Search

Objectives: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). Methods: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (-13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. Results: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged >-65 years, patients without relevant comorbidities, or patients experiencing symptoms for

Background. Threshold analysis is used to determine the threshold value of an input parameter at which a health care strategy becomes cost-effective. Typically, it is performed in a deterministic manner, in which inputs are varied one at a time while the remaining inputs are each fixed at their mean value. This approach will result in incorrect threshold values if the cost-effectiveness model is nonlinear or if inputs are correlated.Objective. To propose a probabilistic method for performing threshold analysis, which accounts for the joint uncertainty in all input parameters and makes no assumption about the linearity of the cost-effectiveness model.Methods. Three methods are compared: 1) deterministic threshold analysis (DTA); 2) a 2-level Monte Carlo approach, which is considered the gold standard; and 3) a regression-based method using a generalized additive model (GAM), which identifies threshold values directly from a probabilistic sensitivity analysis sample.Results. We applied the 3 methods to estimate the minimum probability of hospitalization for typhoid fever at which 3 different vaccination strategies become cost-effective in Uganda. The threshold probability of hospitalization at which routine vaccination at 9 months with catchup campaign to 5 years becomes cost-effective is estimated to be 0.060 and 0.061 (95% confidence interval [CI], 0.058-0.064), respectively, for 2-level and GAM. According to DTA, routine vaccination at 9 months with catchup campaign to 5 years would never become cost-effective. The threshold probability at which routine vaccination at 9 months with catchup campaign to 15 years becomes cost-effective is estimated to be 0.092 (DTA), 0.074 (2-level), and 0.072 (95% CI, 0.069-0.075) (GAM). GAM is 430 times faster than the 2-level approach.Conclusions. When the cost-effectiveness model is nonlinear, GAM provides similar threshold values to the 2-level Monte Carlo approach and is computationally more efficient. DTA provides incorrect results and should not be used. Financial support for this study was provided in part by grants from the Bill and Melinda Gates Foundation (OPP1116967, OPP1151153) (VEP), Research Foundation–Flanders (JB), and the Methusalem financing program of the Flemish government (ZP). The funding agreements ensured the authors’ independence in designing the study, interpreting the data, writing, and publishing the report. Pieters, Z (corresponding author), Univ Antwerp, Hasselt Univ, Data Sci Inst, I BioStat, DS-243,Univ Pl 1, B-2610 Antwerp, Belgium. zoe.pieters@uantwerpen.be

Background Multidrug resistance and fluoroquinolone non-susceptibility (FQNS) are major concerns for the epidemiology and treatment of typhoid fever. The 2018 prequalification of the first typhoid conjugate vaccine (TCV) by WHO provides an opportunity to limit the transmission and burden of antimicrobial-resistant typhoid fever. Methods We combined output from mathematical models of typhoid transmission with estimates of antimicrobial resistance from meta-analyses to predict the burden of antimicrobial-resistant typhoid fever across 73 lower-income countries eligible for support from Gavi, the Vaccine Alliance. We considered FQNS and multidrug resistance separately. The effect of vaccination was predicted on the basis of forecasts of vaccine coverage. We explored how the potential effect of vaccination on the prevalence of antimicrobial resistance varied depending on key model parameters. Findings The introduction of routine immunisation with TCV at age 9 months with a catch-up campaign up to age 15 years was predicted to avert 46–74% of all typhoid fever cases in 73 countries eligible for Gavi support. Vaccination was predicted to reduce the relative prevalence of antimicrobial-resistant typhoid fever by 16% (95% prediction interval [PI] 0–49). TCV introduction with a catch-up campaign was predicted to avert 42·5 million (95% PI 24·8–62·8 million) cases and 506 000 (95% PI 187 000–1·9 million) deaths caused by FQNS typhoid fever, and 21·2 million (95% PI 16·4–26·5 million) cases and 342 000 (95% PI 135 000–1·5 million) deaths from multidrug-resistant typhoid fever over 10 years following introduction. Interpretation Our results indicate the benefits of prioritising TCV introduction for countries with a high avertable burden of antimicrobial-resistant typhoid fever. Funding The Bill & Melinda Gates Foundation.

This tutorial aims to help make the best available methods for generating and presenting cost-effectiveness results with uncertainty common practice. We believe there is a need for such type of tutorial because some erroneous practices persist (e.g., identifying the cost-effective intervention as the one with the highest probability to be cost-effective), while some of the more advanced methods are hardly used (e.g., the net loss statistic ‘NL’, expected net loss curves and frontier). The tutorial explains with simple examples the pros and cons of using ICER, incremental net benefit and NL to identify the cost-effective intervention, both with and without uncertainty accounted for probabilistically. A flowchart provides practical guidance on when and how to use ICER, incremental net benefit or NL. Different ways to express and present uncertainty in the results are described, including confidence and credible intervals, the probability that a strategy is cost-effective (as usually shown with cost-effectiveness acceptability curves (CEACs)) and the expected value of perfect information (EVPI). The tutorial clarifies and illustrates why EVPI is the only measure accounting fully for decision uncertainty, and why NL curves and the NL frontier may be preferred over CEACs and other plots for presenting cost-effectiveness results in the context of uncertainty. The easy calculations and a worked-out real-life example will help users to thoroughly understand and correctly interpret key cost-effectiveness results. Examples with mathematical calculations, interpretation, plots and R code are provided.

