Human Papillomavirus. Genital Warts (2010) Philippine Obstetrical and Gynecological Society (Foundation), Inc.

Transcription

1 Human Papillomavirus Genital Warts (2010) Philippine Obstetrical and Gynecological Society (Foundation), Inc. POGS Bldg., #56 Malakas St., Diliman, Quezon City Telephone Nos.: ; to 85 Fax No.: Website:

2 Philippine Obstetrical and Gynecological Society (Foundation), Inc. POGS Bldg., #56 Malakas St., Diliman, Quezon City Telephone Nos.: ; to 85 Fax No.: Website: Board of Trustees and Officers President Vice-President Secretary Treasurer PRO Trustees Sylvia de las Alas-Carnero, MD Rey H. de los Reyes, MD Christia S. Padolina, MD Jericho Thaddeus P. Luna, MD Efren J. Domingo, MD Mario A. Bernardino, MD Mayumi S. Bismark, MD Virgilio B. Castro, MD Blanca C. de Guia-Fuerte, MD Ramon M. Gonzalez, MD Anne Marie C. Trinidad, MD l Sign up and open your clinic to the world. 167

3 Human Papillomavirus* by Jennifer T. Co, MD, FPOGS The human papillomavirus is a double-stranded nonenveloped DNA virus. Papillomaviruses are extremely host-specific and characterized by their ability to infect and transform epithelial cells. There are more than 120 HPV types identified, and approximately 35 types are classified as anogenital papillomaviruses (Figure 1). The low risk types 6 and 11 are associated with genital warts and a substantial proportion of cases of low-grade cervical squamous intraepithelial lesions, as well as recurrent respiratory papillomatosis. Fifteen types are high risk or oncogenic (most common are, 16, 18, 35, 45, 52, and 58), which are associated with high-grade squamous intraepithelial neoplasia and invasive cervical cancers. HPV types 16 and 18 account for >70% of cervical cancers worldwide. These types are also associated with other anogenital cancers in men and women such as penile, vulvar, vaginal, and anal cancer, including a subset of oropharyngeal cancers.majority of patients infected with HPV are asymptomatic and usually self-limited. Among sexually active people, more than 50% are estimated to become infected at least once. The strongest risk factor for development of precancers and cancers is persistent oncogenic HPV infection. Most of the clinically apparent lesions are the genital warts or condyloma acuminata. Figure 1: Phylogenetic tree of HPV (SOURCE: Chan et al., Virology, 1995;69: ) Table 1: Classification of HPV Types Based on Oncogenic Potential Low risk types HPV 6, 11, 40, 42, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108 High risk types HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 Probably high HPV 26, 53, and 66 risk types Adapted from International Agency for Research on Cancer Multicenter Cervical Cancer Study Group The risk factors for HPV infection include the following: young age, early onset of sexual activity, multiple sexual partners, increased frequency of sexual activity, exposure to sex partner with genital HPV infection, failure to use condom, lack of male circumcision, and smoking. The two major factors that have influence in the incidence of genital HPV are age and sexual behavior. Pregnant women have increased risk for HPV infection and genital warts. Their immunosuppressive states result to increased viral titers of HPV and a faster progression to cervical intraepithelial neoplasia. Cervical squamous cell carcinoma and adenocarcinoma are caused by HPV. Cervical cancer remains the most common gynecologic malignancy worldwide with an estimated 510,000 new cases reported yearly. In the developing countries, cervical cancer is the second most common cause of cancer deaths at 288,000 cases annually. Other conditions associated with HPV infection include clinical (genital warts) and subclinical infection of the cervix, vagina, vulva, perineal body and anus. Many cases are detected cytologically, which include atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL). It is estimated that subclinical HPV infection is times more frequent than cytologically detected infections. The most common clinical manifestations of HPV infection of the genital area are genital warts (condyloma acuminata). These predominantly affect younger individuals especially those in the 16 to 25 year age group. HPV types 6 and 11 cause more