US Pharm. 2008;33(8):HS3-HS8.

Human papillomaviruses (HPVs) are small DNA viruses that infect epithelial tissue.1-3 There are about 100 types, and it has been determined that approximately 40 types infect the anogenital region.1,4-6 These viruses are also present in the mouth, larynx, esophagus, and nipples and under the fingernails.2,7,8

HPVs have been classified as being either high or low risk.1-3,5,7,8 The high-risk types are 16, 18, 31, 33, 35, 39, 45, 50, 51, 52, 53, 56, 58, 59, 68, 73, and 82.1-3,7,8 These types are more likely to develop into a persistent infection.2 They are also responsible for high-grade dysplasia and invasive cancer of the cervix, vulva, vagina, anus, and penis, as well as some of the oropharyngeal cancers.2,3,5,8 Compared to the penis and anus in men, the cervix is more biologically susceptible to malignant carcinoma.

The low-risk HPV types are responsible for genital warts and low-grade dysplasias.5,8 These types include 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81.1

Causes and Risk Factors
HPV is spread by sexual contact.5,9,10 It is the most common sexually transmitted disease and will infect approximately 75% to 80% of the population.2,4,5 It is estimated that 6.2 million people are infected every year in the United States.4 HPV in men has not been studied as much as HPV in women; however, it is estimated that the incidence in both genders is equivalent.11 Although a large portion of the population contracts HPV, only about 1% of affected individuals develop genital warts.2,8

There is evidence that suggests certain risk factors may exist for contracting HPV. Individuals are at highest risk of acquiring HPV within the first five years after becoming sexually active.6 It has been shown by Partridge et al that the time between zero and eight months of sex with a new partner is associated with acquiring HPV infection.10 A large number of lifetime sexual partners, as well as more partners in the past year, are factors that may make individuals more prone to HPV infection.5,9 However, Partridge reported no association with lifetime number of partners.1 This may be because his study participants were healthy university students, not individuals who were already diagnosed with HPV infection

Circumcision appears to decrease the incidence of HPV infection.5,9,12 Circumcision may also prevent recurrences in men who have been previously infected.13 It has been postulated that condoms may prevent the transmission of HPV. However, the use of condoms does not completely prevent HPV infection.14 Since HPV in men may be found in areas not covered by a condom, there is still a risk of spreading the virus.4,5,12 When condoms are used consistently, the risk of contracting oncogenic and nononcogenic types is decreased.5,12 It has also been shown that condom use promotes the regression of cervical HPV disease and flat penile lesions and increases the clearance of HPV infections as well.5 Finally, those who are immunocompromised, in particular those who are HIV positive, are at an increased risk of HPV infection.3,5,8,9

There are three categories of HPV infection: latent, subclinical, and visible clinical infection, which includes carcinoma.8 Most infections are asymptomatic or subclinical. They may spontaneously clear within two years.4,15,16 Since men are the primary mode for transmission, asymptomatic infection can be dangerous.4,9 Partners may unknowingly infect others.

Genital Warts
HPV infection in men is most commonly presented as genital warts or condylomata (benign epithelial tumors).14,15 The incubation period from contracting HPV to developing genital warts is not known, but it is estimated to be about three months.2 There are approximately 1 million new cases each year.2 Studies conducted in both the U.S. and Europe have shown that the peak incidence of genital warts is in the 20- to 24-year-old age group.3

The low-risk HPV types 6 and 11 are found in 70% to 95% of genital warts.5,9,14,15 In approximately 44% of cases, there are coinfections with high-risk HPV types.9,14 Condylomata are also multifocal, meaning that there are multiple sites of infection.14 About 50% of patients have genital warts in multiple sites.2 These occur as multifocal lesions in small groups of warts. In general, there are five to 15 warts, 1 to 10 mm in diameter.14 There are four morphologic types: condyloma acuminatum, flat, popular, and keratotic. Condyloma acuminata resemble cauliflower, and flat-topped warts appear macular or slightly raised. Papular warts are small dome-shaped papules, and keratotic warts appear thick and crustlike.17

The most common site of condylomata in circumcised men is the shaft of the penis.3,14 The sites differ in uncircumcised men. They are most often found on the distal penis, in particular the prepucial cavity, the glans penis, the coronal sulcus, and the frenulum.5,14 In up to 20% of men they occur in the urethra.2,14 Although the incidence of urethral warts is low, the condition is more difficult to treat. In men who have sex with men, the perianal region is commonly affected. Although anal intercourse increases the risk of anal warts, the majority of patients who have anal warts have not engaged in such acts.2

