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1.  Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine: study protocol for a pragmatic randomized controlled trial (CYSCEtrial) 
Trials  2015;16:37.
Background
Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine.
Methods/Design
In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening.
Discussion
Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression.
Trial registration
ClinicalTrials.gov: NCT01778907; registration date: 22 January 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0561-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0561-0
PMCID: PMC4328880  PMID: 25636328
CYP2D6; Pharmacogenetics; Depression; Nortriptyline; Venlafaxine
2.  Efficacy of Standard and Intensive Statin Treatment for the Secondary Prevention of Cardiovascular and Cerebrovascular Events in Diabetes Patients: A Meta-Analysis 
PLoS ONE  2014;9(11):e111247.
Aims
To estimate the efficacy of standard and intensive statin treatment in the secondary prevention of major cardiovascular and cerebrovascular events in diabetes patients.
Methods
A systematic search was conducted in Medline over the years 1990 to September 2013. Randomized, double-blind, clinical trials comparing a standard-dose statin with placebo or a standard-dose statin with an intensive-dose statin for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients were selected. Trial and patient characteristics were extracted independently by two researchers. The combined effect on the composite primary endpoint was measured with a fixed-effect model. Potential publication bias was examined with a funnel plot.
Results
Five trials were included in the analysis comparing standard-dose statins with placebo with a total of 4 351 participants. Four trials were included for comparing standard-dose with intensive-dose statins, including 4 805 participants. Compared with placebo, standard-dose statin treatment resulted in a significant relative risk (RR) reduction of 15% in the occurrence of any major cardiovascular or cerebrovascular event (RR 0.85, 95% CI 0.79–0.91). Compared with standard-dose statin treatment, intensive-dose statin treatment resulted in an additional 9% relative risk reduction (RR 0.91, 95% CI 0.84–0.98).
Conclusion
Treatment with standard-dose statins to prevent cardiovascular or cerebrovascular events in diabetes patients with manifest cardiovascular disease results in an estimated 15% relative risk reduction and intensive-dose statin treatment adds 9%. If proven cost-effective, more intensive statin treatment should be recommended for diabetes patients at high cardiovascular risk.
doi:10.1371/journal.pone.0111247
PMCID: PMC4220992  PMID: 25372483
3.  Direct costs of hypertensive patients admitted to hospital in Vietnam– a bottom-up micro-costing analysis 
Background
There is an economic burden associated with hypertension both worldwide and in Vietnam. In Vietnam, patients with uncontrolled high blood pressure are hospitalized for further diagnosis and initiation of treatment. Because there is no evidence on costs of inpatient care for hypertensive patients available yet to inform policy makers, health insurance and hospitals, this study aims to quantify direct costs of inpatient care for these patients in Vietnam.
Methods
A retrospective study was conducted in a hospital in Vietnam. Direct costs were analyzed from the health-care provider’s perspective. Hospital-based costing was performed using both bottom-up and micro-costing methods. Patients with sole essential or primary hypertension (ICD-code I10) and those comorbid with sphingolipid metabolism or other lipid storage disorders (ICD-code E75) were selected. Costs were quantified based on financial and other records of the hospital. Total cost per patient resulted from an aggregation of laboratory test costs, drug costs, inpatient-days’ costs and other remaining costs, including appropriate allocation of overheads. Both mean and medians, as well as interquartile ranges (IQRs) were calculated. In addition to a base-case analysis, specific scenarios were analyzed.
Results
230 patients were included in the study (147 cases with I10 code only and 83 cases with I10 combined with E75). Median length of hospital stay was 6 days. Median total direct costs per patient were US$65 (IQR: 37 -95). Total costs per patient were higher in the combined hypertensive and lipid population than in the sole hypertensive population at US$78 and US$53, respectively. In all scenarios, hospital inpatient days’ costs were identified as the major cost driver in the total costs.
Conclusions
Costs of hospitalization of hypertensive patients is relatively high compared to annual medication treatment at a community health station for hypertension as well as to the total health expenditure per capita in Vietnam. Given that untreated/undetected hypertension likely leads to more expensive treatments of complications, these findings may justify investments by the Vietnamese health-care sector to control high blood pressure in order to save downstream health care budgets.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0514-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-014-0514-4
PMCID: PMC4221683  PMID: 25348043
Cost analysis; Hypertension; Screening; Vietnam
4.  Comparing Cost-Effectiveness Results for a Vaccine Across Different Countries Worldwide: What Can We Learn? 
Advances in Therapy  2014;31(10):1095-1108.
Introduction
Cost-effectiveness analysis (CEA) using country-specific thresholds tied to gross domestic product (GDP) might not be appropriate in countries with low healthcare investment and a high disease burden as a consequence.
Methods
Using data from previously published CEA of rotavirus vaccination across nine countries worldwide, we calculated the cost neutral price (Pn) for the new intervention that reflects the price resulting in no net increase in health care costs compared with the current situation, and the maximum price (Pm) obtained with an incremental cost-effectiveness ratio (ICER) at the threshold value of 1 × GDP/capita.
