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1.  Cross-border comparison of antibiotic prescriptions among children and adolescents between the north of the Netherlands and the north-west of Germany 
Background
Antibiotic resistance is a worldwide problem and inappropriate prescriptions are a cause. Especially among children, prescriptions tend to be high. It is unclear how they differ in bordering regions. This study therefore examined the antibiotic prescription prevalence among children in primary care between northern Netherlands and north-west of Germany.
Methods
Two datasets were used: The Dutch (IADB) comprises representative data of pharmacists in North Netherland and the German (BARMER GEK) includes nationwide health insurance data. Both were filtered using postal codes to define two comparable bordering regions with patients under 18 years for 2010.
Results
The proportion of primary care patients receiving at least one antibiotic was lower in northern Netherlands (29.8 %; 95 % confidence interval [95 % CI]: 29.3–30.3), compared to north-west Germany (38.9 %; 95 % CI: 38.2–39.6). Within the respective countries, there were variations ranging from 27.0 to 44.1 % between different areas. Most profound was the difference in second-generation cephalosporins: for German children 25 % of the total prescriptions, while for Dutch children it was less than 0.1 %.
Conclusions
This study is the first to compare outpatient antibiotic prescriptions among children in primary care practices in bordering regions of two countries. Large differences were seen within and between the countries, with overall higher prescription prevalence in Germany. Considering increasing cross-border healthcare, these comparisons are highly valuable and help act upon antibiotic resistance in the first line of care in an international approach.
doi:10.1186/s13756-016-0113-8
PMCID: PMC4836103  PMID: 27096086
Antibiotics; Germany; Netherlands; Border research; Health services research
2.  Multivariate Meta-Analysis of Preference-Based Quality of Life Values in Coronary Heart Disease 
PLoS ONE  2016;11(3):e0152030.
Background
There are numerous health-related quality of life (HRQol) measurements used in coronary heart disease (CHD) in the literature. However, only values assessed with preference-based instruments can be directly applied in a cost-utility analysis (CUA).
Objective
To summarize and synthesize instrument-specific preference-based values in CHD and the underlying disease-subgroups, stable angina and post-acute coronary syndrome (post-ACS), for developed countries, while accounting for study-level characteristics, and within- and between-study correlation.
Methods
A systematic review was conducted to identify studies reporting preference-based values in CHD. A multivariate meta-analysis was applied to synthesize the HRQoL values. Meta-regression analyses examined the effect of study level covariates age, publication year, prevalence of diabetes and gender.
Results
A total of 40 studies providing preference-based values were detected. Synthesized estimates of HRQoL in post-ACS ranged from 0.64 (Quality of Well-Being) to 0.92 (EuroQol European”tariff”), while in stable angina they ranged from 0.64 (Short form 6D) to 0.89 (Standard Gamble). Similar findings were observed in estimates applying to general CHD. No significant improvement in model fit was found after adjusting for study-level covariates. Large between-study heterogeneity was observed in all the models investigated.
Conclusions
The main finding of our study is the presence of large heterogeneity both within and between instrument-specific HRQoL values. Current economic models in CHD ignore this between-study heterogeneity. Multivariate meta-analysis can quantify this heterogeneity and offers the means for uncertainty around HRQoL values to be translated to uncertainty in CUAs.
doi:10.1371/journal.pone.0152030
PMCID: PMC4806923  PMID: 27011260
3.  Cost-Analysis of Seven Nosocomial Outbreaks in an Academic Hospital 
PLoS ONE  2016;11(2):e0149226.
Objectives
Nosocomial outbreaks, especially with (multi-)resistant microorganisms, are a major problem for health care institutions. They can cause morbidity and mortality for patients and controlling these costs substantial amounts of funds and resources. However, how much is unclear. This study sets out to provide a comparable overview of the costs of multiple outbreaks in a single academic hospital in the Netherlands.
Methods
Based on interviews with the involved staff, multiple databases and stored records from the Infection Prevention Division all actions undertaken, extra staff employment, use of resources, bed-occupancy rates, and other miscellaneous cost drivers during different outbreaks were scored and quantified into Euros. This led to total costs per outbreak and an estimated average cost per positive patient per outbreak day.
