¹Faculté de médecine, Université de Montréal, Montréal, Québec
²Division of Dermatology, McGill University, Montreal, Quebec

Conflicts of Interest: Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Other authors declare no competing financial interests.

Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted disease. Its lifetime
prevalence is >75% and this rate continues to increase.¹ This virus infects keratinocytes and is primarily transmitted by skin-to-skin contact.²

Chronic HPV infection, especially from low-risk strains such as 6, 11, 42, 43, and 44, plays an important role in the pathogenesis of cutaneous warts.³ For example, HPV strains 6 and 11 are responsible for 90% of anogenital warts (condyloma acuminate).⁴ Warts can also be found in the mouth, throat, penis/vagina and elsewhere on the skin.⁵

While many HPV infections are asymptomatic⁶, some can result in malignancies. A classic example of this in the skin is represented by carcinoma cuniculatum, a rare form of squamous cell carcinoma (SCC) that often presents on feet in the setting of a longstanding exophytic plantar wart, several decades after the initial infection.⁷ High-risks strains with the potential to lead to cancer or squamous intraepithelial lesions include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.³ The Canadian Cancer Society lists HPV as the fifth most preventable cause of cancer.⁸ However, this ranking likely underestimates the role of HPV in carcinogenesis since cutaneous SCCs, where HPV is recognized as a co-carcinogen, are not included in cancer statistics. Cutaneous SCCs and Basal Cell Carcinomas (BCCs), together called keratinocyte carcinomas, are the most common cancers with an estimated ~5.4 million new cases diagnosed every year in the United States alone.⁹

Notably, a high proportion of HPV-associated cancers are diagnosed in males.¹⁰ Since males are under-vaccinated and are increasingly disproportionately affected by certain HPV-associated cancers, namely oropharyngeal and penile cancers, current vaccination efforts should be refocused on male patients.^6,11-13 Effective vaccination protocols can help promote both physical health as well as mental health since male patients with HPV often encounter numerous psychosocial impacts secondary to their infection, namely depression, reduction in quality of life and sexual dysfunction.⁶

Male HPV Vaccination Statistics and Guidelines

HPV vaccination programs and guidelines have changed several times in the past decade, causing important gaps in vaccination rates between males vs. females. In 2007, the first Canadian vaccination program for school-aged females was implemented, and by 2010 all Canadian provinces had established vaccination programs for females.⁶ In Alberta, before the start of the vaccination program for school-aged males, 98.3% of vaccinated individuals were females.¹⁴ The first Canadian public vaccination program for males was launched in 2012, while national coverage for the vaccine was only established in 2017.⁶ In Ontario, even after the sex-neutral school vaccination programs were created, there was still a gap in HPV vaccination rates between males and females.⁶ Hence, most males remain unvaccinated for HPV, especially the middle age population, which is at risk of developing the aforementioned cancers in the future. One narrative review investigating reasons for suboptimal vaccination in males found that lack of information, the misconception that the virus only affects females, vaccine hesitancy, lack of recommendations from healthcare providers, costs and logistics all acted as barriers to vaccination.¹⁵

According to the National Advisory Committee on Immunization (NACI) of Canada, the HPV vaccine was previously only recommended for males ages 9 through 26 years to prevent anogenital warts and other HPV-associated cancers.¹⁶ However, now there is no age limit on receiving a quadrivalent or nonavalent HPV vaccine. While the vaccine before was not routinely recommended for males ages 27 to 45 years, the guidelines state that the vaccine may be administered to this age group if there is an ongoing risk of HPV exposure,⁶ for example, healthcare providers treating warts.¹⁷ Recent reports, however, strongly argued that this vaccine should be given to middle aged males.¹⁸ On the other hand, there is currently insufficient research to encourage HPV vaccination in males over 45 years of age.

Natural Immunity Post HPV Exposure in Males and Cancer Risks

There are important differences between males and females regarding their immune response to HPV. A study has shown that males are 4 to 10 times less likely to seroconvert after an HPV infection, regardless of the infected anatomic site.¹⁹ In fact, within 36 months after HPV DNA was detected as a result of an oral, anal or genital HPV infection (strains 6, 11, 16, 18), only 7.7% of men developed detectable serum HPV antibodies.¹⁹ In the same study, the seroconversion rate following a genital HPV 16 infection was only 4.1% in males compared to 60% in females.¹⁹ Further, the HPV in Men (HIM) study showed that healthy males do not have a reduced risk of subsequent HPV oral infection from natural HPV L1 antibodies (immunoglobulin G antibodies to the L1 capsid protein in serum) following an HPV infection, as it was previously thought.²⁰ Thus, these antibodies are not protective against future HPV infection and, unlike females, males are at risk of reinfection with the same HPV strain.²⁰ On the other hand, females’ existing antibodies confer partial immunity.¹⁹ As such, males acquire HPV infections at a steady rate.²¹ The prevalence of male genital HPV infections, which do not decrease with age (Figure 1), highlights the suboptimal natural immunity against HPV in males.

Importantly, in recent years the number of oropharyngeal SCC cancers has surpassed the number of cervical cancers caused by HPV. In fact, most of the oropharyngeal SCC cancer patients are males (Figure 2).²² Cervical cancer rates are declining, whereas oropharyngeal cancer rates in Canadian males are on the rise (Figure 3).¹² Anal cancer rates are also on the rise, while the incidence rates of penile and oral cancers, unfortunately, remain unchanged (Figure 3).^11-13

Some males are at a particularly higher risk for HPV-associated cancers. Males who have sex with males (MSM), especially MSM who have Human immunodeficiency virus (HIV), have higher rates of anal carcinoma.²³ Males who are solid organ transplant recipients also have higher rates of penile and anal cancer.²³ Additionally, there is currently no approved HPV DNA test for males in Canada.²⁴ In contrast, females who get a Pap test can be co-tested for HPV using a sample of cervical cells taken at the same visit.²⁵

Recommendations for Vaccinations Should Focus on Males and Health Care Professionals at Risk of HPV Exposure

Side Effects of Spironolactone

Taking into consideration the above important points, we recommend that all males at risk of exposure to HPV between the ages of 9 and 45 receive the vaccine. Sufficient data exists to update the current guidelines, which only recommend vaccination for males between the ages of 9 and 27.⁶ The recommended vaccine is HPV9 (GARDASIL^®9) a nonavalent vaccine that prevents HPV infections caused by strains 6, 11, 16, 18, 31, 33, 45, 52 and 58²⁶ and received in 2022 Health Canada approval for the prevention of oropharyngeal cancer and other head & neck cancers (along with the prevention of cervical, vulvar, vaginal and anal intraepithelial neoplasia) caused by HPV.²⁷ The nonavalent vaccine is preferred to the quadrivalent vaccine since it protects against a wider range of high-risk strains.²⁸

The effectiveness of the vaccine in males aged 27 to 45 is inferred from the efficiency data in females of the same age and by the immunogenicity data from the Mid-Adult-Aged Men (MAM) Trial.²⁹ The MAM Trial evaluating response to the quadrivalent vaccine showed a 100% seroconversion rate 6 months after vaccination in 150 males between the ages of 27 and 45.²⁸ Another study reported 95% seroconversion rate 28 weeks following the quadrivalent vaccine administered in males with HIV between the ages of 22 and 61.³⁰

The vaccine is also proven to be safe. In fact, a study demonstrating the safety profile of the quadrivalent HPV vaccine in adult men 27 to 45 years of age with HIV-1 found no grade 4 (life-threatening) or 5 (death) adverse events.²⁹ Most adverse events were of either mild or moderate intensity.²⁹ Given these promising results, the vaccine should be strongly recommended to unvaccinated males aged 27 to 45.

