HPV Infection and Warts: Review and Recent Updates

RELEASE DATE:

April 1, 2017

EXPIRATION DATE:

April 30, 2019

FACULTY:

Adebola A. Adesoye, PharmD, BCPS
Assistant Professor, Ambulatory Care Division
Department of Pharmacy Practice
Texas Tech University Health Sciences Center
School of Pharmacy
Dallas/Fort Worth Campus
Dallas, Texas

Louis Lteif, PharmD, BCPS
Assistant Professor, Department of Pharmacy Practice
The Daniel K. Inouye College of Pharmacy
University of Hawaii
Hilo, Hawaii

Bernard Murray, PharmD, BCPS
Clinical Pharmacist, Internal Medicine
James A. Haley Veterans Hospital
Tampa, Florida

Ayotunde Ayoola, PharmD, BCPS
Nephrology Clinical Pharmacy Specialist
Kaiser Permanente Mid-Atlantic States
Largo Medical Center
Upper Marlboro, Maryland

FACULTY DISCLOSURE STATEMENTS:

Drs. Adesoye, Lteif, Murray, and Ayoola have no actual or potential conflicts of interest and no financial interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
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Credits: 2.0 hours (0. 20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists on human papillomavirus (HPV) infection, including available treatment options and recommended preventive measures.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Describe the prevalence, clinical manifestations, and risk factors associated with HPV infection.
  2. Identify appropriate preventive measures of HPV, including selection of appropriate vaccine products by age and gender.
  3. Discuss appropriate treatment modalities for cutaneous and anogenital warts.
  4. Review general patient education as it relates to HPV.

ABSTRACT: Human papillomavirus (HPV) is the most common sexually transmitted infection. Currently, over 200 types have been identified, with clinical manifestations ranging from asymptomatic infection to self-limiting warts to abnormalities that lead to different types of cancer. An appropriate screening method, along with prevention through vaccination, is key in deterring HPV-related diseases. Different treatment modalities are available for HPVrelated warts, although these do not cure the infection and warts often recur. Pharmacists can play an important role in educating patients and their sexual partners about HPV, screening, and preventive strategies, as well as the different treatment modalities available for cutaneous and genital warts.

Human papillomavirus (HPV) is a small, double-stranded DNA virus that infects the skin and mucous membranes.1-3 There are over 200 identified HPV types, differentiated by their outer capsid protein.1,3 Most of the HPV types infect cutaneous epithelium and can manifest as cutaneous warts.2 Over 40 identified varieties infect mucosal epithelium and are easily transmitted via anal, vaginal, or oral sexual contact; these are categorized according to their association with cervical cancer risk.1-3 Infection with low-risk or noncarcinogenic HPV types (such as HPV-6 and -11) is associated with cutaneous and genital warts, low-grade cervical-cell abnormalities, and laryngeal papillomas; they are responsible for the majority of anogenital wart (AGW) cases.1,2,4 Infection with high-risk or oncogenic HPV types (including HPV-16, -18, -31, -33, and -45) can cause low-grade cervical-cell abnormalities, as well as high-grade cervical abnormalities that are considered precursors to cancer, and these are responsible for the development of cervical cancer and other anogenital cancers.1-4

There is no cure for HPV infection; however, there are several recommended HPV prevention strategies and treatment options for individuals who develop warts as a result of HPV infection. Warts are often self-limiting and resolve without treatment. Therefore, watchful waiting may be an option. Many patients, however, may prefer to seek treatment. Available treatment modalities focus on removing the affected area, but recurrence is common.5 This article aims to review HPV infections, including recent updates in preventive measures, as well as available treatment options for cutaneous and genital warts.