Results
Seven outbreaks that occurred between 2012 and 2014 in the hospital were evaluated. Total costs for the hospital ranged between €10,778 and €356,754. Costs per positive patient per outbreak day, ranged between €10 and €1,369 (95% CI: €49-€1,042), with a mean of €546 and a median of €519. Majority of the costs (50%) were made because of closed beds.
Conclusions
This analysis is the first to give a comparable overview of various outbreaks, caused by different microorganisms, in the same hospital and all analyzed with the same method. It shows a large variation within the average costs due to different factors (e.g. closure of wards, type of ward). All outbreaks however cost considerable amounts of efforts and money (up to €356,754), including missed revenue and control measures.
doi:10.1371/journal.pone.0149226
PMCID: PMC4749280  PMID: 26863145
4.  Comparative Cost-Effectiveness of Drugs in Early versus Late Stages of Cancer; Review of the Literature and a Case Study in Breast Cancer 
PLoS ONE  2016;11(1):e0146551.
Background
Many oncological drugs that are being used in the adjuvant setting were first submitted for reimbursement in the metastatic stage, with differences in incremental cost-effectiveness ratios (ICERs) in both settings having potential implications for reimbursement and pricing. The aim of this study is to identify a possible trend in the cost-effectiveness for the early/adjuvant and late/metastatic stages of oncological drugs through review and case study.
Methods
We reviewed pairs of cost-effectiveness analyses of the same oncological drug in different stages for Scotland and the Netherlands. The case study in this report was directed at trastuzumab in the Dutch situation. Using a simplified Markov model, the cost-effectiveness in early and late stage of breast cancer was calculated and compared to the findings from the review.
Results
Comparable studies were found for cetuximab, bortezomib and bosutinib. Treatments in the late stage were found to be more expensive per QALY by a factor ranging from 1.5 to 12. The case study provided a similar result; late stage treatment was more expensive by a factor 10. Using, for example, a threshold of €80,000/QALY, the early stage of cetuximab, bosutinib and trastuzumab are deemed cost-effective, while their compared late stage is lifted over the threshold and potentially considered not cost-effective.
Conclusion
ICERs of oncological drugs used in different stages are more unfavourable in the late stage than in the early stage. Applying a reasonable threshold may result in early stage treatment being deemed cost-effective while late stage potentially not. Authorities should be aware of this when assessing oncological drugs and interpreting the corresponding ICERs, in the situation where oncological drugs are generally most submitted for reimbursement in the late stage initially.
doi:10.1371/journal.pone.0146551
PMCID: PMC4723090  PMID: 26800029
5.  Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature 
PLoS ONE  2016;11(1):e0146262.
Objective
Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature.
Methods
A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies’ overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument.
Results
We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing.
Conclusions
Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests’ efficacy remains of utmost importance.
doi:10.1371/journal.pone.0146262
PMCID: PMC4709231  PMID: 26752539
6.  The Burden of Tick-Borne Encephalitis in Disability-Adjusted Life Years (DALYs) for Slovenia 
PLoS ONE  2015;10(12):e0144988.
Background
Tick-borne encephalitis (TBE) presents an increasing burden in many parts of Europe, Asian Russia, Siberia, Asian former USSR and Far East. Incidence can be considered as one way to express the burden. A more comprehensive measure concerns disability-adjusted life years (DALYs), better characterizing the full burden of TBE. TBE burden in DALYs has not yet been estimated, nor has it been specified by the Global Burden of Disease (GBD) studies.
Objective
The purpose of the present study is to estimate the burden of TBE in Slovenia, expressed in DALYs, both from the population and individual perspectives. We discuss the impact of TBE burden on public health and potential strategies to reduce this burden in Slovenia.
Methods
The burden of TBE is estimated by using the updated DALYs' methodology first introduced in the GBD project. The DALYs᾽ calculations are based on the health outcomes of the natural course of the disease being modelled. Corrections for under-reporting and under-ascertainment are applied. The impact of uncertainty in parameters in the model was assessed using sensitivity analyses.
Results
From the population perspective, total DALYs amount to 3,450 (167.8 per 100,000 population), while from the individual perspective they amount to 3.1 per case in 2011. Notably, the consequences of TBE present a larger burden than TBE itself.
