Cost of Illness Analysis of Invasive Meningococcal Disease Caused by Neisseria Meningitidis Serogroup B in the Netherlands-a Holistic Approach.

INTRODUCTION: Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a rapidly progressing, rare disease that often presents as meningitis or sepsis. It mostly affects infants and adolescents, with high fatality rates or long-term sequelae. In the Netherlands, serogroup B (MenB) is most prevalent. We aimed to estimate the economic burden of MenB-related IMD between 2015 and 2019, including direct and indirect medical costs from short- and long-term sequelae, from a societal perspective. METHODS: IMD incidence was based on laboratory-based case numbers from the Netherlands Reference Laboratory for Bacterial Meningitis (Amsterdam UMC, Amsterdam, the Netherlands); there were 74 MenB cases on average per year in the study period 2015-2019. Case-fatality rate (3.8%) and percentage of patients discharged with sequelae (46%) were derived from literature. Direct costs included treatment costs of the acute phase, long-term sequelae, and public health response. Indirect costs were calculated using the human capital (HCA) and friction costs (FCA) approaches, in which productivity losses were estimated for patients and parents during the acute and sequelae phases. Costs were discounted by 4% yearly. RESULTS: Estimated costs due to MenB IMD in an annual cohort were €3,094,199 with FCA and €9,480,764 with HCA. Direct costs amounted to €2,974,996, of which 75.2% were related to sequelae. Indirect costs related to sequelae were €52,532 with FCA and €5,220,398 with HCA. CONCLUSION: Our analysis reflects the high economic burden of MenB-related IMD in the Netherlands. Sequelae costs represent a high proportion of the total costs. Societal costs were dependent on the applied approach (FCA or HCA).

Vaccination process of immunocompromised patients in the Netherlands: Current challenges and potential solutions.

Introduction: Immunocompromised patients (ICP) have an increased risk for infectious diseases. Vaccines could help reduce this risk. However, ICP do not always receive or are reimbursed for the specific vaccinations on which they are dependent in the Netherlands. This research aims to gain insights into the current challenges in the vaccination process of ICP in the Netherlands. Moreover, it aims to explore potential solutions for these challenges and the ideal vaccination process. Methods: Twelve semi-structured interviews with relevant stakeholders were conducted. Partly based on the challenges found by the Council for Health and Society (RVS) and the Dutch National Health Care Institute (ZIN) an interview guide was developed. Results: Several newly emerged challenges were identified: fair reimbursement for the efforts of stakeholders; circular reasoning of vaccine reimbursement and guidelines; suboptimal translation from guidelines to practice and no smooth-running infrastructure. Most challenges corresponded with those stated by the RVS and ZIN. Affordability and knowledge deficit in healthcare providers and patients were the most important challenges. Rarely the same solutions were mentioned, and no ideal vaccination process emerged. Conclusions: The various challenges in the vaccination process of ICP in the Netherlands implies the difficulty to solve the problem. It is recommended to focus on solving the most important challenges. A potential solution is to adjust the GVS registration process to make it easier for the pharmaceutical industry to apply for reimbursement towards various high-risk groups. Additionally, vaccination should have a more prominent role in the education of healthcare providers. Furthermore, stakeholders need to cooperate more to solve the reimbursement and guidelines issue.

Cost-effectiveness of a male catch-up human papillomavirus vaccination program in the Netherlands.

In the Netherlands, the Health Council has advised that the human papillomavirus (HPV) vaccination should be offered to both boys and girls. Additionally, boys and men up to the age of 26 years should be included in a catch-up program. In this study, we examine the cost-effectiveness of this HPV catch-up program. We used a static Markov model to estimate the amount of cancers prevented and the incremental cost-effectiveness ratio (ICER) for different scenarios. Vaccinating men from 12 until the age of 26 years would result in an average of 48 cancer cases prevented in every cohort (an estimated total of 720 cases), with an average ICER of €32,256. We found that the catch-up vaccination program results in a relevant number prevented cases against an acceptable cost-effectiveness ratio. Policymakers should take these findings into account when evaluating a gender-neutral HPV vaccination program in the Netherlands.

