Human Papillomavirus (HPV)

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Practice Essentials

Human papillomavirus (HPV) produces epithelial tumors of the skin and mucous membranes. The current classification system for HPV, which is based on similarities in genomic sequences, generally correlates with the 3 clinical categories applied to HPV infection:

See Pediatric Vaccinations: Do You Know the Recommended Schedules?, a Critical Images slideshow, to help stay current with the latest routine and catch-up immunization schedules for 16 vaccine-preventable diseases.

Signs and symptoms

The clinical history and presentation of HPV infection vary according to the anatomic area involved. The predilection of certain viral genotypes for infecting certain epidermal sites largely determines areas of involvement. Conditions with which HPV is associated include the following:

Physical findings vary, depending on the tissues involved, and may include the following:

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of most cutaneous and external genital warts can be made through clinical examination or with application of acetic acid and biopsy. In genital intraepithelial neoplasia, it is essential to determine the extent of disease through careful inspection and colposcopy.

Laboratory studies that may be considered include the following:

In some cases, tissue biopsy can be used to confirm HPV infection. A biopsy is recommended for the following scenarios:

Histologic findings that can help elucidate the diagnosis include the following:

See Workup for more detail.

Management

All medicines used to treat HPV disease are applied topically; they should not be applied to mucosal surfaces and should not be used to treat dysplastic lesions, squamous cell carcinoma, verrucous carcinoma, or Bowenoid papulosis. The following 2 broad categories of medications are effective:

Sinecatechins ointment is another option.

Surgical interventions are commonly considered when a large number of warts are present, a large area is affected, or the patient has refractory disease. Overall, physical destruction or excision has been more effective in eradicating genital warts than medical therapy. Primary surgical therapy can often be accomplished in the office and includes the following options:

Alternative surgical procedures include the following:

Vaccines are available for prevention of HPV infection, and recommended vaccination schedules have been outlined.

See Treatment and Medication for more detail.

Background

HPV produces epithelial tumors of the skin and mucous membranes. More than 100 HPV types are known, and the genomes of more than 80 have been completely sequenced. People with multiple sexual partners and those who already have persistent HPV infection are at increased risk for acquiring additional HPV strains.[2, 3, 4, 5] The current classification system, which is based on similarities in genomic sequences, generally correlates with the 3 clinical categories applied to HPV:

The mucosal HPV infections are classified further as latent (asymptomatic), subclinical, or clinical. Clinical lesions are grossly apparent, whereas latent infections are detected only with tests for viral DNA. Subclinical lesions are identified by application of 3-5% acetic acid and inspection under magnification. Most HPV infections are latent; clinically apparent infections usually result in warts rather than malignancies.

Infections due to HPV are common and lead to a wide variety of clinical manifestations that involve the epidermal surfaces. Condylomata acuminata (genital warts) are generally recognized as benign proliferations of the anogenital skin and mucosa resulting from HPV infection. Genital warts are transmitted by sexual contact. Approximately two thirds of individuals who have sexual contact with an infected partner develop genital warts. The exact incubation time is unknown but estimated to be 3 weeks to 8 months.[6, 7]

Despite the generally benign nature of these proliferations, certain types of HPV can place patients at a high risk for anogenital cancer.[8, 9, 10] Some have also been implicated in laryngeal and oral cancer and some lung cancers.

HPV types 6 and 11 are typically labeled as low risk because infection with these types has low oncogenic potential and usually results in the formation of condylomata and low-grade precancerous lesions. HPV types 16 and 18 have emerged as the high-risk types of HPV because they are responsible for most high-grade intraepithelial lesions that may progress to carcinomas, particularly those in the anogenital or mucosal category.

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process.

Physicians’ understanding of the natural history of HPV disease has significantly improved over the last 20 years, but key issues remain unanswered. Topics requiring further research include HPV age-specific outcomes, the likelihood of progression or regression of disease, and factors important in the acquisition of immunity following infection.[11]

Pathophysiology

Papillomaviruses are nonenveloped viruses of icosahedral symmetry with 72 capsomeres that surround a genome containing double-stranded circular DNA with approximately 8000 base pairs. Their genome is divided into the following 3 major functional regions:

Papillomaviruses are highly species-specific and do not infect other species, even under laboratory conditions. Humans are the only known reservoir for HPV. Papillomaviruses have never been grown in vitro but have been characterized by molecular methods. These viruses are classified by the molecular similarity of their genetic material and are assigned a genotype number.

Although some overlap exists, most papillomaviruses have distinct anatomic predilections, infecting only certain epidermal sites, such as skin or genital mucosa. The virus has the potential to integrate into host DNA, frequently with the loss of the early regulatory function.

HPV infects the basal keratinocyte of the epidermis, presumably through disruptions of the skin or mucosal surface. At this location, the virus remains latent in the cell as a circular episome in low copy numbers. Autoinoculation of virus into opposed lesions is common. Spread of HPV infection is usually through skin-associated virus and not blood-borne infection. Cell-mediated immunity (CMI) probably plays a significant role in wart regression; patients with CMI deficiency are particularly susceptible to HPV infection and are notoriously difficult to treat.[12]

Papillomaviruses are thought to have 2 modes of replication:

As the epidermal cells differentiate and migrate to the surface, the virus is triggered to undergo replication and maturation, and at the keratitic layer, the virus is present in high copy numbers and is shed in the exfoliation cells. The process of virus replication alters the character of the epidermis, resulting in cutaneous or mucosal excrescences known as warts.

Note the figures below detailing the mechanisms of action for HPV.



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The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies....



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The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.



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Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.

Although all cells of a lesion contain the viral genome, the expression of viral genes is tightly linked to the state of cellular differentiation. Most viral genes are not activated until the infected keratinocyte leaves the basal layer. Production of virus particles can occur only in highly differentiated keratinocytes; therefore, virus production occurs only at the epithelial surface where the cells are ultimately sloughed into the environment.

HPV infections have not been shown to be cytolytic; rather, viral particles are released as a result of degeneration of desquamating cells. The HPV virus can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot.

Viral multiplication is confined to the nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis (from Greek koilos “empty”) describes a combination of perinuclear clearing (halo) with a pyknotic or shrunken (raisinoid) nucleus and is a characteristic feature of productive papillomavirus infection.

Numerous viral genotypes have the potential to transform cells and are associated with epidermal malignancies. In benign or low-risk HPV lesions, such as those typically associated with HPV types 6 and 11, the HPV genome exists as a circular episomal DNA separate from the host cell nucleus. In malignant lesions, the genomes of high-risk HPV types 16 and 18 are typically integrated into the host cell DNA. Integration of the viral genome into the host cell genome is considered a hallmark of malignant transformation.

HPV proteins E6 and E7 of high-risk serotypes have been shown to inactivate the host’s tumor suppressor proteins p53 and Rb, thereby resulting in unregulated host cell proliferation and malignant transformation.

Etiology

The definitive cause of anogenital warts is HPV infection.[8, 9, 10, 13] The HPV capsid lacks an envelope, which makes the organism very stable and resistant to various treatments. No serologic typing is available, because of the lack of consistent in vitro culture methods. Typing of HPV is based on genotype, which generally is determined by molecular hybridization using molecularly cloned HPV DNA of known type as the standard. Two HPV are of different types when their DNA hybridize (bind) less than 50% as efficiently to each other as to themselves.

The nearly 40 types of HPV that have been found in genital warts[14] are highly host-specific. These viruses do not infect laboratory animals and are not susceptible to acyclovir. In addition, HPV types demonstrate a high degree of site specificity, with some types only found on certain parts of the skin or mucous membranes. As a rule, HPV types causing common warts of the skin do not infect moist epithelium, and vice versa.

Multiple clinical associations with unique genotypes of HPV have been documented. Some of these associations are listed in the Table below.

Table 1. Diseases Associated With Specific HPV Types



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See Table

Risk factors

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process, particularly in the anogenital-mucosal category. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV, are especially susceptible to HPV infections.

Sexual activity

A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

Women with a history of high-grade squamous intraepithelial lesions (HGSIL) of the cervix or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital-mucosal category, particularly vaginal and anal carcinoma (relative risks, 5.6 and 4, respectively).

Anal cancer has been strongly associated with male homosexuality and with specific male practices, such as engaging in receptive anal intercourse; relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

Tobacco smoking

Women who smoke tobacco have an increased risk of developing cervical neoplasia. Measurable amounts of a potent carcinogen, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents are likely to play a role in the increased prevalence of HPV malignant transformation observed in patients who smoke tobacco.

Oral contraceptive use

Women who take oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma. This risk declines after oral contraceptive use is stopped, and no risk is demonstrated in women who took these agents for less than 5 years.

Chewing Indian betel quid

A high incidence of oral cancer associated with HPV infection has been demonstrated in India among patients who chew betel quid. This stimulant is made from the leaves of the betel plant and is used in a manner similar to chewing tobacco.

Ultraviolet and x-ray irradiation

EV is particularly susceptible to ultraviolet (UV) and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.

Epidemiology

United States statistics

The United States has no reporting system for HPV infections. Infections and the development of warts appear to be common throughout life. In general, genital HPV infection is considered to have become dramatically more frequent over the past several decades.

In the United States, young adults aged 15-24 years account for approximately one half of new HPV infections each year.[18] The frequency of genital infections is associated with the number of sexual partners and the age of sexual debut. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with the human immunodeficiency virus (HIV), are especially susceptible to developing HPV infections.

Using data and self-collected cervicovaginal specimens from 4150 females in 4 consecutive National Health and Nutrition Examination Surveys (2003-2006), Hariri et al found HPV present in 42.5% of US females aged 14-59 years. The highest rate of infection is among young females aged 20-24 years.[19]

The population-based incidence of genital warts was estimated at 106 cases per 100,000 population in Rochester, Minnesota (for 1975-1978)[20] and at 160 cases per 100,000 population in Manitoba, Canada (for 1992),[21] with the highest incidence rate in residents aged 20-24 years.

Figures from 5 Blue Cross/Blue Shield Health Plans projected an incidence of 105 cases per 100,000 population (for 2004).[22] They estimated 340,000 cases nationwide in 2004, with an economic burden of more than $220 million.[22]

These figures differed from those indicated by data collected from STD clinics and private practitioners’ offices. Using data from these sources, the US Centers for Disease Control and Prevention (CDC) suggested much higher figures: an estimated incidence of more than 6 million new patients a year in the United States (in 2008) and an estimated prevalence of more than 20 million.[23, 24, 25, 26, 27] By way of comparison, the CDC estimated that 1.6 million people have genital herpes and 1.6 million have chlamydia or gonorrhea.

According to the “National Disease and Therapeutic Index: United States, 1966–2010, the Initial visits to physicians’ offices for STD,” the increasing trend of HPV infection, after peaking at 351,000 visits in 1987, went down in the following 10 years. Unfortunately, the increasing trend resumed again and reached the highest level ever in 2006 (422,000 visits) before dropping down to 357,000 in 2010.

Studies diagnosing HPV infection through by visual inspection of genital condylomata report the lowest prevalences. The highest prevalences are reported by studies typing HPV from exfoliated genital tract cells. As many as 75% of individuals who have sexual contact with an HPV-infected partner will develop external genital warts.[28]

Condylomata acuminata are clinically apparent in 1% of the sexually active population. Molecular studies indicate that 10-20% of men and women aged 15-49 years have been exposed to HPV. The prevalence of HPV is higher in certain populations. A prevalence of 4-13% has been reported by sexually transmitted disease (STD) clinics.

Several investigators report an increased prevalence of anogenital HPV infections during pregnancy. The prevalence of condyloma increases from the first to third trimester and then decreases significantly post partum. The risk of condyloma acuminatum in pregnancy is 2-fold. Vulvar condylomata can rarely become large enough to obstruct labor. Cesarean delivery decreases, but does not completely prevent, HPV transmission with development of laryngeal papillomas in the infant.[29, 30, 31, 32]

HPV infection causes virtually all cases of cervical cancer.[33, 34] In cervical neoplasias, the HPV genome can be detected in more than 95% of tumors. No deaths due to cervical cancer have been documented in women younger than 20 years. The United States National Cancer Institute publishes data on the prevalence of worldwide cervical cancer via their online database.

The incidence of cervical cancer has decreased dramatically during the last century because of the implementation of the Papanicolaou test (Pap Test, or Pap smear), beginning in the 1930s and 1940s. However, between 1990 and 2001, the annual number of estimated new invasive cervical cancers remained relatively constant (13,500 and 12,900, respectively). In the United States, 2.5 million women are estimated to have an annual cytologic diagnosis of a low-grade cervical cancer precursor.