than 90% of the anogenital warts. Condylomas appear as pinkish, whitish, or pigmented sessile lesions with lobulated or pointed finger-like projections on their surfaces. These are commonly found on the vulvar area. Flat lesions may be missed during routine examination while exophytic lesions are easily recognized (figures 2, 3, and 4). Rapid growth is noted during pregnancy and may extensively involve the cervix, vagina, or vulva such that vaginal birth is precluded. External genital warts are multifocal, presenting with one or more lesions on the same anatomic site. Alternatively, they may be multicentric, presenting with lesions on different anatomic sites. These can be painful, pruritic, friable, and associated with foul odor when secondarily infected. Aceto-white epithelium is another common feature that is detected by colposcopic examination of the cervix after application of 5% acetic acid (Figure 5). Cervical lesions may appear as flat and endophytic. Subclinical infection is the most common manifestation of HPV disease in the cervix. Sexual transmission is the major route for HPV transmission leading to urogenital and anorectal infection. The incidence is highest among sexually active adolescents and young adults, with 75% of new HPV infections encountered among women 15 to 34 years old. HPV infection is highly contagious and more than 65% of the sexual partners are infected after a single exposure. WHO global estimates peg 630 million are currently infected. *Adapted from BREAKING THE CHAIN, A Sourcebook on SEXUALLY TRANSMITTED INFECTIONS (2010) by Jennifer T. Co, MD, FPOGS; copyrighted by the Philippine Obstetrical and Gynecological Society (Foundation), Inc. 168 Figure 2: Anal warts (Source: Sexually Transmitted Disease Resources 2008,)

4 Human Papillomavirus (Genital Warts) Respiratory papillomatosis is not a common disease in the neonate caused by HPV types 6 and 11 (Figure 8). Laryngeal papillomatosis can lead to respiratory distress due to obstruction and may recur following treatment. Transmission is through vertical route. Other potential routes include transplacental and contact during the neonatal period. Figure 3: Vaginal warts (Source: Wisdom A and Hawkins Da. Diagnosis in color sexually transmitted diseases. 2nd ed ) Figure 7. Cervical intraepithelial neoplasia (CIN) 1, 2, 3. (Source: International Agency Research on Cancer 2009.) Figure 4: Pedunculated warts (Cauliflower-like lesions) Figure 5: Cervical warts (Source: Wisdom A and Hawkins DA. Diagnosis in color sexually transmitted diseases. 2nd ed ) Normal-looking cervical epithelium may exhibit cytologic or histologic features of HPV infection. These subclinical cases represent the majority of HPV infections of the cervix, vagina, and vulva. Currently it has been demons trated that there is more than 99% association between HPV infections and changes in the cervical epithelium, which may progress to cervical intraepithelial neoplasia (CIN) and later to invasive carcinoma (Figure 6). CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia), and CIN 3 (severe dysplasia) are subclinical features detected cytologically (Figure 7). Similar epithelial changes may occur in the vulva, vagina, and the anus. Figure 8: Laryngeal papillomatosis (Source: Otolaryngology Houston July 2009.) Diagnosis: Attention is directed to the two major clinical manifestation of genital HPV infections: genital wart and cervical intraepithelial neoplasia. Physical examination is a simple and inexpensive approach in diagnosing genital warts. However, about 10% of cases are missed. Confirmation is made by biopsy. The following are indications for biopsy: (1) uncertain diagnosis, (2) no response to standard therapy, (3) worsening disease during therapy, (4) immunocompromised patients, and (5) pigmented, indurated, fixed, bleeding, or ulcerated warts. HPV nucleic acid tests (Digene Hybrid Capture 2 High Risk HPV DNA test) are not recommended for routine diagnosis and management of external warts. Subclinical infections may require detection of viral nucleic acid. The Digene Hybrid Capture 2 High Risk HPV DNA test (HC2) is the only U.S. FDA-approved test for clinical use. It utilizes liquid nucleic acid hybridization to detect 13 