Publications by authors named "Van Kinh Nguyen"

57 Publications

Implementation of C-reactive protein point of care testing to improve antibiotic targeting in respiratory illness in Vietnamese primary care (ICAT): a study protocol for a cluster randomised controlled trial.

BMJ Open 2020 12 23;10(12):e040977. Epub 2020 Dec 23.

Oxford University Clinical Research Unit, Hanoi, Vietnam.

Introduction: C-reactive protein (CRP), a biomarker of infection, has been used widely in high-income settings to guide antibiotic treatment in patients presenting with respiratory illnesses in primary care. Recent trials in low- and middle-income countries showed that CRP testing could safely reduce antibiotic use in patients with non-severe acute respiratory infections (ARIs) and fever in primary care. The studies, however, were conducted in a research-oriented context, with research staff closely monitoring healthcare behaviour thus potentially influencing healthcare workers' prescribing practices. For policy-makers to consider wide-scale roll-out, a pragmatic implementation study of the impact of CRP point of care (POC) testing in routine care is needed.

Methods And Analysis: A pragmatic, cluster-randomised controlled trial, with two study arms, consisting of 24 commune health centres (CHC) in the intervention arm (provision of CRP tests with additional healthcare worker guidance) and 24 facilities acting as controls (routine care). Comparison between the treatment arms will be through logistic regression, with the treatment assignment as a fixed effect, and the CHC as a random effect. With 48 clusters, an average of 10 consultations per facility per week will result in approximately 520 over 1 year, and 24 960 in total (12 480 per arm). We will be able to detect a reduction of 12% to 23% or more in immediate antibiotic prescription as a result of the CRP POC intervention. The primary endpoint is the proportion of patient consultations for ARI resulting in immediate antibiotic prescription. Secondary endpoints include the proportion of all patients receiving an antibiotic prescription regardless of ARI diagnosis, frequency of re-consultation, subsequent antibiotic use when antibiotics are not prescribed, referral and hospitalisation.

Ethics And Dissemination: The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC, Reference: 53-18), and the ethical committee of the National Hospital for Tropical Diseases in Vietnam (Reference:07/HDDD-NDTW/2019). Results from this study will be disseminated via meetings with stakeholders, conferences and publications in peer-reviewed journals. Authorship and reporting of this work will follow international guidelines.

Trial Registration Details: NCT03855215; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-040977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759760PMC
December 2020

C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study.

BMC Med 2020 02 17;18(1):35. Epub 2020 Feb 17.

Oxford University Clinical Research Unit, Wellcome Trust Asia Programme, Ho Chi Minh City, Vietnam.

Background: Dengue infection can cause a wide spectrum of clinical outcomes. The severe clinical manifestations occur sufficiently late in the disease course, during day 4-6 of illness, to allow a window of opportunity for risk stratification. Markers of inflammation may be useful biomarkers. We investigated the value of C-reactive protein (CRP) measured early on illness days 1-3 to predict dengue disease outcome and the difference in CRP levels between dengue and other febrile illnesses (OFI).

Method: We performed a nested case-control study using the clinical data and samples collected from the IDAMS-consortium multi-country study. This was a prospective multi-center observational study that enrolled almost 8000 participants presenting with a dengue-like illness to outpatient facilities in 8 countries across Asia and Latin America. Predefined severity definitions of severe and intermediate dengue were used as the primary outcomes. A total of 281 cases with severe/intermediate dengue were compared to 836 uncomplicated dengue patients as controls (ratio 1:3), and also 394 patients with OFI.

Results: In patients with confirmed dengue, median (interquartile range) of CRP level within the first 3 days was 30.2 mg/L (12.4-61.2 mg/L) (uncomplicated dengue, 28.6 (10.5-58.9); severe or intermediate dengue, 34.0 (17.4-71.8)). Higher CRP levels in the first 3 days of illness were associated with a higher risk of severe or intermediate outcome (OR 1.17, 95% CI 1.07-1.29), especially in children. Higher CRP levels, exceeding 30 mg/L, also associated with hospitalization (OR 1.37, 95% CI 1.14-1.64) and longer fever clearance time (HR 0.84, 95% CI 0.76-0.93), especially in adults. CRP levels in patients with dengue were higher than patients with potential viral infection but lower than patients with potential bacterial infection, resulting in a quadratic association between dengue diagnosis and CRP, with levels of approximately 30 mg/L associated with the highest risk of having dengue. CRP had a positive correlation with total white cell count and neutrophils and negative correlation with lymphocytes, but did not correlate with liver transaminases, albumin, or platelet nadir.

Conclusions: In summary, CRP measured in the first 3 days of illness could be a useful biomarker for early dengue risk prediction and may assist differentiating dengue from other febrile illnesses.
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http://dx.doi.org/10.1186/s12916-020-1496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025413PMC
February 2020

Epidemiological and Clinical Features of Dengue Infection in Adults in the 2017 Outbreak in Vietnam.

Biomed Res Int 2019 7;2019:3085827. Epub 2019 Nov 7.

Hospital for Tropical Disease, Ho Chi Minh City, Vietnam.

Purpose: The clinical features and laboratory results of dengue-infected adult patients admitted to the hospital during the 2017 outbreak were analyzed in this study.

Method: This is a cross-sectional study. 2922 patients aged 18 years or more with dengue fever in National Hospital for Tropical Diseases (NHTD) in the North and Hospital for Tropical Disease (HTD) in the South of Vietnam were recruited in this study.

Result: Patients were admitted in the hospital around the year and concentrated from August to December, in 53/63 (84.0%) provinces in Vietnam, and patients in all ages were affected. The number of patients with dengue fever was 1675 (57.3%), dengue with warning signs 914 (31.3%), and severe dengue 333 (11.4%), respectively. Among patients with severe dengue, severe plasma leakage and dengue shock account for 238 (8.1%), severe organ impairment 73 (2.5%), and severe bleeding 22 (0.75%). The rate of mortality was 0.8%, and the outcome of dengue patients is worse in the elderly and people with underlying diseases.

