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Treatment of genital warts: Facts and controversies
Clinics in Dermatology (2010) 28, 546–548
Treatment of genital warts: Facts and controversies Ronni Wolf, MD ⁎, Batya Davidovici, MD The Dermatology Unit, Kaplan Medical Center (affiliated to the Hebrew University—Hadassah Medical School, Jerusalem, Israel), 76100 Rechovot, Israel
Abstract There are two opposing approaches in the treatment of genital warts: (1) the traditional approach advocates complete elimination of all lesions, and (2) a second approach regards condyloma as merely a cosmetic nuisance. After a long journey through many arguments and scientific papers, we have concluded that many unknowns, uncertainties, and controversies concerning the value of treatment of genital warts in terms of clearing and curing the disease (ie, eradicating the viruses, preventing cancer, and reducing infectivity). There is no consensus at present of whether treatment of men with evidence of genital human papillomavirus infection influences the natural history of their female sex partner's cervical disease. © 2010 Elsevier Inc. All rights reserved.
Introduction Human papillomavirus (HPV)-associated genital pathology represents one of the major problems among sexually transmitted infections (STI) clinics, mostly due to the high recurrence rate, difficult eradication, and oncogenic potential.1 There has not been specific antiviral and completely satisfactory treatment so far; thus, different methods could be used, such as cryotherapy, podophyllotoxin, curettage, imiquimod, and lasers, depending on the available resources, the provider's experience, and the patient's preference.1 There are two opposite approaches in the treatment of condylomata acuminata. The traditional one advocates complete elimination of all lesions, and a second approach regards condyloma acuminata as merely a cosmetic nuisance. We would like to begin the discussion with a representative case report that exemplifies, illustrates, sharpens, emphasizes, and points out the problem. The case demonstrates what is involved in following the first
⁎ Corresponding author. Fax: +972 9 9560978. E-mail address: [email protected] (R. Wolf). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2010.03.013
approach of trying to eradicate the disease. Many physicians ask: • “What's wrong with some more, extra examinations, or evaluations that are usually noninvasive or minimally invasive, if they might increase our patients' chances to be wart free?” • “Why should we not do everything we can (particularly if we do not harm or risk our patients) to treat our patients' disease?”
Case report A 26-year old women and her 28-year old partner came to our (R.W.) clinic for a second opinion after having been treated for 3 months for genital warts. These patients had attended one of the best gynecologic laser clinics, specializing in diseases of the vulva and cervix. The woman underwent gynecologic examinations, cytologic Papanicolaou testing, vulvoscopy, colposcopy with several biopsies of atypical sites on the cervix and vulva, and several sessions of laser treatments. The man underwent examination with a colposcopy, biopsies, and laser treatments.
Treatment of genital warts They were advised to abstain from sexual intercourse during that time. After this extensive treatment, the histologic examination of biopsy specimens taken from a suspicious perianal area of both patients demonstrated warts. Extensive laser treatment of the area was planed. At this point, they sought a second opinion. After 3 months of total sexual abstinence, after “endless” laser treatments, biopsies, and examinations, and deadly horrified by the thought that their sexually transmitted disease might end up as cancer, they visited R.W.'s clinic. On a careful inspection of the outer anogenital area with a clear and intensive light and optimal conditions, (but with the naked eyes alone) no visible warts were detected, including in the same perianal areas that had demonstrated warts on histology. The deeply rooted policy of many STI clinics is to remove each and every detectable genital wart and to periodically monitor for recurrence. Although the treatment guidelines of sexually transmitted diseases (STD) published by the Centers for Disease Control and Prevention (CDC) in 2006 (http://www.cdc.gov/std/treatment/2006/rr5511.pdf) did not recommend the treatment of subclinical genital HPV infection, many STI clinics treat infection diagnosed by colposcopy of the genital area, by biopsy, acetic acid application, and other techniques. An example of this approach is a letter published in the July 2007 issue of the European Journal of Obstetrics and Reproductive Biology.2 It describes two young women (aged 17 and 30) who “told their gynecologists about small warts in the perineum, but they (the gynecologists) did not pay a lot of attention to them because their cervical Pap smears were negative.” After a delay of more than 8 months, these patients were referred to a special clinic. Carcinoma was detected on histologic examination of the intra-anal condylomata that had been removed from the 30-year-old woman, and recurrent intra-anal condyloma with minor dysplasia was diagnosed in the 17-year-old woman. The authors stated, “that all patients with external anogenital warts should have anoscopy and a histological examination of all intra-anal lesions” and also suggested, “Preventive proctological examinations for women practicing anal sex [means all women, because they often do not disclose having anal sex…] could be beneficial.” This publication is obviously not unique or exceptional in its opinion, and such policies advocating the complete eradication of all lesions, or at least achieving long-lasting remission, tend to appear whenever new treatment modalities enter the scene.3-8
Discussion We will critically evaluate the arguments against aiming to eradicate all existing genital warts.
