Human Papillomavirus

Virology

Human papillomaviruses (HPV) belong to the Papillomaviridae family. They are made of a small, naked, icosahedral capsid (55 nm in diameter) that encloses a circular, double-stranded DNA genome whose organization is common to all papillomaviruses. The genome includes a non-coding region (upstream regulatory region), a region that codes for non-structural genes, mostly expressed early in the viral cycle (E1, E2, E4, E5, E6, and E7), and a region that encodes the only two capsid proteins, which are expressed late (L1 and L2). The sequence of L1 gene is what defines the distinct HPV genotypes, whose numbers do not cease to increase.  There are 92 fully characterized HPV genotypes as of February 2002, but an additional 130 or so have been partially characterized. They all infect the squamous stratified epithelia of the body, but each genotype exhibit a predilection for different anatomic regions. This has led to the recognition of three major groups of HPVs. The first group, the cutaneous HPVs are those that cause infections and diseases, mostly warts, of the hands, feet, and face. The two most important and common genotypes are HPV1 and HPV2. The second group, causes a rare disease called epidermodysplasia verruciformis (EV) in subjects with a genetic predisposition. The singular feature of this condition is the transformation by the second decade of life of the scaly lesions of EV into squamous cell carcinomas in the sun-exposed areas of the patient’s body. Only a subset of the EV-associated HPVs have this high-risk oncogenic potential. One also finds this distinction between low- and high-risk HPVs with the viruses that form the third and most important group for the physician, the genital (or mucosal) group. These HPVs cause benign lesions, warts or condylomas, but also incipient and invasive cancers of the genitalia (cervix, anus, vagina, vulva, penis) and upper aero-digestive tract. HPV6 and to a lesser frequency HPV11 are the most common agents of anogenital warts, whereas HPV16 and to a lesser degree HPV18 are the most common causes of the malignant anogenital lesions.

Epidemiology

HPV infections are extremely common but the vast majority of them are asymptomatic and remain that way. Cutaneous HPVs cause cutaneous warts, a common disease, especially in the school-age population, with a prevalence ranging from about 1 to 20 percent. Three main types of cutaneous warts are recognized: common, plantar, and flat warts, each representing approximately 70%, 25%, and 5% of the lesions. The mode of transmission seems to be through direct contact or fomites, the latter being responsible for plantar warts transmission in communal baths or swimming pools.

Genital infections are mostly acquired through sexual contact. Early initiation of sexual intercourse and multiplicity of sexual partners are the major risk factors. Hence, the peak incidence of genital warts is found in subjects in their early 20's. Incidence rates vary from less than 1% to 13%, with an overall prevalence estimated to be around 1%. In women, HPV infections of the cervix occupy an important place given that they are responsible for the majority of Papanicolaou (Pap) smear abnormalities. The incidence of HPV cervical infections peaks in the third decade with an incidence of about 20%, but that can exceed 50% in some sub-populations. HPV infections result in rates of abnormal Pap smear that range between 1 and 5%. Recurrent respiratory papillomatosis is a disease caused by genital HPVs types 6 or 11. Its bimodal distribution is believed to reflect two different mechanisms of transmission: mostly a peripartum transmission from an infected birth canal for the juvenile form of the disease, which has an incidence of 4.3 per 100,000, and oral sexual contact for the adult form whose incidence is 1.8 per 100,000.

Clinical Manifestations

Plantar warts (verrucae plantaris, myrmecias) are deep-seated, often painful, lesions measuring typically from 2 to 10 mm, made of a sharp margin surrounding a slightly elevated, flat-topped, irregular bundle of cornified fibers. Because flat warts have a predilection for the weight-bearing areas of the foot, they have to be differentiated from corns or calluses. This is accomplished by paring the surface of the lesion with a scalpel, which in the case of a wart reveals bleeding or thrombosed, punctuate capillaries.

Common warts (verrucae vulgaris) are round, well delineated hyperkeratotic papules, 1 to 10 mm in diameter, with a surface that ranges from coarse to cauliflower-like and on which the normal pattern of skin ridges is disrupted. They are typically distributed over the dorsal aspect of the hand, and on the lateral aspects of the fingers, including near the nail beds. On the feet, common warts appear as mosaic warts, at hyperkeratotic, clustered and confluent, painless papules. Plane warts (verrucae plana, juvenile warts) are very at, small, asymmetric, supple, easily missed papules. They are pink to skin-colored, with a dull surface reflection caused by the disruption of the skin ridges. They are found on the face, neck, and the dorsum of the hands. The diagnosis of cutaneous warts is usually easy and is made by history and inspection. Magnifying optics (e.g., a loupe or a magnifying glass) are helpful to reveal the discontinuity of the skin ridges at the edge of the lesion and appreciate the papillomatous surface contour. Paring of the lesion may be necessary to distinguish a plantar wart from a corn or callus.

Genital warts (condylomata acuminata, venereal warts, anogenital warts) are fleshy papules that range from slightly pedunculated dome-shaped lesions with a more or less pronounced mulberry-like appearance, to taller, jagged cockscomb-like structures. In most patients they are asymptomatic or the cause of minimal discomfort. Nevertheless, they have a psychosexual impact in a majority of patients.

Genital warts can be located on the keratinized skin or on the external mucosal surfaces. In circumcised men, genital warts are mostly located on the penile shaft, while the preputial cavity is the site of predilection in circumcised men. On occasion warts can be located in the fossa navicularis, but more proximal involvement of the urethra is extremely rare. In women, warts are more widely spread over the genitalia, involving in particular the posterior introitus, and the labia minora and majora. Perianal anal involvement is not uncommon in women, less so in men. It does not necessarily reflect anal intercourse. However, if the patient reports anal intercourse or anal symptoms, an anoscopic examination is recommended to rule out internal disease.

The diagnosis of genital warts is usually made clinically with the naked eye. The male patient is typically examined in a standing position, and the female patient in the lithotomy position. Because condylomata acuminata may be small and may need to be differentiated from the lesions of several other diseases, the use of magnifying optics (e.g., loupe, magnifying glass, colposcope) can be helpful. The soaking for 3 to 5 minutes in 3% to 5% acetic acid of the genitalia prior to examination is likely to turn the lesions white (acetowhitening) -particularly on the mucosal surfaces-, which make them easier to detect when they are small. Flat aceto-white macules or patches may be recognized. Although they may reflect sub-clinical HPV disease, acetowhitening lacks specificity, and treatment of these sub-clinical lesions is not recommended.

Anogenital HPV infection may lead to the development of incipient cancers, also called intraepithelial neoplasias or dysplasias. On the external anogenital areas, these lesions may appear as pigmented papules or erythematous plaques or macules. They may assume the appearance of a giant papilloma or a verrucous mass. Ulceration or bleeding may occur. Ultimately, one has to be concerned that these lesions may represent invasive squamous carcinomas. In the anal canal, the vagina, and on the cervix the same array of benign lesions (condylomas), intraepithelial neoplasias, and carcinomas may occur as a result of HPV infection. They are the province of the specialist.

Two other areas where HPV lesions may manifest are the oral cavity and the larynx. Genital HPV types cause squamous papillomas and condylomata acuminata, and cutaneous HPV types cause verrucae vulgaris. These entities are more aptly distinguished by histology, than by clinical features, and therefore may all fall under the convenient label of oral warts. An altered cry in infants or voice hoarseness in speaking older individuals are the main symptoms that lead to the diagnosis of recurrent respiratory papillomatosis.

Laboratory Diagnosis

The diagnosis of cutaneous warts is clinical and rarely requires the need of a biopsy for histologic confirmation. The same applies for the anogenital HPV lesions, except for cervical lesions. For anogenital lesions, biopsy should be considered if there is a doubt on the diagnosis, in particular if an intraepithelial neoplasia or carcinoma is of concern. This can be the case if indicative clinical features are present, or if the lesions are large, form plaques, bleed, are present in atypical locations, or if a lesion is resistant to treatment. Although when to collect a biopsy is a matter of judgment, the threshold is lowered when dealing with an immunosuppressed or immunodeficient patient.

Cervical lesions are typically detected by cytology (Pap smear). The Bethesda system, initially proposed in 1988 and most recently revised in 2001 (http://www.bethesda2001.cancer. gov), is a widely used interpretation scheme (1). It assesses the adequacy of the specimen, classifies its finding, and offers guidelines for management and follow-up. Squamous cell abnormalities, which are pertinent to HPV infection, are classified into four categories: (1) atypical squamous cell of (a) undetermined significance (ASC-US), or (b) cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (( a) and ( b) used to be grouped under a single category of ASCUS); (2) low-grade squamous intraepithelial lesion (LSIL), a diagnosis that regroups the previous cytologic and histologic diagnoses of koilocytotic or condylomatous atypia, mild dysplasia, and cervical intraepithelial neoplasia (CIN) 1; (3) high-grade squamous intraepithelial lesion (HSIL), encompassing the previous categories of moderate and severe dysplasias, CIN 2 and CIN 3/carcinoma in-situ (CIS); and (4) squamous cell carcinoma (SCC). Management guidelines are available (2).

The role of colposcopy, which is the examination of the cervix with special magnifying optics- the colposcope- and after application of acetic acid and/or Lugol solutions, is to establish whether a biopsy is necessary and where. Criteria and scoring schemes have been developed that allow a presumptive diagnostic based on the colposcopic appearance. Cervicography, the interpretation of photographs of the cervix taken with a special colposcopic camera, has been developed as a patented independent screening tool for cervical cancer. The principles and methods of colposcopy have been applied to the examination of the anal canal in the human immunodeficiency virus-infected population. This promising approach, named high resolution anoscopy, has not yet been routinely validated and integrated in the management of these patients.

