Key Publications External Genital Warts

External Genital Warts Publications

External Genital Warts Background

External Genital Warts Epidemiology and Quality of Life Impact

  • Impact of human papillomavirus-related genital diseases on quality of life and psychosocial wellbeing: results of an observational, health-related quality of life study in the UK. Dominiak-Felden G, Cohet C, Atrux-Tallau S, et al. BMC Public Health. 2013 Nov 12;13:1065.
  • Background: Data on the psychosocial burden of human papillomavirus (HPV)-related diseases other than cervical cancer are scarce. The objectives of this study were to measure and compare the psychosocial burden and the impact on health-related quality of life (HRQoL) of HPV-related lower genital tract diseases and genital warts (GW) using several generic and disease-specific instruments.
  • Methods: Overall, 842 individuals with normal cervical cytology (n = 241), borderline nuclear abnormalities and/or mild dyskaryosis (n = 23), cervical intraepithelial neoplasia (CIN)1 (n = 84), CIN2/3 (n = 203), vulval intraepithelial neoplasia (VIN)2/3 (n = 43), GW (n = 186) and a history of GW (non-current) (n = 62) were included. The generic European Quality of Life Index Version 5D (EQ-5D) questionnaire was completed by patients with GW and VIN2/3. Sexual functioning was evaluated using the Change in Sexual Functioning Questionnaire (CSFQ). Psychosocial impact was measured in women using the HPV Impact Profile (HIP) questionnaire. HRQoL was assessed using a GW-specific questionnaire, the Cuestionario Especifico en Condilomas Acuminados (CECA) (completed by patients with GW and history of GW). For each instrument, scores were compared between groups using the Student’s t-test. In addition, utility loss due to GW and VIN2/3 was evaluated by comparing mean EQ-5D scores weighted by age and sex with the UK general population normal values.
  • Results: A significant psychosocial impact was found in women diagnosed with HPV-related genital diseases, particularly in those with GW. The health state of younger adults with GW was significantly impaired compared with UK normal values (mean EQ-5D index score 0.86 vs 0.94, p < 0.001 for 18-24-year-olds; 0.87 vs 0.93, p = 0.030 for 25-34-year-olds). VIN2/3 was found to have a significant negative impact on sexual functioning, and women with VIN2/3 had a highly impaired health state compared with women in the UK general population (weighted mean EQ-5D index score 0.72 vs 0.89, p < 0.001; weighted mean Visual Analogue Scale score 62 vs 85, p < 0.001).
  • Conclusions: HPV-related lower genital tract lesions and GW significantly impair psychosocial wellbeing and HRQoL. The psychosocial aspects of HPV-related diseases need to be considered when evaluating the potential benefit of HPV vaccination.
  • Economic and Humanistic Burden of External Genital Warts. Raymakers AJ, Sadatsafavi M, Marra F, et al. Pharmacoeconomics. 2012 Jan;30(1):1-16.
  • External genital warts (EGW) are a sexually transmitted infection caused by various strains of human papillomavirus (HPV). Several studies have described the direct and indirect costs of EGW, while others have reported on the burden of EGW in terms of the impact on the quality of life (QOL) of patients. The arrival of a quadrivalent HPV vaccine that protects against both cervical cancer and EGW requires a proper understanding of the impact of vaccines on costs and QOL. Using pre-defined search terms and inclusion/exclusion criteria, we performed a systematic review of the economic and humanistic burden of EGW. The focus of our review was on literature describing the direct and indirect costs of EGW per episode of care (EoC) or per year, as well as the impact of EGW on disease-specific, generic, or preference-based QOL measures. We also reviewed the literature on the national economic burden of EGW from the perspectives of different countries. Other aspects of EGW management that can inform economic modelling studies, such as length of EoC, number of physician visits and indirect costs, were also explored. Our review sheds light on the high economic and humanistic burden of EGW and important differences in the costs between men and women, as well as the differences in health resource utilization and costs across countries. Our study also highlights the dearth of information on the impact of EGW on the QOL and productivity of patients.
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  • Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. Park IU, Introcaso C, Dunne EF. Clinical Infectious Diseases. 2015 Dec;61(8) S849–S855.