high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). The HC2 is approved for triage of women with pap smear results identified as ASCUS and combined with pap test for cervical cancer screening in women more than 30 years old. Cytologic studies may demonstrate koilocytosis (squamous cells with enlarged, wrinkled, dark raisinoid nuclei surrounded by a halo), dyskaryosis, atypical parabasal cells, and multinucleation. Colposcopic examination with acetic acid allows detection of 70% of subclinical infections. Figure 6: Natural history of HPV infection and CIN, cervical cancer, and genital warts (Source: Sweet R and Gibbs R. Infectious diseases in the female genital tract. 5th ed. 2009;80-94.) Histologic examination reveals basal cell hyperplasia, papillomatosis, koilocytosis (Figure 9), and parakeratosis. Koilocytosis is a marker for HPV infection. Learn to access drug info on your cellphone. Send PPD to 2600 for Globe/Smart/Sun users. 169

5 Figure 9: Koilocytes (Source: W.B. Saunders Company 1999) Antigen to HPV can be detected in Cytologic and Histologic specimens by using immunostaining techniques with antiserum from rabbit immunized with bovine papillomavirus. Cloning techniques have the ability to demonstrate specific HPV DNA. Treatment: CDC 2010 STD Guidelines The treatment of external genital warts depends on the anatomic location of the lesions, clinical presentation, and extent of the disease. No therapy has been shown to be 100 percent curative or to eliminate the HPV (Table 2). Elimination of clinical disease and the prevention of cervical, vulvar, and vaginal cancer are the primary goals of treatment. Recommended Regimen for External Genital Warts Patient-Applied: Podofilox 0.5% solution applied with a cotton swab, or podofilox gel with a finger, twice a day for 3 days, followed by four days of no therapy. Cycle may be repeated, as necessary, for up to four cycles. Total wart area treated should not exceed 10 cm2, and total volume of podofilox should be limited to 0.5 ml per day. Safety during pregnancy has not been established. Sinecatechin ointment, a green-tea extract with an active ingredient (catechins), is applied three times daily until complete clearance of warts. This product should not be washed off after use and should not be used longer than 16 weeks. The most common side effects of sinecatechins 15% are erythema, pruritis/ burning, pain, ulceration, edema, induration, and vesicular rash. Compared with other available anogenital wart treatment modalities, no clinical data are available regarding the efficacy or safety of sinecatechins. The safety and efficacy of the medication has not been established in HIV-infected persons, immunocompromised persons, or persons with clinical genital herpes. Hence, it is not recommended. The safety of sinecatechins during pregnancy also is unknown. Imiquimod 5% cream is applied once daily at bedtime, three times a week for up to 16 weeks. The treatment area should be washed with soap and water 6 to 10 hours after application. Safety during pregnancy has not been established. Provider-Administered: Cryotherapy with liquid nitrogen or cryoprobe repeated every 1 to weeks. Podophyllin resin 10% to 25% in a compound of benzoin applied to wart and allowed to air dry. Treatment can be repeated weekly. To avoid complications associated with systemic absorption and toxicity, two important guidelines should be followed: 1) application should be limited to, 0.5 ml of podophyllin or an area of <10 cm 2 of warts per session, and 2) no open lesions or wounds should exist in the area to which treatment is administered. Some specialists suggest that the preparation should be thoroughly washed off 1 to 4 hours later application to reduce local irritation. Safety during pregnancy has not been established. Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80% to 90% is applied only to0 the warts and allowed to dry, at which time a white frosting develops. If an excess amount of acid develops, the treated area should be powdered with talc, sodium bicarbonate (i.e., baking soda), or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. Surgical removal by tangential scissor excision, tangential shave excision, curettage, or electrosurgery. Alternative Regimens Intralesional interferon Laser surgery Photodynamic therapy Topical cidofovir Table 2: Treatment Options for External Genital Warts Treatment Mechanism Adverse Effect and incidence (%) Clearance Recurrence of action Rate (%) Rate (%) Surgical Surgical excision Pain (100%), bleeding (40%), scarring (10%) 35-70% 20% Excision Cryotherapy Chemical/ Pain or blisters at application site (20%) 60-90% 20-40% physical destruction Interferon-a Chemical/ Burning, itching, and irritation at the 20-60% Insufficient physical destruction injection site; headache, fever, data chills (6%) Laser Chemical/ Pain (100%), bleeding (40%), 25-50% 5-50% Treatment physical destruction scarring (10%) Imiquimod Topical Erythema (70%), irritation, 30-50% 15% Patient applied ulceration and pain (<10%) Podofilox Topical Burning at the application site (75%), 45-80% 5-30% patient-applied pain (50%), inflammation (70%) Podophyllin Topical Local irritation, erythema, burning, 30-80% 20-65% Resin Physician applied soreness at the application site (75%) Trichloro- Topical acetic Acid Physician applied Local pain and irritation, no systemic 50-80% 35% side effects Adapted from Kodner CM, Nasraty S. American Family Physician 2004;70 n(12):2335,2342,

6 These regimens may have more side effects and less data on efficacy. Recommended Regimens for Cervical Warts For exophytic cervical warts, high-grade SIL should be excluded before treatment is initiated. Recommended Regimens for Vaginal Warts Cryotherapy with liquid nitrogen in the vagina is not recommended because of the risk of vaginal perforation and fistula formation. TCA or BCA 80% to 90% is applied to the warts in small amounts only and allowed to dry, at which a white frosting develops. If an excess amount of acid is applied, the treated area should be powdered with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid. This treatment can be repeated weekly, if necessary. Recommended Regimens for Urethral Meatus Warts Cryotherapy with liquid nitrogen Podophyllin 10% to 25% in compound tincture of benzoin Recommended Regimens for Anal Warts Cryotherapy with liquid nitrogen TCA or BCA 80% to 90% applied to warts Surgical removal Management of Sex Partners Sex partners might benefit from counseling and examination to assess the presence of genital warts and other STIs. The counseling of sex partners provides an opportunity for these partners to 1) learn that HPV infection is common and probably shared between partners, and 2) receive STD evaluation and Pap smear to screen cervical cancer. Examination of sex partners is not necessary for the management of genital warts because no data indicate that reinfection plays a role in recurrences. Pregnancy Imiquimod, sinecathechins, podophyllin, and podofilox are contraindicated during pregnancy. Genital warts can proliferate and become friable during pregnancy, hence, many specialists advocate their removal at this time. HPV types 6 and 11can cause respiratory papillomatosis in infants and children. The route of transmission (i.e., transplacental, perinatal, or postnatal) is not established. Caesarian delivery should not be performed solely to prevent HPV transmission to the newborn since it is not clear whether caesarian section is preventive. There are no controlled studies on this. Caesarian section might be indicated if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding. Pregnant women with genital warts should be counseled on the risk for warts, however low, on the larynx (recurrent respiratory papillomatosis) of their infants. Prevention HPV can be prevented by the following approaches: (1) sexual abstinence, which is the most ideal but not practical for long term prevention, (2) lifetime mutual monogamous relationship, (3) limiting the number of sexual partners, (4) limiting contact to men who have been abstinent for a long period of time, (5) having a circumcised partner,(6) condom use, and (7) HPV vaccine. Prophylactic HPV vaccines have been developed to reduce the risk for genital warts, precursor lesions of Human Papillomavirus (Genital Warts) cervical cancer (CIN 2/3 and AIS), and invasive cancer. Two HPV vaccines are currently available. The quadrivalent vaccine (Gardasil) contains viral-like particles (VLPs) of the L1 