The diagnosis of HPV infection, as opposed to HPV disease, is based in clinical practice on the demonstration of HPV DNA in cells or tissues. The Hybrid Capture II assay (Digene Diagnostics Inc.) is presently the only commercially available assay. It is based on a liquid-phase hybridization reaction in which the sample DNA is reacted with RNA probes contained in two pools. The probes in pool A correspond to genital low-risk HPVs, while those of poll B represent high-risk genital HPVs. The assay is slightly less sensitive overall than investigational assays based on the polymerase chain reaction (PCR), but its performance characteristics are superior for those conditions (e.g., LSIL) that are relevant for screening. HPV DNA testing has now been integrated in the cervical cancer screening guidelines (2).

Pathogenesis

Most HPV infections are latent and do not cause any cellular alterations, however during an active infection, HPV stimulate the growth of the squamous stratified epithelium. This process is directly responsible for the characteristics histologic features of benign HPV lesions, namely the proliferation of the stratum spinosum (acanthosis), stratum granulosum (parakeratosis), and stratum corneum (hyperkeratosis). In addition, there is an increase of the normal undulation of the basement membrane (rete ridges) and of the epithelium above that accounts for the papillomatosis. Finally, the presence of koilocytes (large cells with a shriveled nucleus surrounded by a halo) in the upper stratum spinosum is an almost pathognomonic signature of HPV benign disease. The viral cycle starts with the infection of the basal cells, however most of the viral replication occurs in the stratum spinosum, and the viral cycle is tied to the differentiation of the epithelium. Viral particles form in the upper layers of the epithelium and are released in the desquamating cornified shells.

HPV DNA infection is a necessary but not sufficient condition for the development of cervical cancer. Two viral proteins are important to the oncogenic process: E6 and E7. With high-risk HPVs these two proteins associate and neutralize the function of two important tumor suppressor cellular proteins, p53 (E6) and the retinoblastoma protein (RB) (E7). The abnormal proliferation of the basal cell layer and the presence of mitoses, normal and abnormal, much above the basal membrane defines the process of intraepithelial neoplasia. Based on how many thirds of the thickness of the epithelium are involved, the intraepithelial neoplasia is graded from 1 to 3. Rupture of the basement membrane defines invasive squamous cell carcinoma.

SUSCEPTIBILITY IN VITRO AND IN VIVO

There are no routine tests available for the screening and testing of anti-HPV drugs. Depending on the targeted gene or protein, in vitro assays can be designed to screen for potential drugs (3). Organotypic skin culture systems have been used to produce artficial skin (or mucosa) infected with HPV (4-7). However, these systems are complex and have not been used to any large extent for the evaluation of potential drugs (8).

The cottontail rabbit (Shope) papillomavirus (CRPV) is a virus that can also infect the domestic rabbit in whom it induces within 1-6 weeks skin papillomas (9). They may either regress, persist, or progress to carcinomas. This model has been used for the evaluation of drugs against papillomaviruses (5-fluorouracil, CTC-96 [doxovir], and various nucleoside analogues, including ribavirin, and cidofovir) (10-15), as well as surgical treatments (photodynamic therapy) (16, 17) and vaccines (18-21).

 One has to use HPV-infected human xenografts (usually foreskin fragments) implanted in immunodeficient mice (e.g., athymic [nude] and severe combined immunodeficiency [SCID] mice) for the study in vivo of drugs against HPV (limited to types 6, 11, 16, and 40 at present) (22). These models have been used for the evaluation of 9-(2-phosphonylmethoxy) ethylgua nine (PMEG) an antisense oligonucleotide, and various microbicides (11, 23-25). A similar murine model has been used to study antivirals against CRPV (26).

ANTIVIRAL THERAPy

There are presently no true antimicrobial therapy available for HPV infections. Consequently, the current therapeutic strategies to deal with HPVs are different from those available for other viral infections, because they are not directed at infections but at associated diseases, and the relief of their symptoms. Given that HPVs cause both benign and malignant tumors many of the therapeutic options are destructive or excisional, and are usually more accessible to a surgeon than to the primary care practitioner. Therefore, the emphasis of this chapter is on the diseases and therapies relevant to the primary care provider, the surgical techniques being presented to facilitate the choice of a referral. The medical armamentarium is very eclectic, often unbounded by the absence of comparative data.

Drugs of Choice

Acids

Salicylic acid, on the account of its keratolytic properties, has been a very common agent used alone or in combination with lactic acid for the treatment of cutaneous warts (Table 1). It is found in many over-the-counter medications. It is well tolerated, but when mixed with collodion, hypersensitivity reaction to collophony, a component of collodion, may occur. Table 1 lists some of its formulations and the expected complete response rates.

Bichloracetic acid (BCA) and more commonly trichloracetic acid (TCA) enjoy a great popularity with gynecologists (Table 2). They are cauterizing and keratolytic agents that are employed for the treatment of warts on the mucosal (moist) surfaces, which in addition to the non-hairy vulva also include the anal canal (27). Only one of 14 treated condylomata was found to retain HPV DNA after treatment (28). The treatment is painful and may cause discomfort, ulcerations, and scabbing more readily than cryotherapy (29, 30). Therefore, these compounds can be applied on relatively small areas while avoiding the healthy surrounding tissues. Given the favor these compounds enjoy, there is surprising little published about them (Table 2). TCA has been found equivalent in efficacy to cryotherapy (29, 30), and podophyllin plus TCA was not superior to podophyllin alone at three month follow-up (31). These acids are regarded safe to use during pregnancy, although this impression is based on collective experience more than experiment. One study of 32 pregnant women with condylomata acuminata treated with TCA and laser therapy, had wart clearance in 31 patients (97%), with 2 cases of recurrence (32).

The above two classes of acids have been used in combination for the treatment of plantar warts. Monochloracetic acid in combination with 60% salicylic acid resulted in a greater rate of wart clearance than placebo, 83% versus 54% (33) .

Fixatives

 Plantar warts have been successfully treated with tissue fixatives such as formaldehyde (40%) and glutaraldehyde (10%) solutions (Table 1) (34, 35). These compounds are potentially sensitizing. Formaldehyde has been associated with the development of painful plantar fissures, and glutaraldehyde causes a brown discoloration of the skin (Table 1).  

Bleomycin

Bleomycin is a mixture of glycopeptides isolated from Streptomyces verticillus that creates breaks in single and double stranded DNA. This cytotoxic agent, which is used in oncology, has been evaluated for the intralesional treatment of cutaneous warts, particularly those located around the nails (Table 1) (36-45). It has been used on occasion for the treatment of genital warts, giant condylomas, and oral warts (46-48). Efficacy results, which are based on case series, are summarized in Table 1. Bleomycin sometimes causes severe local pain that can be reduced by the addition of lidocaine to the bleomycin (49). The drug is devoid of systemic adverse reactions at the recommended doses (< 5 mg per patient). Because of the pain and tediousness, the intralesional route of administration limits the number of lesions that can be treated at each session. This has prompted the search for alternate modes of delivery, which have included so far the use of a bifurcated needle, a tatooing machine, and a medicated topical dressing (37, 50-52). Bleomycin use is contraindicated in children, during pregnancy, and in the presence of peripheral vascular disease.

Cantharidine

Cantharidin is a compound extracted from the blister beetle, Cantharis vesicatoria (Spanish fly). Topical application causes acantholysis, a painful, non-scarring blistering of the skin. Several reports have described its usage for the treatment of cutaneous warts (Table 1) (53-55). Because of its vesicant properties, cantharidin should not be applied on healthy skin and the mucous membranes, particularly the conjunctiva. Ingestion of cantharidin causes severe toxicities (56).

Silver Nitrate

Silver nitrate sticks are one of the oldest therapies of cutaneous warts still in use. Silver nitrate is known as a cautery. Its efficacy for the treatment of common warts was demonstrated in a single blind trial in which the patients were randomized to receive three applications at three day intervals of either silver nitrate or ink (placebo) (57). Complete wart clearance was noted in 15/35 (43%) in the silver nitrate group and in 4/35 (11%) in the placebo group (p = 0.006).

Imiquimod

Imiquimod, (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine), is with resiquimod an imidazoquinolineamine derivative with biological response modifying activity (58). Imiquimod induces the production of IFN-a and of other cytokines, including interleukins 1,5,6,8,10,12, tumor necrosis factor a, macrophage chemotactic protein (MCP-1) and other chemokines (59). Wart clearance after treatment with imiquimod is associated with an increased expression of the IFN-a , -b , -g, and TNF-a genes (60).

Imiquimod has been approved by the Food and Drug Administration (FDA) as a 5% cream (Aldara) for the topical self-treatment of condylomata acuminata (Table 2). This represents a significant recent addition to the medical armamentarium. Several randomized controlled trials have defined the therapeutic profile of the preparation (61). In one of the first studies, 108 patients with genital warts were randomized to the 5% cream or vehicle only (62). They applied the preparation 3 times a week, every other day for up to 8 weeks. 37% of the imiquimod-treated patients had complete wart clearance at the end of treatment compared to none in the vehicle group (p < 0.001). Remarkably, only 3 of 16 patients (19%) had recurrences after 10 weeks of follow-up. A second study examined imiquimod treatment with a 5%, 1%, and a vehicle cream for up to 16 weeks (63). Wart clearance rates at 16-week in these three groups were 54/109 (50%), 21/102 (21%), and 11/100 (11%), respectively; the 5% cream preparation being significantly superior to either of the two others (p < 0.001). In the three groups, complete response rates were higher among women than men. Recurrence rates were also low, 13%, 0%, and 10%, respectively. The study was replicated, but the frequency of treatment was increased from thrice weekly to daily (64). At the end of the treatment phase, wart clearance rates in the 5%, 1%, and vehicle groups were 49/94 (52%), 13/90 (14%) and 3/95 (4%), respectively (p < 0.0001). As in the previous trial, women responded better than men, 27/42 (64% ) versus 22/52 (42%).