The percentages of other cancers caused by oncogenic HPV are as follows[34] :

International statistics

Globally, HPV infection is the most common STD.[35, 36] Genital warts have affected as many as 30 million individuals worldwide. A study in Finland in the mid-1980s found that the annual incidence of cytologic cervical HPV infection was 7%.[37] A study of Finnish males determined that 6.5% had evidence of HPV in exfoliative cells obtained from the urethra and genital epithelium.[38]

In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.[39] However, a single round of HPV screening has been demonstrated to be far superior to conventional cytology in reducing the incidence of cervical cancer morbidity and mortality.[40]

The prevalence of high-risk HPV in women with normal cervical cytology varies among the different regions of the world. Although the global HPV prevalence was estimated to be approximately 12%, higher prevalences were noted in sub-Saharan Africa (24%), eastern Europe (21.4%), and Latin America (16.1%).[41]

In many developing nations, cervical cancer is the leading cause of cancer mortality among women. Worldwide, it is the second most common cause of cancer mortality among women. The World Health Organization (WHO) estimates that 570,000 new cases of cervical cancers occurred globally in 2018, and approximately 311,000 women died of cervical cancer during the same year.[42]

Age-related demographics

People of any age may develop common warts. HPV infects more than 50% of sexually active adults. Genital infection generally occurs during the sexually active period in a person’s life, and infections increase with the number of sexual partners.

The prevalence of anogenital mucosal HPV infections is highest among college-aged women and men. The prevalence of HPV infection stratified by age in US females is as follows[43] :

Thus, the highest rates of genital HPV infection are in young, sexually active females. This incidence is independent of the number of lifetime sexual partners. Most of these infections (90%) are transient.[44, 45, 46] An estimated 5.6% of sexually active adults in the United States aged 18-59 years have been diagnosed with genital warts by a medical provider.[47]

A cytologic screening of the cervix in more than 400,000 women supported a higher incidence of HPV in young women. This study found that the rate of HPV infection in women younger than 30 years is double that in women older than 30 years.[48]

The reason for the higher prevalence in younger women is not completely understood. Some investigators hypothesize that older women have fewer sexual partners and, consequently, less exposure to HPV. An alternative theory is that by age 30 years, women have acquired immunity to HPV.[49]

The presence of genital condyloma in the pediatric population presents a diagnostic and therapeutic challenge.[50] Vertical transmission of HPV can occur via in utero exposure to amniotic fluid or transmission of HPV from the maternal genital tract.

An incubation period of several months is usually required between virus infection at delivery and clinical manifestations in the infant. The average latency period is 3 months, but periods as long as 20 months have been reported.[51] Cases of childhood condylomata outside a reasonable incubation period after vertical transmission should arouse suspicion of child abuse. Treatment of condyloma in the infant includes excision under general anesthesia or the use of podophyllin.[52]

Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years.

EV develops at an average age of onset of 6 years. Beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC.

Sex-related demographics

The overall prevalence of HPV in women is reported to be 22-35%. In men, the prevalence is reported to be 2-35%, depending on the sexual practices of the population being studied. However, a well-defined population study found the female-to-male ratio to be 1.4:1,[20] and CDC reports demonstrated that this disease affects females more frequently than males.

The prevalence of condyloma acuminatum seems to be similar in men and women. A study from an STD clinic found that 13% of men and 9% of women had condylomata acuminata.[23] HPV infections are reported more frequently in US college females[53] than in male counterparts. This presumed higher incidence of HPV infection in females may be the result of detection of HPV infection in cytologic smears performed for cervical cancer screening. Females seek medical care for genital warts more frequently than men do.[26]

Race-related demographics

In the United States, African Americans have a rate of HPV infection that is 1.5 times higher than their white counterparts. However, most studies indicate that no racial predilection exists for the acquisition of genital warts.

Dinh et al analyzed data from the 1999-2004 National Health and Nutrition Examination Surveys, which collected data from a random sample of the United States civilian population. These investigators reported that the prevalence of genital warts was higher in non-Hispanic whites than in other racial or ethnic groups.[47] One US survey reported that among women, the prevalence of HPV infection due to any HPV type was 39% for non-Hispanic blacks, and 24% for non-Hispanic whites and Mexican Americans.[43]

From 1987 to 1991, the age-adjusted cervical cancer death rate reported by the US National Cancer Institute was higher among black women than among white women, with a ratio of 6:1.

Prognosis

HPV infection primarily involves the basal epithelial cells. As a result, both recurrences and regressions are common. Prognosis is good, and most cases of genital warts are amenable to treatment. Patients who do not develop immunity to HPV can develop potentially serious sequelae.

Genital warts may spontaneously regress, remain unchanged, or increase in size. Treatment of these lesions does not affect the development of cervical cancer. Approximately two thirds of patients with nongenital cutaneous warts experience a spontaneous regression within 2 years; however, some new warts may appear.

HPV infection of the vulva can result in the development of vulvar intraepithelial neoplasia (dysplasia) or squamous cell carcinoma of the vulva. Most research indicates that HPV infection is strongly associated with the development of cervical dysplasia and cervical carcinoma. HPV confers more than 99% of the attributable risk for the development of cervical dysplasia.[54] Vaginal dysplasia and vaginal cancer are also associated with HPV exposure.

Histologic evidence of HPV infection on a cervical Pap smear is similar to mild dysplasia. This subclinical disease often spontaneously regresses.

A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of HGSIL of the cervix or invasive SCC of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital-mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4.

Women who are immunocompromised as a result of immunosuppressive drug therapy or HIV infection are at higher risk for persistent disease. These women are more likely to develop dysplasia or cancer of the vulva, vagina, or cervix.

Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

Men who are infected with HPV are at risk for genital warts. The 24-month risk varied from 57.9% in men who were infected with HPV type 6 or type 11 to 2% in men who were infected with other HPV types.[55]

Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. About 10% of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).

Most patients with EV experience progression of their disease in the third or fourth decades of life. Malignant transformation usually arises from actinic keratoses, particularly in patients who are exposed to irradiation. Patients who remain protected from x-rays and sun exposure generally have satisfactory health.

As many as 20% of patients with genital warts have other sexually transmitted diseases concurrently (Rochester, Minnesota).[22] In an Australian sexual health clinic, 5% of genital wart patients were found to also have chlamydia and/or gonorrhea.[56]

Patient Education

Treatment of genital warts can be difficult and lengthy. Patient expectations should be set appropriately. Counsel patients on their risk of infectivity to others, and advise them of their increased risk of having acquired other STDs. Remind them that genital warts resolve spontaneously in 20-30% of women within 3 months.[28]

Educating women, particularly those who are socially and economically disadvantaged, about behaviors that enhance sexual risk reduction has a proven benefit in reducing the incidence of STDs. Reducing the incidence of STDs potentially could decrease HPV transmission and, consequently, the incidence of cervical carcinoma.

Inform patients that genital HPV is an STD and that the only way to prevent HPV infection is to avoid direct contact with the virus, which is transmitted by skin-to-skin contact. Instruct them to use condoms with vaginal, anal, or oral sex because the virus may be found in the semen in the absence of visible warts. Remind them that latex condoms offer some, but not complete, protection from transmission.

The benefit of evaluating sex partners of patients with genital warts has been apparent. Several consort studies documented that 30% of female consorts and 80% of male consorts had HPV infection. Usually, the same type of HPV involved both parties, and often they were HPV 6, 11, 16, and 18. If the sexual partner has visible genital warts, sexual contact should be avoided until treatment is completed.

For patient education resources, see the Women’s Health Center, the Pregnancy Center, and the Cancer Center, as well as Genital Warts, Plantar Warts, and Pap Smear.

History

The clinical history and presentation of human papillomavirus (HPV) infection vary according to the anatomic area involved. The predilection of certain genotypes of virus to infect certain epidermal sites largely determines areas of involvement.

Genital infection manifests as a warty lesion on the genital or anal area, although these warts are often not initially recognized. Cervical infection generally goes unnoticed and is discovered during cervical examination or Papanicolaou (Pap) testing.

Anogenital warts

Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.

Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.

Flat condylomata (squamous intraepithelial neoplasia) are the most common lesions of the cervix but may also develop on the vulva, anus, and male genitalia. They appear as white plaquelike growths.

An additional malignant variant is the giant condyloma, or Buschke-Löwenstein tumor, generally regarded as a verrucous carcinoma. These most often involve the glans penis, perianal area, and foreskin. In addition to their large cauliflower shape, they tend to form abscesses and fistulas and tend to invade locally.

Genital warts generally do not become clinically apparent until several months after inoculation with HPV. They follow a slow and indolent course and may develop by inoculation from opposing surfaces.

Condylomata acuminata are often asymptomatic. These lesions are generally not painful, but they can be associated with pruritus; bleeding may be observed if the lesions become confluent and are irritated by clothing. Most patients seek medical care when they notice lumps on the vulva, perianal area, or periclitoral area, or because they experience pruritus or occasional bleeding.

Cervical disease

Most cervical infections are either latent or subclinical and therefore asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of HPV-triggered dysplasia.

Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.

Anal cancer

The most common presenting symptoms of squamous cell carcinoma (SCC) of the anus are rectal bleeding and sensation of a mass. These symptoms may be attributed mistakenly to hemorrhoids.

Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.

Nonanogenital mucosal disease

Oral warts represent infection of the oral mucosa. Although they are subtle and easily missed, they are fairly common. HPV types 6 and 11 have been isolated from nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.

HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas most frequently present with hoarseness at an average age of 3 years.

Focal epithelial hyperplasia (Heck disease) is a disseminated HPV infection of the oral mucosa most commonly associated with HPV 32 and HPV 13. This condition may have a family predilection.

Nongenital cutaneous HPV

Common cutaneous warts (verruca vulgaris) generally appear on keratinized skin, presumably at the site of inoculation. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface (so-called kissing warts).

Common cutaneous warts appear as circumscribed, rough, hyperkeratotic papulonodules or plaques with irregular scaly surfaces and develop most often on the hands, fingers, feet, and knees. Such warts are frequently discovered when the patient notices changes in the skin. In general, they are asymptomatic, but they may be painful with application of pressure. Typically, they are benign and self-limited.

Palmoplantar warts appear on the acral surfaces of the feet and hands. They are notable for their thickness, which complicates treatment. Deep plantar warts occur most commonly as solitary lesions that may become black and painful before spontaneously regressing. They may contain small black “seeds,” which are thrombosed capillaries.



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Plantar warts.

Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.

Flat warts (verruca plana) most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. They often are not obvious but may induce significant disturbances of pigmentation. Regression usually occurs spontaneously after several years, and pruritus or erythema occurs several weeks before their disappearance.



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Flat wart.

Lloyd described Bowenoid papulosis as multicentric pigmented Bowen disease of the groin. It manifests as multiple, warty, red-brown papules in the anogenital region. These papules may coalesce.

Malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually arise first on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.

Epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is an autosomal recessive familial trait that increases susceptibility to a subset of wart generally not observed in populations without EV. HPV genotypes associated with EV have been observed in patients who are immunosuppressed for organ transplantation or in patients with HIV infection. These individuals are at increased risk for skin cancer if not recognized and treated.

EV generally begins in childhood and can affect almost any area of the body. The warts are generally subtle and flat and may initially be mistaken for tinea versicolor. EV tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.

Physical Examination

The findings on physical examination depend on the tissues involved. They include a variety of cutaneous lesions with characteristic appearances (see History).

Typical condylomata are discrete, papillary, cauliflowerlike lesions that involve multiple sites on moist surfaces. Keratotic warts are often seen on dry surfaces like the labia majora. Warts vary in size and can form large, exophytic, cauliflowerlike masses (see the images below). Discrete papules 1-3 mm in size can present on the shaft of the penis. The growth can extend into the vagina, urethra, cervix, perirectal epithelium, anus, and rectum. Cervical intraepithelial lesions may be found upon examination of the cervix.



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Human papillomavirus (HPV). Condyloma acuminatum in a patient with a history of an allograft renal transplant.



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Human papillomavirus (HPV). Note the extensive labial involvement.



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Human papillomavirus (HPV). Anal condyloma acuminatum.



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Human papillomavirus (HPV). These condylomata extend to the anal verge.



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"Cauliflower" condyloma of penis.



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Small papilloma on shaft of penis.

Subclinical infection is another common presentation of condyloma. Tiny, slightly raised areas can be felt or visualized on the vagina or cervix. These flat warts are best visualized by using 3-5% acetic acid and a colposcope. Areas infected with HPV appear acetowhite (ie, white when “painted” with the acetic acid). Often, a biopsy is needed to distinguish these lesions from cervical squamous intraepithelial lesions or vaginal intraepithelial lesions.