HPV Vaccination for Healthcare Professionals

HPV vaccination is also recommended to all physicians, nurses and residents in obstetrics and gynecology, oncology, dermatology and any staff that treat patients with warts.³¹ HPV DNA was found in the vapour of 62% and 57% of plantar warts treated with ablative laser and electrocautery, respectively.³² Normal non-lesioned skin was shown to contain in >60% of cases pathogenic HPV strains.³³ Hence, use of cautery on normal skin can too produce plume with HPV particles. This poses an occupational risk for dermatologists and other health care providers,¹⁷ which is why the vaccine is highly recommended in this group. In addition, reports indicate that (1) using local exhaust ventilation, (2) general room ventilation and (3) full personal protective equipment including a fit tested particulate respirator of at least N95 grade can decrease operator from HPV inhalation exposure.³⁴ Another study mentions that even though protective equipment, mainly gloves, can get contaminated with HPV, transmissions to medical professional is less likely to occur if the equipment is disposed of properly.³⁵

Conclusion

While the incidence of cervical cancer is decreasing in females, the incidence of oropharyngeal and other HPV-driven cancers is increasing at an alarming rate, especially in males. As such, vaccination efforts should be aimed at addressing this important public health concern. Males are significantly under-vaccinated compared to females and acquire HPV infections at a steady rate, with a very low rate of seroconversion following infection. Therefore, we advocate to provide routine vaccination against HPV in all males between the ages of 27 and 45, and continue to actively vaccinate males ages 9 to 26. Vaccines are effective, as shown by the high rate of post-vaccination seroconversion, which is an important factor in preventing oropharyngeal SCCs and other HPV-related cancers. Finally, it is crucial to routinely promote the HPV vaccination for all patients and healthcare professionals at risk of exposure to HPV, the same way we promote sun safety for all.

¹Virginia Tech Carilion School of Medicine; Roanoke, VA, USA
² Section of Dermatology and Mohs Surgery, Department of Internal Medicine, Carilion Clinic; Roanoke, VA, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract:
Human papillomavirus (HPV)-induced cutaneous disease is a common complaint for patients presenting for dermatology evaluation. Infection by HPV is the major etiologic factor in the development of cutaneous warts, epidermodysplasia verruciformis, and possibly a subset of cutaneous squamous cell carcinoma. Carcinoma of the genitourinary tract, most notably cervical carcinoma, is the most severe manifestation of infection with specific serotypes of HPV. For this reason, the HPV immunization (Gardasil) was developed in 2006 and upgraded in 2018 to a nonavalent formulation that includes serotypes 6, 11, 16, 18, 31, 33, 45, 52, 58. While immunization is highly effective at preventing infection with serotypes included in the formulation, it is less clear if the immunization can aid in managing active HPV infection. This review examines the available literature regarding the role of HPV immunization in managing common warts, genital warts, keratinocyte carcinoma, and epidermodysplasia verruciformis.

Key Words:
human papillomavirus, HPV, HPV immunization, Gardasil, Cervarix, common warts, verruca vulgaris, genital warts, condyloma acuminata, epidermodysplasia verruciformis, keratinocyte carcinoma, squamous cell carcinoma

Introduction

Human papilloma virus (HPV) is a non-enveloped, double-stranded circular DNA virus. Transmission usually occurs through skin-to-skin contact, but the virus can also be transmitted vertically and via fomites, such as transvaginal ultrasounds and colposcopes.¹ Over 100 HPV strains exist. HPV types 1, 2, 4, 7, 27, 57, and 65 frequently cause common, plantar, and flat warts,² while types 6 and 11 are the usual agents behind genital warts and recurrent respiratory papillomatosis.^3,4 The high-risk HPV types, 16 and 18, are responsible for the majority of HPV-induced carcinomas of the cervix, vagina, vulva, anus, rectum, penis, and oropharynx, with a minority caused by the less prevalent high-risk types (31, 33, 35, 45, 52, 58).^4-6 Other dermatologic conditions associated with HPV infection include keratinocyte carcinomas of the skin^7,8 and epidermodysplasia verruciformis (EV), which is caused by mutations that increase susceptibility to β-genus HPV strains.⁹

The first formulation of the HPV vaccine (quadrivalent Gardasil®), US FDA approved in 2006, covered types 6, 11, 16, and 18. The vaccine was designed mainly to aid in the prevention of cervical carcinomas, as reflected in its initial target population of female patients aged 9-26 years. Like other non-living vaccines, the immunization employed an adjuvant (aluminum hydroxide, 225 mg) that served to amplify the immune response. In 2009, a bivalent formulation (Cervarix®) that covered just serotypes 16 and 18 was approved by the FDA. Cervarix contains a proprietary adjuvant (3-O-desacyl-4 monophosphoryl lipid A [AS04]) that has increased potencycompared to aluminum hydroxide.¹⁰ Also in 2009, FDA approval was extended to include males between 9-26 years of age. Most recently, Gardasil upgraded to a nonavalent formulation that includes 9 serotypes (6, 11, 16, 18, 31, 33, 45, 52, 58) as well as an increase in adjuvant dose to 500 mg of aluminum hydroxide.¹¹ Additionally, approved coverage was expanded by the FDA in 2018 to include all individuals (from 9 years of age), male and female, up to 45 years old.

The effectiveness of HPV immunization in preventing HPV infection in naive individuals and subsequent cervical dysplasia and carcinoma is excellent and well-documented.^5,12 An interesting question that has arisen since widespread acceptance of the HPV immunization is what role does immunization play, if any, in the management of active HPV infection. Anecdotal reports and case series have described improvement or resolution of common and genital warts with administration of HPV vaccination, but conflicting reports documenting little to no benefit have also been published. This article provides a brief review of the literature exploring the potential utility of the HPV immunization in treating HPV-related dermatologic conditions.