547 1. “Common genital warts,” or so-called benign condylomata acuminata, are caused by low-risk HPV DNA types in most cases, either HPV-6 or HPV-11.1,9-12 Eradicating clinically detectable warts of this type— even if we assume that all viruses are eliminated by the treatment—will not necessarily prevent the risk of the development of cervical, vulval, penile, or anal carcinoma; however, 20% to 50% of the condylomata from otherwise healthy individuals and nearly 100% of condylomata from immunosuppressed patients also contain coinfection with high-risk HPV types.11,13,14 Because most of the high-risk HPV infections are asymptomatic,15-19 it is impossible to tell whether the existence of these viruses in condylomata acuminata is not just an incidental finding and whether they are there because they are also present in other genital areas. If so, eradicating the condylomata would not eliminate all high-risk viruses. Until this issue is solved, one cannot exclude the possible beneficial effect of treatment of all warts with the aim to eliminate or to reduce high-risk HPV viruses, existing in part of the genital or extragenital warts, or both. 2. HPV is considered a transient infection that tends to clear spontaneously, especially in women, as do warts anywhere on the body.9,20-23 Low-risk types of HPV and younger age are associated with a higher rate of spontaneous clearing of the infection9,20-23; thus, young women with acuminate genital warts might have the best chance of healing without treatment. Recent studies24,25 indicate that 16% to 20% of women have persistence of HPV infection. Factors associated with persistence include age younger than 21 years at first intercourse, four or more sexual partners during their lifetime, and most importantly, the presence of genital warts.25 Consequently, one cannot regard HPV infection as a transient infection. 3. Perhaps, the main controversial question is whether treatment by itself is effective in clearing the infection. Anogenital HPV infection is inherently multifocal (one or more lesions on one anatomic site), or multicentric (lesions on disparate anatomic sites, eg, vulva, perineum, anal, and cervical). Thus, cell-destructive therapies that have been the standard of treatment for several decades, with the goal of removing all HPV infected epithelial cells from the patient, might not do so. Keratinocytes surrounding visible lesions may be infected in a latent manner, harboring viral DNA. Such epithelial cells present the source of relapsing infections and stimulate the growth of new lesions. Indeed, in a well-designed study performed 2 decades ago, a strong association was found between the presence of HPV-16 genomes and histologically normal tissue within 2 to 5 cm of the tumors,26 thus indicating the existence of viruses in the surrounding of the visible tumor or wart. Israeli researchers3 showed with sophisticated methods that most
548 patients treated with loop electrosurgical excision have no viruses 20 mm from the center of the lesion, which could indicate complete eradication of HPV genomes with this method. Some have argued that treatment or eradication of visible genital warts might reduce (although not erase) infectivity, transmission to partners, and ping-pong transmission27,28; however, evidence-based data to support this argument are lacking.
Conclusions Many unknowns, uncertainties, and controversies remain with regard to the value of treatment of genital warts in terms of clearing or curing the disease, that is, eradicating the viruses, preventing cancer, and reducing infectivity. There is no consensus at present whether treatment of men with evidence of genital HPV infection influences the natural history of their female sex partner's cervical disease.
References 1. Skerlev M, Grce M, Sirotkoviae-Skerlev M, Husnjak K, Lpozencic J. Human papillomavirus male genital infections: clinical variations and the significance of DNA typing. Clin Dermatol 2002;20:173-8. 2. Mlakar B. Anoscopy could be beneficial for women with external anogenital condyloma. Eur J Obstet Gynecol Reprod Biol 2007;133: 121-2. 3. Schoenfeld A, Ziv E, Levavi H, Samra Z, Oadia J. Laser versus loop electrosurgical excision in vulvar condyloma for eradication of subclinical reservoir demonstrated by assay for 2′5′ oligosynthetase human papillomavirus. Gynecol Obstet Invest 1995;40:46-51. 4. Syed TA, Lndin S. Topical treatment of penile condylomata acuminata with podophyllotoxin 0.3% solution, 0.3% cream and 0.15% cream. A comparative open study. Dermatology 1993;187:30-3. 5. Padilla-Ailhaud A. Carbon dioxide laser vaporization of condyloma acuminata. J Low Genit Tract Dis 2006;10:238-41. 6. Mayeaux Jr EJ, Harper MB, Barksdale W, Pope JB. Noncervical human papillomavirus genital infections. Am Fam Physician 1995;52:1137-50. 7. Savoca S, Nardo LG, Rosano TF, D'Agosta S, Nrdo F. CO(2) laser vaporization as primary therapy for human papillomavirus lesions. A prospective observational study. Acta Obstet Gynecol Scand 2001;80: 1121-4. 8. Lacey CJ, Goodall RL, Tennvall GR, et al. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect 2003;79:270-5. 9. Ault KA. Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol 2006; 14:40470.
