Mauro Picardo

Anti-HPV vaccination: A review of recent economic data for Italy

The total cost of HPV-related diseases accounts for euro 200-250 million of which euro 210 million is absorbed by the prevention and treatment of precancerous lesions and cervical cancer. Although both available HPV vaccines are below the threshold value for economic convenience (euro 9,569 and euro 26,361 per QALY-gained for the quadrivalent and bivalent vaccines, respectively), at this point in time long-term economic models developed for Italy seem to indicate the quadrivalent vaccine as the most cost-effective option. Recent publications by official bodies, including the World Health Organization and the Supervisory Authority for Public Contracts in Italy, recommend that the decision-making process be based on both the quality of goods and services as well as the best achievable price.

Novel Health Economic Evaluation of a Vaccination Strategy to Prevent HPV-related Diseases The BEST Study

Background:The development of human papillomavirus (HPV)-related diseases is not understood perfectly and uncertainties associated with commonly utilized probabilistic models must be considered. The study assessed the cost-effectiveness of a quadrivalent-based multicohort HPV vaccination strategy within a Bayesian framework. Methods:A full Bayesian multicohort Markov model was used, in which all unknown quantities were associated with suitable probability distributions reflecting the state of currently available knowledge. These distributions were informed by observed data or expert opinion. The model cycle lasted 1 year, whereas the follow-up time horizon was 90 years. Precancerous cervical lesions, cervical cancers, and anogenital warts were considered as outcomes. Results:The base case scenario (2 cohorts of girls aged 12 and 15 y) and other multicohort vaccination strategies (additional cohorts aged 18 and 25 y) were cost-effective, with a discounted cost per quality-adjusted life-year gained that corresponded to &OV0556;12,013, &OV0556;13,232, and &OV0556;15,890 for vaccination programs based on 2, 3, and 4 cohorts, respectively. With multicohort vaccination strategies, the reduction in the number of HPV-related events occurred earlier (range, 3.8–6.4 y) when compared with a single cohort. The analysis of the expected value of information showed that the results of the model were subject to limited uncertainty (cost per patient=&OV0556;12.6). Conclusions:This methodological approach is designed to incorporate the uncertainty associated with HPV vaccination. Modeling the cost-effectiveness of a multicohort vaccination program with Bayesian statistics confirmed the value for money of quadrivalent-based HPV vaccination. The expected value of information gave the most appropriate and feasible representation of the true value of this program.

Cost-Effectiveness Analysis of Universal Human Papillomavirus Vaccination Using a Dynamic Bayesian Methodology: The BEST II Study

BACKGROUNDnHuman papillomavirus (HPV) plays a role in the development of benign and malign neoplasms in both sexes. The Italian recommendations for HPV vaccines consider only females. The BEST II study (Bayesian modelling to assess the Effectiveness of a vaccination Strategy to prevent HPV-related diseases) evaluates 1) the cost-effectiveness of immunization strategies targeting universal vaccination compared with cervical cancer screening and female-only vaccination and 2) the economic impact of immunization on various HPV-induced diseases.nnnOBJECTIVEnThe objective of this study was to evaluate whether female-only vaccination or universal vaccination is the most cost-effective intervention against HPV.nnnMETHODSnWe present a dynamic Bayesian Markov model to investigate transmission dynamics in cohorts of females and males in a follow-up period of 55 years. We assumed that quadrivalent vaccination (against HPV 16, 18, 6, and 11) is available for 12-year-old individuals. The model accounts for the progression of subjects across HPV-induced health states (cervical, vaginal, vulvar, anal, penile, and head/neck cancer as well as anogenital warts). The sexual mixing is modeled on the basis of age-, sex-, and sexual behavioral-specific matrices to obtain the dynamic force of infection.nnnRESULTSnIn comparison to cervical cancer screening, universal vaccination results in an incremental cost-effectiveness ratio of €1,500. When universal immunization is compared with female-only vaccination, it is cost-effective with an incremental cost-effectiveness ratio of €11,600. Probabilistic sensitivity analysis shows a relatively large amount of parameter uncertainty, which interestingly has, however, no substantial impact on the decision-making process. The intervention being assessed seems to be associated with an attractive cost-effectiveness profile.nnnCONCLUSIONSnUniversal HPV vaccination is found to be a cost-effective choice when compared with either cervical cancer screening or female-only vaccination within the Italian context.

