ESCMID Online Lecture Library. by author

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1 . Gender and age inequity in public health strategies of HPV vaccination Mario Poljak Institute of Microbiology and Immunology Faculty of Medicine, University of Ljubljana, Slovenia

2 HPV Viral characteristics - non-enveloped viruses; icosahedral capsid - remarkably diverse BUT remarkably genetically stable - classified by the homology of their genome into 200+ genotypes - etiologically linked to various benign and malignant neoplastic lesions of mucosal and skin epithelium of both genders

3 Low-risk alpha HPV genotypes HPV-6, HPV-11

4 High-risk alpha HPV genotypes related cancers HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59 Schiller JT, Lowy DR. Nat Rev Microbiol 2012;10:

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6 secondary prevention (screening) + primary prevention (vaccination)

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8 primary and secondary prevention act additively by intervening at different points in the natural history of cervical cancer and imply actions in women of different ages

9 Cumulative incidence of HPV infection among women sexually active and HPV negative at enrollment in Washington State, Winer RL et al. Am J Epidemiol 2003; 157:218-26

10 Natural history of HPV infection in females Moscicki AB et al. Vaccine 30S (2012) F24 F33

11 Natural immunity against HPV 54% 69% of women seroconvert; low-level antibodies

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13 Natural immunity against HPV 54% 69% of women seroconvert; low-level antibodies vs. Vaccine induced immunity against HPV virtually all women seroconvert; high-level antibodies

14 Why are vaccines better than nature??

15 Why are vaccines better than nature? Natural infection no viraemia, poor access of virus to lymph nodes HPV vaccines - delivered intramuscularly rapid access of VLPs to blood vessels and local lymph nodes

16 Why are vaccines better than nature?? Natural infection no viraemia, poor access of virus to lymph nodes HPV vaccines - delivered intramuscularly rapid access of VLPs to blood vessels and local lymph nodes VLPs are very immunogenic: BONUS - display many neutralising epitopes (more than native virion) - induce good T-cell helper responses for B-cells - important for robust antibody and B-cell memory responses

17 >232 million doses distributed worldwide (end of 2014) > 178 million doses quadrivalent HPV vaccine > 54.4 million doses bivalent HPV vaccine

18 Real life efficacy data

19 HPV immunization program in Australia - introduced in school-based program - publicly funded program: quadrivalent vaccine - target age group: year-old girls - catch-up programs ( ) - 2 year catch-up for those years in schools - 2 year catch-up for females not in school up to age 26 years - vaccine delivered by primary care providers - included boys in national program in 2013

20 HPV vaccination program coverage in Australia, catch-up program cohorts , as notified to the National Register, Australia HPV Today 2013; No 28-29, p.9

21 National HPV three dose vaccination coverage for all females turning 15 years of age Australia,

22 HPV vaccine introduction through national immunization programs - 32 European countries had implemented routine HPV vaccination program - 10 countries had introduced catch-up program - financing and delivery of the vaccines vary Belgium France Germany Italy Spain Gibraltar Greece Luxembourg Portugal San Marino Switzerland UK 3-dose coverage range from 17% to 84% countries with 3-dose coverage ~80%: - Portugal, United Kingdom, Denmark, Sweden, (Belgium) Denmark Macedonia Norway Slovenia Sweden Ireland Latvia Netherlands Romania Iceland Monaco Bulgaria Czech Rep. Malta Finland Austria Hungary Croatia Uzbekistan EUROGIN 2015;MSS2-3

23 HPV infections (vaccine types) time

24 Lancet Infect Dis 2014; 14: women aged years who attended Pap screening vs

25 Br J Cancer 2014;110: 2804

26 HPV infections (vaccine types) genital warts time

27 Numbers of in-patient treatments for vulval/vaginal warts in women by age-group, ; Australia

28 Sex Transm Infect 2015; in press All new patients attending Melbourne Sexual Health Centre from July 2004 to June 2014, stratified by different risk groups and age.