The sexual partner or partners of a woman with condylomata should be examined by a physician and treated if indicated. Often, the examination of the male fails to reveal any visible condylomata.

Complications

Some consider most common warts to be of only cosmetic concern and to cause few problems, unless their anatomic location induces mechanical problems. However, some patients may experience anxiety, guilt, and angst when they discover genital condyloma.

Plantar warts can disrupt ambulation because of their location. Laryngeal papillomas may disrupt breathing or speaking. Genital warts occasionally cause problems such as urethral obstruction. Condylomata acuminata can become extremely large, resulting in tissue breakdown or secondary infection. In the context of immune deficiency, such as HIV infection, the growth of warts due to HPV can be augmented, significantly enhancing the associated anatomic problems (see the image below).



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Verrucous warts in patient with HIV infection.

However, disease complications can include progression to malignancy and transmission to other sexual contacts. In the setting of genital warts active during a pregnancy delivery, there is a small risk of laryngeal papillomatosis. Whereas the vast majority of genital HPV infections resolve spontaneously, persistent infection can lead to neoplastic changes. Cervical cancer is the second most common cause of morbidity and death in women in the United States. Malignancies such as Bowen tumors may also lead to morbidity and death.

Patients who develop condylomata acuminata have usually been exposed to low-risk HPV types such as HPV-6 and HPV-11. These HPV infections are associated with mild dysplasia that is often transient in nature. Many patients with mild dysplasia of the vulva, vagina, or cervix experience spontaneous regression of these lesions. Patients who are exposed to high-risk HPV types, such as HPV-16 or HPV-18, usually do not develop condylomata. These patients are at risk for high-grade dysplasia or anogenital carcinoma.

Approach Considerations

The diagnosis of most cutaneous and external genital warts can be made on clinical examination or with application of acetic acid and biopsy. In the case of genital intraepithelial neoplasia, determining the extent of disease is essential. This involves careful inspection, as well as colposcopy.

Detection of human papillomavirus (HPV) DNA is now approved by the US Food and Drug Administration (FDA) and is valuable as a screening tool in women older than 30 years. Identification of genotypes is available only in research laboratories through the use of DNA hybridization techniques,[55] including Southern blot (highly sensitive but time-consuming), dot blot, and in situ hybridization. Others methods include enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) antibody (Ab) against HPV 16 capsid.

Patients who present with condylomata acuminata do not necessarily need other laboratory studies. Patients who are diagnosed with condylomata are at an increased risk for other sexually transmitted diseases (STDs). Consider testing for chlamydia, gonorrhea, syphilis, hepatitis B, hepatitis C, herpes, and HIV, depending on the clinical situation. These patients need a Papanicolaou (Pap) test of the cervix in accordance with the guidelines of the American College of Obstetricians and Gynecologists.

In general, imaging studies have a limited role in diagnosing HPV infections. Computed tomography (CT) or magnetic resonance imaging (MRI) can be used to determine the extent of spread of cervical carcinoma and extensive anogenital papillomatosis that has spread into the pelvis.

Histologic examination of the vulvar lesions to detect vulvar condyloma is sometimes difficult. Non-HPV conditions, such as vestibular papillomatosis and inflammatory squamous metaplasia, may be difficult to distinguish from condylomata with light microscopy. The pathologist may report microscopic features from a biopsy of the vulva that are suggestive, but not diagnostic, of HPV. When the histologic diagnosis of condyloma is questionable, HPV testing may be useful.

The following are 2015 guidelines on HPV screening and management from a guidance panel cosponsored by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology:[57, 58]

Cytologic Testing

Cervical cytologic testing with the Pap test is the standard screening procedure for cervical neoplasia. Guidelines for cervical cancer screening now include a delay in the initiation of screening and longer intervals between subsequent screens.[1] The initial Pap test should be performed at age 21 years and then every 3 years until age 30 years. The interval can be increased to every 5 years in women 30 years and older who receive a Pap test and co-testing for HPV. An alternative is to continue every 3 years with only a Pap test.[59, 60] Pap test screening can be discontinued after age 65 years if the patient had no previous abnormal Pap test results in the previous 20 years.

Although cervical metaplasia is prevalent among sexually active adolescents, placing them at increased risk for HPV infection, immune system clearance within 1-2 years is common. In addition, invasive cervical cancer is rare among adolescents, and most cervical dysplasias resolve spontaneously. While some studies have suggested women undergoing excisional procedures for cervical dysplasia have an increased risk of preterm births, a 2012 study by Kalliala et all suggests excisional procedures do not appear to increase preterm birth risk.[61] Because adolescents have most of their childbearing years ahead of them, however, delaying cervical cancer screening may be a prudent strategy in this population.

Pap smears should contain samples of cells from the ectocervix, the transformation zone, and the endocervical canal. Perform the test when the patient is not menstruating, so that the cytologic specimen is not occluded with blood. Furthermore, if the patient has a cervicovaginal infection with a mucopurulent vaginal discharge, consider performing the test after the bacterial infection has resolved. If the test must be performed, the discharge should be gently cleared with a saline-moistened cotton swab.

This test may be modified as required to sample any tissues from of the vagina, vulva, or perianal region that are suspicious for intraepithelial neoplasia (see Cervical Cancer). Although this is not an established routine, consider performing annual anal Pap smears on men who are at high risk and who participate in receptive anal intercourse.

Liquid-based Pap smears improve the diagnostic sensitivity of cervical cytology screening. They have the additional benefit of enabling easy testing for human papillomavirus (HPV). Thin Prep and SurePath are 2 methods currently approved by the FDA.

The US Centers for Disease Control (CDC) has specified Clinical Laboratory Improvement Amendments (CLIA) standards for successful participation in a cytology proficiency testing program to ensure the accuracy of interpretation of Pap smears. These guidelines can be found on the CDC Web site under the CLIA section for Gynecologic Cytology Standards. To maintain certification for assessment of Pap smears and other laboratory testing, laboratories in the United States must follow these standards.

HPV DNA Typing

The two common methods for HPV DNA testing are the Hybrid Capture II (HC II) and the polymerase chain reaction (PCR) enzyme immunosorbent assay. The 2 methods have similarly high sensitivities and are suitable tools for detection of HPV and posttreatment follow-up of cervical intraepithelial neoplasia (CIN).

HPV DNA testing is the preferred approach in the treatment of women whose Pap test results show atypical squamous cells of undetermined significance (ASC-US) whenever liquid-based cytology is used or co-collection is available. HPV DNA testing is also useful in the management of CIN in certain situations. Detailed consensus guidelines for management of abnormal Pap test results and management of CIN are available from the American Society for Colposcopic and Cervical Pathology.

A trial comparing more than 12,000 women who self-collected vaginal HPV specimens with a similar number who underwent cervical cytology screening found that whereas self-collected HPV had a positive predictive value of only 12%, it was 3.4 times more sensitive for detecting CIN II than cervical cytology was and detected 4.2 times more invasive cervical cancers.[62] These findings suggest that self-collected vaginal HPV testing might be a viable surveillance option in communities where cytology screening programs are limited by resources.

Newer HPV tests that are being developed include DNA chip, Linear Array, and cycle sequencing.[63]

The US Food and Drug Administration (FDA) has approved an expanded indication for an HPV DNA test, making it the first such test that can be used alone for primary cervical cancer screening in women aged 25 years or older. The test, the cobas HPV Test, detects DNA from 14 high-risk HPV types in cervical cell samples. A positive test for HPV type 16 or 18 is considered an indication for a colposcopy; a positive test for any of the 12 other high-risk HPV types is considered an indication for a Papanicolaou (Pap) test, in order to determine the need for colposcopy. The cobas HPV Test was first approved in 2011 for use in conjunction with or as a follow-up to a Pap test.[64]

Research supporting the expanded indication included a study of more than 40,000 women aged 25 years or older. The women underwent routine cervical exams, with a colposcopy and cervical tissue biopsy performed on those who had a positive Pap test or whose cervical cells screened positive for HPV, as well as on a subset of women with negative Pap and HPV tests. Comparison of the biopsy results with those from the Pap and cobas HPV tests showed that the HPV test would be effective even when used alone.[64]

Acetic Acid Test

The acetic acid test can be helpful in the diagnosis of genital warts. In particular, soaking acetic acid into suspicious lesions can enhance the degree of suspicion in lesions without classic features.

The method involves applying a 3-5% acetic acid–moistened gauze pad for 5-10 minutes on suspected lesions of the penis, cervix, labia, or perianal area. Inconspicuous, flat, genital lesions that might be difficult to assess become visible. Dysplastic and neoplastic tissues turn white (acetowhite). False-positive results are common and can result from anything that causes parakeratosis (eg, candidiasis, psoriasis, lichen planus, healing epithelium, sebaceous glands).

The acetic acid test can be used in conjunction with colposcopy to examine cervical lesions. However, this test is reserved only for suspicious lesions and should not be used for routine screening.

Tissue Biopsy

In general, tissue biopsy can be used to confirm HPV infection if the diagnosis is uncertain, particularly if warts are abnormally pigmented, ulcerated, or indurated.

Patients who appear to have classic condylomata acuminata that fail to respond to therapy should have one of the lesions biopsied. This prevents inappropriate treatment of a lesion unrelated to HPV.

Postmenopausal women who present with lesions resembling condylomata should undergo biopsy before initiation of therapy. These women have a greater chance of having vulvar dysplasia or vulvar cancer than younger women.

Patients who present with typical-appearing condylomata acuminata usually do not need a vulvar biopsy. A biopsy is recommended for the following scenarios:

To perform the biopsy, the base of the lesion is injected with 1% lidocaine, and an alligator-mouth biopsy forceps is used to obtain the specimen. Application of silver nitrate to the base of the biopsy site generally controls any bleeding, though in rare cases, suture placement may be required to achieve hemostasis.

Histologic Findings

Histopathology can elucidate the diagnosis in most cases. Verrucae consist of acanthotic epidermis with papillomatosis, hyperkeratosis, and parakeratosis. Elongated rete ridges may point to the center of the wart, and dermal capillary vessels may be thrombosed. An electron microscope may show viral particles in nuclei. Immunohistochemical staining with the peroxidase-antiperoxidase technique stains cells infected by viral particles.

Virus multiplication is confined to the host cell nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. The presence of abnormal koilocytes (keratinocytes with pyknotic, deeply blue nuclei surrounded by a halo and clear cytoplasm with a paucity of keratohyaline granules), or koilocytosis, is a characteristic feature of productive HPV infection. Other cytologic markers of HPV infection include acanthosis, dyskeratosis, and multinucleation.

The histology of common cutaneous warts demonstrates marked hyperkeratosis, acanthosis, parakeratosis, and papillomatosis. Three features used to distinguish warts from other papillomas include the presence of koilocytes, vertical columns of parakeratosis, and foci of clumped keratohyaline granules.

The histology of condyloma acuminatum generally demonstrates disruption of the epidermis with hyperkeratosis, coarse keratohyaline granules, and koilocytes in a prominent granular layer. The epidermis or mucosa of flat condylomata demonstrates acanthosis.

The histology of Bowenoid papulosis reveals psoriasiform hyperplasia and hyperkeratosis of the epidermis. Mitotic figures are increased at all epidermal levels. Keratinocytes display enlarged pleomorphic and hyperchromic nuclei.

Approach Considerations

There is no single curative treatment for condylomata acuminata.[65] Eradication or reduction of symptoms is the primary goal of treating warts, but elimination of dysplastic lesions is the goal in treating squamous intraepithelial lesions (SILs). Treatment is reserved for patients with visible warts. The general treatment strategy is to eliminate as many of the visible lesions as possible until the host immune system can control viral replication.

Treatment is not recommended for subclinical anogenital or mucosal human papillomavirus (HPV) infection in the absence of coexistent dysplasia. No evidence demonstrates that treatment eliminates HPV infection or that it decreases infectivity. In fact, warts may recur after treatment because of activation of latent virus present in healthy skin adjacent to the lesion.

Although standard therapies for genital warts can remove most warts, the superiority of any single treatment modality has not been demonstrated, nor is any individual modality ideal for all types of warts.[66] Factors that influence treatment of HPV disease include the size, morphology, number, and anatomic site of lesions, as well as cost, adverse effects, patient characteristics and preferences, previous therapy, and provider experience.

The treatment of most HPV infections involves agents that directly ablate the lesions (eg, surgical excision, chemical ablation, and cryotherapy). Inappropriate use of these agents may cause extensive and unnecessary tissue injury and loss.