Cutaneous Warts

Common, plantar, and flat warts are notoriously difficult to treat, many recurring or failing to regress with multiple treatment modalities.¹³ For this reason, additional treatments for recalcitrant warts would benefit patients and physicians. Nofal et al. published a study documenting their use of the bivalent HPV vaccine (Cervarix) in 44 patients with common warts who were randomly assigned to receive either standard Cervarix immunization (0, 1, and 6 months) or intralesional injection of Cervarix into the largest wart every 2 weeks until complete clearance or for a maximum of 6 sessions.¹³ Each participant had multiple, recalcitrant common warts that had been present for more than 2 years duration and failed to respond to at least 2 treatment modalities. Complete clearance was observed in 18 patients (81.8%) of the intralesional group and 14 patients (63.3%) of the intramuscular group; however, this was not statically significant. No recurrence was noted in the 6-month follow-up period. Additionally, a retrospective analysis of 30 patients documented complete clearance of common and plantar warts for 14 patients (46.67%) following administration of 3 doses of quadrivalent Gardasil.¹⁴ An additional 5 patients (16.67%) showed a partial response while 11 patients (36.67%) showed no response at all. Although the HPV strains most associated with common warts are not specifically targeted in the HPV vaccinations, the therapeutic effect is possibly due to antigenic similarity of the L1 capsid proteins across types or by nonspecific immune stimulation by the adjuvant contained within the formulation. The latter may partially explain the higher clearance rate observed with administration of Cervarix compared to Gardasil since a more potent adjuvant (AS04) is utilized in the Cervarix formulation.^5,13 Alternatively, the vaccine may alter the cytokine environment enhancing the native immune response.^4,13

Additional literature examining the role of HPV immunization in treating conventional warts is limited to case reports and small case series.^15-21 Abeck & Holst studied the effect of quadrivalent HPV immunization on 6 children with a 2-year history of recalcitrant extragenital warts.¹⁵ After the second dose, all but 1 child had complete resolution of warts, the sixth child was noted to respond after the third dose. A similarly designed study documented complete clearance of chronic verruca vulgaris in 4 patients following quadrivalent HPV administration intramuscularly.¹⁶ Moscato et al. described a single case of complete remission of plantar warts after 2 of 3 doses of the HPV quadrivalent vaccine. Interestingly, this patient also had genital condylomata, which did not regress following HPV vaccination.¹⁷ Kreuter et al. described an immunocompromised patient with disseminated cutaneous extragenital warts that significantly regressed starting 4 weeks after single dose of HPV quadrivalent vaccine with further regression noted 1 year after the third dose. This patient also had concurrent genital warts, which did not regress with treatment.¹⁸ Finally, a more recent case report described remarkable improvement of disseminated verruca vulgaris in an immunosuppressed patient after administration of the nonavalent formulation of Gardasil.¹⁹

Genital Warts

The quadrivalent and nonavalent formulations of the HPV immunization specifically cover serotypes 6 and 11, which are implicated in most genital warts. Large studies reporting significant efficacy of Gardasil or Cervarix for treatment of condyloma acuminatum are lacking. Lee at al. reported responses to quadrivalent Gardasil in a 44-year-old male with significant perianal condylomata recalcitrant to imiquimod therapy.²² Near complete resolution of perianal warts was observed 8 weeks after the first dose of quadrivalent Gardasil. Resolution was confirmed by biopsies and histologic analysis and there was no evidence of recurrence at his 3-month follow-up. In a more recent 2019 exploratory study, 10 patients with condyloma acuminata were treated with all 3 doses of quadrivalent Gardasil.²³ Of these 10 patients, 6 (60%) had a complete response, 1 (10%) had a partial response, and 3 (30%) did not respond at all.

Although few published case studies and small trials point to a possible benefit with administration of HPV immunization, larger trials with adequate control arms are necessary to better understand the extent of their effects.

Keratinocyte Carcinomas

Clinicians have long suspected HPV as having an etiologic role in the development of cutaneous squamous cell carcinoma (SCC). A meta-analysis by Wang et al. confirmed this association and suggested HPV may serve as a co-carcinogen in conjunction with other factors that increase the risk of cutaneous SCC.⁷ Nichols et al. examined the effect of quadrivalent Gardasil vaccination in 2 patients with a history of multiple keratinocyte carcinomas.⁸ Both patients were immunocompetent and received standard schedule HPV immunization with full skin examinations performed every 3 months during the study period. Each patient subsequently demonstrated a reduced rate in the development of new SCCs and basal cell carcinomas (BCC) compared to their baseline rates. Patient 1 experienced a decrease in SCC by 62.5% per year and a decrease in BCC incidence from 1 to 0 per year. Patient 2 experienced a decrease in SCC incidence by 66.5% per year and had a similar decrease in BCC incidence.⁸

Nichols et al. subsequently employed the 9-valent HPV vaccine in the treatment of an immunocompetent female in her 90s with numerous basaloid SCCs on her right leg.²⁴ The patient was treated with 2 intramuscular injections of nonavalent Gardasil (given 6 weeks apart) followed by intratumoral injection into 3 of the largest tumors. She subsequently received 3 additional intratumoral injections over the following 8 months. Clinical improvement in size and number of tumors was noted within 2 weeks of administration of the second intratumoral dose. Eleven months after the first intratumoral dose, the patient had no remaining SCCs and sustained clinical remission for at least 24 months.

Epidermodysplasia Verruciformis

Epidermodysplasia verruciformis (EV) is a rare autosomal recessive condition caused by mutations in the EVER1 and EVER2 genes on chromosome 17q25. These mutations confer increased susceptibility to certain β-HPV types, resulting in persistent infections.²⁵ There is also an acquired form of EV, which is seen in immunocompromised patients with a predisposing condition.^9,25,26 Ninety percent of patients with EV are identified as having chronic infection with HPV 5 and/or 8, and persistent infection of these and other β-HPV strains can lead to nonmelanoma skin cancers.^9,25 Maor et al. described the efficacy of quadrivalent Gardasil in the treatment of acquired EV in a 50-year-old female with medical immunosuppression following renal transplant.²⁶ Her EV had progressed despite initial treatment with topical tretinoin and imiquimod, as well as oral acitretin. Twenty-seven months after initial presentation, 3 doses of quadrivalent Gardasil were administered over a 6-month period. During this time, the patient continued tretinoin, imiquimod, and acitretin therapy. One month following the final Gardasil dose, the patient’s clinical disease was significantly improved and HPV DNA was negative by PCR of a skin swab. Although there are several confounding factors, this is the only report examining the use of HPV immunization for treatment for EV.

Conclusion

In conclusion, HPV vaccines (Gardasil and Cervarix) may indeed have a therapeutic role in patients who suffer from dermatologic conditions that are associated with various strains of HPV. Anecdotal reports and case series have described improvement or resolution of cutaneous lesions with administration of HPV immunization, but conflicting reports documenting little to no benefit have also been published. An additional, ancillary question is whether the improvement in HPV-related disease is solely due to immune sensitization to viral antigen or if nonspecific stimulation of the immune system by the vaccine adjuvant plays a role. While the studies cited in this review are suggestive of potential benefit, larger, randomized trials with matched control groups are the necessary next steps to confirm the utility of HPV immunization in managing common cutaneous conditions associated with HPV.

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¹Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:None reported
ABSTRACT

External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common sexually transmitted infection and cause significant impairments in patient quality of life and sexual well-being. Therapeutic options for EGWs can be provider assisted, but many patients opt for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher efficacy and lower recurrence rates compared to currently available patient-applied treatments. Therefore, sinecatechins 10% ointment presents an alternative self-administered topical treatment for EGWs.

Key Words:
catechins, condylomata acuminata, EGCG, epigallocatechin-3-gallate, genital warts, green tea extract, human papillomavirus, HPV, sinecatechins, Veregen, Polyphenon E

Introduction

It is estimated that 10-30% of the adult population in Canada is infected with human papilloma virus (HPV).¹ While high-risk strains of HPV cause various types of cancer, low-risk strains can cause condyloma acuminate, also known as external anogenital warts (EGWs). EGWs are highly contagious and are, therefore, one of the most common forms of sexually transmitted infections. The prevalence of EGWs in Canada is an estimated 1.8%, with an annual incidence rate of 154/100,000 for males and 120/100,000 for females.² Patients with EGWs present with one or several cauliflower-like growths on the genitals and/or anal regions and clinical appearance is often sufficient for a diagnosis. EGWs are associated with a significant burden of illness and considerable impairment of patients’ emotional and sexual well-being.³ Although up to 50% of untreated cases spontaneously regress at 6 months⁴, it is impossible to predict which lesions will regress, remain unchanged, or proliferate⁵; therefore it is recommended that treatment be offered to all patients with EGWs.