Conclusions
TBE presents a relatively high burden expressed in DALYs compared with estimates for other infectious diseases from the GBD 2010 study for Slovenia. Raising awareness and increasing vaccination coverage are needed to reduce TBE and its consequences.
doi:10.1371/journal.pone.0144988
PMCID: PMC4684505  PMID: 26672751
7.  Use of Value of Information in Healthcare Decision Making: Exploring Multiple Perspectives 
Pharmacoeconomics  2015;34:315-322.
Background
Value of information (VOI) is a tool that can be used to inform decisions concerning additional research in healthcare. VOI estimates the value of obtaining additional information and indicates the optimal design for additional research. Although it is recognized as good practice in handling uncertainty, it is still hardly used in decision making in the Netherlands.
Objective
This paper aims to examine the potential value of VOI, barriers and facilitators and the way forward with the use of VOI in the decision-making process for reimbursement of pharmaceuticals in the Netherlands.
Methods
Three focus group interviews were conducted with researchers, policy makers, and representatives of pharmaceutical companies.
Results
The results revealed that although all stakeholders recognize the relevance of VOI, it is hardly used and many barriers to the performance and use of VOI were identified. One of these barriers is that not all uncertainties are easily incorporated in VOI, and the results may be biased if structural uncertainties are ignored. Furthermore, not all research designs indicated by VOI may be feasible in practice.
Conclusions
To fully embed VOI into current decision-making processes, a threshold incremental cost-effectiveness ratio and guidelines that clarify when and how VOI should be performed are needed. In addition, it should be clear to all stakeholders how the results of VOI are used in decision making.
doi:10.1007/s40273-015-0346-z
PMCID: PMC4766221  PMID: 26578403
8.  Utilities of Patients with Hypertension in Northern Vietnam 
PLoS ONE  2015;10(10):e0139560.
Objectives
The study aims to inform potential cost-effectiveness analysis of hypertension management in Vietnam by providing utilities and predictors of utilities in patients with hypertension.
Methods
Hypertensive patients up to 80 years old visiting the hospital were invited to participate in a survey using Quality Metric’s Short-form 36v2TM translated into Vietnamese. Health-state utilities were estimated by applying a previously published algorithm.
Results
The mean utility of the 691 patients interviewed was 0.73. Controlling for age, sex, blood pressure (BP) stage, and history of stroke, the utilities in older patients were lower than those in younger ones, and statistically significantly different between the extremes of youngest and oldest groups (p = 0.03). Utility in males was higher than in females (p = 0.002). As expected, patients with a history of stroke appeared to exhibit lower utilities than patients without such history, but the difference was not statistically significant (p = 0.73). Patients with more than three comorbidities did have lower utilities than patients without comorbidity (p = 0.01).
Conclusions
Health-state utilities found among hypertensive patients in Vietnam were similar to those found in other international studies. It is suggested that lower of health-state utilities exist among those patients who were older, female or had more than three comorbidities in comparison with respective reference groups. However, further research for confirmation is required. The data from this study provide a potential reference on health-state utilities of hypertensive patients in Vietnam as an input for future cost-effectiveness analysis of interventions. Also, it may serve as a reference for other similar populations, especially in the context of similar environments in low income countries.
doi:10.1371/journal.pone.0139560
PMCID: PMC4623979  PMID: 26506444
9.  Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community 
Pharmacoeconomics  2015;34:227-244.
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.
doi:10.1007/s40273-015-0335-2
PMCID: PMC4766233  PMID: 26477039
10.  Namibia’s transition from whole blood–derived pooled platelets to single-donor apheresis platelet collections 
Transfusion  2015;55(7):1685-1692.
BACKGROUND
Few African countries separate blood donations into components; however, demand for platelets (PLTs) is increasing as regional capacity to treat causes of thrombocytopenia, including chemotherapy, increases. Namibia introduced single-donor apheresis PLT collections in 2007 to increase PLT availability while reducing exposure to multiple donors via pooling. This study describes the impact this transition had on PLT availability and safety in Namibia.
STUDY DESIGN AND METHODS
Annual national blood collections and PLT units issued data were extracted from a database maintained by the Blood Transfusion Service of Namibia (NAMBTS). Production costs and unit prices were analyzed.
