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Changing Patterns of Dengue Epidemiology and Implications for Clinical Management and Vaccines
Cameron P. Simmons ,Jeremy Farrar
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000129
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
Marcel Wolbers, Dorothee Heemskerk, Tran Chau, Nguyen Yen, Maxine Caws, Jeremy Farrar, Jeremy Day
Trials , 2011, DOI: 10.1186/1745-6215-12-26
Abstract: 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.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.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 × 2 factorial design to detect effects of individual drugs would require at least 8-fold the sample size of the combination trial.Current Controlled Trials ISRCTN61649292Tuberculous meningitis (TBM) is the most severe form of M. tuberculosis infection, and kills or disables more than half of those affected [1]. Effective new intervention strategies are thus urgently needed. The study hypothesis of
Kinetics of Viremia and NS1 Antigenemia Are Shaped by Immune Status and Virus Serotype in Adults with Dengue
Vianney Tricou ,Nguyet Nguyen Minh,Jeremy Farrar,Hien Tinh Tran,Cameron P. Simmons
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001309
Abstract: Background Dengue is a major public health problem in tropical and subtropical countries. Exploring the relationships between virological features of infection with patient immune status and outcome may help to identify predictors of disease severity and enable rational therapeutic strategies. Methods Clinical features, antibody responses and virological markers were characterized in Vietnamese adults participating in a randomised controlled treatment trial of chloroquine. Results Of the 248 patients with laboratory-confirmed dengue and defined serological and clinical classifications 29 (11.7%) had primary DF, 150 (60.5%) had secondary DF, 4 (1.6%) had primary DHF and 65 (26.2%) had secondary DHF. DENV-1 was the commonest serotype (57.3%), then DENV-2 (20.6%), DENV-3 (15.7%) and DENV-4 (2.8%). DHF was associated with secondary infection (Odds ratio = 3.13, 95% CI 1.04–12.75). DENV-1 infections resulted in significantly higher viremia levels than DENV-2 infections. Early viremia levels were higher in DENV-1 patients with DHF than with DF, even if the peak viremia level was often not observed because it occurred prior to enrolment. Peak viremias were significantly less often observed during secondary infections than primary for all disease severity grades (P = 0.001). The clearance of DENV viremia and NS1 antigenemia occurs earlier and faster in patients with secondary dengue (P<0.0001). The maximum daily rate of viremia clearance was significantly higher in patients with secondary infections than primary (P<0.00001). Conclusions Collectively, our findings suggest that the early magnitude of viremia is positively associated with disease severity. The clearance of DENV is associated with immune status, and there are serotype dependent differences in infection kinetics. These findings are relevant for the rational design of randomized controlled trials of therapeutic interventions, especially antivirals.
Prior Knowledge, Older Age, and Higher Allowance Are Risk Factors for Self-Medication with Antibiotics among University Students in Southern China
Hui Pan, Binglin Cui, Dangui Zhang, Jeremy Farrar, Frieda Law, William Ba-Thein
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041314
Abstract: Background Self-medication with antibiotics (SMA) has been reported among university students in many countries, but little research has been done on this issue in China. The objective of this study was to evaluate knowledge and behaviors of university students and risk factors concerning SMA. Methodology/Principal Findings Using a novel questionnaire-based data collection instrument, an anonymous online survey was conducted with the students of Shantou University (STU), a university comprising 8 schools/colleges in eastern Guangdong, China. Of 1,300 respondents (13.8% of total eligible participants), 47.8% had self-treated with antibiotics. Logistic regression analysis identified prior knowledge of antibiotics (PKA), older age, and higher monthly allowance as independent risk factors for SMA. PKA significantly influenced students' knowledge about antibiotics, their uses, and common adverse reactions (all p<0.05). Among self-medicated students, 61.7% used antibiotics at least twice in the previous year. Community pharmacies were the major source of self-prescribed antibiotics. Reported common indications for SMA were sore throat (59.7%), fever (38.2%), cough (37.4%), runny nose (29.3%), and nasal congestion (28.7%). While 74.1% of self-medication episodes were based on students' own experiences, only 31.1% of students claimed to understand the package insert. Alteration of antibiotics and dosage during the course of self-treatment was made by 63.8% and 55.6% of students, respectively. At least two kinds of antibiotics were simultaneously taken by 82.6% of students. The majority of self-medicated students failed to complete the course of antibiotics. Adverse reactions were reported by 16.3% of students. Amoxicillin was the most common antibiotic used for self-medication. Conclusions High prevalence of SMA was noted among STU students. Presence of risk factors and risk-associated behaviors/attitudes in the study population calls for focused educational intervention and stricter governmental legislation and regulation of antibiotic use and sale in pharmacies.
Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population
Nguyen Hue, Jean Charlieu, Tran Chau, Nick Day, Jeremy J Farrar, Tran Hien, Sarah J Dunstan
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-152
Abstract: Eighty-two haemoglobinuria patients and 524 healthy controls were screened for G6PD deficiency using either the methylene blue reduction test, the G-6-PDH kit or the micro-methaemoglobin reduction test. The G6PD gene variants were screened using SSCP combined with DNA sequencing in 82 patients with haemoglobinuria, and in 59 healthy controls found to be G6PD deficient.This study confirmed that G6PD deficiency is strongly associated with haemoglobinuria (OR = 15, 95% CI [7.7 to 28.9], P < 0.0001). Six G6PD variants were identified in the Vietnamese population, of which two are novel (Vietnam1 [Glu3Lys] and Vietnam2 [Phe66Cys]). G6PD Viangchan [Val291Met], common throughout south-east Asia, accounted for 77% of the variants detected and was significantly associated with haemoglobinuria within G6PD-deficient ethnic Kinh Vietnamese (OR = 5.8 95% CI [114-55.4], P = 0.022).The primary frequency of several G6PD mutations, including novel mutations, in the Vietnamese Kinh population are reported and the contribution of G6PD mutations to the development of haemoglobinuria are investigated.Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is one of the most common enzymatic disorders of red blood cells in humans and has a varied clinical presentation [1]. The World Health Organization has defined the different G6PD variants according to the magnitude of the enzyme deficiency and the severity of haemolysis. The clinical expression of G6PD deficiency varies from severe enzyme deficiency to increased enzyme activity (class I to class V). The commonest clinical patterns are; 1) neonatal jaundice, 2) congenital haemolytic anaemia, 3) drug-induced haemolysis and 4) favism.G6PD is the initial enzyme involved in the pentose phosphate pathway of erythrocyte metabolism. It is involved in the production of NADPH and indirectly of reduced glutathione necessary for the protection of the cells from oxidative stress. This enzyme is encoded by the G6PD gene, which is located at chromoso
Isoniazid, Pyrazinamide and Rifampicin Content Variation in Split Fixed-Dose Combination Tablets
Thomas Pouplin, Pham Nguyen Phuong, Pham Van Toi, Julie Nguyen Pouplin, Jeremy Farrar
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0102047
Abstract: Setting In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. Objective To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Design Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. Results All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. Conclusion In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.
Phylogeography of Recently Emerged DENV-2 in Southern Viet Nam
Maia A. Rabaa,Vu Thi Ty Hang,Bridget Wills,Jeremy Farrar,Cameron P. Simmons,Edward C. Holmes
PLOS Neglected Tropical Diseases , 2010, DOI: 10.1371/journal.pntd.0000766
Abstract: Revealing the dispersal of dengue viruses (DENV) in time and space is central to understanding their epidemiology. However, the processes that shape DENV transmission patterns at the scale of local populations are not well understood, particularly the impact of such factors as human population movement and urbanization. Herein, we investigated trends in the spatial dynamics of DENV-2 transmission in the highly endemic setting of southern Viet Nam. Through a phylogeographic analysis of 168 full-length DENV-2 genome sequences obtained from hospitalized dengue cases from 10 provinces in southern Viet Nam, we reveal substantial genetic diversity in both urban and rural areas, with multiple lineages identified in individual provinces within a single season, and indicative of frequent viral migration among communities. Focusing on the recently introduced Asian I genotype, we observed particularly high rates of viral exchange between adjacent geographic areas, and between Ho Chi Minh City, the primary urban center of this region, and populations across southern Viet Nam. Within Ho Chi Minh City, patterns of DENV movement appear consistent with a gravity model of virus dispersal, with viruses traveling across a gradient of population density. Overall, our analysis suggests that Ho Chi Minh City may act as a source population for the dispersal of DENV across southern Viet Nam, and provides further evidence that urban areas of Southeast Asia play a primary role in DENV transmission. However, these data also indicate that more rural areas are also capable of maintaining virus populations and hence fueling DENV evolution over multiple seasons.