Results
In countries with low GDP/capita, the paradoxical finding for rotavirus vaccination is that the Pm is much higher than in countries with a high GDP/capita. On the other hand, the Pn for the low GDP/capita countries is much lower than for high GDP/capita countries because of the low investment in health care.
Conclusion
In countries with low healthcare investment and a high disease burden, the difference between the Pn and Pm for rotavirus vaccine which is the price range within which the ICER is below the World Health Organization (WHO) threshold value, is large. One reason could be that the WHO threshold value may not properly account for the local opportunity cost of health care expenditures. Therefore, either alternative threshold values should be selected or alternative economic assessment tools should be considered, such as budget optimisation or return on investment, if we want to communicate about real economic value of new vaccines in those countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0160-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-014-0160-6
PMCID: PMC4209096  PMID: 25331617
Budget optimisation; Cost-effectiveness analysis; Cost neutral price; Economic evaluation; Gross domestic product per capita; Maximum price; Return on investment; Threshold value; Vaccination
5.  Discontinuing Inappropriate Medication in Nursing Home Residents (DIM-NHR Study): protocol of a cluster randomised controlled trial 
BMJ Open  2014;4(10):e006082.
Introduction
Nursing home residents often have a high number of comorbidities resulting in polypharmacy. Inappropriate prescribing is therefore likely to occur, which in turn is expected to worsen cognitive impairment, to increase the fall risk and to decrease residents’ quality of life. The objective of the ‘Discontinuing Inappropriate Medication in Nursing Home Residents’ (DIM-NHR) study is to examine the efficacy and cost-effectiveness of the Multidisciplinary Multistep Medication Review (3MR) that is aimed at optimising prescribing and discontinuing inappropriate medication.
Methods
A cluster randomised controlled trial will be conducted. Elderly care physicians and their wards (clusters) will be randomised. Data will be collected at baseline and 4 months after the 3MR has taken place. Six hundred nursing home residents will be recruited of whom more than half are expected to suffer from dementia. The 3MR will be based on consensus criteria and the relevant literature and will be performed by the patient’s elderly care physician in collaboration with a pharmacist.
Analysis
Primary outcomes—the difference in proportion of residents who successfully discontinued inappropriate medication between the intervention and control group at follow-up. Secondary outcomes—undertreatment, exposure to anticholinergic and sedative medicines, neuropsychiatric symptoms, cognitive function, falls, hospital admission, quality of life and cost-effectiveness.
Ethics and dissemination
Participant burden will be kept at a minimum. The elderly care physician will remain free to adjust medication when symptoms relapse or adverse events occur, rendering serious adverse events highly unlikely. Study findings will be published in peer-reviewed journals and a 3MR toolkit will be developed.
Trial registration number
This study has been registered at http://www.ClinicalTrials.gov (trial registration number: NCT01876095)
doi:10.1136/bmjopen-2014-006082
PMCID: PMC4194752  PMID: 25296655
CLINICAL PHARMACOLOGY; GERIATRIC MEDICINE; HEALTH ECONOMICS; MEDICAL EDUCATION & TRAINING
6.  Economic Evaluation of Apixaban for the Prevention of Stroke in Non-Valvular Atrial Fibrillation in the Netherlands 
PLoS ONE  2014;9(8):e103974.
Background
Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.
Objective
To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.
Methods
Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).
Results
Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.
Conclusions
In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.
doi:10.1371/journal.pone.0103974
PMCID: PMC4122386  PMID: 25093723
7.  Incidence and pattern of 12 years of reported transfusion adverse events in Zimbabwe: a retrospective analysis 
Blood Transfusion  2014;12(3):362-367.
Background
Haemovigilance hinges on a systematically structured reporting system, which unfortunately does not always exist in resource-limited settings. We determined the incidence and pattern of transfusion-related adverse events reported to the National Blood Service Zimbabwe.
Materials and methods
A retrospective review of the transfusion-event records of the National Blood Service Zimbabwe was conducted covering the period from 1 January 1999 to 31 December 2011. All transfusion-related event reports received during the period were analysed.
Results
A total of 308 transfusion adverse events (0.046%) were reported for 670,625 blood components distributed. The majority (61.6%) of the patients who experienced an adverse event were female. The median age was 36 years (range, 1–89 years). The majority (68.8%) of the adverse events were acute transfusion reactions consisting of febrile non-haemolytic transfusion reactions (58.5%), minor allergies (31.6%), haemolytic reactions (5.2%), severe allergic reactions (2.4%), anaphylaxis (1.4%) and hypotension (0.9%). Two-thirds (66.6%) of the adverse events occurred following administration of whole blood, although only 10.6% of the blood was distributed as whole blood. Packed cells, which accounted for 75% of blood components distributed, were associated with 20.1% of the events.