RESULTS
In 2006, NAMBTS issued 771 single and pooled PLT doses from 3054 whole blood (WB) donations (drawn from 18,422 WB donations). In 2007, NAMBTS issued 486 single and pooled PLT doses from 1477 WB donations (drawn from 18,309 WB donations) and 131 single-donor PLT doses. By 2011, NAMBTS issued 837 single-donor PLT doses per year, 99.1% of all PLT units. Of 5761 WB donations from which PLTs were made in 2006 to 2011, a total of 20 (0.35%) were from donors with confirmed test results for human immunodeficiency virus or other transfusion-transmissible infections (TTIs). Of 2315 single-donor apheresis donations between 2007 and 2011, none of the 663 donors had a confirmed positive result for any pathogen. As apheresis replaced WB-derived PLTs, apheresis production costs dropped by a mean of 8.2% per year, while pooled PLT costs increased by an annual mean of 21.5%. Unit prices paid for apheresis- and WB-derived PLTs increased by 9 and 7.4% per year on average, respectively.
CONCLUSION
Namibia’s PLT transition shows that collections from repeat apheresis donors can reduce TTI risk and production costs.
doi:10.1111/trf.13049
PMCID: PMC4607307  PMID: 25727921
11.  Profiles of blood and blood component transfusion recipients in Zimbabwe 
Blood Transfusion  2015;13(4):600-609.
Background
There are limited published data on the characteristics of blood transfusion recipients in sub-Saharan Africa. This study describes the demographic characteristics of blood transfusion recipients and patterns of blood and blood component use in Zimbabwe.
Materials and methods
Data on the characteristics of the blood transfusion recipients (age, sex, blood group), blood components received (type, quantity), discharge diagnoses and outcomes following transfusion (discharge status, duration of stay in hospital), were retrospectively collected from four major hospitals for the period from January 1, 2012 to December 31, 2012. Diagnoses were grouped into broad categories according to the disease headings of the International Classification of Diseases (ICD-10). Surgical procedures were grouped into broad categories according to organ system using ICD-9.
Results
Most of the 1,793 transfusion recipients studied were female (63.2%) and in the reproductive age group, i.e. 15–49 years (65.3%). The median age of the recipients was 33 years (range, 0–93). The majority of these recipients (n=1,642; 91.6%) received a red blood cell transfusion. The majority of the patients were diagnosed with conditions related to pregnancy and childbirth (22.3%), and diseases of blood and blood-forming organs (17.7%). The median time spent in hospital was 8 days (range, 0–214) and in-hospital mortality was 15.4%.
Discussion
Our sample of blood transfusion recipients were fairly young and most of them received red blood cell transfusions. The majority of patients in the reproductive age group received blood transfusions for pregnancy and childbirth-related diagnoses.
doi:10.2450/2015.0019-15
PMCID: PMC4624536  PMID: 26192782
blood usage; diagnosis; transfusion; International Classification of Diseases (ICD)
12.  The ‘Dynamic’ Marriage Between Varicella and Zoster 
EBioMedicine  2015;2(10):1302-1303.
doi:10.1016/j.ebiom.2015.09.014
PMCID: PMC4634844  PMID: 26629519
13.  Cost-effectiveness of vaccination against herpes zoster 
Human Vaccines & Immunotherapeutics  2014;10(7):2048-2061.
Herpes zoster (HZ) is a common disease among elderly, which may develop into a severe pain syndrome labeled postherpetic neuralgia (PHN). A live-attenuated varicella zoster virus vaccine has been shown to be effective in reducing the incidence and burden of illness of HZ and PHN, providing the opportunity to prevent significant health-related and financial consequences of HZ. In this review, we summarize the available literature on cost-effectiveness of HZ vaccination and discuss critical parameters for cost-effectiveness results. A search in PubMed and EMBASE was performed to identify full cost-effectiveness studies published before April 2013. Fourteen cost-effectiveness studies were included, all performed in western countries. All studies evaluated cost-effectiveness among elderly above 50 years and used costs per quality-adjusted life year (QALY) gained as primary outcome. The vast majority of studies showed vaccination of 60- to 75-year-old individuals to be cost-effective, when duration of vaccine efficacy was longer than 10 years. Duration of vaccine efficacy, vaccine price, HZ incidence, HZ incidence and discount rates were influential to the incremental cost-effectiveness ratio (ICER). HZ vaccination may be a worthwhile intervention from a cost-effectiveness point of view. More extensive reporting on methodology and more detailed results of sensitivity analyses would be desirable to address uncertainty and to guarantee optimal comparability between studies, for example regarding model structure, discounting, vaccine characteristics and loss of quality of life due to HZ and PHN.
doi:10.4161/hv.28670
PMCID: PMC4186035  PMID: 25424815
herpes zoster; shingles; vaccination; vaccine; zostavax; postherpetic neuralgia; cost-effectiveness
15.  Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data 
PLoS ONE  2015;10(8):e0135054.
