Current Update on the Treatment of Genital Warts

Valerie R Yanofsky; Rita V Linkner; David Pompei; Gary Goldenberg

Disclosures

Expert Rev Dermatol. 2013;8(3):321-332. 

In This Article

Preventative Treatments: The Role of the HPV Vaccine

Gardasil® (HPV4)

In 2006, the FDA approved the use of the first vaccine aimed at preventing infection with specifically targeted HPV types. Gardasil® (HPV4; Merck & Co., NJ, USA) is a recombinant, quadrivalent vaccine that protects against infection with HPV-6, -11, -16 and -18 by triggering the formation of host type-specific neutralizing antibodies directed against these specific types. Taken together, these generate immunity against those types responsible for 70% of cervical cancers, 80% of anal cancers, 60% of vaginal cancers, 40% of vulvar cancers and 90% of genital warts.[78] The vaccine has also been shown to prevent potentially precancerous dysplastic lesions of the cervix such as CIN grades I/II/III, as well as precursor lesions of the anus, vulva, vagina and penis.[79–81]

Gardasil injections are administered in three separate doses, at baseline, and 1 and 6 months. Vaccination is most effective in the HPV-naive population, and accordingly was initially recommended for young women between the ages of 9 and 25 years who had yet to be exposed. The vaccine is thought to be 99% effective in preventing genital wart formation in this population.[82] Current evidence suggests, however, that Gardasil may be of additional benefit to women up to the age of 45 years provided they have not yet contracted at least one of the HPV types targeted by the vaccine. This is likely due to the ability of Gardasil to reduce the incidence of recurrent or persistent HPV infection, which is associated with an increased risk of malignant progression.[83]

Evidence, which supports the efficacy of HPV4 includes multiple randomized, placebo-controlled, double-blinded Phase II and III clinical studies that evaluated over 20,000 adolescent and young women between the ages of 16 and 26 years. These studies found that, among the HPV-naive population, the efficacy of the quadrivalent vaccine in preventing CIN grade II and other severe HPV-related disease was 97–100%. This number dropped significantly to 44% when participants with prior HPV infection were included. The administration of HPV4, however, was able to significantly reduce the need for definitive therapies in the treatment of HPV-related genital lesions among all trial participants. This included a reduction in loop electrosurgical excision by 16.5% (95% CI: 2.9–28.2), as well as a drop in surgical lesion excision by 36.5% (95% CI: 3.6–44.2). This is due to the fact that individuals previously infected with one or more vaccine-related types were still protected from clinical disease caused by the remaining vaccine types. Gardasil therefore proved effective in providing sustained protection against both low- and high-grade lesions attributable to HPV types 6, 11, 16 and 18, as well as precipitating a substantial reduction in HPV-related morbidity and burden of disease.[84] Long-term follow-up studies have confirmed the ongoing protective effects of Gardasil up to 5 years postvaccination with no evidence of waning immunity.[85]

Side effects of HPV4 administration tend to be mild and include fainting, swelling at the injection site, headache, nausea and fever. These are thought to occur largely as a result of the method of administration rather than the vaccine content, since similar effects were seen with comparable frequency following the administration of placebo vaccines.[85] Although some controversy still persists with respect to Gardasil and possible adverse events, there is currently no evidence to support a causal link between vaccination and any serious complication including illness, hospitalization, permanent disability or death.[84]

The FDA recently expanded the therapeutic use of HPV4 to include boys and young men between the ages of 9 and 26 years.[86] The vaccine was shown to be equally as effective in males when compared with females in the prevention of EGW and the induction of a long-lasting immunogenic response. It was also found to be effective in reducing the incidence of precursor lesions to anal cancers, which, like CIN, are strongly associated with HPV infection.[84,87,88] Expanding the use of this vaccine to males has the additive benefit of reducing the incidence of infection in females by preventing viral transmission and directly targeting the viral pool. Decreasing the viral burden of HPV by potentially eliminating the host reservoir necessary for viral incubation is a critical step in the eventual eradication of the virus.[89] Furthermore, important population-based reports on the reduction of EGW in a real-life setting due to high coverage of HPV vaccination have now been reported in Australia, demonstrating not only a decrease in frequency of EGWs in females of vaccine-eligible age, but also protective effects in heterosexual men through herd immunity.[90] Four years after commencing this vaccination program, the disappearance of EGW in women and men under 21 years of age within this population has recently been reported.[91] In addition, similar results demonstrating a decline in the incidence of genital warts within target populations following HPV vaccination programs have been reported in both New Zealand and the USA.[92,93]

Cervarix (HPV2)

In the fall of 2009, the FDA approved the use of a second recombinant HPV vaccine (HPV2; GlaxoSmithKline, UK) in females between the ages of 10 and 25 years. Vaccinated women have been shown to benefit after treatment of EGW, demonstrating substantially less subsequent HPV-related disease.[94] Cervarix is similar to HPV4 in terms of dosing and administration schedules; however, it is a bivalent vaccine directed only against high-risk HPV types 16 and 18. These two oncogenic types are most commonly associated with cervical cancer, CIN grade I/II/III and adenocarcinoma in situ. Cervarix does not provide protection against the types commonly associated with genital warts. HPV2 was evaluated in two Phase II and III randomized, double-blind, placebo-controlled clinical trials that followed over 18,000 females for a mean duration of 35 months. Results of these trials revealed Cervarix to be 93% (95% CI: 79.9–98.3) effective in the prevention of HPV-related CIN grade II or III and adenocarcinoma in situ in the HPV-naive population. Again, this number dropped significantly to less than 30% when all trial participants were included. Side effects following HPV2 administration occurred significantly more frequently compared with HPV4, and included injection site pain, redness and swelling. Additionally, general systemic symptoms such as fatigue, headache and myalgia were also more significantly reported.

To date, there has been only one randomized, observer-blinded head-to-head comparison of the efficacy, safety and immunogenicity of HPV4 and HPV2 in a single controlled population. The study included a well-defined population of over 1100 healthy females aged 18–45 years. Results of this study revealed that, for all ages, serum-neutralizing antibodies to HPV-16 and -18 were significantly higher following Cervarix administration than after treatment with Gardasil (p < 0.0001). This discrepancy in immune response may be explained by differences in the precise formulation of each vaccine. In particular, the use of unique adjuvant factors may serve to activate and enhance immune signals through highly specific adjuvant-dependent pathways. The clinical implication of this observed effect remains largely unknown, and a direct link between the level of serum antibody titers and the degree of immune protection is yet to be established.[83] Currently, the American Cancer Society and Advisory Committee on Immunization Practices continues to recommend routine vaccination for all females beginning at 9 years of age up to 26 years of age, for all males from 9 years of age up to 21 years of age, and for males who have sex with males up to 26 years of age with either HPV2 or HPV4.[5,95]

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