Background and Objective Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone. Methods Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed. Results Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: euro17 [0-95% Crl: 16-19] vs. euro24 [5-100% Crl: 18-29]; healthcare provider: euro37 [28-67] vs. euro44 [25-55]; healthcare payers: euro54 [45-85] vs. euro68 [45-81]; and society: euro423 [399-478] vs. euro451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences. Conclusion The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant. The ALIC4E trial and the contributions of AWV, EB, SC, NF, PS, NJH, PaB, AGS, DG, KK, RMP, RRJ, BS, NT, RA, CCB and PB were funded by the European Commission’s Seventh Framework Programme: Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant HEALTH-F3-2013-602525). PB, XL, JB and RB acknowledge partial Methusalem funding from the VAXIDEA and ASCID Centres of Excellence in vaccination and infectious diseases at the University of Antwerp. JB and RB were funded by their personal postdoctoral grants from the Research Foundation—Flanders (FWO). PS acknowledges that The Healthcare Committee, Region Västra Götaland, Sweden, partially funded the Swedish part of the study.

Background. New health technologies are more likely adopted when they have lower incremental cost-effectiveness ratios (ICERs) and/or when their ICER is presented with more certainty. Industry-funded (IF) health economic evaluations use often more favorable base-case values, leading to more favorable conclusions. Purpose. To study whether IF health economic evaluations of varicella-zoster virus vaccination in the elderly use more favorable base-case values and account for less uncertainty than non–industry-funded (NIF) evaluations. Methods. Data source: PubMed. Data extracted: funding source; incremental cost per quality-adjusted life year (QALY) gained; vaccine price; study quality score; base-case values, uncertainty ranges, and data sources for influential parameters: duration of vaccine protection, utility loss due to herpes zoster (HZ) disease, percentage of HZ patients developing postherpetic neuralgia (PHN), and duration of PHN. Data synthesis: qualitative comparisons; Fisher exact test for differences in study quality score and 1-sided Mann-Whitney U tests for differences in base-case values and uncertainty ranges. Results. Despite using the same data sources, IF studies ( n = 10) assume a longer duration of vaccine protection ( U = 56, P = 0.03), have a higher percentage of HZ patients developing PHN ( U = 22/33, P = 0.02/0.03 for ages 60–64/65–69), and tend to use higher HZ utility loss than NIF studies ( n = 11) for their baseline. IF studies show lower ICERs given similar or even higher vaccine prices than NIF studies, consider less uncertainty around the duration of vaccine protection ( U = 8, P < 0.001), and tend to use less uncertainty around the duration of PHN. Yet their quality has been rated equally well, using current standard quality rating tools. Conclusion. Researchers and decision makers should be aware of potential sponsorship bias in health economic evaluations, especially in the way source data are used to specify base-case values and uncertainty ranges.

Background Individual-based models (IBMs) are useful to simulate events subject to stochasticity and/or heterogeneity, and have become well established to model the potential (re)emergence of pathogens (e.g., pandemic influenza, bioterrorism). Individual heterogeneity at the host and pathogen level is increasingly documented to influence transmission of endemic diseases and it is well understood that the final stages of elimination strategies for vaccine-preventable childhood diseases (e.g., polio, measles) are subject to stochasticity. Even so it appears IBMs for both these phenomena are not well established. We review a decade of IBM publications aiming to obtain insights in their advantages, pitfalls and rationale for use and to make recommendations facilitating knowledge transfer within and across disciplines. Methods We systematically identified publications in Web of Science and PubMed from 2006-2015 based on title/abstract/keywords screening (and full-text if necessary) to retrieve topics, modeling purposes and general specifications. We extracted detailed modeling features from papers on established vaccine-preventable childhood diseases based on full-text screening. Results We identified 698 papers, which applied an IBM for infectious disease transmission, and listed these in a reference database, describing their general characteristics. The diversity of disease-topics and overall publication frequency have increased over time (38 to 115 annual publications from 2006 to 2015). The inclusion of intervention strategies (8 to 52) and economic consequences (1 to 20) are increasing, to the detriment of purely theoretical explorations. Unfortunately, terminology used to describe IBMs is inconsistent and ambiguous. We retrieved 24 studies on a vaccine-preventable childhood disease (covering 7 different diseases), with publication frequency increasing from the first such study published in 2008. IBMs have been useful to explore heterogeneous between- and within-host interactions, but combined applications are still sparse. The amount of missing information on model characteristics and study design is remarkable. Conclusions IBMs are suited to combine heterogeneous within- and between-host interactions, which offers many opportunities, especially to analyze targeted interventions for endemic infections. We advocate the exchange of (open-source) platforms and stress the need for consistent “branding”. Using (existing) conventions and reporting protocols would stimulate cross-fertilization between research groups and fields, and ultimately policy making in decades to come. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2699-8) contains supplementary material, which is available to authorized users.