EGW treatment includes provider-assisted and patient-applied therapies or a combination of these modalities. Treatment can be categorized as ablative, antiproliferative, or immunomodulatory.⁶ CO2 laser, trichloroacetic acid, excision, cryotherapy, and electrocautery are ablative therapies that necessitate the assistance of a trained healthcare professional. Until recently, patient-applied therapies were either antiproliferative or immunomodulatory in nature. Podophyllin 10-25% and podophyllotoxin 0.5% are patient-applied antiproliferative agents, while imiquimod is an immunomodulatory agent that is available in both 5% and 3.75% formulations. Podophyllotoxin and imiquimod are considered the first choice among patient-applied treatment options;⁷ however, despite the greater ease and autonomy offered by patient-applied therapy, clearance rates with these treatments are lower than those achieved with physician-assisted options.⁸ Furthermore, lesion reappearance is common regardless of treatment choice as there is no way to eradicate the underlying viral infection.⁶

Sinecatechins ointment 10% (Veregen®), a new patient-applied treatment formulated from green tea (Camellia sinensis) extracts, has recently been licensed in Canada for the treatment of EGWs.⁹ Sinecatechins 10% ointment is comprised of >85% catechins, which are flavonoids responsible for the antioxidant effects of green tea. Sinecatechins 10% ointment contains eight different catechins, of which >55% is epigallocatechin-3-gallate (EGCG), the most abundant and potent catechins.¹⁰ Although the exact mechanisms of action of sinecatechins 10% ointment in regression of EGWs are currently unknown, they are likely multimodal, consisting of antiviral, pro-apoptotic and antiinflammatory responses.¹¹ The antiviral properties of EGCG may result from the inhibition of activator protein 1 (AP-1) transcriptional activity that effectively down-regulate expression of HPV genes. Transcription of anti-apoptotic HPV genes by the infected cell could be counteracted by EGCG directly activating pro-apoptotic proteins as well as upregulating and downregulating the expression of pro- and anti-apoptotic proteins, respectively, resulting in cell death.¹² EGCG also possesses anti-inflammatory activity by inducing anti-inflammatory interleukin (IL)-12 and reducing pro-inflammatory IL-10 activity. This would shift towards a T helper cell type 1 (Th1)-mediated immune response promoting the elimination of HPV-infected cells by the immune system. The various catechins and other molecular constituents of sinecatechins ointment likely work synergistically to modulate these complex biologic pathways to promote the regression of EGWs.¹⁰ Therefore, although the exact mechanisms of action of sinecatchins 10% ointment have not been fully elucidated, its efficacy in treating EGWs may be attributable to its antioxidant, antiproliferative, antiviral, and antitumor properties.¹¹

Clinical Efficacy

Gross et al. conducted a Phase II/III, randomized, double-blind trial to assess the efficacy and safety of two formulations of sinecatechins ointment for the treatment of EGW.¹³ Two hundred and forty-two participants (125 males, 117 females) with 2-30 warts (wart area of 12-600 mm²) were randomized to receive either sinecatechins 15% ointment, sinecatechins 10% cream, or placebo (two placebo arms pooled for analyses). Participants were instructed to apply their respective treatments three times a day for 12 weeks and those who achieved complete clearance at the end of 12 weeks were followed for an additional 12 weeks. Rates of complete clearance of baseline warts and of all warts (baseline and new) as well as recurrence rates for sinecatechins 10% cream and vehicle are displayed in Table 1. No significant differences between sinecatechins 10% cream and placebo groups were found.

The efficacy of sinecatechins 10% ointment in the treatment of EGWs was further assessed in two identically-designed, randomized, double-blind, Phase III trials,^14,15 the pooled results were also reported.¹⁶ A total of 1,005 participants (535 men and 470 women) with 2-30 EGWs and a lesion area of 12-600 mm² were allocated in a 2:2:1 ratio to receive sinecatechins 15% ointment, sinecatechins 10% ointment or vehicle. Treatment was applied at 8-hour intervals three times a day for 16 weeks or until complete resolution of all baseline warts was observed. Complete responders were followed for an additional 12 weeks. Phase III trial results are displayed in Table 1. Rates of complete clearance of all warts in both sinecatechins ointment groups were significantly superior to vehicle (Ps<0.001). Time to complete clearance was also shorter for participants treated with sinecatechins 15% and 10% ointment than those treated with vehicle (P<0.01). Median time to complete wart clearance in the two trials was 16 weeks and 10 weeks in the sinecatechins 15% and 10% ointment groups, respectively. In all studies, recurrence rates were low and complete clearance rates were higher in women than in men.

Safety and Adverse Events

No serious adverse events (AEs) were reported in the Phase II/III study.¹³ Only two participants in the sinecatechins 10% group had AEs considered possibly or probably related to the study drug and these included hyperkeratosis and skin discoloration. A number of local skin reactions were reported, but no significant differences in severe local reactions between active treatment groups and placebo were found. AE rates were also similar between treatment groups and vehicle in the Phase III trials.¹⁶ One patient in the sinecatechins 10% group developed severe pustular vulvovaginitis, which was considered related to study drug.¹⁴ Three patients in the other Phase III trial developed moderate lymphadenitis, moderate rash, and moderate phimosis, all were considered possibly related to the study medication.¹⁵ The overall incidence of any local reaction during treatment was higher in active treatment groups than vehicle (85.9% and 82.9% vs. 60.4%).¹⁶ Incidence of most common application-site reactions are presented in Table 2. In all studies, application-site reactions declined over the study period regardless of initial intensity. It has been suggested that local reactions such as erythema are associated with the release of pro-inflammatory cytokines; thus, patients should be advised that these signs may be indicative of clinical response and are correlated with higher clearance rates.¹⁵ Sinecatechins 10% ointment is contraindicated in individuals with a history of hypersensitivity to any of its components and treatment should be discontinued if hypersensitivity occurs.

Discussion

Sinecatechins 10% ointment was the first botanical drug approved by the US FDA and is now available in Canada for the treatment of EGWs. Although provider-assisted therapies have higher efficacy rates than patient-applied therapies, they are subject to the patient’s pain tolerance and aesthetic concerns, as some can cause considerable discomfort and/or result in scarring. Provider-assisted therapies are also dependent upon the doctors’ and patients’ schedules and patients may be hesitant to comply with repeat clinic visits because of the sensitive nature of this condition. Consequently, many patients opt for more convenient treatment that can be self-administered in the privacy and comfort of their home. Efficacy rates from the Phase III trials of sinecatechins 10% ointment are higher than those achieved with podophyllotoxin 0.5% or imiquimod 5% and 3.75%. However, it is recommended that sinecatechins 10% ointment be applied three times a day in comparison to thrice weekly application with imiquimod 5% and once daily application with imiquimod 3.75%. Therefore, patient adherence to the dosing regimen may need to be considered, as compliance is an important factor in achieving treatment effectiveness. Unlike other at-home treatments, it is not necessary to wash off the ointment prior to the next application. Sinecatechins 10% ointment has lower recurrence rates relative to other patient-applied therapies and is also the first EGW treatment to possess several disease-fighting mechanisms, such as anti-inflammatory, antiviral, and antiproliferative properties. Therefore, sinecatechins 10% ointment presents a botanically based alternative to currently available treatments for EGWs that offers a satisfactory balance of clearance rates, reduced frequency of lesion recurrence after successful treatment, and favorable adverse event profile.

