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HPV Vaccination in Males: Is There Value?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas, M.D. Anderson Cancer, Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships to this field of study.
Synopsis: Although males have a lower immune response to HPV compared to females, the impact of the quadrivalent HPV vaccine on HPV-associated disease was significantly better than placebo in both the intent-to-treat and per-protocol analysis.
Source: Giuliano AR, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. New Engl J Med 2011;364:401-411.
HPV infection is a major cause of morbidity in both genders. HPV vaccination (both bivalent and quadrivalent) has proved effective in girls and women, including those outside of the original age indications and those with prior sexual activity. Much less is known of vaccine efficacy in boys and men for the prevention of HPV-associated diseases. To address this issue, a randomized, Phase 3, double-blind, placebo-controlled clinical trial was conducted in healthy boys and men aged 16 to 26 years. The authors recruited 4065 subjects from 18 countries and randomized 1:1 to either quadrivalent vaccination (HPV serotypes 6, 11, 16, 18) or placebo. The primary endpoint was the incidence of HPV-6, 11, 16, or 18 associated genital lesions relative to placebo. Analysis included both the intention-to-treat (ITT, received at least one dose) and per-protocol (PPT, received all three doses) populations. In the ITT population, overall vaccine efficacy (relative to placebo) for the appearance of external genital lesions (any HPV type) was 60%; for external genital lesions related to HPV-6, 11, 16, or 18, efficacy was 66%. In the PPT population, efficacy against lesions associated with the four valent types was 90%. Efficacy against persistent HPV infection was 48% and 86% in the ITT and PPT populations, respectively; similarly, prevention against HPV infection at any time in surveillance period (up to 36 months) was 27% and 45% in the two populations, respectively. Adverse events were reported in 69% of vaccine patients and 64% of placebo patients. Fever was uncommon and not significantly different between cohorts. Injection-site pain was significantly higher in the vaccine group (57% vs 51%, P < 0.001). The authors conclude the quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age.
The relationship of HPV infection to anogential pathology is well established, contributing to more than 99% of cancers of the cervix and a majority of cancers of the penis, anus, and oropharynx. However, non-invasive pathology, such as condyloma accuminata and dysplasia, are a major source of morbidity in a far greater number of men and women. Vaccination against HPV has proved meritorious in girls and women, particularly when enabled before sexual debut. Much less is known of the efficacy in boys and men, although globally, bigender vaccination programs already have been enacted.
The current report, designed very similarly to the several prospective efficacy trials of bivalent and quadrivalent vaccines in girls and women, demonstrates significant efficacy against HPV-related infection and anogential lesions. Of interest, the population was stratified for both heterosexual and men who have had sex with men populations. Primary endpoint efficacy was no different in these subgroups. Also similar to the experience in the female population, a significant number of study participants did not complete the prescribed vaccination schedule, although the rate of completion in this trial was higher than in the FUTURE trials (female population 16-26 years, quadrivalent vaccine), 69% vs 54%. Although both sexes were evaluated in these trials according to ITT principles, including a subcohort of "real world" type patients (those with prevalent infection), restrictions on age (age 16 to 23 years for heterosexual males, age 16 to 26 years for men who have sex with men, and age 16 to 26 years for in the female studies), number of sexual partners (in the current study, no more than 5; in the female studies, 0 to 4), and HPV-genotypes studied (14 of 40 known to infect the anogenital tract) limit this inference. Notable efficacy parameters that differed between the male and female studies were the number of cases of intraepithelial neoplasia. The primary event in the current trial was HPV-associated anogenital lesions, which were nearly all condyloma. Since the trial was event driven, efficacy analysis was undertaken when the minimal number of cases were diagnosed; the impact on intraepithelial neoplasia in boys and men is unknown. Although the overall efficacy of the vaccine is numerically lower in this population compared with female vaccination studies, the confidence intervals overlap, suggesting the vaccine has similar bigender efficacy. Nevertheless, intraepithelial neoplasia appears to be an obligate precursor for cancer development in the genital tract. The impact of male vaccination for this endpoint is unknown and, thus, may not be cost-effective in reducing HPV-associated anogenital cancer.