A Very Common Intimate Concern: “Will My Genital Warts Ever Stop Recurring?”

(See the Major Article by Giuliano et al on pages 703–10.) In this issue of The Journal of Infectious Diseases, an article by Giuliano et al, from the Human Papillomavirus Infection in Men (HIM) study team, has confirmed the high rate and long-term burden of genital warts (GWs) recurrence among men [1]. The rate of GW recurrence, defined as the detection of GWs and the same human papillomavirus (HPV) genotype at a site where they were previously detected, was found to be 44.3% after the first GW episode. The number of recurrent episodes could be as high as 10 during the median follow-up of 50.4 months. The proportion of GWs associated with HPV-6 and/or HPV-11 remained stable during the study, at 44.2% and 10.1%, respectively. In addition, 65.7% of GWs tested positive for at least one of the 9 HPV types included in the 9-valent HPV prophylactic vaccine. In the pre-HPV prophylactic vaccine era, the comprehensive sexually transmitted infection surveillance system in the United Kingdom reported not only that the incidence of GWs was high among male participants and greater than that among female participants, but also that there might be as many recurrent cases as incident cases [2]. In the HPV prophylactic vaccine era, as the number of GW cases decreases in the United Kingdom, male individuals continue to be more affected than female individuals [3]. Before the study by Giuliano et al, recurrent GWs were known to affect a large number of male individuals, but now we know that the burden involves a large age range of the male population, not just the younger population. Most HPV infections will clear on their own, but why is the GW recurrence rate so high in men? The HIM research group had previously published information stating that men had a higher cumulative probability than women of acquiring HPV, irrespective of age; had a lower prevalence of antibodies to HPV after natural infection; and, compared with people with circulating antibodies, had lower antibody titers [4]. Men also had higher rates of reinfection and reactivation of infections [4]. Seropositive men were not shown to have protection from future infections [5, 6]. Men had a similar probability of acquiring oncogenic (ie, high-risk) and nononcogenic (ie, low-risk) HPV types, contrary to what has been observed in women, who have a greater probability of acquiring oncogenic HPV types [7]. Homologous immunity was not shown in men but was shown in women [8]. Men had a 3-times higher prevalence of oral HPV infection, compared with women [9]. In addition, previous studies demonstrated that women 16–26 years old in the FUTURE 1 trial who cleared HPV from the cervix had the highest frequency of reappearance of cervical infection at 36 months, with an HPV-6 recurrence rate of 16.1% and an HPV-11 recurrence rate of 9.1%, which, after the HPV-16 recurrence rate (ie, 11.0%) was the third highest [10]. Recurrence rates after home and clinic-based treatment of GWs vary widely and are quite difficult to compare since all studies use different intervals for assessment of recurrence and different definitions of treatment success and GW recurrence [11]. All treatments are effective at removing a high proportion of the GWs, but they are not effective at removing the infecting HPV genotypes. The effective prevention of recurrent GWs starts by prevention of HPV infections causing GWs. Excellent data show that the 4-valent and 9-valent HPV prophylactic vaccines are very effective, are safe, and provide long-term efficacy at protecting acquisition of the 2 most frequent low-risk HPV and high-risk types found in GWs and GWs per se in both sexes [12–14]. But there seems to be unforeseen value in vaccinating people who have GW lesions. A post hoc analysis in the FUTURE I trials and FUTURE II trials evaluated the effectiveness of the 4-valent HPV prophylactic vaccine against GW recurrence among women aged 15–26 years. Although results were not statistically significant, there were 46.8% fewer cases among vaccinated women (10 cases vs 33 cases in the placebo group), showing that the 4-valent vaccine could protect some women who received a diagnosis of and cleared GWs [15]. If all low-grade lesions of the vagina and vulva were added to the analysis, the 4-valent vaccine was associated with a statistically significant decrease of 60.3% (95% confidence interval, 21.7%–81.5%) in the number of lesions due to vaccine-type HPV, compared with placebo recipients. A study was undertaken with men who have sex with men (age of participants, ≥26 years) who received a diagnosis of anal warts. Statistically significant prevention of recurrent anal warts was seen at 3- and 4-year follow-up visits in those who received the 4-valent vaccine as compared those who received no vaccine [16]. Twelve years after the availability of HPV prophylactic vaccines, some people still argue that we do not need these vaccines, since most infections will clear without treatment. The HIM study team makes a point that GWs may go away on their own but will return quite rapidly and, for some men, for a long time. Even if herd immunity were shown in heterosexual men in Australia, where GWs almost disappeared before men even received free HPV vaccination, this level of decline was not shown in other countries, and was not seen in the Australian population of men who have sex with men. Questions about recurrences remain a major concern for people with GWs [17]. Questions about the use of HPV prophylactic vaccines in men are frequent since most studies have been done in women. For instance, how frequently do results in women apply to heterosexual or homosexual male individuals? This study shows the importance of GW recurrence in mostly unvaccinated male populations and makes the case that we need sex-neutral vaccination programs to better protect men against HPV infection not only because of the risk of cancer but also because of the risk of GWs. The annual cost associated with low-risk HPV-6 and HPV-11 infections in British Columbia was estimated to be 18% of the cost of all HPV-related diseases [18]. GWs involve a huge proportion of the HPV burden, and since treatment does not prevent recurrences, we need to emphasize that 4-valent and 9-valent HPV prophylactic vaccines are safe and effective against GWs and remain effective for >10 years after vaccination. Although these vaccines may not have a therapeutic effect against GWs, they may act as an adjuvant to existing therapies for the prevention of recurrences. Acknowledgments. The author thanks George J, Wurtak for assistance for the revision of the text. Potential conflicts of interest. M. S. received honoraria for serving as a member of the Merck advisory board and for delivering lectures for Merck, Valeant, and Paladin, and he received a grant for the development of accredited continuing medical education workshops from Merck. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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