EPIDEMIOLOGY

It is estimated that approximately 14 million new HPV infections occur annually in the United States, with half of these presenting among persons aged 15 to 24 years, and about 79 million Americans are currently infected with HPV.2,5,6 HPV is the most common sexually transmitted infection; the CDC estimates that more than one-half of all sexually active men and women will be infected with at least one HPV type at some point during their lifetime.1,5,6 Although the host immune system most often successfully clears these infections within 2 years, a number of infected individuals will develop clinically manifested disease such as cutaneous warts, AGWs, cervical dysplasia, and in severe cases, invasive cervical cancer. Persistent HPV infection—infection that does not spontaneously resolve—may also present without any symptomatic manifestation.1

Nongenital cutaneous warts are more common in children and adolescents than in infants and adults, with a peak incidence in adolescence, but sexually active men and women have a greater risk for AGWs.1,2 AGWs are highly infectious and also carry a high viral load, such that approximately 65% of individuals who have sexual contact with infected partners develop genital warts within 3 to 8 months.7-9 Reported annual incidence rates of AGW worldwide range from 100 to 200 new cases per 100,000 general adult population.8 It is thought, however, that the prevalence data are limited, as patients may have a limited capacity to recognize genital warts or are unwilling/unable to seek treatment.8

Ninety-nine percent of cervical cancer cases are linked to high-risk HPV types.2 HPV-16 is responsible for approximately 50% of cervical cancers worldwide.2 In addition to cervical cancer, HPV is believed to be responsible for 90% of anal cancers; 71% of vulvar, vaginal, or penile cancers; and 72% of oropharyngeal cancers.2 Cervical cancer represents the second most common malignancy in women around the world, contributing to approximately 10% of all cancers in the female population, and approximately a quartermillion deaths among women each year.10,11 Cervical cancer has a peak incidence at age 40, and testing for persistent HPV infection is most useful only between the ages of 30 and 40 years.11,12 Cervical cancer also was the first cancer to be recognized as 100% attributable to an infection, and it is usually preceded by many years of persistent HPV infection.11,12

TRANSMISSION

Humans are the only natural reservoir of HPV, and the primary mode of transmission is through direct epithelialand mucosal-tissue contact, most commonly via the sexual (vaginal, anal, or oral) route.5 Infection with HPV is not limited to the genital tract; it can also be transmitted via nonsexual routes such as perinatal transmission, a rare mode of transmission.3-5,13 Genital HPV infection is highly transmissible even when the male wears a condom (through noncovered areas), although the use of physical barriers can reduce the risk of transmission.2 Male partners are more likely to be co-infected with multiple HPV types, including nononcogenic HPV, suggesting a less effective immune clearance of the virus in this population.12-14

PATHOPHYSIOLOGY AND EPIDEMIOLOGY

HPV is nonenveloped with an icosahedral capsid containing a double-stranded circular DNA of 8,000 base pairs that codes for early nonstructural genes (E1, E2, E4, E5, E6, and E7); a noncoding region; and the late structural genes (L1, L2), which encode the capsid.3,18 Both the early genes and the noncoding region are involved in the regulation of replication and gene function, as well as the interaction with the host genome.3,18 The E6 and E7 genes encode viral oncoproteins and are more active in high-risk HPV types; they interfere with the tumor-suppressor protein p53 and retinoblastoma, respectively, resulting in cell immortalization.14,19

Infection with HPV is thought to occur through microlacerations that expose the basal cells to viral entry. In the course of infection, the HPV accesses the continuously dividing basal cells of differentiating epithelium, integrating itself into the nuclei of the infected host genome and establishing its genome as multicopy episomes.3,19 The viral DNA is then replicated with the host cellular DNA.19 The incubation period can be as long as 8 months, with an average of approximately 3 months.12

Most HPV types are specific, infecting only certain epithelial sites, such as the anogenital region (the cervix included), hands, or feet.19 HPV is thought to be transmissible during acute and persistent infection; however, the study of transmission remains a difficult task given that the virus cannot be cultured.2

Identified risk factors for infection with HPV include younger age, Hispanic or African American ethnicity, high number of sexual partners and high frequency of sexual intercourse, co-infection with other microbes, anal sex, and alcohol use.4,5,14,20 Identified risk factors for developing malignancies include persistent infection with the high-risk HPV type (which poses the greatest risk), smoking, high number of lifetime sexual partners, HIV co-infection, and immunosuppression.19,21

CLINICAL MANIFESTATIONS

HPV infections can manifest as clinical, subclinical, or latent infections.3 Clinical HPV infections, such as warts, are typically symptomatic and easily identified, whereas subclinical and latent infections can be difficult to detect.3 The most common epithelial manifestations resulting from HPV infection are warts. These are typically caused by low-risk types and can differ in characteristics based on causative HPV type as well as epithelial site of infection on the body. These lesions can be classified as cutaneous, anogenital, or extracutaneous warts.3,22

