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Infection with high-risk "oncogenic" types of human papillomavirus (HPV) is the cause of 100% of cervical cancers, 90% of anal cancers, 40% of vulvar and vaginal cancers, at least 12% of oropharyngeal cancers, and 3% of oral cancers.2 Worldwide, HPV types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cases of cervical cancer.3,4

Vaccines against HPV-16 and HPV-18 appear to be highly efficacious in preventing HPV-16 and HPV-18 infections and cervical lesions in girls and women who have not previously been infected with these types.5,6,7,8,9 The vaccine currently licensed in the United States also prevents HPV types 6 and 11 (HPV-6 and HPV-11), which are responsible for most genital warts and juvenile-onset recurrent respiratory papillomatosis.10

There are important questions regarding the appropriate target population for prophylactic vaccination against HPV-16 and HPV-18. Since the vaccine is most efficacious before the onset of sexual activity, most investigators agree that the target population for routine immunization should be adolescents who are approximately 12 years of age.11,12 Recommended temporary catch-up programs to provide vaccine coverage to girls and women 13 years of age and older range from an upper age limit of 18 to 26 years.11,12

The impact of HPV vaccination on the rate of cervical cancer will not be observable for decades; thus, decisions regarding a vaccination policy will inevitably rely on studies reporting intermediate outcomes. Estimating the magnitude of the benefit of vaccination is further complicated when one considers the extensive secondary-prevention program in the United States. This program, which involves the use of cytology-based screening, is recommended annually or biennially, starting 3 years after the first sexual intercourse and no later than 21 years of age.13,14,15 HPV DNA testing is recommended as a triage test for equivocal results of cytologic analysis and in combination with cytologic tests for primary screening in women 30 years of age or older.16

Before long-term data become available, mathematical models used in a decision-analytic framework that synthesize the best available data while ensuring consistency with epidemiologic observations can project outcomes beyond those reported in clinical trials, provide insight into key drivers of cost-effectiveness, and be revised as new information emerges. Extending previous studies of HPV vaccination,17,18,19,20,21,22 we evaluated the cost-effectiveness of vaccinating 12-year-old girls and of temporary catch-up programs. We considered the dynamics of HPV transmission, the duration of vaccine efficacy, the potential benefits of preventing noncervical HPV-related conditions, the anticipated changes in screening practice, and potential disparities in access to care.

Discussion

Vaccination against HPV-16 and HPV-18 is expected to be economically attractive (i.e., <$50,000 per QALY) if high coverage can be achieved in the primary target group of 12-year-old girls and if vaccine-induced immunity is lifelong. Under these conditions, if we are willing to pay $100,000 per QALY, a catch-up program for girls between 13 and 18 years of age appears to be reasonable, especially when we include the benefits of averting genital warts (with the use of the quadrivalent vaccine) or the benefits of cross-protection against other high-risk types of HPV not including HPV-16 and HPV-18 (as reported with the bivalent vaccine). Extending the catch-up program to 21 years of age is less cost-effective, but it also becomes more favorable when the potential benefits of preventing noncervical HPV-16–associated and HPV-18–associated cancers in women are included.

Extending vaccine coverage to women up to 26 years of age generally exceeds $130,000 per QALY. This result is not unexpected, since nearly 90% of women in the United States have had vaginal intercourse by 24 years of age47 and up to 30% of women may be exposed to HPV in the first year of intercourse.54 The cost of extending a catch-up program to women up to 26 years of age is less than $100,000 per QALY only in the context of 100% lifelong efficacy against other outcomes associated with HPV-16, HPV-18, HPV-6, and HPV-11 in women; these outcomes include cervical cancer, warts, other cancers, and juvenile-onset recurrent respiratory papillomatosis. The cost of extending this program is more than $200,000 per QALY when a booster is required to maintain lifelong immunity, when there are disparities in screening and vaccination coverage, and when vaccinated girls undergo frequent screening in adulthood. The benefits of vaccine in most HPV-16 and HPV-18 noncervical cancers and HPV-6 and HPV-11 juvenile-onset recurrent respiratory papillomatosis have not been shown in clinical studies.

Our results were sensitive to the duration of vaccine-induced immunity; if immunity lasted 10 years, the vaccination of preadolescent girls exceeded $140,000 per QALY, and all catch-up strategies were less cost-effective than screening alone. Although immunologic data have provided support for a strong initial immune response with antibody levels persisting at a level higher than the level after natural infection,9,55,56 observations in published reports are limited to 5 years after vaccination. With partial natural immunity to type-specific infection, if a vaccinated girl loses vaccine-induced protection and becomes susceptible at a later age when the risk of cancer may be higher, an increased risk of cervical cancer is plausible. There are no empirical data to show whether reinfection or reactivation of a previous infection predominates in older women; as previously described,17 which one of these predominates will influence the implications of waning vaccine protection. There are other important uncertainties. Although HPV infections may be independent from one another,56 our exploratory analysis showed that replacement of the vaccine-targeted types of HPV with other high-risk types could be influential. Vaccination against HPV may also alter sexual behavior in the population or lead to a misperception that screening is no longer necessary. These uncertainties highlight the priorities for surveillance of epidemiologic characteristics and behaviors after vaccination against HPV.

Our results of vaccinating preadolescent girls were consistent with those of other studies.17,18,19,20,21,22,57,58 Elbasha et al.21 reported that the cost of a catch-up program in women up to 24 years of age was less than $5,000 per QALY; none of our strategies had a cost-effectiveness ratio this low, and the cost of a catch-up program in women up to 26 years of age generally exceeded $100,000 per QALY. Differences in assumptions have been summarized in several review articles.59,60,61 Our findings, which were consistent with those of others,20,22 were that high vaccination coverage warranted modification of screening protocols and that the cost-effectiveness of vaccination was enhanced with less frequent screening with more sensitive tests and beginning at later ages.

Our analysis has important limitations. Data on sexual behavior were primarily based on population averages from large surveys, and there were limited data on type-specific HPV transmission according to age and sex. By means of a model-fitting process, we estimated probabilities of transmission that were higher than those of some other analyses62,63; as better data become available, the estimation of these variables may be refined. Other limitations of the data included the incidence, mortality, and quality of life associated with noncervical HPV-related cancers, the long-term efficacy of the vaccine against cervical lesions and warts, and the efficacy of the vaccine against noncervical cancers. As with all model-based analyses, there are trade-offs with regard to the choice of model structure; we used two different modeling techniques to try to best capture the features of HPV infection and cervical carcinogenesis that were most relevant to the key policy questions. The complexities that are introduced with the use of multiple models should be explored further.24

A decision-analytic approach allows for acknowledgment of uncertainty while informing decisions that need to be made now. Accordingly, we emphasized broad qualitative themes that we found to be consistent throughout a range of assumptions. The cost-effectiveness of HPV vaccination in the United States will likely be optimized by achieving universal coverage in young adolescent girls and targeting initial catch-up efforts to girls and women younger than 21 years of age. Optimal synergies between vaccination and screening will involve revisions to current screening practice. Priorities for empirical data collection include surveillance to understand the HPV type-specific epidemiologic factors and screening behavior in vaccinated populations, the duration of vaccine-induced protection, and the long-term impact on other HPV-related conditions.

Supported by grants from the National Cancer Institute (R01 CA93435), the Centers for Disease Control and Prevention, and the American Cancer Society, and by the Bill and Melinda Gates Foundation (30505) for related work in developing countries.