Background
Vitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs) such as dabigatran, with lower rates of (major) intracranial bleeding compared to VKAs and not requiring monitoring, may be considered.
Objectives
To estimate resource utilization and costs of patients treated with the VKAs acenocoumarol and phenprocoumon, for the indication DVT. Furthermore, a formal cost-effectiveness analysis of dabigatran compared to VKAs for DVT treatment was performed, using these estimates.
Methods
A retrospective observational study design in the thrombotic service of a teaching hospital (Deventer, The Netherlands) was applied to estimate real-world resource utilization and costs of VKA monitoring. A pooled analysis of data from RE-COVER and RE-COVER II on DVT was used to reflect the probabilities for events in the cost-effectiveness model. Dutch costs, utilities and specific data on coagulation monitoring levels were incorporated in the model. Next to the base case analysis, univariate probabilistic sensitivity and scenario analyses were performed.
Results
Real-world resource utilization in the thrombotic service of patients treated with VKA for the indication of DVT consisted of 12.3 measurements of the international normalized ratio (INR), with corresponding INR monitoring costs of €138 for a standardized treatment period of 180 days. In the base case, dabigatran treatment compared to VKAs in a cohort of 1,000 DVT patients resulted in savings of €18,900 (95% uncertainty interval (UI) -95,832, 151,162) and 41 (95% UI -18, 97) quality-adjusted life-years (QALYs) gained calculated from societal perspective. The probability that dabigatran is cost-effective at a conservative willingness-to pay threshold of €20,000 per QALY was 99%. Sensitivity and scenario analyses also indicated cost savings or cost-effectiveness below this same threshold.
Conclusions
Total INR monitoring costs per patient were estimated at minimally €138. Inserting these real-world data into a cost-effectiveness analysis for patients diagnosed with DVT, dabigatran appeared to be a cost-saving alternative to VKAs in the Netherlands in the base case. Cost savings or favorable cost-effectiveness were robust in sensitivity and scenario analyses. Our results warrant confirmation in other settings and locations.
doi:10.1371/journal.pone.0135054
PMCID: PMC4524689  PMID: 26241880
16.  Retrospective public health impact of a quadrivalent influenza vaccine in the United States 
Introduction
Vaccination is an effective preventive strategy against influenza. However, current trivalent influenza vaccines (TIVs) contain only one of the two influenza B lineages that circulate each year. Vaccine mismatches are frequent because predicting which one will predominate is difficult. Recently licensed quadrivalent influenza vaccines (QIVs) containing the two B lineages should address this issue. Our study estimates their impact by assessing what would have been the US public health benefit of routinely vaccinating with QIV in 2000–2013.
Methods
We developed a dynamic compartmental model that accounts for interactions between influenza B lineages (natural or vaccine-induced) and simulates the multiyear influenza dynamics for 2000–2013. Age-structured population dynamics, vaccine efficacy (VE) per strain, and weekly ramp-up of vaccination coverage are modeled. Sensitivity analyses were performed on VE, duration of immunity, and levels of vaccine-induced cross-protection between B lineages.
Results
Assuming a cross-protection of 70% of the VE of the matched vaccine, the model predicts 16% more B lineage cases prevented by QIV. Elderly (≥65 years) and young seniors (50–64 years) benefit most from QIV, with 21% and 18% reductions in B lineage cases. Reducing cross-protection to 50%, 30%, and 0% of the VE of the matched vaccine improves the relative benefit of QIV to 25%, 30%, and 34% less B lineage cases.
Conclusion
Using a dynamic retrospective framework with real-life vaccine mismatch, our analysis shows that QIV routine vaccination in the United States has the potential to substantially reduce the number of influenza infections, even with relatively high estimates of TIV-induced cross-protection.
doi:10.1111/irv.12318
PMCID: PMC4549101  PMID: 26256294
Dynamic model; influenza; quadrivalent influenza vaccine; trivalent influenza vaccine; vaccine effectiveness; vaccines
17.  Within-Gender Changes in HIV Prevalence among Adults between 2005/6 and 2010/11 in Zimbabwe 
PLoS ONE  2015;10(7):e0129611.
