marneffei infection in HIV. Curr Opin Infect Dis, 21 (1), pp. 31-36. | Show Abstract | Read more

PURPOSE OF REVIEW: Since the start of the HIV pandemic, systemic infection with Penicillium marneffei has developed from a very rare diagnosis to the third most common opportunistic infection in HIV co-infected patients in South East Asia. HIV patients who have travelled to or lived in Asia may present with this infection in nonendemic countries, and it has therefore become important for all those working in the field of HIV to recognize, understand and treat this emerging disease. RECENT FINDINGS: The clinical features, diagnosis and treatment of this infection are reviewed. Recent data exploring antigen-based serodiagnostics, the role of newer antifungals such as voriconazole, and the possibility of discontinuation of secondary prophylaxis after immune restoration from highly active antiretrovirals are discussed. SUMMARY: Large series from endemic areas and case reports from nonendemic regions have been published and provide insights into clinical features and presentation. Novel diagnostics are evolving, with galactomannan and other assays looking promising. Present therapy is largely based on noncontrolled studies, and further research into optimal therapy and the potential to discontinue secondary itraconazole prophylaxis is required.

Hien TT, Truong NT, Minh NH, Dat HD, Dung NT, Hue NT, Dung TK, Tuan PQ, Campbell JI, Farrar JJ, Day JN. 2008. A randomized controlled pilot study of artesunate versus triclabendazole for human fascioliasis in central Vietnam. Am J Trop Med Hyg, 78 (3), pp. 388-392. | Show Abstract

Human fascioliasis caused by Fasciola hepatica or Fasciola gigantica is an increasing global problem. The mainstay of current treatment is triclabendazole, but resistance in animals has been described, and it is not available in many countries. The antimalarial artesunate has an excellent safety profile, and there is increasing evidence of its efficacy against other parasites both in vitro and in vivo. We performed a study to investigate the usefulness of artesunate in symptomatic human fascioliasis; 100 patients were enrolled. Patients treated with artesunate were significantly more likely to be free of abdominal pain at hospital discharge (50/50 versus 44/50, P = 0.027, relative risk 1.14, 95% confidence interval 1.03-1.26), but the complete response rate at 3 months was lower than for patients treated with triclabendazole (38/50 versus 46/50, P = 0.05, RR 0.83, 95% CI 0.69-0.98, artesunate versus triclabendazole). There may be a role for artesunate in fascioliasis.

Pandit A, Arjyal A, Paudyal B, Campbell JC, Day JN, Farrar JJ, Basnyat B. 2008. A patient with paratyphoid A fever: an emerging problem in Asia and not always a benign disease. J Travel Med, 15 (5), pp. 364-365. | Show Abstract | Read more

A 15-year-old Nepalese boy with fever was thought to have enteric fever and started on cefixime. His blood culture grew Salmonella paratyphoid A. On the sixth day, he developed gastrointestinal bleeding, disseminated intravascular coagulation, and later, acute respiratory distress syndrome. He succumbed to his illness despite treatment in the intensive care unit with ceftriaxone, intravenous fluids, and mechanical ventilation. Salmonella paratyphoid A, for which there is no commercial vaccine, may not be a benign disease as perceived, and cefixime that is recommended for enteric fever may be an ineffective choice.

Pandit A, Arjyal A, Day JN, Paudyal B, Dangol S, Zimmerman MD, Yadav B, Stepniewska K, Campbell JI, Dolecek C et al. 2007. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS One, 2 (6), pp. e542. | Show Abstract | Read more