TABLE 1 lists the various types of cutaneous warts and the most common skin locations. Approximately 70% of all warts are common warts.7,22 A commonly used term, condyloma acuminata, refers to wart manifestation in the anogenital region. Over 90% of condyloma acuminata are caused by infection with the low-risk HPV-6 or HPV-11.7 AGWs can involve the vulva, vagina, penis, scrotum, urethra, and rectum.7,22 HPV infection of the genital tract can also manifest as low-grade lesions, termed dysplasias, or cervical intraepithelial neoplasia grade I or high-grade lesions.3,8 Extracutaneous warts, although rare, are those that involve the conjunctiva, oral region, or larynx.7,22 A rare case of clinical manifestation of HPV infection in the oropharynx, caused by low-risk types, is recurrent respiratory papillomatosis, the mechanism of which is not yet fully understood.1,3,14


Warts are often mistaken for other hyperkerotic lesions; however, these can be distinguished by eroded skin patterns, such as the ridges of the soles in the case of plantar warts, and pinpoint bleeding when the skin surface layer is removed.15

In most cases, the HPV infection is cleared through cell-mediated immunity and resolves spontaneously, with 90% of infected persons achieving complete resolution within 2 years. However, in rare cases, the infection persists as different stages over decades.3,12,18,19 It is not well understood why HPV infection spontaneously resolves in some individuals, but not in others.4

SCREENING

The incidence of invasive cervical cancer and associated mortality could be significantly reduced with appropriate screening. Recommendations are provided by many major U.S. organizations, including the American Cancer Society, the American College of Obstetricians and Gynecologists, and the U.S. Preventive Services Task Force, all of which tend to be in accordance. Screening methods include cervical cytology (conventional vs. liquid-based), HPV testing, HPV co-testing (cytology plus HPV testing), and colposcopy.23-25 TABLE 2 briefly outlines the recommendations for screening.


Screening Methods
Cervical cytology may be performed as conventional cytology or liquid-based cytology.23 Conventional cytology refers to the direct transfer and smearing of cervical scrapings on microscopic slides and is commonly referred to as Papanicolaou (Pap) smear, Pap test, or cervical smear. Liquid cytology applies the same principles; however, the collected sample is first transferred to a vial of liquid preservative and later processed to produce a slide.23

Another screening method is HPV DNA testing.26 This is utilized for detection of high-risk oncogenic strains if results from cervical cytology warrant further investigation. Most tests commonly target HPV-16 and -18, while some FDA-approved tests detect more than 14 high-risk oncogenic strains. HPV DNA testing alone is not recommended as a routine screening method.26Colposcopy is useful in finding the areas of cervix with the highest degree of disease and determining the presence of epithelial lesions. A direct biopsy to be sent for histology can also be obtained through colposcopy.24

PREVENTION

HPV is one of the few vaccine-preventable sexually transmitted infections. Currently, three different prophylactic vaccines aimed at reducing rates of HPV infection are available in the U.S., and they contain different HPV types: Cervarix (bivalent or 2-valent HPV; recently, the manufacturer stopped supplying to the U.S. market due to very low sales), Gardasil (quadrivalent or 4-valent HPV), and Gardasil 9 (9-valent HPV). TABLE 3 lists the currently available vaccines.


The efficacy of the 4-valent vaccine was evaluated in a placebo-controlled trial of males aged 16 to 26 years.27 Study findings revealed 90% efficacy against development of genital lesions and 86% efficacy against persistence of HPV in HPV-naïve males who completed the three-dose series.27 Lesser efficacy was observed for the overall population with or without HPV infection at enrollment (66% and 48%, respectively), thus demonstrating enhanced efficacy of vaccination prior to HPV infection.27 A subgroup analysis of men who have sex with men also found that the vaccine demonstrated superior efficacy in prevention of anal cancer in a HPVnaïve population (78% vs. 50%).27