Cost-effectiveness analysis of a gender-neutral human papillomavirus vaccination program in the Netherlands.

BACKGROUND: Vaccinating girls against human papillomavirus (HPV) infection is a highly effective and cost-effective intervention to provide protection against HPV-induced cancers. Since vaccination coverage rates among girls is modest in the Netherlands, additional strategies should be implemented to improve the protection against HPV-related cancer. Here we assessed the benefits and cost-effectiveness of gender-neutral vaccination. METHODS: We designed a static Markov model with a lifelong time horizon to simulate a cohort of 100,000 12-year-old Dutch boys. The model compares health and economic effects of HPV vaccination taking the current female vaccination coverage into consideration. HPV prevalence in boys was corrected for the predicted herd effects of the female programme in 2017. We extracted transition probabilities from peer-reviewed literature and previously constructed models. The robustness of the model was tested with multiple sensitivity analyses. RESULTS: Vaccinating 30% of 100,000 12-year-old boys prevents 18, 13 and 25 cases of anal, penile, and oropharyngeal cancers in men, respectively. A total of 205 quality-adjusted life-years (QALYs) are saved by preventing cancer-related morbidity and mortality. Assuming a vaccine price of €50 per dose, the incremental cost-effectiveness ratio (ICER) is €17,907 per QALY. In addition, due to vaccine-induced herd effects, we estimated that 110 cases of cancer in females would be additionally prevented and 246 QALYs would be gained in the female cohort, bringing the total to 166 cancers prevented and 451 QALYs gained. Taking these additional benefits of boys' vaccination into account, the overall ICER was estimated at €7310 per QALY gained. The model outcomes are most sensitive to variation in vaccine price, herd immunity from females and vaccine efficacy. CONCLUSIONS: Vaccination of boys, additional to girls, will prevent a relevant number of cancers in both boys and girls. Based on the current Dutch situation vaccination of HPV in boys is likely cost-effective. GSK Study identifier: HO-18-19169.

Equity in human papilloma virus vaccination uptake?: sexual behaviour, knowledge and demographics in a cross-sectional study in (un)vaccinated girls in the Netherlands.

BACKGROUND: In the Netherlands, human papillomavirus (HPV) vaccination is part of a national program equally accessible for all girls invited for vaccination. To assess possible inequalities in vaccine uptake, we investigated differences between vaccinated and unvaccinated girls with regard to various characteristics, including education and ethnicity, (both associated with non-attendance to the national cervical screening program), sexual behaviour and knowledge of HPV. METHODS: In 2010, 19,939 nationwide randomly-selected 16-17 year-old girls (2009 vaccination campaign) were invited to fill out an online questionnaire. A knowledge scale score and multivariable analyses identified variables associated with vaccination status. RESULTS: 2989 (15%) of the selected girls participated (65% vaccinated, 35% unvaccinated). The participants were comparable with regard to education, ethnicity, most sexual risk behaviour and had similar knowledge scores on HPV transmission and vaccination. However, unvaccinated girls lived in more urbanised areas and were more likely to have a religious background. Irrespective of vaccination status, 81% of the girls were aware of the causal relationship between HPV and cervical cancer, but the awareness of the necessity of cervical screening despite being vaccinated was limited. CONCLUSIONS: HPV vaccine uptake was not associated with knowledge of HPV and with factors that are known to be associated with non-attendance to the cervical cancer screening program in the Netherlands. Furthermore, most sexual behaviour was not related to vaccination status meaning that teenage unvaccinated girls were not at a disproportionally higher risk of being exposed to HPV. Routine HPV vaccination may reduce the social inequity of prevention of cervical cancer.

Reviewing and piloting methods for decreasing discount rates; someone, somewhere in time.

There has been substantial debate on the need for decreasing discounting for monetary and health gains in economic evaluations. Next to the discussion on differential discounting, a way to identify the need for such discounting strategies is through eliciting the time preferences for monetary and health outcomes. In this article, the authors investigate the perceived time preference for money and health gains through a pilot survey on Dutch university students using methods on functional forms previously suggested. Formal objectives of the study were to review such existing methods and to pilot them on a convenience sample using a questionnaire designed for this specific purpose. Indeed, a negative relation between the time of delay and the variance of the discounting rate for all models was observed. This study was intended as a pilot for a large-scale population-based investigation using the findings from this pilot on wording of the questionnaire, interpretation, scope and analytic framework.