Discussion
The incidence of suspected transfusion adverse events was generally lower than the incidences reported globally in countries with well-established haemovigilance systems. The administration of whole blood was disproportionately associated with transfusion adverse events. The pattern of the transfusion adverse events reported here highlights the probable differences in practice between different settings. Under-reporting of transfusion events is rife in passive reporting systems.
doi:10.2450/2014.0156-13
PMCID: PMC4111818  PMID: 24887217
transfusion reactions; blood transfusion; haemovigilance; adverse events
8.  Improving inhaler adherence in patients with Chronic Obstructive Pulmonary Disease: a cost-effectiveness analysis 
Respiratory Research  2014;15(1):66.
Background
The PHARMACOP-intervention significantly improved medication adherence and inhalation technique for patients with COPD compared with usual care. This study aimed to evaluate its cost-effectiveness.
Methods
An economic analysis was performed from the Belgian healthcare payer’s perspective. A Markov model was constructed in which a representative group of patients with COPD (mean age of 70 years, 66% male, 43% current smokers and mean Forced Expiratory Volume in 1 second of % predicted of 50), was followed for either receiving the 3-month PHARMACOP-intervention or usual care. Three types of costs were calculated: intervention costs, medication costs and exacerbation costs. Outcome measures included the number of hospital-treated exacerbations, cost per prevented hospital-treated exacerbation and cost per Quality Adjusted Life-Year. Follow-up was 1 year in the basecase analysis. Sensitivity and scenario analyses (including long-term follow-up) were performed to assess uncertainty.
Results
In the basecase analysis, the average overall costs per patient for the PHARMACOP-intervention and usual care were €2,221 and €2,448, respectively within the 1-year time horizon. This reflects cost savings of €227 for the PHARMACOP-intervention. The PHARMACOP-intervention resulted in the prevention of 0.07 hospital-treated exacerbations per patient (0.177 for PHARMACOP versus 0.244 for usual care). Results showed robust cost-savings in various sensitivity analyses.
Conclusions
Optimization of current pharmacotherapy (e.g. close monitoring of inhalation technique and medication adherence) has been shown to be cost-saving and should be considered before adding new therapies.
doi:10.1186/1465-9921-15-66
PMCID: PMC4067522  PMID: 24929799
Adherence; Cost-effectiveness; Inhalation technique; Intervention; Pharmacist
9.  Cost-effectiveness of vaccination against meningococcal B among Dutch infants 
Human Vaccines & Immunotherapeutics  2013;9(5):1129-1138.
Objective: Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands. Therefore, we re-assessed the potential incremental cost-effectiveness ratio (ICER) of vaccinating infants in the Netherlands with a MenB vaccine.
Methods: A cohort of 185,000 Dutch newborns was followed in a Markov model to compare routine vaccination against MenB disease with no vaccination. The ICER was estimated for different disease incidences. The study was performed from a societal perspective.
Results: Routine infant vaccination (2, 3, 4+11 mo) could prevent 39 cases of MenB disease in a single birth cohort, corresponding to a total gain of 133 quality-adjusted life years (QALYs). However, this strategy is unlikely to be cost-effective if the vaccine costs €40 per dose (€243,778 per QALY). At a disease incidence of 5.7 per 100,000 person-years or a vaccine price of €10 per dose including administration costs, the ICER becomes more acceptable and remains below a threshold of €50,000 per QALY.
Conclusions: At the current low level of disease incidence, introduction of routine infant vaccination, following a 2, 3, 4+11 mo schedule, against MenB disease is unlikely cost-effective in the Netherlands. If the MenB disease incidence increases or the vaccine price is substantially lower than €40, routine infant vaccination has the potential to be cost-effective.
doi:10.4161/hv.23888
PMCID: PMC3899149  PMID: 23406816
meningococcal B; cost-effectiveness; vaccine; infants; disease incidence
10.  Economics of vaccines revisited 
Human Vaccines & Immunotherapeutics  2013;9(5):1139-1141.
Performing a total health economic analysis of a vaccine newly introduced into the market today is a challenge when using the conventional cost-effectiveness analysis we normally apply on pharmaceutical products. There are many reasons for that, such as: the uncertainty in the total benefit (direct and indirect) to be measured in a population when using a cohort model;1 appropriate rules about discounting the long-term impact of vaccines are absent jeopardizing therefore their value at the initial investment;2 the presence of opposite contexts when introducing the vaccine in developed vs. the developing world with high benefits, low initial health care investment for the latter vs. marginal benefit and high cost for the former; with a corresponding paradox for the vaccine becoming very cost-effective in low income countries but rather medium in middle low to high middle income countries;3 and the type of trial assessment for the newer vaccines is now often performed with immunogenicity reaction instead of clinical endpoints which still leaves questions on their real impact and their head-to-head comparison.4
doi:10.4161/hv.23447
PMCID: PMC3899150  PMID: 23364247
health economics; new approaches; modeling; cost-effectiveness; perspectives
11.  Optimising Assessments of the Epidemiological Impact in the Netherlands of Paediatric Immunisation with 13-Valent Pneumococcal Conjugate Vaccine Using Dynamic Transmission Modelling 
PLoS ONE  2014;9(4):e89415.