References

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6. Vender R, Bourcier M, Bhatia N, et al. Therapeutic options for external genital warts. J Cutan Med Surg. 2013 Dec;17 Suppl 2:S61-7.
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9. Medigene press release. Medigene’s drug Veregen® receives market approval in Canada [Internet]. September 10, 2013. Available at: http://www.medigene.com/presse-investoren/news/pressemitteilungen/medigenes-drug-veregen-receives-market-approval-in-canada. Accessed November 24, 2014.
10. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin- 3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011 Dec 15;82(12):1807-21.
11. Veregren® (sinecatechins) ointment 10%
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    . Paladin Labs Inc., St-Laurent, QC. Revised October 28, 2014. Available at: http://www.paladin-labs.com/our_products/Veregen-PM-En.pdf. Accessed November 24, 2014.
12. Stockfleth E, Meyer T. The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. Expert Opin Biol Ther. 2012 Jun;12(6):783-93.
13. Gross G, Meyer KG, Pres H, et al. A randomized, double-blind, four-arm parallel-group, placebo-controlled Phase II/III study to investigate the clinical efficacy of two galenic formulations of Polyphenon E in the treatment of external genital warts. J Eur Acad Dermatol Venereol. 2007 Nov;21(10):1404-12.
14. Tatti S, Swinehart JM, Thielert C, et al. Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized controlled trial. Obstet Gynecol. 2008 Jun;111(6):1371-9.
15. Stockfleth E, Beti H, Orasan R, et al. Topical Polyphenon E in the treatment of external genital and perianal warts: a randomized controlled trial. Br J Dermatol. 2008 Jun;158(6):1329-38.
16. Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.

ABSTRACT

Imiquimod 3.75% cream has recently been approved by both the U.S. Federal Drug Administration and Health Canada for the treatment of external genital warts. Herein, we provide an overview of external genital warts, review the phase 3 clinical trials leading to the approval of imiquimod 3.75% cream, and compare its efficacy and clinical use with imiquimod 5% cream. Moreover, therapeutic options have further expanded with the relatively recent introduction of sinecatechins 15% ointment, an extract of green tea leaves.

Key Words:
condylomata acuminata, external genital warts, human papilloma virus, HPV, imiquimod, sinecatechins, sexually transmitted infection, STI, topical immunotherapy

External Genital Warts

External genital warts (EGW) have been reported to affect approximately 1.4 million people in the US.¹ More than a half a million new cases develop annually and 10% of all adults will have EGW in their lifetime.¹ The etiology of EGW has been clearly linked to infection with non-oncogenic strains (types 6 and 11) of the human papilloma virus (HPV) transmitted through sexual contact.¹

EGW commonly manifest on fully or partially keratinized skin, such as the penis, vulva, groin, perineum, and perianal areas.² While EGW can be asymptomatic, patients can experience pruritus, dyspareunia, and burning in the anogenital region. EGW can obstruct the urethral orifice and vagina, and impede normal activity. Additionally, large warts can cause obstruction of the anus and rectum.³

Besides physical pain and discomfort, EGW can cause complicated psychological morbidity. Since the disease targets areas of the genitalia and carries the psychosocial stigma of being a sexually transmitted infection, patients can experience a range of emotions, including anger, shame, depression, and low self-worth as potential partners.^4-6 Additionally, the disease can impact the sexual activity of affected individuals, either through actual physiologic pain (in cases of dyspareunia) or through abstinence due to either fear of transmitting to partners or embarrassment of the lesions.⁷ Finally, EGW induces anxiety over treatment efficacy^6,8 and/or recurrences,⁶ as well as the lesion’s potential to develop into a malignancy.⁶ The health and economic burden of EGW is significant, e.g., average number of care days per episode was approximately 96 in 2004.⁹ From 1999 to 2008 the average yearly number of initial physician office visits increased from 240,000 to 385,000.¹⁰

Although EGW spontaneously regresses 30%^2,3 of the time without treatment, there is no way to determine whether a specific lesion will regress, remain unchanged, or increase in size. Treatment should be offered to all patients with EGW resulting from unprotected sexual contact or ineffective prophylactic measures (e.g., condoms, abstinence, or HPV vaccine). Treatment options are available including surgical excision, destructive modalities (e.g., cryosurgery and laser ablation), and topically applied preparations. It is not uncommon for multiple modalities to be used (e.g., excision/destruction with imiquimod). It is outside the scope of this paper to present a cogent review of all therapies, the discussion will instead focus on topically applied imiquimod 3.75%, which received recent regulatory clearance for the treatment of EGW.

Topical Immunotherapy for EGW

Imiquimod 3.75% cream (Zyclara®) is US FDA approved for the treatment of external genital (EGW) and perianal warts – it is marketed in Canada under the trade name Vyloma™ for EGW and Zyclara® for actinic keratoses. Imiquimod, an imidazoquinoline heterocyclic amine, demonstrates antiviral and antitumor properties that are thought to stem, at least in part, from its ability to induce interferon-α as shown in animal studies.¹¹ Specifically, it is an agonist of Toll-like receptor-7 (TLR-7), a member of a pathogen-recognition receptor family.¹² Activation of TLR-7 ultimately enhances antigen-presenting cell activity, migration of Langerhans cells, and cytokine (IFN-α, TNF-α, and IL-1, 6, 8, 10, and 12) release.¹³ Upregulation of IFN-α, β, and γ and TNF-α has a strong association with EGW regression, as well as with a reduction in human papilloma virus DNA and mRNA.^13,14

Elicitation of these immunobiologic changes by imiquimod is not just theoretical. Imiquimod 3.75% was challenged in a clinical study against a vehicle control.¹² Study inclusion criteria required patients to be >12 years of age with 2 to 48 visually diagnosed lesions. The wart size was at least a 6 mm², measured by the two longest axes. The location of the warts included the penis, scrotum, vulva, and inguinal, perineal, or perianal regions. Assessment of treatment was based on number of warts, with a cluster of warts considered as 1 lesion. At each visit, the number of warts was tallied with no differentiation as to whether the lesion was a new growth or an older lesion that had decreased in size. The study was conducted for a maximum of 8 weeks or until complete clearance occurred. The primary endpoint of the study was complete clearance by the end of the study. Secondarily, the researchers observed the sustained complete clearance for a 12-week period. This latter parameter demanded the sustained complete clearance in all areas. Of notable mention, it is very possible that new warts arising very close to the end of the study may not have received any treatment. Resultantly, such patients would have failed to meet the primary endpoint of the study.¹²

