History is unfolding before us in a way that often means only one thing in the field of infectious diseases—the effective rollout of an effective vaccine. In this issue, Baandrup et al.1 add Denmark to the short list of countries or regions that have documented the population impact of a human papillomavirus (HPV) vaccination program.2–6 Although the modelers had anticipated population declines in HPV infection and disease (at least for HPV type 167), everyone likes to see more tangible outcomes.
The surveillance strategies vary between these studies, yet they yield consistent results—the slope of the decline in genital wart diagnoses in young women reflects the population coverage of the quadrivalent HPV vaccine in young women.1–6 Only in populations where the vaccine coverage of young women exceeds 50% has a herd protection effect been documented in unvaccinated young heterosexual men.4–6 It is encouraging to see that the Danish authorities have since decided to improve their HPV vaccination coverage by distributing it freely and by expanding the age range of the women to be vaccinated up to 26 years.1
As in Denmark,1 in those few countries where it has been measured, the incidence of genital warts had been increasing over recent decades.8 In the absence of any other effective public health interventions, the arrival of the quadrivalent HPV vaccine seems to have begun to quietly turn around a generalized epidemic that would have otherwise quietly consumed considerably more resources and produced substantial psychosocial morbidity.9
By contrast, HPV types 16 and 18, the other 2 targets of the quadrivalent vaccine, cause cancers decades after initial infection, so the full protective effect and cost savings will not be realized for many years. That said, in the most highly vaccinated population of young women in Australia, a rapid reduction in high-grade cervical abnormalities has already been documented.10 Declines in the vaginal carriage of the 4 vaccine target HPV types have recently been described in women transiting family planning clinics in 3 Australian cities, adding biological evidence to these clinical and ecological findings.11
When several countries originally evaluated the cost-effectiveness of publically funded HPV vaccination programs when the vaccines were first licensed around 2006, they focused on the prevention of one disease—cervical cancer. The science, including epidemiological trends, around noncervical cancers and other HPV-related diseases was less well understood at that time. To simplify the model, often only cervical disease attributable to HPV type 16—the dominant oncogenic virus—was taken into account.12 Since that time, we have learnt that cervical cancer may only account for around half of the HPV-related cancers in wealthier countries, and up to a quarter of HPV-related cancers may be in men.13 Improved understanding of vulval, vaginal, anal, penile, oropharyngeal, and perhaps other cancers attributable to HPV infections also need to be factored into decisions about implementing and evaluating vaccination programs.
Ominously, HPV-related cancers of the oropharynx and anus have been increasing over decades, particularly in men, although the causes for these increases are not entirely clear. The Australian government has seen it as appropriate to expand its national HPV vaccination program to include boys from 2013, despite early evidence of a herd immunity benefit conferred by the high vaccine coverage of young women.5,6 That herd immunity has not been shown to extend to gay men5,6—a group that is disproportionately vulnerable to a range of HPV-related diseases.12,13 In the absence of a male vaccination program, issues of equity and discrimination against gay men and men acquiring infections from unvaccinated women would have inevitably gained traction. The additional protection for unvaccinated women was also seen as important.
A further hindrance to publically funding HPV vaccination programs is the long delay between vaccination and cancer prevention. Although it is likely that there will be some savings in the clinical management of precancerous lesions measured within a few years,10 the incubation period for HPV-related cancers is numbered in decades. Discounting a clinical benefit at 3% to 5% per year that is not realized for decades is a tough hurdle to overcome in cost-benefit calculations. Roughly speaking, 3% discounting means that $1 in health care saving from genital warts that do not need treatment this year is equivalent to 40 cents saved treating cancer 20 years from now ($1 less 3% per annum for 20 years).
For the quadrivalent HPV vaccine, there is some early relief for the authorities that have to decide whether to fund a vaccine program. Genital and anal warts are the earliest manifestation of infection with HPV types 6 and 11, with a median incubation period of approximately 3 months in women, although observations from the placebo arm of the HPV vaccine trials suggest that this could range out to 45 months after initial HPV infection.14 Around 1% of 16- to 24-year-olds are affected by genital warts each year, and the financial15 and psychosocial costs9 are large. Gay men are affected at even higher rates.13 The savings in health care resources of preventing genital warts are being rapidly realized and partially offset the cost of vaccine programs in the short term. Fewer genital wart cases also free up much needed clinical capacity to address epidemics of other sexually transmissible infections.5 If, as anticipated, the quadrivalent HPV vaccine also protects against recurrent respiratory papillomatosis in infants,8,16 further short- to medium-term savings will result.
It is too early to tell where the HPV vaccination programs will eventually take us, but it is gratifying to see that the Global Alliance for Vaccines and Immunization has recently announced its support to roll out the vaccine in poorer countries where cervical cancer is often the most common cancer in women. In the absence of cervical screening programs, more than 80% of cervical cancers occur in poorer countries where women with cervical cancer experience much higher mortality rates.17
In the meantime, we look forward to future reports from wealthier countries with sophisticated information systems and high vaccine coverage evaluating the evolving population effectiveness, safety, and programmatic issues associated with the HPV vaccine. Because the spectrum of HPV-related disease is wide and protracted, and not fully understood, such surveillance systems need to be broad based and sustainable.8,16
1. Baandrup L, Blomberg M, Dehlendorff C, et al.. Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program. Sex Transm Dis This issue.
2. Leval A, Herweijer E, Arnheim-Dahlström L, et al.. Incidence of genital warts in Sweden before and after quadrivalent human papillomavirus vaccine availability. J Infect Dis 2012; 206: 860–866.
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4. Oliphant J, Perkins N. Impact of the human papillomavirus (HPV) vaccine on genital wart diagnoses at Auckland Sexual Health Services. N Z Med J 2011; 124: 1339.
5. Read THR, Hocking JS, Chen MY, et al.. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus programme. Sex Transm Infect 2011; 87: 544–547.
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8. Wong CA, Saraiya M, Hariri S, et al.. Approaches to monitoring biological outcomes for HPV vaccination: Challenges of early adopter countries. Vaccine 2011; 29: 878–885.
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10. Brotherton JML, Fridman M, May CL, et al.. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: An ecological study. Lancet 2011; 377: 2085–2092.
11. Tabrizi SN, Brotherton JML, Kaldor JM, et al.. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis 2012; doi:10.1093/infdis/jis590
12. Grulich AE, Jin F, Conway EL, et al.. Cancers attributable to human papillomavirus infection. Sex Health 2010; 7: 244–252.
13. Jin F, Prestage GP, Kippax SC, et al.. Risk factors for genital and anal warts in a prospective cohort of HIV-negative homosexual men: The HIM Study. Sex Transm Dis 2007; 34: 488–493.
14. Garland SM, Steben M, Sings HL, et al.. Natural history of genital warts: Analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis 2009; 199: 805–813.
15. Lanitis T, Carroll S, O’Mahoney C, et al.. The cost of managing genital warts in the UK. Int J STD AIDS 2012; 23: 189–194.
16. Brotherton JML, Kaldor JM, Garland SM. Monitoring the control of human papillomavirus (HPV) infection and related diseases in Australia: Towards a national surveillance strategy. Sex Health 2010; 7: 310–319.
17. Parkin DM, Bray F. The burden of HPV-related cancers. Vaccine 2006; 24 (suppl 3): S11–S25.