Conclusion: The 2017 dengue outbreak occurred in a larger scale than in the previous years in terms of time, location, and number of patients. More elderly patients were infected by dengue in this outbreak, and this may contribute to the mortality rate. Clinical manifestations of dengue patients in Southern Vietnam are more typical than the northern, but the rate of severe dengue is not different. The mortality risk and underlying conditions associated with dengue-infected elderly patients are worthy of further investigations in the future.
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http://dx.doi.org/10.1155/2019/3085827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877935PMC
April 2020

Antimicrobial susceptibility testing and antibiotic consumption results from 16 hospitals in Viet Nam: The VINARES project 2012-2013.

J Glob Antimicrob Resist 2019 09 12;18:269-278. Epub 2019 Jun 12.

Oxford University Clinical Research Unit, Viet Nam; Department of Medical Microbiology and Radboudumc Center for Infectious Diseases, Radboudumc, Nijmegen, Netherlands.

Objective: To establish a hospital-based surveillance network with national coverage for antimicrobial resistance (AMR) and antibiotic consumption in Viet Nam.

Methods: A 16-hospital network (Viet Nam Resistance: VINARES) was established and consisted of national and provincial-level hospitals across the country. Antimicrobial susceptibility testing results from routine clinical diagnostic specimens and antibiotic consumption data in Defined Daily Dose per 1000 bed days (DDD/1000 patient-days) were prospectively collected and analysed between October 2012 and September 2013.

Results: Data from a total of 24 732 de-duplicated clinical isolates were reported. The most common bacteria were: Escherichia coli (4437 isolates, 18%), Klebsiella spp. (3290 isolates, 13%) and Acinetobacter spp. (2895 isolates, 12%). The hospital average antibiotic consumption was 918 DDD/1000 patient-days. Third-generation cephalosporins were the most frequently used antibiotic class (223 DDD/1000 patient-days, 24%), followed by fluoroquinolones (151 DDD/1000 patient-days, 16%) and second-generation cephalosporins (112 DDD/1000 patient-days, 12%). Proportions of antibiotic resistance were high: 1098/1580 (69%) Staphylococcus aureus isolates were methicillin-resistant (MRSA); 115/344 isolates (33%) and 90/358 (25%) Streptococcus pneumoniae had reduced susceptibility to penicillin and ceftriaxone, respectively. A total of 180/2977 (6%) E. coli and 242/1526 (16%) Klebsiella pneumoniae were resistant to imipenem, respectively; 602/1826 (33%) Pseudomonas aeruginosa were resistant to ceftazidime and 578/1765 (33%) to imipenem. Of Acinetobacter spp. 1495/2138 (70%) were resistant to carbapenems and 2/333 (1%) to colistin.

Conclusions: These data are valuable in providing a baseline for AMR among common bacterial pathogens in Vietnamese hospitals and to assess the impact of interventions.
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http://dx.doi.org/10.1016/j.jgar.2019.06.002DOI Listing
September 2019

A randomised controlled trial of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF-MS) versus conventional microbiological methods for identifying pathogens: Impact on optimal antimicrobial therapy of invasive bacterial and fungal infections in Vietnam.

J Infect 2019 06 23;78(6):454-460. Epub 2019 Mar 23.

Centre for Tropical Medicine & Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Department of Medical Microbiology, RadboudUMC, Nijmegen, The Netherlands.

Objectives: We assessed the impact of MALDITOF-MS on the timeliness of optimal antimicrobial therapy through a parallel-arm randomised controlled trial in two hospitals in Vietnam.

Methods: We recruited patients with a pathogen (bacterial or fungal) cultured from a normally sterile sample. Samples were randomly assigned (1:1) to identification by MALDITOF-MS or conventional diagnostics. The primary outcome was the proportion on optimal antimicrobial therapy within 24 h of positive culture, determined by a blinded independent review committee. Trial registered at ClinicalTrials.gov (NCT02306330).

Results: Among 1005 randomised patients, pathogens were isolated from 628 (326 intervention, 302 control), with 377 excluded as likely contaminants or discharged/died before positive culture. Most isolates were cultured from blood (421/628, 67.0%). The proportion receiving optimal antimicrobial therapy within 24 h (the primary outcome) or 48 h of growth was not significantly different between MALDITOF-MS and control arms (135/326, 41.4% vs 120/302, 39.7%; Adjusted Odds ration (AOR) 1.17, p = 0.40 and 151/326, 46.3% vs 141/302, 46.7%; AOR 1.05 p = 0.79, respectively).

Conclusions: MALDITOF-MS, in the absence of an antimicrobial stewardship programme, did not improve the proportion on optimal antimicrobial therapy at 24 or 48 h after first growth in a lower-middle income setting with high rates of antibiotic resistance.
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http://dx.doi.org/10.1016/j.jinf.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529875PMC
June 2019

Clinical Manifestations and Molecular Diagnosis of Scrub Typhus and Murine Typhus, Vietnam, 2015-2017.

Emerg Infect Dis 2019 04;25(4)

Rickettsioses are endemic to Vietnam; however, only a limited number of clinical studies have been performed on these vectorborne bacteria. We conducted a prospective hospital-based study at 2 national referral hospitals in Hanoi to describe the clinical characteristics of scrub typhus and murine typhus in northern Vietnam and to assess the diagnostic applicability of quantitative real-time PCR assays to diagnose rickettsial diseases. We enrolled 302 patients with acute undifferentiated fever and clinically suspected rickettsiosis during March 2015-March 2017. We used a standardized case report form to collect clinical information and laboratory results at the time of admission and during treatment. We confirmed scrub typhus in 103 (34.1%) patients and murine typhus in 12 (3.3%) patients. These results highlight the need for increased emphasis on training for healthcare providers for earlier recognition, prevention, and treatment of rickettsial diseases in Vietnam.
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http://dx.doi.org/10.3201/eid2504.180691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433017PMC
April 2019

Discovery of Leptospira spp. seroreactive peptides using ORFeome phage display.