Overall, the imiquimod 3.75% cream achieved 27% and 29% significant complete clearance in two different studies, compared with 10% and 9% complete clearance in the respective controls. Females, who for the most part exhibited better response over males, showed a significant complete clearance of 37% in the active treatment group compared to females in the vehicle control group, who demonstrated 14% complete clearance. In treated males, 19% achieved complete clearance as opposed to 4% of males in the control group. After a 12-week observation period of patients who had achieved complete clearance, 85% treated with imiquimod 3.75% cream remained clear.¹²

A recent study comparing imiquimod 3.75% with placebo in female EGW patients found similar results.¹⁵ The study group had a mean wart count of 8.7 with the total mean area of 166.3 mm². Patients receiving imiquimod treatment demonstrated superior clearance over placebo; the median time to clearance was 57 days for imiquimod 3.75% compared with 71 days for placebo. Some other interesting variables that may have contributed to a higher complete clearance rate for imiquimod therapy over placebo include non-white patients, ≤7 warts, total wart area ≤150 mm², diagnosis at ≤6 months, and first episode vs. recurrence. The researchers also looked at the ≥75% clearance and found that again imiquimod 3.75% exhibited greater efficacy compared with placebo. However, the sustained clearance during a 12-week follow up was only 60.4% in imiquimod-treated patients vs. 100% in placebo.

How does Zyclara® differ from Aldara®?

Imiquimod 5% cream (Aldara®) has been FDA approved for the treatment of EGW since 1997. While imiquimod 5% is efficacious for EGW treatment, it is associated with localized adverse effects, including erythema, pruritus, burning, and pain. The standard treatment course requires dosing at 3 times weekly for up to 16 weeks, which may discourage adherence to the regimen.¹⁶ Tolerance of burning and itching for close to 4 months in the anogenital areas can be challenging for patients to endure. A compounding complication is the cumbersome number of treatment days per week, potentially contributing to unintentional noncompliance due to forgetfulness, missed dosing, and confusion as to how to proceed when therapy deviates from the prescribed regimen. Treatment complexity can frustrate patients and contribute to premature termination of therapy. This thought process is confirmed by Murphy and Coster, who have noted that long treatment duration and adverse affects have been associated with decreased compliance.¹⁷ In addition, they suggest linking treatment times with daily habits as one of the strategies to increase compliance,¹⁷ which can be quite difficult if the regimen is 3 times per week.

Development of imiquimod 3.75% focused in part on increasing tolerability and simplifying the treatment regime. Investigation of the 3.75% formulation was undertaken with the intention of reducing the incidence and severity of local skin reactions commonly associated with imiquimod 5%. The total treatment period for imiquimod 3.75% is 8 weeks¹¹ as opposed to 16 weeks for imiquimod 5% cream.¹⁶ The significantly reduced treatment duration and simplified once-daily application offers a more intuitive dosing regimen that can enhance patient adherence.

Another favorable aspect of imiquimod 3.75% that may encourage treatment compliance is its improved tolerability profile as compared with the 5% formulation. In the phase 3 trials, pruritus only occurred in 3% of all imiquimod 3.75% treated patients and irritation was experienced by 6%.¹² Burning was not listed as an independent parameter.¹² Similarly, Baker et al. reported pruritus in 7.8% of treatment patients and irritation in 5.5%.¹⁵ To put these findings into perspective, in patients treated with imiquimod 5%, pruritus was reported by 32% of female patients and 22% of males; burning was experienced by 26% of female subjects and 9% of males.¹⁶ Therefore, imiquimod 3.75% not only shortens a course of therapy by half, but it also demonstrates increased tolerability and dosing simplicity, thereby encouraging treatment follow-through and optimizing outcomes.

Sinecatechins (Green Tea Extract)

It is appropriate to briefly mention sinecatechins 15% ointment (Veregen®), the first botanical drug product approved by the FDA for the treatment of external genital and perianal warts. It contains sinecatechins, including epigallocatechin gallate, derived from green tea leaves. Sinecatechins 15% ointment is applied 3 times a day for up to 16 weeks.¹⁸ Two randomized, double-blind, vehicle controlled studies of both men and women with EGW reported an overall clearance rate of 54.9%; after 6 weeks of therapy, statistically significant differences in clearance rates were observed in patients receiving active treatment.¹⁸ The 12-week sustained clearance was 93.5% of fully cleared patients. Interestingly, the comparator vehicle group showed a complete clearance rate of 35.4% and a sustained clearance rate of 94.2%.

Insights into the possible mechanism(s) of action of sinecatechins in treating EGW were recently presented.¹⁹ In vitro experiments indicated inhibition of matrix metalloproteinase 1, 2, 7, and 9, as well as 20S proteasome activity. In addition, significant suppression of human epidermal growth factor receptor (EGFR) kinase and partial inhibition of extracellular signal-regulated kinases ERK-1 and ERK-2 were also implicated. Furthermore, suppression of inflammatory mediators COX-1 and COX-2 and the lipoxygenase (LO) 12 and 15 proteins were detected. These pathways are involved in the pathogenesis of HPV infection and epidermal proliferation, thereby leading the author to reasonably conclude that these inhibitory activities confer immunostimulant, antiviral, and antitumor properties to sinecatechins that contribute to EGW clearance.¹⁹

Conclusion

In our opinion, imiquimod 3.75% (Zyclara®/Vyloma™) offers a more tolerable and simplified therapeutic option for EGW patients to adhere to therapy. In addition, the recent US regulatory approval of this agent in a pump dispenser further widens the dosing options (established forms consist of individual packets of Aldara® and generic 5% imiquimod cream), such a vehicle advance can facilitate ease of use, improve patient acceptability, and enhance compliance. A study determining the combined effectiveness of sequential cryotherapy followed by a course of imiquimod 3.75% is warranted, as in clinical practice many patients, if not most, are treated with both modalities.