Two large placebo-controlled trials, also evaluating the efficacy of the 4-valent vaccine, reported 97% to 100% efficacy in preventing cervical cancer in HPVnaïve females followed for up to 3 years, versus 44% in the total population, including nonnaïve patients.28,29A large study involving 18,000 females aged 15 to 25 years that assessed the efficacy of the bivalent vaccine (Cervarix) demonstrated 93% efficacy in preventing cervical cancer in HPV-naïve females followed for up to 3 years versus 53% in the total population, including nonnaïve patients.30

The newest approved vaccine, the 9-valent is indicated for use in both males and females and contains nine of the high-risk HPV types. Evidence demonstrated efficacy of prevention when the 9-valent was directly compared to the 4-valent in a randomized trial involving 14,125 females aged 16 to 26 years followed for 54 months and assigned to either the 9-valent or 4-valent vaccine.31,32 Forty-eight percent of the study population were HPV-positive at baseline. Results showed that the 9-valent vaccine had 96% efficacy in preventing cervical cancer due to HPV types 31, 33, 45, 52, and 58, and was noninferior in preventing cervical cancer due to types 6, 11, 16, and 18 when compared to the 4-valent vaccine.31 Serologic response to the 9-valent vaccine seems to be similar among males and females aged 9 to 15 years compared to females aged 16 to 26 years. One study evaluated anti-HPV serologic assays at Day 1 and 7 months after completion of the threeseries dose.32 The three groups included females aged 9 to 15 years, males aged 9 to 15 years, and females aged 16 to 26 years; all groups demonstrated >99% seroconversion at 7 months postvaccination.32

Recently, the Advisory Committee on Immunization Practices recommended a two-dose schedule for patients aged 9 to 14 years instead of the previously approved three-dose schedule for this patient population. Patients aged 15 to 26 years are to continue with the three-dose schedule.33 The recommendation is based on a thorough review of clinical trials that demonstrated a similar or higher immune response of the two-dose schedule in patients aged 9 to 14 years compared to the three-dose schedule in patients aged 15 to 26 years. Two visits to the office separated by at least 6 months, along with the proven safe, effective, and long-lasting protection should facilitate greater vaccination, and thus protection rates, against HPV.33

TREATMENT OF WARTS

Warts are often self-limiting, and many will resolve without treatment. However, different treatment modalities are available for their removal and/or symptom management. These treatments are not a cure for HPV infection. Without any available high-quality evidence demonstrating efficacy and safety of these treatment options, existing data on their effectiveness should be carefully interpreted due to significant possible placebo effect.13,17 The FDA recommends restricting self-treatment of warts to common and plantar warts.34 Other warts should be treated under medical supervision.

The primary reasons for treating warts are to 1) alleviate symptoms associated with the warts; 2) prevent spread of the virus to adjacent anatomical sites or other people; and 3) removal of the wart, usually for aesthetic reasons. Treatment modalities are generally either immunemodulating or ablative.17,22,34

The focus of nonpharmacologic management is preventing the spread of HPV either through autoinoculation or spread to others. This includes hand washing before and after handling warts; avoiding picking, cutting, or shaving warts; keeping feet clean and dry; designating a towel to dry only specific body areas with warts; avoiding sharing towel, razors, or other objects capable of carrying the infectious agent; keeping warts covered; and avoiding walking barefoot, especially in public areas.17

Cutaneous Warts
Salicylic acid is considered the first-line agent for the majority of cutaneous warts. It is a keratolytic agent that slowly breaks down the HPV-infected epithelial tissues. It may also cause an immune response to be mounted in clearing the infective agent through mild irritation.13,16 Advantages of salicylic acid include its availability in nonprescription formulations, ease of access, low cost, and reasonable effectiveness. Disadvantages include its need for consistent, frequent, and lengthy duration of application (daily treatments for up to 12 weeks) for effectiveness and the resulting potential damage of surrounding healthy epithelial tissue.13,16,17 Salicylic acid is generally well tolerated; however, possible adverse effects include skin irritation, blistering, pain, contact dermatitis, and potential systemic toxicity.13,16,17 Concentrations of salicylic acid utilized in the majority of randomized, controlled trials ranged from 11% to 60%; nevertheless, 17% is the most commonly used concentration.13,16 Each salicylic acid product is provided along with its directions for use. The affected area may be soaked in warm water for 5 minutes prior to application of salicylic acid to aid in removal of the wart.13,16