Meningococcal serogroup A, C, W135 and Y conjugated vaccine: a cost-effectiveness analysis in the Netherlands.

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.

Economic evaluation of vaccines: specificities and future challenges illustrated by recent European examples.

This study reviews the current challenges in the economic evaluation of vaccines with a focus on European countries. In particular, the type of clinical evidence generally available, the impact of discounting for time preference and the use of modeling to derive valid cost-effectiveness assessments are considered. First, the characteristics of evidence for vaccines are discussed, as well as potential difficulties faced when using evidence-based medicine applied to curative drugs to interpret vaccine evidence. Then, discounting is considered and specific examples illustrating issues with different types of discounting are described, taking HPV as the example. Finally, the need for sometimes complex dynamic models for vaccines is explored, and specific types of models are reviewed, keeping into consideration the adage "complex when needed, straightforward if allowed."

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.

Dynamic models for health economic assessments of pertussis vaccines: what goes around comes around....

Despite childhood vaccination programs, pertussis remains endemic. To reduce the burden of pertussis, various extended pertussis vaccination strategies have been suggested. The aim of this article is to evaluate dynamic models used to assess the cost-effectiveness of vaccination. In total, 16 studies using a dynamic model were included, of which four also studied the cost-effectiveness of extended pertussis vaccination strategies. Generally, adolescent vaccination was found to be cost effective, but not highly effective in protecting infants too young to be vaccinated. The models also predicted that owing to age shifts, reduced pertussis disease in adolescents and young adults comes with an increase in later stages of life. This underpins the use of dynamic transmission models for interventions directed against pertussis. In future, dynamic transmission models for pertussis should be used widely to further enhance understanding of pertussis epidemiology and of extended pertussis vaccination programs that are currently considered in various countries.

On discounting of health gains from human papillomavirus vaccination: effects of different approaches.

OBJECTIVES: Discounting has long been a matter of controversy in the field of health economic evaluations. How to weigh future health effects has resulted in ongoing discussions. These discussions are imminently relevant for health care interventions with current costs but future benefits. Different approaches to discount health effects have been proposed. In this study, we estimated the impact of different approaches for discounting health benefits of human papillomavirus (HPV) vaccination. METHODS: An HPV model was used to estimate the impact of different discounting approaches on the present value of health effects. For the constant discount approaches, we varied the discount rate for health effects ranging from 0% to 4%. Next, the impact of relevant alternative discounting approaches was estimated, including hyperbolic, proportional, stepwise, and time-shifted discounting. RESULTS: The present value of health effects gained through HPV vaccination varied strongly when varying discount rates and approaches. The application of the current Dutch guidelines resulted in a present value of health effects that was eight or two times higher than that produced when using the proportional discounting approach or when using the internationally more common 4% discount rate for health effects, respectively. Obviously, such differences translate into large variations in corresponding incremental cost-effectiveness ratios. CONCLUSION: The exact discount rate and approach chosen in an economic evaluation importantly impact the projected value of health benefits of HPV vaccination. Investigating alternative discounting approaches in health-economic analysis is important, especially for vaccination programs yielding health effects far into the future. Our study underlines the relevance of ongoing discussions on how and at what rates to discount.

Until which age should women be vaccinated against HPV infection? Recommendation based on cost-effectiveness analyses.