A fourth trial, limited to men, examined different schedules of self-treatment with 5% imiquimod cream: thrice weekly, once daily, twice daily, and thrice a day (65). There was no overall statistically significant difference in the wart clearance rate among the four groups (range 14% to 35%), and no suggestion of a dose-response effect. However, this and the previous trials demonstrated that the local side-effects were related to the dose, and were most severe when the drug was applied more than once a day. In another open label study, 90 women were randomized to the same treatment groups except for the thrice a day application (66). There were no differences in wart clearance rates among groups. They ranged from 62% to 73%, but the incidence of the side effects was directly related to the frequency of administration. Imiquimod 5% cream applied thrice weekly every other day was as effective as daily application for the treatment of foreskin-associated warts in uncircumcised men, with complete clearance rates of 21/34 (62%) and 17/30 (57%), respectively (67). These observations have been replicated in another study (68).

The results of large international, open-label trial of imiquimod self-administered thrice weekly for up to 16 weeks summarize the therapeutic expectations with the compound (69). Initial complete response rate was 451/943 (48%) within a 6-month follow-up period. Patients who failed or who had recurrences were offered a second course of treatment that resulted in wart clearance in an additional 52 patients (5.5%). Females were 1.3 times more likely to have a complete clearance than males. The recurrence rates were 9% and 23% at 3 and 6 months of follow-up, respectively.

A 2% imiquimod cream has been under evaluation for the European market. Two randomized, placebo-controlled trials in men and women have shown excellent results (70, 71).

Limited anecdotal evidence suggests that imiquimod may be useful in the treatment of common, plantar, and flat warts (72-75). Imiquimod may also have a place in the treatment of Bowen's disease (76-78).

Local erythema, usually mild or moderate is reported by about two-thirds of patients. About a third of patients report erosions. Other adverse effects include edema, scabbing, induration, ulceration, and vesicles. About a third of the patient will report pain or itching at least once, burning and tenderness being less frequent. These adverse events rarely lead to drug discontinuation. There are no data on the use of imiquimod in pregnant women or nursing mothers.

Podophyllin and Podofilox

 Podophyllin was for a long time the mainstay of genital wart therapy. This is a resin that is extracted from the rhizome of the American mandrake (May apple, Podophyllum peltatum) or, outside North America, the more potent but dwindling Himalayan P. emodi (hexandrum). Used originally as a cathartic, it is now prepared in a benzoin tincture, podophyllum (USP) 25% for the treatment of warts (Table 2). It consists of two major groups of chemicals: avonoids and lignans. The latter are responsible for the anti-wart activity, in particular the chemical podophyllotoxin. Podophyllin contains about 10% of podophyllotoxin, whose generic name has become podofilox in the United States (79). Podofilox is synthesized and purified fromPodophyllum and Juniperus plant species.

Podophyllin and podofilox, like colchicine bind to tubulin and block tubule polymerization (80). The most obvious consequence is the disruption of the mitotic spindle, which causes mitotic arrest of the cell. Because HPV-infected tissues divide more actively than the surrounding healthy epithelium, they are primarily affected by podophyllin. Podofilox may also damage HPV DNA itself (28).

The variable content in podofilox of podophyllin affects its potency and toxicity (81). Therefore the introduction of purified podofilox as a commercial product (Table 2) made available a product that was less toxic and more active on a weight basis (82). An important consequence was that podofilox became the first drug for genital warts that could be self-administered by the patient (83, 84).

 Podophyllin has been compared to various therapies but not to placebo for the treatment of genital warts. There has been either no difference between podophyllin and podofilox (85-89), or the latter has been superior to the former in yielding a complete response (90, 91). Podophyllin was inferior to either cryotherapy or electrosurgery (92), and to cold-blade excisional surgery (93,94) in clearing warts.

Podophyllin has been used for the treatment of extra-genital warts, such as plantar warts (95) and oral warts (96), but this represents an uncommon use (Table 1).

Podofilox 0.5% solution, which is now commercially available (Table 2), has been superior to placebo vehicle (97-99). Formulation of podofilox in a viscous vehicle was desirable because the solution tends to run-off on the healthy skin. A 0.5% cream formulation has been evaluated in Scandinavia, and was found to be superior to the placebo vehicle (100-103), or interferon cream (102, 103). It was as effective as the solution formulation in inducing wart clearance (104-106). A podofilox 0.5% gel formulation that was also approved for the treatment of perianal warts has been introduced on the American market. In a randomized, double blind, placebo-controlled study, 81 of 181 (45%) patients treated with the podofilox gel formulation had complete wart clearance after 8 weeks, compared to only 5 of 93 (4%) vehicle recipients (107). The sex of the patient or the location, perianal or external genital, of the warts did not affect the treatment response. A shortcoming of podofilox, and of podophyllin as well, is the high rate of relapse or recurrence (Table 2). Prophylactic application of podofilox has been found to prevent recurrences during the prophylaxis period, but this is not likely to be a convenient solution for most patients (108).

Podophyllin and podofilox may cause local and systemic side-effects (81, 109, 110). Itching, pain, inflammation, erosions or ulcerations, bleeding, burns are found in decreasing order of frequency, with rates ranging from 17% to 1% (87, 90-94, 111-113). Occasionally this may lead to scarring or fecal incontinence (90, 94). Also, contact dermatitis to the benzoin vehicle or guaiacum wood contaminants can occur at the site of application. Because of the risk of severe inflammation and tissue necrosis, painting the healthy skin and leaving the medication more than 24 hours should be avoided.

Podophyllin should not be applied more than once a week (114). One should be aware that the histology of the treated skin may exhibit the presence of large keratinocytes (podophyllin cells) and abnormal mitoses in the lower third of the epidermis; features that may be confused with intraepithelial neoplasia (115, 116). Systemic side-effects, particularly with podophyllin, may develop after topical therapy because the drug is readily absorbed by the skin. Typically, nausea and vomiting precede neurological signs of sensory and motor neuropathy, seizure, and coma. Death may occur (82, 114). Hematologic (neutropenia, leucocytyosis, pancytopenia), pulmonary (tachypnea, respiratory failure), and renal (hematuria, renal insufficiency) may also develop systemic side-effects (114). Podophyllin use is contraindicated during pregnancy because the compound is mutagenic and abortifacient (117,118).

5-Fluorouracil

 5-Fluorouracil (5-FU) is a structural analog of thymidine, a pyrimidine, that blocks the methylation of deoxyuridylic acid into thymidylic acid thus interfering with the synthesis of DNA and, to a lesser extent, RNA. Dividing cells are particularly susceptible to its action, and it has been used topically in dermatology for the treatment of varied condition, including genital warts (Tables 1 and 2).

A great variety of regimens, most with a 5% cream, have been reported in the literature for the treatment and prophylaxis of genital warts (119-132). The results are difficult to evaluate given the diverse dosings, from twice a day to weekly and from a few days to 10 weeks, and the paucity of comparative studies. In a randomized study, 5-FU 5% cream applied at bedtime for two weeks was not different than podophyllin applied weekly for 4 weeks in the rate of genital warts resolution in males, 6 of 18 (33%) versus 10 of 19 (53%) patients, respectively (p = 0.33) (123). No statistically significant difference was noted in female patients with past genital warts in the prophylactic activity of 5-FU compared to no intervention (126). Intrameatal warts in the male appear to be one of the few first-line treatment indications of 5-FU. Daily administration for 3 to 14 days has produced lesion resolution rates of up to 95% (121, 122, 133). 5-FU can also be used for the treatment of mosaic warts (134).

Adverse reactions to topical application of 5-FU vary greatly in their frequency and nature, according to the regimens used. Pain, itching, burning, erosions, hyperpigmentation are the more common local side-effects, encountered in up to half of the patients. Fair-skinned individuals might be particularly susceptible (135). Not as frequent but more serious events may include contact and allergic dermatitis, and, with vaginal therapeutic use, chronic vaginal ulcerations (136-138). The development of vaginal adenosis and vaginal clear cell carcinomas have been linked to 5-FU intravaginal use. 5-FU has also caused hematologic complications (leukopenia, thrombocytopenia, toxic granulations, and eosinophilia) (139). The administration of 5-FU during pregnancy has not been associated with adverse effects on the baby, but safety cannot be considered to be established (140-142).

Interferons

 Interferons (IFN) are cytokines with immunomodulatory, antitumor, and antiviral properties (143). Three major classes are recognized: a, b, and g (Table 2) . IFN-a and -b share the same cellular receptor, while IFN-( uses a different one. Mucosal high-risk HPVs oncogenes (especially E7) downregulate the expression of IFN-responsive genes, including the tumor suppressor protein interferon regulatory factor-1, and a net effect is the reversal of the antiproliferative and antitumoral functions of IFN (144-148). The results of in vitro experiments suggest that these effects may vary from individual to individual, thus accounting for heterogeneity in treatment response (149). IFNs are manufactured as full, truncated, consensus, or hybrid gene products in human lymphoid cell cultures (e.g., IFN-b, IFN-a-2a) or by recombinant technology (e.g., IFN-a-2a, -2b, -2c). Further molecular alterations, such as pegylation, has been used to alter the pharmacologic pro le of IFN-a-2a and -2b and lengthen their half lives (150).

Topical IFN preparations are not available in the United States. By and large they have proven ineffective for the treatment of genital warts (151-154), despite some investigators reporting favorable results with a natural IFN-a ceam or gel (102, 103, 155). It is unclear if the efficacy differences among trials can be accounted by the vehicle used (103, 153). An IFN-b gel may be useful for the prevention of recurrences after excisional or ablative therapy (156).