OBJECTIVE: To assess the efficacy of gatifloxacin versus cefixime in the treatment of uncomplicated culture positive enteric fever. DESIGN: A randomized, open-label, active control trial with two parallel arms. SETTING: Emergency Room and Outpatient Clinics in Patan Hospital, Lagankhel, Lalitpur, Nepal. PARTICIPANTS: Patients with clinically diagnosed uncomplicated enteric fever meeting the inclusion criteria. INTERVENTIONS: Patients were allocated to receive one of two drugs, Gatifloxacin or Cefixime. The dosages used were Gatifloxacin 10 mg/kg, given once daily for 7 days, or Cefixime 20 mg/kg/day given in two divided doses for 7 days. OUTCOME MEASURES: The primary outcome measure was fever clearance time. The secondary outcome measure was overall treatment failure (acute treatment failure and relapse). RESULTS: Randomization was carried out in 390 patients before enrollment was suspended on the advice of the independent data safety monitoring board due to significant differences in both primary and secondary outcome measures in the two arms and the attainment of a priori defined endpoints. Median (95% confidence interval) fever clearance times were 92 hours (84-114 hours) for gatifloxacin recipients and 138 hours (105-164 hours) for cefixime-treated patients (Hazard Ratio[95%CI] = 2.171 [1.545-3.051], p<0.0001). 19 out of 70 (27%) patients who completed the 7 day trial had acute clinical failure in the cefixime group as compared to 1 out of 88 patients (1%) in gatifloxacin group(Odds Ratio [95%CI] = 0.031 [0.004 - 0.237], p<0.001). Overall treatment failure patients (relapsed patients plus acute treatment failure patients plus death) numbered 29. They were determined to be (95% confidence interval) 37.6 % (27.14%-50.2%) in the cefixime group and 3.5% (2.2%-11.5%) in the gatifloxacin group (HR[95%CI] = 0.084 [0.025-0.280], p<0.0001). There was one death in the cefixime group. CONCLUSIONS: Based on this study, gatifloxacin is a better treatment for uncomplicated enteric fever as compared to cefixime. TRIAL REGISTRATION: Current Controlled Trials ISRCTN75784880.

Maskey AP, Day JN, Phung QT, Thwaites GE, Campbell JI, Zimmerman M, Farrar JJ, Basnyat B. 2006. Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal. Clin Infect Dis, 42 (9), pp. 1247-1253. | Show Abstract | Read more

BACKGROUND: Enteric fever is a major global problem. Emergence of antibacterial resistance threatens to render current treatments ineffective. There is little research or public health effort directed toward Salmonella enterica serovar Paratyphi A, because it is assumed to cause less severe enteric fever than does S. enterica serovar Typhi. There are few data on which to base this assumption, little is known of the serovar's antibacterial susceptibilities, and there is no readily available tolerable vaccination. METHODS: A prospective study was conducted of 609 consecutive cases of enteric fever (confirmed by blood culture) to compare the clinical phenotypes and antibacterial susceptibilities in S. Typhi and S. Paratyphi A infections. Variables independently associated with either infection were identified to develop a diagnostic rule to distinguish the infections. All isolates were tested for susceptibility to antibacterials. RESULTS: Six hundred nine patients (409 with S. Typhi infection and 200 with S. Paratyphi A infection) presented during the study period. The infections were clinically indistinguishable and had equal severity. Nalidixic acid resistance, which predicts a poor response to fluoroquinolone treatment, was extremely common (75.25% of S. Paratyphi A isolates and 50.5% of S. Typhi isolates; P < .001). S. Paratyphi A was more likely to be resistant to ofloxacin (3.6% vs. 0.5%; P = .007) or to have intermediate susceptibility to ofloxacin (28.7% vs. 1.8%; P < .001) or ciprofloxacin (39.4% vs. 8.2%; P < .001). MICs for S. Paratyphi A were higher than for S. Typhi (MIC of ciprofloxacin, 0.75 vs. 0.38 microg/mL [P < .001]; MIC of ofloxacin, 2.0 vs. 0.75 microg/mL [P < .001]). CONCLUSIONS: The importance of S. Paratyphi A has been underestimated. Infection is common, the agent causes disease as severe as that caused by S. Typhi and is highly likely to be drug resistant. Drug resistance and lack of effective vaccination suggest that S. Paratyphi A infection may become a major world health problem.