R. Wolf, B. Davidovici 10. Lacey CJ. Therapy for genital human papillomavirus-related disease. J Clin Virol 2005;32(Suppl 1):S82-S90. 11. Lacey CJ, Lowndes CM, Sah KV. Chapter 4: burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 2006;24(Suppl 3):S35-S41. 12. Gross G, Ikenberg H, Gissmann L, Hgedorn M. Papillomavirus infection of the anogenital region: correlation between histology, clinical picture, and virus type. Proposal of a new nomenclature. J Invest Dermatol 1985;85:147-52. 13. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005;192: 2099-107. 14. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Ffe KH. Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol 1999;37:3316-22. 15. Sheary B, Dyan L. Cervical screening and human papillomavirus. Aust Fam Physician 2005;34:578-80. 16. Mao C, Hughes JP, Kiviat N, et al. Clinical findings among young women with genital human papillomavirus infection. Am J Obstet Gynecol 2003;188:677-84. 17. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997;102:3-8. 18. Koutsky LA, Galloway DA, Hlmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122-63. 19. Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005;191:1796-807. 20. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132:277-84. 21. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423-8. 22. Franco EL, Villa LL, Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis 1999;180: 1415-23. 23. Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis 1995;171:1026-30. 24. Rosa MI, Fachel JM, Rosa DD, Medeiros LR, Igansi CN, Bozzetti MC. Persistence and clearance of human papillomavirus infection: a prospective cohort study. Am J Obstet Gynecol 2008;199:617.e1-7. 25. Sycuro LK, Xi LF, Hughes JP, et al. Persistence of genital human papillomavirus infection in a long-term follow-up study of female university students. J Infect Dis 2008;198:971-8. 26. Macnab JC, Walkinshaw SA, Cordiner JW, Clements JB. Human papillomavirus in clinically and histologically normal tissue of patients with genital cancer. N Engl J Med 1986;315:1052-8. 27. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55:1-94. 28. Centers for Disease Control and Prevention. Report to Congress: prevention of genital human papillomavirus infection (Jan 2004). Atlanta (Ga): CDC; 2004.
Treatment of genital warts: Facts and controversies Ronni Wolf, MD ⁎, Batya Davidovici, MD The Dermatology Unit, Kaplan Medical Center (affiliated to the Hebrew University—Hadassah Medical School, Jerusalem, Israel), 76100 Rechovot, Israel
Abstract There are two opposing approaches in the treatment of genital warts: (1) the traditional approach advocates complete elimination of all lesions, and (2) a second approach regards condyloma as merely a cosmetic nuisance. After a long journey through many arguments and scientific papers, we have concluded that many unknowns, uncertainties, and controversies concerning the value of treatment of genital warts in terms of clearing and curing the disease (ie, eradicating the viruses, preventing cancer, and reducing infectivity). There is no consensus at present of whether treatment of men with evidence of genital human papillomavirus infection influences the natural history of their female sex partner's cervical disease. © 2010 Elsevier Inc. All rights reserved.
Introduction Human papillomavirus (HPV)-associated genital pathology represents one of the major problems among sexually transmitted infections (STI) clinics, mostly due to the high recurrence rate, difficult eradication, and oncogenic potential.1 There has not been specific antiviral and completely satisfactory treatment so far; thus, different methods could be used, such as cryotherapy, podophyllotoxin, curettage, imiquimod, and lasers, depending on the available resources, the provider's experience, and the patient's preference.1 There are two opposite approaches in the treatment of condylomata acuminata. The traditional one advocates complete elimination of all lesions, and a second approach regards condyloma acuminata as merely a cosmetic nuisance. We would like to begin the discussion with a representative case report that exemplifies, illustrates, sharpens, emphasizes, and points out the problem. The case demonstrates what is involved in following the first
⁎ Corresponding author. Fax: +972 9 9560978. E-mail address: [email protected] (R. Wolf). 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2010.03.013
approach of trying to eradicate the disease. Many physicians ask: • “What's wrong with some more, extra examinations, or evaluations that are usually noninvasive or minimally invasive, if they might increase our patients' chances to be wart free?” • “Why should we not do everything we can (particularly if we do not harm or risk our patients) to treat our patients' disease?”