Cryotherapy is another nonprescription option that may be considered as second-line treatment, and it has been used for many years in physicians’ offices.13,16 Cryotherapy destroys infected tissue by freezing, with a resulting tissue irritation that induces the immune system to clear the infection.13,16 Liquid nitrogen typically used in physicians’ offices can freeze the tissue up to a temperature of –321oF (–196oC), while OTC cryotherapy (FDA-approved mixture of dimethyl ether and propane) can freeze tissue only to –94oF (–70oC) but may be just as effective.13 Most trials suggest no superiority when comparing cryotherapy with salicylic acid. However, an advantage of cryotherapy is its less frequent need of application (once every 2-3 weeks for up to 3 months) for effectiveness.13,16,17 Cryotherapy is directly applied to the wart (SIDEBAR 1), a blister forms after approximately 10 days, and the wart falls off. Patients should be cautioned to avoid application to surrounding healthy tissue and to change applicators with each application to avoid reinfection. Greater effectiveness was found when cryotherapy was utilized in combination with salicylic acid treatment than when either treatment modality was used by itself.13,16 Adverse effects of cryotherapy include potential pain, blistering, hypoor hyperpigmentation, scarring, and potential damage to surrounding healthy tissue.16 There is no evidence of cryotherapy efficacy in the treatment of filiform warts.16


Another treatment option involves intralesional injections of Candida and mumps skin antigen to induce a localized, cellular-mediated immune response against the HPV in the affected tissue. Treatment may be repeated every 3 to 4 weeks for up to three treatments. This method also showed a reasonable efficacy; however, patients should be pretested with 0.1 mL to 0.3 mL injection into the largest wart or split between two warts to confirm an immune response to the antigen for greatest efficacy.13,16 The most common adverse effect associated with this treatment option is pruritus; other possible side effects include pain, burning, skin peeling, and swelling.13,16

Photodynamic therapy (PDT), which involves treatment with aminolevulinic acid followed by phototoxicity, is considered likely beneficial, although it is expensive and not as readily available.13,16 Aminolevulinic acid acts as a photosensitizer, inducing oxidation in the abnormal cells following exposure to visible light. It is applied to the wart for 3 to 8 hours, after which the treated wart is exposed to a range of light sources.13 Adverse effects associated with PDT are considered mild and include burning sensation, mild-to-moderate pain, pigmentation changes, and erythema.13,16

Other treatment options with unknown efficacy include occlusion with duct tape, thought to act by causing local irritation that stimulates an immune response; intralesional bleomycin, which causes acute tissue necrosis that may stimulate an immune response; pulse dye laser, which destroys the dilated capillaries of a wart and is well tolerated but requires expensive equipment; intralesional interferon-α, a low-molecularweight glycoprotein that may be involved in inhibition of viral replication; imiquimod, which is well established for genital and perianal warts but lacks published evidence for use in cutaneous warts; and surgical removal of warts.13,16

Anogenital Warts
There is no evidence to demonstrate the superiority of any particular treatment option for AGWs. Patient preference, resources, and the healthcare provider should guide treatment.34 Factors that can influence treatment selection include wart size, number of warts, anatomic site, morphology, cost of treatment, provider experience, and other patient-specific parameters, including adverse effects, patient preference, and convenience.34 The patient’s immune status and compliance with therapy can affect response to the selected treatment modality. However, most genital warts respond to therapy within 3 months.34 In general, warts found in moist or intertriginous anatomical sites respond best to topical treatment. Alternative treatment should be considered if there is no improvement or significant side effects develop.34 Some possible rare complications include disabling chronic pain syndromes (e.g., vulvodynia) and painful defecation or fistulas, in the case of anal warts.34

Treatment modalities can be either patient-applied or provider-applied, with the former preferred by patients who want the option to administer treatment in private. Treatment adherence is crucial for effectiveness. Response to therapy should be evaluated throughout the course of therapy; follow-up after several weeks may be appropriate to evaluate treatment response, adherence, and side effects.34