Condylomata may also present as giant condylomata, which are benign tumors that grow at a much faster rate than the common genital wart. They are most often associated with HPV 6 and 11, but giant condylomata may also be coinfected with the oncogenic HPV types such as HPV 16 or 18.14 They cause considerable morbidity and are resistant to treatment. The risk factors for developing giant condylomata are poor hygiene, liver disease, immunodeficiency, and smoking. Patients who smoke are encouraged to quit smoking, as it is not only a risk factor, but it also delays the clearance of lesions.14 Giant condylomata most often have the same histologic features as benign genital warts, but since they may be coinfected with high-risk HPV types, atypical cells may be found. Biopsies must be performed to rule out invasive carcinoma.14

Genital warts are often asymptomatic, but they may be painful and pruritic. Burning, itching, and bleeding may occur in warts found in the urethra or anal canal. Giant condylomata may cause bleeding and, rarely, obstruction of the urethra and anus.14

In approximately one-third of patients, genital warts spontaneously regress.5,13,14 They may also increase in number and size.5,18 If untreated, they may persist for months or years. The major concern of long-term HPV infection is the development of cancer.2,14 It is critical that HPV patients be continually monitored for the development of warts and evidence of advancing disease.2 There are several treatment options that may be performed by the physician or the patient.

Treatment Options
The primary goal of treatment is permanent wart removal.14,18 Treatment may result in wart-free periods, but recurrence is common.13,18 There is no treatment available that will completely eliminate HPV infection, but there is evidence suggesting that the infection will be reduced by treating the genital warts.14,18 With treatment, the majority of warts will respond within three months.18

Many treatment options exist, but few of them are highly effective.13 In the first three months after treatment, many patients will relapse and require additional treatment.2,13 Smaller lesions are easier to treat.9 The selection of treatment modality should be based on the preference of the patient, the experience of the health care provider, and the resources available.3,18 Condylomata may be treated by providers in the office or by patient-applied therapies.18

Procedures that may be administered by a physician include cryotherapy with liquid nitrogen, 10% to 25% podophyllin resin in a tincture of benzoin, 80% to 90% trichloroacetic or bichloroacetic acid, fluorouracil, or surgery.9,13,1

If patients can see and reach the lesion, they may be able to treat their genital warts using prescription medication. There is no evidence to suggest that one form of treatment is more effective than another.18 Podofilox (Condylox) and imiquimod (Aldara) are the topical medications approved to treat external genital warts.2,9,18 Imiquimod enhances the immune system by stimulating the production of interferon and other cytokines.18 Podofilox is an antimitotic; however, the exact mechanism of action is unknown.18,19 Patients should be counseled on the proper use of these medications (Tables 1 and 2).

Imiquimod should be applied three times per week until lesions clear or for a maximum of 16 weeks. It should be applied at bedtime and then washed off six to 10 hours later.20 Podofilox should be applied twice daily for three consecutive days, then discontinued for four days. This weekly cycle may be repeated until lesions are gone or for a maximum of four cycles.19

Adverse reactions, which may occur with either drug, include pain, inflammation, burning (blister or ulcer), itching, skin peeling, and bleeding.19,20 Sometimes these adverse events are severe enough to warrant discontinuation of treatment. If the condition does not improve with one treatment modality, another therapy should be used.18 It should be noted that if the warts are located on the rectum, the application of lidocaine ointment or jelly may be needed before bowel movements.13

Anal Carcinoma
Squamous cell carcinoma of the anus is rare.2,8 It often presents with rectal bleeding, pain, and mass sensation. Diagnosis is frequently delayed because rectal bleeding is ascribed to hemorrhoids.8 HPV 16 has been detected in 70% of cases of anal carcinoma.5,8,9,15

Risk factors for HPV-positive anal carcinoma include immunodeficiency (i.e., HIV or immunosuppression following a solid organ transplant).2,9 Infection with multiple HPV genotypes (i.e., 16, 18, 31, 33), low CD4 count, smoking, and anal intercourse are also risk factors.2,8,13

Penile Cancer
Penile cancer is rare and its incidence differs by country.9 In the U.S. and Europe, where circumcision is common, occurrences of penile carcinoma are rare.9,14,21 HPV infection is a risk factor for developing penile cancer, and HPV 16 has been implicated in most of the HPV-positive tumors.2,3,8,21 In fact, HPV 16 has been found in 40% to 55% of all cases of penile carcinoma.14,21

Heidemen et al conducted a study of 83 patients with penile squamous cell carcinoma.21 By analyzing RNA, DNA, and antibodies to the HPV L1 capsid and E6 and/or E7 oncoproteins, the presence and biological activity of the various HPV types in penile carcinoma were determined. HPV DNA was found in 46 of the 83 cases (55%). Twenty-four of the 46 (52%) cases of HPV-positive tumors contained HPV 16. HPV 8 was the second most prevalent type, present in 10 of 46 (22%). Coinfection with HPV 16 occurred in four of the 10 (40%) HPV-8 positive tumors.21