Intralesional administration of IFN has been widely assessed for the treatment of condylomata acuminata, especially in randomized, controlled trials. It has shown superiority to placebo, but the net effect has been modest, imperfectly sustained, and limited usually to the injected lesions (113, 114, 143, 157-169). Pain on injection is the main adverse effect. This and the fastidious mode of delivery limit the number of lesions that can be treated at each session. Intralesional IFN has been ineffective for the treatment of plantar warts (170).

Parenteral (intramuscular or subcutaneous) IFNs for the treatment of genital warts have not been found to be superior to placebo or to add anything in combined treatments in most randomized studies (162-165, 171-183). Parenteral IFN has probably a biologic effect on benign genital disease, but one that is usually too weak. This impression is based on the results of a couple of placebo-controlled, randomized clinical trials in which a statistically significant treatment effect was found, with relative risks of 4.5 (184) and 1.8 (185). It also takes into consideration the results observed with parental IFN in the treatment of recurrent respiratory papillomatosis (186, 187).

 The adverse reactions associated with IFNs are well known. They are in part dose-related and usually reversible after drug cessation. The most common symptoms resemble those of influenza except for the respiratory component and include fever, chills, malaise, headache, myalgias, and fatigue. They appear within 2 to 8 hours of the drug administration and wane within 24 to 48 hours. In the clinical trials of IFN for the treatment of genital warts, these clinical symptoms have been almost the only ones encountered. They can be curbed by the intake of acetaminophen or nonsteroidal anti-inflammatory agents at the time of IFN administration. The intensity of these symptoms progressively wanes during treatment. More serious adverse reactions include lethargy, confusion, anxiety, depression, suicide, insomnia, weight loss, anorexia, nausea, vomiting, alopecia, cutaneous necrosis, and peripheral neuropathies. Biological abnormalities, mostly asymptomatic, may include neutropenia, thrombocytopenia, high serum transaminases, and occasionally anemia and hypertriglyceridemia. Patients may develop binding, and possibly neutralizing, antibodies to IFN. Pregnancy is a contraindication to the use of IFN. Although there are differences in efficacy and the intensity of the side-effects among IFNs, they are small and usually of no clinical significance (160, 168, 172, 173, 188).

Non-Drug Therapies of Choice

Curettage and Cold-Blade Excision

 Surgical curettage has been used to treat cutaneous warts, especially plantar, and occasionally genital warts (189-191). This old technique has not been rigorously evaluated (192). Its main shortcoming is the possible formation of scars, which may be painful. Curettage has to be done under local anesthesia by local injection. The EMLA cream (lidocaine and prilocaine) has been unsatisfactory for the topical anesthesia of plantar warts (193).

Genital warts can be excised with scissors, especially if they are few in number. Thomson and Grace described a widely used technique (194). This is an effective treatment, and although scarring may occur in up to 10% of patients, it is usually minimal in extent (Table 2) (93, 195, 196). In comparative trials, excision has proven superior to podophyllin, notably because of the much smaller recurrence rates, thus giving at 9-12 months net wart clearance rates of 13/18 (72%) and 20/30 (67%) in two different studies (93, 94).

Cryotherapy

Cryotherapy is the treatment by cold. Cold is delivered by either spraying the lesion with liquid nitrogen (boiling point, BP = -196°C), or applying a cryoprobe, a cryogenic pencil, or a cotton swab cooled with liquid nitrogen, nitrous oxide (BP = -89.5°C), or carbon dioxide (BP = -78.5°C). Spraying is not necessarily superior to contact freezing at the same temperature. However, because HPV DNA can be recovered on fomites and because cryogenic pencils have been associated with wart transmission, liquid nitrogen spraying is the preferred method of cryotherapy delivery unless disposable contact equipment is used (197-199). Cotton swabs are preferable to freeze lesions that are close to fragile structure such as the eye. Freezing techniques vary, but they aim at the abrupt cooling of the lesion and a surrounding halo of normal skin, thus causing them to turn white (200-202). The duration of freezing varies with the lesion size, but typically ranges from 20 to 30 seconds. Some practitioners recommend after thawing the application of a second freezing, which might be advantageous for the treatment of plantar warts, and perhaps hand warts (203). Very often several sessions, one to two weeks apart are necessary to achieve a complete clearance. Cryotherapy leads to tissue necrosis but not in the destruction of HPV DNA (28, 204, 205).

 An intense pain is associated with the application of the cryogenic. Because of its brevity, most patients tolerate it. Should local anesthesia be used, the EMLA cream is a convenient and effective solution, as long as the patient can apply it about 1 hour before the procedure (206-208). After thawing, up to half the patients will experience mild to moderate discomfort, itching, burning, or pain (177, 209). Excessive freezing may cause blistering and edema. This should be avoided. Long-term, skin discoloration was noted 6 months after cryotherapy in a quarter of patients treated for genital warts (177). This is likely to disappear with time. Joint damage and neuropathies have resulted from cryotherapy (210, 211). Pregnancy is not a contraindication.

Cryotherapy is one of the most often used treatment modalities for genital warts (Table 2). Its efficacy has been established mostly in open studies without a control group (111, 212-217), and in a few instances in comparison to established therapies (30, 92,218, 219). Complete response rates typically range from 65% to 85%, but recurrences occur in 20 to 40% of patients. Therefore, the net clearance rate is about 60%. This rate allows to gauge the relative efficacy of cryotherapy (Table 2). This comparative ranking has been confirmed by several randomized comparative trials. Hence cryotherapy is superior to podophyllin (92, 219) and podofilox, but equivalent to TCA (29, 30), and probably electrosurgery (92). Cryotherapy appears to be well-suited to the treatment of intrameatal warts (220).

Cryotherapy is also used for the treatment of cutaneous warts, and is favored by patients for the treatment of hand warts (Table 1) (221). Long-term clearance rates of about 50% can be expected (222). The technique is the same as with genital warts (197, 222, 223). Plantar warts tend to be more resistant to cryotherapy than hands warts (224, 225).

Electrosurgery

Electrosurgery includes various techniques that ablate tissue with electric current (226). These techniques are not necessarily interchangeable. They vary according to the amperage, voltage, and wave-form of the current, whether one or two electrodes are used, and whether they touch the treated tissue. Hence the names of electrocautery, electrodiathermy, electrodessication, electrofulguration, electrocoagulation, and electrosection in a nomenclature that is not always consistent among authors. Although commonly used by dermatologists and surgeons, the methods of electrosurgery have not been compared to one another, and only rarely with other techniques for the treatment of genital warts or cutaneous warts.

For the treatment of genital warts, electrocoagulation has yielded a clearance rate of 58/100 (227), while in another study comparing podophyllin, cryotherapy, and electrodessication, the net clearance rates at 3 month, assuming that subjects lost to follow-up were failures, were 9/63 (14%), 36/83 (43%), and 33/68 (49%), respectively (92). These differences were statistically significant among treatment groups ( p < 10-4), but not when electrosurgery was compared to cryotherapy. Another study comparing electrocautery to cryotherapy was unable to demonstrate a statistically significant difference, with genital wart clearance rates of 10/11 (91%) and 10/16 (63%), respectively (218). Electrodiathermy was superior to either intramuscular or subcutaneous IFN (228). Intralesional IFN-a may reduce the number of recurrence after electrocautery (163, 229).

Electrofulguration is suitable for the treatment of facial warts (230). However, electrosurgery is usually not recommended for the treatment of plantar warts because the painful scarring that may ensue (230).

 Regardless of the site and method used, scarring, with the possibility of sphincter strictures, is the main risk of electrosurgery. The technique should be left to the hands of the expert. The procedure itself is painful and requires local anesthesia, which can be provided by the application of the EMLA cream (193, 231, 232).

Electrosurgery, like laser surgery, emits a plume of smoke that contains HPV DNA (233, 234). This is a potential infectious risk for the operator and the assistants that can be handled by smoke evacuation systems.

Laser Surgery

Lasers emit a narrow monochromatic light that is in phase and whose waves travel in separate parallel planes, thus without loss of energy in transparent media. A great variety of medical lasers exist, and among them the pulse dye, Er:YAG, and Nd:YAG lasers, which are pulsed-wave instruments, and the argon, and KTP lasers, which are continuous-wave lasers, have been used for the treatment of warts (235-237). However, it is the CO2 laser, a continuous wave instrument that has been the most extensively used for the treatment of anogenital disease. It has a wavelength (10,600 nm) that is absorbed by water and is converted into heat. This allows the vaporization of the treated tissues. The laser can be used for cutting when using a narrow, intense beam (238). By using a broader spot the lesion itself can be destroyed. A lower intensity beam ("brushing technique") will cause tissue coagulation and hemostasis.

Laser surgery destroys the treated tissue but not the HPV DNA (239). Indeed, as with electrosurgery, HPV DNA can be found in the plume of smoke produced by the vaporizing laser. This HPV DNA can also be detected in the operator's upper airways and on the walls of the surgical suite (233, 234, 240, 241). This appears to represent a real infectious risk because a higher incidence of hand and nasopharyngeal warts has been reported in laser surgeons (242). Consequently, a smoke evacuation system should be part of the equipment, and the operator should wear gloves, gown, mask, and goggles. This infectious risk probably varies with the type of laser used, for example, the erbium: YAG laser does not seem to release HPV DNA (243).