Patient-applied treatment options include sinecatechins 15% ointment, podofilox 0.5% solution or gel, and imiquimod 5% cream.34 Sinecatechins 15% , a mixture of major polyphenols found in green tea leaves, was FDA-approved in 2006 for the topical treatment of external genital warts and perianal warts (condyloma acuminata) in immunocompetent patients aged 19 years and older.35 Sinecatechins 15% is approved as a dose of a 0.5-cm strand of ointment applied topically to each wart three times daily until complete clearance of warts or up to 16 weeks.35 The FDA approval of the ointment was based on a review of three randomized, controlled trials enrolling >1,000 immunocompetent adults that found that 53.6% of adults achieved complete visual clearance of warts by Week 16 as compared to 35.3% of subjects assigned to placebo.35 The most common adverse effects noted with sinecatechins 15% include pruritus, burning pain, erythema, ulceration, edema, induration, and vesicular rash.35,36 Sinecatechins 15% was not evaluated for use for warts found in the vagina, the cervix, or inside the anus, and sexual intercourse should be avoided when the ointment is applied.34,37 The CDC does not recommend the use of sinecatechins during pregnancy.36

Podofilox works as an ablative therapy—an antimitotic drug that destroys warts. Its relatively inexpensive cost, ease of use, safety, and self-applicability offer some advantages.34,37 In a double-blind, randomized, multicenter, vehicle-controlled study of 326 patients with AGWs, 0.5% podofilox gel was shown to be significantly better than vehicle gel in successfully eliminating and reducing the number and size of AGWs.38 Thirty-seven percent of podofilox-treated patients achieved complete resolution of warts, compared to 2.3% of vehicle gel– treated patients, within 4 weeks of treatment. An additional 31% of podofilox-treated patients achieved complete resolution with an additional 4 weeks of treatment compared to only 2% of patients in the vehicle-gel group.38 Podofilox solution, applied with a cotton swab (or a finger, if gel formulation), should be applied to visible genital warts twice daily for 3 consecutive days per week—that is, 4 days of no application. The cycle can be repeated as necessary for up to four cycles, and no greater than 0.5 mL should applied in a day.34,37 Having a healthcare provider apply the first dose will be useful in demonstrating appropriate technique, as well as identifying which warts should be treated.34 Noted side effects are primarily mild-to-moderate local adverse reactions, including burning, inflammation, pain, itching, erosion, and pain, typically diminishing over time.38 Podofilox did not demonstrate teratogenicity with topical application in animal studies; however, its use has not been well studied in pregnant women. The CDC does not recommend the use of podofilox during pregnancy.36

Imiquimod acts as an immune enhancer that stimulates production of interferon and other cytokines when applied topically.34,39 A systematic review of randomized controlled trials of imiquimod found that 51% of imiquimod-treated patients, compared to 2% of placebotreated patients, achieved complete clearance of warts with a number needed to treat of 1.9; however, the review also found imiquimod ineffective in one trial involving HIV-positive patients.40 Imiquimod 5% cream is applied at bedtime three times weekly for up to 16 weeks.34,39Imiquimod 3.75% cream may be applied nightly at bedtime.34The area should be washed with soap and water 6 to 10 hours after application.34 Common side effects include local skin reactions such as redness, induration, irritation, ulceration/erosions, and vesicle formation.34,39 Hypopigmentation of the treated area is another possible side effect.34 Importantly, imiquimod may weaken condoms and vaginal diaphragms.34 The safety of imiquimod during pregnancy has not been established, although it may be considered lowrisk.34,36,37

Provider-applied treatment options include cryotherapy, trichloroacetic acid (TCA), and bichloroacetic acid (BCA) 80%-90%, podophyllin resin 10%-25% in compound tincture of benzoin, and surgical removal of warts.34 Provider-applied therapies should be selected based on the provider’s experience and comfort with treatment modality. Healthcare providers must be trained in the proper use of cryotherapy to ensure adequate efficacy with treatment, as well as to prevent complications of therapy.34 Cryotherapy may be considered for both external and internal genital warts.34 Application of liquid nitrogen is commonly followed by pain, then necrosis and sometimes blistering. Local anesthesia may be employed with therapy.34 Both TCA and BCA are caustic agents, and their use involves chemical removal of the warts. Although their use is widespread, they have not been thoroughly investigated.34 In addition to external genital warts, these agents may also be considered in cases of vaginal and anal warts.34 Podophyllin, previously designated as provider-applied therapy, is no longer generally recommended due to its risk for systemic toxicities.34 Surgical removal of warts can be done via electrocautery, by tangential excision with fine scissors or scalpel, by laser, or by curettage. An advantage of surgical removal is the elimination of the wart with just one visit. This option is most beneficial for individuals with an extensive area or large number of warts.34 Surgical removal is also an option in cases of anal warts.34