Nickel-induced keratinocyte proliferation and up-modulation of the keratinocyte growth factor receptor expression

Abstract: Keratinocytes play a key role in the pathogenesis of allergic contact dermatitis (ADC) induced by the sensitizing agent nickel. We analyzed here the effects of treatment with nickel and of the pretreatment with zinc on HaCaT cells and primary human keratinocytes. Cell counting, 5‐bromo‐2′‐deoxyuridine incorporation assay and adenosine triphosphate (ATP) bioluminescence detection showed that treatment with NiSO4 induced DNA synthesis and cell proliferation and that pretreatment with ZnSO4 was able to abrogate this proliferative effect. This nickel‐induced cell growth appeared enhanced when primary human keratinocytes were co‐cultured with fibroblasts. Western blot analysis demonstrated that nickel ions induced up‐modulation of the expression of the keratinocyte growth factor receptors (KGFR) without affecting the keratinocyte differentiation, whereas the protein levels of the epidermal growth factor receptor (EGFR) and of its ligand transforming growth factor‐alpha (TGF‐α) appeared unmodified by the treatment. Double immunofluorescence showed that the effect of nickel on DNA synthesis was mainly exerted on KGFR expressing cells, suggesting that KGFR up‐modulation could be required for the nickel‐induced cell proliferation. These results indicate that KGFR and its ligands may play a role in the mechanism of action of nickel ions and in the protective effect of zinc pretreatment.

The effect of herd immunity in different human papillomavirus vaccination strategies : an economic evaluation of the Best II Study

PCN101 The effeCT of herd ImmuNITy IN dIffereNT humaN PaPIllomavIrus vaCCINaTIoN sTraTegIes: aN eCoNomIC evaluaTIoN of The BesT II sTudy Haussler K.1, Marcellusi A.2, Mennini F.S.3, Favato G.4, Picardo M.5, Garganese G.6, Bononi M.7, Scambia G.8, Capone A.9, Baio G.1 1University College London, London, UK, 2University of Rome “La Sapienza”, Italy, Rome, Italy, 3University of Rome “Tor Vergata”, Italy, Rome, Italy, 4Kingston University, Kingston, UK, Kingston, UK, 5San Gallicano Dermatological Institute (IRCCS), Rome, Italy, 6Catholic University, 7University of Rome “La Sapienza”, 8University of the Sacred Heart, Rome, Italy, 9Kingston University London, London, UK Objectives: Italian recommendations for human papillomavirus (HPV) immunization currently consider females only. However, males can be vectors in viral transmission and at risk of infection. The BEST II study was designed to evaluate: the cost-effectiveness (CE) of different interventions targeting females as well as males; and the economic impact of vaccination on a wide range of HPV-induced diseases. MethOds: A dynamic Bayesian Markov model was developed to investigate the transmission between sexual partners and the cost-effectiveness of vaccination targeting female and male cohorts in comparison to screening and female cohorts only. A range of HPV-induced diseases was considered (cervical, vaginal, vulvar, anal, head and neck and penile cancer, the associated pre-cancerous stages and anogenital warts). The process of sexual mixing was calculated based on age, gender and sexual behavioural specific matrices to estimate th force of infection dynamically. Increased susceptibility to the virus, associated with early sexual début, a high number of partners, smoking and previous STDs, were included. We considered several scenarios; the baseline assumes universal vaccination to be implemented for 12-year-old females and males. The follow-up period was 55 years. Results: According to our preliminary analysis, universal vaccination resulted in incremental CE ratios (ICERs) corresponding to € 910 and € 5,770, when compared to screeningonly and female-only vaccination, respectively. We performed extensive sensitivity analysis, which confirmed the good CE profile of universal vaccination in Italy. cOnclusiOns: A universal HPV vaccination of male and female programme is more cost-effective than screening and female-only vaccination when accounting for all HPV-related diseases. Universal vaccination programme increase herd immunity and provide indirect protection to unvaccinated girls against HPV. The herd immunity plays a significant role in the economic evaluation of HPV immunization programmes. A universal vaccination may be further useful considering that males are both at risk of infection and vectors in viral transmission.