Most patients with warts require multiple treatments over a course of several weeks or months. If substantial improvements have not occurred after 3 physician-administered treatments or if complete clearance has not occurred after 6 treatments, a different treatment modality should be used.

Patients who are HIV positive or are immunosuppressed as a result of taking immunosuppressive drugs usually require more than one treatment method. Often, the condylomata in these patients are refractory to therapy.

Regardless of the mode of therapy chosen, recurrence rates are high for any patient with condylomata acuminata. This can result in a high level of frustration for both the patient and the physician.

Considerations in Specific Patient Subgroups

Pregnant women

Higher HPV infection rates have been reported in pregnant women. If condyloma develops, rapid growth can be observed. Factors responsible include suppression of immunity during pregnancy and hormonal changes.[48] Small asymptomatic lesions need not be treated; larger lesions can be treated with keratolytics or cryotherapy.[67] Occasionally, condylomata in pregnant women become large and macerated, requiring surgical excision after the first trimester. Interferon, podophyllin, and 5-fluorouracil (5-FU) should not be used in pregnancy.

The risk of perinatal HPV transmission to the oropharyngeal mucosa of the neonate is low for mothers with latent infections or genital warts. The time between rupture of the amnion and delivery may be a critical factor in predicting transmission.

Garland et al, in a study analyzing pregnancy and infant outcomes in women who received prophylactic quadrivalent HPV vaccine before becoming pregnant, observed no significant differences among live birth, fetal loss, or spontaneous abortion.[68] During the study period, 1796 vaccine recipients and 1824 placebo recipients became pregnant, resulting in 2008 and 2029 pregnancies with known outcomes, respectively.

In this study, neonates with one or more congenital anomalies were observed in 40 births to vaccinated women and in 30 births to women given placebo.[68] The anomalies were varied and consistent with those commonly observed in the general population. These findings suggest that administration of quadrivalent HPV vaccine before pregnancy does not increase fetal risk. Surveillance continues to evaluate the vaccine further for any associated congenital anomalies.

Patients at increased risk for anogenital malignancy

Patients with genital warts are an increased risk for anogenital malignancy. Infection with HPV is the primary cause of cervical malignancy, though most patients with HPV-infected cervices have a benign outcome. Accordingly, annual screening and Pap testing are mandatory for female patients with genital warts. As many as 90% of cervical cancers are caused by HPV infection of the cervix.

Strong epidemiologic evidence suggests that 10% of patients who had a high-grade squamous intraepithelial lesion (HGSIL, which includes so-called moderate-to-severe dysplasia, carcinoma in situ [CIS], and cervical intraepithelial neoplasia [CIN] II and III) would have persistent lesions that eventually would progress to invasive cancer without treatment.

Patients with perianal warts, those who are HIV positive, and those with a history of receptive anal intercourse are at increased risk for anal HGSIL. There is no direct evidence to suggest that this would progress to invasive anal cancer, as lesions of the cervix are capable of doing. Nonetheless, penile, vulvar, vaginal, anal carcinomas, and head and neck cancers have been linked to HPV infection.[69]

Children with anogenital warts

Anogenital warts are rare in the general pediatric population. In more than one half of children with anogenital warts, the lesions are a manifestation either of viral inoculation at birth or of incidental spread of cutaneous warts. Such cases often are caused by nongenital HPV types. The diagnosis of genital warts in a child requires that the clinician report suspected abuse to begin an evaluation process that may or may not confirm sexual abuse.[25, 70]

Neonates and infants with laryngeal papillomatosis

Pregnant women with genital warts can transmit the virus to the newborn; the method of transmission is unknown. As a result of the frequency of HPV infection, about 5% of all births in the United States are at risk for neonatal HPV exposure. Infants can develop laryngeal papillomatosis in the first 5 years of life. Approximately 60% of mothers with infants with laryngeal papillomatosis report having genital warts.

The frequency of childhood laryngeal papillomatosis is extremely low: 2000 cases per year in the United States. This implies that the transmission rate from mother to infant is low and that recommending cesarean delivery for prevention of laryngeal papillomatosis is not warranted. However, if the mother has a huge condyloma that interferes with labor or delivery, a cesarean delivery may be needed.

Patients who are immunosuppressed

Patients who are immunosuppressed, such as those with AIDS and those currently receiving immunosuppressive therapy (eg, patients with renal transplants), are more likely to develop persistent HPV infection and subsequent dysplasia and malignancy.

Patients with verrucous carcinoma of genitalia

Verrucous carcinoma of the genitalia (giant condyloma of Buschke-Löwenstein) is a low-grade, locally invasive squamous cell carcinoma that is associated with HPV types 6 and 11 and should be considered in the differential diagnosis of lesions greater than 1 cm in diameter. The only appropriate treatment is radical surgical extirpation.

Pharmacologic Therapy

Both provider-applied treatments and patient-applied treatments are available. All medicines used to treat HPV disease are applied topically on cutaneous surfaces. Local skin reactions and pain are common adverse effects. Do not apply any of these medications to mucosal surfaces, and do not use them to treat dysplastic lesions, squamous cell carcinoma (SCC), verrucous carcinoma, or Bowenoid papulosis.

Two broad categories of medications are effective in treating HPV disease:

None of these medicines have been shown to be uniformly effective or directly antiviral. The keratolytics are the only agents that are recommended for treatment of nongenital cutaneous warts.

Imiquimod

Although imiquimod has no direct antiviral activity, it is a powerful cytokine inducer that stimulates production of interferon alfa, tumor necrosis factor, interleukin (IL) – 1, IL-6, and IL-8. It is the authors’ second choice in a nonpregnant woman with vulvar condyloma. Several randomized trials have demonstrated that application of imiquimod 5% cream can result in complete resolution of genital warts in up to 50% of patients. Recurrence rates range from 19-23% at 6 months.[71]

Imiquimod is applied is 3 times weekly at bedtime and is continued until the warts have completely cleared, up to a maximum of 16 weeks.[72] Imiquimod should be washed off 8 hours after application[73] ; local skin reactions are common, especially after contact with mucosal surfaces. The primary side effects are erythema, itching, and burning. This drug is expensive and is often not a treatment option in many health insurance plans.

Interferon alfa

Interferons have been used in the United States for the treatment of genital warts in various doses and preparations. Topical, intralesional, and systemic therapy have been used. Currently, no convincing evidence suggests that topical or systemic therapy is better than placebo.[74, 75, 76, 77]

Interferon alfa is a naturally occurring cytokine that may be produced either through recombinant DNA technology or from pooled human leukocytes. It has potent immunomodulatory, as well as direct antiviral, effects.

Interferon alfa is used for intralesional treatment of external anogenital warts and condyloma acuminatum. It is injected into the base of each wart, preferably via a 30-gauge needle, in a dosage of 3 million IU 3 times per week for 3 weeks. For large warts, it may be injected at several points around the periphery in a total dose of 250,000 IU per wart. Direct the needle at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximating the angle used in the commonly used purified protein derivative [PPD] test).

Local injection of interferon appears to be more effective than systemic injection. A meta-analysis of 7 randomized controlled trials comparing interferon and placebo for the treatment of genital warts reported complete response rate of 45% and 16%, respectively. Recurrence rates were 21% for interferon and 34% for patients in the placebo group.[78] Side effects included flulike symptoms, fatigue, and pain. Interferon is contraindicated in pregnancy.

The maximum response usually occurs 4-8 weeks after initiation of the first treatment course. If results at 12-16 weeks following the initial treatment course with interferon alfa-2b are not satisfactory, a second course of treatment using the same dosage schedule may be instituted, providing that clinical symptoms and signs or changes in laboratory parameters (eg, liver function tests, white blood cell [WBC] count, or platelet count) do not preclude this step.

Patients with 6-10 condylomata may receive a second (sequential) course of treatment using the same dosage schedule to treat up to 5 additional condylomata per course of treatment. Patients with more than 10 condylomata may receive additional sequences, depending on how many condylomata are present.

Podofilox

In a nonpregnant patient, podofilox gel or solution is the authors’ first choice. This antimitotic agent is either chemically synthesized or purified from naturally occurring podophyllin resin. Podofilox is used in the treatment of external genital warts or condyloma acuminatum. It is applied twice daily for 3 consecutive days and repeated for up to 4 weeks. Application stimulates visible necrosis of wart tissue. Side effects are minimal.

To ensure that the patient is fully aware of the correct method of therapy and to identify which specific warts should be treated, the prescriber should demonstrate the technique for initial application of the medication. No more than 0.5 g of gel per day should be used. Limit the total wart tissue treated to 10 cm2 or less.

Podophyllin

Podophyllin, a resin derived from the May apple (Podophyllum peltatum Linné), contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase. It is a physician-applied medicine used in the treatment of external genital warts and condyloma acuminatum. It can be applied weekly for up to 6 weeks. Warts visible after 6 treatments usually do not respond to further therapy.[79]

Podophyllin is applied directly to warts, but no more than 0.5 mL should be used with 1 treatment. Before application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly, and allow it to dry thoroughly. The initial application should be for 30-40 minutes; subsequent applications can be for 1-4 hours. Remove dried podophyllin with alcohol or with soap and water. Do not treat large areas or numerous warts at once.

Ulceration and pain are potential side effects of podophyllin therapy. In addition, special care must be taken in using this agent because it not only causes tissue injury but also can be absorbed systemically and cause neurologic toxicity. Deaths have occurred with the use of podophyllin on exuberant perianal warts; the surface area of the lesions increases the absorption of the drug. Podophyllin is contraindicated in pregnancy.

The authors prefer podofilox to podophyllin because podofilox results in less toxicity and can be self-administered by the patient.

5-Fluorouracil

Another option is 5-FU cream, which interferes with DNA and RNA synthesis, thereby creating a thymine deficiency that resulting in unbalanced cellular growth and cell death. Limited data exist concerning the efficacy of this therapy for genital warts. Three case series indicated wart clearance in 10-50% of participants.[80] A meta-analysis of 6 trials involving 645 women concluded that topical treatment with 5-FU has a therapeutic effect; the data were unclear on the risks and benefits, and further studies were recommended.[81]

5-FU is applied to genital warts to cause a chemical desquamation. Although this patient-applied treatment is not formally indicated for treatment of HPV disease, the 5% cream formulation can be helpful in the treatment of some genital warts.

5-FU is applied 1-3 times per week for several weeks as needed. Before application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly, and allow it to dry thoroughly. Remove dried cream 3-10 hours after application. Protection of the normal surrounding skin is imperative for preventing pain, burning, and ulceration. This therapy is often not tolerated by patients. Use of this agent should be limited.

Keratolytics

TCA and BCA are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. The cauterizing effect is comparable to the effect of cryotherapy or electrodesiccation. These physician-applied agents can be used on all types of cutaneous warts. Salicylic acid is a milder keratolytic that is typically purchased in nonprescription formulations. This patient-applied medicine is used primarily to treat nongenital cutaneous warts.

TCA, in a 80-90% concentration, is the authors’ first choice for treatment of vulvar or vaginal condyloma in pregnant women. TCA should be applied to the condyloma after pretreatment of the surrounding normal skin with petroleum jelly. As the acid dries, a white frosting develops and should be powdered with sodium bicarbonate to remove any unreacted acid.

Effective treatment usually requires weekly application for 4-6 weeks. The principal side effect is pain and burning if the TCA comes in contact with the normal skin. Although TCA is caustic, it causes less local irritation and systemic toxicity than other agents in the same class; however, response is often incomplete and recurrence common.[82]

Sinecatechins

Sinecatechins ointment is another option. Several randomized, double-blind, placebo-controlled trials demonstrated good clearance of external genital warts. In a trial of patients treated with 15% sinecatechins ointment 3 times per week for up to 16 weeks, complete clearance of all baseline and newly occurring anogenital warts was obtained in 57% of 502 patients treated.[83] The primary side effects were erythema, pruritus, and pain.[84] This agent is cheaper than imiquimod,[85] and the recurrence rate is as low as 5%.

Surgical Ablation

Various surgical techniques are available for the treatment of HPV disease. With the exception of cryosurgery, these modalities usually have the common advantage of complete treatment following one application. However, surgical modalities typically require local anesthesia and more time and equipment to implement. Consequently, they are often used when a large number of warts is present or a large area is affected or on patients with refractory disease.

Primary surgical therapy can often be accomplished in the office and includes the following options:

Alternative surgical procedures requiring more advanced equipment and training include carbon dioxide laser ablation, Cavitron Ultrasonic Surgical Aspiration (CUSA), and Mohs surgery.