  • To provide updates for the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines on human papillomavirus (HPV) and anogenital warts (AGWs), a review of the literature was conducted in key topic areas: epidemiology and burden of disease; transmission and natural history; diagnosis and management of AGWs; occupational exposure of healthcare workers; anal cancer screening among men who have sex with men (MSM); and HPV vaccine recommendations. Most sexually active persons will have detectable HPV at least once in their lifetime; 14 million persons are infected annually, and 79 million persons have prevalent infection. HPV is transmitted frequently between partners; more frequent transmission has been reported from females to males than from males to females. A new formulation of imiquimod (3.75% cream) is recommended for AGW treatment. Appropriate infection control, including performing laser or electrocautery in ventilated rooms using standard precautions, is recommended to prevent possible transmission to healthcare workers who treat anogenital warts, oral warts, and anogenital intraepithelial neoplasias (eg, cervical intraepithelial neoplasia). Data are insufficient to recommend routine anal cancer screening with anal cytology in persons living with human immunodeficiency virus (HIV)/AIDS or HIV-negative MSM. An annual digital anorectal examination may be useful for early detection of anal cancer in these populations. HPV vaccine is recommended routinely for 11- or 12-year-olds, as well as for young men through age 21 years and young women through age 26 years who have not previously been vaccinated. HPV vaccine is also recommended for MSM, people living with HIV/AIDS, and immunocompromised persons through age 26 years.
  • Trends in the Prevalence of Anogenital Warts Among Patients at Sexually Transmitted Disease Clinics—Sexually Transmitted Disease Surveillance Network, United States, 2010–2016. Mann LM, Llata E, Flagg EW, et al. Journal of Infectious Disease. 2019;219:1389–97.
  • Background. Approximately 90% of genital warts are caused by human papillomavirus (HPV) types 6 and 11. In the United States, HPV vaccination has been recommended for girls and women aged ≤26  years, and since 2011, for boys and men aged ≤21 years and for gay, bisexual, and other men who have sex with men (MSM) aged ≤26 years.
  • Methods. Data were obtained from 27 clinics participating in the STD Surveillance Network. Trends in the annual prevalence of anogenital warts (AGW) from 2010–2016 were described by sex and by the sex of sex partners.
  • Results. During 2010–2016, significant declines in the prevalence of AGW were observed in women aged <40  years, men who have sex with women only (MSW) aged <40  years, and MSM of all age categories. An inflection in trend in 2012 was noted for MSW aged 20–24 or 25–29 years and for MSM aged 20–24 years.
  • Conclusions. The observed declines in the prevalence of AGW suggest that HPV morbidity is declining among populations attending STD clinics, including MSW, MSM, and women. Declines in younger age groups are consistent with what would be expected following the implementation of HPV vaccination. However, declines were also observed in older age groups and are not likely to be the result of vaccination.
  • Systematic review of the incidence and prevalence of genital warts. Patel H, Wagner M, Singhal P, et al. BMC Infectious Diseases. 2013,13:39.
  • Background: Anogenital warts (AGWs) are a common, highly infectious disease caused by the human papillomavirus (HPV), whose high recurrence rates contribute to direct medical costs, productivity loss and increased psychosocial impact. Because of the lack of a systematic review of the epidemiology of AGWs in the literature, this study reviewed the published medical literature on the incidence and prevalence of AGWs.
  • Methods: A comprehensive literature search was performed on the worldwide incidence and prevalence of AGWs between 2001 and 2012 using the PubMed and EMBASE databases. An additional screening of abstracts from relevant sexual health and infectious disease conferences from 2009 to 2011 was also conducted. Only original studies with general adult populations (i.e., at least including ages 20 through 40 years) were included.
  • Results: The overall (females and males combined) reported annual incidence of any AGWs (including new and recurrent) ranged from 160 to 289 per 100,000, with a median of 194.5 per 100,000. New AGW incidence rates among males ranged from 103 to 168 per 100,000, with a median of 137 per 100,000 and among females from 76 to 191 per 100,000, with a median of 120.5 per 100,000 per annum. The reported incidence of recurrent AGWs was as high as 110 per 100,000 among females and 163 per 100,000 among males. Incidence peaked before 24 years of age in females and between 25 and 29 years of age among males. The overall prevalence of AGWs based on retrospective administrative databases or medical chart reviews or prospectively collected physician reports ranged from 0.13% to 0.56%, whereas it ranged from 0.2% to 5.1% based on genital examinations.
  • Conclusions: The literature suggests that AGWs are widespread and the prevalence depends on study methodology as suggested by higher rates reported from routine genital examinations versus those from treatment records. However, there remains a need for more population-based studies from certain regions including Africa, Latin America and Southern Asia to further elucidate the global epidemiology of this disease.