Anogenital warts are amenable to laser surgery (Table 2) (135, 235, 236, 244-246). However, it is very difficult to ascertain the true merit of this modality because most of the literature is made of case-series, and techniques and operator’s experience vary (247). One randomized controlled trial has compared laser surgery to a treatment consisting of either cold-blade surgery, electrosurgery, or both (196). Fourteen of 21 (67%) patients remained free of lesions at up to 6 months follow-up in the laser treated group, compared to 13/22 (59%) in the other group. The other available randomized controlled trials have only compared laser surgery to laser surgery plus something else given to reduce the recurrence risk. Table 2 summarizes the clearance rates observed in the laser surgery alone arm of these trials.

Laser surgery has been also used to eradicate cutaneous warts, particularly plantar warts, common warts, including the periungual and subungual variants (Table 1). No comparative, randomized studies are available to permit a reliable assessment of an efficacy that is otherwise reported to be good. As with genital warts, the CO2 laser has been the favored instrument (236, 248-254). However, a greater diversity of lasers are used, including the pulse dye laser (255-262), the KTP laser (263), the Nd:YAG laser (264), and the Er:YAG laser (265, 266). The Er:YAG laser induces little thermal damage, yet the hyperthermia may be sufficient to eliminate plantar warts and the HPV particles present within (205).

Laser surgery requires anesthesia usually delivered locally by injection or by the application of EMLA cream (267-269). Nevertheless, general anesthesia may be needed, especially if the lesions are extensive. This of course adds to the cost, usually high, of the procedure. The side effects of laser surgery, which occur in up to a quarter of patients, include postoperative pain, bleeding, discharge, swelling, dysuria, meatal stenosis and scarring (135, 196, 270-273). Laser surgery can be used during pregnancy.

Special Infections

This chapter is limited to the treatment of cutaneous and external anogenital warts. Other HPV-associated lesions such as warts, papillomas, intraepithelial and invasive neoplasias affecting the internal teguments (upper airways, mouth, cervix, vagina, anal canal) are the province of different specialists, as is the treatment of external pre-invasive and invasive neoplasias.

In addition to possible symptoms, cosmetic considerations are important in deciding to treat warts. It is therefore important to select and apply treatments that not only are unlikely to cause permanent symptoms, but also will not leave scars or other unsightly results. It is important to remember that cutaneous and external anogenital warts are very rarely life-threatening, progress almost never to malignancy in the presence of an intact immune system, and are likely to spontaneously resolve over time. For example, in children the rates of spontaneous resolution of cutaneous warts are 50% and 90% at 1 and 5 years, respectively (274). A meta-analysis of the placebo arm of several clinical trials suggest a 30% clearance rate at 10 weeks (275). Adults are expected to have lower rates of spontaneous clearance. For genital warts, the rate of spontaneous resolution may be as high as 10-20% after 3-4 months of follow-up (172, 173). It is unfortunately impossible to predict which patients will have a spontaneous regression.

Failure to respond to previous treatment defines a recalcitrant or refractory wart. Most patients with recalcitrant warts, especially anogenital, are not necessarily more likely to fail the next treatment than a patient treated for the first time (113, 161, 276). It does not seem that size or number of anogenital warts is a reliable predictor of failure (113, 159, 277). Long disease duration seems a better predictor of refractoriness of anogenital warts (157, 159, 172, 277). Immunosuppression or immunodeficiency is a major hindrance to wart clearance.

Cutaneous Warts

Most cutaneous warts remain untreated because they cause little or no inconvenience and resolve spontaneously. When treatment is requested and/or is appropriate, the practitioner is confronted with many treatment options for which, unfortunately, the current literature and its dearth of comparative trials fail to provide good objective decision criteria (Table 1). Consequently, availability, familiarity, safety, and cost of the treatment modalities are the major elements in making a decision. Several guidelines try to offer further guidance (52, 275, 278, 279). As a general principle, plantar warts, especially mosaic warts, are more difficult to eradicate than hand warts. Flat warts clear best (Table 3).

Home treatment should be privileged, and among them salicylic acid preparations, which are 4 times more effective than placebo (275). As a second line of home treatments, one may prescribe glutaraldehyde or formaldehyde. Before applying these paints, it is recommended to eliminate the excess of keratin by abrasion with a pumice stone, sand paper, or an emery board. This is particularly important for the treatment of plantar warts. Softening of the warts by soaking the area in hot water may help. Occlusive bandages improves the clearance of plantar warts. For the products in a collodion base, the collodion film needs to be removed before the next treatment. Silver nitrate sticks may also be tried by the patient.

Cryotherapy is among the favored of office-based therapies. In addition to abrasive tools, the practitioner may pare the wart with a scalpel to remove the excess of keratin prior to treatment. Complete curettage of the lesion may be done, although the risk of scarring should be considered. If cryogenics are not available, several drugs may be used, such as podophyllin, but preferably podofilox (81), or cantharidin. Bleomycin is another option, particularly for warts around the nails. Electrosurgery or laser surgery is more expeditious modalities, but they are also more expensive and cumbersome to implement because of the equipment required and the need to administer local or general anesthesia. Flart warts respond well, but plantar warts are a relative contraindication to electrosurgery. Lasers offer many choices that can be tailored to the specific location. In particular they can be useful for the removal of peri-and subungual warts.

Other treatments, including 5-FU, retinoids, cidofovir, allergic sensitization, and heat therapy are fourth line options.

Anogenital Warts

Patients with condylomata acuminata often seek treatment. One of the reasons, particularly among women, is the significant psychosexual impact of the disease (280-284).

It is not clear how treatment affects potential HPV transmission to a sexual partner or, during pregnancy, to the baby, but it is likely that it diminishes it. Because the risk of progression to malignancy of condyloma acuminata in the normal host is extremely low, it is unknown how this risk is affected by treatment.

There is no evidence that treating the male diseased partner of a woman with genital warts is indicated to prevent relapses, reinfection, or the risk of CIN development (285, 286). However, in the reverse situation, that of the female partner of a male patient with warts, we do not know the impact of partner treatment and evaluation. At present the Centers for Disease Control and Prevention (CDC) does not recommend partner evaluation and treatment (287). Yet, in practice the partner might be evaluated because of (a) the concern for other sexually transmitted diseases for which partner treatment is desirable; (b) the psychosexual burden on the patient of not knowing if one's partner is "clean"; and (c) the opportunity the encounter with the partner offers for couple counseling.

Anogenital warts in infants and children present the particular problem of possible sexual abuse (288, 289). Evaluation guidelines are available, and referral to an experienced pediatrician is recommended (290). The concern of sexual abuse should also be present when evaluating an adolescent with anogenital warts, but in addition, the presence of risky sexual practices (e.g., anal intercourse, multiplicity of partners, lack of barrier protection) and behavior (alcohol and drug use) should receive particular attention.

Treatment options for anogenital warts are varied, but none is totally satisfactory (Tables 2 and 3). The patient should also be informed of the risk of treatment failure and lesion recurrence. Location of lesions may affect outcome. Lesions in moist areas appear to resolve better than ones on dry areas, but not necessarily because of treatment received (63, 172). Furthermore, warts located within the occluded foreskin have a favorable outcome (277).

Several detailed consensus treatment guidelines that also offer a review of the literature according to evidence-based criteria can be consulted for additional information (114, 286, 287, 291). Although costs of the different therapies vary considerably and should be considered in recommending a particular treatment, none of the available cost-benefit analyses provide consistent results (292-295).

Self-treatment offers privacy and convenience, and is rated highly by patients (296). Therefore, imiquimod and podofilox are the two first-line options (Table 3). The main disadvantages of these treatments is the length of treatment duration for imiquimod, and a relatively high relapse rate for podofilox. Patients may want immediate removal of lesions, in which case of ce-based methods are required. Usually, experience and availability guide the choice of the treatment modality. Excision with a cold-blade is particularly suitable for few and relatively small lesions. Otherwise, electrosurgery, infrared coagulation ablation or laser surgery are alternate choices. Laser surgery is well-suited for the removal of large and extensive lesions. Often, however, these two methods are used as a second-line of approach because of cost and availability. The patient may accept an office-based treatment that usually requires several visits. In that regard application of BCA or TCA and cryotherapy are two widely used options. The requirement for several visits may be appreciated by some patients as it offers greater exibility and effectiveness for education and counseling.

Podophyllin is an obsolescent drug and it should be avoided unless in settings where costs and ease of access to drugs are major considerations. For warts that are recalcitrant, one may try repeating the same therapy after a pause (perhaps with a more intense regimen as with imiquimod) or, preferably, using an alternate standard modality. Among the more ultimate options, one may choose among allergic sensitization, IFN -notably intralesional IFN for the large single lesion-, cidofovir either topically or intralesionally, 5-FU, photodynamic surgery. One may also use as adjunct therapy I3C/DIM dietary supplements. 5-FU, along with cryotherapy has a place in the treatment of meatal warts (121, 122, 133, 220).

Pregnancy restricts the treatment options to cryotherapy, BCA/TCA, electrosurgery, cold-blade excision, and laser surgery. Although the possibility of transmitting the HPV infection to the baby is cause for concern, the risk is low enough that cesarean section is not advocated (297, 298). Obstruction of the birth canal by the warts is a treatment indication.

The treatment of HPV diseases and anogenital warts specifically, in the immunodeficient host is a challenge because lower clearance rates should be expected. Therefore the management goal may be limited to controlling the extent of the disease and screening for possible malignancies.

Patient follow-up after treatment is useful to assess response to therapy. Typically, a 3 month visit will detect most recurrences. However, often when the disease recurs, the patient will initiate the encounter. More sustained follow-up, perhaps yearly, is probably wise in patients who are immunocompromised or whose lesions presented a particular therapeutic challenge.