PLoS Negl Trop Dis 2019 01 24;13(1):e0007131. Epub 2019 Jan 24.

Institute for Biochemistry, Biotechnology and Bioinformatics, Braunschweig University of Technology, Braunschweig, Germany.

Background: Leptospirosis is the most common zoonotic disease worldwide. The diagnostic performance of a serological test for human leptospirosis is mainly influenced by the antigen used in the test assay. An ideal serological test should cover all serovars of pathogenic leptospires with high sensitivity and specificity and use reagents that are relatively inexpensive to produce and can be used in tropical climates. Peptide-based tests fulfil at least the latter two requirements, and ORFeome phage display has been successfully used to identify immunogenic peptides from other pathogens.

Methodology/principal Findings: Two ORFeome phage display libraries of the entire Leptospira spp. genomes from five local strains isolated in Malaysia and seven WHO reference strains were constructed. Subsequently, 18 unique Leptospira peptides were identified in a screen using a pool of sera from patients with acute leptospirosis. Five of these were validated by titration ELISA using different pools of patient or control sera. The diagnostic performance of these five peptides was then assessed against 16 individual sera from patients with acute leptospirosis and 16 healthy donors and was compared to that of two recombinant reference proteins from L. interrogans. This analysis revealed two peptides (SIR16-D1 and SIR16-H1) from the local isolates with good accuracy for the detection of acute leptospirosis (area under the ROC curve: 0.86 and 0.78, respectively; sensitivity: 0.88 and 0.94; specificity: 0.81 and 0.69), which was close to that of the reference proteins LipL32 and Loa22 (area under the ROC curve: 0.91 and 0.80; sensitivity: 0.94 and 0.81; specificity: 0.75 and 0.75).

Conclusions/significance: This analysis lends further support for using ORFeome phage display to identify pathogen-associated immunogenic peptides, and it suggests that this technique holds promise for the development of peptide-based diagnostics for leptospirosis and, possibly, of vaccines against this pathogen.
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http://dx.doi.org/10.1371/journal.pntd.0007131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363232PMC
January 2019

A non-contact infection screening system using medical radar and Linux-embedded FPGA: Implementation and preliminary validation.

Inform Med Unlocked 2019 15;16:100225. Epub 2019 Aug 15.

Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo, 182-8585, Japan.

Objectives: In this study, an infection screening system was developed to detect patients suffering from infectious diseases. In addition, the system was also designed to deal with the variability in age and gender, which would affect the accuracy of the detection. Furthermore, to enable a low-cost, non-contact and embedded system, multiple vital signs from a medical radar were measured and all algorithms were implemented on a Field Programmable Gate Array, named PYNQ-Z1.

Methods: The system consisted of two main stages: digital signal processing and data classification. In the former stage, Butterworth filters, with flexible cut-off frequencies depending on age and gender, and a time-domain peak detection algorithm were deployed to compute three vital signs, namely heart rate, respiratory rate, and standard deviation of heart beat-to-beat interval. For the classification problem, two machine learning models, Support Vector Machine and Quadratic Discriminant Analysis, were implemented.

Results: The Student's -test showed that our proposed digital signal processing algorithms coped well with the variability of human cases in age and gender. Meanwhile, the f-score of roughly 98.0% represented the high sensitivity and specificity of our proposed machine learning methods.

Conclusion: This study outlines the implementation of an infection screening system, which achieved competent performance. The system might be beneficial for fast screening of infected patients at public health centers in underdeveloped areas, where people have little access to healthcare.
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http://dx.doi.org/10.1016/j.imu.2019.100225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103934PMC
August 2019

Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.

Lancet Gastroenterol Hepatol 2019 02 14;4(2):127-134. Epub 2018 Dec 14.

Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes.

Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed.

Findings: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment.

Interpretation: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(18)30343-1DOI Listing
February 2019

Effect of Macrolide Prophylactic Therapy on AIDS-Defining Conditions and HIV-Associated Mortality.

J Acquir Immune Defic Syndr 2019 04;80(4):436-443

Research Institute for Tropical Medicine, Muntinlupa, Philippines.

Background: Mycobacterium avium complex prophylaxis is recommended for patients with advanced HIV infection. With the decrease in incidence of disseminated Mycobacterium avium complex infection and the availability of antiretroviral therapy (ART), the benefits of macrolide prophylaxis were investigated. This study examined the impact of macrolide prophylaxis on AIDS-defining conditions and HIV-associated mortality in a cohort of HIV-infected patients on ART.

Methods: Patients from TREAT Asia HIV Observational Database (September 2015 data transfer) aged 18 years and older with a CD4 count <50 cells/mm at ART initiation were included. The effect of macrolide prophylaxis on HIV-associated mortality or AIDS-defining conditions (as a combined outcome) and HIV-associated mortality alone were evaluated using competing risk regression. Sensitivity analysis was conducted in patients with a CD4 <100 cells/mm at ART initiation.

Results: Of 1345 eligible patients, 10.6% received macrolide prophylaxis. The rate of the combined outcome was 7.35 [95% confidence interval (CI): 6.04 to 8.95] per 100 patient-years, whereas the rate of HIV-associated mortality was 3.14 (95% CI: 2.35 to 4.19) per 100 patient-years. Macrolide use was associated with a significantly decreased risk of HIV-associated mortality (hazard ratio 0.10, 95% CI: 0.01 to 0.80, P = 0.031) but not with the combined outcome (hazard ratio 0.86, 95% CI: 0.32 to 2.229, P = 0.764). Sensitivity analyses showed consistent results among patients with a CD4 <100 cells/mm at ART initiation.

Conclusions: Macrolide prophylaxis is associated with improved survival among Asian HIV-infected patients with low CD4 cell counts and on ART. This study suggests the increased usage and coverage of macrolide prophylaxis among people living with HIV in Asia.
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http://dx.doi.org/10.1097/QAI.0000000000001933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391185PMC
April 2019

Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.