External Genital Warts Pathology and Risk of Malignancy

  • Risk factors for and prevention of human papillomaviruses (HPV), genital warts and cervical cancer. Chelimoa C, Wouldesb TA, Cameron LD, et al. J Infect. 2013 Mar;66(3):207-17.
  • Genital HPV infection is associated with development of cervical cancer, cervical neoplasia, anogenital warts, and other anogenital cancers. A number of reviews have primarily addressed the role of HPV infection in cervical carcinogenesis, and differences in human papillomavirus (HPV) subtypes found in cervical cancer cases by histology and geographical region. This review provides an informative summary of the broad body of literature on the burden of HPV, the risk factors for HPV infection, genital warts and cervical cancer, and preventive measures against these conditions in females. Studies have identified the main risk factors for genital HPV infection in females as follows: acquisition of new male partners; an increasing number of lifetime sexual partners both in females and their male partners; and having non-monogamous male partners. Cervical cancer screening and HPV vaccination are the primary measures currently recommended to prevent cervical cancer. There is also an ongoing debate and conflicting findings on whether male circumcision and condom use protect against HPV infection and subsequent development of HPV-related illnesses in females.
  • Risk of cancer in patients with genital warts: A nationwide, population-based cohort study in Taiwan. Cho CY, Lo YC, Hung MC, et al. (2017) PLOS ONE 12(8): e0183183.
  • Background: Condyloma acuminata currently affects around 1% of sexually active adults, and its incidence is increasing. The coexistence of genital warts (GW) and certain cancers and an association between human papillomavirus (HPV) and various malignancies have been reported. Therefore, we conducted this large national study to analyze the risk of malignancies among men and women with GW in Taiwan.
  • Methods and findings: Between January 2000 and December 2013, approximately 3 million patients were reported to the National Health Insurance Research Database of Taiwan. Of these patients, 21,763 were diagnosed with GW. In the same time period, a total of 213,541 cancer cases were reported to the registry, of which 1002 were recorded among patients with GW. The age-specific incidence rates of GW and standardized incidence ratios (SIRs) of malignancies compared to the general population were calculated. Women acquired GW earlier than men, with a mean age at diagnosis of 32.63±12.78 years. The highest incidence rate for both genders peaked at 20–29 years. Of the 1002 patients with GW and malignancies, the SIR was 1.95 (95%CI 1.83–2.07). The most markedly increased risk was found for HPV-related cancers, with a SIR of 9.74 (95%CI 3.70–15.77). Significantly elevated risks were also noted for smoking-related cancers, anogenital cancers, cervix in situ, colon, rectum, lung, kidney, and prostate cancers. Most cancers developed within 10 years after the diagnosis of GW.
  • Conclusions: Patients with GW have an increased risk of HPV-related cancers, especially anogenital malignancies in Taiwan. The elevated risk of other cancers highlights differences in exposure and risk factors among patients with GW compared to the general population. Cancer screening and HPV vaccination programs should be emphasized for at-risk patients.
  • Condylomata Acuminata (Anogenital Warts) Contain Accumulations of HIV-1 Target Cells That May Provide Portals for HIV Transmission. Pudney J, Wangu Z, Panther L, et al. J Infect Dis. 2019;219(2):275-283.
  • Background: Condylomata acuminata (anogenital warts [AGWs]) are prevalent in human immunodeficiency virus (HIV)–infected individuals and sexually active populations at risk for HIV acquisition and have been associated with HIV transmission. We compared AGW specimens to control tissue specimens for abundance, types, and location of HIV target cells and for susceptibility to HIV infection in vitro, to provide biologic evidence that AGWs facilitate HIV transmission.
  • Methods: We used immunohistologic staining to identify HIV target cells in AGW and control specimens. We also inoculated HIV in vitro into AGW and control specimens from HIV-negative men and assessed infection by means of TZM-bl and p24 assays.
  • Results: CD1a+ dendritic cells, CD4+ T cells, and macrophages were significantly more abundant in the epidermis of AGW specimens than control specimens. These HIV target cells also often appeared in large focal accumulations in the dermis of AGW specimens. Two of 8 AGW specimens versus 0 of 8 control specimens showed robust infection with HIV in vitro.
  • Conclusions: Compared with normal skin, AGWs contain significantly higher concentrations of HIV target cells that may be susceptible to HIV infection. Condylomata may thus promote HIV transmission, especially in the setting of typical lesion vascularity and friability. Prevention or treatment of AGWs may decrease the sexual transmission of HIV.