To identify determinants of health-related quality-of-life in the Belgian population and to provide age-specific population norms of health-related quality-of-life. Between September 2010 and February 2011, a representative sample of 1774 persons (age 0-99) was surveyed using the standard Euroqol questionnaire (EQ-5D-3L) with a Visual Analogue Scale (VAS). Significant determinants were identified using multivariate beta (VAS) and one-inflated beta (EQ-5D) regression, the latter modelling the probability to be in perfect health separately from the average EQ-5D score if not in perfect health. Health-related quality-of-life depends largely on age and experience with severe disease. The probability to be in perfect health is highest for children. For 0-2 years children who are not in perfect health, proxies report EQ-5D and VAS scores as low as that of the elderly. Also smoking behaviour, educational attainment, pet ownership, working or having worked in health care, and potentially household size and 60+ living on their own (yes/no) are associated with health-related quality-of-life, whereas no association was found with gender, living in a single-parent home, educational attainment of mothers, alcohol consumption of 60+, having (grand-) children and the frequency of seeing them. The same determinants are significant for VAS and the probability to be in perfect health, but not for the average EQ-5D score if not in perfect health. The population norms provided can be used directly as input in health economic evaluations. Estimating health-related quality-of-life in children and developing statistical tools capturing the particular features of health-related quality-of-life measures are important areas for future research. JB is supported by a postdoctoral grant from the Research Foundation-Flanders (FWO). Support from the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) is gratefully acknowledged. This study was supported by the Research Foundation Flanders project G0D5917N. NH gratefully acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed in 2009-2015 by a gift from Pfizer. The authors acknowledge support of the Antwerp Study Centre for Infectious Diseases (ASCID) at the University of Antwerp. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Background Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of health-seeking behaviours on those costs. Methods A knowledge, attitudes and practices (KAP) survey was applied to 680 households of fifteen communities in Mazan-Loreto in March 2017, then a socio-economic survey was conducted in September 2017 among 161 individuals with confirmed uncomplicated malaria in the past 3 months. Total costs per episode were estimated from both provider (Ministry of Health, MoH) and patient perspectives. Direct costs were estimated using a standard costing estimation procedure, while the indirect costs considered the loss of incomes among patients, substitute labourers and companions due to illness in terms of the monthly minimum wage. Sensitivity analysis evaluated the uncertainty of the average cost per episode. Results The KAP survey showed that most individuals (79.3%) that had malaria went to a health facility for a diagnosis and treatment, 2.7% received those services from community health workers, and 8% went to a drugstore or were self-treated at home. The average total cost per episode in the Mazan district was US$ 161. The cost from the provider’s perspective was US$ 30.85 per episode while from the patient’s perspective the estimated cost was US$ 131 per episode. The average costs per Plasmodium falciparum episode (US$ 180) were higher than those per Plasmodium vivax episode (US$ 156) due to longer time lost from work by patients with P. falciparum infections (22.2 days) than by patients with P. vivax infections (17.0 days). The delayed malaria diagnosis (after 48 h of the onset of symptoms) was associated with the time lost from work due to illness (adjusted mean ratio 1.8; 95% CI 1.3, 2.6). The average cost per malaria episode was most sensitive to the uncertainty around the lost productivity cost due to malaria. Conclusions Despite the provision of free malaria case management by MoH, there is delay in seeking care and the costs of uncomplicated malaria are mainly borne by the families. These costs are not well perceived by the society and the substantial financial impact of the disease can be frequently undervalued in public policy planning.

Summary Background Typhoid fever is a major cause of morbidity and mortality in low-income and middle-income countries. In 2017, WHO recommended the programmatic use of typhoid Vi-conjugate vaccine (TCV) in endemic settings, and Gavi, The Vaccine Alliance, has pledged support for vaccine introduction in these countries. Country-level health economic evaluations are now needed to inform decision-making. Methods In this modelling study, we compared four strategies: no vaccination, routine immunisation at 9 months, and routine immunisation at 9 months with catch-up campaigns to either age 5 years or 15 years. For each of the 54 countries eligible for Gavi support, output from an age-structured transmission-dynamic model was combined with country-specific treatment and vaccine-related costs, treatment outcomes, and disability weights to estimate the reduction in typhoid burden, identify the strategy that maximised average net benefit (ie, the optimal strategy) across a range of country-specific willingness-to-pay (WTP) values, estimate and investigate the uncertainties surrounding our findings, and identify the epidemiological conditions under which vaccination is optimal. Findings The optimal strategy was either no vaccination or TCV immunisation including a catch-up campaign. Routine vaccination with a catch-up campaign to 15 years of age was optimal in 38 countries, assuming a WTP value of at least US$200 per disability-adjusted life-year (DALY) averted, or assuming a WTP value of at least 25% of each country's gross domestic product (GDP) per capita per DALY averted, at a vaccine price of $1·50 per dose (but excluding Gavi's contribution according to each country's transition phase). This vaccination strategy was also optimal in 48 countries assuming a WTP of at least $500 per DALY averted, in 51 with assumed WTP values of at least $1000, in 47 countries assuming a WTP value of at least 50% of GDP per capita per DALY averted, and in 49 assuming a minimum of 100%. Vaccination was likely to be cost-effective in countries with 300 or more typhoid cases per 100 000 person-years. Uncertainty about the probability of hospital admission (and typhoid incidence and mortality) had the greatest influence on the optimal strategy. Interpretation Countries should establish their own WTP threshold and consider routine TCV introduction, including a catch-up campaign when vaccination is optimal on the basis of this threshold. Obtaining improved estimates of the probability of hospital admission would be valuable whenever the optimal strategy is uncertain. Funding Bill & Melinda Gates Foundation, Research Foundation–Flanders, and the Belgian–American Education Foundation.