Counseling is an important component of the therapeutic encounter with adults and adolescents (299). Educational materials and addresses of support groups for the patient can be found on the web sites of the Centers for Diseases Control and Prevention (CDC) (http://www.cdc.gov/nchstp/dstd/dstdp.html) and of American Social Health Association (ASHA) (http://www.ashastd.org). Both organizations also operate hotlines: CDC's is 1-800-227-8922 (Monday through Friday from 8: 00 a. m. to 11: 00 p. m., ET) and ASHA's is (919) 361-4848 (Monday through Friday from 2: 00 p. m. to 7: 00 p. m., ET).

Underlying Diseases

Immunodeficiency presents a challenge for the treatment of cutaneous and anogenital warts, as well as other HPV-associated diseases. Cutaneous warts and anogenital warts are more common in these patients. The incidence of cutaneous warts increases by about ten-fold in patients with lymphomas, and by 4-12-fold in HIV-seropositive patients (300-302). Three years after renal allograft transplantation, between 25% and 42% of patients have cutaneous warts; a number that rises to 92% after 5 years or more (303). The risk of developing anogenital warts is similarly increased in that population (304). In HIV patients, the odds of having anogenital warts are 3 to 8 times higher than in HIV-seronegative controls (305, 306). In an immunocompromised host, these lesions tend to be resistant to therapy. For example, the odds of anogenital wart relapse after treatment were found to be 22-fold higher in HIV patients (307).

 response of cutaneous warts to specific treatment in HIV patients has been little studied. Anecdotes suggest that imiquimod is effective for the treatment of labial and at warts (308, 309).

Several treatment modalities have been evaluated in HIV patients, mostly in individual cases or small case series. Podophyllin or podofilox seems largely ineffective (310-312). Cold-blade excision in combination to electrosurgery may offer some benefit in the treatment of anal condylomas (310, 313). Although intralesional IFN-a alone has proven to be ineffective (314), it appears useful when used with electrosurgery for the treatment of intra-anal warts (229). A randomized, controlled study has examined the efficacy of imiquimod 5% cream in HIV seropositive patients with a CD4 count equal or greater than 100 cell/mm3(315). Complete clearance rates of the anogenital warts were 7/65 (11%) and 2/25 (6%) in the imiquimod and placebo groups (p = 0.49), respectively. Nevertheless, the rate of partial (50% or more) responses was significantly higher with imiquimod than with placebo, 50% versus 14% (p = 0.01). This suggests that imiquimod could be used to control the disease. Imiquimod has also been advocated as adjunctive therapy, but this has not been rigorously evaluated (316).

Topical cidofovir 1% gel has been shown in a case-series and a small placebo-controlled study to be effective in the clearance of anogenital warts (317, 318, 319). Another randomized study compared surgery alone, topical 1% cidofovir gel daily 5 days a week for up to 6 weeks alone, and surgery followed by topical cidofovir (319). At the end of treatment, the clearance rates were 17/29 (93%), 20/26 (76%), and 19/19 (100%), respectively. At 6 month follow-up, the relapse rates in 49 patients who were followed were 74% , 35% , and 27% ( p = 0.02), respectively.

Antiretroviral treatment, particularly the highly active antiretroviral treatment (HAART), does have an impact on HPV disease, but it is at present a confusing one. It appears that HAART is associated with an increased incidence of condylomata acuminata (320). HAART has also been associated with an increased incidence of oral warts (321). A decrease in HIV viral load, although not antiretroviral therapy itself, was also linked to an increased incidence of oral warts in a case-control studies (322). In contrast, HAART was not noted to affect the incidence of anal intraepithelial lesions, while discordant results, increases and decreases in incidence, were reported for CIN (323-330). Anecdotally, antiretroviral treatment has contributed to the clearance of common warts in one patient (331).

Alternative Therapy

Drug Therapy, Immunotherapy, Allergic Sensitization

1-nitro, 2, 4-dinitrochlorobenzene (DNCB) is a potent allergic sensitizer that has been used in dermatology to treat various benign skin conditions, including recalcitrant cutaneous and genital warts (332). The subject is first sensitized by the application of DNCB on the volar aspect of the arm (333). A week later the warts are painted with DNCB. The resultant inflammatory reaction is thought to trigger the wart clearance that, in uncontrolled small studies and case reports, has been reported to be about 80% -100% for cutaneous warts (334-337). The occurrence of severe allergic reactions with DNCB has led to a disaffection for this agent (338). It is now largely replaced by safer sensitizing compounds such as 2, 3-diphenylcyclopropenone, squaric acid dibutyl ester, and 10% masoprocol cream (Actinex) (332). Another seemingly successful approach has been the intralesional injection in cutaneous warts of either mumps or candida commercial antigens in subjects with a positive intra-dermal reaction to one of these antigens (339). Warts cleared completely in 29/39 (74%) of the patients.

Recombinant Therapeutic Vaccines

Therapeutic vaccines are in development. One that merit attention is the HPV16 HspE7 vaccine (StressGen Biotechnologies) that is developed for the treatment of anal HSIL. The HPV16 E7 protein is covalently linked to the p65 heat-shock protein (Hsp) from Mycobacterium bovis BCG strain that serves as adjuvant. A retrospective review of patients with anal HSIL treated with the vaccine indicated that of 14 patients who also had anogenital warts, 2 had a complete resolution, and 10 had a partial resolution (340).

Cidofovir

Cidofovir, or (S)-1-( 3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC) is an acyclic nucleotide analog that is available for the intravenous treatment of cytomegalovirus retinitis. Cidofovir is converted by the cell into cidofovir diphosphate, which is incorporated into the growing CMV DNA and blocks the CMV DNA polymerase. HPVs do not possess a DNA polymerase, yet cidofovir was found to have an antiproliferative activity in in vitro and in vivo models of HPV infection (341, 342) (14, 343). The mechanism of action is not well understood but appears to involve the formation of the triphophorylated form of cidofovir and the induction of apoptosis (341, 342).

Intralesional injection of the compound has been found effective in a small number of patients with condyloma acuminatum or upper digestive HPV tumors (344, 345). However, it is for the treatment of recurrent respiratory papillomatosis that intralesional cidofovir has attracted the greatest enthusiasm after a case-series of 17 patients with severe disease, often an untractable problem, reported a complete clearance of 82% (346). Other favorable anecdotal evidence was subsequently added about intralesional and/or parenteral cidofovir as an adjunct therapy of laryngeal and lung papillomas (347-349).

Although a commercial preparation is not available, cidofovir can be compounded and several authors have reported favorably on the use of topical formulations for the treatment of various HPV diseases, including condylomata acuminata, VIN, CIN 3, recalcitrant oral papillomatosis, common and plantar warts (350-356).

A decisive demonstration of the efficacy of cidofovir was given in a double-blind trial that enrolled men and women with condylomata acuminata (357). Patients were randomized 2:1 to receive cidofovir 1% gel or the vehicle gel. The treatment was applied daily for 5 consecutive days every other week, up to 6 cycles. Patients with complete clearance were given an additional cycle and were evaluated 1 and 6 months later. At the end of 12 weeks of treatment, 9/19 (47%) patients in the cidofovir group compared to none of 11 in the vehicle groups had a complete wart clearance (p = 0.006). Only one of the 9 patients in the cidofovir group had a recurrence. There were no differences in the incidence rates of adverse reactions between the two groups. Pain, pruritus, or rash was noted in 68% of the cidofovir recipients and 64% of the vehicle recipients. Erosions or ulcerations were observed in 32% and 45% of the two groups, respectively. It should be noted that cidofovir is a potential carcinogen and its long-term safety in humans is not well-known.

Retinoids

Retinoids, which include tretinoin, isotretinoin, etretinate, are synthetic compounds derived from the vitamin A analog retinol (358). They have been evaluated for the prevention and treatment of anogenital HPV diseases because they stimulate the desquamation and curb the proliferation of keratinocytes, including those infected by HPV (359). In addition, low levels of vitamin A and beta-carotene have been linked to the development of CIN (360, 361). Although topical 0.372% tretinoin cream might cause the regression of CIN 2 (but not of CIN 3) lesions, retinoids have been ineffective the treatment of condylomata acuminata (362,363).

Daily application of a 0.05% tretinoin cream has been effective for the treatment of at warts in children, with a complete response rate of 85% in 25 tretinoin treated children compared to 32% in 25 controls (364). Oral retinoids have also been found to be beneficial for the treatment of plantar and common warts in case reports (365, 366). In a case series of 20 children with extensive cutaneous warts, daily treatment with 1 mg/kg of etretinate for up to 3 months led to a complete response, free of relapse, in 16 subjects (367).

Cimetidine

Cimetidine, an H2 -blocker, has known a fad as a treatment of cutaneous warts. However, two randomized, double-blind, placebo-controlled trials have failed to confirm any activity (368, 369).

Homeopathy

Homeopathy is one of the leading modalities of "alternative" medicine and is used for the treatment of cutaneous warts (370). However, three randomized, double-blind trials have failed to demonstrate a difference with placebo, or even detect a trend (371-373).

Non-Drug Therapy

Heat

Heat is another agent used to treat warts. An infrared coagulation causes circumscribed necrosis of the skin (374). This technique has been used for the removal of tatoos, as well as the treatment of skin and cervical lesions (375-377). In an open study, 61 of 74 (82%) women treated for condylomata acuminata remained free of lesions at 6 month follow-up (376). Eleven of 21 patients (52%) with hand or plantar warts had wart clearance after treatment with the infrared coagulator (377). Local anesthesia is necessary, but the technique is otherwise well-tolerated. An intriguing application of heat has been the successful treatment of cutaneous warts by raising the local temperature of the lesion to 40-50°C in a water bath or by using a radiofrequency current (378-380).