This work is the first attempt to quantify the overall effects of a 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programme in the Dutch population taking into account all the direct and indirect effects of the vaccine on invasive pneumococcal disease. Using available Dutch data, a dynamic transmission model for the spread of pneumococci and potential subsequent invasive pneumococcal disease has been adapted to the Dutch setting. Overall, invasive pneumococcal disease cases in the Netherlands are predicted to decrease from a pre-vaccination level of 2623 cases annually to 2475, 2289, 2185, 2179, and 2178 cases annually 5-, 10-, 20-, 30-, and 40-years, respectively, post-vaccination. Therefore, vaccination with PCV13 in the Netherlands is predicted to lower invasive pneumococcal disease cases per year by up to 445 cases in the medium- to long-term. The results are quite robust for the sensitivity analyses performed on the parameters that regulate herd immunity and competition between vaccine and non-vaccine types.
doi:10.1371/journal.pone.0089415
PMCID: PMC3973563  PMID: 24694656
12.  Budget constraint and vaccine dosing: a mathematical modelling exercise 
Background
Increasing the number of vaccine doses may potentially improve overall efficacy. Decision-makers need information about choosing the most efficient dose schedule to maximise the total health gain of a population when operating under a constrained budget. The objective of this study is to identify the most efficient vaccine dosing schedule within a fixed vaccination budget from a healthcare payer perspective.
Methods
An optimisation model is developed in which maximizing the disease reduction is the functional objective and the constraint is the vaccination budget. The model allows variation in vaccination dosing numbers, in cost difference per dose, in vaccine coverage rate, and in vaccine efficacy. We apply the model using the monovalent rotavirus vaccine as an example.
Results
With a fixed budget, a 2-dose schedule for vaccination against rotavirus infection with the monovalent vaccine results in a larger reduction in disease episodes than a 3-dose scheme with the same vaccine under most circumstances. A 3-dose schedule would only be better under certain conditions: a cost reduction of >26% per dose, combined with vaccine efficacy improvement of ≥5% and a target coverage rate of 75%. Substantial interaction is observed between cost reduction per dose, vaccine coverage rate, and increased vaccine efficacy. Sensitivity analysis shows that the conditions required for a 3-dose strategy to be better than a 2-dose strategy may seldom occur when the budget is fixed. The model does not consider vaccine herd effect, precise timing for additional doses, or the effect of natural immunity development.
Conclusions
Under budget constraint, optimisation modelling is a helpful tool for a decision-maker selecting the most efficient vaccination dosing schedule. The low dosing scheme could be the optimal option to consider under the many scenarios tested. The model can be applied under many different circumstances of changing dosing schemes with single or multiple vaccines.
doi:10.1186/1478-7547-12-3
PMCID: PMC3904011  PMID: 24450591
Rotavirus; Vaccination; Economic evaluation; Budget optimisation modelling
13.  Economic evaluations of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in type 2 diabetic nephropathy: a systematic review 
BMC Nephrology  2014;15:15.
Background
Structured comparison of pharmacoeconomic analyses for ACEIs and ARBs in patients with type 2 diabetic nephropathy is still lacking. This review aims to systematically review the cost-effectiveness of both ACEIs and ARBs in type 2 diabetic patients with nephropathy.
Methods
A systematic literature search was performed in MEDLINE and EMBASE for the period from November 1, 1999 to Oct 31, 2011. Two reviewers independently assessed the quality of the articles included and extracted data. All cost-effectiveness results were converted to 2011 Euros.
Results
Up to October 2011, 434 articles were identified. After full-text checking and quality assessment, 30 articles were finally included in this review involving 39 study settings. All 6 ACEIs studies were literature-based evaluations which synthesized data from different sources. Other 33 studies were directed at ARBs and were designed based on specific trials. The Markov model was the most common decision analytic method used in the evaluations. From the cost-effectiveness results, 37 out of 39 studies indicated either ACEIs or ARBs were cost-saving comparing with placebo/conventional treatment, such as amlodipine. A lack of evidence was assessed for valid direct comparison of cost-effectiveness between ACEIs and ARBs.
Conclusion
There is a lack of direct comparisons of ACEIs and ARBs in existing economic evaluations. Considering the current evidence, both ACEIs and ARBs are likely cost-saving comparing with conventional therapy, excluding such RAAS inhibitors.
doi:10.1186/1471-2369-15-15
PMCID: PMC3913790  PMID: 24428868
14.  Effect of breastfeeding promotion interventions on cost-effectiveness of rotavirus immunization in Indonesia 
BMC Public Health  2013;13:1106.
