Human papillomavirus (HPV) is a non-enveloped double-stranded circular DNA virus in the Papillomaviridae family. There are over 150 different types of HPV, with 40 affecting the anogenital area and 15 being oncogenic in nature.
Low-risk types of HPV, such as HPV-6 and HPV-11, are responsible for causing genital warts, which is the most common type of viral sexually transmitted infection (STI).
High-risk HPV types can lead to the formation of malignant tumors - worldwide, they are estimated to cause around 5% of all cancer cases, primarily in the cervix, vulva, vagina, anus, penis, head, and neck.
HPV is highly prevalent, with nearly all sexually active men and women being infected in their lifetime. Forty percent of women are estimated to acquire HPV infection within the first two years of sexual activity.
Genital warts, which are caused by low-risk HPV-6 and HPV-11, is the most common viral STI worldwide. In 2019, there were 50,700 diagnoses of the first episode of genital warts; however, this number decreased to 27,473 in 2020 - attributed to an expanded HPV vaccine programme and a reduction of face-to-face consultations during the COVID-19 pandemic.
In the UK, high-risk HPV is present in 16% of the population, with the most common type being HPV-16 (12%). High-risk HPV types can cause cancer through the mechanisms described below.
Human Papillomavirus (HPV) belongs to the Papillomaviridae family and includes over 200 different types which are grouped according to their genome. Although all HPV types can cause proliferative lesions, the most prevalent types are classified as high-risk or low-risk according to their risk of causing malignant neoplasms or benign lesions, such as genital warts.
Important high-risk types include HPV-16 and HPV-18, which contribute to over 70% of cervical cancer, and 31, 33, 35, 45, 52 and 58, which account for an additional 20% of cervical cancers. Low-risk HPV capable of causing genital warts include HPV-6 and HPV-11.
Microtrauma to the epithelial cells of the skin, oral and genital mucosa provides the virus access to basal keratinocytes. HPV utilizes its L1 and L2 capsid proteins to bind and enter the cell via endocytosis.
The undifferentiated basal layer acts as a reservoir, proliferating symmetrically to form more basal cells, wherein HPV establishes a persistent infection, or asymmetrically, whereby one daughter cell moves up through the epithelium. As these infected basal cells differentiate into epithelial cells, the virus begins expressing its early (E) genes, allowing it to replicate and produce new virions to be released from the differentiated epithelial cell surface.
The majority (70-90%) of HPV infections are asymptomatic and are cleared within 12-14 months by the immune system via a Th1 pro-inflammatory and cell-mediated response.
This immune response may be sufficient to completely clear the viral infection or to keep the virus in very low copy numbers which avoid detection. However, only 70-80% of genital HPV infection results in antibody production, which is insufficient to control for new infections.
HPV employs several strategies to induce hyperproliferation of the infected epithelia, resulting in warts:
High-risk HPV types can remain intraepithelial by proliferating through the undifferentiated layer of cells, thereby avoiding the host immune response. These oncogenic types demonstrate increased activity of viral E6 and E7 oncoproteins, which respectively inhibit p53 and pRb tumour suppressor genes. This results in cell cycle dysregulation, uncontrolled cellular proliferation and the accumulation of mutations that can lead to invasive malignancy.
HPV is transmitted primarily through direct skin-skin contact during sexual intercourse.
Other modes of transmission include contact with contaminated surfaces or objects, oro-genital contact, transmission from mother to child during birth, and autoinoculation.
Risk factors associated with HPV include early age of first sexual intercourse, having multiple sexual partners, having unprotected sex, and immunosuppression including HIV.
Most HPV infections (70-90%) are asymptomatic and are cleared by the immune system within 12-14 months. Warts tend to present as single or multiple cauliflower-like growths, which may be soft and non-keratinised on non-hairy skin or firm and keratinised on hairy skin. Symptoms may include itching and irritation, pain and bleeding, and urinary flow obstruction due to intra-meatal warts. A sexual history should be taken to assess relevant risk factors.
The anogenital area, external genitalia, perineum, and anus should be examined to confirm the diagnosis and determine the extent of the lesions. Other examinations may include a vaginal speculum exam, meatoscopy, proctoscopy, and anoscopy in patients with recurrent perianal warts.
Table 1. Differential diagnoses to consider in the context of anogenital lesions.
Differential diagnosisClinical summaryCondyloma latum
Molluscum contagiosum
Pearly penile papules
Skin tags
Carcinoma in situ
Genital warts are diagnosed following clinical examination. Swabs and blood tests are not routinely performed. However, it is important to offer a full sexual health screen.
At the bedside, diagnostic testing may include taking a urine sample and swabs from the vagina, cervix, rectum and oropharynx to screen for chlamydia and gonorrhoea. Other laboratory investigations may involve a full blood count, CRP and serology for HIV, syphilis, HBV and HCV.
Biopsy could be considered if the wart is indurated, fixed, bleeding, ulcerated or pigmented.
Although there is no specific treatment for HPV infection, treatments are available to destroy or remove warts and lesions. Self-administered treatment includes topical treatment with podophyllotoxin, imiquimod and sinecathins. Specialists may treat with trichloroacetic acid, or use ablative methods such as cryotherapy, excision or electrocautery.
All patients should be advised to quit smoking and use barrier methods of contraception. Patients may also suggest that sexual partners may benefit from assessment for undetected genital warts and other STIs. Patients should also be reassured that a recent diagnosis does not always imply partner infidelity due to the long latency of HPV.
Protective factors against HPV infection include condom usage, male circumcision, limiting the number of sexual partners and vaccination.
HPV vaccines contain particles from the major protein of the viral capsid. Currently, the following groups are eligible:
The bivalent vaccine against HPV 16 and 18 was introduced in the national immunisation programme in 2008, and this has since been replaced by the quadrivalent vaccine Gardasil (against HPV 6, 11, 16 and 18). This is planned to be replaced again in 2022 by the 9-valent vaccine Gardasil 9 (against HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58) to offer more protection against cancer and genital warts. Vaccination programmes are aimed at both girls and boys aged 11-14, and other eligible groups. As of 2020, there is 85% coverage for girls and 53% for boys.
The main complications are caused by anxiety and distress relating to the appearance of warts. Side effects of topical treatments may include persistent hypo- or hyper-pigmentation and hypertrophic scarring.
In around 20% of people, warts disappear within 6 months, requiring no treatment.