29 Proportion of Australian born heterosexual men diagnosed as having genital warts at first visit, by age group,

30 HPV infections (vaccine types) genital warts CIN 2/3 time

31 Trends in histologically-confirmed high-grade cervical abnormalities by age, , Australia Cervical screening in Australia Australian Institute of Health and Welfare 2015

32 Int J Cancer 2015;137:

33 Reduction in cervical lesions following qhpv vaccination Denmark - all girls and women born in Denmark in the period information on individual HPV vaccination status from nationwide registries P<0.001 Birth cohort Risk for cervical lesions among vaccinated vs. nonvaccinated women, October 2006 March 2012 J Natl Cancer Inst 2014;106:djt460

34 Br J Cancer 2014;111: First study to show a reduction of low- and high-grade CIN associated with high uptake of the HPV bivalent vaccine at the population level

35 Countries with HPV vaccine in the national immunization program (status 05 March 2015) Introduced* to date (63 countries or 32.5%) Not available, Not introduced (131 countries or 67.5%) GAVI supported nationwide introduction GAVI demo projects (started to date) GAVI demo projects (start 2015/2016) = 2 countries = 14 countries = 7 countries

36 Gender-neutral vaccination

37 High-risk HPV responsible for: - 98 % AIN-2 in AIN % anal cancers anal cancer incidence increased from 0.5 cases per 100,000 in 1974 to 1.8 cases per 100,000 in 2014

38 Disproportionally affected: - MSM - HIV positives Prevalence of persistent hr-hpv anal infection in HIV-positive MSM > 90%

39 High-risk HPV responsible for: - 75 % PIN-1-93 % PIN % PIN % penile carcinoma

40 HPV-positive vs. HPV-negative oropharyngeal cancer two distinct carcinogenetic pathways for the development of HNSCC: (i) driven by carcinogenic effects of tobacco, alcohol, or both (ii) driven by HPV-induced genomic instability

41 HPV-positive vs. HPV-negative oropharyngeal cancer HPV-associated cancer: - younger age - often nonsmokers and nondrinkers - men and women equally affected - wild-type TP53 and RB1 genes - low levels of p53 and prb proteins, down-regulation of cyclin D, lower expression of EGFR? - p16 often upregulated (negatively regulated by prb) Tobacco/alcohol-associated cancer: - older age - more frequent in men (3:1) - mutated TP53 and RB1 genes - high levels of p53 and prb proteins, increased cyclin D - p16 downregulated due to mutation, deletion, or gene methylation

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43 while oral HPV-16 infection and oropharyngeal cancer are rare, men are disproportionately affected, with cancer incidence fourfold higher than that observed in women HPV-16 has now replaced tobacco as the primary cause of oropharyngeal cancers, shifting the epidemiology of these cancers from older, lifetime tobacco users to men aged years

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46 Giuliano AR et al. Lancet 2011; 377:

47 Giuliano AR et al. Lancet 2011; 377:

48 Eur Urol 2015; [Epub ahead of print]. Cumulative incidence of anogenital warts with the same HPV type detected in the lesion among men in the HIM study with a genital HPV infection

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50 Prevalence of oral HPV infection across age in the US population aged 14 to 69 years by sex and HPV types

51 Papillomavirus Research 2015; doi: /j.pvr sera specimens collected 36 months after HPV incident infection seroconversion to 1 HPV type (6/11/16/18) varied by anatomic site seroconversions: 6.3%, 18.9%, and 0.0% following anal, genital, and oral HPV infection only 7.7% of men developed detectable serum HPV antibodies regardless of anatomic site, seroconversion was highest for HPV-6 (19.3%) seroconversion was highest following anal HPV 6 infection (69.2%)

