In November 2011, the Pharmaceutical Benefits Advisory Committee[a] (PBAC) recommended extension of Australia’s National Immunisation Program (NIP) listing of quadrivalent HPV (qHPV) vaccine to include ongoing administration to males ~12-13 years of age in a school-based program, and for two catch-up cohorts in the two year groups above the ongoing cohort. This recommendation followed consideration of detailed applications on the clinical- and cost-effectiveness of the proposed vaccination program from the sponsor and advice from the Australian Technical Advisory Group on Immunisation (ATAGI) on the strength of evidence relating to the vaccine’s effectiveness and use in Australian populations.[b][c]
Burden-of-disease and mathematical models to investigate the population-level impact of vaccination on HPV transmission and HPV-related disease were developed as part of the HPV Evaluation Linkage Project Australia (HELPA), an Australian Research Council Linkage Grant involving a team of researchers from the University of New South Wales, the Australian National University, the University of Melbourne, and La Trobe University, in partnership with CSL Ltd. and Victorian Cytology Service Inc.[d]
Analysis of invasive anal and potentially HPV-associated oropharyngeal squamous cell carcinomas over the period from 1982-2005 showed significant increases in incidence (and survival), which were more pronounced in men than women. Using this analysis to project cancer incidence for the 2000 birth cohort, the cumulative lifetime risk of anal cancer was estimated to be three- to nine-times higher than if the current cross-sectional incidence was used. Similarly, the cumulative lifetime risk of oropharyngeal cancer in the 2000 birth cohort was estimated to be two- to three-times higher than if the current cross-sectional incidence was used.
Closed, heterosexual dynamic transmission models were developed for HPV-6/11 and -16/18 and calibrated to genital warts incidence, HPV DNA prevalence, and seroprevalence. These were used to estimate the long-term reductions in incidence of HPV-6/11/16/18 infection under the current female-only vaccination program and the proposed female-plus-male vaccination (at 80% vaccination coverage). Using vaccine efficacy against persistent infection, as measured in the qHPV vaccine clinical trials, the models predict female-only vaccination will reduce HPV-6 incidence by 92% and 80% in females and males, respectively, compared to 97% and 95% under female-plus-male vaccination.
Female-only vaccination is predicted to reduce HPV-16 incidence by 74% and 42% in females and males, respectively, compared to 81% and 73% under female-plus-male vaccination.
Estimates of the herd immunity benefit obtained from the transmission models were applied to a cohort model of HPV disease with arms for heterosexual males (HM), men who have sex with men (MSM) and females. This was used to predict the “real-world” impact of female-plus-male versus female-only qHPV vaccination on HPV-16/18 anogenital cancers and HPV-6/11 genital warts.[e]
The incidence of HPV-associated cancers was projected for the 2000 birth cohort as described above. Vaccine efficacy against disease was derived from the qHPV vaccine trials. The population proportion of MSM and the relative risks of HPV-associated diseases in MSM versus HM were derived from the literature. The results are summarised in Figure 1. In the base case analysis, female-only vaccination is predicted to prevent 6806 of 8508 HPV-6/11 genital warts and 97 of 256 HPV-16/18 anal cancers in HM, but none of 3756 HPV-6/11 genital warts and 389 HPV-16/18 anal cancers in MSM.
Female-plus-male vaccination is predicted to prevent 8180 HPV-6/11 genital warts (76% directly and 26% through herd immunity) and 208 HPV-16/18 anal cancers (88% directly and 12% through herd immunity) in HM and 2728 HPV-6/11 genital warts and 274 HPV-16/18 anal cancers directly in MSM. Reductions in oropharyngeal cancers were also predicted but are not shown as these were not considered in the base case at the second PBAC review (see below).
The cost-effectiveness of qHPV vaccination was investigated in the real-world cohort model described above. Utility valuations for HPV disease health states were derived from a population sample  and the literature. Costs of management of HPV disease were derived from Australian treatment practices and costs. The cumulative costs (including vaccination costs and costs of HPV disease management) and outcomes (quality adjusted life years) of a female-plus-male vaccination program were compared to a female-only program for the 2000 birth cohort of males and females using the standard discount rate of 5%. Although vaccine price remains confidential, the requested price for male vaccination did take account of the different disease burden in males and females, with the Public Summary Document noting a weighted price for the program.
On first review the PBAC rejected the application due to unacceptably high and uncertain cost-effectiveness.
The key clinical uncertainties indicated by the PBAC related to the extrapolation of efficacy against surrogate markers reported in the trials to efficacy against HPV cancers (from AIN in MSM to anal cancer in males and females, from limited data on PIN to penile cancer, and to oropharyngeal cancer with no direct clinical data) and to the assumption of lifetime duration of vaccine efficacy. The PBAC considered the strength of the evidence linking AIN to anal cancer to be weaker than that linking CIN to cervical cancer. Another key uncertainty related to projecting the rates of anal and oropharyngeal cancers into the future. These clinical uncertainties flowed into the modelled economic evaluation.
In the second application the uncertainties in the modelled evaluation were addressed with a revised base case, which excluded penile cancer, set efficacy against oropharyngeal cancer to 0%, and used the lower 95% and 99% confidence intervals of the annual percentage change in incidence to project anal and oropharyngeal cancers. It also included a lower vaccine price. The PBAC accepted the base case cost effectiveness ratio of between $15,000 and $45,000 per QALY and recommended ongoing male vaccination and catch-up cohorts on the basis of acceptable cost-effectiveness.
In July 2012, the Australian Government announced that the NIP qHPV program in males will commence in February 2013. This decision ensures that Australia remains at the forefront of HPV immunisation as the first country in the world to have a routine, publically funded male vaccination program.