For both vaccinated and unvaccinated women, age-based screening protocols that use HPV DNA testing as a triage test for equivocal results in younger women and as a primary screening test in older women have the potential to be more effective than current screening recommendations. For women who will not be vaccinated, screening by cervical cytology with HPV triage starting between the ages of 21 and 25 years and HPV DNA testing with cytology triage for women older than 30 years was found to be more cost-effective than screening all ages by cervical cytology alone, cervical cytology with HPV DNA testing as a triage for equivocal results, or by combination cytology and HPV DNA testing, when a threshold of $50 000–$100 000 per QALY was used. For girls vaccinated by age 12 years, screening by cervical cytology with HPV triage every 5 years starting at age 25 years and switching at age 35 years to HPV testing with cytology triage was also found to be cost-effective at the same threshold. Ensuring that vaccination is preferentially targeted to achieve high coverage in preadolescent females, especially those who may be at a future disadvantage for regular screening, and emphasizing the need for continued screening even in vaccinated women will be critical to achieving population reductions in cervical cancer.
There is great promise in the availability of accurate HPV diagnostics, new screening strategies, and a preventive vaccine against both HPV-16 and HPV-18 for cervical cancer prevention in the United States. As consensus guidelines are developed, decision analyses of how best to use these new options alone or in combination can provide insight for policy deliberations and identify priority research areas. Given current data limitations, particularly with respect to the long-term effects of HPV-16,18 vaccination, analyses should reflect uncertainties related to the natural history of type-specific HPV infections, the performance of HPV-16,18 vaccination and of new screening strategies, and the response of women in the general population to new screening guidelines in the context of an overwhelming amount of new information about HPV-16,18 vaccination and HPV DNA testing. Because not all women in the United States have benefited equally from cervical cancer screening, it is also important to highlight the potential for widening or narrowing of disparities that could accompany changes in cervical cancer prevention policies.
Reports from the last major update to US cervical cancer screening guidelines were published between 2001 and 2003 (2
). These reports recommended 1) initiating screening 3 years after women become sexually active or between the ages of 18 and 21 years, 2) screening yearly with conventional cytology methods or every 2–3 years with liquid-based cytology methods, 3) using HPV DNA testing only to determine whether diagnostic follow-up is necessary for women with equivocal cytology results (ie, ASCUS), and 4) discontinuing screening between ages 65 and 70 years for women without indicators of elevated risk. Food and Drug Administration approval was expanded to include the use of cytologic evaluation and HPV DNA testing in combination for women older than 30 years, although only interim guidelines have been published that recommend 3-year screening intervals and repeat screening at 6- to 12-month intervals for women whose results are positive on both screening tests (6
). Our findings indicate that it may be worthwhile to consider strategies that differ according to age and vaccination status and to revisit screening options recommended for older women with specific consideration of the role of HPV DNA testing with cytology as triage for HPV-positive results.
If we assume that newly available HPV vaccines provide protection in the community that is commensurate with efficacy results from clinical trials, then preadolescent vaccination of girls before beginning sexual activity followed by cytologic screening every 3–5 years, to begin in a woman aged 25 years, and then switching to HPV DNA testing with cytology triage in a woman aged 35 years was more effective and cost-effective than current screening. This strategy was the most efficient identified for a cost-effectiveness threshold of less than $100 000 per QALY. If the sensitivity of cytology testing were to drop substantially in a vaccinated population but the specificity of HPV testing were to remain stable, then HPV DNA testing with cytology triage every 5 years may eventually be an attractive option for women of all ages.
If high levels of vaccine coverage are attainable in all preadolescents, and in particular for those at greater risk for inadequate screening in their future, we would expect that cervical cancer mortality in this country would decrease and that the current disparities in cervical cancer outcomes could decrease. However, in the hypothetical scenario of low vaccine coverage in preadolescents, opportunistic vaccination of women aged 21–29 years who are already adherent to screening recommendations, and no change in the access to improved screening technology (eg, HPV DNA testing) for women not currently being screened, disparities would be expected to worsen, with little change in overall rates of cervical cancer. In select scenarios that are admittedly based on extreme assumptions about age of vaccine uptake, vaccine efficacy, and screening behavior in a partially vaccinated population, quality-adjusted life expectancy might actually be worse than that under current screening practice. We emphasize that the hypothetical scenarios that we constructed are not based on empiric data but were developed to simulate plausible situations that could occur. Our intent was to provide qualitative insight to policy makers about the consequences, both negative and positive, of differential uptake and utilization of new screening technology and HPV vaccination. The results of these exploratory analyses highlight the importance of careful deliberation and responsible planning for introducing HPV vaccination in the United States and for providing clear messages to women about appropriate screening strategies that will be conditional on their vaccination status and age.