Current Management of Genital Warts

  • Update on the treatment of genital warts. Scheinfeld, N. Dermatol Online J. 2013 Jun 15;19(6):18559.
  • This review summarizes new treatments from the last seven years employed for the treatment of genital warts caused by human papillomavirus (HPV). Imiquimod 3.75%is a new agent with fewer side effects and perhaps a better dosing schedule than imquimod 5%, but is not more effective. Sinecatechins/Polyphenon E 15%, a novel extract from green tea can be effective against genital warts but requires three times a day dosing and is not more effective than existing treatments; the treatment course is 12-16 weeks. Photodynamic therapy combined with other destructive modalities might increase the cure rate for genital warts.  The quadrivalent vaccine against HPV 6, 11, 16, 18 is decreasing the incidence of warts in the western world but the evidence does not support vaccination as a treatment for those already infected by HPV. Hyperthermia and immunomodulators might be positive additions to the armamentarium of clinicians.  In sum, there are new tools that physicians can use but none is really a great advance over what was available a decade ago.
  • Genital warts: a comprehensive review. Yanofsky VR, Patel RV, Goldenberg G. J Clin Aesthet Dermatol. 2012 Jun;5(6):25-36.
  • External genital warts, also known as condylomata acuminata, are extremely common, with between 500,000 to one million new cases diagnosed each year in the United States alone. To date, more than 120 distinct subtypes of human papillomavirus have been identified. Human papillomavirus types 6 and 11 rarely give rise to cervical cancers, but are responsible for 90 percent of the cases of genital warts. The current treatment options are largely centered upon removal of the warts rather than elimination of the underlying viral infection. A wide range of therapies are presently in use, which are highly variable and can differ dramatically with respect to cost, side-effect profiles, dosing schedules, duration of treatment, and overall effectiveness. As of yet, no definitive therapy has emerged as the ideal standard of care in the treatment of genital warts, and therapy selection generally occurs in a patient-specific manner.
  • Infections after photodynamic therapy in Condyloma acuminatum patients: incidence and management. Yu X, Zheng H. Environ Sci Pollut Res Int. 2018 May;25(14):14000-14005.
  • Condyloma acuminatum (CA), or genital wart, is a sexually transmitted infection caused by human papillomaviruses. Increasing evidences demonstrated that photodynamic therapy (PDT) is effective in eliminating latent HPV infection, the major reason for CA recurrence. We observed an increasing number of infections after PDT in CA patients, which has not been reported before. This study aims to evaluate the incidence and management of infection in CA patients after PDT procedure. CA patients received PDT from January 2015 to February 2016 at the outpatient setting. Patients were randomly divided into two groups: the control group and fusidic acid group. Patients in the fusidic acid group used topical fusidic acid (2%) and recombinant human interferon after 5-aminolevulinic acid (ALA)-PDT procedure, while patients in the control group only used recombinant human interferon. Patients came to our department for follow-up evaluations at 4, 8, and 12 weeks after treatment for three times of PDT. Patients with ALA-PDT-associated infection were then randomly divided into two groups: the fusidic acid group and mupirocin group. During the 13-month study period, a total of 718 patients with 2154 times of PDT procedures were enrolled. The infection rate after PDT was 8.5% in the control group, while it was 1.1% in the prophylactic topical fusidic acid group. The cure rate of PDT-associated infection was 85.7% in the fusidic acid group and 86.7% in the mupirocin group. In conclusion, prophylactic topical antibiotic was useful for reduction of PDT-associated infection and optimal wound healing in CA patients.
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Use of VP-102 for External Genital Warts*