52 interesting differences between men and women in the immune response to natural genital HPV infection women - peak prevalence in the late teens and twenties declining steadily throughout the subsequent decades - 70% seroconvert after detectable cervical HPV infection men - acquire infection in the late teens and the prevalence remains constant throughout the subsequent decades - less then 10% of men seroconvert after detectable HPV infection low rates of seroconversion following HPV infection in men, coupled with a lack of demonstrated protection against infection among those that do seroconvert, may leave men susceptible to recurrent infections, especially with HPV16, the cause of anal, oropharyngeal, and penile cancers in men nearly 100% seroconversion to all included types following HPV vaccination has been documented in men HPV vaccination is the only reliable method to ensure immune protection against new HPV infections and subsequent disease in males

53 The overall rate of HPV transmission: from the penis to the cervix: from the cervix to the penis: Emerging Infectious Diseases 2008; 14: /100 person-months 17.4/100 person-months

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56 burden of HPV associated cancers in men is comparable to that in women HPV vaccination is the only reliable method to ensure immune protection against new HPV infections and subsequent disease in males

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58 Gender-neutral vaccination - United States (2012) - Australia (2013) - Austria (2014) - Croatia (2015) - Canada (Prince Edward Island, Alberta, Nova Scotia.) - Italy (few regions) - Germany (Saxony)

59 MMWR Morb Mortal Wkly Rep 2015;64:

60 National HPV three dose vaccination coverage for males turning 15 years of age Australia,

61 Austria has recommended sex neutral HPV vaccination since 2006 with only very low uptake (around 2%) until government funding for the program commenced in 2014, with coverage now around 54% personal communication, Elmar Joura, April 2015.

62 November 2014 JCVI chose GUM clinics as the setting to be considered when assessing the impact and cost-effectiveness of a program for the vaccination of MSM substantial benefit from the prevention of anogenital warts (AGW) cost-effectiveness of a targeted program was reliant on the prevention of AGW infections in MSM any vaccine used for a program targeting MSM should also provide protection against HPV6/11 responsible for the majority of cases of AGW vaccination of MSM aged 16 to 40 years should be implemented in GUM and HIV clinics in the UK using the quadrivalent HPV vaccine, subject to the programme being commissioned and implemented at a cost-effective price

63 Gender-neutral vaccination?? I didn t even know boys could get the vaccine

64 Gender-neutral vaccination??

65 the bulk of the evidence used to inform government policy on whether or not to subsidize the costs of HPV vaccination programs for boys is derived from cost effectiveness studies is it appropriate to use cost effectiveness outcomes as the sole or primary criterion for a policy with such a significant impact on public health?

66 It is difficult to compare cost effectiveness across countries, given differences in healthcare systems, financing mechanisms, vaccine delivery programs and existing coverage rates for girls a number of key components of cost effectiveness calculations of HPV vaccines have been recently challenged: - lack of inclusion of non-cervical-related outcomes in mathematical models - assumptions that vaccination coverage among women is at the level required to confer herd immunity - lack of consideration of differential rates of uptake among underserved racial, ethnic and socioeconomic groups within countries - the exclusion of MSM from cost effectiveness calculations - the assumption of fixed high baseline costs of the HPV vaccine

67 vaccine price has been one of the most influential parameters in assessing the cost effectiveness of adding boys to female-only HPV vaccination programs the use of fixed baseline vaccine price thresholds limits the ability to consider the impact of alternative pricing on cost effectiveness, such as cost reductions negotiated by some governments the lowest price per dose considered was US$120

68 Targeted versus universal vaccination? several lines of argument support the advantages of a universal, genderneutral approach to vaccination and identify substantial challenges in the implementation of targeted vaccination universal approach through publicly funded HPV vaccination of both males and females would achieve herd immunity more quickly, yielding population health benefits and maximizing the prevention of cervical cancer lessons from the past: HBV vaccination, vaccination against rubella