Influenza A H5N1 and HIV co-infection: case report
Annette Fox, Peter Horby, Nguyen Ha, Le Nguyen Hoa, Nguyen Lam, Cameron Simmons, Jeremy Farrar, Nguyen Van Kinh, Heiman Wertheim
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-167
Abstract: A 30-year-old male was admitted on day 4 of influenza-like-illness with tachycardia, tachypnea, hypoxemia and bilateral pulmonary infiltrates. Influenza A/H5N1 and HIV tests were positive and the patient was treated with Oseltamivir and broad-spectrum antibiotics. Initially his condition improved coinciding with virus clearance by day 6. He clinically deteriorated as of day 10 with fever recrudescence and increasing neutrophil counts and died on day 16. His admission CD4 count was 100/μl and decreased until virus was cleared. CD8 T cells shifted to a CD27+CD28- phenotype. Plasma chemokine and cytokine levels were similar to those found previously in fatal H5N1.The course of H5N1 infection was not notably different from other cases. Virus was cleared despite profound CD4 T cell depletion and aberrant CD8 T cell activation but this may have increased susceptibility to a fatal secondary infection.Influenza A/H5N1 infection is characterized by high viral loads, overproduction of pro-inflammatory cytokines and chemokines, direct lung tissue destruction, pulmonary oedema and extensive inflammatory infiltration [1-3]. The prevailing view is that alveolar damage is the primary pathology leading to acute respiratory distress, multiple organ dysfunction syndrome and death [3]. Likewise, 2009 H1N1 infection can cause acute respiratory distress syndrome and death in previously healthy young adults very similar to the clinical syndrome seen in H5N1 [4].It remains unclear whether lung pathology in severe influenza is a direct consequence of high viral loads and/or of ensuing inflammatory responses. The involvement of innate versus adaptive immunity in inflammation or controlling viremia is also poorly defined. Further understanding of the pathological processes is necessary to develop interventions that prevent severe lung disease. The occurrence of H5N1 infection in a patient with HIV infection offered a unique opportunity to study the pathological and immunological process when
Modelling the progression of pandemic influenza A (H1N1) in Vietnam and the opportunities for reassortment with other influenza viruses
Maciej F Boni, Bui Manh, Pham Thai, Jeremy Farrar, Tran Hien, Nguyen Hien, Nguyen Van Kinh, Peter Horby
BMC Medicine , 2009, DOI: 10.1186/1741-7015-7-43
Abstract: We developed an age- and spatially-structured mathematical model in order to estimate the potential impact of pandemic H1N1 in Vietnam and the opportunities for reassortment with animal influenza viruses. The model tracks human infection among domestic animal owners and non-owners and also estimates the numbers of animals may be exposed to infected humans.In the absence of effective interventions, the model predicts that the introduction of pandemic H1N1 will result in an epidemic that spreads to half of Vietnam's provinces within 57 days (interquartile range (IQR): 45-86.5) and peaks 81 days after introduction (IQR: 62.5-121 days). For the current published range of the 2009 H1N1 influenza's basic reproductive number (1.2-3.1), we estimate a median of 410,000 cases among swine owners (IQR: 220,000-670,000) with 460,000 exposed swine (IQR: 260,000-740,000), 350,000 cases among chicken owners (IQR: 170,000-630,000) with 3.7 million exposed chickens (IQR: 1.9 M-6.4 M), and 51,000 cases among duck owners (IQR: 24,000 - 96,000), with 1.2 million exposed ducks (IQR: 0.6 M-2.1 M). The median number of overall human infections in Vietnam for this range of the basic reproductive number is 6.4 million (IQR: 4.4 M-8.0 M).It is likely that, in the absence of effective interventions, the introduction of a novel H1N1 into a densely populated country such as Vietnam will result in a widespread epidemic. A large epidemic in a country with intense human-animal interaction and continued co-circulation of other seasonal and avian viruses would provide substantial opportunities for H1N1 to acquire new genes.In early 2009 a novel influenza A (H1N1) variant emerged which spread globally causing the first influenza pandemic in over 40 years. The dynamics and impact of this pandemic are difficult to predict, especially since the world has changed significantly in 40 years - the global population has almost doubled, more people live in cities, people travel more frequently and over longer
Influenza A viral loads in respiratory samples collected from patients infected with pandemic H1N1, seasonal H1N1 and H3N2 viruses
Nathamon Ngaosuwankul, Pirom Noisumdaeng, Pisut Komolsiri, Phisanu Pooruk, Kulkanya Chokephaibulkit, Tawee Chotpitayasunondh, Chariya Sangsajja, Charoen Chuchottaworn, Jeremy Farrar, Pilaipan Puthavathana
Virology Journal , 2010, DOI: 10.1186/1743-422x-7-75
Abstract: Copy numbers of M gene were obtained through the extrapolation of Ct values of the test samples against the corresponding standard curve. Among a total of 29 patients with severe influenza enrolled in this study (12 cases of the 2009 pandemic influenza, 5 cases of seasonal H1N1 and 12 cases of seasonal H3N2 virus), NPA was found to contain significantly highest amount of viral loads and followed in order by NS and TS specimen. Viral loads among patients infected with those viruses were comparable regarding type of specimen analyzed.Based on M gene copy numbers, we conclude that NPA is the best specimen for detection of influenza A viruses, and followed in order by NS and TS.Influenza A viruses are classified into 16 hemagglutinin (H) and 9 neuraminidase (N) subtypes [1]. Since the emergence of Russian influenza A (H1N1) in 1977 [2] to the emergence of pandemic influenza A (H1N1) in April 2009, only A/H1N1, A/H3N2 and influenza B viruses have been recognized as human or seasonal influenza. Influenza virus spreads via respiratory secretion. After an incubation period of about 1-3 days, the viruses are shed from various kinds of respiratory samples. Upper respiratory tract specimens, such as nasopharyngeal wash (NPW) or nasopharyngeal aspirate (NPA), nasal swab (NS), throat swab (TS), endothracheal swab, bronchoalveolar lavage and tissues, are recommended for virus detection in patients with respiratory tract infection. These specimens could be used for viral antigen detection, virus isolation and molecular methods for genome detection. Nevertheless, there is no documented data which addresses the type of specimen that gives the best yield for the disease diagnosis [3].Genomes of influenza A and B viruses are composed of 8 negative sense, single-stranded RNA segments encoded for 10-11 proteins essential for infection and replication [1]. The genomic RNA has been used as targets for amplification by conventional and real time reverse transcription-polymerase chain react
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