Background
Rotavirus infection has been reported to be responsible for the majority of severe diarrhea in children under-5-years-old in Indonesia. Breast milk is considered to give protection against rotavirus infection. Increasing breastfeeding promotion programs could be an alternative target to reduce the incidence of rotavirus diarrhea. This study aims to investigate the effect of breastfeeding promotion interventions on cost-effectiveness of rotavirus immunization in Indonesia, focusing on breastfeeding education and support interventions.
Methods
An age-structured cohort model was developed for the 2011 Indonesia birth cohort. We compared four interventions in scenarios: (i) base-case ( I 0 ) reflecting the current situation for the population of under-5-years-old, (ii) with an additional breastfeeding education intervention ( I 1 ), (iii) with a support intervention on initiation and duration ( I 2 ) and (iv) with both of these two interventions combined ( I 3 ). The model applied a 5-years time horizon, with 1 month analytical cycles for children less than 1 year of age and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of rotavirus vaccination.
Results
Rotavirus immunization would effectively reduce severe cases of rotavirus during the first 5 years of a child's life even assuming various breastfeeding promotion interventions. The total yearly vaccine cost would amount to US$ 64 million under the market vaccine price. Cost-effectiveness would increase to US$ 153 per quality-adjusted-life-year (societal perspective) with an optimal breastfeeding promotion intervention. Obviously, this is much lower than the 2011 Gross Domestic Product (GDP) per capita of US$ 3,495. Affordability results showed that at the market vaccine price, rotavirus vaccination could be affordable for the Indonesian health system.
Conclusions
Rotavirus immunization would be a highly cost-effective public health intervention for Indonesia even under various breastfeeding promotion interventions based on the WHO’s criteria for cost-effectiveness in universal immunization.
doi:10.1186/1471-2458-13-1106
PMCID: PMC3879064  PMID: 24289227
Rotavirus; Cost-effectiveness; Vaccination; Breastfeeding; Affordability
15.  Economic impact of childhood/adolescent ADHD in a European setting: the Netherlands as a reference case 
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder in children/adolescents. This study reviews available European-based studies of ADHD-related costs and applies the findings to the Netherlands to estimate annual national costs for children/adolescents from a societal perspective. A systematic literature search was conducted for primary studies in Europe, published January 1, 1990 through April 23, 2013. Per-person cost estimates were converted to 2012 Euros and used to estimate annual national ADHD-related costs based on the Dutch 2011 census, ADHD prevalence rates, family composition, and employment rates. Seven studies met the inclusion criteria. The average total ADHD-related costs ranged from €9,860 to €14,483 per patient and annual national costs were between €1,041 and €1,529 million (M). The largest cost category was education (€648 M), representing 62 and 42 % of the low- and high-value overall national estimates, respectively. By comparison, ADHD patient healthcare costs ranged between €84 M (8 %) and €377 M (25 %), and social services costs were €4.3 M (0.3–0.4 %). While the majority of the costs were incurred by ADHD patients themselves, €161 M (11–15 %) was healthcare costs to family members that were attributable to having an ADHD child/adolescent. In addition, productivity losses of family members were €143–€339 M (14–22 %). Despite uncertainties because of the small number of studies identified and the wide range in the national cost estimates, our results suggest that ADHD imposes a significant economic burden on multiple public sectors in Europe. The limited number of European-based studies examining the economic burden of ADHD highlights the need for more research in this area.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-013-0477-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-013-0477-8
PMCID: PMC4077218  PMID: 24166532
Attention-deficit/hyperactivity disorder; Children; Adolescents; Cost of illness; Societal costs
16.  Modelling the impact of chlamydia screening on the transmission of HIV among men who have sex with men 
BMC Infectious Diseases  2013;13:436.
Background
Recent studies have found high prevalences of asymptomatic rectal chlamydia among HIV-infected men who have sex with men (MSM). Chlamydia could increase the infectivity of HIV and the susceptibility to HIV infection. We investigate the role of chlamydia in the spread of HIV among MSM and the possible impact of routine chlamydia screening among HIV-infected MSM at HIV treatment centres on the incidence of chlamydia and HIV in the overall MSM population.
Methods
A mathematical model was developed to describe the transmission of HIV and chlamydia among MSM. Parameters relating to sexual behaviour were estimated from data from the Amsterdam Cohort Study among MSM. Uncertainty analysis was carried out for model parameters without confident estimates. The effects of different screening strategies for chlamydia were investigated.
Results
Among all new HIV infections in MSM, 15% can be attributed to chlamydia infection. Introduction of routine chlamydia screening every six months among HIV-infected MSM during regular HIV consultations can reduce the incidence of both infections among MSM: after 10 years, the relative percentage reduction in chlamydia incidence would be 15% and in HIV incidence 4%, compared to the current situation. Chlamydia screening is more effective in reducing HIV incidence with more frequent screening and with higher participation of the most risky MSM in the screening program.
