Evaluating human papillomavirus vaccination programs.(Research)

Human papillomavirus (HPV) has been implicated as the primary etiologic agent of cervical cancer. Potential vaccines against high-risk HPV types are in clinical trials. We evaluated vaccination programs with a vaccine against HPV-16 and HPV-18. We developed disease transmission models that estimated HPV prevalence and infection rates for the population overall, by age group, by level of sexual activity within each age group, and by sex. Data were based on clinical trials and published and unpublished sources. An HPV-16/18 vaccine for 12-year-old girls would reduce cohort cervical cancer cases by 61.8%, with a cost-effectiveness ratio of $14,583 per quality-adjusted life year (QALY). Including male participants in a vaccine rollout would further reduce cervical cancer cases by 2.2% at an incremental cost-effectiveness ratio of $442,039/QALY compared to female-only vaccination. Vaccination against HPV-16 and HPV-18 can be cost-effective, although including male participants in a vaccination program is generally not cost-effective, compared to female-only vaccination.

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With 370,000 cases per year and a death rate of approximately 50%, cervical cancer is the third most common malignancy in women worldwide (1,2). Epidemiologic and laboratory evidence has implicated certain types of human papillomavirus (HPV) as the etiologic agents of cervical cancer (3,4). On the basis of this evidence, effort is under way to develop an HPV vaccine that targets these oncogenic HPV types (5).

Clinical trials of preliminary vaccines in humans began in the late 1990s (6). Recent data from an ongoing phase II trial (7) look very positive, demonstrating that an HPV-16 vaccine can prevent HPV infection and precancerous lesions in vaccinated women. These data provide hope that an HPV vaccine may be a reality within 5 to 10 years. Public health officials will then need to make important decisions regarding who and when to vaccinate and what level of vaccine penetration is necessary to substantially reduce disease prevalence.

Central to this discussion is the question of whether both sexes should be vaccinated. The general assumption in the literature is that men and boys should be vaccinated (5,6,8,9). Although long-term sequelae of HPV infection for men is on average less serious (particularly for heterosexual men), men act as vectors for infection. Including men and boys in a vaccine program would enhance herd immunity and decrease overall incidence of cervical cancer. In this article, we evaluate the benefit and cost-effectiveness of adopting a vaccination strategy for both sexes, compared with that of adopting a female-only strategy. The incremental cost-effectiveness of a vaccination rollout strategy is calculated by dividing the difference in costs between strategies by the difference in quality-adjusted life expectancy.

Because results of the long-term phase III/IV trial are not available, the efficacy of the HPV vaccine is still unknown. Also, acceptance of an HPV vaccine is likely to vary substantially. Resistance to a vaccine may arise because HPV is a sexually transmitted disease (6,10), although recent studies suggest that an HPV vaccine may be reasonably well accepted (11). We therefore evaluated a wide range of vaccine efficacies and population penetrations to understand what is required for a female-only program to achieve sizeable benefit and to identify the scenarios in which incremental male vaccination makes most sense.

Methods

To capture the effect of a male vaccination program on female HPV infection rates and cervical cancer incidence, we needed to directly model the effect of vaccination on HPV disease transmission dynamics. Therefore, we developed disease-transmission models for HPV-16 and HPV-18, the types associated with most cervical cancer cases and the most likely to be included in HPV vaccines (3,6). For both types, the transmission models estimated HPV prevalence and infection rates for the U.S. population overall, by age group, level of sexual activity, and sex. The models also enabled us to evaluate the effect of various vaccination programs on prevalence and infection rates.

Long-term equilibrium infection rates by age group, by level of sexual activity, and by sex for each vaccination scenario were determined in the transmission model. These infection rates were then incorporated into a probabilistic decision model. This model estimated the annual incidence of HPV-related precancerous lesions, lifetime cases of invasive cervical cancer, resulting cervical cancer deaths, and total cost of care for a given set of age-specific infection rates. By using the combination of the transmission and decision model, we estimated the effectiveness and cost-effectiveness of alternative vaccine rollout strategies.

Transmission Model Structure

We used Stella software (v7.0.3, High Performance Systems, Hanover, NH) to develop deterministic transmission models for heterosexual transmission of HPV types 16 and 18. Because level of sexual activity and HPV prevalence are highly age-dependent, we divided the population into nine age categories, from age 12 to age 50. We further divided each age category into four subcategories based on level of sexual activity (Table 1). HPV prevalence among their pool of sex partners, infectivity per infected partner, HPV shedding duration, and HPV infection rates were estimated for each age and activity group to develop a natural history transmission model. Vaccine penetration and efficacy were added to evaluate the effect of potential vaccine programs.

In our analysis, persons of both sexes were either HPV infected or uninfected at the beginning of each time period. In each period, uninfected persons could…