Introduction
Zimbabwe has reported significant declines in HIV prevalence between 2005/06 and 2010/11 Demography and Health Surveys; a within-gender analysis to identify the magnitude and factors associated with this change, which can be masked, is critical for targeting interventions.
Methods
We analyzed change in HIV prevalence for 6,947 women and 5,848 men in the 2005/06 survey and 7,313 women and 6,250 men in 2010/11 surveys using 2005/06 as referent. The data was analyzed taking into consideration the survey design and therefore the svy, mean command in Stata was used in both linear and logistic regression.
Results
There were similar proportional declines in prevalence at national level for males (15% p=0.011) and females (16%,p=0.008). However, there were variations in decline by provincial setting, demographic variables of age, educational level and some sexual risk behaviours. In logistic regression analysis, statistically significant declines were observed among men in Manicaland, Mashonaland East and Harare (p<0.01) and for women in Manicaland, Mashonaland Central and Harare (p<0.01). Although not statistically significant, numerical increases were observed among men in Matebeleland North, Matebeleland South, Midlands and for both men and women in Bulawayo. Young women in the age range 15-34 experienced a decline in prevalence (p<0.01) while older men 30-44 had a statistically significant decline (p<0.01). Having a secondary and above education, regardless of employment status for both men and women recorded a significant decline. For sexual risk behaviours, currently in union for men and women and not in union for women there was a significant decline in prevalence.
Conclusion
Zimbabwe has reported a significant decline among both men and women but there are important differentials across provinces, demographic characteristics and sexual risk behaviours that suggest that the epidemic in Zimbabwe is heterogeneous and therefore interventions must be targeted in order to achieve epidemic control.
doi:10.1371/journal.pone.0129611
PMCID: PMC4514831  PMID: 26208134
18.  Pre-eclampsia Diagnosis and Treatment Options: A Review of Published Economic Assessments 
Pharmacoeconomics  2015;33(10):1069-1082.
Background
Pre-eclampsia is a pregnancy complication affecting both mother and fetus. Although there is no proven effective method to prevent pre-eclampsia, early identification of women at risk of pre-eclampsia could enhance appropriate application of antenatal care, management and treatment. Very little is known about the cost effectiveness of these and other tests for pre-eclampsia, mainly because there is no clear treatment path. The aim of this study was to provide a comprehensive overview of the existing evidence on the health economics of screening, diagnosis and treatment options in pre-eclampsia.
Methods
We searched three electronic databases (PubMed, EMBASE and the Cochrane Library) for studies on screening, diagnosis, treatment or prevention of pre-eclampsia, published between 1994 and 2014. Only full papers written in English containing complete economic assessments in pre-eclampsia were included.
Results
From an initial total of 138 references, six papers fulfilled the inclusion criteria. Three studies were on the cost effectiveness of treatment of pre-eclampsia, two of which evaluated magnesium sulphate for prevention of seizures and the third evaluated the cost effectiveness of induction of labour versus expectant monitoring. The other three studies were aimed at screening and diagnosis, in combination with subsequent preventive measures. The two studies on magnesium sulphate were equivocal on the cost effectiveness in non-severe cases, and the other study suggested that induction of labour in term pre-eclampsia was more cost effective than expectant monitoring. The screening studies were quite diverse in their objectives as well as in their conclusions. One study concluded that screening is probably not worthwhile, while two other studies stated that in certain scenarios it may be cost effective to screen all pregnant women and prophylactically treat those who are found to be at high risk of developing pre-eclampsia.
Discussion
This study is the first to provide a comprehensive overview on the economic aspects of pre-eclampsia in its broadest sense, ranging from screening to treatment options. The main limitation of the present study lies in the variety of topics in combination with the limited number of papers that could be included; this restricted the comparisons that could be made. In conclusion, novel biomarkers in screening for and diagnosing pre-eclampsia show promise, but their accuracy is a major driver of cost effectiveness, as is prevalence. Universal screening for pre-eclampsia, using a biomarker, will be feasible only when accuracy is significantly increased.