Torok ME, Day JN, Hien TT, Farrar JJ. 2005. Immediate or deferred antiretroviral therapy for central nervous system opportunistic infections? AIDS, 19 (5), pp. 535-536. | Read more

Day JN, Hien TT, Farrar J. 2004. Expiry-date tampering. Lancet, 363 (9403), pp. 172. | Read more

Day JN. 2004. cryptococcal meningitis Practical Neurology, 4 (5), pp. 274-285. | Read more

Day JN, Lalloo DG. 2004. Neurological syndromes and the traveller: an approach to differential diagnosis. J Neurol Neurosurg Psychiatry, 75 Suppl 1 (90001), pp. i2-i9. | Show Abstract | Read more

Despite the large number of exotic infecting agents that may cause neurological syndromes, the returning traveller is more likely to be infected with an organism that is well known to the temperate physician. Meningitis will most likely be due to organisms indigenous to the UK, encephalitis will most likely be due to herpes simplex virus. The two most commonly imported life threatening tropical infections are malaria and typhoid, and these illnesses should be excluded quickly in all patients. Detailed history taking, particularly regarding travel, activities while away, sexual history and immunisation history helps to narrow the differential diagnosis. A methodical approach and basic knowledge of incubation periods can help to limit unnecessary investigation.

Molloy SF, Chiller T, Greene GS, Burry J, Govender NP, Kanyama C, Mfinanga S, Lesikari S, Mapoure YN, Kouanfack C et al. 2017. Cryptococcal meningitis: A neglected NTD? PLoS Negl Trop Dis, 11 (6), pp. e0005575. | Read more

Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. 2013. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother, 68 (11), pp. 2435-2444. | Show Abstract | Read more

Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis.

Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ et al. 2013. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med, 368 (14), pp. 1291-1302. | Show Abstract | Read more

BACKGROUND: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (-0.42 log10 colony-forming units [CFU] per milliliter per day vs. -0.31 and -0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.).

Day JN, Chau TT, Lalloo DG. 2013. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med, 368 (26), pp. 2522-2523. | Read more

Henk DA, Shahar-Golan R, Devi KR, Boyce KJ, Zhan N, Fedorova ND, Nierman WC, Hsueh PR, Yuen KY, Sieu TP et al. 2012. Clonality despite sex: the evolution of host-associated sexual neighborhoods in the pathogenic fungus Penicillium marneffei. PLoS Pathog, 8 (10), pp. e1002851. | Show Abstract | Read more

Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei.

Ho Dang Trung N, Le Thi Phuong T, Wolbers M, Nguyen Van Minh H, Nguyen Thanh V, Van MP, Thieu NT, Van TL, Song DT, Thi PL et al. 2012. Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study. PLoS One, 7 (5), pp. e37825. | Show Abstract | Read more

BACKGROUND: Infectious diseases of the central nervous system (CNS) remain common and life-threatening, especially in developing countries. Knowledge of the aetiological agents responsible for these infections is essential to guide empiric therapy and develop a rational public health policy. To date most data has come from patients admitted to tertiary referral hospitals in Asia and there is limited aetiological data at the provincial hospital level where most patients are seen. METHODS: We conducted a prospective Provincial Hospital-based descriptive surveillance study in adults and children at thirteen hospitals in central and southern Viet Nam between August 2007-April 2010. The pathogens of CNS infection were confirmed in CSF and blood samples by using classical microbiology, molecular diagnostics and serology. RESULTS: We recruited 1241 patients with clinically suspected infection of the CNS. An aetiological agent was identified in 640/1241 (52%) of the patients. The most common pathogens were Streptococcus suis serotype 2 in patients older than 14 years of age (147/617, 24%) and Japanese encephalitis virus in patients less than 14 years old (142/624, 23%). Mycobacterium tuberculosis was confirmed in 34/617 (6%) adult patients and 11/624 (2%) paediatric patients. The acute case fatality rate (CFR) during hospital admission was 73/617 (12%) in adults and to 42/624 (7%) in children. CONCLUSIONS: Zoonotic bacterial and viral pathogens are the most common causes of CNS infection in adults and children in Viet Nam.

