Human Papillomavirus Vaccine Should Be Given before Sexual Debut for Maximum Benefit

In this issue of the Journal, the Merck-sponsored FUTURE II Study Group presents an analysis of the prophylactic efficacy of its quadrivalent human papillomavirus (HPV) vaccine (Gardasil) among a subgroup of 4722 women from the FUTURE I and FUTURE II studies with evidence of current or past infection with at least 1 HPV vaccine type (6, 11, 16, or 18) at the time of vaccination [1]. It reports an efficacy of 100% against cervical intraepithial neoplasia 2/3 or adenocarcinoma in situ and of 94% against vulvar or vaginal HPV-related lesions among women who, at the time of vaccination, were seropositive or polymerase chain reaction positive for 1 of the HPV vaccine types but were naive for the type detected in histological sections of the lesion defined as an outcome. This report follows closely the publication of the main findings from the FUTURE I and FUTURE II trials of 17,622 women, which also reported very high prophylactic efficacy against these same conditions [2, 3]. Although reassuring, the results presented are not unexpected, given that the near-complete protection observed for the entire FUTURE I/II cohort by definition requires equally high protection within all subgroups, including the subgroup of exposed women evaluated in the present report. The results observed are also consistent with the biological assumption that the prophylactic efficacy against an HPV type for which a woman is naive should not vary on the basis of present or past infection with other HPV types. The results reported by the FUTURE II Study Group [1] are from according-toprotocol (ATP) efficacy analyses that evaluate only the prophylactic effect of vaccination rather than the overall impact of vaccination on disease burden among women already infected with 1 or more HPV types. Although such restricted ATP analyses are necessary and important for licensure, they are incomplete for subsequent discussions and for the formulation of vaccine implementation guidelines. The development of evidence-based public health guidelines require well-formulated intent-to-treat (ITT) analyses to determine overall effectiveness at the population level, including all-HPV-type outcomes. It is therefore an important limitation of the analysis presented that no data on the absolute effectiveness of vaccinating previously exposed or infected women are presented in the report by the FUTURE II Study Group. In its report, the FUTURE II Study Group concludes that universal catch-up vaccination of young adult women is desirable because, even among women with evidence of previous or current infection with 1 or more HPV vaccine types, residual benefit remains from the prophylactic effect of the vaccine against the types to which these women are not known to be exposed. This conclusion does not take into account the decline in the proportion of naive individuals remaining in each successive age cohort; as women age and become increasingly exposed to HPV, the pool of naive women is reduced, thereby reducing the marginal benefit of vaccination. We disagree with the authors' conclusions leading to the generalization that residual benefit among older women, no matter how small, justifies universal vaccination of women years into their sexual life. Some have gone so far as to suggest that the vaccine should be offered to women into their 40s and 50s. Although universal vaccination of women into their adult life might be reasonable for an inexpensive and totally risk-free product, this is not the case for the currently available vaccine—it is not inexpensive, nor has it accumulated sufficiently large and long-term safety data to ensure its absolute safety. Previous reports from the FUTURE I/II studies did present some results from ITT analyses, which indicated that the overall impact of vaccinating women 16–26 years of age (including the subgroup of already-exposed or -infected women included in the present report) on all-HPV-type lesions was 17%–20% over 3 years [2, 3]. Although numbers are not provided to allow for a similar evaluation restricted to already-exposed or -infected women, it is safe to say that the 19 high-grade cervical lesions (0.3/100 person-years at risk reported in the placebo arm in table 5) preventable by vaccinating women who are already exposed or infected pales in comparison to the ∼450 such outcomes observed overall in the FUTURE I/II cohorts during the same period (∼1.5–2.0/100 person-years at risk), particularly given that a large fraction of the overall disease burden caused by all HPV types is expected to occur among the subset of women who are already infected at the time of vaccination. Data presented by the FUTURE II Study Group should not be interpreted as providing evidence that vaccination of infected or previously exposed women prevents the reappearance of HPV types a woman has already been infected with or that HPV vaccination has any therapeutic effect against existing infections. With respect to the latter, a recent report from the US National Cancer Institute—sponsored community-based HPV vaccine trial in Costa Rica has demonstrated the lack of a therapeutic effect of HPV L1 virus-like-particle—based vaccination on preexisting HPV infections [4]. In a separate report in this issue of the Journal, Kjær et al. evaluated age and cohort trends for genital warts in various Scandinavian countries [5]. Results from their study indicated that rates of genital warts increase sharply with age (with rate increases starting at around the age of average sexual debut) and that rates are highest in the youngest cohorts of women. Together with the results from the FUTURE II Study Group suggesting a limited marginal benefit of the vaccine observed among previously exposed or infected women, these findings argue for public health vaccination programs that emphasize the vaccination of young, adolescent girls before sexual debut. We are thankful for the critical review of this commentary by Ana Cecilia Rodriguez, Mark Schiffman, Diane Solomon, and Sholom Wacholder.