J Gastroenterol Hepatol 2019 Jan 9;34(1):12-21. Epub 2018 Dec 9.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, New South Wales, Australia.

Background And Aim: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL).

Methods: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group.

Results: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%).

Conclusions: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.
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http://dx.doi.org/10.1111/jgh.14509DOI Listing
January 2019

Parameter Estimation in Mathematical Models of Viral Infections Using R.

Methods Mol Biol 2018 ;1836:531-549

Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany.

In recent years, mathematical modeling approaches have played a central role in understanding and quantifying mechanisms in different viral infectious diseases. In this approach, biology-based hypotheses are expressed via mathematical relations and then tested based on empirical data. The simulation results can be used to either identify underlying mechanisms and provide predictions of infection outcomes or to evaluate the efficacy of a treatment.Conducting parameter estimation for mathematical models is not an easy task. Here we detail an approach to conduct parameter estimation and to evaluate the results using the free software R. The method is applicable to influenza virus dynamics at different complexity levels, widening experimentalists' capabilities in understanding their data. The parameter estimation approach presented here can be also applied to other viral infections or biological applications.
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http://dx.doi.org/10.1007/978-1-4939-8678-1_25DOI Listing
April 2019

Neuraminidase Inhibitors in Influenza Treatment and Prevention⁻Is It Time to Call It a Day?

Viruses 2018 08 25;10(9). Epub 2018 Aug 25.

Frankfurt Institute for Advanced Studies, 60438 Frankfurt am Main, Hessen, Germany.

Stockpiling neuraminidase inhibitors (NAIs) such as oseltamivir and zanamivir is part of a global effort to be prepared for an influenza pandemic. However, the contribution of NAIs for the treatment and prevention of influenza and its complications is largely debatable due to constraints in the ability to control for confounders and to explore unobserved areas of the drug effects. For this study, we used a mathematical model of influenza infection which allowed transparent analyses. The model recreated the oseltamivir effects and indicated that: (i) the efficacy was limited by design, (ii) a 99% efficacy could be achieved by using high drug doses (however, taking high doses of drug 48 h post-infection could only yield a maximum of 1.6-day reduction in the time to symptom alleviation), and (iii) contributions of oseltamivir to epidemic control could be high, but were observed only in fragile settings. In a typical influenza infection, NAIs' efficacy is inherently not high, and even if their efficacy is improved, the effect can be negligible in practice.
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http://dx.doi.org/10.3390/v10090454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163920PMC
August 2018

High-resolution epidemic simulation using within-host infection and contact data.

BMC Public Health 2018 07 17;18(1):886. Epub 2018 Jul 17.

Frankfurt Institute for Advanced Studies, Ruth-Moufang-Str. 1, Frankfurt am Main, 60438, Germany.

Background: Recent epidemics have entailed global discussions on revamping epidemic control and prevention approaches. A general consensus is that all sources of data should be embraced to improve epidemic preparedness. As a disease transmission is inherently governed by individual-level responses, pathogen dynamics within infected hosts posit high potentials to inform population-level phenomena. We propose a multiscale approach showing that individual dynamics were able to reproduce population-level observations.

Methods: Using experimental data, we formulated mathematical models of pathogen infection dynamics from which we simulated mechanistically its transmission parameters. The models were then embedded in our implementation of an age-specific contact network that allows to express individual differences relevant to the transmission processes. This approach is illustrated with an example of Ebola virus (EBOV).

Results: The results showed that a within-host infection model can reproduce EBOV's transmission parameters obtained from population data. At the same time, population age-structure, contact distribution and patterns can be expressed using network generating algorithm. This framework opens a vast opportunity to investigate individual roles of factors involved in the epidemic processes. Estimating EBOV's reproduction number revealed a heterogeneous pattern among age-groups, prompting cautions on estimates unadjusted for contact pattern. Assessments of mass vaccination strategies showed that vaccination conducted in a time window from five months before to one week after the start of an epidemic appeared to strongly reduce epidemic size. Noticeably, compared to a non-intervention scenario, a low critical vaccination coverage of 33% cannot ensure epidemic extinction but could reduce the number of cases by ten to hundred times as well as lessen the case-fatality rate.

Conclusions: Experimental data on the within-host infection have been able to capture upfront key transmission parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. The population of interest in epidemic assessments could be modelled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios to explore multilevel aspects in infectious diseases epidemics are underway.
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http://dx.doi.org/10.1186/s12889-018-5709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050668PMC
July 2018

The 2017 plague outbreak in Madagascar: Data descriptions and epidemic modelling.

Epidemics 2018 12 2;25:20-25. Epub 2018 Jun 2.

Frankfurt Institute for Advanced Studies, Ruth-Moufang-Str. 1, 60438, Frankfurt am Main, Germany. Electronic address:

From August to November 2017, Madagascar endured an outbreak of plague. A total of 2417 cases of plague were confirmed, causing a death toll of 209. Public health intervention efforts were introduced and successfully stopped the epidemic at the end of November. The plague, however, is endemic in the region and occurs annually, posing the risk of future outbreaks. To understand the plague transmission, we collected real-time data from official reports, described the outbreak's characteristics, and estimated transmission parameters using statistical and mathematical models. The pneumonic plague epidemic curve exhibited multiple peaks, coinciding with sporadic introductions of new bubonic cases. Optimal climate conditions for rat flea to flourish were observed during the epidemic. Estimate of the plague basic reproduction number during the large wave of the epidemic was high, ranging from 5 to 7 depending on model assumptions. The incubation and infection periods for bubonic and pneumonic plague were 4.3 and 3.4 days and 3.8 and 2.9 days, respectively. Parameter estimation suggested that even with a small fraction of the population exposed to infected rat fleas (1/10,000) and a small probability of transition from a bubonic case to a secondary pneumonic case (3%), the high human-to-human transmission rate can still generate a large outbreak. Controlling rodent and fleas can prevent new index cases, but managing human-to-human transmission is key to prevent large-scale outbreaks.
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http://dx.doi.org/10.1016/j.epidem.2018.05.001DOI Listing
December 2018

Multiscale model within-host and between-host for viral infectious diseases.

