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 9-valent (Gardasil 9) is the only HPV vaccine available in the United States. 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.
Table 2. HPV Vaccine: Indications Approved in the United States for Females (Open Table in a new window)
| Disease | HPV 9-valent |
|---|---|
| Cervical cancer, vulvar cancer, vaginal cancer, anal cancer | HPV 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 3 | HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 |
| Anal intraepithelial neoplasia (AIN) grades 1-3 | HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 |
Table 3. HPV Vaccine: Indications Approved in the United States for Males (Open Table in a new window)
| Disease | HPV 9-valent |
|---|---|
| Anal cancer | HPV 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 3 | HPV types 16, 18, 31, 33, 45, 52, and 58 |
Immunomodulators
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.
Imiquimod (Aldara, Zyclara)
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)
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)
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).
Keratolytic Agents
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.
Podofilox (Condylox)
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)
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)
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)
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.
Antineoplastics, Antimetabolite
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.
Fluorouracil topical (Efudex, Carac, Fluoroplex)
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.
Topical Skin Products
Class Summary
Sinecatechins is another topical product that has gained FDA approval for genital warts.
Sinecatechins (Veregen)
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.
Vaccines, Inactivated, Viral
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 2, not 3, doses of the HPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The immunization schedule for older adolescents and young adults aged 15-45 years is 2-3 inoculations (depending on immunization history) within 6 months. [92]
Human papillomavirus vaccine, nonavalent (Gardasil 9)
Induces humoral immune response to 9 HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated for routine immunization in males and females aged 9-26 years to prevent HPV-associated diseases. Immunization for adults aged 27-47 years is based on shared decision making between the patient and clinician.
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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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Verrucous warts in patient with HIV infection.
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Plantar warts.
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Flat wart.
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"Cauliflower" condyloma of penis.
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Small papilloma on shaft of penis.
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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.
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This is a verruca vulgaris of the anterior maxillary gingiva in a healthy young male. He had recently resolved a wart on his finger.
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These small papillomas on the lateral tongue of a young woman showed histologic evidence of HPV in the form of extensive koilocytosis.
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Human papillomavirus (HPV) lesion on the lingual frenum. Some patients with condyloma acuminatum present with multiple oral lesions. Courtesy of A.K. ElGeneidy, DDS.
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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.
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Human papillomavirus (HPV). Heck disease in the buccal mucosa of a 7-year-old boy. Courtesy of Sheldon Mintz, DDS.
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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.
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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.
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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.
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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.
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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 to the site of human papillomavirus infection.
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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.
Tables
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 warts |
2, 27, 57 |
Ungual squamous cell carcinoma |
16 |
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 lesions |
37, 38 |
Nongenital Mucosal Disease |
HPV Type |
6, 11 |
|
6, 11, 16, 18 |
|
Laryngeal papilloma (recurrent respiratory papillomatosis) [15] |
2, 6, 11, 16, 30, 40, 57 |
6, 11 |
|
Maxillary sinus papilloma |
57 |
Squamous cell carcinoma of the sinuses |
16, 18 |
Conjunctival papillomas |
6, 11 |
Conjunctival carcinoma |
16 |
Oral focal epithelial hyperplasia (Heck disease) |
13, 32 |
16, 18 |
|
16, 18 |
|
16, 18 |
|
Anogenital Disease |
HPV Type |
1-6, 10, 11, 16, 18, 30, 31, 33, 35, 39-45, 51-59, 70, 83 |
|
16, 18, 34, 39, 40, 42, 45 |
|
16, 18, 31, 34 |
|
Giant condylomata (Buschke-Löwenstein tumors) |
6, 11, 57, 72, 73 |
Unspecified intraepithelial neoplasia |
30, 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 |
6, 11, 16, 18 |
|
Carcinoma of vagina |
16 |
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82 |
|
Carcinoma of anus |
16, 31, 32, 33 |
Carcinoma in situ of penis (erythroplasia of Queyrat) |
16 |
16, 18 |
| Disease | HPV 9-valent |
|---|---|
| Cervical cancer, vulvar cancer, vaginal cancer, anal cancer | HPV 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 3 | HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 |
| Anal intraepithelial neoplasia (AIN) grades 1-3 | HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 |
| Disease | HPV 9-valent |
|---|---|
| Anal cancer | HPV 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 3 | HPV types 16, 18, 31, 33, 45, 52, and 58 |