protein of HPV types 6, 11, 16, and 18. The bivalent (Cervarix) contains the L1 protein of HPV types 16 and 18. Both vaccines offer protection against the HPV types that cause 70% of cervical cancers (i.e., types 16 and 18). In addition, the quadrivalent HPV vaccine also covers against the types that cause 90% of genital warts (i.e., types 6 and 11). The quadrivalent vaccine (GARDASIL) is also highly efficacious for preventing vaccine type HPV-related VIN and VaIN (HPV 16/18 detected in 76% of vulvar intraepithelial neoplasia (VIN) 2/3 and 42% of vulvar carcinoma). Since both vaccines are prophylactic, they do not affect the course of existing HPV infection, if any. Either vaccine can be given to young girls aged years (as early as 9 years of age); girls and women ages years (GARDASIL) or 10 years onward (CERVARIX). The greatest benefit is seen in this age because they have no prior sexual activity. Immunologic bridging studies have demonstrated that the neutralizing antibody level to HPV after vaccination was greater in year-old girls than year-old women. The quadrivalent HPV vaccine (GARDASIL) can also be used in males aged 9 26 years to prevent genital warts and the recent approved indication is for preventing HPV-related anal cancer. Administering the vaccine to boys before the onset of sexual activity is optimal. Both HPV vaccines are administered as a 3-dose series of IM injections over a 6- month period, with the second and third doses given 1 2 and then 6 months after the first dose. Both vaccines are generally well-tolerated and have good safety profile. The most frequent systemic adverse events are headache, gastroenteritis, and fever. Local adverse events include pain, swelling, erythema, and pruritus. Even with complete vaccination, routine cervical cancer screening is still recommended because 30% of cervical cancers are caused by other oncogenic HPV types. Suggested Readings: 1. American College of Obstetricians and Gynecologists. Human papillomavirus vaccination. ACOG Committee Opinion No Obstet Gynecol 2006; 108: Center for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MWRR 2007;56 (RR-2): Center for Disease Control and Prevention. Sexually Transmitted Disease Treatment Guidelines, MWWR 2006;55 (RR-11): Cestero RM. Risk of high-grade cervical intraepithelial neoplasia (CIN 2/3) or cancer during follow-up of human papillomavirus infection or CIN1. Am J Obstet Gynecol 2006,195; Garland Sm, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital disease. N Eng J Med 2007;356: Monif GR and Baker DA. Infectious diseases in obstetrics and gynecology. 6th ed. 2008;15: Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Eng J Med 2003;348: Sweet R and Gibbs R. Infectious diseases of the female genital tract. 5th ed. 2009; The FUTURE II Study Group. Quadrivalent Vaccine against human papillomavirus to prevent high grade cervical lesions. New Eng J Med 2007;356: The FUTURE Study Group. The Effect of Prophylactic Human Papillomavirus L1 virus-like particle vaccine on the risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomized clinical trials. Lancet 2007;369: Wiley DJ, Douglas J, Beutner K, et al. External genital warts: diagnosis, treatment and prevention. Clin Infect Dis 2002;35 (Supp 2): s210-s Wisdom A and Hawkins DA. Diagnosis in color sexually transmitted diseases. 2nd ed Woodman CBJ, Collins S, Winter H, et al. Natural History of cervical human paipillomavirus infection in young women: a longitudinal cohort study. Lancet 2001;357: l Sign up and open your clinic to the world. 171

7 Recommended Therapeutics The following index lists therapeutic classifications as recommended by the treatment guideline. For the prescriber's reference, available drugs are listed under each therapeutic class. For drug information, please refer to the Philippine Drug Directory System (PPD, PPD Pocket Version, PPD Text, PPD Tabs). Human Papillomavirus (HPV) Vaccine Human Papillomavirus Vaccine Types 16 & 18 (Recombinant, ASO4-adjuvanted) Cervarix Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine Gardasil Immunologicals Interferon Betaferon Intron A Uniferon Keratolytics Imiquimod Aldara cream Liquid nitrogen Podofilox Podophyllin resin Sinecathenin Trichloroacetic/Bichloroacetic acid 172