We conducted a systematic literature review and meta-analysis and estimated the case fatality rate of enteric fever to be 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), 2.5 times higher than what was assumed up until now., Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%–6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below Euro300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about Euro83000, Euro60000 and Euro52000 per QALY gained in 50-64, 65-74 and 75-84year olds, whereas for PCV13 this is about Euro171000, Euro201000 and Euro338000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in

Background. Two vaccines (Rotarix and RotaTeq) are highly effective at preventing severe rotavirus disease. Rotavirus vaccination has been introduced in the United Kingdom and other countries partly based on modeling and cost-effectiveness results. However, most of these models fail to account for the uncertainty about several vaccine characteristics and the mechanism of vaccine action. Methods. A deterministic dynamic transmission model of rotavirus vaccination in the United Kingdom was developed. This improves on previous models by 1) allowing for 2 different mechanisms of action for Rotarix and RotaTeq, 2) using clinical trial data to understand these mechanisms, and 3) accounting for uncertainty by using Markov Chain Monte Carlo. Results. In the long run, Rotarix and RotaTeq are predicted to reduce the overall rotavirus incidence by 50% (39%−63%) and 44% (30%−62%), respectively but with an increase in incidence in primary school children and adults up to 25 y of age. The vaccines are estimated to give more protection than 1 or 2 natural infections. The duration of protection is highly uncertain but has only impact on the predicted reduction in rotavirus burden for values lower than 10 y. The 2 vaccine mechanism structures fit equally well with the clinical trial data. Long-term postvaccination dynamics cannot be predicted reliably with the data available. Conclusion. Accounting for the joint uncertainty of several vaccine characteristics resulted in more insight into which of these are crucial for determining the impact of rotavirus vaccination. Data for up to at least 10 y postvaccination and covering older children and adults are crucial to address remaining questions on the impact of widespread rotavirus vaccination.

Aim: To assess the effectiveness and cost-effectiveness of a universal childhood varicella-zoster vaccination programme in Belgium (1) using the most recent Belgian data on varicella-zoster burden, (2) exploring different options for the timing of the second dose, (3) obtaining results with and without exogenous natural boosting, and (4) investigating the possible additional benefit of zoster booster vaccination for adults at age 50 or 60 years. Methods: An extensively studied and improved dynamic model is used to estimate primary and breakthrough chickenpox and zoster cases over time. For a range of vaccination options, we compared the direct costs (health care payer perspective) and health outcomes (including Quality-Adjusted Life-Years (QALYs) lost) associated with chickenpox and herpes zoster. Estimates of social contact patterns, health care use, costs and QALY losses are almost exclusively based on Belgian databases and surveys. Results and Conclusions: If exogenous natural boosting exists, a net loss in QALYs is expected for several decades after implementing a universal chickenpox vaccination programme, due to an increase in zoster mainly in persons aged 50-80 years. This result holds also for scenarios that minimise or counteract the expected increase in zoster incidence (e.g. additional booster vaccinations in adults). However, if the boosting hypothesis is not true or if costs and QALYs are cumulated over at least 33 to more than 100 years after vaccination (depending on the assumptions made), different options for universal 2-dose vaccination against chickenpox in Belgium would be cost-effective at a vaccine price of 43/dose or lower.

Introduction The estimation of herpes zoster (HZ) vaccine efficacy by time since vaccination and age at vaccination is crucial to assess the effectiveness and cost-effectiveness of HZ vaccination. Published estimates for the duration of protection from the vaccine diverge substantially, although based on data from the same trial for a follow-up period of 5 years. Different models were used to obtain these estimates, but it is unclear which of these models is most appropriate (if any). Only one study estimated vaccine efficacy by age at vaccination and time since vaccination combined. Recently, data became available from the same trial for a follow-up period of 7 years. Aim and methods We aim to elaborate on estimating HZ vaccine efficacy (1) by estimating it as a function of time since vaccination and age at vaccination, (2) by comparing the fits of a range of models, and (3) by fitting these models on data for a follow-up period of 5 and 7 years. Results Although the models’ fit to data are very comparable, they differ substantially in how they estimate vaccine efficacy to change as a function of time since vaccination and age at vaccination. Discussion An accurate estimation of HZ vaccine efficacy by time since vaccination and age at vaccination is hampered by the lack of insight in the biological processes underlying HZ vaccine protection, and by the fact that such data are currently not available in sufficient detail. Uncertainty about the choice of model to estimate this important parameter should be acknowledged in cost-effectiveness analyses.