The location, size, or extent of the lesion and the potential for malignant transformation largely dictate treatment. Uncomplicated lesions can be treated with chemical ablation, cryoablation, surgical excision, or laser treatment. Treatment options for cervical neoplasia depend on the stage of the disease.

Overall, physical destruction or excision has been more effective in eradicating genital warts than medical therapy. Recurrences are common due to the virus residing in the basal layer of the epidermis in a latent state. Retreatment is frequently necessary. Recurrence of HPV disease is less common after surgical treatment compared with medical therapy, but the rate remains relatively high (25-55%).

Cryosurgery

Cryosurgery is a rapid and effective means of treating simple HPV disease. It works by freezing the intracellular water, resulting in cellular destruction. This method is effective for most simple cutaneous warts and for low-grade cervical intraepithelial neoplasia (CIN I). The primary drawbacks of the procedure are discomfort, ulceration, and scabbing at the treatment site.

Warts on the shaft of the penis and vulva respond very well to cryotherapy. Cryotherapy of the rectum is painful and less successful. Cryotherapy is not recommended for use in the vagina because the depth of ablation cannot be controlled and damage to adjacent structures, such as the bladder and rectum, is possible.

Because cryotherapy does not result in any systemic absorption, it is safe for women who are pregnant during the second and third trimesters of pregnancy, as well as for the fetus. It is the authors’ treatment of choice for pregnant women when TCA fails to eliminate vulvar condyloma.

Liquid nitrogen is applied to the wart using a cotton-tipped applicator, a cryoprobe, or a fine spray. Gases, such as nitrous oxide and carbon dioxide, can also be used. Although the procedure is somewhat painful, local anesthesia typically is not employed.

The freeze-thaw-freeze method is considered more effective than a single freeze. Application is continued until up to a 5-mm margin of surrounding skin or mucosa is frozen. After the skin turns white, freezing is continued for 30 seconds, after which time the skin is allowed to thaw. If the patient can tolerate the pain, a second cycle is applied. Within 24 hours after treatment, a bulla forms over the treated area. An additional course of treatment can be applied in 1-2 weeks as necessary.

After 2-4 treatments in a 6- to 12-week period, 75-80% of patients experience a complete clearing of warts. Data from several clinical trials reported a 63-88% clearance 3 months after therapy. A trial evaluating cryotherapy alone against cryotherapy combined with podophyllotoxin failed to demonstrate an improved outcome with the combination therapy.[86] The recurrence rate (22%) is similar to that of electrosurgery.

Electrosurgery

Electrosurgical modalities use high-frequency current to cut and coagulate warts. Electrodesiccation with a bipolar needle is most effective with external genital warts; LEEP is primarily used to treat cervical squamous intraepithelial lesions (SILs) after confirmation with a cervical biopsy but may also be used to remove large external genital warts.

Electrosurgical methods usually require only local anesthesia and may be employed in an outpatient setting if the appropriate equipment is available. Because HPV DNA has been found in smoke plumes, procedures to evacuate the smoke and prevent inhalation must be followed.

Electrosurgery is quite effective for a limited number of lesions on the shaft of the penis. Large unresponsive lesions around the rectum or vulva can be treated with scissor excision of the bulk of the mass followed by electrocautery of the remaining tissue down to the skin surface. Removal of a very large mass of warts is a painful procedure, best performed with the patient under either general or spinal anesthesia.

Pain after surgery is common and can be treated with narcotic analgesics. Topical analgesics, such as lidocaine jelly, can be beneficial to some patients. The recurrence rate in one trial was 22%, compared with 44% for podophyllin.

Surgical excision

Simple surgical excision with a scalpel, scissors, or curette can be performed to remove warts (especially large genital warts) and treat SILs of the genital tract. It is generally reserved for refractory cases or extensive disease. The procedure is usually performed in an outpatient surgical suite. The individual lesions are removed with a knife after general or regional anesthesia is administered, and the surgical specimen is submitted for microscopic analysis.

Reports in the literature indicate that within one year of surgery, complete wart clearance occurs in 35-72% of individuals treated with surgical excision. One report found surgical excision as effective as laser surgery.[87]

Patients with a few small lesions can have their vulvar condylomata removed in the office under local anesthesia. The underlying skin is anesthetized with 1% lidocaine, and the warts are removed with a No. 15 knife blade. One or 2 sutures may be needed to reapproximate the healthy skin.

For recurrent carcinoma, Mohs surgery is a good choice. Mohs surgery can be performed by specially trained dermatologists to excise tissue in areas where maximum conservation is required. This method uses dermatopathology in conjunction with conservative excision of malignant lesions. It may be of particular assistance in managing verrucous carcinomas.

Laser surgery

Carbon dioxide laser vaporization is generally performed in an outpatient setting with general or regional anesthesia. Most patients experience significant discomfort beginning 24 hours after surgery and require narcotic analgesia.

Carbon dioxide laser vaporization is typically used for treatment of refractory HPV disease or extensive warts of the anogenital-mucosal category and is particularly useful in the treatment of periurethral and vaginal warts and vaginal SILs. It is the treatment of choice for pregnant women with extensive lesions or lesions that do not respond to TCA.

Carbon dioxide laser therapy is an efficient therapeutic modality because of its precision and rapid healing without scarring. Laser treatment of vulvar condylomata acuminata effectively destroys the lesions while sparing adjacent healthy tissue. As in electrosurgery smoke plumes, HPV DNA has been found in laser smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.

The amount of energy needed to remove a condylomatous lesion with the laser depends on several parameters controlled by the surgeon, including the following:

Some researchers calculate the power density, which equals the power (watts) divided by the area (cm2). No exact power density is needed to remove vulvar or vaginal condylomata. The surgeon must therefore be flexible in applying laser therapy to an individual patient. If the laser is calibrated to 20 W in continuous mode, the spot size can easily be adjusted to provide the proper power density.[88]

Complete wart clearance after laser surgery has been reported to occur in 23-52% of patients within 3 years of surgery, and primary cure rates as high as 91% have been reported. The recurrence rates are similar to those of surgical excision.[89]

Pulsed-dye lasers and other types of lasers have been used by some, with varying degrees of success.

Cavitron Ultrasonic Surgical Aspirator

The CUSA vibrates at a frequency of 23 kHz, which is an order of magnitude lower than the frequency of a diagnostic ultrasound scan. It destroys tissue through heat and cavitation. This device has been used extensively for cytoreduction of intra-abdominal tumors because of its ability to remove epithelium without damaging underlying tissue. Consequently, it has been employed as an alternative therapy for extensive anogenital warts.

Complications of Treatment

Overall, complications of wart treatment are rare. They are generally confined to the treatment site and include scarring and, in the case of genital warts, vulvodynia or hyperesthesia.

Each therapeutic modality carries its own unique set of risks. Expected effects of cryosurgery include pain, edema, vesicles, bullae, weeping, and some necrosis. There is a small risk of infection, bleeding, abnormal scarring, pigment alteration, paresthesias, and alopecia with cryosurgery. Similarly, laser therapy for genital warts may result in pigment alteration, abnormal scarring, and infection. Special care must be taken to prevent respiratory infection from the laser plume generated by vaporization of virally infected tissue.

Surgical complications of treating SILs are discussed in the individual articles involving those diseases, as follows:

Diet and Activity

Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis. Folate deficiency apparently facilitates incorporation of HPV DNA at a fragile chromosomal site, thereby establishing a basis for malignant transformation.

The patient should refrain from sexual contact after any surgical procedure for condylomata acuminata. No other activity restrictions exist, although patients often have trouble sitting for long periods in the first week after surgery. Patients who have condylomata removed from the periurethral area may also experience dysuria.

Soaking the genital area in warm water or sitz baths usually offers excellent pain relief; topical analgesics can be beneficial. The genital area should be dried gently with a towel or a hair dryer. Loose-fitting cotton underwear is helpful to prevent chafing.

Prevention

Initially approved in 2014, the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) is the only available vaccine in the United States shown to decrease the risk of certain cancers and precancerous lesions in males and females aged 9-45 years. 9vHPV vaccine covers HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. Cervarix (2vHPV) and Gardasil (4vHPV) were discontinued in the United States in October 2016. Children and adolescents aged 15 years and younger need two, not three, doses of the 9vHPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The schedule for older adolescents and young adults aged 15-45 years is three inoculations within 6 months.

The World Health Organization (WHO) recommends vaccination against HPV subtypes 16 and 18.[42]

Approval for adults aged up to 45 years was based on a study of approximately 3200 women aged 27-45 years monitored for an average of 3.5 years. 9vHPV vaccine was 88% effective in preventing the combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine.[90, 91]

Effectiveness of 9vHPV in men aged 27-45 years is inferred from the data described above in women, as well as efficacy data in younger men (aged 16-26 years) and immunogenicity data from a clinical trial in which 150 men aged 27-45 years received a 3-dose regimen over 6 months.[91]

9vHPV indications

9vHPV is indicated for prevention of the following neoplastic diseases in women:

9vHPV is indicated for prevention of the following precancerous or dysplastic lesions in females:

9vHPV is indicated for prevention of the following neoplastic diseases in males:

9vHPV is indicated for prevention of anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 in males.

The vaccine is most effective when given before the onset of sexual activity. Its impact on the incidence of cervical cancer will not be observable for years.[92] Effectiveness will depend on the duration of immunity and will be optimized by achieving maximum coverage of the target population.[93] Vaccination against particular HPV types is most effective in preventing infections from these viruses in individuals who have not previously been infected with these types.[94]

Catch-up vaccinations are recommended in previously unvaccinated children and adults.[95]

A report from the CDC indicated that HPV vaccine uptake among teens continues to increase. In 2017, an average of 65.5% of teens aged 13-17 years had received at least 1 HPV vaccination, an increase of 5.1% compared with 2016. In addition, 48.6% had received the complete vaccination regimen appropriate for their age, an improvement of 5.2% compared with 2016. As in 2016, HPV vaccination coverage (ie, 1 or more doses) was lower among adolescents living in nonmetropolitan statistical areas (MSAs) (59.3%) than among those living in MSA principal cities (70.1%).[96]

A randomized double-blinded trial in more than 2000 young females given placebo or HPV-16 vaccine indicated that vaccine protection was potentially efficacious against HPV infection.[97] The females in the vaccine group did not develop HPV-16 infection or cervical dysplasia during the study period. The seroconversion rate with antibody titers to HPV-16 was almost 100%. In comparison, 41 females in the placebo group developed HPV-16 infection, and cervical dysplasia was diagnosed in 9 of them.

In a double-blinded placebo-controlled trial that tested a quadrivalent HPV vaccine (HPV types 6, 11, 16, and 18) in 277 young females who were observed on average for 3 years, women who received the vaccine had a 90% reduction in infection with these 4 HPV types in comparison with females who received placebo.[98] Other studies have also yielded good results,[99, 100] but further data on the safety of the vaccine and the longevity of immune responses to the vaccine are still needed.

Routine use of the vaccine may be expected to reduce the incidence of HPV-associated anogenital diseases in young women. In 2009, a sexual health center in Australia reported a rapid and marked reduction in the incidence of genital warts among vaccinated women. This benefit was extended to heterosexual males, in that fewer men presented to this health center with genital warts.[101] The HPV vaccine is neither intended nor proved to treat genital warts.[102]

Another Australian report, a case-control study of 108,353 young women, found that the quadrivalent vaccine provided significant protection against cervical abnormalities.[103, 104]

A large retrospective study from California found that routine administration of quadrivalent HPV vaccine to females was not associated with any new safety concerns.[105, 106] This trial included a total of 189,629 patients aged 9 to 26 years who received at least 1 dose of the quadrivalent vaccine (any-dose population) and a subset of 44,001 patients who received all 3 recommended doses within 12 months (3-dose population). Study findings included the following:

These findings[105, 106] were consistent with those of a previous study documenting a higher rate of reporting syncope to the passive Vaccine Adverse Event Reporting System after administration of quadrivalent vaccine; however, they conflict with those of the Vaccine Safety Datalink study, which did not detect a comparable increase. The investigators suggested that within this age group, injections, rather than the vaccine specifically, could be related to syncope. Further studies will be needed to clarify the issue.

With regard to other possible adverse effects, a self-controlled case series using data from Danish national registries found no increased risk of venous thromboembolism (VTE) among women who had received quadrivalent HPV vaccination. The rate of VTE was 0.126 per person-year in the 42 days following receipt of a vaccine dose and 0.159 per person-year during control periods.[107, 108]

Some research groups remain skeptical of the value of the HPV vaccine, arguing that the design of the relevant clinical trials and the interpretation of the efficacy and safety data have not been sufficiently rigorous and that vaccines have not actually been shown to prevent a single case of cervical cancer. From this perspective, it might be preferable to focus on cervical screening and targeting other factors of the disease rather than on vaccination.