Electronic supplementary material
The online version of this article (doi:10.1007/s40273-015-0291-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s40273-015-0291-x
PMCID: PMC4575369  PMID: 26048352
19.  Cost-Effectiveness of Extended-Release Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder Sub-Optimally Treated with Immediate Release Methylphenidate 
PLoS ONE  2015;10(5):e0127237.
Background
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug response and economic efficiency.
Objective
To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated.
Methods
A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1) optimal response, (2) sub-optimal response, (3) discontinued treatment, and (4) natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS) and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs). Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios.
Results
Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations.
Conclusions
This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.
doi:10.1371/journal.pone.0127237
PMCID: PMC4449164  PMID: 26024479
20.  A few years later 
Human Vaccines & Immunotherapeutics  2014;10(7):1841-1849.
This study aimed to calculate the cost-effectiveness of infant pneumococcal vaccination in the Netherlands, using the 13-valent PCV13 vs. the currently used 10-valent PCV10. We adapted a previously published model, using recent estimates of epidemiological and efficacy data. In 12 scenarios, we explored the impact of different assumptions on the incremental cost-effectiveness ratio (ICER) of PCV13 over PCV10.Taking only direct effects on invasive pneumococcal disease into account, PCV13 was not found to be cost-effective at a price difference of €11 per dose. If herd protection, replacement and non-invasive disease were also taken into account, the ICER of PCV13 compared with PCV10 was below €30 000/QALY gained in 11 of 12 scenarios. PCV13 was considered dominant in the primary scenario with a price difference below €2.63 per dose.
doi:10.4161/hv.29008
PMCID: PMC4186027  PMID: 25424791
Pneumococcal; cost-effectiveness; vaccines; infant vaccination; Netherlands; PCV
21.  Cost-Minimization Model of a Multidisciplinary Antibiotic Stewardship Team Based on a Successful Implementation on a Urology Ward of an Academic Hospital 
PLoS ONE  2015;10(5):e0126106.
Background
In order to stimulate appropriate antimicrobial use and thereby lower the chances of resistance development, an Antibiotic Stewardship Team (A-Team) has been implemented at the University Medical Center Groningen, the Netherlands. Focus of the A-Team was a pro-active day 2 case-audit, which was financially evaluated here to calculate the return on investment from a hospital perspective.
Methods
Effects were evaluated by comparing audited patients with a historic cohort with the same diagnosis-related groups. Based upon this evaluation a cost-minimization model was created that can be used to predict the financial effects of a day 2 case-audit. Sensitivity analyses were performed to deal with uncertainties. Finally, the model was used to financially evaluate the A-Team.
Results
One whole year including 114 patients was evaluated. Implementation costs were calculated to be €17,732, which represent total costs spent to implement this A-Team. For this specific patient group admitted to a urology ward and consulted on day 2 by the A-Team, the model estimated total savings of €60,306 after one year for this single department, leading to a return on investment of 5.9.
Conclusions
The implemented multi-disciplinary A-Team performing a day 2 case-audit in the hospital had a positive return on investment caused by a reduced length of stay due to a more appropriate antibiotic therapy. Based on the extensive data analysis, a model of this intervention could be constructed. This model could be used by other institutions, using their own data to estimate the effects of a day 2 case-audit in their hospital.
doi:10.1371/journal.pone.0126106
PMCID: PMC4425554  PMID: 25955494
22.  Financial evaluations of antibiotic stewardship programs—a systematic review 
Introduction: There is an increasing awareness to counteract problems due to incorrect antimicrobial use. Interventions that are implemented are often part of an Antimicrobial Stewardship Program (ASPs). Studies publishing results from these interventions are increasing, including reports on the economical effects of ASPs. This review will look at the economical sections of these studies and the methods that were used.
Methods: A systematic review was performed of articles found in the PubMed and EMBASE databases published from 2000 until November 2014. Included studies found were scored for various aspects and the quality of the papers was assessed following an appropriate check list (CHEC criteria list).
Results: 1233 studies were found, of which 149 were read completely. Ninety-nine were included in the final review. Of these studies, 57 only mentioned the costs associated with the antimicrobial medication. Others also included operational costs (n = 23), costs for hospital stay (n = 18), and/or other costs (n = 19). Nine studies were further assessed for their quality. These studies scored between 2 and 14 out of a potential total score of 19.
