Original Title: Vacuna frente al VPH en varones adolescentes: coste-efectividad e impacto presupuestario

Authors' objectives: MAIN OBJECTIVE: Determine the cost-effectiveness and budgetary impact of the introduction of HPV vaccination in men in Spain. SPECIFIC OBJECTIVES: • Determine the cost-effectiveness of the gender-neutral vaccination strategy of adolescents (boys and girls) against HPV compared to the strategy of vaccinating girls only. • Estimate the budgetary impact for the National Health System (NHS) that would entail the extension of the HPV vaccination strategy to men. • Analyze the ethical, patient, social, legal, and organizational considerations related to HPV vaccination and identify future research needs.

Authors' results and conclusions: RESULTS: EFFECTIVENESS AND SAFETY: The key points of the effectiveness of the HPV vaccine in men, according to the Irish HTA report and the ECDC, were the following: Regarding clinical outcomes in men, there is only evidence for the 4-valent vaccine, which is effective in preventing persistent infections related to HPV 6, 11, 16, or 18, external genital lesions, and anogenital warts at three years in adult males aged 16 to 26 years. There is insufficient evidence for penile, perineal, and perianal intraepithelial lesions or for HPV-related infection or disease of the anus and head and neck. Regarding immunogenicity, the 2-valent and 4-valent vaccines have shown high seroconversion ratios and a non-inferior immunogenicity in adolescent males (9-15 years) compared to females of the same age; the 9-valent vaccine showed non-inferiority compared to the 4-valent vaccine. The main findings on the safety of the HPV vaccine were, according to the Irish report: 1) The risk of serious adverse events is similar in HPV vaccines compared to control vaccines (placebo or vaccines against another infection); 2) The mortality rate is similar. COST-EFFECTIVENESS: The systematic review of Ireland's report with 29 included studies was updated with 5 new studies. In total, 34 economic evaluations were analyzed, 17 of them conducted in Europe. The majority were dynamic models of transmission and in 18 there was some kind of conflict of interest. The methodological quality of the economic evaluations included was considered moderate to good. The main problem areas were the use of old data sources and/or other countries' data, the lack of systematic synthesis of the evidence to estimate the parameters of the models, or the brevity of the modeling information. An evolution has been observed over time of the conclusions on the cost-effectiveness of gender-neutral vaccination; the studies of the last 3 years are more in favor of gender-neutral vaccination than in previous years, especially before 2011, when 3 doses of the vaccine were used and the price was higher. Sixteen studies (10 with conflict of interest) were assessed as relevant to the Spanish context, of which 5 favor gender-neutral vaccination, another 5 concluded against, and 6 studies found gender-neutral vaccination to be cost-effective in some of the scenarios considered. Four studies evaluated the new 9-valent vaccine (3 of them with conflict of interest) and only one of them, conducted in Italy, found gender-neutral vaccination cost-effective compared to girls-only vaccination. The parameters with the most influence on the cost-effectiveness of gender-neutral vaccination were the price of the vaccine, the vaccine coverage, and the cost-effectiveness threshold. The price per dose has been falling over the past 12 years and large differences were observed between official market prices and those negotiated between the manufacturer and the health authorities in each country. A dynamic transmission model developed by the manufacturer (MSD) in the US and adapted to the situation in Spain in 2019, simulated the epidemiological impact and cost-effectiveness of 5 HPV vaccination strategies. In the base case, no protection against oropharyngeal cancer was considered. The vaccination coverage was 77.8% in girls and 55% in boys. Costs and benefits were discounted at 3%. The list prices (€ 78.03, € 104, and € 120 per dose of the 2-, 4-, and 9-valent vaccine) were considered as well as tender prices (€ 29.16, € 29.16, and € 40 per dose of the 2-, 4-, and 9-valent vaccine). Using the 9-valent vaccine with list prices, gender-neutral vaccination would not be cost-effective (ICER € 53,244 / QALY); however, with tender prices, it would be cost-effective (ICER € 12,142 / QALY). The univariate deterministic analysis demonstrated the influence (a) of vaccination coverage (increasing coverage worsens the cost-effectiveness of gender-neutral vaccination), (b) the benefit discount rate (when using 1.5% instead of 3%, gender-neutral vaccination is cost-effective even with list prices), and (c) the inclusion of oropharyngeal cancer protection in the analysis (gender-neutral vaccination is cost-effective even with list prices). No sensitivity analysis is available for negotiated prices. The MSD model was assessed positively in terms of its structure, consistency, data used, analysis performed, and interpretation of results. The main