INTRODUCTION: Cervical cancer is caused by infection with human papillomavirus (HPV). Several countries have implemented vaccination programs against HPV for teenage girls before sexual debut. However, recent clinical trials have demonstrated that vaccination of older women is highly effective as well. Accordingly, it has been suggested that these older women should also be offered vaccination. Here, the cost-effectiveness of HPV vaccination for older women was assessed. METHODS: A Markov model was used to estimate age-specific health benefits and cost savings of HPV vaccination for women 12-50 years of age, in the Netherlands. Sensitivity analyses were performed to test the robustness of the outcomes. State-of-the-art health-economic methods were used, and international health-economic guidelines were followed. RESULTS: HPV vaccination is highly cost-effective for girls aged 12-16 years. Remarkably, cost-effectiveness only slowly declines with increasing age of the vaccinees up to 25 years. Indeed, substantial health benefits can be obtained by vaccinating women in this age group at acceptable costs. Beyond this age, cost-effectiveness of HPV-vaccination rapidly declines. CONCLUSIONS: Not only HPV vaccination of girls before sexual debut is a highly effective and cost-effective strategy for prevention of cervical cancer, but also vaccination of women until the age of 25 years is generally cost-effective.

Behavioral pattern analysis and dopamine release in quinpirole-induced repetitive behavior in rats.

Obsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disease with a lifetime prevalence of 2-3%. People with OCD suffer from intrusive, unwanted and recurrent thoughts (obsessions) and/or repetitive ritualistic behaviors (compulsions). The aim of this study is to quantify the dimensions of ritualistic 'compulsive-like' behavior in quinpirole-induced behavior in rats by using T-pattern behavioral analysis. In addition, we investigated whether the behavioral effects elicited by quinpirole sensitization remained after 2 weeks of cessation of treatment. Finally, to study the neurobiological underpinnings of this 'compulsive-like' behavior, we investigated the effect of quinpirole treatment on the extracellular dopamine levels in the nucleus accumbens. Once established, 'compulsive-like' behavior is dependent upon quinpirole administration, as this behavior rapidly normalized after cessation of treatment. After a single dose of quinpirole the dopamine level decreased more in saline pre-treated animals as compared with animals given quinpirole treatment continuously. Furthermore, T-pattern analysis revealed that quinpirole-induced behavior consists, unlike OCD rituals, of a smaller behavioral repertoire. As seen in patients with OCD, quinpirole-treated animals performed these behaviors with a high rate of repetition. These findings suggest that quinpirole-induced behavior mimics only part of the compulsive behavior as shown in OCD patients.

Cost-effectiveness of adolescent pertussis vaccination for the Netherlands: using an individual-based dynamic model.

BACKGROUND: Despite widespread immunization programs, a clear increase in pertussis incidence is apparent in many developed countries during the last decades. Consequently, additional immunization strategies are considered to reduce the burden of disease. The aim of this study is to design an individual-based stochastic dynamic framework to model pertussis transmission in the population in order to predict the epidemiologic and economic consequences of the implementation of universal booster vaccination programs. Using this framework, we estimate the cost-effectiveness of universal adolescent pertussis booster vaccination at the age of 12 years in the Netherlands. METHODS/PRINCIPAL FINDINGS: We designed a discrete event simulation (DES) model to predict the epidemiological and economic consequences of implementing universal adolescent booster vaccination. We used national age-specific notification data over the period 1996-2000--corrected for underreporting--to calibrate the model assuming a steady state situation. Subsequently, booster vaccination was introduced. Input parameters of the model were derived from literature, national data sources (e.g. costing data, incidence and hospitalization data) and expert opinions. As there is no consensus on the duration of immunity acquired by natural infection, we considered two scenarios for this duration of protection (i.e. 8 and 15 years). In both scenarios, total pertussis incidence decreased as a result of adolescent vaccination. From a societal perspective, the cost-effectiveness was estimated at €4418/QALY (range: 3205-6364 € per QALY) and €6371/QALY (range: 4139-9549 € per QALY) for the 8- and 15-year protection scenarios, respectively. Sensitivity analyses revealed that the outcomes are most sensitive to the quality of life weights used for pertussis disease. CONCLUSIONS/SIGNIFICANCE: To our knowledge we designed the first individual-based dynamic framework to model pertussis transmission in the population. This study indicates that adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands. The model is suited to investigate further pertussis booster vaccination strategies.

Cost-effectiveness analysis of various pertussis vaccination strategies primarily aimed at protecting infants in the Netherlands.