Additional information is available in the following clinical guideline summaries:

A randomized, double-blind, placebo-controlled trial demonstrated that the quadrivalent HPV vaccine prevents infection with HPV types 6, 11, 16, and 18 and prevents the development of related external genital lesions in males aged 16-26 years.[109]

Vaccination of men who have sex with men (MSM) appears to decrease the incidence of anal cancer and genital warts. In one study, vaccination with the quadrivalent vaccine reduced the rate of anal intraepithelial neoplasia (AIN) in comparison with placebo.[110] In the 2 MSM populations studied (551 in the intention-to-treat population and 402 in the per-protocol population), the vaccine had 77.5% efficacy against AINs associated with HPV 6, 11, 16, or 18 in the per-protocol population and 50.3% efficacy in the intention-to-treat population.

The cost effectiveness of this intervention is maximized when vaccination is given as early as age 12 years.[111]

Assessment of sex partners

Because genital warts are sexually transmitted, the risk of acquiring HPV is primarily dependent on several factors related to sexual activity, including the following:

Although a high prevalence of HPV-associated penile SILs exists in the male sex partners of women with cervical SILs, examination of these men is not necessary for management of HPV disease. Nevertheless, sex partners of patients with HPV disease may benefit from examination and a detailed evaluation for sexually transmitted diseases (STDs).

Women should avoid skin-to-skin contact with partners if genital warts are visible. Condom use may reduce the transmission of HPV to uninfected sex partners, but it does not eliminate the risk. Furthermore, patients must be made aware that treatment does not eliminate the possibility of HPV transmission, because latent virus still may be present in tissues adjacent to treated areas.

A study by Wawer et al showed that women were less likely to acquire high-risk infection with HPV if their partners were circumcised.[112] However, circumcision does not eliminate the risk of HPV transmission.

Consultations

Consult a gynecologic oncologist for assistance in management of genital tract SILs and carcinomas, as well as exophytic cervical warts and giant condylomata.

Consult a urologist or a urogynecologist for assistance with surgical management of urethral warts, penile condylomata, SILs, or carcinomas.

Consult a colorectal surgeon for assistance with the surgical management of perianal condylomata or anal SILs or carcinomas.

Consult an otolaryngologist for assistance with management of oropharyngeal papillomas or SCC.

Consult a dermatologist for assistance with management of epidermodysplasia verruciformis (EV). Bleeding warts, moles, birthmarks, or unusual warts with hair growing from them can be confused with HPV disease; refer these types of lesions to a dermatologist for diagnostic clarification. Dermatologists who specialize in Mohs surgery may be of particular assistance in managing verrucous carcinomas.

Consult an infectious disease specialist for assistance in management of HPV disease in patients who are immunocompromised.

Consider consulting a proctologist for individuals who have perianal or anal warts or in whom anal dysplasia is suspected. This is especially true for individuals infected with HIV.

Long-Term Monitoring

Because HPV resides in the basal layer of the epidermis in a latent state, recurrences are common and retreatment is often necessary. Patients typically are monitored on a periodic basis to assess for efficacy of treatment, unwanted side effects, and the development of complications. Outpatient follow-up care also provides an opportunity to evaluate for other STDs and provides patient education on an ongoing basis.

Patients who complete therapy for condylomata acuminata should undergo clinical examination 3 months and 6 months after treatment. Most patients who develop recurrent or persistent disease are diagnosed within 6 months of therapy. If the patient appears disease-free at the 6-month visit, yearly visits are recommended. For anal and rectal lesions in the context of HIV infection, frequent follow-up is essential.

The sexual partner or partners of a woman with condyloma acuminatum should be examined by a physician and treated if indicated. Often, examination of the male fails to reveal any visible condyloma.

For genital neoplasia, careful follow-up is mandatory. High-risk (oncogenic) DNA testing is appropriate as routine cervical cancer screening in conjunction with cervical cytology in women aged 30 years and older. In women with negative cytology results but positive HPV results, repeat both tests in 12 months. When results of both cytology and HPV testing are negative, repeat both tests at 3-year intervals.

Treatment of CIN I may be monitored safely with serial cytology, HPV DNA detection, and colposcopy in reliable patients. Perform Pap tests every 6 months and colposcopy every 2 years. Treatment options include carbon dioxide laser ablation or excision, cryotherapy for lesions of 2 quadrants or less, cone biopsy, and LEEP.

Guidelines on Human Papillomavirus Vaccination by the American Cancer Society

Guidelines on human papillomavirus vaccination by the American Cancer Society (ACS) are as follows:[113]

Advisory Committee on Immunization Practices Guidelines on Human Papillomavirus Vaccination

The following are the Advisory Committee on Immunization Practices (ACIP) guidelines on human papillomavirus vaccination:[114]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The medications used to treat human papillomavirus (HPV) infections are primarily designed to ablate the lesion by virtue of their corrosive properties. Although medical treatments have historically been destructive, immunomodulatory agents have now been introduced into practice.

Keratolytic agents like TCA and bichloracetic acid (BCA) are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. They can be used to treat nongenital cutaneous warts, as well as external genital warts (EGWs) or condylomata acuminata.

For most patients, simple topical therapies are the initial treatments of choice; they are cost effective and result in minimal toxicity. Most such therapies successfully eliminate visible condylomata in 30-90% of cases. However, many clinical studies examining topical therapies are not well designed, making comparisons between therapies difficult.

The HPV 2-valent vaccine (Cervarix), which covered types 16 and 18, and the HPV 4-valent vaccine (Gardasil), which covered types 6, 11, 16, and 18, were discontinued in the United States in October 2016. The HPV 9-valent (Gardasil 9) is the only HPV vaccine available in the United States.

Table 2. HPV Vaccine: Indications Approved in the United States for Females



View Table

See Table

Table 3. HPV Vaccine: Indications Approved in the United States for Males



View Table

See Table

Imiquimod (Aldara, Zyclara)

Clinical Context:  Imiquimod is an imidazoquinolinamine derivative that has no in vitro antiviral activity but does induce macrophages to secrete cytokines such as interleukin (IL)-2 and interferon alfa and gamma. Its mechanisms of action are unknown. Imiquimod has been studied extensively and is a new therapy relative to other EGW treatments. It may be more effective in women than in men.

Imiquimod is dispensed as an individual dose. Patients are advised to wash the affected area with mild soap and water upon awakening and to remove residual drug.

Interferon alfa-n3 (Alferon N)

Clinical Context:  Interferon alfa is a protein product either manufactured from a single-species recombinant DNA process or obtained from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus.

The mechanisms by which interferon alfa exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).

Interferon alfa-2b (Intron A)

Clinical Context:  This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).

Class Summary

Immune response modifiers have immunomodulatory effects and are used for treatment of external anogenital warts (EGWs) or condylomata acuminata. Interferon alfa, beta, and gamma may be administered topically, systemically, and intralesionally. They stimulate production of cytokines and demonstrate strong antiviral activity.

Podofilox (Condylox)

Clinical Context:  Podofilox is a topical antimitotic that can be synthesized chemically or purified from the plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum). It is the active agent of podophyllin resin and is available as a 0.5% solution. Treatment results in necrosis of visible wart tissue; the exact mechanism of action is unknown. Treatment should be limited to no more than 10 cm2 of wart tissue, and no more than 0.5 mL/day of solution should be given. This is a patient-applied therapy.

Podophyllum resin (Podocon-25)

Clinical Context:  Podophyllin is derived from May apple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, a cytotoxic substance that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of podophyllotoxin that Indian podophyllum does. The potency of podophyllin varies considerably between batches. The exact mechanism of action is unknown.

Podophyllin is used as a topical treatment for benign growths, including external genital and perianal warts, papillomas, and fibroids. It results in necrosis when applied to anogenital warts. Only a trained medical professional can apply it, and it cannot be dispensed to a patient.

Trichloroacetic acid 85% (Tri-Chlor)

Clinical Context:  Trichloroacetic acid (TCA) is a highly corrosive desiccating agent that cauterizes skin, keratin, and other tissues and is used to burn lesions. Although it is caustic, it causes less local irritation and systemic toxicity than other agents in the same class. However, response often is incomplete, and recurrence is common.

Most clinicians use 25-50% TCA, although some use concentrations as high as 85% and then neutralize with either water or bicarbonate. Tissue sloughs and subsequently heals in 7-10 days. TCA therapy is less destructive than laser surgery, electrocautery, or cryotherapy.

Salicylic acid (Compound W, Dr. Scholl's Clear Away Warts, Freezone)

Clinical Context:  By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin without affecting the structure of viable epidermis. It is used for removal of nongenital cutaneous warts, particularly common or plantar warts. Before application, wash the affected area. The wart may be soaked in warm water for 5 minutes. Dry the area thoroughly.

Class Summary

Antimitotic drugs arrest dividing cells in mitosis, resulting in the death of proliferating cells. They cause cornified epithelium to swell, soften, macerate, and then desquamate. Many of them are chemotherapeutic agents. The drugs listed below are used specifically for treatment of EGWs or condylomata acuminata.

Keratolytic agents are used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.

Fluorouracil topical (Efudex, Carac, Fluoroplex)

Clinical Context:  Topical 5-FU interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid and inhibits thymidylate synthetase, which subsequently reduces cell proliferation. Its primary indication is for topical treatment of actinic keratoses. Although it is not approved by the US Food and Drug Administration (FDA) for the treatment of warts, it has been used in adults, particularly for warts resistant to other forms of treatment. It is used for management of superficial basal cell carcinomas.

The solution contains either 2% or 5% 5-FU in propylene glycol, tris (hydroxymethyl) aminomethane, hydroxypropyl cellulose, paraben, and disodium edetate. The cream contains 5% 5-FU in white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and paraben. When topical 5-FU is applied to the lesion, the area undergoes a sequence of erythema, vesiculation, desquamation, erosion, and reepithelialization.

Class Summary

Antimetabolites interfere with nucleic acid synthesis and inhibit cell growth and proliferation. These are topical preparations that contain the fluorinated pyrimidine 5-fluorouracil (5-FU). Although these chemotherapeutic agents are not formally approved for use against warts, some studies have demonstrated a benefit against EGWs or condylomata acuminata.

Sinecatechins (Veregen)

Clinical Context:  Sinecatechins ointment is a botanical drug product for topical use that consists of extract from green tea leaves. It contains 15% sinecatechins and is available in 15- and 30-g tubes. Its mode of action is unknown, but it does elicit antioxidant activity in vitro. Sinecatechins ointment is indicated for topical treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients.

Class Summary

Sinecatechins is another topical product that has gained FDA approval for genital warts.

Human papillomavirus vaccine, nonavalent (Gardasil 9)

Clinical Context:  Induces humoral immune response to 9 HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated in males and females aged 9-45 years to prevent HPV-associated diseases.

Class Summary

The 9-valent HPV vaccine is indicated for prevention of HPV-associated neoplasias and precancerous genital lesions. The 2-valent and 4-valent vaccines were discontinued from the US market in 2016.

Children and adolescents aged 15 years and younger need two, not three, doses of the HPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The schedule for older adolescents and young adults aged 15-45 years is three inoculations within 6 months.