Conclusions: This review gives an extensive overview of the current financial evaluation of ASPs and the quality of these economical studies. We show that there is still major potential to improve financial evaluations of ASPs. Studies do not use similar nor consistent methods or outcome measures, making it impossible draw sound conclusions and compare different studies. Finally, we make some recommendations for the future.
doi:10.3389/fmicb.2015.00317
PMCID: PMC4399335  PMID: 25932024
antibiotic stewardship; antibiotic resistance; health economics and outcomes research; costs and costs analysis; economic evaluation
23.  The impact of external donor support through the U.S. President’s Emergency Plan for AIDS Relief on the cost of red cell concentrate in Namibia, 2004–2011 
Blood Transfusion  2015;13(2):240-247.
Background
External assistance can rapidly strengthen health programmes in developing countries, but such funding can also create sustainability challenges. From 2004–2011, the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) provided more than $ 8 million to the Blood Transfusion Service of Namibia (NAMBTS) for supplies, equipment, and staff salaries. This analysis describes the impact that support had on actual production costs and the unit prices charged for red cell concentrate (RCC) units issued to public sector hospitals.
Material and methods
A costing system developed by NAMBTS to set public sector RCC unit prices was used to describe production costs and unit prices during the period of PEPFAR scale-up (2004–2009) and the 2 years in which PEPFAR support began to decline (2010–2011). Hypothetical production costs were estimated to illustrate differences had PEPFAR support not been available.
Results
Between 2004–2006, NAMBTS sold 22,575 RCC units to public sector facilities. During this time, RCC unit prices exceeded per unit cost-recovery targets by between 40.3% (US$ 16.75 or N$ 109.86) and 168.3% (US$ 48.72 or N$ 333.28) per year. However, revenue surpluses dwindled between 2007 and 2011, the final year of the study period, when NAMBTS sold 20,382 RCC units to public facilities but lost US$23.31 (N$ 170.43) on each unit.
Discussion
PEPFAR support allowed NAMBTS to leverage domestic cost-recovery revenue to rapidly increase blood collections and the distribution of RCC. However, external support kept production costs lower than they would have been without PEPFAR. If PEPFAR funds had not been available, RCC prices would have needed to increase by 20% per year to have met annual cost-recovery targets and funded the same level of investments as were made with PEPFAR support. Tracking the subsidising influence of external support can help blood services make strategic investments and plan for unit price increases as external funds are withdrawn.
doi:10.2450/2014.0122-14
PMCID: PMC4385072  PMID: 25369616
blood safety; Namibia; costing; PEPFAR
24.  Probabilistic Markov Model Estimating Cost Effectiveness of Methylphenidate Osmotic-Release Oral System Versus Immediate-Release Methylphenidate in Children and Adolescents: Which Information is Needed? 
Pharmacoeconomics  2015;33(5):489-509.
Background
Incidence of attention deficit hyperactivity disorder (ADHD) in children and adolescents has been increasing. The disorder results in high societal costs. Policymakers increasingly use health economic evaluations to inform decisions on competing treatments of ADHD. Yet, health economic evaluations of first-choice medication of ADHD in children and adolescents are scarce and generally do not include broader societal effects.
Objectives
This study presents a probabilistic model and analysis of methylphenidate osmotic-release oral system (OROS) versus methylphenidate immediate-release (IR). We investigate and include relevant societal aspects in the analysis so as to provide cost-effectiveness estimates based on a broad societal perspective.
Methods
We enhanced an existing Markov model and determined the cost effectiveness of OROS versus IR for children and adolescents responding suboptimally to treatment with IR. Enhancements included screening of a broad literature base, updated utility values, inclusion of costs and effects on caregivers and a change of the model type from deterministic to probabilistic.
Results
The base case scenario resulted in lower incremental costs (€−5815) of OROS compared with IR and higher incremental quality-adjusted life-year (QALY) gains (0.22). Scenario analyses were performed to determine sensitivity to changes in transition rates, utility of caregivers, medical costs of caregivers and daily medication dose.
Conclusions
The results indicate that, for children responding suboptimally to treatment with IR, the beneficial effect of OROS on compliance may be worth the additional costs of medication. The presented model adds to the health economic information available for policymakers and to considerations on a broader perspective in cost-effectiveness analyses.
doi:10.1007/s40273-015-0259-x
PMCID: PMC4544537  PMID: 25715975
25.  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

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