Heat delivered by ultrasound has been used to treat genital and cutaneous, particularly plantar warts (381-385). It is difficult to assess the efficacy of this approach given the absence of proper controls. A different approach is the use of high-energy ultrasound to ablate tissues. This requires general anesthesia. In one study of women with recalcitrant vulvar condylomata acuminata, 14 of 18 (78%) of the women treated had no recurrence (386).

Photodynamic Therapy

Photodynamic therapy (PDT) relies on laser light to activate the cytotoxicity of a compound either applied topically to the lesion (5-aminolevulinic acid, 5-ALA) or parenterally (such as meso-tetra (m-hydroxyphenyl) porphyrin -m- THPP - or 5 - ALA) (387, 388). The technique has been used for various internal HPV diseases, but only on a limited basis for the treatment of recalcitrant hand and foot warts (389, 390). Nevertheless, a randomized placebo-controlled trial has demonstrated with PDT results superior to placebo when clearance of individual warts was compared (390). It is unclear how these results translate for the patient.

Suggestion and Hypnosis

The idea that cutaneous warts respond to suggestion has been has been perpetuated by several authors (391-396). However, only few randomized, controlled studies have been conducted, and they have failed to provide convincing evidence of a suggestion effect (395, 397). Some have argued that hypnosis is superior to suggestion for the treatment of cutaneous warts, but the studies available show inconsistent results and defective methods (392-395, 397-399).

Combination Therapy

Combination therapy is not part of the standard approaches to the treatment of cutaneous or anogenital warts. It is impossible in the absence of comparison groups to judge the relative benefits of combination therapy for plantar warts including for example cryotherapy plus salicylic acid, or salicylic acid, podophyllin, and cantharidin (400, 401).

Imiquimod has been used in combination with podofilox for the treatment of anogenital warts in children or with other treatment modalities in HIV patients (316, 402). Several randomized controlled studies have been conducted evaluating combinations including either IFN, laser surgery, or both (113, 162-165, 174-183, 196, 403). In these studies, IFN was added to surgical ablative methods to prevent recurrence. The results of this extensive effort only showed that intralesional IFN-alpha plus podophyllotoxin was superior to podophyllotoxin alone, and that when combined with laser surgery +/- TCA, IF-alpha was better than either laser surgery +/- TCA and 5-FU or laser surgery +/- TCA alone (113, 181).

ADJUNCTIVE THERAPY

Contraception, Smoking, and Shaving

The discontinuation of oral contraception may help eradicate condylomata acuminata. (406). Smokers should also be encouraged to stop because smoking may increase the risk of anogenital wart development (407). Shaving of the pubic hair should be discouraged as it disseminates the virus and probably favors the development of lesions by creating a wound epithelium.

Indole-3-Carbinol and Diindolylmethane

Indole-3-carbinol (I3C) is a molecule that is derived from the autolysis of glucobrassicin in cruciferous vegetables (broccoli, cabbage, cauliflower, etc.) (408). I3C and its main active metabolite, diindolylmethane (DIM) , the dimer condensate of I3C, increase the 2 hydroxylation of estradiol. This results in the formation of 2-hydroxyestrone, a non-estrogenic, antiproliferative, anti-angiogenic, and apoptotic compound instead of 16 alpha-hydroxyestrone. 16 alpha-hydroxyestrone and estradiol stimulate the growth of papillomas in tissues that are estrogen sensitive, such as the cervix and the larynx (408, 409). The inhibitory effect of I3C/DIM on the growth of HPV-11-infected papillomas has been demonstrated in the nude mouse xenograft model (410). On the basis of several uncontrolled evaluations, I3C (Theranaturals Inc., PO. Box 344, Orem UT 84059-0344, tel. 801-224-8893) has become a popular dietary supplement used as an adjunctive therapy for the treatment of recurrent respiratory papillomatosis (408). A recent randomized, placebo-controlled study of oral I3C for the treatment of biopsy-proven CIN 2 or 3 has brought more credible evidence of its efficacy (411). Patients were administered 400, 200, or 0 mg a day of I3C for 12 weeks, and at the end of treatment a biopsy was done showing regression in 4 of 9 patients in the high dose group, 4 of 8 patients in the low dose group, and in none of the 10 patients in the placebo groups. It is likely that these results will encourage the study of this compound in the adjunctive treatment of condylomata acuminata. DIM is available as Phytosorb-DIM (Bio-Response Nutrients L.L.C., P.O. Box 288, Boulder, CO 80306, tel. 303-447-3841) and the manufacturer recommends a 5-8 mg/kg daily oral dose. The safety profile appears to be excellent. I3C/DIM induce phase I and II enzymes (specifically CYP1A1 and CYP1A2), which has resulted in the inactivation of certain drugs, including phenytoin (412). Otherwise, because of their anti-estrogenic activity, these compounds have a theoretical risk of osteoporosis and infertility that has not been yet seen (408).

 

ENDPOINTS FOR MONITORING THERAPY

The endpoints for monitoring the treatment of anogenital warts, cutaneous warts, and HPV-associated diseases in general (with the exception of invasive cancers) are purely clinical: the eradication of lesions. The eradication of HPV DNA is not presently a treatment goal.

 

VACCINES

Since June 2006, the first prophylactic vaccine against human papillomaviruses (HPV) has been available for the prevention of diseases related to HPV types 6, 11, 16, and 18. HPV-6 and -11 account for over 90% of genital warts, and types 16 and 18 for over 70% of cervical cancers (7a, 19a). This quadrivalent vaccine, Gardasil (Merck), has received indications in the United States for the prevention in women of cervical cancer, adenocarcinoma in situ, cervical intraepithelial neoplasia grades 1, 2, and 3, vaginal intraepithelial neoplasia (VAIN) grades 2 and 3, vulvar  intraepithelial neoplasia (VIN) grades 2 and 3, and genital warts. The vaccine is now approved in at least 85 countries. An bivalent vaccine, Cervarix (GlaxoSmithKline),  directed at HPV-16 and -18, has been first approved early 2007 in Australia. Since then licenses have been granted in the Philippines, Kenya, the United Arab Emirates, and in the European Union.

Both vaccines are based on the expression of the gene coding for the major capsid protein (L1) of HPV in either a yeast (Gardasil) or baculovirus (Cervarix) system, which leads to the self-assembly of the proteins into a virus-like particle (VLP) that has the same size, appearance, and immunologic properties as of the native capsid, but is not infectious because it is devoid of HPV DNA.

Early work had shown that these HPV VLP induce a strong immune response that neutralizes the homologous papillomavirus infection (23a, 24a). This concept of using papillomavirus VLPs as a vaccine was validated in animal papillomavirus infection models (5a). These experiments established that protection is conferred by the development of neutralizing antibodies. This was followed by phase I studies in man demonstrating the immunogenicity and tolerance of an HPV L1 VLP vaccine (9a, 13a).

The ability of the vaccine to prevent HPV infection was demonstrated in a randomized trial in which 1533 evaluable  females aged 16-23 years received either an HPV-16 L1 VLP intramuscular immunization in an aluminum hydroxide adjuvant or the adjuvant alone at day 0, month 2, and month 6. After a median follow up of 17.4 months, 41 subjects in the control group had developed a persistent HPV-16 infection versus none in the vaccine group (17a).

The current indications of Gardasil are supported by a series of Phase III studies (1a, 10a, 15a, 16a). They have been summarized elsewhere (2a, 4a). Gardasil was shown to be 99% effective in preventing CIN 2 or 3, and AIS caused by HPV-16 or -18 in pooled studies totaling 17,000 females ages 16-26 years, comparing the vaccine versus the adjuvant alone (1a). This endpoint, with up to 3 years of follow-up, was assessed in the per-protocol susceptible population of women who were negative at entry by serology and cervical viral DNA testing for the HPV types included in the vaccine. By the same criteria, the vaccine was found to be 100% effective preventing any CIN grades and AIS caused by any of the vaccine types, VAIN and VIN, as well as external genital warts.

Even by including subjects who had not received all three immunizations, or might have had an abnormal Pap smear, and by counting cases after the first immunization the efficacy of the vaccine still ranged from 82 to 98% for the the different end-points enumerated above. This as long as the subjects were HPV seronegative and DNA negative at entry. Including these subjects in the analysis impacted on the vaccine efficacy, which ranged from 44% for CIN2/3 and AIS, to 76% for genital warts. These efficacy figures are likely to increase with time failures accrued faster in the control arm than in the vaccine arm of the studies.  It is clear that the greatest impact of the vaccine is when it is administered prior to the onset of sexual activity, that is prior to the likely acquisition of any genital HPV infection. It has been feared that the vaccine impact might be minimal when administered to a less selective population especially when looking at all cervical lesions irrespective of HPV types (25a). However, early results show that at 3-year follow-up, the vaccine leads to a reduction by half of all high-grade squamous intraepithelial lesions (the cytologic equivalent of CIN2/3), including those caused by non-vaccine HPV types,  irrespective of serostatus or HPV infection at baseline (20a).

Very comparable efficacy results have been observed with Cervarix in the Phase II studies so far reported (11a, 12a). Cervarix also offered cross-protection against infections caused by HPV-31, which is related to HPV-16, and HPV-45, which is related to HPV-18 (12a). Gardasil also exhibit some cross-protection against infections caused by types not included in the vaccine (6a).

Neutralizing titers are induced by Gardasil in young girls aged 9-15 years, titers that are actually higher than in older females (3a, 21a, 22a). These results are the basis for the vaccine approval in females from age 9 to 26 years (18a).