Smoking, lack of circumcision, poor hygiene, phimosis (constriction of the prepuce, preventing the foreskin from being drawn back), HIV infection, lack of condom use, and history of genital warts are additional risk factors.2,10,12,21 However, even though evidence shows that circumcision may prevent penile cancer (and other conditions as well), the American Medical Association does not recommend routine neonatal circumcision.7

There are no commonly accepted methods to diagnose penile lesions. Therefore, it is difficult to determine the presence of genital warts, precancerous lesions, or carcinoma. Magnification with the application of acetic acid is commonly accepted as a method of determining whether any abnormal cells can be found. This method has low specificity because false-positives can occur with the presence of scars, abrasions, and other forms of inflammation.10,14 When applied, acetic acid (3%-5%) causes abnormal cells to "whiten." A positive result is defined as "a sharply demarcated grayish-white area with visible vasculature."14 Using Lugol's solution (iodine) may be more specific than acetic acid. Abnormal tissue will appear light yellow, while the normal tissue will stain dark brown due to the presence of glycogen in the cells.9 Neither imiquimod nor podofilox have been approved for the treatment of cancer of the anogenital region.19,20 Treatment of anal and penile carcinoma must be done by a physician.

Oropharyngeal Cancer
Each year there are approximately 30,000 new cases of oral and oropharyngeal cancer in the U.S. There is a high fatality rate associated with these carcinomas, with a five-year survival rate of only 50%.5 Smoking and heavy drinking have always been significant risk factors for head and neck cancer. Public health campaigns have been successful in reducing the incidence of smoking, thus resulting in the reduction of the rates for larynx, oral cavity, and hypopharynx carcinomas. However, a decline has not been seen in the incidence of oropharyngeal cancer. The reason for this is the increase in the incidence of HPV-associated squamous cell carcinoma.22

HPV-positive cancer presents in younger patients with less of a history of smoking. Approximately 25% to 35% of oropharyngeal cancer cases are HPV positive.3,5,22 Multiple sexual partners, infrequent condom use, early age of first intercourse, and oral-genital sex are risk factors for oropharyngeal carcinoma.22,23

D'Souza et al conducted a study of 100 patients with newly diagnosed squamous cell carcinoma of the head and neck and 200 control participants before any treatment was started.23 All participants completed a computer-assisted interview that provided information about demographic characteristics, oral hygiene, medical history, family history of cancer, lifetime sexual behaviors, and lifetime history of marijuana, tobacco, and alcohol use. The study results concluded that HPV 16 alone was found in 90% of HPV-positive cases of head and neck carcinoma. The study also determined that oral HPV infection is sexually acquired, with oral-genital sex being strongly associated. It is unclear, though, if mouth-to-mouth or other means of transmission is possible. Another interesting point resulting from the study data suggests that there is no synergy between HPV-related cancers and HPV-negative cancers associated with smoking or drinking. There is only an additive effect seen with HPV and smoking or drinking.23 This corresponds to findings from other studies.24

HPV 16 has been shown to be the predominant type in HPV-positive tumors, followed by HPV 18.23-25 HPV-related cancers have a better prognosis, and, in more than half of these cases, there was a negative history for smoking.24,25

Since there is such a strong correlation between HPV and certain cancers, it would seem to make sense to develop screening guidelines to identify HPV infection before it can progress to carcinoma. Expanding the indication of the HPV vaccine from young females to include young males may also seem prudent.

Currently, there are no guidelines for HPV screening in men. In fact, it is not recommended. The reasons for this include the high incidence of HPV infection, no FDA-approved screening tests available for men, and no evidence indicating that the presence of HPV infection increases the risk for disease or cancer for men or their sex partners.3,4,9 For those who are at high risk for developing carcinoma of the anus, penis, or oropharynx (not related to smoking or alcohol consumption), screening may prove beneficial. Further research should be done to determine the value of HPV screening in men, especially anal screening.5,8,9

It is difficult to detect HPV in men who have latent (dormant) or subclinical infection (asymptomatic and not visible without aid). Many of the methods used for determining the presence of HPV in men are either low in sensitivity and/or lowin specificity.3 As mentioned earlier, the application of acetic acid or Lugol's solution allows for a cursory inspection, but that method is not specific. The physician must be very experienced in order to discern which lesions are abnormal cells and which are simply another condition.9

The presence of HPV can sometimes be determined from swabbing exfoliated cells from the external genitalia. When sampling for DNA, the best anatomical sites seem to be the glans, corona, prepuce, and shaft of the penis. The samples are adequate, and the collection is painless and easy.4 However, Anaya-Saavedra et al found that exfoliated cells from case patients were not detected more frequently than those in the control subjects.24 HPV was not even detected in the exfoliated cells from 90% of the patients with HPV-positive biopsies.24

There is also a discrepancy between the presence of antibodies in the blood serum and HPV infection. This may be due to low sensitivity of polymerase chain reaction tests used, low antibody titers, or the absence of antibodies altogether.3

An FDA-approved screening test for cervical HPV is available. It is called the digene High-Risk HPV hc2 Test. It is able to detect, with high sensitivity, 13 high-risk HPV types and five low-risk HPV types.26 If approved guidelines for HPV screening in men are developed, the technology used in this product may be beneficial.