limitations are in (a) the existence of the conflict of interest since the study is financed by the industry; (b) comparison strategies that do not include gender-neutral vaccination with vaccines other than 9-valent; (c) the sources of some data that do not come from Spain or are relatively old; (d) a too limited sensitivity analysis. COST-EFFECTIVENESS MODEL FOR SPAIN: The model adapted for this report assumed, for the base case, a vaccination coverage of 80% in girls and 70.16% in boys and it used the tender prices per dose: € 27.09 for 2-valent; € 29.16 for 4-valent and € 45 for 9-valent. The two most effective strategies were compared: the ICER of gender-neutral vaccination with the 9-valent vaccine, compared to girls-only 9-valent vaccination, was estimated at € 34,040 / QALY, therefore, in the base case, the gender-neutral vaccination would not be cost-effective. In terms of disease cases avoided, 20 years after the change in strategy, the gender-neutral immunization would prevent 207 cases of cervical cancer per year and 15,330 episodes of anogenital warts, compared to girls-only 4-valent vaccination. The sensitivity analysis revealed that gender-neutral vaccination with the 9-valent vaccine becomes a cost-effective strategy when: (a) the protection of the vaccine against oropharyngeal and penile cancer is included (€ 21,353 / QALY); (b) a mixed schedule is used with one dose of the 2-valent vaccine and one of the 9-valent vaccine (€ 19,649 / QALY); (c) the price per dose falls at € 27.9 (€ 24,999 / QALY); (d) the discount rate for benefits drops to 1.5% (€ 23,994 / QALY). BUDGET IMPACT ANALYSIS: The cumulative five-year budget impact of vaccinating all 12-year-old adolescents, compared to only girls, would be estimated at a total of 82.7 million Euros with the 9-valent vaccine and 49.8 million Euros with the 2-valent vaccine, for the total of Spain, assuming the tender prices and the uptake rate in boys 70.16% and in girls 80%. ORGANIZATIONAL, ETHICAL, SOCIAL AND/OR LEGAL ASPECTS RELATED TO PATIENTS: Most of the ethical arguments found are favorable to the universalization of vaccination in terms of justice, equity, and non-discrimination. The extension of vaccination coverage to men avoids inequalities since not all people are in the same socio-economic situation or have practices within heteronormativity. The arguments against the vaccination of men refer to safety and are refuted by the evidence in this regard. No robust ethical arguments have been found against vaccination to the population as a whole, except for a temporary recommendation from WHO to suspend the implementation of gender-neutral vaccination programs due to a shortage of doses in the world market. The general acceptability of the vaccine is positive, especially when recommended by the Ministry of Health, Consumption, and Social Welfare. Knowledge about HPV and its vaccination for boys is low. More information about HPV, its transmission and consequences, as well as the effectiveness and safety of the vaccine, is demanded. Informed consent prior to vaccination must include clear, relevant, and updated information about the benefits and risks associated with the vaccine. RESEARCH NEEDS: More data on the efficacy and effectiveness of HPV vaccines are needed for the male population, as well as data on cross-protection, duration of protection, patterns of sexual transmission, and efficacy of the single dose or the mixed schedule, among others. It is essential to establish epidemiological surveillance that combines clinical data from different areas of the health system. CONCLUSIONS: • The cost-effectiveness of gender-neutral vaccination against HPV has been evaluated in numerous economic studies. The conclusions are varied and depend on a number of factors, such as the price of the vaccine, vaccination coverage, the cost-effectiveness threshold of the country, the discount of benefits or the diseases included in the analysis. The manufacturer’s (MSD) model adapted for Spain suggests that gender-neutral vaccination using the 9-valent vaccine could be cost-effective. • The economic model carried out in this report estimated that the gender-neutral vaccination in Spain, using the 9-valent vaccine, offer more benefits than any other strategy, but in comparison with the girls-only vaccination it is not cost-effective in the conservative base case. • This model shows that the gender-neutral HPV vaccination would be cost-effective in Spain, if the model includes the vaccine protection against additional cancers (oropharyngeal and penile) or if the vaccine price decreases. Also, a mixed schedule, using 9-valent and 2-valent vaccines, could be a cost-effective strategy, but more robust evidence on its effectiveness is needed. • The annual budgetary impact of gender-neutral vaccination would be between 10 and 16 million Euros, depending on the vaccine used. • Gender-neutral vaccination would comply with ethical considerations of justice, equity and non-discrimination. In some countries, good acceptability to gender-neutral vaccination has been observed, as well as its increase by improving knowledge about the disease and the vaccines.