J Math Biol 2018 10 8;77(4):1035-1057. Epub 2018 May 8.

Frankfurt Institute for Advanced Studies, Ruth-Moufang-Straße 1, 60438, Frankfurt am Main, Germany.

Multiscale models possess the potential to uncover new insights into infectious diseases. Here, a rigorous stability analysis of a multiscale model within-host and between-host is presented. The within-host model describes viral replication and the respective immune response while disease transmission is represented by a susceptible-infected model. The bridging of scales from within- to between-host considered transmission as a function of the viral load. Consequently, stability and bifurcation analyses were developed coupling the two basic reproduction numbers [Formula: see text] and [Formula: see text] for the within- and the between-host subsystems, respectively. Local stability results for each subsystem, including a unique stable equilibrium point, recapitulate classical approaches to infection and epidemic control. Using a Lyapunov function, global stability of the between-host system was obtained. Our main result was the derivation of the [Formula: see text] as an increasing function of [Formula: see text]. Numerical analyses reveal that a Michaelis-Menten form based on the virus is more likely to recapitulate the behavior between the scales than a form directly proportional to the virus. Our work contributes basic understandings of the two models and casts light on the potential effects of the coupling function on linking the two scales.
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http://dx.doi.org/10.1007/s00285-018-1241-yDOI Listing
October 2018

Tenofovir disoproxil fumarate co-administered with lopinavir/ritonavir is strongly associated with tubular damage and chronic kidney disease.

J Infect Chemother 2018 Jul 27;24(7):549-554. Epub 2018 Mar 27.

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan; Center for AIDS Research, Kumamoto University, Kumamoto, Japan. Electronic address:

Backgroud: With expanding antiretroviral therapy (ART) in a resource-limited setting, the use of second line ART with ritonavir boosted lopinavir (LPV/r) is increasing. However, little is known regarding the renal safety of tenofovir (TDF) co-administered with LPV/r.

Methods: In total 1382 HIV-infected patients were enrolled and data were recorded twice (October 2014 and 2015) in Vietnam. Tubular dysfunction (TD) was defined as urinary beta 2 microglobulin (β2MG) > 1000 μg/L at both timepoints or increase in β2MG by > 2000 μg/L. Chronic kidney disease (CKD) was defined as creatinine clearance ≤60 ml/min or urinary protein/creatinine ratio ≥ 0.15 g/gCre at both timepoints.

Results: The patients'mean weight and age were 55.9 kg and 38.4 years, respectively, and 41.5% were female. Additionally, 98.2% were on ART, 76.3% were on TDF (mean exposure duration was 35.4 months), and 22.4% had never TDF exposure. TD and CKD were diagnosed in 13% and 8.3% of all patients, respectively. In multivariate analyses, age (OR = 1.057; 95%CI, 1.034-1.081), being female (OR = 0.377; 95%CI, 0.221-0.645), HBsAg positive (OR = 1.812; 95%CI, 1.134-2.894), HCVAb positive (OR = 1.703; 95%CI, 1.100-2.635), TDF exposure (OR = 9.226; 95%CI, 2.847-29.901) and LPV/r exposure (OR = 5.548; 95%CI, 3.313-9.293) were significantly associated with TD. Moreover, age (OR = 1.093; 95%CI, 1.068-1.119), being female (OR = 0.510; 95%CI, 0.295-0.880), weight (OR = 0.909; 95%CI, 0.879-0.939), hypertension (OR = 3.027; 95%CI, 1.714-5.347), TDF exposure (OR = 1.963; 95%CI, 1.027-3.7 53) and LPV/r exposure (OR = 3.122; 95%CI, 1.710-5.699) were significantly associated with CKD.

Conclusions: TDF and LPV/r exposure were strongly associated with TD and CKD, in addition to their known risks. Therefore, attention to renal safety for patients on second line ART is necessary.
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http://dx.doi.org/10.1016/j.jiac.2018.03.002DOI Listing
July 2018

Ventilator-associated respiratory infection in a resource-restricted setting: impact and etiology.

J Intensive Care 2017 19;5:69. Epub 2017 Dec 19.

Oxford University Clinical Research Unit, Hanoi, Vietnam.

Background: Ventilator-associated respiratory infection (VARI) is a significant problem in resource-restricted intensive care units (ICUs), but differences in casemix and etiology means VARI in resource-restricted ICUs may be different from that found in resource-rich units. Data from these settings are vital to plan preventative interventions and assess their cost-effectiveness, but few are available.

Methods: We conducted a prospective observational study in four Vietnamese ICUs to assess the incidence and impact of VARI. Patients ≥ 16 years old and expected to be mechanically ventilated > 48 h were enrolled in the study and followed daily for 28 days following ICU admission.

Results: Four hundred fifty eligible patients were enrolled over 24 months, and after exclusions, 374 patients' data were analyzed. A total of 92/374 cases of VARI (21.7/1000 ventilator days) were diagnosed; 37 (9.9%) of these met ventilator-associated pneumonia (VAP) criteria (8.7/1000 ventilator days). Patients with any VARI, VAP, or VARI without VAP experienced increased hospital and ICU stay, ICU cost, and antibiotic use ( < 0.01 for all). This was also true for all VARI ( < 0.01 for all) with/without tetanus. There was no increased risk of in-hospital death in patients with VARI compared to those without (VAP HR 1.58, 95% CI 0.75-3.33,  = 0.23; VARI without VAP HR 0.40, 95% CI 0.14-1.17,  = 0.09). In patients with positive endotracheal aspirate cultures, most VARI was caused by Gram-negative organisms; the most frequent were (32/73, 43.8%) (26/73, 35.6%), and (24/73, 32.9%). 40/68 (58.8%) patients with positive cultures for these had carbapenem-resistant isolates. Patients with carbapenem-resistant VARI had significantly greater ICU costs than patients with carbapenem-susceptible isolates (6053 USD (IQR 3806-7824) vs 3131 USD (IQR 2108-7551),  = 0.04) and after correction for adequacy of initial antibiotics and APACHE II score, showed a trend towards increased risk of in-hospital death (HR 2.82, 95% CI 0.75-6.75,  = 0.15).