Nga TV, Parry CM, Le T, Lan NP, Diep TS, Campbell JI, Hoang NV, Dung LET, Wain J, Dolecek C et al. 2012. 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. Trans R Soc Trop Med Hyg, 106 (1), pp. 26-34. | Show Abstract | Read more

The etiological spectrum of bloodstream infections is variable between industrialized and developing countries and even within a defined location over time. We investigated trends in bloodstream infections at an infectious disease hospital in Ho Chi Minh City, Vietnam, from 1994-2008. Amongst 66,111 blood cultures performed, a clinically relevant pathogen was isolated in 7645 episodes (positivity rate; 116/1000 cultures). Salmonella Typhi was the predominant pathogen until 2002; however, a considerable annual decline in the proportion of S. Typhi was observed (OR 0.6993, 95% CI [0.6885, 0.7103], p<0.0001). Conversely, there was a significant increase in the proportions of non-typhoidal Salmonella (NTS), Cryptococcus neoformans and Penicillium marneffei, concurrent with increasing HIV prevalence. These data document a substantial longitudinal shift in bloodstream infection etiology in southern Vietnam. We propose such changes are related to increasing economic prosperity and HIV prevalence, and this pattern marks a substantial change in the epidemiology of invasive salmonellosis in Southeast Asia.

Le T, Wolbers M, Chi NH, Quang VM, Chinh NT, Lan NP, Lam PS, Kozal MJ, Shikuma CM, Day JN, Farrar J. 2011. Epidemiology, seasonality, and predictors of outcome of AIDS-associated Penicillium marneffei infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis, 52 (7), pp. 945-952. | Show Abstract | Read more

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.

Heemskerk D, Day J, Chau TT, Dung NH, Yen NT, Bang ND, Merson L, Olliaro P, Pouplin T, Caws M et al. 2011. Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. Trials, 12 (1), pp. 25. | Show Abstract | Read more

BACKGROUND: Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin. METHODS/DESIGN: A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events. DISCUSSION: Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN61649292.

Wolbers M, Heemskerk D, Chau TT, Yen NT, Caws M, Farrar J, Day J. 2011. Sample size requirements for separating out the effects of combination treatments: randomised controlled trials of combination therapy vs. standard treatment compared to factorial designs for patients with tuberculous meningitis. Trials, 12 (1), pp. 26. | Show Abstract | Read more

BACKGROUND: In certain diseases clinical experts may judge that the intervention with the best prospects is the addition of two treatments to the standard of care. This can either be tested with a simple randomized trial of combination versus standard treatment or with a 2 x 2 factorial design. METHODS: We compared the two approaches using the design of a new trial in tuberculous meningitis as an example. In that trial the combination of 2 drugs added to standard treatment is assumed to reduce the hazard of death by 30% and the sample size of the combination trial to achieve 80% power is 750 patients. We calculated the power of corresponding factorial designs with one- to sixteen-fold the sample size of the combination trial depending on the contribution of each individual drug to the combination treatment effect and the strength of an interaction between the two. RESULTS: In the absence of an interaction, an eight-fold increase in sample size for the factorial design as compared to the combination trial is required to get 80% power to jointly detect effects of both drugs if the contribution of the less potent treatment to the total effect is at least 35%. An eight-fold sample size increase also provides a power of 76% to detect a qualitative interaction at the one-sided 10% significance level if the individual effects of both drugs are equal. Factorial designs with a lower sample size have a high chance to be underpowered, to show significance of only one drug even if both are equally effective, and to miss important interactions. CONCLUSIONS: Pragmatic combination trials of multiple interventions versus standard therapy are valuable in diseases with a limited patient pool if all interventions test the same treatment concept, it is considered likely that either both or none of the individual interventions are effective, and only moderate drug interactions are suspected. An adequately powered 2 x 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61649292.