Conclusions
Chlamydia infection could contribute to the transmission of HIV among MSM. Preventive measures reducing chlamydia prevalence, such as routine chlamydia screening of HIV-infected MSM, can result in a decline in the incidence of chlamydia and HIV.
doi:10.1186/1471-2334-13-436
PMCID: PMC3851177  PMID: 24047261
HIV; Chlamydia trachomatis; Men who have sex with men; Mathematical model; Chlamydia screening
17.  Is Adding HCV Screening to the Antenatal National Screening Program in Amsterdam, The Netherlands, Cost-Effective? 
PLoS ONE  2013;8(8):e70319.
Introduction
Hepatitis C virus (HCV) infection can lead to severe liver disease. Pregnant women are already routinely screened for several infectious diseases, but not yet for HCV infection. Here we examine whether adding HCV screening to routine screening is cost-effective.
Methods
To estimate the cost-effectiveness of implementing HCV screening of all pregnant women and HCV screening of first-generation non-Western pregnant women as compared to no screening, we developed a Markov model. For the parameters of the model, we used prevalence data from pregnant women retrospectively tested for HCV in Amsterdam, the Netherlands, and from literature sources. In addition, we estimated the effect of possible treatment improvement in the future.
Results
The incremental costs per woman screened was €41 and 0.0008 life-years were gained. The incremental cost-effectiveness ratio (ICER) was €52,473 which is above the cost-effectiveness threshold of €50,000. For screening first-generation non-Western migrants, the ICER was €47,113. Best-case analysis for both scenarios showed ICERs of respectively €19,505 and €17,533. We estimated that if costs per treatment were to decline to €3,750 (a reduction in price of €31,000), screening all pregnant women would be cost-effective.
Conclusions
Currently, adding HCV screening to the already existing screening program for pregnant women is not cost-effective for women in general. However, adding HCV screening for first-generation non-Western women shows a modest cost-effective outcome. Yet, best case analysis shows potentials for an ICER below €20,000 per life-year gained. Treatment options will improve further in the coming years, enhancing cost-effectiveness even more.
doi:10.1371/journal.pone.0070319
PMCID: PMC3741285  PMID: 23950920
18.  A critical review of cost-effectiveness analyses of vaccinating males against human papillomavirus 
Human Vaccines & Immunotherapeutics  2013;9(11):2285-2295.
A critical review of cost-effectiveness analyses of HPV vaccination in males was conducted and nine studies were identified in different countries. Due to the heterogeneity among these studies in terms of modeling approach, vaccination strategies, health outcomes considered, assumptions and parameters, limited conclusions can be drawn with regard to the absolute cost-effectiveness. Nevertheless, key drivers were identified. More favorable cost-effectiveness appeared when all HPV-related diseases outcomes were considered, a suboptimal vaccine coverage among girls and/or lower vaccine prices were assumed. There was a general lack of transparency to fully describe the details of the methodological approach of modeling and calibration. Further research should be conducted to generate robust evidence-based data sets (HPV-related diseases epidemiology, costs and quality of life). The best modeling practice for HPV vaccination and how to better capture the true economic value of vaccination beyond cost-effectiveness in a broader policy context need to be investigated.
doi:10.4161/hv.25754
PMCID: PMC3981835  PMID: 23880955
human papillomavirus; vaccine; strategy; males; cost-effectiveness; economic evaluation
19.  Economic evaluation of influenza pandemic mitigation strategies in the us using a stochastic microsimulation transmission model 
Objectives
To project the potential economic impact of pandemic influenza mitigation strategies from a societal perspective in the United States.
Methods
We use a stochastic agent-based model to simulate pandemic influenza in the community. We compare 17 strategies: targeted antiviral prophylaxis (TAP) alone and in combination with school closure as well as prevaccination.
Results
In the absence of intervention, we predict a 50% attack rate with an economic impact of $187 per capita as loss to society. Full TAP is the most effective single strategy, reducing number of cases by 54% at the lowest cost to society ($127 per capita). Prevaccination reduces number of cases by 48% and is the second least costly alternative ($140 per capita). Adding school closure to full TAP or prevaccination further improves health outcomes, but increases total cost to society by approximately $2700 per capita.
Conclusion
Full targeted antiviral prophylaxis is an effective and cost-saving measure for mitigating pandemic influenza.
doi:10.1111/j.1524-4733.2008.00437.x
PMCID: PMC3710126  PMID: 18671770
Influenza; Human Disease Outbreaks; Cost-Benefit Analysis; Economics; Pharmaceutical Models; Theoretical; Computer Simulation
20.  Effectiveness of A(H1N1)pdm09 Influenza Vaccine in Adults Recommended for Annual Influenza Vaccination 
PLoS ONE  2013;8(6):e66125.
Introduction
Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness.
Methods
VE against influenza and/or pneumonia was assessed in the cohort study (n>25000), and vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza was assessed in a matched case-control study (16 pairs). Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated by using multivariate logistic regression; vaccine effectiveness was estimated as (1-odds ratio)*100%.