Conclusions: VARI in a resource-restricted setting has limited impact on mortality, but shows significant association with increased patient costs, length of stay, and antibiotic use, particularly when caused by carbapenem-resistant bacteria. Evidence-based interventions to reduce VARI in these settings are urgently needed.
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http://dx.doi.org/10.1186/s40560-017-0266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738227PMC
December 2017

Windows of opportunity for Ebola virus infection treatment and vaccination.

Sci Rep 2017 08 21;7(1):8975. Epub 2017 Aug 21.

Frankfurt Institute for Advanced Studies, Ruth-Moufang-Strasse 1, 60438, Frankfurt am Main, Germany.

Ebola virus (EBOV) infection causes a high death toll, killing a high proportion of EBOV-infected patients within 7 days. Comprehensive data on EBOV infection are fragmented, hampering efforts in developing therapeutics and vaccines against EBOV. Under this circumstance, mathematical models become valuable resources to explore potential controlling strategies. In this paper, we employed experimental data of EBOV-infected nonhuman primates (NHPs) to construct a mathematical framework for determining windows of opportunity for treatment and vaccination. Considering a prophylactic vaccine based on recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (rVSV-EBOV), vaccination could be protective if a subject is vaccinated during a period from one week to four months before infection. For the case of a therapeutic vaccine based on monoclonal antibodies (mAbs), a single dose might resolve the invasive EBOV replication even if it was administrated as late as four days after infection. Our mathematical models can be used as building blocks for evaluating therapeutic and vaccine modalities as well as for evaluating public health intervention strategies in outbreaks. Future laboratory experiments will help to validate and refine the estimates of the windows of opportunity proposed here.
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http://dx.doi.org/10.1038/s41598-017-08884-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567060PMC
August 2017

Factors associated with pre-treatment HIV RNA: application for the use of abacavir and rilpivirine as the first-line regimen for HIV-infected patients in resource-limited settings.

AIDS Res Ther 2017 5;14:27. Epub 2017 May 5.

Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Bangkok, 10400 Thailand.

Background: Abacavir and rilpivirine are alternative antiretroviral drugs for treatment-naïve HIV-infected patients. However, both drugs are only recommended for the patients who have pre-treatment HIV RNA <100,000 copies/mL. In resource-limited settings, pre-treatment HIV RNA is not routinely performed and not widely available. The aims of this study are to determine factors associated with pre-treatment HIV RNA <100,000 copies/mL and to construct a model to predict this outcome.

Methods: HIV-infected adults enrolled in the TREAT Asia HIV Observational Database were eligible if they had an HIV RNA measurement documented at the time of ART initiation. The dataset was randomly split into a derivation data set (75% of patients) and a validation data set (25%). Factors associated with pre-treatment HIV RNA <100,000 copies/mL were evaluated by logistic regression adjusted for study site. A prediction model and prediction scores were created.

Results: A total of 2592 patients were enrolled for the analysis. Median [interquartile range (IQR)] age was 35.8 (29.9-42.5) years; CD4 count was 147 (50-248) cells/mm; and pre-treatment HIV RNA was 100,000 (34,045-301,075) copies/mL. Factors associated with pre-treatment HIV RNA <100,000 copies/mL were age <30 years [OR 1.40 vs. 41-50 years; 95% confidence interval (CI) 1.10-1.80, p = 0.01], body mass index >30 kg/m (OR 2.4 vs. <18.5 kg/m; 95% CI 1.1-5.1, p = 0.02), anemia (OR 1.70; 95% CI 1.40-2.10, p < 0.01), CD4 count >350 cells/mm (OR 3.9 vs. <100 cells/mm; 95% CI 2.0-4.1, p < 0.01), total lymphocyte count >2000 cells/mm (OR 1.7 vs. <1000 cells/mm; 95% CI 1.3-2.3, p < 0.01), and no prior AIDS-defining illness (OR 1.8; 95% CI 1.5-2.3, p < 0.01). Receiver-operator characteristic (ROC) analysis yielded area under the curve of 0.70 (95% CI 0.67-0.72) among derivation patients and 0.69 (95% CI 0.65-0.74) among validation patients. A cut off score >25 yielded the sensitivity of 46.7%, specificity of 79.1%, positive predictive value of 67.7%, and negative predictive value of 61.2% for prediction of pre-treatment HIV RNA <100,000 copies/mL among derivation patients.

Conclusion: A model prediction for pre-treatment HIV RNA <100,000 copies/mL produced an area under the ROC curve of 0.70. A larger sample size for prediction model development as well as for model validation is warranted.
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http://dx.doi.org/10.1186/s12981-017-0151-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420083PMC
March 2018

Influenza epidemic surveillance and prediction based on electronic health record data from an out-of-hours general practitioner cooperative: model development and validation on 2003-2015 data.

BMC Infect Dis 2017 01 18;17(1):84. Epub 2017 Jan 18.

Epidemiology and Social Medicine (ESOC), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Background: Annual influenza epidemics significantly burden health care. Anticipating them allows for timely preparation. The Scientific Institute of Public Health in Belgium (WIV-ISP) monitors the incidence of influenza and influenza-like illnesses (ILIs) and reports on a weekly basis. General practitioners working in out-of-hour cooperatives (OOH GPCs) register diagnoses of ILIs in an instantly accessible electronic health record (EHR) system. This article has two objectives: to explore the possibility of modelling seasonal influenza epidemics using EHR ILI data from the OOH GPC Deurne-Borgerhout, Belgium, and to attempt to develop a model accurately predicting new epidemics to complement the national influenza surveillance by WIV-ISP.