Day JN, Hoang TN, Duong AV, Hong CT, Diep PT, Campbell JI, Sieu TP, Hien TT, Bui T, Boni MF et al. 2011. Most cases of cryptococcal meningitis in HIV-uninfected patients in Vietnam are due to a distinct amplified fragment length polymorphism-defined cluster of Cryptococcus neoformans var. grubii VN1. J Clin Microbiol, 49 (2), pp. 658-664. | Show Abstract | Read more

Cryptococcal disease most commonly occurs in patients with an underlying immune deficit, most commonly HIV infection, and is due to Cryptococcus neoformans var. grubii. Occasionally disease due to this variety occurs in apparently immunocompetent patients. The relationship between strains infecting immunosuppressed and immunocompetent patients is not clear. Amplified fragment length polymorphism (AFLP) analysis was used to characterize the relationship between strains infecting HIV-infected and uninfected patients. Isolates from 51 HIV-uninfected patients and 100 HIV-infected patients with cryptococcal meningitis were compared. C. neoformans var. grubii VNI was responsible for infections in 73% of HIV-uninfected and 100% of HIV-infected patients. AFLP analysis defined two distinct clusters, VNIγ and VNIδ. The majority (84%) of isolates from HIV-uninfected patients were VNIγ, compared with only 38% of isolates from HIV-infected patients (odds ratio, 8.30; 95% confidence interval [CI], 3.04 to 26.6; P < 0.0001). In HIV-uninfected patients, underlying disease was less frequent in those with VNIγ infections. Two clusters of C. neoformans var. grubii VN1 are responsible for the majority of cases of cryptococcal meningitis in Vietnam. The distribution of these clusters differs according to the immune status of the host.

Chau TT, Mai NH, Phu NH, Nghia HD, Chuong LV, Sinh DX, Duong VA, Diep PT, Campbell JI, Baker S et al. 2010. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis, 10 (1), pp. 199. | Show Abstract | Read more

BACKGROUND: Most cases of cryptococcal meningitis occur in patients with HIV infection: the course and outcome of disease in the apparently immunocompetent is much more poorly understood. We describe a cohort of HIV uninfected Vietnamese patients with cryptococcal meningitis in whom underlying disease is uncommon, and relate presenting features of patients and the characteristics of the infecting species to outcome. METHODS: A prospective descriptive study of HIV negative patients with cryptococcal meningitis based at the Hospital for Tropical Diseases, Ho Chi Minh City. All patients had comprehensive clinical assessment at baseline, were cared for by a dedicated study team, and were followed up for 2 years. Clinical presentation was compared by infecting isolate and outcome. RESULTS: 57 patients were studied. Cryptococcus neoformans var grubii molecular type VN1 caused 70% of infections; C. gattii accounted for the rest. Most patients did not have underlying disease (81%), and the rate of underlying disease did not differ by infecting species. 11 patients died while in-patients (19.3%). Independent predictors of death were age > or = 60 years and a history of convulsions (odds ratios and 95% confidence intervals 8.7 (1 - 76), and 16.1 (1.6 - 161) respectively). Residual visual impairment was common, affecting 25 of 46 survivors (54.3%). Infecting species did not influence clinical phenotype or outcome. The minimum inhibitory concentrations of flucytosine and amphotericin B were significantly higher for C. neoformans var grubii compared with C. gattii (p < 0.001 and p = 0.01 respectively). CONCLUSION: In HIV uninfected individuals in Vietnam, cryptococcal meningitis occurs predominantly in people with no clear predisposing factor and is most commonly due to C. neoformans var grubii. The rates of mortality and visual loss are high and independent of infecting species. There are detectable differences in susceptibility to commonly used antifungal drugs between species, but the clinical significance of this is not clear.

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