Review
Cost-effectiveness analyses of human papillomavirus vaccination

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Summary

With a human papillomavirus (HPV) vaccine soon to become available for widespread use, several studies have modelled the cost-effectiveness of vaccination. These pioneer studies are likely to be influential on the design of further analyses, and we have therefore summarised and critically reviewed the strengths and limitations of their methods and assumptions. Despite a lack of transparency in some key elements, the most influential assumptions were identified as relating to vaccine effectiveness, cervical screening, and model design. Although the studies suggest that the introduction of an HPV vaccine could be cost effective compared with current practice in the USA, there is still substantial uncertainty around key variables, and model validation seems insufficient. The desirability of vaccinating boys in addition to girls has been explored in only one study. Further refinements to model design and epidemiological variables of (type-specific) HPV disease progression, and expansions on the options for vaccine use, are required for policy making.

Introduction

Worldwide, 500 000 new cases of cervical cancer are estimated to occur each year, resulting in 250 000 deaths.1 In recent years, the link between human papillomavirus (HPV) and cervical cancer has been conclusively proven.2 HPV is now thought to be a necessary but not sufficient cause of cervical cancer.3 This type of necessary causal relation offers substantial scope for both primary and secondary prevention strategies.4

HPV is primarily spread through sexual contact,5 and is associated with a wide range of diseases, including genital warts6 and many forms of cancer.7 Although several HPV types are defined as highly carcinogenic (known as high-risk or oncogenic types), those most commonly responsible for cervical cancer are HPV16 and HPV18.8 Worldwide, HPV16 and HPV18 have been estimated to account for approximately 70% of cervical cancers.9 The non-oncogenic types HPV6 and HPV11 are the main cause of condylomata acuminata (genital warts).

The incidence of cervical cancer differs between regions, particularly between high-income and low-income countries.10 The variation is mainly a function of cytological screening efforts and the quality of the screening programmes. Through Papanicolaou screening, cervical cancer is largely preventable.9 However, the precursors of cancer and ambiguous cytology results still represent a major burden to health-care systems.9 In the USA, the costs of screening represent up to two-thirds of the direct economic burden of cervical HPV-related disease.11

To date the most promising prophylactic vaccines have been based on virus-like particles.4 Currently, there are two vaccine candidates: a bivalent vaccine targeted at the oncogenic HPV16 and HPV18,12 and a quadrivalent vaccine targeted at the oncogenic HPV types and the HPV types primarily responsible for genital warts (HPV6 and HPV11).13 Both vaccines have been shown to be safe, immunogenic, and highly effective against type-specific persistent infection.12, 13 Several countries have licensed the quadrivalent vaccine.

Section snippets

Models of cost-effectiveness

Mathematical models can play an important role in our understanding of the effect of a new intervention, as well as identifying the best strategies for its introduction. In the context of HPV vaccination, an additional complexity is introduced by the existence of effective cytological screening programmes. Since there are more oncogenic HPV types than those targeted by current vaccine candidates, vaccination cannot yet replace screening in high-income countries, and must be assessed as a

Epidemiological assumptions

Two of the studies14, 15 adapted a previous model by Myers and colleagues18 to simulate both high-risk and low-risk HPV types. Taira and colleagues17 generated infection rates through the dynamic modelling process, and then incorporated these rates into the natural history model of Sanders and Taira.14 Therefore, three studies adapted the same progression and screening model.18 Kulasingam and Myers15 gave no detail of progression rates, instead referring readers to previous studies.18, 19, 20

Vaccine and screening assumptions

Details of vaccine and screening base-case assumptions are shown in table 1. In their base-case models, all four studies assumed that vaccination occurred at age 12 years and examined various vaccination ages in their sensitivity analyses. In the only dynamic model,17 ICERs were sensitive to vaccination coverage assumptions, particularly when vaccination of both boys and girls was considered. The ICERs in the three static models were insensitive to the level of coverage assumed, since

Health outcome measures

All four studies included quality-of-life (QOL) measures. However, Kulasingam and Myers15 reported base-case results in cost per life-year saved. There was a wide variation in the grouping and definition of health states to which QOL weights were applied, which makes comparison difficult. However, health states that do correspond show differences. For instance, the range of stage I cervical cancer follow-up utility weights was 0·90–0·97.14, 16 This lack of consistency is surprising given that

Economic factors

Goldie and colleagues' base-case analysis16 adopted the widest costing perspective (table 1). Direct cost estimates are shown to vary widely for some disease categories (table 2). All four studies used an annual discount rate of 3% in their base-case analyses for both costs and benefits. Only one study presented their results over a range of discount rates (0–5%).14 As in any economic evaluation of a prevention strategy with long-term effects, the initial intervention costs and the choice of

Model validation

Ideally, we would have liked to see a comparison of the model results to type-specific and age-specific data on rates of HPV infection, cervical intraepithelial neoplasia, and cancer. However, none of the studies provided such a comparison. Two studies15, 16 reported that their models gave approximately a 3·5% lifetime risk of developing cancer in the absence of control, but no other comparison was presented. Even the original model provides no comparison of age-specific results to the data

Methodological issues and limitations

Uncertainty, particularly around vaccine efficacy and duration of protection, has been accounted for through the wide range of values used in sensitivity analyses. However, although all four studies did sensitivity analyses, only two of the studies did two-way15 or multi-way analyses.14 All studies found that their results were fairly robust around changes in vaccine efficacy, although Taira and colleagues17 found that when they modelled female plus male vaccination, cost-effectiveness was

Modelling design

Three of the economic analyses used static Markov models.14, 15, 16 This type of modelling design is unable to take into account the dynamics of viral transmission within a host population, and therefore is unable to properly assess herd immunity (ie, the protective effect conferred on a population by immune individuals within the population).22, 35, 36 If the contribution of herd immunity is ignored, then the effectiveness and cost-effectiveness of a vaccination programme is likely to be

Future directions

Ideally, future HPV vaccine cost-effectiveness studies should be based on dynamic modelling. However, the validity of future dynamic models will be dependent on the accuracy of the data used to determine the transmission dynamics. Given the uncertainty around many of the variables, studies should do comprehensive sensitivity analyses, involving both univariate sensitivity analysis and multivariate probabilistic sensitivity analysis. The results should be presented as incremental (ie, compared

Conclusions

Overall, and with the assumption that the main model input variables (eg, HPV incidence, disease progression, QALY weights) are accurate, the three static models are likely to have underestimated the cost-effectiveness of HPV vaccination.14, 15, 16 Their base-case results therefore suggest that the introduction of HPV vaccination could be considered cost effective compared with current practice in the USA. The only published economic analysis based on a dynamic model found vaccination (of girls

Search strategy and selection criteria

Publications were primarily identified through Medline and EconLit searches and from citations from identified publications. Search terms included “papillomavirus, human”, “cost-benefit analysis”, “models, theoretical”, and “vaccination”. This process identified five English language cost-effectiveness analyses of HPV vaccination, four of which were included in the study. An early, crude, explorative assessment, which was made for the US Institute of Medicine,23 was not reviewed here in view of

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