Joke Bilcke

Rotavirus disease and vaccination: impact on genotype diversity

Temporal and spatial fluctuations in the genotype distribution of human rotaviruses are continuously observed in surveillance studies. New genotypes, such as G9 and G12, have emerged and spread worldwide in a very short time span. In addition, reassortment events have the potential to contribute substantially to genetic diversity among human and animal rotaviruses. With the recent introduction of the two rotavirus vaccines, RotaTeq and Rotarix, in many countries, it appears that the total number of hospitalizations due to rotavirus infections is being reduced, at least in developed countries that implemented a universal immunization program. However, continued surveillance is warranted, especially regarding the long-term effects of the vaccines. No data analyses are available to clarify whether rotavirus vaccine introduction would allow other rotavirus P and G genotypes, which are not covered by the current vaccines, to emerge into the human population and fill the apparent gap. This kind of data analysis is essential, but its interpretation is hampered by natural and cyclical genotype fluctuations.

An update to "the cost-effectiveness of rotavirus vaccination: comparative analyses for five European countries and transferability in Europe".

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

Accounting for methodological, structural, and parameter uncertainty in decision-analytic models: a practical guide.

Accounting for uncertainty is now a standard part of decision-analytic modeling and is recommended by many health technology agencies and published guidelines. However, the scope of such analyses is often limited, even though techniques have been developed for presenting the effects of methodological, structural, and parameter uncertainty on model results. To help bring these techniques into mainstream use, the authors present a step-by-step guide that offers an integrated approach to account for different kinds of uncertainty in the same model, along with a checklist for assessing the way in which uncertainty has been incorporated. The guide also addresses special situations such as when a source of uncertainty is difficult to parameterize, resources are limited for an ideal exploration of uncertainty, or evidence to inform the model is not available or not reliable. Methods for identifying the sources of uncertainty that influence results most are also described. Besides guiding analysts, the guide and checklist may be useful to decision makers who need to assess how well uncertainty has been accounted for in a decision-analytic model before using the results to make a decision.

Reviewing the Cost Effectiveness of Rotavirus Vaccination: The Importance of Uncertainty in the Choice of Data Sources

AbstractPublished health economic evaluations of rotavirus vaccination up until July 2008 were reviewed. We assess whether differences in the results and conclusions of the various studies are due to differences in methodological and modelling choices, and/or the way parameter uncertainty was taken into account, or whether these are merely the result of genuine country/region-specific differences.No unambiguous single answer emerged as to whether universal rotavirus vaccination is or is not cost effective. The relevance and merits of each study need to be assessed within its context. This is illustrated by the fact that comparisons of different analyses for a single country show that one of the most important explanations for the variations in results and conclusions seems to be the use of different information sources for the estimation of input parameters.Future studies should gather reliable and relevant information focusing on the most influential input parameters, i.e. rotavirus mortality (and efficacy against rotavirus deaths) for low- and middle-income countries, and a range of variables for high-income countries, including the incidence and cost of rotavirus hospitalization. Moreover, if no information is available for an important input parameter, the impact of a wide range of values should be explored rather than excluding it from the analysis or specifying a single-point value. Furthermore, future analyses may have to consider ways of accounting for herd immunity (e.g. by using a dynamic model).

Detection of human papillomavirus DNA in urine. A review of the literature

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

The cost-effectiveness of varicella and combined varicella and herpes zoster vaccination programmes in the United Kingdom

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

The health and economic burden of chickenpox and herpes zoster in Belgium

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

Estimating the incidence of symptomatic rotavirus infections: a systematic review and meta-analysis.

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

An update to "The cost-effectiveness of rotavirus vaccination

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

Childhood varicella-zoster virus vaccination in Belgium: cost-effective only in the long run or without exogenous boosting?

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