Authors' recommendations: According to the cost-effectiveness criterion in the base case, gender-neutral vaccination would not be a cost-effective strategy. However, the inclusion of protection against other types of cancer, as well as the decrease of the vaccine price, would make it a cost-effective option. In addition, there are arguments in favor regarding the ethical considerations of justice, equity and non-discrimination. For all these reasons, it would be advisable to introduce the gender-neutral HPV vaccination strategy with a vaccination schedule of two doses at 12 years of age for both sexes in Spain, with the condition of revising its cost-effectiveness with new evidences on the effectiveness, costs or alternative schedules.

Authors' methods: EFFECTIVENESS AND SAFETY: A search for recent HTA evaluations and reviews was performed. Their relevance, reliability, and transferability were evaluated. Finally, it was decided to adopt the results of effectiveness and safety of the systematic review of the Irish HTA Agency (HIQA) published in December 2018. COST-EFFECTIVENESS: We adapted and updated the systematic review of cost-effectiveness of the HIQA report, which was previously assessed with the EUnetHTA tool as relevant to the objectives of this report. Selection criteria: Complete economic evaluations of a gender-neutral vaccination program against HPV compared to a vaccination program for girls or non-vaccination, for girls and boys from 9 years of age, with 2 or 3 doses of one of the three vaccines available. The search was performed in 3 electronic databases (Medline, EMBASE, and WOS) in April 2019 and was complemented by manual search. The relevance of the included studies for the Spanish context was considered and the quality was evaluated with two specific tools for economic models (Philips et al. and ISPOR group). A cost-effectiveness analysis carried out by the manufacturer (MSD) for Spain was analyzed in detail and critically evaluated. COST-EFFECTIVENESS MODEL FOR SPAIN: A cost-effectiveness analysis of gender-neutral vaccination versus girls-only vaccination in Spain was carried out, adapting a model developed by the Irish HTA agency. It is a dynamic population-based model with a discrete-time Markov approach, in which the population moves between 5 mutually exclusive states (susceptible - vaccinated and not infected - not vaccinated and infected - vaccinated and infected - dead). Seven different strategies were compared, combining the three vaccines available in gender-neutral or girls-only programme, plus the option not to vaccinate. Costs and benefits were discounted with a rate of 3%. The benefits of immunization were measured with quality-adjusted life years (QALYs), which are achieved by reducing the incidence of diseases attributable to HPV: cervical intraepithelial neoplasia (CIN), cervical cancer, anal cancer, vulvar intraepithelial neoplasia (VIN), vulvar cancer, vaginal intraepithelial neoplasia (VaIN), and recurrent respiratory papillomatosis (RRP). Oropharyngeal and penile cancers were considered in a scenario analysis. The final outcome measure was the incremental cost-effectiveness ratio (ICER), which was compared with the cost-effectiveness threshold (or willingness to pay) in Spain. BUDGET IMPACT ANALYSIS: A budget impact analysis reports the cost to the SNS of implementing the gender-neutral vaccination strategy against HPV compared to the girls-only strategy. The vaccination strategy was considered with two doses at 12 years of age, with different vaccine prices and different vaccination coverage. ORGANIZATIONAL, ETHICAL, SOCIAL, LEGAL AND PATIENT-RELATED ASPECTS: A narrative review of primary and secondary studies covering organizational, ethical, social, legal, and patient-related aspects has been carried out. The inclusion criteria and the sources of information were the same as those of the cost-effectiveness review of this report, except that the relevance of the studies for the analysis of the mentioned aspects was taken into account.

Project Status: Completed

Year Published: 2020

URL for published report: https://sescs.es/vacuna-frente-al-vph-en-varones-adolescentes-coste-efectividad-e-impacto-presupuestario/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Canary Health Service

Contact Address: Dirección del Servicio. Servicio Canario de la Salud, Camino Candelaria 44, 1ª planta, 38109 El Rosario, Santa Cruz de Tenerife

Contact Name: sescs@sescs.es

Contact Email: sescs@sescs.es