The detection of human papillomavirus (HPV) DNA in urine, a specimen easily obtained by a non-invasive self-sampling method, has been the subject of a considerable number of studies. This review provides an overview of 41 published studies; assesses how different methods and settings may contribute to the sometimes contradictory outcomes; and discusses the potential relevance of using urine samples in vaccine trials, disease surveillance, epidemiological studies, and specific settings of cervical cancer screening. Urine sampling, storage conditions, sample preparation, DNA extraction, and DNA amplification may all have an important impact on HPV DNA detection and the form of viral DNA that is detected. Possible trends in HPV DNA prevalence in urine could be inferred from the presence of risk factors or the diagnosis of cervical lesions. HPV DNA detection in urine is feasible and may become a useful tool but necessitates further improvement and standardization.

Aim . To estimate the cost-effectiveness of universal childhood rotavirus vaccination in Belgium, taking into account the impact of caregiver burden and the burden of sick children for whom no medical care is sought (``no medical care''). Methods . A cohort of newborns is modeled in relation to costs and health outcomes for rotavirus disease, distinguishing episodes leading to consultations, hospitalizations, and deaths from no medical care episodes. Fully funded universal vaccination is compared with no vaccination as well as with the current situation in Belgium, whereby the 2-dose Rotarix or the 3-dose RotaTeq vaccine can be bought at market prices, which are partially reimbursed. Results . Compared with no vaccination, fully funded universal rotavirus vaccination would cost 51,030 per quality-adjusted life year (QALY) gained with Rotarix and 65,767 with RotaTeq (for society, 7572 and 30,227 per QALY, respectively). However, there is considerable uncertainty due to some analytical choices: the proportion of simulations with an acceptable incremental cost-effectiveness ratio (given a willingness to pay 50,000 for an additional QALY), increases from 2%/0.6% (Rotarix/RotaTeq) to 86%/59% when considering no medical care, and including 2 caregivers to estimate QALY loss instead of zero. Uncertainty is greater still under the societal than under the health care payer perspective. Conclusion . For the Belgian health care payer, at current vaccine prices, universal childhood rotavirus vaccination is unlikely to be judged cost-effective versus no vaccination but would be a more efficient and equitable choice than continuing with current practice.

For health economic evaluations of rotavirus vaccination, estimates of the health and cost burden of rotavirus are required. Due to differences in health care systems and surveillance organisations, this is difficult to achieve by imputing estimates from one country to others. This study aimed to estimate the burden of rotavirus disease in Belgium. In children younger than 7 years of age, rotavirus is predicted to account annually for about 5,600 hospitalisations (676:100,000 children); 26,800 outpatient, general practitioner and paediatrician visits; and about 44,600 episodes for which no medical care is sought. This burden is estimated to represent direct costs of 7.7 million and indirect costs of 12.8 million . Rotavirus disease causes a substantial health and economic burden in Belgium.

Background: A recent trial demonstrated the 13 valent conjugate pneumococcal vaccine (PCV13) to be effective against invasive and non-invasive pneumococcal disease in healthy adults. PCV13 might therefore be considered as an alternative to the 23 valent polysaccharide vaccine (PPV23). Aim: To explore the cost-effectiveness of vaccinating healthy adults over 50, with either PCV13 or PPV23 alone, or with a combined strategy using both PCV13 and PPV23. Methods: A static multi-cohort model was developed simulating the consequences of pneumococcal vaccination in adults over 50 from a health care payer's perspective, for different scenarios of duration of vaccine protection and serotype evolution. Results: At currently expected prices, PCV13 vaccination of healthy adults over 50 is unlikely to be cost-effective either compared with no vaccination or in combination with PPV23 versus PPV23 only. Conclusion: Further research is needed on vaccine efficacy of the combination strategy and of risk groups, as well as the duration of vaccine protection. Serotype evolutions under the influence of the childhood PCV program should be closely monitored. (C) 2016 Elsevier Ltd. All rights reserved.

Vaccination can place selective pressures on viral populations, leading to changes in the distribution of strains as viruses evolve to escape immunity from the vaccine. Vaccine-driven strain replacement is a major concern after nationwide rotavirus vaccine introductions. However, the distribution of the predominant rotavirus genotypes varies from year to year in the absence of vaccination, making it difficult to determine what changes can be attributed to the vaccines. To gain insight in the underlying dynamics driving changes in the rotavirus population, we fitted a hierarchy of mathematical models to national and local genotype-specific hospitalization data from Belgium, where large-scale vaccination was introduced in 2006. We estimated that natural- and vaccine-derived immunity was strongest against completely homotypic strains and weakest against fully heterotypic strains, with an intermediate immunity amongst partially heterotypic strains. The predominance of G2P[4] infections in Belgium after vaccine introduction can be explained by a combination of natural genotype fluctuations and weaker natural and vaccine-induced immunity against infection with strains heterotypic to the vaccine, in the absence of significant variation in strain-specific vaccine effectiveness against disease. However, the incidence of rotavirus gastroenteritis is predicted to remain low despite vaccine-driven changes in the distribution of genotypes. ispartof: Scientific Reports vol:5 issue:1 pages:18585- ispartof: location:England status: published