Method: Validity of the OOH GPC data was assessed by comparing OOH GPC ILI data with WIV-ISP ILI data for the period 2003-2012 and using Pearson's correlation. The best fitting prediction model based on OOH GPC data was developed on 2003-2012 data and validated on 2012-2015 data. A comparison of this model with other well-established surveillance methods was performed. A 1-week and one-season ahead prediction was formulated.

Results: In the OOH GPC, 72,792 contacts were recorded from 2003 to 2012 and 31,844 from 2012 to 2015. The mean ILI diagnosis/week was 4.77 (IQR 3.00) and 3.44 (IQR 3.00) for the two periods respectively. Correlation between OOHs and WIV-ISP ILI incidence is high ranging from 0.83 up to 0.97. Adding a secular trend (5 year cycle) and using a first-order autoregressive modelling for the epidemic component together with the use of Poisson likelihood produced the best prediction results. The selected model had the best 1-week ahead prediction performance compared to existing surveillance methods. The prediction of the starting week was less accurate (±3 weeks) than the predicted duration of the next season.

Conclusion: OOH GPC data can be used to predict influenza epidemics both accurately and fast 1-week and one-season ahead. It can also be used to complement the national influenza surveillance to anticipate optimal preparation.
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http://dx.doi.org/10.1186/s12879-016-2175-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241973PMC
January 2017

Analysis of Practical Identifiability of a Viral Infection Model.

PLoS One 2016 30;11(12):e0167568. Epub 2016 Dec 30.

Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Mathematical modelling approaches have granted a significant contribution to life sciences and beyond to understand experimental results. However, incomplete and inadequate assessments in parameter estimation practices hamper the parameter reliability, and consequently the insights that ultimately could arise from a mathematical model. To keep the diligent works in modelling biological systems from being mistrusted, potential sources of error must be acknowledged. Employing a popular mathematical model in viral infection research, existing means and practices in parameter estimation are exemplified. Numerical results show that poor experimental data is a main source that can lead to erroneous parameter estimates despite the use of innovative parameter estimation algorithms. Arbitrary choices of initial conditions as well as data asynchrony distort the parameter estimates but are often overlooked in modelling studies. This work stresses the existence of several sources of error buried in reports of modelling biological systems, voicing the need for assessing the sources of error, consolidating efforts in solving the immediate difficulties, and possibly reconsidering the use of mathematical modelling to quantify experimental data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201286PMC
June 2017

Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection.

Sci Rep 2016 11 22;6:37045. Epub 2016 Nov 22.

Systems Medicine of Infectious Disease Group, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.

In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contributions of cytokines remain largely unclear. In the current study, mathematical modelling based on murine experimental data dissects IFN-γ as a cytokine candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. We also found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was not as distinct as for IFN-γ. Our numerical simulations suggested a detrimental effect of IFN-γ alone and in synergism with IL-6 but no conclusive pathogenic effect of IL-6 and TNF-α alone. This work provides a rationale to understand the potential impact of how to manipulate temporal immune components, facilitating the formulation of hypotheses about potential therapeutic strategies to treat coinfections.
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http://dx.doi.org/10.1038/srep37045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181841PMC
November 2016

Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study.

J Infect Dis 2016 Sep 26;214(5):697-706. Epub 2016 May 26.

Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Hanoi Nuffield Department of Medicine, University of Oxford, United Kingdom.

Background: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown.

Methods: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points.

Results: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated.

Conclusions: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.
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http://dx.doi.org/10.1093/infdis/jiw220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978369PMC
September 2016

Genetic characterization of Enterovirus 71 strains circulating in Vietnam in 2012.

Virology 2016 08 3;495:1-9. Epub 2016 May 3.

Duke-NUS Medical School, 8 College Rd, Singapore; Department of Pathology, Singapore General Hospital, Singapore. Electronic address:

Background: Enterovirus 71 subgenogroup C4 caused the largest outbreak of Hand, Foot and Mouth Disease (HFMD) in Vietnam during 2011-2012, resulting in over 200,000 hospitalisations and 207 fatalities.

Methods: A total of 1917 samples with adequate volume for RT-PCR analysis were collected from patients hospitalised with HFMD throughout Vietnam and 637 were positive for EV71. VP1 gene (n=87) and complete genome (n=9) sequencing was performed. Maximum-likelihood phylogenetic analysis was performed to characterise the B5, C4 and C5 strains detected.

Results: Sequence analyses revealed that the dominant subgenogroup associated with the 2012 outbreak was C4, with B5 and C5 strains representing a small proportion of these cases.

Conclusions: Numerous countries in the region including Malaysia, Taiwan and China have a large influence on strain diversity in Vietnam and understanding the transmission of EV71 throughout Southeast Asia is vital to inform preventative public health measures and vaccine development efforts.
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http://dx.doi.org/10.1016/j.virol.2016.04.026DOI Listing
August 2016

Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries.

BMC Infect Dis 2016 Mar 11;16:120. Epub 2016 Mar 11.

Oxford University Clinical Research Unit, 764 Vo Van Kiet Street, District 5, Ho Chi Minh City, Vietnam.

Background: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course.

Method/design: This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged ≥ 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later.

Discussion: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for "Integrated Management of Childhood Illness" used in dengue-endemic countries.

