Human Papillomavirus (HPV) Treatment & Management

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.

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.

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:

• Immune response modifiers – These include imiquimod and interferon alfa and are primarily used in treatment of external anogenital warts or condylomata acuminata

• Cytotoxic agents - These include the antiproliferative drugs podofilox, podophyllin, and 5-FU, as well as the chemodestructive or keratolytic agents salicylic acid, trichloroacetic acid (TCA), and bichloracetic acid (BCA)

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%.

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:

• Cryosurgery

• Electrosurgery with either electrodesiccation or loop electrosurgical excision procedure (LEEP)

• Simple surgical excision with a scalpel, scissors, or curette

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:

• Wattage of the laser

• Length of time for which the beam is fired

• Spot size on the tissue

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.

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:

• Benign Vulvar Lesions

• Carbon Dioxide Laser Surgery of the Lower Genital Tract

• Complications of Dermatologic Laser Surgery

• Cervical Cancer

• Conization of Cervix

• Gynecologic Cryosurgery

• Urethral Warts

• Surgical Treatment of Vulvar Cancer

• Malignant Vulvar Lesions

• Penile Cancer

• Surgical Treatment of Vaginal Cancer

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.

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 2-3 inoculations (depending on immunization history) 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]} For adults aged 27-45 years, the need for vaccination is based on shared decision making between patient and clinician. ^[92]

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:

• Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11

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

• Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ
• Cervical intraepithelial neoplasia (CIN) grade 1
• Vulvar intraepithelial neoplasia (VIN) grades 2 and 3
• Vaginal intraepithelial neoplasia (VaIN) grades 2 and 3
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

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

• Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11

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. ^[93] Effectiveness will depend on the duration of immunity and will be optimized by achieving maximum coverage of the target population. ^[94] 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. ^[95]

Catch-up vaccinations are recommended in previously unvaccinated children and adults. ^[96]

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%). ^[97]

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. ^[98] 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. ^[99] Other studies have also yielded good results, ^{[100, 101]} 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. ^[102] The HPV vaccine is neither intended nor proved to treat genital warts. ^[103]

Another Australian report, a case-control study of 108,353 young women, found that the quadrivalent vaccine provided significant protection against cervical abnormalities. ^{[104, 105]}

A large retrospective study from California found that routine administration of quadrivalent HPV vaccine to females was not associated with any new safety concerns. ^{[106, 107]} 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:

• Vaccination may be associated with syncope on the day of vaccination and skin infections occurring 1 to 14 days after immunization
• Vaccination was not associated with any major adverse effects

These findings ^{[106, 107]} 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. ^{[108, 109]}

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:

• Centers for Disease Control and Prevention - HPV infection and genital warts. Sexually transmitted diseases treatment guidelines 2006
• Society of Obstetricians and Gynaecologists of Canada - Treatment of external genital warts and pre-invasive neoplasia of the lower tract. In: Canadian consensus guidelines on human papillomavirus
• American Cancer Society - American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors

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. ^[110]

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. ^[111] 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. ^[112]

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:

• Number of sexual partners

• Frequency of sexual intercourse

• Presence of genital warts on sexual partners

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. ^[113] However, circumcision does not eliminate the risk of HPV transmission.

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.

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.