What is human papillomavirus (HPV)?Which medical conditions are associated with human papillomavirus (HPV)?Which physical findings are characteristic of human papillomavirus (HPV) infection?How is human papillomavirus (HPV) diagnosed?What is the role of lab testing in the diagnosis of human papillomavirus (HPV) infection?When is a biopsy indicated for the diagnosis of human papillomavirus (HPV) infection?Which histologic findings suggest human papillomavirus (HPV) infection?Which medications used in the treatment of human papillomavirus (HPV) infection?What are the primary surgical treatments of human papillomavirus (HPV) infection?What are alternative surgical procedures for the treatment of human papillomavirus (HPV) infection?What is the role of vaccination for the prevention of human papillomavirus (HPV) infection?Which areas of human papillomavirus (HPV) disease infection require further research?What is human papillomavirus (HPV)?How are mucosal human papillomavirus (HPV) infections classified?What are the clinical manifestations of human papillomavirus (HPV) infections?What are the different types of human papillomavirus (HPV)?How does human papillomavirus (HPV) infection result in malignancy?What type of virus is human papillomavirus (HPV)?What are characteristics of human papillomavirus (HPV)?What are the anatomic predilections for human papillomavirus (HPV)?What is the pathogenesis of human papillomavirus (HPV) infection?How does the human papillomavirus (HPV) replicate?What is the process of replication for human papillomavirus (HPV)?What is the expression of viral genes in human papillomavirus (HPV)?What is the pathophysiology of human papillomavirus (HPV)?What is the role of koilocytosis in the pathophysiology of human papillomavirus (HPV)?How does the genetic make-up vary among the viral genotypes of papillomavirus (HPV)?How are human papillomavirus (HPV) typed?What are the etiologic characteristics of human papillomaviruses (HPVs)?Which diseases are caused by human papillomaviruses (HPVs)?Which patients are at higher risk for malignant transformation of human papillomavirus (HPV) infection?What is the etiologic relationship between sexual activity and human papillomavirus (HPV) infection?What is the etiologic relationship between tobacco smoking and human papillomavirus (HPV)-caused malignancy?What is the etiologic relationship between oral contraceptive use and human papillomavirus (HPV)-related malignancy?What is the etiologic relationship between chewing betel quid and human papillomavirus (HPV)-related malignancy?What is the etiologic relationship between ultraviolet and x-ray irradiation and human papillomavirus (HPV)-related malignancy?What is the reporting system for human papillomavirus (HPV) infections in the US?What is the prevalence of human papillomavirus (HPV) infection in the US?Which population group has the highest rate of human papillomavirus (HPV) infection in the US?What is the incidence of genital warts the US?What are the Center for Disease Control and Prevention (CDC) estimates of human papillomavirus (HPV) prevalence?What are the trends in human papillomavirus (HPV) infection according to the National Disease and Therapeutic Index in the US?Which studies in the US report the lowest and highest prevalences of human papillomavirus (HPV) infection?What is the prevalence of condylomata in the US?How prevalent is papillomavirus (HPV) infection in cervical cancer in the US?What percentage of cancers are caused by human papillomaviruses (HPVs)?What is the global incidence of human papillomavirus (HPV) infection?What is the most common cancer caused by human papillomavirus (HPV) infection in developing countries?What is the global prevalence of high-risk human papillomavirus (HPV) in women with normal cervical cytology?What is the leading cause of cancer mortality among women with human papillomavirus (HPV) infection in developing nations?How does the prevalence of human papillomavirus (HPV) infection vary by age?What is the prevalence of human papillomavirus (HPV) infection stratified by age in US females?Which population group has the highest rates of genital human papillomavirus (HPV) infection?How does the prevalence of human papillomavirus (HPV) vary between women older than 30 years and younger than 30 years?Why is the prevalence of human papillomavirus (HPV) higher in younger women?How is genital human papillomavirus (HPV) infection transmitted from mothers to infants?What are the incubation and latency periods for human papillomavirus (HPV) in infants?Which population groups are at highest risk for nongenital warts due to human papillomavirus (HPV) infection?When does epidermodysplasia verruciformis (EV) develop from human papillomavirus (HPV) infection?How does the prevalence of human papillomavirus (HPV) infectionvary by sex?What are the racial predilections for human papillomavirus (HPV)?What is the prognosis of papillomavirus (HPV) infection?What is the disease progression of warts due to human papillomavirus (HPV) infection?What are clinical manifestations of human papillomavirus (HPV) infection of the vulva?What is the histologic evidence of human papillomavirus (HPV) infection on a cervical Pap smear?What are the risk factors for anogenital human papillomavirus (HPV) infection?Which factors increase the risk of persistent disease due to human papillomavirus (HPV) infection?What are the risk factors for anal cancer due to human papillomavirus (HPV) infection?What are the clinical manifestations of human papillomavirus (HPV) infection in males?What are the risk factors for epidermodysplasia verruciformis (EV) human papillomavirus (HPV) infection?What is the progression of disease in epidermodysplasia verruciformis (EV) human papillomavirus (HPV) infection?What is the prevalence of comorbid sexually transmitted diseases (STDs) in patients with genital warts?What is included in patient education information about genital warts and human papillomavirus (HPV) infection?What measures may reduce the risk for human papillomavirus (HPV) infection in women?How is human papillomavirus (HPV) infection prevented?What is the benefit of evaluating sex partners of patients with genital warts due to human papillomavirus (HPV) infection?What determines the clinical presentation of human papillomavirus (HPV) infection?What are the manifestations of genital infection due to human papillomavirus (HPV)?What are condylomata acuminata located in human papillomavirus (HPV) infection?How are genital warts characterized in human papillomavirus (HPV) infection?Which lesions are most common in human papillomavirus (HPV) infection of the cervix?What is the presentation of giant condyloma in human papillomavirus (HPV) infection?When do genital warts due to human papillomavirus (HPV) infection become clinically apparent?What are the signs and symptoms of condylomata acuminata in human papillomavirus (HPV) infection?How are papillomavirus (HPV) cervical infections usually diagnosed?What are the signs and symptoms of high-grade squamous intraepithelial lesion (HGSIL) in human papillomavirus (HPV) infection?What are the signs and symptoms of anal cancer in human papillomavirus (HPV) infection?What is the presentation of oral human papillomavirus (HPV) infection?What are the characteristics of common cutaneous warts (verruca vulgaris) in human papillomavirus (HPV) infection?What are the signs and symptoms of palmoplantar warts in human papillomavirus (HPV) infection?What is the presentation of warts in meat and fish handlers with human papillomavirus (HPV) infection?How are flat warts characterized in patients with human papillomavirus (HPV) infection?How is Bowenoid papulosis characterized in human papillomavirus (HPV) infection?What is the process of malignant conversion of skin lesions in patients with human papillomavirus (HPV) infection?What are the signs and symptoms of epidermodysplasia verruciformis (EV) in human papillomavirus (HPV) infection?Which factor determines the physical findings of human papillomavirus (HPV) infection?Which physical findings are typical of condylomata in human papillomavirus (HPV) infection?What are the physical findings of subclinical condyloma in human papillomavirus (HPV) infection?What are the possible complications of warts in human papillomavirus (HPV) infection?What are the complications of human papillomavirus (HPV) disease?What is the disease progression of condylomata acuminata in human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnosis of genital warts due to human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnoses of Bowenoid papulosis due to human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnoses of human papillomavirus (HPV) infection?What are the differential diagnoses for Human Papillomavirus (HPV)?How is human papillomavirus (HPV) diagnosed?What is the role of DNA testing in the evaluation of human papillomavirus (HPV) infection?What is the role of lab testing in the evaluation of condylomata acuminata?What is the role of imaging studies in the diagnosis of human papillomavirus (HPV) infections?What is the role of histology in the evaluation of human papillomavirus (HPV) infection?What are the Society of Gynecologic Oncology (SGO)/ American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines on human papillomavirus (HPV) screening and management?What is the role of cytologic testing in the evaluation of human papillomavirus (HPV) infection?What is the role of cervical metaplasia in the of human papillomavirus (HPV) infection?What is the role of Pap smear in the evaluation of human papillomavirus (HPV) infection?What are the benefits of liquid-based Pap smears for the diagnosis of human papillomavirus (HPV) infection?Where are the CDC guidelines for cytology proficiency testing in the diagnosis of human papillomavirus (HPV)?What are the methods for human papillomavirus (HPV) DNA testing?What is the role of human papillomavirus (HPV) DNA testing in the management of women with atypical squamous cells of undetermined significance (ASC-US)?What is the role of self-collected vaginal human papillomavirus (HPV) specimens in the surveillance of cervical intraepithelial neoplasia (CIN)?Which human papillomavirus (HPV) tests are under development?What are the FDA-approved indications for the human papillomavirus (HPV) DNA test?What is the role of the acetic acid test in the diagnosis of human papillomavirus (HPV) infection?How is the acetic acid test used to diagnose human papillomavirus (HPV) infection?What is the role of tissue biopsy in the diagnosis of human papillomavirus (HPV) infection?When is tissue biopsy indicated for the diagnosis of human papillomavirus (HPV)?When is biopsy of typical-appearing condylomata acuminata indicated?How is biopsy performed in the diagnosis of human papillomavirus (HPV) infection?What is the role of histopathology in the diagnosis of human papillomavirus (HPV) infection?Which histologic findings are characteristic of human papillomavirus (HPV) infection?Which histologic findings are characteristic of common cutaneous warts in human papillomavirus (HPV) infection?Which histologic findings are characteristic of condyloma acuminatum in human papillomavirus (HPV) infection?Which histologic findings are characteristic of Bowenoid papulosis in human papillomavirus (HPV) infection?What are the treatment options for condylomata acuminata due to human papillomavirus (HPV) infection?When is treatment of human papillomavirus (HPV) infection not recommended?Which factors influence treatment selection for human papillomavirus (HPV) genital warts?How are most human papillomavirus (HPV) infections treatment?What is the initial treatment for human papillomavirus (HPV) caused warts?How is human papillomavirus (HPV) infection managed in patients who are immunosuppressed?How frequently do human papillomavirus (HPV) caused condylomata acuminate recur?How is human papillomavirus (HPV) infection managed during pregnancy?What is the risk of perinatal human papillomavirus (HPV) transmission?How does maternal human papillomavirus (HPV) infection affect infant outcomes?How frequently is human papillomavirus (HPV) infection the cause of cervical cancer?Which patients with human papillomavirus (HPV) infection are at a higher risk of persistent lesions and malignancy?Which patients with human papillomavirus (HPV) infection are at increased risk for anal high-grade squamous intraepithelial lesion (HGSIL)?How are human papillomavirus (HPV) anogenital warts diagnosed in children?What are the risks of transmission of human papillomavirus (HPV) during pregnancy?When is cesarean delivery considered in mothers with human papillomavirus (HPV) infection?What risk is increased in immunosuppressed patients with human papillomavirus (HPV)?What is verrucous carcinoma of genitalia and how is it managed?How are medicines administered in the treatment of human papillomavirus (HPV) disease?What is the role of pharmacologic therapy in the treatment of human papillomavirus (HPV) disease?What is the role of imiquimod in the treatment of human papillomavirus (HPV) infection?What is the regimen for imiquimod in the treatment of human papillomavirus (HPV) infection?What is the role of interferons in the treatment of human papillomavirus (HPV)?What properties of interferon alfa may be beneficial in the treatment of human papillomavirus (HPV)?How is interferon alfa used in the treatment of human papillomavirus (HPV)?What is the efficacy of interferon in the treatment of human papillomavirus (HPV)?When is a second course of interferon given in the treatment of human papillomavirus (HPV) infection?What is the role of podofilox in the treatment of human papillomavirus (HPV) infection?What is the role of podophyllin in the treatment of human papillomavirus (HPV) infection?How is podophyllin administered in the treatment of human papillomavirus (HPV)?What are potential adverse effects of podophyllin therapy in the treatment of human papillomavirus (HPV) infection?What are the benefits of podofilox compared to podophyllin in the treatment of human papillomavirus (HPV) infection?What is the role of 5-fluorouracil (FU) in the treatment of human papillomavirus (HPV)?How is 5-fluorouracil (FU) administered in the treatment of human papillomavirus (HPV)?What is the role of keratolytic agents in the treatment of human papillomavirus (HPV) infection?What is the first choice for treatment fir vulvar or vaginal condyloma in pregnant women with human papillomavirus (HPV) disease?What is the duration of trichloroacetic acid (TCA) therapy for the treatment of human papillomavirus (HPV)?What is the role of sinecatechins ointment in the treatment of human papillomavirus (HPV) infection?How is cryosurgery used to treat human papillomavirus (HPV)?What is the role of surgery in the treatment of human papillomavirus (HPV) disease?What are the primary surgical therapies for the treatment of human papillomavirus (HPV) infection?What are alternative surgical procedures for the treatment of human papillomavirus (HPV)?What factors determine the selection of surgical procedure for the treatment of human papillomavirus (HPV) infection?Which treatment is most effective in eradicating genital warts in patients with human papillomavirus (HPV) infection?What is the role of cryotherapy in the treatment of human papillomavirus (HPV) disease?How safe is cryotherapy for treatment of human papillomavirus (HPV) infection?How is cryosurgery performed in the treatment of human papillomavirus (HPV) infection?What is the freeze-thaw-freeze cryosurgery method for the treatment of human papillomavirus (HPV) infection?What is the prognosis of human papillomavirus (HPV) infection following cryosurgery?How is electrosurgery used to treat human papillomavirus (HPV) disease?What is required for electrosurgery to treat human papillomavirus (HPV) disease?What is the effectiveness of electrosurgery for the treatment of human papillomavirus (HPV) infection?How is pain managed following electrosurgery for the treatment of human papillomavirus (HPV) infection?What is the role of simple surgical excision in the treatment of human papillomavirus (HPV) infection?How effective is surgical excision for the treatment of human papillomavirus (HPV) infection?How is surgical excision performed in the treatment of human papillomavirus (HPV) infection?What is the role of Mohs in the treatment of human papillomavirus (HPV) infection?What is the role of carbon dioxide laser vaporization in the treatment of human papillomavirus (HPV) infection?When is carbon dioxide laser vaporization typically used for the treatment of human papillomavirus (HPV) infection?What is the efficacy of carbon dioxide laser vaporization for the treatment of human papillomavirus (HPV) infection?How is the power density determined in laser vaporization of condylomatous lesions in human papillomavirus (HPV)?What is the efficacy of laser vaporization in the treatment of human papillomavirus (HPV) infection?What is the role of the Cavitron Ultrasonic Surgical Aspirator (CUSA) in the treatment of human papillomavirus (HPV) disease?What are the possible complications of warts in patients with human papillomavirus (HPV) disease?What are the risks of different therapeutic modalities for the treatment of human papillomavirus (HPV) infection?Where can information be found on the surgical complications of treating squamous intraepithelial lesions (SILs)?What is the role of folate deficiency in the malignant transformation of human papillomavirus (HPV) infection?Which activity modifications are required during treatment of human papillomavirus (HPV) disease?What are the options for pain management in human papillomavirus (HPV) disease?What is the role of the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) in the prevention of human papillomavirus (HPV) infection?What are the indications for the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) for prevention of human papillomavirus (HPV) infection?When is administration of the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) most effective?What is the efficacy of the human papillomavirus (HPV) 16 vaccine in females?What is the efficacy of quadrivalent vaccines against human papillomavirus (HPV) infection in females?What is an expected benefit of routine use of vaccines against human papillomavirus (HPV)?What is the efficacy of the quadrivalent human papillomavirus (HPV) in the prevention of cervical abnormalities?What is the safety data for the quadrivalent human papillomavirus (HPV) vaccines?What are possible adverse effects of the human papillomavirus (HPV) vaccine?What are possible limitations of the human papillomavirus (HPV) vaccine?Which organizations have provided guidelines for prevention of human papillomavirus (HPV) infection?What is the efficacy of the quadrivalent human papillomavirus (HPV) vaccines in males?What are the benefits of vaccination against human papillomavirus (HPV) in men who have sex with men?What is the cost effectiveness of human papillomavirus (HPV) vaccination?What percentage of teenagers have received the human papillomavirus (HPV) vaccine?What are the sexual risk factors of acquiring human papillomavirus (HPV) infection?How should male partners of women with human papillomavirus (HPV) infection be managed?What are limitations in the prevention of human papillomavirus (HPV) infection?What role does circumcision play in the prevention of human papillomavirus (HPV)?When should a gynecologic oncologist be consulted in the management of human papillomavirus (HPV) infection?When should an urologist be consulted in the management of human papillomavirus (HPV) infection?When should a colorectal surgeon be consulted in the management of human papillomavirus (HPV) infection?When should an otolaryngologist be consulted in the management of human papillomavirus (HPV) infection?When should a dermatologist be consulted in the management of human papillomavirus (HPV) infection?When should an infectious disease specialist be consulted in the management of human papillomavirus (HPV)?When should a proctologist be consulted in the management of human papillomavirus (HPV)?Why is recurrence of human papillomavirus (HPV) infection common?What monitoring is need following treatment of condylomata acuminata in patients with human papillomavirus (HPV) infection?How should sexual partners of women with condyloma acuminatum be managed?What is included in the long-term monitoring of genital neoplasia in patients with human papillomavirus (HPV) infection?How is the treatment of cervical intraepithelial neoplasia (CIN) monitored in women with human papillomavirus (HPV) infection?What are the American Cancer Society (ACS) guidelines on human papillomavirus (HPV) vaccination?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines on human papillomavirus (HPV) vaccination?What are the goals of drug treatment for human papillomavirus (HPV) disease?What is the role of keratolytic agents in the treatment of human papillomavirus (HPV) infection?What are the initial treatments for most patients with human papillomavirus (HPV) infection?Which vaccines for the prevention of human papillomavirus (HPV) infection are available in the US?Which medications in the drug class Vaccines, Inactivated, Viral are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Topical Skin Products are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Keratolytic Agents are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Immunomodulators are used in the treatment of Human Papillomavirus (HPV)?