Previous modeling studies have found that HPV DNA testing, whether used to triage cervical cytologic abnormalities as a primary screening test in combination with cytologic examination or as a primary screening test alone, can be cost-effective when compared with primary screening with cytologic examination, provided there are longer intervals between screenings (31
). Several previous modeling studies considered the potential benefits of type-specific vaccination and the cost-effectiveness of vaccination in both developed (57
) and developing (64
) countries. Our model expands on this previous work in light of questions raised in the development of the last cervical cancer prevention guidelines. We incorporate new epidemiologic data from multiple sources, account for HPV types not targeted by the vaccine, reflect complexities such as HPV-type–specific natural immunity and vaccine-induced immunity, and consider multiple policy-relevant screening and vaccination technologies, including the previously unevaluated strategy of HPV DNA testing with cytology triage. By using systematic, empirical calibration methods, we explicitly incorporated the uncertainty about the natural history of HPV and cervical cancer into the policy results.
This analysis has several important limitations. Key influential uncertainties include the nature and duration of natural vs vaccine-induced type-specific immunity, whether clearance and reinfection or reactivation predominates in older women, the nature of interactions between HPV types, the behavior of non–vaccine-targeted HPV types over time as an increasing number of birth cohorts achieve high vaccination coverage rates and prevalence of HPV-16 and HPV-18 declines, and the presence of cross protection to non-16 and non-18 types of HPV (66
). In addition to monitoring long-term outcomes, it will be imperative to monitor the HPV type distribution and changes, if any, in screening test performance within a vaccinated population. Our exploratory analyses of the effect of screening behavior illustrate how the benefits of HPV vaccination could potentially be eroded by lower adherence to screening. It will be important to repeat these analyses as data become available from studies of vaccine uptake, screening compliance, and behavior in subgroups of women defined by vaccination status, race, access to preventive care, and other factors. Additionally, a number of methodologic limitations have already been described in a previous publication (17
). For this analysis, we made a deliberate trade-off in choosing a detailed stochastic simulation model that accommodates complex screening strategies and individual history and that represents all HPV types instead of a model that reflects the transmission dynamics of HPV-16 and HPV-18. Although our group has also developed a transmission model that can be linked to this microsimulation model (22
), it increased the complexity considerably and did not add substantially to our main goal of assessing screening guidelines for both unvaccinated and vaccinated women. Other analyses that focus on assessing the cost-effectiveness of immunizing boys in addition to girls, the optimal age range of a catch-up program in the United States, and the incremental benefits of vaccinating older women (22
) used this additional component of our transmission model, although they did not include all possible screening strategies. By design, we aimed to obtain results that would be relevant to both the bivalent and quadrivalent HPV vaccines, focusing on the prevention of HPV-16 and HPV-18 infections, which are responsible for more than half of the invasive cervical cancers worldwide. Including the costs and benefits of preventing noncervical cancers caused by HPV-16 and HPV-18 will improve estimates of cost-effectiveness. Finally, although the price of the vaccine is available, the true cost associated with delivering this vaccine to adolescents in the United States—including education, counseling, and delivery mechanisms—is not yet known. Similarly, no estimates are available yet for the costs of monitoring and surveillance. As these data become available, this analysis should be revisited.
There are more than 75 million women in the United States at risk of developing invasive cervical cancer who may not benefit directly from vaccination because they are older than the currently recommended age range for routine vaccination. They do, however, have the opportunity to benefit from new technology and improved screening strategies. For these women, screening using cervical cytology with HPV triage starting between the ages of 21 and 25 years and switching to HPV DNA testing with cytology triage for women older than 30 years is more cost-effective than a single recommendation to use cervical cytology, HPV DNA testing, or both in women of all ages. For the nearly 40 million girls who could be vaccinated in the next 20 years (68
), if HPV-16,18 vaccines provide long-lasting immunity, vaccination of preadolescent girls combined with less frequent screening that begins by the age of 25 years would provide comparable protection from invasive cancer and would be considered to be cost-effective. Achieving this potential is likely to depend on high vaccine coverage in preadolescent girls, communication of clear messages to both vaccinated and unvaccinated women about continuing screening and following appropriate age-based guidelines, and targeted efforts to recruit and screen women with historically poor access to cervical cancer prevention.