BACKGROUND: Pertussis is a highly contagious respiratory disease. Despite a high rate of vaccine coverage through the Dutch national immunization program, the incidence of pertussis remains high in the Netherlands and the risk of infection continues. Because pertussis is most severe in unimmunized infants and infants who have only received some of the recommended doses, new pertussis immunization strategies should be considered to protect this vulnerable population. OBJECTIVE: This study was designed to estimate the cost-effectiveness of 3 new immunization strategies for possible addition to the current Dutch national immunization program: immunization of the infant at birth, immunization of the parents immediately after birth of the child (cocooning), and maternal immunization during the third trimester of pregnancy. METHODS: A literature search was performed in the PubMed database for articles published in English, German, and Dutch using the following terms: pertussis, whooping cough, vaccination strategies, maternal immunization, cocooning, at birth, vaccine efficacy, mortality, underreporting, prevalence, incidence, and cost-effectiveness. A decision-tree model was developed for this analysis, and data on pertussis morbidity and costs were collected consistently for different age groups (infants <1 year of age and adults 25 to 34 years of age). The size of the infant cohort was set at 200,000 to approximate previous Dutch birth cohorts. The size of the adult cohort was set at 401,380 parents for the cocooning strategy and 201,380 mothers for the maternal immunization strategy. Health benefits (quality-adjusted life-years [QALYs]) and costs were estimated in both cohorts for each of the 3 immunization strate- gies. Incremental cost-effectiveness ratios were calculated from both a payer's and a societal perspective. The robustness of the results was determined through sensitivity analysis. RESULTS: In the base-case analysis, cocooning and maternal immunization were found to be effective in reducing the incidence of pertussis among infants (123 and 174 infant cases were expected to be prevented, respectively). Furthermore, cocooning and maternal immunization were estimated to be cost-effective from a payer's perspective (euro4600 [US $6400]/QALY and euro3500 [$4900]/QALY, respectively) and even cost-saving from a societal perspective (savings of up to euro7200 [$10,100] and euro5000 [$7000], respectively). Sensitivity analyses revealed that favorable cost-effectiveness was generally robust. In the sensitivity analysis, the cost-effectiveness of cocooning and maternal immunization was mostly sensitive for changes in assumptions on underreporting (200-fold increase in reported number of symptomatic cases) of pertussis disease and infection. With no underreporting, the ICER was estimated at euro211,900 ($296,700)/QALY for cocooning and euro81,600 ($114,200)/QALY for maternal immunization from a payer's perspective. However, even at much lower levels of underreporting (20- to 30-fold increase in incidence), cost-effectiveness remained favorable. The cost-effectiveness of the third strategy, at-birth immunization, was highly unfavorable (euro329,900 [$461,900]/QALY from a payer's perspective and euro330,100 [$462,100]/ QALY from a societal perspective). CONCLUSIONS: This study estimated that the addition of cocooning or maternal immunization to the current Dutch national immunization program likely would be cost-effective or even cost-saving. These estimates were mainly due to reduction in the number of cases among parents, which are likely to be mild and therefore would largely remain unreported. Immunization at birth was not a cost-effective strategy. Cocooning was the most expensive intervention to implement; however, it resulted in the highest number of QALYs gained (mainly in adults). Maternal immunization would offer better protection of infants, due to maternally acquired antibodies.

[Efficiency of human papillomavirus vaccination--estimates based on Dutch cost effectiveness analyses]. / Doelmatigheid van Humaan papillomavirus-vaccinatie--schattingen op basis van Nederlandse kosteneffectiviteitanalyses.

Up to now the turnout for the human papillomavirus (HPV) vaccination programme implemented this year in the Netherlands has been lower than expected. This may be the result of negative publicity and doubts about the efficacy of the vaccination programme. To provide some clarity about the efficacy, this article gives an overview of the cost effectiveness analyses carried out on the introduction of HPV vaccination in the Netherlands. These studies have shown that vaccination of a cohort of 12-year-old girls using the HPV vaccine may ultimately prevent per year 217-421 cases of cervical cancer and 93-173 deaths caused by this disease in the Netherlands. It has also been shown that HPV vaccination is a cost effective strategy and that about 1000 girls must be vaccinated to prevent 1 death. The actual health benefits gained by HPV vaccination are strongly dependent on vaccination coverage. It is therefore important that this remains high (85-100%).