Author

Peter A Gearhart, MD, Assistant Professor of Obstetrics and Gynecology, University of Pennsylvania School of Medicine

Disclosure: Received honoraria from Merck for speaking and teaching.

Coauthor(s)

Robert V Higgins, MD, Clinical Associate Professor, Department of Obstetrics/Gynecology, University of North Carolina School of Medicine; Residency Program Director, Vice-Chairman of Academic Affairs, Associate Director of Gynecologic Oncology, Department of Obstetrics/Gynecology, Carolinas Medical Center

Disclosure: Nothing to disclose.

Roland Michael Buckley, Jr, MD, Clinical Professor of Medicine, University of Pennsylvania School of Medicine; Consultant, Department of Medicine, Division of Infectious Diseases, Pennsylvania Hospital

Disclosure: Nothing to disclose.

Thomas C Randall, MD, Associate Professor of Clinical Obstetrics and Gynecology University of Pennsylvania School of Medicine; Director, Gynecologic Oncology, Pennsylvania Hospital

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Jeffrey D Band, MD Professor of Medicine, Oakland University William Beaumont School of Medicine; Director, Division of Infectious Diseases and International Medicine, Corporate Epidemiologist, William Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Ryan Brashear, MD Staff Physician, Department of Dermatology, Indiana University School of Medicine

Ryan Brashear, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Association

Disclosure: Nothing to disclose.

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Tsu-Yi Chuang, MD, MPH Clinical Professor, Department of Dermatology, Keck School of Medicine of the University of Southern California; Staff Dermatologist, Desert Oasis Healthcare

Tsu-Yi Chuang, MD, MPH is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, and International Society of Dermatology

Disclosure: Nothing to disclose.

Mark W Cobb, MD Consulting Staff, WNC Dermatological Associates

Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Society of Dermatopathology

Disclosure: Nothing to disclose.

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Mary D Nettleman, MD, MS, MACP Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Mary D Nettleman, MD, MS, MACP is a member of the following medical societies: American College of Physicians, Association of Professors of Medicine, Central Society for Clinical Research, Infectious Diseases Society of America, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha Omega Alpha, American Association for the Advancement of Science, American Association of University Professors, American Clinical and Climatological Association, American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Foundation for AIDS Research, American GeriatricsSociety, American Lung Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics and Gynecology, Infectious Diseases Societyof America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Nothing to disclose.

John D Shanley, MD, MPH Professor Emeritus, University of Connecticut; Professor of Preventive Medicine, Stony Brook Medical Center

John D Shanley, MD, MPH is a member of the following medical societies: American Association for the Advancement of Science, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.

Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.

The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies to the site of human papillomavirus infection.

The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.

Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.

Plantar warts.

Flat wart.

Human papillomavirus (HPV). Condyloma acuminatum in a patient with a history of an allograft renal transplant.

Human papillomavirus (HPV). Note the extensive labial involvement.

Human papillomavirus (HPV). Anal condyloma acuminatum.

Human papillomavirus (HPV). These condylomata extend to the anal verge.

"Cauliflower" condyloma of penis.

Small papilloma on shaft of penis.

Verrucous warts in patient with HIV infection.

Human papillomavirus (HPV). Condyloma acuminatum in a patient with a history of an allograft renal transplant.

Human papillomavirus (HPV). Note the extensive labial involvement.

Human papillomavirus (HPV). Anal condyloma acuminatum.

Human papillomavirus (HPV). These condylomata extend to the anal verge.

Verrucous warts in patient with HIV infection.

Plantar warts.

Flat wart.

"Cauliflower" condyloma of penis.

Small papilloma on shaft of penis.

Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.

This is a verruca vulgaris of the anterior maxillary gingiva in a healthy young male. He had recently resolved a wart on his finger.

These small papillomas on the lateral tongue of a young woman showed histologic evidence of HPV in the form of extensive koilocytosis.

Human papillomavirus (HPV) lesion on the lingual frenum. Some patients with condyloma acuminatum present with multiple oral lesions. Courtesy of A.K. ElGeneidy, DDS.

Human papillomavirus (HPV). Condylomata on the lower lip, as well as other sites at the initial presentation. This presentation is unusually extensive. Multiple condylomata may be synchronous or metachronous. This patient did not present with genital condylomata. Courtesy of A.K. ElGeneidy, DDS.

Human papillomavirus (HPV). Heck disease in the buccal mucosa of a 7-year-old boy. Courtesy of Sheldon Mintz, DDS.

Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.

Human papillomavirus (HPV). Condyloma acuminatum generally has a papillary architecture and may microscopically resemble verruca vulgaris and papilloma (hematoxylin and eosin stain, original magnification X10). Courtesy of AK ElGeneidy, DDS.

Human papillomavirus (HPV). Koilocytes in the upper epithelium are a helpful, although not completely reliable, indication that a lesion is associated with human papillomavirus. Koilocytes display a dark small nucleus with clear cytoplasm (hematoxylin and eosin stain, original magnification X100). Courtesy of Sheldon Mintz, DDS.

Human papillomavirus (HPV). Condyloma acuminatum may show brisk mitotic activity, although oral condyloma acuminatum is not considered a premalignant lesion (hematoxylin and eosin stain, original magnification X40). Courtesy of A.K. ElGeneidy, DDS.

The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies to the site of human papillomavirus infection.

The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.

Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.

Nongenital Cutaneous Disease HPV Type
Common warts (verrucae vulgaris)1, 2, 4, 26, 27, 29, 41, 57, 65, 75-78
Plantar warts (myrmecias)1, 2, 4, 60, 63
Flat warts (verrucae planae)3, 10, 27, 28, 38, 41, 49
Butcher’s warts (common warts of people who handle meat, poultry, and fish)1-4, 7, 10, 28
Mosaic warts2, 27, 57
Ungual squamous cell carcinoma16
Epidermodysplasia verruciformis (benign)2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign)5, 8-10, 14, 17, 20-25, 37, 38
Nonwarty skin lesions37, 38
Nongenital Mucosal Disease HPV Type
Respiratory papillomatosis 6, 11
Squamous cell carcinoma of the lung 6, 11, 16, 18
Laryngeal papilloma (recurrent respiratory papillomatosis)[15] 2, 6, 11, 16, 30, 40, 57
Laryngeal carcinoma 6, 11
Maxillary sinus papilloma57
Squamous cell carcinoma of the sinuses16, 18
Conjunctival papillomas6, 11
Conjunctival carcinoma 16
Oral focal epithelial hyperplasia (Heck disease)13, 32
Oral carcinoma 16, 18
Oral leukoplakia 16, 18
Squamous cell carcinoma of the esophagus 16, 18
Anogenital Disease HPV Type
Condylomata acuminata 1-6, 10, 11, 16, 18, 30, 31, 33, 35, 39-45, 51-59, 70, 83
Bowenoid papulosis 16, 18, 34, 39, 40, 42, 45
Bowen disease 16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors)6, 11, 57, 72, 73
Unspecified intraepithelial neoplasia30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66-69
Low-grade squamous intraepithelial lesions (LGSIL)6, 11, 16, 18, 26, 27, 30, 31, 33-35, 40, 42-45, 51-58, 61, 62, 67-69, 71-74, 79, 81-84
High-grade squamous intraepithelial lesions (HGSIL)6, 11, 16, 18, 31, 33, 35, 39, 42, 44, 45, 51, 52, 56, 58, 59, 61, 64, 66, 68, 82
Carcinoma of vulva 6, 11, 16, 18
Carcinoma of vagina16
Carcinoma of cervix [16, 17] 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82
Carcinoma of anus16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat)16
Carcinoma of penis 16, 18
DiseaseHPV 9-valent
Cervical cancer, vulvar cancer, vaginal cancer, anal cancerHPV types 16, 18, 31, 33, 45, 52, and 58
Genital warts (condyloma acuminata)HPV types 6 and 11
Cervical intraepithelial neoplasia (CIN) grade 1-3 and cervical adenocarcinoma in situ (AIS)HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
Vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN) grades 2 and 3HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
Anal intraepithelial neoplasia (AIN) grades 1-3HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58
DiseaseHPV 9-valent
Anal cancerHPV types 16, 18, 31, 33, 45, 52, and 58
Genital warts (condyloma acuminata)HPV types 6 and 11
Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3HPV types 16, 18, 31, 33, 45, 52, and 58