References

1. Hsueh PR. Human papillomavirus, genital warts, and vaccines. J Microbiol Immunol Infect. 2009 Apr;42(2):101-6.
2. Wiley D, Masongsong E. Human papillomavirus: the burden of infection. Obstet Gynecol Surv. 2006 Jun;61(6 Suppl 1):S3-14.
3. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003 Sep;189(3 Suppl):S3-11.
4. Clarke P, Ebel C, Catotti DN, et al. The psychosocial impact of human papillomavirus infection: implications for health care providers. Int J STD AIDS. 1996 May-Jun;7(3):197-200.
5. Jeynes C, Chung MC, Challenor R. ‘Shame on you’–the psychosocial impact of genital warts. Int J STD AIDS. 2009 Aug;20(8):557-60.
6. Sheppard S, White M, Walzman M. Genital warts: just a nuisance? Genitourin Med. 1995 Jun;71(3):194-5.
7. Voog E, Lowhagen GB. Follow-up of men with genital papilloma virus infection. Psychosexual aspects. Acta Derm Venereol. 1992;72(3):185-6.
8. Persson G, Dahlof LG, Krantz I. Physical and psychological effects of anogenital warts on female patients. Sex Transm Dis. 1993 Jan-Feb;20(1):10-3.
9. Hoy T, Singhal PK, Willey VJ, et al. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009 Oct;25(10):2343-51.
10. Centers for Disease Control and Prevention. STD Surveillance 2008. Table 43. Selected STDs and complications – initial visits to physicians’ offices, National Disease and Therapeutic Index: United States, 1966-2008. Available at: http://www.cdc.gov/std/stats08/tables/43.htm. Accessed: February 28, 2012.
11. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol. 1998 Jan;134(1):25-30.
12. Zyclara® cream, 3.75% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2011.
13. Scott M, Nakagawa M, Moscicki AB. Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol. 2001 Mar;8(2):209-20.
14. Diamantis ML, Bartlett BL, Tyring SK. Safety, efficacy & recurrence rates of imiquimod cream 5% for treatment of anogenital warts. Skin Therapy Lett. 2009 Jun;14(5):1-3, 5.
15. Baker DA, Ferris DG, Martens MG, et al. Imiquimod 3.75% cream applied daily to treat anogenital warts: combined results from women in two randomized, placebo-controlled studies. Infect Dis Obstet Gynecol. 2011;2011:806105.
16. Aldara® cream, 5% [prescribing information]. Graceway Pharmaceuticals, LLC. Bristol, TN, 2010.
17. Murphy J, Coster G. Issues in patient compliance. Drugs. 1997 Dec;54(6):797- 800.
18. Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.
19. Tyring SK. Sinecatechins: effects on HPV-induced enzymes involved in inflammatory mediator generation. J Clin Aesthet Dermatol. 2012 Jan; 5(1):19-26.

Skin Therapy Letter uses reasonable efforts to include accurate and up-to-date information, we make no warranties or representations as to the accuracy, completeness, timeliness or reliability of the content and assume no liability or responsibility for any error or omission in the content.

¹Center for Clinical Studies, Houston, TX, USA
²University of Texas School of Medicine at San Antonio, San Antonio, TX, USA
³Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

ABSTRACT
Human papillomavirus (HPV) has a predilection for infecting epidermal and mucosal surfaces such as those of the anogenital region. HPV causes substantial pre-malignant, malignant, and benign disease in both women and men, ranging from cervical, vulvar, penile, and anal cancers to condyloma acuminata (genital warts). Although HPV vaccination is becoming more common, infection rates remain high in both genders. Perception of HPV vaccine has largely centered on its ability to prevent cervical cancer in women, though indication for its use in men is expanding. The benefits to men include prevention of genital warts and, more recently, regulatory approval was expanded in the US for prevention of anal cancer. Herein, we review HPV vaccine with a focus on its new indication in men and existing controversies.

Key Words:
cancer, HPV, human papillomavirus, vaccine, warts, Gardasil®, Cevarix®

Background

Genital human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the US.¹ An estimated 20 million Americans are currently infected, with 6.2 million new cases occurring each year in people 14-44 years of age. Seventy-four percent of new cases occur in persons aged 15-24 years, and it is suggested >80% of sexually active women will acquire genital HPV by age 50. The majority of infections are asymptomatic and self-limited; however, persistent HPV infection with an oncogenic type can cause cervical cancer. HPV infection is also common among men. Approximately 1 million American men have genital warts caused by HPV, with 2 of every 1,000 men newly diagnosed.²

More than 130 HPV types have been identified, with greater than 40 causing genital infection. Genital HPV is divided into two groups based on potential to cause cancer: high-risk or oncogenic types and low-risk or nononcogenic types. High-risk types (such as 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, and 73) can cause low-grade and high-grade cervical cell abnormalities as well as anogenital carcinoma. Together HPV-16 and 18 account for about 70% of cervical cancers.³

Low-risk types (mainly 6 and 11) cause most (90%) of the genital warts in males and females, recurrent respiratory papillomatosis, and nasopharyngeal papillomas, as well as low-grade disease of the cervix in women.²

HPV Vaccines

Two HPV vaccines are currently available in the US, quadrivalent (Gardasil®) and bivalent (Cevarix®) vaccines. The Food and Drug Administration (FDA) approved the quadrivalent vaccine in 2006 and bivalent vaccine in 2009.²

The quadrivalent vaccine is composed of four HPV type-specific virus-like particles (VLPs) prepared from the capsid protein of HPV-6, 11, 16, and 18 combined with aluminum adjuvant. This vaccine is recommended for females 9-26 years (in Canada the approved indication includes girls and women 9-45 years of age) and is administered intramuscularly according to a 3-dose schedule at 0, 2, and 6 months. The bivalent vaccine is composed of two VLPs of HPV-16 and 18 and is recommended for females 10-25 years through intramuscular injection according to a 3-dose schedule at 0, 1, and 6 months.^2,4

The efficacy of quadrivalent vaccine is well established. In a per-protocol analysis (two Phase III trials), vaccine efficacy was 100% (95% CI, 80.9-100) for prevention of HPV-16 or 18 related cervical intraepithelial neoplasia (CIN) grades 2/3. In Protocol 013, which included 5,442 females aged 16-23 years, vaccine efficacy was 100% (95% CI, 89.5-100) for prevention of any grade CIN related to the vaccine types. The three studies (Protocol 007, 013, and 015) demonstrated vaccine efficacy of 98.9% (95% CI, 93.7-100) for prevention of HPV-6, 11, 16, and 18 related genital warts and 100% (95% CI, 55.5-100) for prevention of HPV-16 or 18 related vulvar intraepithelial neoplasia (VIN) 2/3 or vaginal intraepithelial neoplasia (VaIN) 2/3.^5,6

The efficacy of bivalent vaccine is also well established. In a Phase III trial, which included 18,644 females aged 15-25 years, perprotocol cohort vaccine efficacy was 98.1% (96.1% CI, 88.4-100) for prevention of HPV-16 or 18 related CIN 2/3.⁷

New Indications

Although < 25% of all HPV-related cancers occur in men, specific groups, such as men who have sex with men, have significantly higher rates of HPV-related diseases, including anal cancer. HPV- 16 and 18 cause approximately 90% of anal cancers. Around 340,000 new cases of genital warts are reported in the US each year.⁸ In 2009, the FDA approved the quadrivalent vaccine for prevention of genital warts in young men. The Advisory Committee on Immunization Practices (ACIP) recommended permissive use but not routine use of the vaccine for males aged 9-26 years.⁹ More recently, regulatory approval was expanded in the US for prevention of anal cancer.

Recent data has demonstrated the quadrivalent vaccine to be effective in preventing anal intraepithelial neoplasia in males. A randomized, placebo-controlled, double-blind study conducted by Guiliano et al.¹⁰ included 4,065 males aged 16-26 years from 71 sites throughout 18 countries. Of these participants, 3,463 were heterosexual. At screening, subjects who had clinically detectable anogenital warts or genital lesions suggestive of existing HPV infection were excluded from the study. The participants were followed for 2.9 years.

