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.
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.
human papillomavirus, HPV, HPV immunization, Gardasil, Cervarix, common warts, verruca vulgaris, genital warts, condyloma acuminata, epidermodysplasia verruciformis, keratinocyte carcinoma, squamous cell carcinoma
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 skin7,8 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.
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
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.
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 (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.
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.
- Sabeena S, Bhat P, Kamath V, et al. Possible non-sexual modes of transmission of human papilloma virus. J Obstet Gynaecol Res. 2017 Mar;43(3):429-35.
- Vinzon SE, Rosl F. HPV vaccination for prevention of skin cancer. Hum Vaccin Immunother. 2015 11(2):353-7.
- Chirila M, Bolboaca SD. Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis. Eur Arch Otorhinolaryngol. 2014 May;271(5):1135-42.
- Nakagawa M, Greenfield W, Moerman-Herzog A, et al. Cross-reactivity, epitope spreading, and de novo immune stimulation are possible mechanisms of cross-protection of nonvaccine human papillomavirus (HPV) types in recipients of HPV therapeutic vaccines. Clin Vaccine Immunol. 2015 Jul;22(7):679-87.
- Harper DM, DeMars LR. HPV vaccines – a review of the first decade. Gynecol Oncol. 2017 Jul;146(1):196-204.
- Chabeda A, Yanez RJR, Lamprecht R, et al. Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Res. 2018 Jun;5:46-58.
- Wang J, Aldabagh B, Yu J, et al. Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta-analysis. J Am Acad Dermatol. 2014 Apr;70(4):621-9.
- Nichols AJ, Allen AH, Shareef S, et al. Association of human papillomavirus vaccine with the development of keratinocyte carcinomas. JAMA Dermatol. 2017 Jun 1;153(6):571-4.
- Jacobelli S, Laude H, Carlotti A, et al. Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. Arch Dermatol. 2011 May;147(5):590-6.
- Handler NS, Handler MZ, Majewski S, et al. Human papillomavirus vaccine trials and tribulations: Vaccine efficacy. J Am Acad Dermatol. 2015 Nov;73(5):759-67.
- Cervantes JL, Doan AH. Discrepancies in the evaluation of the safety of the human papillomavirus vaccine. Mem Inst Oswaldo Cruz. 2018;113(8):e180063. Epub 2018 May 28.
- Hancock G, Hellner K, Dorrell L. Therapeutic HPV vaccines. Best Pract Res Clin Obstet Gynaecol. 2018 Feb;47:59-72.
- Nofal A, Marei A, Ibrahim AM, et al. Intralesional versus intramuscular bivalent human papillomavirus vaccine in the treatment of recalcitrant common warts. J Am Acad Dermatol. 2020 Jan;82(1):94-100.
- Yang MY, Son JH, Kim GW, et al. Quadrivalent human papilloma virus vaccine for the treatment of multiple warts: a retrospective analysis of 30 patients. J Dermatolog Treat. 2019 Jun;30(4):405-9.
- Abeck D, Folster-Holst R. Quadrivalent human papillomavirus vaccination: a promising treatment for recalcitrant cutaneous warts in children. Acta Derm Venereol. 2015 Nov;95(8):1017-9.
- Daniel BS, Murrell DF. Complete resolution of chronic multiple verruca vulgaris treated with quadrivalent human papillomavirus vaccine. JAMA Dermatol. 2013 Mar;149(3):370-2.
- Moscato GM, Di Matteo G, Ciotti M, et al. Dual response to human papilloma virus vaccine in an immunodeficiency disorder: resolution of plantar warts and persistence of condylomas. J Eur Acad Dermatol Venereol. 2016 Jul;30(7):1212-3.
- Kreuter A, Waterboer T, Wieland U. Regression of cutaneous warts in a patient with WILD syndrome following recombinant quadrivalent human papillomavirus vaccination. Arch Dermatol. 2010 Oct;146(10):1196-7.
- Ferguson SB, Gallo ES. Nonavalent human papillomavirus vaccination as a treatment for warts in an immunosuppressed adult. JAAD Case Rep. 2017 Jul;3(4):367-9.
- Venugopal SS, Murrell DF. Recalcitrant cutaneous warts treated with recombinant quadrivalent human papillomavirus vaccine (types 6, 11, 16, and 18) in a developmentally delayed, 31-year-old white man. Arch Dermatol. 2010 May;146(5):475-7.
- Landis MN, Lookingbill DP, Sluzevich JC. Recalcitrant plantar warts treated with recombinant quadrivalent human papillomavirus vaccine. J Am Acad Dermatol. 2012 Aug;67(2):e73-4.
- Lee HJ, Kim JK, Kim DH, et al. Condyloma accuminatum treated with recombinant quadrivalent human papillomavirus vaccine (types 6, 11, 16, 18). J Am Acad Dermatol. 2011 Jun;64(6):e130-2.
- Choi H. Can quadrivalent human papillomavirus prophylactic vaccine be an effective alternative for the therapeutic management of genital warts? an exploratory study. Int Braz J Urol. 2019 Mar-Apr;45(2):361-8.
- Nichols AJ, Gonzalez A, Clark ES, et al. Combined systemic and intratumoral administration of human papillomavirus vaccine to treat multiple cutaneous basaloid squamous cell carcinomas. JAMA Dermatol. 2018 Aug 1;154(8):927- 30.
- Myers DJ, Kwan E, Fillman EP. Epidermodysplasia verruciformis. [Updated 2020 Sep 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK534198/
- Maor D, Brennand S, Goh MS, et al. A case of acquired epidermodysplasia verruciformis in a renal transplant recipient clearing with multimodal treatment including HPV (Gardasil) vaccination. Australas J Dermatol. 2018 May;59(2):147-8.