HIV-infected patients are more prone to develop genital warts than are persons who are HIV-negative. Lesions may also be more unresponsive to treatment due to immunosuppression. However, no data suggest that treatment options for external genital warts should be any different in the presence of HIV infection due to lower efficacy or safety.36

GENERAL PATIENT EDUCATION

Patients should receive education on HPV infections and the vaccine options available to help prevent HPVrelated diseases. Female patients should be encouraged to receive cervical cancer screening per current guideline recommendations. Patients should also be reassured that not all cases of HPV infection will lead to cancer development. HPV-infected patients who develop warts should be informed that warts do not pose a serious health risk and can be treated, if desired. Patients should be reminded that warts are often self-limiting, treatment options are noncurative of the infection, and warts often recur, especially in the first few months of treatment.13,34-37 Patients should be instructed to wash their hands before and after handling of warts to prevent spread via autoinoculation or spread to others.17,37 All sexual partners of individuals with genital warts can benefit from sexually transmitted–infection screening, and both patients and their sexual partners can benefit from counseling.36

CONCLUSION

HPV infects the cutaneous and mucosal epithelium and is easily transmitted through direct person-toperson contact. The most common route of transmission is through sexual contact. Sexually transmitted HPV types—low risk and high risk—are grouped based on risk of association with cervical cancer. Although HPV infection is often self-limiting, persistent infection with HPV may lead to manifestation of epidermal abnormalities, including cutaneous and genital warts and laryngeal papillomas, and in severe cases, cancer. The incidence of HPV-related diseases may be significantly reduced through appropriate screening and prevention with available vaccines. Warts are often self-limiting and do not require treatment. However, treatment of warts is often sought due to the stigma associated with them.36 Treatment of warts is noncurative of the infection, and warts often recur.

