There is great promise in the availability of accurate HPV diagnostics, new screening strategies, and a preventive vaccine against HPV-16 and HPV-18 for cervical cancer prevention in the U.S. Model-based decision analyses of how to best use these new options alone or synergistically can provide insight for policy deliberations and professional guidelines, as well as aid in identifying research priorities. Although previous analyses have evaluated the HPV vaccine in the context of current guidelines for catch-up programs up to age 26 (16
), to our knowledge, our study is the first to assess the vaccine’s routine use in an older population of U.S. women. Consistent with the general consensus that the value of HPV vaccination diminishes with increasing age of vaccination (16
), we found that HPV vaccination provides nominal benefits in the context of current screening recommendations and practice among women in their 30s and 40s. Considering the lifetime risk of cervical cancer in the U.S. is less than 1% (1
), the absolute risk reductions provided by HPV vaccination in this age group are quite low. Likewise, the incremental cost-effectiveness ratios associated with adding vaccination to screening, given currently available information, exceeded $100,000 per QALY in most instances. These results were stable even when evaluating new, promising screening algorithms using HPV DNA testing with cytology triage, which is expected to have a higher positive predictive value than cytology testing alone post-vaccination (46
There is no universal criterion that defines a threshold cost-effectiveness ratio, below which an intervention would be considered “good value for money.” Unlike some countries, the U.S. has not adopted an absolute cost-effectiveness threshold. Rather, informal heuristics have been cited, including the cost-effectiveness ratio associated with renal dialysis through the Medicare entitlement program (ranging from $55,000 to $108,500 per QALY (47
)) to those associated with widely-adopted interventions, such as diabetes care, knee replacement, and mammography screening (generally below $100,000 - and often below $50,000 - per QALY (51
)). Most recently, Shiroiwa et al. (54
) measured thresholds in selected countries and reported $62,000 per QALY gained in the U.S. Based on these considerations, we feel that a range of $50,000 to $100,000 per QALY gained is a reasonable benchmark for cost-effectiveness in the U.S., although it is important to note that societal willingness to pay more than $100,000 per QALY may be based on other considerations. Using this threshold range, our results suggest that a policy of HPV vaccination in older women does not represent good value for resources expended, implying that more health can be gained by investing in alternative health interventions, such as screening previously unscreened women.
The vaccine’s impact in an older population is influenced in part by the level of prior exposure to the vaccine-targeted HPV types. Clinical trials have reported that the majority of female participants up to age 26 were not exposed to any vaccine-type at enrollment (55
), and therefore stand to benefit completely from the vaccine; however, because the trials excluded women with more than four sexual partners, it is unclear whether the trial population is representative of the general U.S. population with respect to exposure status and how these data extend to women up to 45 years of age. In order to explore the uncertainty in the natural history of disease, including prior exposure to HPV, we conducted a probabilistic analysis using 50 distinct parameter sets that fit well to the empirical data on HPV and cervical disease in the U.S. We found that the probability of HPV vaccination being cost-effective for screened women ages 35 to 45 was quite low at a threshold of $100,000 per QALY, even at extended screening intervals.
This analysis captures the average health and economic impact of the interventions over an entire population, intended primarily to inform the comparative effectiveness of health services, a priority recently highlighted in the American Recovery and Reinvestment Act of 2009 (57
). Despite its policy focus, the analysis can also provide insights into clinical decision-making for women with particular screening histories who may benefit differentially from vaccination and screening. Specifically, our study provides estimates of the potential added value of vaccination compared not only to the counterfactual scenario (i.e., continuation of screening without vaccination), but also to new strategies that could involve revised screening algorithms and testing options (e.g., HPV DNA testing with cytology triage). Although, on average, we found that HPV vaccination does not provide good value among women of older age groups, there are undoubtedly individuals who could benefit from the vaccine. Because there is no conclusive test to identify an individual’s prior infection history, decision making for an individual will need to involve information about the person’s risk of HPV exposure (i.e., number of sexual partners) and particular screening history (i.e., compliance and frequency), as well as the woman’s preferences.
Limitations include uncertainty in the natural history of cervical disease, particularly in older women. As previously noted (58
), whether an HPV infection detected at older ages is a newly-acquired infection or one that was acquired many years before and has re-emerged will influence the vaccine’s impact in older women, but is subject to much uncertainty and debate. Our probabilistic analysis attempts to explore plausible scenarios of natural history uncertainties, while maintaining a good fit to data that are available from empirical studies. Also, vaccine efficacy data using HPV infection and cervical disease endpoints are only available for five years and are only recently being presented for women in older age groups (59
). In our analysis, we optimistically assumed that women up to age 45 were fully compliant to the three-dose vaccine series, and that those without prior exposure to vaccine-types received complete lifelong protection from the vaccine. Given these optimistic assumptions, our results could be considered a “best-case scenario”; to the extent that efficacy is lower or of shorter duration, cost-effectiveness ratios for vaccination strategies may be even less attractive than presented in the current study.
This analysis did not consider the effects of reduced HPV transmission attributable to vaccination of older women, resulting in herd immunity benefits. We also did not include the vaccine’s potential cross-protective effects against other high-risk HPV infections nor the benefits related to other HPV-associated conditions, such as other anogenital, oral, and oropharyngeal cancers; the natural histories of these conditions - and contribution of HPV-16,-18 - are far less certain, and vaccine efficacy data on these outcomes are limited. Previous cost-effectiveness studies that have included some or all of these factors have suggested that their inclusion does not offset the diminished efficacy among women of older ages (16
It is important to note that we did not incorporate the risks of adverse events or diminished quality of life from vaccination (e.g., side effects) or screening (e.g., overtreatment). Even though small risks of minor adverse events from either intervention will likely be outweighed by the overall average benefits at the population level, as data become available, studies should incorporate all risks and costs associated with a vaccination program. We also assumed that a woman’s screening interval would not change post-vaccination; since a woman’s particular history of vaccine-type HPV exposure - and therefore her level of vaccine protection - is unknowable with certainty in clinical practice, we assumed that extending a woman’s screening interval without more information would be unjustifiable. Finally, this analysis is not relevant for women who have never been screened, who may comprise up to 5% of screen-eligible women in the U.S. (29
). Both vaccination and screening will likely have beneficial effects in this population, but the magnitude of benefit from either approach will depend on important factors, such as prior exposure to vaccine-targeted HPV types and compliance with the three necessary doses and screening visits.
Using information that is available now, our results indicate that HPV vaccination of older women participating in the U.S. screening program provides much lower benefits than vaccination of pre-adolescent girls and does not provide good health value for the resources invested, compared with well-accepted health interventions in the U.S. It will be important to revisit this analysis as more information becomes available regarding the natural history of HPV and vaccine impact in older women.