Methods
We previously constructed a model of human papillomavirus transmission, vaccination, and screening to explore the population level effect and cost effectiveness of various options for three dose human papillomavirus vaccination of females in the United Kingdom. More recently, this model was adapted to incorporate a two dose option and to explore the differential epidemiological impact of two and three dose schedules on incidence of cervical cancer.
Women were assumed to undergo cytological screening, with women aged 25-49 years screened every three years on average and women aged 50-64 years screened every five years, as recommended by the 2010 National Cervical Screening Programme guidelines. Uptake, sensitivity, and specificity of screening and efficacy of treatment were based on values used in our previous analyses. Use of human papillomavirus DNA testing either as triage or as the primary screen was not incorporated.
Modelling and data analysis were conducted in C++ and R. For this analysis, we extended our recent exploration of cervical cancer outcomes to capture the full range of human papillomavirus related outcomes (vulvar, vaginal, anal, penile, and oropharyngeal cancer; anogenital warts; and recurrent respiratory papillomatosis). We assumed the quadrivalent vaccine to provide some protection against all these outcomes and the bivalent vaccine to protect only against vulvar, vaginal, anal, penile, and oropharyngeal cancer. Cross protection against non-vaccine types was assumed at the level reported in a recent meta-analysis, with better cross protection from the bivalent vaccine than the quadrivalent one.
We then used all outcomes to compare healthcare costs (from a healthcare provider's perspective) and health related utilities (measured in quality adjusted life years or QALYs) for different schedules for a time horizon of 100 years. We used this to estimate the incremental cost effectiveness of two dose schedules (compared with no vaccination) and three dose schedules (compared with two dose schedules). We assumed vaccination to be given annually to 12 year old girls at 80% coverage, with a catch-up campaign in the first year to age 18. For the two dose schedules, we assumed girls up to age 14 to be given two doses and girls older than this to be given three doses. We assumed no booster doses at any age. Economic parameters and the detailed model structure used for the cost effectiveness analysis have been previously described. We did probabilistic sensitivity analysis by Latin hypercube sampling from the joint distribution of the economic parameters together with 100 outcome scenarios from the vaccine impact model that best fits pre-vaccination epidemiological data.
Clearly, if two doses of human papillomavirus vaccine are equivalent in every way to three doses for disease prevention, then giving the third dose has no health or economic advantage. To explore situations in which this is not the case, we assumed that three dose schedules gave lifelong protection, with full protection against cervical infection and disease due to human papillomavirus 16/18. We estimated efficacy against human papillomavirus 31/33/45/52/58 from a meta-analysis of quadrivalent vaccine trials. We then assumed two dose schedules either to provide reduced duration of protection (10, 20, or 30 years) or to lose efficacy against human papillomavirus 31/33/45/52/58. We assumed girls to be given quadrivalent human papillomavirus vaccine. We then explored the predicted impact of two dose schedules in terms of reduction in cervical cancer.
As the cost of vaccine procurement is unknown, we assumed a single dose of vaccine to cost £80.50 (€101.65; $126.57) or £86.50 (the current list price for bivalent and quadrivalent vaccines in the United Kingdom), with £9.33 administration cost per dose. UK tender prices are unknown but are likely to be substantially lower, so we also did a threshold analysis to find the maximum price at which two dose vaccination and three dose vaccination become cost effective. We used a threshold of £30,000 for an intervention to be cost effective, which is the upper limit of the threshold used by the National Institute for Health and Care Excellence (NICE). All other costs came from our previous work, but inflated to 2012-13 prices.
Costs and benefits were discounted at 3.5% per annum, as recommended in the NICE reference case. As NICE guidelines also suggest that a discount rate of 1.5% per annum can be considered for public health interventions or interventions that have long term health benefits, we also did sensitivity analyses using this rate.
We also explored the same scenarios about two and three dose vaccination by using HPV-ADVISE, an individual based, transmission dynamic model of human papillomavirus vaccination fitted to Canadian data. We retained the original model structure and parameters governing infection transmission and disease natural history; however, we adjusted parameters governing cancer mortality, incidence and costs of anogenital warts, and some utility losses associated with human papillomavirus related disease to reflect UK data (see Table 1 and Supplementary Table A and Table B for details).