Trial Registration: NCT01550016. Registration Date: March 7, 2012.
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http://dx.doi.org/10.1186/s12879-016-1440-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788847PMC
March 2016

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

N Engl J Med 2016 Feb;374(6):542-54

From the Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme Vietnam (J.B., M.W., J.F., L.M., G.T., J.N.D.), Hospital for Tropical Diseases (N.T.K.C., N.V.V.C.), Cho Ray Hospital (T.Q.B., L.P.), Ho Chi Minh City, and the National Hospital for Tropical Diseases (N.V.K.) and Bach Mai Hospital (P.T.T.), Hanoi - all in Vietnam; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford (J.B., M.W., J.F., L.M., G.T., M.M., D.D., J.N.D.), University College London, London (R.H.), and Liverpool School of Tropical Medicine, Liverpool (D.G.L.) - all in the United Kingdom; MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda (F.M.K., A.-B.M.G., A.K.); Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok (W.C.), Ubon Sappasithiprasong Hospital, Ubon (S.S., W.S.), and Udon Thani Hospital, Udon Thani (E.T., S.O.) - all in Thailand; Dignitas International, Zomba (A.K.C., E.M., J.J.O.), and Malawi-Liverpool-Wellcome Trust, Clinical Research Programme (R.H., D.G.L.), and University of Malawi College of Medicine (R.H., J.J.O.), Blantyre - all in Malawi; Sunnybrook Health Sciences Centre, University of Toronto, Toronto (A.K.C.); Cipto Mangunkusumo Hospital (D.I.) and Eijkman Oxford Clinical Research Unit (H.B.) - both in Jakarta, Indonesia; and Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital (M.M., D.D., P.P., S.R.), and University of Health Sciences (M.M.) - both in Vientiane, Laos.

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.).
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http://dx.doi.org/10.1056/NEJMoa1509024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778268PMC
February 2016

Modeling Influenza Virus Infection: A Roadmap for Influenza Research.

Viruses 2015 Oct 12;7(10):5274-304. Epub 2015 Oct 12.

Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.

Influenza A virus (IAV) infection represents a global threat causing seasonal outbreaks and pandemics. Additionally, secondary bacterial infections, caused mainly by Streptococcus pneumoniae, are one of the main complications and responsible for the enhanced morbidity and mortality associated with IAV infections. In spite of the significant advances in our knowledge of IAV infections, holistic comprehension of the interplay between IAV and the host immune response (IR) remains largely fragmented. During the last decade, mathematical modeling has been instrumental to explain and quantify IAV dynamics. In this paper, we review not only the state of the art of mathematical models of IAV infection but also the methodologies exploited for parameter estimation. We focus on the adaptive IR control of IAV infection and the possible mechanisms that could promote a secondary bacterial coinfection. To exemplify IAV dynamics and identifiability issues, a mathematical model to explain the interactions between adaptive IR and IAV infection is considered. Furthermore, in this paper we propose a roadmap for future influenza research. The development of a mathematical modeling framework with a secondary bacterial coinfection, immunosenescence, host genetic factors and responsiveness to vaccination will be pivotal to advance IAV infection understanding and treatment optimization.
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http://dx.doi.org/10.3390/v7102875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632383PMC
October 2015

Tenofovir-based antiretroviral therapy in 
HBV-HIV coinfection: results from the TREAT Asia HIV Observational Database.

Antivir Ther 2016 12;21(1):27-35. Epub 2015 Jun 12.

The Kirby Institute, UNSW Australia, Sydney, Australia.

Background: The World Health Organization recommends HBV-HIV-coinfected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in coinfected patients in Asia.

Methods: HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observational Database who started first-line antiretroviral therapy were included. Logistic regression adjusted for period of treatment initiation was used to determine factors associated with tenofovir use. Generalized estimating equations were used to evaluate factors associated with alanine transaminase levels and CD4(+) T-cell count on treatment.

Results: There were 548 eligible patients, of whom 149 (27.2%) started tenofovir. Patients treated in high/high-middle income countries (odds ratio 4.4 versus low/low-middle, 95% CI 2.6, 7.4; P<0.001) and those with elevated baseline alanine transaminase (odds ratio 4.2 versus normal, 95% CI 2.4, 7.2; P<0.001) were more likely to receive tenofovir. Hepatitis C antibody positive patients (odds ratio 0.4 versus negative, 95% CI 0.2, 0.8; P=0.008) were less likely. In those starting antiretroviral therapy with elevated alanine transaminase, mean reduction after tenofovir initiation was 11.2 IU/l (95% CI 0.9, 21.6; P=0.034) lower compared with those using a non-tenofovir-based regimen although this did not significantly increase the chance of alanine transaminase normalization. Tenofovir use was not associated with a superior CD4(+) T-cell response.

Conclusions: HBV-HIV-coinfected patients in Asia are most likely to receive tenofovir if they are treated in a high/high-middle income country, have elevated alanine transaminase levels and are hepatitis C antibody negative. Compared to other antiretroviral therapies, tenofovir-based regimens more effectively reduce liver inflammation in HBV-HIV-coinfection but do not result in superior CD4(+) T-cell recovery.
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http://dx.doi.org/10.3851/IMP2972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757505PMC
December 2016

Ebola virus infection modeling and identifiability problems.

Front Microbiol 2015 9;6:257. Epub 2015 Apr 9.

Systems Medicine of Infectious Diseases, Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research Braunschweig, Germany.

The recent outbreaks of Ebola virus (EBOV) infections have underlined the impact of the virus as a major threat for human health. Due to the high biosafety classification of EBOV (level 4), basic research is very limited. Therefore, the development of new avenues of thinking to advance quantitative comprehension of the virus and its interaction with the host cells is urgently needed to tackle this lethal disease. Mathematical modeling of the EBOV dynamics can be instrumental to interpret Ebola infection kinetics on quantitative grounds. To the best of our knowledge, a mathematical modeling approach to unravel the interaction between EBOV and the host cells is still missing. In this paper, a mathematical model based on differential equations is used to represent the basic interactions between EBOV and wild-type Vero cells in vitro. Parameter sets that represent infectivity of pathogens are estimated for EBOV infection and compared with influenza virus infection kinetics. The average infecting time of wild-type Vero cells by EBOV is slower than in influenza infection. Simulation results suggest that the slow infecting time of EBOV could be compensated by its efficient replication. This study reveals several identifiability problems and what kind of experiments are necessary to advance the quantification of EBOV infection. A first mathematical approach of EBOV dynamics and the estimation of standard parameters in viral infections kinetics is the key contribution of this work, paving the way for future modeling works on EBOV infection.
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http://dx.doi.org/10.3389/fmicb.2015.00257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391033PMC
April 2015