Guiliano’s study showed prophylactic administration of quadrivalent vaccine to be efficacious in the prevention of genital lesions associated with HPV-6, 11, 16, and 18 in males aged 16-26 years. In the intention-to-treat population, vaccine efficacy was 65.5% (95% CI, 45.8-78.6) for prevention of vaccine type lesions and 60.2% (95% CI, 40.8-73.8) for prevention of any external genital lesion regardless of HPV type. When the per-protocol population was analyzed, vaccine efficacy for prevention of external genital lesions related to HPV-6, 11, 16, and 18 was 90.4% (95% CI, 69.2-98.1) and the efficacy against condyloma acuminata was 89.4% (95% CI, 65.5-97.9). No cases of PIN (penile, perianal, or perineal intraepithelial neoplasia) lesions were observed in the perprotocol vaccine group, however, this finding was not statistically significant in the study. Limitations of the study include the narrow age-range of the subjects and the relatively short followup period. Additionally, subjects had no more than five lifetime sexual partners, which could result in overrepresentation of subjects with a low likelihood of HPV exposure at baseline and subsequent exposure.¹⁰

Controversies

Several questions have arisen concerning the use of HPV vaccine in females, which have further expanded with approval of the vaccine for males.

Will the vaccine prevent not only genital lesions, but also cervical and anal cancer and ultimately death?
An answer to this question will likely depend on decades of observation. However, benefits of the quadrivalent and bivalent vaccines have been consistently reported. HPV vaccine also has other early benefits. As reported in end-of-study data from Phase IIB and Phase III (FUTURE I and II) trials, vaccination in the negative to 14 HPV types population reduced the proportion of women who experienced a cervical therapy by 42% (95% CI, 28-54), which may reduce adverse pregnancy outcomes related to these procedures.¹¹ HPV vaccine may also reduce the number of preterm deliveries due to cervical therapies.¹²

The probability of infection with HPV-6, 11, 16, and 18 in young women pre-sexual debut is very low, however, almost all women will come into contact with at least one type with only 0-4 sexual partners, thus, almost all young women may benefit from the vaccine. Studies have also shown that in women with evidence of current infection with at least one HPV vaccine type, quadrivalent vaccine may prevent disease caused by the remaining nonexposed vaccine types. Further, in women with cleared infections by an HPV vaccine type, quadrivalent vaccine has been shown to prevent recurrent disease caused by the same type.^13,14

Australia is the first country to mount a fully funded HPV immunization program for all females 12-26 years of age. Within the first two years the country witnessed a 59% (95% CI, 54-61) reduction in genital warts in this age group of females, with the proportion of women diagnosed declining from 11.7% to 4.8%. In heterosexual males aged 12-26 years, a 39% (95% CI, 33-46) reduction in men diagnosed with genital warts from 17.3% to 10.5% was observed within the same two-year period. This finding in men is suggestive of herd immunity attributable to reduced exposure to HPV in vaccinated women.¹⁵

How long will protection conferred by the vaccine last?
Antibody titers reach their peak after the third dose, then decline gradually until month 24 and remain higher than those naturally infected. Phase IIB trials showed complete protection for the monovalent HPV-16 vaccine after 9.5 years, 6.4 years for the bivalent vaccine, and 4 years for the quadrivalent vaccine.¹⁶ HPV vaccine follow-up continues, with recent data indicating a rapid and strong anamnestic response induced by a fourth dose of HPV vaccine 6.8 years after the initial 3-dose vaccination course; all subjects demonstrated an approximate eight-fold increase in HPV-16 and 18 antibody titers 7 days after the fourth dose and a >16-fold increase after 1 month.¹⁷

Since most HPV infections are easily cleared by the immune system, how will vaccination affect natural immunity against HPV, and with what implications?
Although most HPV infections are easily cleared by the immune system, interim lesions represent a substantial burden on the health care system and can cause psychosexual distress in patients. As well, persistent infections have significant implications as a cause of cervical cancer. Antibody response to HPV, in general, is specific for the HPV type; however, cross-reactivity has been noted. Recent studies suggest that the quadrivalent vaccine may also provide cross-protection against HPV strains not contained in the vaccine, but are closely related.^18,19 Notwithstanding, the durability of immunity and the importance of these findings remain to be established.

Will type replacement be seen?
With the introduction of HPV vaccines, “type replacement” is a concern. Type replacement is a viral population dynamics phenomenon defined as elimination of some types causing an increase of others. It occurs when partial competition exists among different types during natural infection and the vaccine does not provide cross-protection against competing types. In HPV, natural competition does not appear to exist, therefore type replacement is unlikely.⁴

How will the vaccine affect other oncogenic strains of HPV?
There is risk of change in population dynamics for existing HPV types and viral mutations may occur to generate new variants that are equally oncogenic but not recognized by vaccine-induced antibodies. However, HPV uses host cell DNA polymerases, and thus, has a very slow mutation rate, suggesting this risk is very low.⁴

How will vaccination affect screening practices?
Cytological screening practices should not be modified since the endpoint of the vaccine (cervical cancer) may take decades before incidence change can be measured. It has been suggested by HPV vaccine biologic models that the vaccine may increase the screening intervals.⁴ Positive predictive value will drop, making viral testing more appealing.

Other Vaccine Benefits

All HPV lesions, including genital warts, are associated with significant physical and psychological morbidity, high treatment failure and recurrence rates, as well as substantial cost.

The incidence of HPV infection is similar among both males and females, however, prevalence of infections is higher in males. Differences in immune response to HPV between genders have been described. A US study found HPV-seropositivity was higher in females than males (17.9% vs. 7.9%, respectively).²⁰ The higher prevalence of HPV infections in men may be explained in part by the lower immune response to natural infection.

The ACIP recommends routine vaccination of females aged 11-12 years (the vaccination series may be started as early as 9 years) and catch-up vaccination for females aged 13-26 years. Similarly, the European Centre for Disease Control and Prevention recommends that the primary target population for HPV vaccination should be young girls before they become sexually active, with catch-up vaccination administered in older girls and young women. These measures will likely accelerate the public health impact of vaccination while also increasing short-term benefits.

Conclusion

HPV vaccination represents an important approach in cancercontrol strategies aimed at reducing the global incidence of cervical cancer. Routine vaccination of girls is already recommended and catch-up immunization programs have also been instituted for older girls not yet vaccinated in order to complete the schedule. The increasing prevalence of HPVrelated cancers in males coupled with a lack of anal cancer screening underscores the importance of routine vaccination of boys, not only to benefit the boys themselves but also to reduce transmission to unvaccinated girls, thus further widening the impact of HPV vaccination.

References

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3. Monsonego J, Cortes J, Greppe C, et al. Benefits of vaccinating young adult women with a prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) vaccine. Vaccine 28(51):8065-72 (2010 Nov).
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5. Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila) 2(10):868-78 (2009 Oct).
6. Munoz N, Manalastas R, Jr., Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet 373(9679):1949-57 (2009 Jun).
7. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)- 16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374(9686):301-14 (2009 Jul).
8. Barroso LF, 2nd, Wilkin T. Human papillomavirus vaccination in males: the state of the science. Curr Infect Dis Rep 13(2):175-81 (2011 Apr).
9. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention 2010.
10. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 364(5):401-11 (2011 Feb).
11. Munoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst 102(5):325-39 (2010 Mar).
12. Sjoborg KD, Eskild A. Vaccination against human papillomavirus–an impact on preterm delivery? Estimations based on literature review. Acta Obstet Gynecol Scand 88(3):255-60 (2009).
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14. Olsson SE, Kjaer SK, Sigurdsson K, et al. Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection. Hum Vaccin 5(10):696-704 (2009 Oct).
15. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis 11(1):39-44 (2011 Jan).
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