Transparency or proper study valuation procedures missed

To the Editor: n nWe wish to thank the Editor for giving us the opportunity to think about and resolve a few potential issues with our paper. Garattini and colleagues have questioned the meaningfulness of the evidence used to inform some of the crucial parameter used in our model. This is because of a misalignment in the reference list, as a result of which, Table u200bTable11 in the paper points to the wrong references. We have fixed this and present the corrected version of Table u200bTable11 below. n n n nTABLE 1 n nDistribution of Variables Used in the Model n n n nIncidentally, we notice that the online appendix to the paper1 actually has all the correct references and describes in detail all the aspects of the modeling presented in the paper. We find it slightly bizarre that Garattini and colleagues have taken such a critical stance on our work, but have failed to cross-check the most technical aspects with all the available material. n nGarattini and colleagues also raise a few criticisms to our general methodology. Firstly, they question the relevance of data from the region of Basilicata on the parameter representing vaccination coverage. We would like to point out that, although not covering a very large area, Basilicata was the only Italian region to implement a multicohort vaccination program, including 4 cohorts of girls aged 12, 15, 18, and 25 years. The empirical evidence derived by the Basilicata vaccination register has been published in a full paper (the GIOVE study2). In addition, this information is not used at face value, but the uncertainty underlying the estimation is fully acknowledged and propagated through the entire Bayesian model. The prior distribution of parameters that play a relevant role in the cost-effectiveness of vaccination, such as coverage rates in 4 cohorts, were drawn directly from the real-world data (information uniquely registered in the Basilicata Region) rather than from assumptions. The rates of coverage are particularly important when levels ≤50% are achieved in a single cohort of girls; and in this situation, a vaccination including a cohort of both boys and girls can improve the cost-effectiveness as a result of the increased clinical benefits determined by herd immunity. Actually, we must be wondering whether the most economic and clinically effective decision is provided by the immunization of both sexes or by an increase in the coverage rate in a single cohort of females. Probably, the latter might be more complicated and less effective than expected. Increasing the coverage rate may require complex interventions, a long period of time, and a significant incremental cost that could determine a diseconomy of scale. Truly, a scarce result when compared with the huge investment that is needed to increase the baseline rate value by 1 percentage point. Our study reported some indirect and preliminary indication; however, a specific Bayesian dynamic model addressing the cost-effectiveness of a vaccination program that includes a cohort of boys and girls has already been designed and results will be assessed and published shortly. n nAs for patients’ health-state preferences, we agree with Garattini and colleagues that they represent a highly sensitive variable for the economic evaluations. In this case, we developed an algorithm for the fully computerized administration of a Time Trade-Off questionnaire; this was validated and published in 2011.3 In that publication, the standardized elicitation of utilities was focused on cervical intraepithelial neoplasia (grades 2 and 3), anogenital warts, and cervical cancer exclusively.3 Thus, to include a broader range of human papillomavirus (HPV)-induced pathologies (which were indeed considered in the model developed in the BEST study) and a larger sample size, we used data from an ongoing study that involved >450 patients. Preliminary results from this large study have been communicated or presented in several congresses (including HTAi4) and the overall evaluation will be published as soon as it is completed. We believe that it is noteworthy that the elicitation of each utility used to inform our model relied on a solid and well-acknowledged procedure.3,5,6 Similarly to the point we have made earlier, by using a fully Bayesian model, we incorporated the uncertainty in the estimated values of utilities. n nAnother issue is about the vaccine price. We modeled this parameter using a probability distribution eliciting the information about the mean unit price of €69.13 and encoding the assumption that 95% of the most plausible values were included in the interval between €60.16 and €79.58. This was based on Regional tenders that occurred in 2008 and 2009 in Italy. Although in a commentary published in early 2012,7 neither an accurate mean price nor a SD were specifically reported for HPV vaccines, a mean price per quadrivalent vial seems to be very close to the range of values we used to inform our model. Although an effective public health intervention is not exclusively a matter of price,8 any value below the lower limit of the range adopted in our study would have had a favorable effect on the cost-effectiveness of the vaccination strategy that we evaluated using a Bayesian framework. n nFinally, Garattini and colleagues wonder about the reliability of the results of our model. We are seeking to produce a structured research program, building on the findings of the GIOVE study, which was related to the effectiveness of a multicohort quadrivalent-based vaccination program. Consequently, the BEST study was specifically designed to assess the cost-effectiveness of this predefined vaccination strategy. Although a potential direct comparison evaluating the most cost-effective option between the 2 available vaccines might be interesting, this is an objective that was not consistent with the aim of the BEST study. n nAlthough some biological characteristics of HPV are uncertain, the value of information derived from current clinical trials is improved and the accuracy is increased by the incorporation of prior information in a Bayesian modeling. Further, prior distribution of parameters significantly influencing the impact of vaccination (ie, coverage rates and risk factors having an effect on the dynamic transmission of HPV infection) were directly drawn from the health programs already implemented in Italy and not from assumptions. Although financing and sustaining immunization programs are health governance challenges that public health authorities have to deal with, an assessment of a multicohort or both sexes vaccination strategy with a Bayesian model can inform decision-makers with more reliable data about both the cost-effectiveness of interventions as well as its budgetary implications. In conclusion, Bayesian analytic models have a wide range of uses and can be deemed as important and powerful tool for economic evaluations in health care.9 n nEspecially when associated with the expected value of information, Bayesian models can provide with an accurate valuation of any future implementation of a quadrivalent-based HPV vaccination program.

Ionic mechanism of somatic action potential in the nervous system of the snail Heobania vermiculata

Abstract 1. 1. The somatic action potential of individual neurones of the land snail Heobania vermiculata has been recorded using intracellular techniques. 2. 2. In the suboesophageal ganglionic ring, the somata can be classified into 3 groups according to the external cation sensitivity of the action potential: (a) calcium-dependent; (b) sodium-dependent, (c) calcium- and sodium-dependent. 3. 3. In Ca-free saline, the overshoot of the Na-dependent spikes varies with sodium concentration approximately in the manner predicted for a sodium electrode. In sodium-free saline the overshoot of the Ca-dependent spikes varies with calcium concentration in the manner predicted for a calcium electrode. 4. 4. Cobalt ions block the Ca-component of the spike; barium ions on the contrary, substitute for calcium ions. 5. 5. It is concluded that Caions may carry, alone or with Na ions, the inward charges of the somatic spike of Heobania nerve cells.