In 2006, Belgium was the first country in the European Union to recommend rotavirus vaccination in the routine infant vaccination schedule and rapidly achieved high vaccine uptake (86-89% in 2007). We used regional and national data sources up to 7 years post-vaccination to study the impact of vaccination on laboratory-confirmed rotavirus cases and rotavirus-related hospitalisations and deaths. We showed that (i) from 2007 until 2013, vaccination coverage remained at 79-88% for a complete course, (ii) in children 0-2 years, rotavirus cases decreased by 79% (95% confidence intervals (CI): 68-89%) in 2008-2014 compared to the pre-vaccination period (1999-2006) and by 50% (95% CI: 14-82%) in the age group >= 10 years, (iii) hospitalisations for rotavirus gastroenteritis decreased by 87% (95% CI: 84-90%) in 2008-2012 compared to the pre-vaccination period (2002-2006), (iv) median age of rotavirus cases increased from 12 months to 17 months and (v) the rotavirus seasonal peak was reduced and delayed in all post-vaccination years. The substantial decline in rotavirus gastroenteritis requiring hospitalisations and in rotavirus activity following introduction of rotavirus vaccination is sustained over time and more pronounced in the target age group, but with evidence of herd immunity. JB is supported by a postdoctoral grant from the Research Foundation - Flanders (FWO). BO is supported by a PhD fellowship from the Research Foundation - Flanders (FWO). AB is supported by the University of Antwerp's concerted research action number 23405 (BOF-GOA). The authors thank the sentinel laboratory network for their collaboration.

Background: Incremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community. Objective: The objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe. Methods: A systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on ‘mathematical modelling’, ‘health economics’ and ‘decision making’ were debated in group-work sessions (GWS) to formulate recommendations and/or—if applicable—to state ‘pros’ and ‘contras’. Results: A total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine-induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated. Conclusions: There was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions, including vaccines. However, proper evaluation of vaccines implies using tools that are not commonly used for therapeutic drugs. Due to the complexity of and uncertainties around vaccination, transparency in the documentation of HEEs and during subsequent decision making is essential. © 2015, The Author(s). Federal Ministry of Health Germany

Summary Objectives We assessed the association between herpes zoster (HZ) and herpes simplex (HS) occurrence whilst controlling for risk factors of HZ. Methods Using a Belgian general practitioner network, a retrospective cohort study with 3736 HZ patients and 14,076 age-gender-practice matched controls was performed, covering over 1.5 million patient-years. Multiple logistic regression was used with HZ as outcome and several diagnoses (malignancy, depression, diabetes mellitus, auto-immune diseases, asthma, multiple sclerosis, HIV, fractures), medications (systemic corticosteroids, biologicals, vaccination), HS and other infections as variables. Results HS was significantly associated with HZ for all analysed time intervals (up to five years) post HZ (OR of 3.51 [2.09 5.88] 95%CI one year post HZ) and to a lesser extent for time ranges pre HZ. Registration of other infections was significantly associated with HZ in all time intervals pre and post HZ (OR up to 1.37). Malignancy up to five years pre HZ, depression up to one year pre or post HZ, fractures up to two years pre HZ, asthma, auto-immune diseases, and immunosuppressive medication one year pre or post HZ were also associated with HZ. Conclusions HZ and HS occurrences are significantly associated and potentially share a common susceptibility beyond the known risk factors.

Risk groups with increased vulnerability for influenza complications such as pregnant women, persons with underlying illnesses as well as persons who come into contact with them, such as health care workers, are currently given priority (along with other classic target groups) to receive seasonal influenza vaccination in Belgium. We aimed to evaluate this policy from a health care payer perspective by cost-effectiveness analysis in the three specific target groups above, while accounting for effects beyond the target group. Increasing the coverage of influenza vaccination is likely to be cost-effective for pregnant women (median (sic)6589 per quality-adjusted life-year (QALY) gained [(sic)4073-(sic)10,249]) and health care workers (median (sic)24,096/QALY gained [(sic)16,442-(sic)36,342]), if this can be achieved without incurring additional administration costs. Assuming an additional physician's consult is charged to administer each additional vaccine dose, the cost-effectiveness of vaccinating pregnant women depends strongly on the extent of its impact on the neonate's health. For health care workers, the assumed number of preventable secondary infections has a strong influence on the cost-effectiveness. Vaccinating people with underlying illnesses is likely highly cost-effective above 50 years of age and borderline cost-effective for younger persons, depending on relative life expectancy and vaccine efficacy in this risk group compared to the general population. The case-fatality ratios of the target group, of the secondary affected groups and vaccine efficacy are key sources of uncertainty. (C) 2014 Elsevier Ltd. All rights reserved. This study was commissioned and co-financed by the Health Care Knowledge Centre (KCE) of the Belgian Federal government. Adriaan Blommaert acknowledges support from the University of Antwerp concerted research action number 23405 (BOE-GOA); Joke Bilcke is supported by a postdoctoral grant from the Research Foundation Flanders (FWO); Yannick Vandendijck is supported by a doctoral grant of Hasselt University (BOF11D04FAEC). We also gratefully acknowledge financial support by the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy).