REFERENCES

  1. National Institutes of Health National Cancer Institute. Human Papillomavirus (HPV) Vaccines [fact sheet]. www.cancer.gov/about-cancer/causesprevention/risk/infectious-agents/hpv-vaccine-fact-sheet#q7. Accessed May 15, 2016.
  2. Hamborsky J, Kroger A. Epidemiology and Prevention of Vaccine-preventable Diseases, E-book: The Pink Book. Public Health Foundation; 2015.
  3. Schneider A. Pathogenesis of genital HPV infection. Genitourin Med. 1993;69(3):165-173.
  4. Steben M, Duarte-Franco E. Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol. 2007;107(2):S2-S5.
  5. Ault KA. Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol. 2006;(Suppl): 40470.
  6. CDC. Genital HPV Infection—CDC Fact Sheet. March 2014. www.cdc. gov/std/hpv/hpv-factsheet-march-2014.pdf. Accessed March 21, 2017.
  7. Monk BJ, Tewari KS. The spectrum and clinical sequelae of human papillomavirus infection. Gynecol Oncol. 2007;107(2):S6-S13.
  8. Patel H, Wagner M, Singhal P, Kothari S. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis. 2013;13(1):1.
  9. Pray WS, Pray GE, Pray M. Removing warts with nonprescription treatments. US Pharm. 2011;36(8):15-23
  10. De Sanjosé S, Diaz M, Castellsagué X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007;7(7):453-459.
  11. Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol. 2004;4(1):46-55.
  12. Juckett G, Hartman-Adams H. Human papillomavirus: clinical manifestations and prevention. Am Fam Physician. 2010;82(10):1209-1213.
  13. Mulhem E, Pinelis S. Treatment of nongenital cutaneous warts. Am Fam Physician. 2011;84(3):288-293.
  14. Taliercio S, Cespedes M, Born H, et al. Adult-onset recurrent respiratory papillomatosis: a review of disease pathogenesis and implications for patient counseling. JAMA Otolaryngol–Head Neck Surg. 2015;141(1):78-83.
  15. Pray WS, Pray JJ. Treatment of warts. US Pharm. 2005;30(4):17-22.
  16. Dall’Oglio F, D’Amico V, Nasca MR, Micali G. Treatment of cutaneous warts. Am J Clin Dermatol. 2012;13(2):73-96.
  17. Adkins DM. Warts. In: Krinsky DL, et al. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 18th ed. Washington, DC: American Pharmaceutical Association; 2015.
  18. Steben M, Duarte-Franco E. Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol. 2007;107(2):S2-S5.
  19. Longworth MS, Laimins LA. Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev. 2004;68(2):362-372.
  20. Chelimo C, Wouldes TA, Cameron LD, Elwood JM. Risk factors for and prevention of human papillomaviruses (HPV), genital warts and cervical cancer. J Infect. 2013;66(3):207-217.
  21. Stanley M. Prevention strategies against the human papillomavirus: the effectiveness of vaccination. Gynecol Oncol. 2007;107(2):S19-S23.
  22. Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for warts: human papillomavirus. J Am Acad Dermatol. 1995;32(1):98-103.
  23. Committee on Practice Bulletins—Gynecology. ACOG practice bulletin number 131: screening for cervical cancer. Obstet Gynecol. 2012;120:12221238.
  24. Saslow D, Solomon D, Lawson HW, et al. American cancer society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. CA Cancer J Clin. 2012;62(3):147-172.
  25. U.S. Preventive Services Task Force. Final Update Summary: Cervical Cancer: Screening. www.uspreventiveservicestaskforce.org/Page/Document/ UpdateSummaryFinal/cervical-cancer-screening. July 2015. Accessed May 21, 2016.
  26. Solomon D, Papillo JL, Davey DD. Statement on human papillomavirus DNA test utilization. Cancer Cytopathology. 2009;117(3):154-156.
  27. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011;364(5):401-411.
  28. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928-1943.
  29. Villa LL, Perez G, Kjaer SK, et al. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915-1927.
  30. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a doubleblind, randomised study in young women. Lancet. 2009;374(9686):301-314.
  31. Joura EA, Giuliano AR, Iversen O, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711-723.
  32. Van Damme P, Olsson SE, Block S, et al. Immunogenicity and safety of a 9-valent HPV vaccine. Pediatrics. 2015;136(1):e28-e39.
  33. Robinson CL. Advisory Committee on Immunization Practices recommended immunization schedules for persons aged 0 through 18 years—United States, 2016. Am J Transplant. 2016;16(6):1928-1929.
  34. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines. Reprod Endocrinol. 2015(24):51-56.
  35. U.S. Food and Drug Administration. Veregen (Kunecatechins) ointment, 15%. 2008.
  36. Dunne EF, Friedman A, Datta SD, et al. Updates on human papillomavirus and genital warts and counseling messages from the 2010 sexually transmitted diseases treatment guidelines. Clin Infect Dis. 2011;53 (Suppl 3):S143-152.
  37. Wilson JA, Waghel RC. HPV: an updated guide to treatment and prevention. US Pharm. 2015;40(9):HS22-HS24.
  38. Tyring S, Edwards L, Cherry LK, et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol. 1998;134(1):33-38.
  39. Gotovtseva EP, Kapadia AS, Smolensky MH, Lairson DR. Optimal frequency of imiquimod (aldara) 5% cream for the treatment of external genital warts in immunocompetent adults: a meta-analysis. Sex Transm Dis. 2008;35(4):346-351.
  40. Moore RA, Edwards JE, Hopwood J, Hicks D. Imiquimod for the treatment of genital warts: a quantitative systematic review. BMC Infect Dis. 2001;1:3.
  41. Cervarix (human papillomavirus bivalent [types 16, 18] vaccine, recombinant) package insert. Research Triangle Park, NC: GSK, 2014.
  42. Gardasil (human papillomavirus quadrivalent [types 6, 11, 16, and 18] vaccine, recombinant) package insert. Whitehouse Station, NJ: Merck & Co, Inc. 2014.
  43. Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant) package insert. Whitehouse Station, NJ: Merck & Co, Inc. Revised December 2015. www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ UCM426457.pdf. Accessed May 16, 2016.