Results
Vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia was 98% (84–100%) and 33% (2–54%) respectively. The vaccine did not prevent influenza and/or pneumonia in 18–59 years old subjects, and was 49% (16–69%) effective in 60 years and older subjects.
Conclusions
Even though we cannot entirely rule out that selection bias, residual confounding and/or cross-protection has played a role, the present results indicate that the MF59-adjuvanted A(H1N1)pdm09 influenza vaccine has been effective in preventing laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia, the latter notably in 60 years and older subjects.
doi:10.1371/journal.pone.0066125
PMCID: PMC3688717  PMID: 23840413
21.  Meningococcal Serogroup A, C, W135 and Y Conjugated Vaccine: A Cost-Effectiveness Analysis in the Netherlands 
PLoS ONE  2013;8(5):e65036.
Background
In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was introduced in the Netherlands for all children aged 14 months. Despite its success, herd immunity may wane over time. Recently, a serogroup A,C,W135,Y meningococcal conjugate vaccine (MenACWY) was licensed for use in subjects of 12 months of age and above.
Objectives
To evaluate the cost-effectiveness of meningococcal vaccination at 14 months and an additional vaccination at the age of 12 years, both with the MenACWY vaccine.
Methods
A decision analysis cohort model, with 185,000 Dutch newborns, was used to evaluate the cost-effectiveness of different immunization strategies. For strategies including a vaccination at 12 years of age, an additional cohort with adolescents aged 12 years was followed. The incremental cost-effectiveness ratio (ICER) was estimated for the current disease incidence and for a scenario when herd immunity is lost.
Results
Vaccination with MenACWY at 14 months is cost-saving. Vaccinating with MenACWY at 14 months and at 12 years would prevent 7 additional cases of meningococcal serogroup A,C,W135,Y disease in the birth cohort and adolescent cohort followed for 99 years compared to the current vaccine schedule of a single vaccination with MenC at 14 months. With the current incidence, this strategy resulted in an ICER of €635,334 per quality adjusted life year. When serogroup C disease incidence returns to pre-vaccination levels due to a loss of vaccine-induced herd-immunity, vaccination with MenACWY at 14 months and at 12 years would be cost-saving.
Conclusions
Routine vaccination with MenACWY is cost-saving. With the current epidemiology, a booster-dose with MenACWY is not likely cost-effective. When herd immunity is lost, a booster-dose has the potential of being cost-effective. A dynamic model should be developed for more precise estimation of the cost-effectiveness of the prevention of disappearance of herd immunity.
doi:10.1371/journal.pone.0065036
PMCID: PMC3669019  PMID: 23741448
22.  Economic analysis of pandemic influenza mitigation strategies for five pandemic severity categories 
BMC Public Health  2013;13:211.
Background
The threat of emergence of a human-to-human transmissible strain of highly pathogenic influenza A(H5N1) is very real, and is reinforced by recent results showing that genetically modified A(H5N1) may be readily transmitted between ferrets. Public health authorities are hesitant in introducing social distancing interventions due to societal disruption and productivity losses. This study estimates the effectiveness and total cost (from a societal perspective, with a lifespan time horizon) of a comprehensive range of social distancing and antiviral drug strategies, under a range of pandemic severity categories.
Methods
An economic analysis was conducted using a simulation model of a community of ~30,000 in Australia. Data from the 2009 pandemic was used to derive relationships between the Case Fatality Rate (CFR) and hospitalization rates for each of five pandemic severity categories, with CFR ranging from 0.1% to 2.5%.
Results
For a pandemic with basic reproduction number R0 = 1.8, adopting no interventions resulted in total costs ranging from $441 per person for a pandemic at category 1 (CFR 0.1%) to $8,550 per person at category 5 (CFR 2.5%). For severe pandemics of category 3 (CFR 0.75%) and greater, a strategy combining antiviral treatment and prophylaxis, extended school closure and community contact reduction resulted in the lowest total cost of any strategy, costing $1,584 per person at category 5. This strategy was highly effective, reducing the attack rate to 5%. With low severity pandemics costs are dominated by productivity losses due to illness and social distancing interventions, whereas higher severity pandemic costs are dominated by healthcare costs and costs arising from productivity losses due to death.
Conclusions
For pandemics in high severity categories the strategies with the lowest total cost to society involve rigorous, sustained social distancing, which are considered unacceptable for low severity pandemics due to societal disruption and cost.
doi:10.1186/1471-2458-13-211
PMCID: PMC3606600  PMID: 23496898
Pandemic influenza; Economic analysis; Antiviral medication; Social distancing; Pandemic severity; Case fatality ratio
23.  Inclusion of the benefits of enhanced cross-protection against cervical cancer and prevention of genital warts in the cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands 
Background
Infection with HPV 16 and 18, the major causative agents of cervical cancer, can be prevented through vaccination with a bivalent or quadrivalent vaccine. Both vaccines provide cross-protection against HPV-types not included in the vaccines. In particular, the bivalent vaccine provides additional protection against HPV 31, 33, and 45 and the quadrivalent vaccine against HPV31. The quadrivalent vaccine additionally protects against low-risk HPV type 6 and 11, responsible for most cases of genital warts. In this study, we made an analytical comparison of the two vaccines in terms of cost-effectiveness including the additional benefits of cross-protection and protection against genital warts in comparison with a screening-only strategy.