Reexposure to viruses is assumed to strengthen humoral and cellular immunity via the secondary immune response. We studied the effects of frequent exposure to viral infectious challenges on immunity. Furthermore, we assessed whether repetitive exposures to varicella-zoster virus (VZV) elicited persistently high immune responses. Blood samples from 11 pediatricians and matched controls were assessed at 3 time points and 1 time point, respectively. Besides the assessment of general immunity by means of measuring T-cell subset percentages, antibody titers and gamma interferon (IFN-γ)/interleukin 2 (IL-2)-producing T-cell percentages against adenovirus type 5 (AdV-5), cytomegalovirus (CMV), tetanus toxin (TT), and VZV were determined. Pediatricians had lower levels of circulating CD4+-naive T cells and showed boosting of CD8+effector memory T cells. Although no effect on humoral immunity was seen, repetitive exposures to VZV induced persistently higher percentages of IFN-γ-positive T cells against all VZV antigens tested (VZV glycoprotein E [gE], VZV intermediate-early protein 62 [IE62], and VZV IE63) than in controls. T cells directed against latency-associated VZV IE63 benefitted the most from natural exogenous boosting. Although no differences in cellular or humoral immunity were found between the pediatricians and controls for AdV-5 or TT, we did find larger immune responses against CMV antigens in pediatricians. Despite the high infectious burden, we detected a robust and diverse immune system in pediatricians. Repetitive exposures to VZV have been shown to induce a stable increased level of VZV-specific cellular but not humoral immunity. Based on our observations, VZV IE63 can be considered a candidate for a zoster vaccine.

Background: Socioeconomic support reduced nonretention in a community-based antiretroviral therapy (ART) program in Uganda. However, resource implications of expanding socioeconomic support are large, and cost-effectiveness analysis can inform budget priorities. We compared the incremental benefits and costs of providing education, food, or both forms of support (dual support) with existing ART services from a health care provider's perspective. Methods: Costs and outcome data were collected from a cohort of 2371 adult patients with HIV receiving education, food, or dual support from Reach Out Mbuya between 2004 and 2010. The primary outcome was averted loss to follow-up. The number of follow-up days was calculated for each patient along with accrued service and fixed program costs for the alternative forms of socioeconomic support in USD by standard costing methods. The socioeconomic support types were compared incrementally over the study period. Results: After 7 years, 762 (33%) of the patients were loss to follow-up with 42% of them receiving food. In the presence of providing ART, education support was less costly and more effective than the alternatives. The average unit cost for education, food, and dual support were $237, $538, and $776, respectively. The average total annual costs were $88,643 for education, $538,005 for food, and $103,045 for dual support. Conclusions: Compared with food or dual support, investing in education of the children of ART patients is less costly and more effective in improving patient retention. Reach Out Mbuya should embrace this paradigm shift and channel its resources more efficiently and effectively by focusing on education support.

SUMMARYVaricella-zoster virus causes chickenpox (CP) and after reactivation herpes zoster (HZ). Vaccines are available against both diseases warranting an assessment of the pre-vaccination burden of disease. We collected data from relevant Belgian databases and performed five surveys of CP and HZ patients. The rates at which a general practitioner is visited at least once for CP and HZ are 346 and 378/100 000 person-years, respectively. The average CP and HZ hospitalization rates are 5·3 and 14·2/100 000 person-years respectively. The direct medical cost for HZ is about twice as large as the direct medical cost for CP. The quality-adjusted life years lost for ambulatory CP patients consulting a physician is more than double that of those not consulting a physician (0·010vs. 0·004). In conclusion, both diseases cause a substantial burden in Belgium.

Aim To assess the cost-effectiveness of vaccinating all or subgroups of adults aged 60 to 85 years against herpes zoster. Methods A deterministic compartmental static model was developed (in freeware R), in which cohorts can acquire herpes zoster according to their age in years. Surveys and database analyses were conducted to obtain as much as possible Belgian age-specific estimates for input parameters. Direct costs and Quality-Adjusted Life-Year (QALY) losses were estimated as a function of standardised Severity Of Illness (SOI) scores (i.e. as a function of the duration and severity of herpes zoster disease). Results Uncertainty about the average SOI score for a person with herpes zoster, the duration of protection from the vaccine, and the population that can benefit from the vaccine, exerts a major impact on the results: under assumptions least in favour of vaccination, vaccination is not cost-effective (i.e. incremental cost per QALY gained >48,000 for all ages considered) at the expected vaccine price of 90 per dose. At the same price, but under assumptions most in favour of vaccination, vaccination is found to be cost-effective (i.e. incremental cost per QALY gained

Background Despite the existence of varicella vaccine, many developed countries have not introduced it into their national schedules, partly because of concerns about whether herpes zoster (HZ, shingles) will increase due to a lack of exogenous boosting. The magnitude of any increase in zoster that might occur is dependent on rates at which adults and children mix – something that has only recently been quantified – and could be reduced by simultaneously vaccinating older individuals against shingles. This study is the first to assess the cost-effectiveness of combined varicella and zoster vaccination options and compare this to alternative programmes. Methods and findings The cost-effectiveness of various options for the use of varicella–zoster virus (VZV) containing vaccines was explored using a transmission dynamic model. Underlying contact rates are estimated from a contemporary survey of social mixing patterns, and uncertainty in these derived from bootstrapping the original sample. The model was calibrated to UK data on varicella and zoster incidence. Other parameters were taken from the literature. UK guidance on perspective and discount rates were followed. The results of the incremental cost-effectiveness analysis suggest that a combined policy is cost-effective. However, the cost-effectiveness of this policy (and indeed the childhood two-dose policy) is influenced by projected benefits that accrue many decades (80–100 years or more) after the start of vaccination. If the programme is evaluated over shorter time frames, then it would be unlikely to be deemed cost-effective, and may result in declines in population health, due to a projected rise in the incidence of HZ. The findings are also sensitive to a number of parameters that are inaccurately quantified, such as the risk of HZ in varicella vaccine responders. Conclusions Policy makers should be aware of the potential negative benefits in the first 30–50 years after introduction of a childhood varicella vaccine. This can only be partly mitigated by the introduction of a herpes zoster vaccine. They have to decide how they value the potential benefits beyond this time to consider childhood vaccination cost effective.