Gardasil is a quadrivalent, noninfectious vaccine prepared from highly purified viruslike particles of the major capsid (L1). It is effective against HPV types 6, 11, 16, and 18.27 The FDA has approved it for use in females 9 to 26 years of age for the prevention of HPV infection.

It has not been approved for use in males yet, but there are data demonstrating immunogenicity and safety in males 9 to 15 years of age.28 Some experts are concerned that if only females are vaccinated, the result will be less efficacious. The benefits of widespread vaccination include reduced HPV transmission and increased "herd immunity."5,9,15 Merck is conducting an investigational study to determine the efficacy of Gardasil in prevention of anogenital warts in young men. The participants are males aged 16 to 26 years with no prior history of genital warts. The trial is in Phase III.29

GlaxoSmithKline has developed a bivalent vaccine named Cervarix.5 The vaccine is effective against the two most common high-risk types, HPV 16 and 18. Cervarix is currently undergoing Phase III trials.30

Role of the Pharmacist
The pharmacist is in a perfect position to educate patients about the transmission and treatment of HPV. When a prescription is filled for podofilox or imiquimod, the pharmacist should counsel the patient on the proper application and removal of the medication. The patient should also be advised of the adverse reactions that may occur. If adverse events become too severe, the need to discontinue treatment temporarily should be discussed with the physician. By counseling the patient on the mode of transmission, the pharmacist can greatly impact the spread of HPV. It is important to educate the patient about the sites of transmission, including the oral cavity. Of equal importance is impressing upon patients that condoms do not completely prevent transmission of the virus.

HPV is a public health threat that cannot be ignored. Approximately 80% of the U.S. population has been infected with HPV at some point in their lives. It is difficult to detect in males, and there is no cure.

In men, HPV can cause genital warts, precancerous lesions, and cancer of the anus, penis, and oropharynx. Men are the primary mode of transmission to women. Since HPV is associated with 100% of cervical carcinomas, prevention and detection in men may be beneficial in preventing HPV disease and possibly eradicating the virus altogether. There are currently no screening guidelines for HPV in men and no effective means to do so.

Gardasil is a quadrivalent vaccine approved for females aged 9 to 26 years. Studies are currently being conducted to determine the vaccine's efficacy in young men, and it may be available for males in the future.

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13. Genital warts. The Merck Manual of Diagnosis and Therapy. Accessed May 18, 2008.
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15. Giuliano AR. Human papillomavirus vaccination in males. Gynecol Oncol. 2007;107(suppl 1):S24-S26.
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18. HPV infection and genital warts. Sexually transmitted diseases guideline 2006. Centers for Disease Control and Prevention. Accessed May 17, 2008.
19. Condylox (podofilox) package insert. Corona, CA: Watson Pharmaceuticals; November 2007.
20. Aldara (imiquimod) package insert. Bristol, TN: Graceway Pharmaceuticals; November 2007.
21. Heideman D, Waterboer T, Pawlita M, et al. Human papillomavirus-16 is the predominant type etiologically involved in penile cell carcinoma. J Clin Oncol. 2007;25:4550-4556.
22. Sturgis E, Cinciripini P. Trends in head and neck cancer incidence in relation to smoking prevalence: emerging epidemic of HPV-associated cancers? Cancer. 2007;110:1429-1435.
23. D'Souza G, Kreimer A, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-1956.
24. Anaya-Saavedra G, Ramírez-Amador V, Irigoyen-Camacho ME, et al. High association of human papillomavirus with oral cancer: a case-control study. Arch Med Res. 2008;39:189-197.
25. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709-720.
26. digene High-Risk HPV hc2 Test. Qiagen. Accessed May 19, 2008.
27. Gardasil (human papillomavirus quadrivalent [types 6, 11, 16, and 18] vaccine, recombinant) package insert. Whitehouse Station, NJ: Merck & Co, Inc; December 2007.
28. Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1-24.
29. An investigational study of Gardasil (V501) in reducing the incidence of anogenital warts in young men. Merck. Accessed May 17, 2008.
30. Evaluation of the immunogenicity and safety of a commercially available vaccine when co-administered with GlaxoSmithKline Biologicals' HPV vaccine (580299) in healthy female subjects. Accessed July 4, 2008.

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