The American Committee on Immunization Practices (ACIP) has issued guidelines for the administration of Gardasil (18a). The vaccine is given in a volume of 0.5 ml, by an intra-muscular injection in the deltoid area at day 0, month 2, and month 6. The contraindications are hypersensitivity to the active substances or excipients of the vaccine (the vaccine is made in Saccharomyces cerevisiae). Subjects who develop an hypersensitivity reaction should not receive another dose. Pregnancy is a contra-indication (pregnancy category B) and, if initiated, the immunization series should be completed after delivery. Breast feeding is not a contra-indicated. The vaccine can be administered with other childhood immunizations, although data showing safety and maintenance of efficacy are only available for the concomitant administration of the hepatitis B vaccine. An abnormal cervical cytology or the presence of cervical HPV DNA are not contra-indications to the vaccine, as it may still protect against diseases caused by at least some of the HPV types in the vaccine.

The use of hormonal contraceptive does not affect the vaccine efficacy, but the effectiveness of the vaccine in immunosuppressed or immunodeficient subjects is not established; yet, being an inert, non-infectious vaccine, it is not contra-indicated in that population. One should emphasize that the vaccine has no therapeutic effect on existing lesions, and that it does not substitute for the routine cervical cytology screening (14a, 18a).

The ACIP recommends vaccinating 11-12 year-old girls (but the vaccine may be given from 9 to 26 years). They also recommend a catch-up vaccination for 13-18 year-old girls (18a). The cost of the vaccine to the provider is $120 per shot. Poor children are the beneficiaries of the Vaccine for Children Fund that makes the vaccine available free of charge.

There are unresolved issues regarding the vaccine. The durability of the protective antibody response is not known yet, but appears to be at least 5 years with both Gardasil and Cervarix (12a, 26a). Long term follow-up studies that are in place should answer this question. The issue of replacement of the vaccine HPV types by non-vaccine HPV types has been raised. Such phenomenon has not been seen yet (12a), and epidemiologic modeling actually suggests a possible indirect reduction of the non-vaccine HPV types (8a). The efficacy of the vaccine in women older than 26 years and in  men is being examined and results should be available in 2008. It will be important to determine the role the HPV VLP vaccine may have in preventing recurrent respiratory papillomatosis and head and neck cancers. Although the vaccine has no therapeutic effect on existing lesions, its impact on disease recurrence and natural history also needs to be evaluated.

PREVENTION

HPV transmission can be prevented by the proper sterilization of surgical instruments, the disposal of reusable instruments and materials that may be contaminated. Contaminated surfaces can be sterilized with household bleach (5.25% sodium hypochlorite) diluted 1:10 in water. During electrosurgery or laser surgery, a smoke evacuation system should be available and the operator should wear gloves, gown, mask, and goggles.

Little is known of the effectiveness of barrier methods in preventing HPV transmission. However, wart dressing while swimming has been effective in preventing the incidence of plantar warts (413). It is unclear at present whether condoms protect against HPV transmission, but there is some evidence that they may offer a degree of protection against cervical cancer, CIN, and anogenital warts (414). Condom use should be encouraged for patients with multiple sex partners or who engage in anal intercourse. They are also advocated during the treatment period and during the following three months (291). Although circumcision reduces the risk of HPV transmission, it is not possible at the moment to offer firm recommendations about its use (415).

Cesarian section is not advocated for the delivery of babies from a mother with condylomata acuminata (297, 298).

The presence of anogenital warts is associated with an increased risk of cervical and anal cancer (416, 417). It is therefore important to make sure that women are appropriately screened for cervical cancer with Pap smears, using any of the guidelines currently available (418, 419). According to the guidelines of the American Cancer Society modified by the recommendations of the Centers for Disease Control and Prevention, (a) one should obtain the first Pap smear when the patient becomes sexually active or reaches her 18th birthday. This should be followed by at least two other annual Pap smears; (b) the Pap smear should be obtained every 6 months the year that follows the diagnosis of HIV infection and annually thereafter; (c) in the absence of HIV infection or other sexually transmitted diseases (including anogenital warts) in the previous year, the frequency of Pap smears is left to the discretion of the physician, but probably could be decreased to every 3-5 years, providing a good follow-up is possible. Otherwise Pap smear should be obtained annually (287, 420). At this time, no routine screening strategy has been validated for anal cancer, including in HIV seropositive patients.

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Table 1. Some Common Treatment Modalities of Cutaneous Warts [Download PDF]

Agent (U.S. commercial preparations)	Usual Formulation and Regimen	Wart Type*	Complete Response RateH (%)	References
Salicylic acid     sa1icylic acid 17%:lactic acid:collodion 1:1:4     (e.g., Duofilm, Occlusal-HP, Wart-Off)	daily for up to 12 weeks	HW single PW MW	67% 84% 50%	(35) (35) (134)
Fixatives     formaldehyde 3%     glutaraldehyde	daily (bedtime) daily	PW MW	94% 47%	(34) (35)
Bleomycin	1 mg/ml solution, 0.1-0.2 ml/wart, intralesional, x1 0.7% solution,	HW MW  PW	-70% -55% -90%	(44, 45) (45, 43) (41, 39, 37)
Cantharidine     (Cantharone,Verr-Canth)	topical, x1	CW	87%	(53)
Podophyllin     (Podocon-25 or Podofin)	podophyllin 15%, qd	single PW	81%	(95)
5-fluorouracil (5-FU)     (Effudex cream 5%)	2% 5-FU in propylene glycol, once daily   5% 5-FU in dimethyl sulfoxide (DMSO), once daily	MW     MW	47%     53%	(134)     (134)
Cryotherapy	every 3 weeks, up to x6	CW HW PW	41-45% -75% 29-50%	(203) (35) (203)
Electrosurgery	x1	PW	65%	(95)
CO2 laser surgery	x1	CW periungual PW	32% 71% 50-90%	(251) (254) (421, 252,253)
*  CW: cutaneous warts; HW: hand warts; PW: plantar warts; MW: mosaic warts †  These rates are derived from the referenced studies. Because of great dissimilarities between the studies and the usual absence of controls, these rates are not necessarily comparable, and are provided for indication only.

 

Table 2. Common Treatment Modalities of Anogenital Warts [Download PDF]

Agent (U.S. commercial preparations)	Usual Formulation and Regimen	Complete Response Rate* (%)	Relapse Rate* (%)	Selected References
Imiquimod (Aldara, box of 12 single-use 250 mg packets)	5% cream; self-applied, tiw, qod hs, # 16wk	48	9, 23†	(63)
Podophyllin (Podophyllum USP; Podocon-25 or Podofin; 15 ml bottles)	25% in benzoin solution; qwk up to x6	35-51	60-85	(94, 112, 422)
Podofilox (Condylox; 3.5 ml bottle with cotton-tipped applicators)	0.5% solution; self-applied; bid x3 d	57-72	32-50	(87, 97, 98,100, 423)
Trichloracetic acid (Bichloracetic acid 80%, 10 ml bottle; Tri-Chlor 80%; 15 ml bottle)	50%-90% solution; q wk up to x6	64-83	55	(29, 30)
5-fluorouracil (Effudex cream; 25 g tube)	5% cream; highly variable regimens	43-58	-	(122-125, 128,131)
Intralesional interferon α2b or n3 (Intron A, Alteron N)	1 MU; tiw x3-8 weeks; from 1 to all lesions injected	40-52	18-37	(157- 161)
Cold blade surgery	scissor excision	87-94	20-31	(93, 94, 194,424-426)
Cryotherapy	liquid nitrogen spray; 1 or 2 cycles qwk up to x6	64-76	19-40	(29, 30, 92,427)
Electrosurgery	variable techniques (e.g., electrocoagulation, electrocautery, fulguration,...)	58-94	22	(92, 227)
CO2 laser surgery	variable techniques	93-99	49-65††	(164, 178, 180,183)

Abbreviations: qwk, once a week; d, day; bid, twice a day; tiw, thrice weekly; MU, million units.

* These numbers represent the 95% confidence limits, whenever appropriate, derived from the results of the selected studies.

† At 3 and 6 month follow-up, repectively.

†† Based on randomized, comparative studies.

 

Table 3. Suggested Approaches to the Treatment of Warts [Download PDF]

Type of Wart or Lesion	Treatment Options*
Plantar and hand warts	First line    salicylic acid-based paints (H)    cryotherapy (O)   Second line    formaldehyde (H)    glutaraldehyde (H)    cantharidine (O)    bleomycin (esp., periungual warts) (O)	Third line    electrosurgery (O)    laser surgery (O)
Flat warts	First line    no treatment	Second line    cryotherapy    electrocautery
Condylomata acuminata	First line    podofilox (H)    cryotherapy (O)    trichloracetic acid (O)    podophyllin (O)    scissor excision (O) (if few and small lesions)	Second line    electrosurgery (O)    laser surgery (O)    interferon (O)
* H: home treatment; O: office-based treatment

What's New

Huo W, et al. Local Hyperthermia at 44 degrees C for the Treatment of Plantar Warts: a Randomized, Patient-Blinded, Placebo-Controlled Trial. J Infect Dis. 2010 Apr 15;201:1169-72.

The Future II Study Group.  Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade Cervical Lesions.  NEJM 2007;356:1915.

Garland SM, et al.  Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases.  NEJM 2007;356:1928.

D'Souza G, et al.  Case-Control Study of Human Papillomavirus and Oropharyngeal Cancer.  NEJM 2007;356:1944.

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Epidemiology

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Review articles

Adhikari P, Mietzner T.  Cell Mediated Immunity.

Chin-Hong PV, Lough JB, Robles JA. Human papillomavirus in Transplant Recipients

Simon RQ.  The 2008 Nobel Prize in Medicine: Dr. Harald zur Hausen for his work on: Human Papillomavirus and Cervical Cancer. 2009

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History

ACIP: Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females.  MMWR. May, 2010.

ACIP: Quadrivalent Human Papillomavirus Vaccine (HPV4, Gardasil) for Use in Males.  MMWR, May, 2010.

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Human Papillomavirus