A cost-effectiveness analysis of rotavirus vaccination in Belgium, England and Wales, Finland, France and the Netherlands published in 2009 was updated based on recent studies on rotavirus burden of disease and vaccine efficacy. All the qualitative conclusions in the previous study were found to remain valid. Vaccination remains cost-effective in Finland only when using plausible tender prices.

Background We conducted for the first time a systematic review, including a meta-analysis, of the incidence of symptomatic rotavirus (RV) infections, because (1) it was shown to be an influential factor in estimating the cost-effectiveness of RV vaccination, (2) multiple community-based studies assessed it prospectively, (3) previous studies indicated, inconclusively, it might be similar around the world. Methodology Pubmed (which includes Medline) was searched for surveys assessing prospectively symptomatic (diarrheal) episodes in a general population and situation, which also reported on the number of the episodes being tested RV+ and on the persons and the time period observed. A bias assessment tool was developed and used according to Cochrane guidelines by 4 researchers with different backgrounds. Heterogeneity was explored graphically and by comparing fits of study-homogenous ‘fixed effects’ and -heterogeneous ‘random effects’ models. Data were synthesized using these models. Sensitivity analysis for uncertainty regarding data abstraction, bias assessment and included studies was performed. Principal Findings Variability between the incidences obtained from 20 studies is unlikely to be due to study groups living in different environments (tropical versus temperate climate, slums versus middle-class suburban populations), nor due to the year the study was conducted (from 1967 to 2003). A random effects model was used to incorporate unexplained heterogeneity and resulted in a global incidence estimate of 0.31 [0.19; 0.50] symptomatic RV infections per personyear of observation for children below 2 years of age, and of 0.24 [0.17; 0.34] when excluding the extreme high value of 0.84 reported for Mayan Indians in Guatemala. Apart from the inclusion/exclusion of the latter study, results were robust. Conclusions/Significance Rather than assumptions based on an ad-hoc selection of one or two studies, these pooled estimates (together with the measure for variability between populations) should be used as an input in future cost-effectiveness analyses of RV vaccination.

Cost-effectiveness analyses are usually not directly comparable between countries because of differences in analytical and modelling assumptions. We investigated the cost-effectiveness of rotavirus vaccination in five European Union countries (Belgium, England and Wales, Finland, France and the Netherlands) using a single model, burden of disease estimates supplied by national public health agencies and a subset of common assumptions. Under base case assumptions (vaccination with Rotarix, 3% discount rate, health care provider perspective, no herd immunity and quality of life of one caregiver affected by a rotavirus episode) and a cost-effectiveness threshold of euro30,000, vaccination is likely to be cost effective in Finland only. However, single changes to assumptions may make it cost effective in Belgium and the Netherlands. The estimated threshold price per dose for Rotarix (excluding administration costs) to be cost effective was euro41 in Belgium, euro28 in England and Wales, euro51 in Finland, euro36 in France and euro46 in the Netherlands.

This is one of the first studies to (1) describe the out-of-hospital burden of influenza-like-illness (ILI) and clinically diagnosed flu, also for patients not seeking professional medical care, (2) assess influential background characteristics, and (3) formally compare the burden of ILI in patients with and without a clinical diagnosis of flu. A general population sample with recent ILI experience was recruited during the 2011-2012 influenza season in Belgium. Half of the 2250 respondents sought professional medical care, reported more symptoms (especially more often fever), a longer duration of illness, more use of medication (especially antibiotics) and a higher direct medical cost than patients not seeking medical care. The disease and economic burden were similar for ambulatory ILI patients, irrespective of whether they received a clinical diagnosis of flu. On average, they experienced 5-6 symptoms over a 6-day period; required 1.6 physician visits and 86-91% took medication. An average episode amounted to is an element of 51-is an element of 53 in direct medical costs, 4 days of absence from work or school and the loss of 0.005 quality-adjusted life-years. Underlying illness led to greater costs and lower quality-of-life. The costs of ILI patients with clinically diagnosed flu tended to increase, while those of ILI patients without clinically diagnosed flu tended to decrease with age. Recently vaccinated persons experienced lower costs and a higher quality-of-life, but this was only the case for patients not seeking professional medical care. This information can be used directly to evaluate the implementation of cost-effective prevention and control measures for influenza. In particular to inform the evaluation of more widespread seasonal influenza vaccination, including in children, which is currently considered by many countries.