69 Health equity perspective - further support for universal coverage as both genders are responsible for HPV transmission, both genders should get vaccinated to share the burden in reducing the risk of HPV-related disease, as well as have equal access to direct vaccine benefits an important negative consequence of exclusively targeting women and girls for vaccination is that it conveys or reinforces the message that HPV-related diseases are limited to females, who are thereby represented as responsible for transmitting HPV; the result is the shaming, blaming and stigmatizing of young women, with a disproportionate focus on sexual health as if uniquely a women's issue and on monitoring women's sexual lives a gender-neutral approach to HPV vaccination programs, in addition to promoting gender equity, would be inclusive of MSM, since men at highest risk for HPV infection and subsequent cancers are largely excluded from policy decisions regarding the inclusion of boys in HPV vaccination programs Newman PA, et al. Future Virol 2014;9:

70 Additional arguments: the cancer burden of MSM will decrease only by vaccinating boys irrespective of the mode of implementing HPV vaccination, it is most probable that marginalized (deprived) young women will neither be vaccinated nor screened for cervical cancer it is likely that unexpected drops in vaccine coverage or waning of vaccine-induced immunity can be tackled by the gender-neutral vaccination strategy simply due to effective breakage of simple transmission chains of sexually transmitted HPV infections gender-neutral vaccination of early adolescents will ultimately lead to control of HPVrelated diseases in both women and men and provides greater gains than femalefocused vaccination for both women and men Lehtinen M, et al. Curr Opin Obstet Gynecol 2015; [Epub ahead of print].

71 Cost Effectiveness and Resource Allocation 2015: DOI /s

72 Cancer 2015;121:

73 Burden of HPV associated cancers in men in the Netherlands in relation to vaccine coverage of girls BMJ 2015;350:h2016.

74 BMJ 2015;350:h2016.

75 in contrast to cervical screening programs, population-wide screening for HPV infection or related disease in males is not recommended; hence real-time monitoring of HPV vaccine effectiveness in males will require dedicated surveillance strategies monitoring the prevalence of circulating genital HPV types using a sentinel surveillance model could offer a good surrogate marker of early vaccine effectiveness in males careful consideration of the most appropriate anatomical sites from which to collect specimens, the best sampling methods and the most sensitive assays to use the effect of herd protection will need to be assessed, as most male programs will commence in the setting of established female programs an interesting epidemiological challenge Clin Microbiol Infect 2015;21:

76 MODELS: Clin Microbiol Infect 2015;21: incremental benefits of including males in routine vaccination programs will differ between countries 1. countries that introduce male vaccination against a background of high female vaccine coverage (Australia) 2. countries that introduce male vaccination against a background of moderate female coverage (USA) 3. countries that introduce both female and male vaccination simultaneously (Austria)

77 CONCLUSIONS (i) in developed countries the burden of HPV associated cancers in men is comparable to that in women only a few countries have so far recommended universal vaccination of boys - in others, a cautious approach has been due, in part, to uncertainties around the population level impact and cost effectiveness of vaccination of boys cost effectiveness studies, which predominantly inform government policy on whether or not to finance HPV vaccination programs that are inclusive of boys, are subject to methodological and substantive shortcomings that tend to underestimate the benefits of providing subsidized HPV vaccine coverage for boys and young men

78 CONCLUSIONS (ii) a universal approach through publicly funded HPV vaccination of both males and females would yield population health benefits for men as well as maximizing prevention of cervical cancer heterosexual men will benefit from reduced HPV circulation in females, so if coverage in girls is high the incremental benefit of vaccinating boys is driven by prevention of the residual burden of anal cancer in MSM targeted approaches for populations at highest risk of HPV exposure (MSM) may seem attractive in cost effectiveness models, but are subject to substantial obstacles likely to severely constrain their effective implementation

79 CONCLUSIONS (iii) from a health equity perspective, targeting women only reinforces the message that HPV-related diseases are limited to women, stigmatizes women, negates the importance of men's health and discriminates against MSM a comprehensive approach, including evaluation of emerging evidence from countries that have implemented publicly financed, gender-neutral HPV vaccination programs and school-based delivery, consideration of health equity and the benefits of universal approaches, in addition to cost effectiveness, will support more balanced decision-making for HPV vaccine programs and policy

80 failure to implement gender-neutral HPV vaccination looks like a missed public health opportunity