Methods
We used a Markov model, simulating the progression from HPV infection to cervical cancer or genital warts. The model was used to estimate the difference in future costs and health effects of both HPV-vaccines separately.
Results
In a cohort of 100,000 women, use of the bivalent or quadrivalent vaccine (both at 50% vaccination coverage) reduces the cervical cancer incidence by 221 and 207 cases, corresponding to ICERs of €17,600/QALY and €18,900/QALY, respectively. It was estimated that the quadrivalent vaccine additionally prevents 4390 cases of genital warts, reducing the ICER to €16,300/QALY. Assuming a comparable willingness to pay for cancer and genital warts prevention, the difference in ICERs could justify a slightly higher price (~7% per dose) in favor of the quadrivalent vaccine.
Conclusions
Clearly, HPV vaccination has been implemented for the prevention of cervical cancer. From this perspective, use of the bivalent HPV vaccine appears to be most effective and cost-effective. Including the benefits of prevention against genital warts, the ICER of the quadrivalent HPV vaccine was found to be slightly more favourable. However, current decision-making on the introduction of HPV is driven by the primary cervical cancer outcome. New vaccine tenders could consider the benefits of cross-protection and the benefits of genital warts, which requires more balanced decision-making.
doi:10.1186/1471-2334-13-75
PMCID: PMC3575363  PMID: 23390964
Cervical cancer; HPV-vaccination; Cost-effectiveness; Genital warts; Cross-protection; Pricing of vaccines
24.  An update of “Cost-effectiveness of rotavirus vaccination in the Netherlands: the results of a Consensus Rotavirus Vaccine model” 
Background
To update a cost-effectiveness analysis of rotavirus vaccination in the Netherlands previously published in 2011.
Methods
The rotavirus burden of disease and the indirect protection of older children and young adults (herd protection) were updated.
Results
When updated data was used, routine infant rotavirus vaccination in the Netherlands would potentially become an even more cost-effective strategy than previously estimated with the incremental cost per QALY at only €3,000-4,000. Break-even total vaccination costs were indicated at €92–122, depending on the applied threshold.
Conclusions
We concluded that the results on potentially favourable cost-effectiveness in the previous study remained valid, however, the new data suggested that previous results might represent an underestimation of the economic attractiveness of rotavirus vaccination.
doi:10.1186/1471-2334-13-54
PMCID: PMC3568412  PMID: 23363553
Cost-effectiveness analysis; Rotavirus vaccination; the Netherlands
25.  Impact of Rotavirus Vaccination on Hospitalisations in Belgium: Comparing Model Predictions with Observed Data 
PLoS ONE  2013;8(1):e53864.
Background
Published economic assessments of rotavirus vaccination typically use modelling, mainly static Markov cohort models with birth cohorts followed up to the age of 5 years. Rotavirus vaccination has now been available for several years in some countries, and data have been collected to evaluate the real-world impact of vaccination on rotavirus hospitalisations. This study compared the economic impact of vaccination between model estimates and observed data on disease-specific hospitalisation reductions in a country for which both modelled and observed datasets exist (Belgium).
Methods
A previously published Markov cohort model estimated the impact of rotavirus vaccination on the number of rotavirus hospitalisations in children aged <5 years in Belgium using vaccine efficacy data from clinical development trials. Data on the number of rotavirus-positive gastroenteritis hospitalisations in children aged <5 years between 1 June 2004 and 31 May 2006 (pre-vaccination study period) or 1 June 2007 to 31 May 2010 (post-vaccination study period) were analysed from nine hospitals in Belgium and compared with the modelled estimates.
Results
The model predicted a smaller decrease in hospitalisations over time, mainly explained by two factors. First, the observed data indicated indirect vaccine protection in children too old or too young for vaccination. This herd effect is difficult to capture in static Markov cohort models and therefore was not included in the model. Second, the model included a ‘waning’ effect, i.e. reduced vaccine effectiveness over time. The observed data suggested this waning effect did not occur during that period, and so the model systematically underestimated vaccine effectiveness during the first 4 years after vaccine implementation.
Conclusions
Model predictions underestimated the direct medical economic value of rotavirus vaccination during the first 4 years of vaccination by approximately 10% when assessing hospitalisation rates as compared with observed data in Belgium.
doi:10.1371/journal.pone.0053864
PMCID: PMC3548809  PMID: 23349754

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