Phase 2 Safety and Efficacy of VP-102, a Drug-Device Combination Product Containing Cantharidin (0.7% w/v), for the Treatment of External Genital Warts (CARE-1).  Guenthner S, McFalda W, Tate M, et al. Winter Clinical Dermatology Symposium 2021

  • Background: External genital warts (EGW) are caused by the human papilloma virus, which is spread through direct skin-to-skin contact. Approximately 1% of people in the US have genital warts.  Cantharidin has been used to treat EGW for decades, however there are no FDA-approved cantharidin products and no reliable or controlled source of cantharidin available.
  • Objective: VP-102 is a drug-device combination product that contains cantharidin (0.7% w/v). The primary objective of this Phase 2 study was to determine the optimal exposure duration for treatment, as well as the safety and efficacy of VP-102 in the treatment of EGW compared to vehicle.
  • Methods: This Phase 2, randomized, double-blind, vehicle-controlled trial included two parts (A and B). Participants in study Part A (dose regimen finding) were randomized in a 5:1 ratio to receive either a 2-hour, 6-hour, or 24-hour exposure duration of VP-102 or vehicle. Participants in Part B received VP-102 or vehicle in a 3:2 ratio with a 6- or 24-hour exposure duration.  Study drug application occurred to any existing EGW every 21±4 days until complete clearance, or a maximum of 4 applications. Study drug was applied and covered with 3M® Dermablend surgical tape and removed at the designated exposure group time.  An end of treatment (EOT) visit occurred at Day 84.  Efficacy was measured by the percentage of subjects with complete clearance of all baseline and new treatable EGW at EOT.  Safety was measured by incidence of adverse events (AEs) including local skin reactions (LSRs). Data for Part A and B were pooled for each individual treatment and exposure duration for safety and efficacy outcomes.
  • Results: Subjects presented with a mean wart count of 8.2 with a range of 2 to 30 EGW at baseline. Approximately 50% of subjects had EGW for one year or longer; with approximately 23% of subjects having EGW for more than five years. Pooled results from the 6- or 24-hour VP-102 treatment exposure groups showed 36.7% and 33.3% of subjects achieved complete clearance of all treatable EGW at Day 84 compared to 4.5% (P<0.05) and 0% (P<0.01) of subjects treated with vehicle.  AEs experienced by the VP-102 treated subjects were consistent with the pharmacodynamic action of cantharidin as a vesicant. These side effects were primarily mild-to-moderate.  The most common side effects included application site vesicles, pain and erythema. No subjects discontinued from the study due to adverse events and there were no serious adverse events reported that were deemed related to treatment by the investigator.
  • Conclusions: Treatment of EGW with VP-102 resulted in statistically significantly higher complete clearance of all EGW at the end of study visit compared to vehicle. VP-102 was well-tolerated and safety outcomes were consistent with the pharmacokinetic action of cantharidin as a vesicant.
*VP-102 has not been approved by the FDA.