Case report A 26-year old women and her 28-year old partner came to our (R.W.) clinic for a second opinion after having been treated for 3 months for genital warts. These patients had attended one of the best gynecologic laser clinics, specializing in diseases of the vulva and cervix. The woman underwent gynecologic examinations, cytologic Papanicolaou testing, vulvoscopy, colposcopy with several biopsies of atypical sites on the cervix and vulva, and several sessions of laser treatments. The man underwent examination with a colposcopy, biopsies, and laser treatments.
Treatment of genital warts They were advised to abstain from sexual intercourse during that time. After this extensive treatment, the histologic examination of biopsy specimens taken from a suspicious perianal area of both patients demonstrated warts. Extensive laser treatment of the area was planed. At this point, they sought a second opinion. After 3 months of total sexual abstinence, after “endless” laser treatments, biopsies, and examinations, and deadly horrified by the thought that their sexually transmitted disease might end up as cancer, they visited R.W.'s clinic. On a careful inspection of the outer anogenital area with a clear and intensive light and optimal conditions, (but with the naked eyes alone) no visible warts were detected, including in the same perianal areas that had demonstrated warts on histology. The deeply rooted policy of many STI clinics is to remove each and every detectable genital wart and to periodically monitor for recurrence. Although the treatment guidelines of sexually transmitted diseases (STD) published by the Centers for Disease Control and Prevention (CDC) in 2006 (http://www.cdc.gov/std/treatment/2006/rr5511.pdf) did not recommend the treatment of subclinical genital HPV infection, many STI clinics treat infection diagnosed by colposcopy of the genital area, by biopsy, acetic acid application, and other techniques. An example of this approach is a letter published in the July 2007 issue of the European Journal of Obstetrics and Reproductive Biology.2 It describes two young women (aged 17 and 30) who “told their gynecologists about small warts in the perineum, but they (the gynecologists) did not pay a lot of attention to them because their cervical Pap smears were negative.” After a delay of more than 8 months, these patients were referred to a special clinic. Carcinoma was detected on histologic examination of the intra-anal condylomata that had been removed from the 30-year-old woman, and recurrent intra-anal condyloma with minor dysplasia was diagnosed in the 17-year-old woman. The authors stated, “that all patients with external anogenital warts should have anoscopy and a histological examination of all intra-anal lesions” and also suggested, “Preventive proctological examinations for women practicing anal sex [means all women, because they often do not disclose having anal sex…] could be beneficial.” This publication is obviously not unique or exceptional in its opinion, and such policies advocating the complete eradication of all lesions, or at least achieving long-lasting remission, tend to appear whenever new treatment modalities enter the scene.3-8
Discussion We will critically evaluate the arguments against aiming to eradicate all existing genital warts.
547 1. “Common genital warts,” or so-called benign condylomata acuminata, are caused by low-risk HPV DNA types in most cases, either HPV-6 or HPV-11.1,9-12 Eradicating clinically detectable warts of this type— even if we assume that all viruses are eliminated by the treatment—will not necessarily prevent the risk of the development of cervical, vulval, penile, or anal carcinoma; however, 20% to 50% of the condylomata from otherwise healthy individuals and nearly 100% of condylomata from immunosuppressed patients also contain coinfection with high-risk HPV types.11,13,14 Because most of the high-risk HPV infections are asymptomatic,15-19 it is impossible to tell whether the existence of these viruses in condylomata acuminata is not just an incidental finding and whether they are there because they are also present in other genital areas. If so, eradicating the condylomata would not eliminate all high-risk viruses. Until this issue is solved, one cannot exclude the possible beneficial effect of treatment of all warts with the aim to eliminate or to reduce high-risk HPV viruses, existing in part of the genital or extragenital warts, or both. 2. HPV is considered a transient infection that tends to clear spontaneously, especially in women, as do warts anywhere on the body.9,20-23 Low-risk types of HPV and younger age are associated with a higher rate of spontaneous clearing of the infection9,20-23; thus, young women with acuminate genital warts might have the best chance of healing without treatment. Recent studies24,25 indicate that 16% to 20% of women have persistence of HPV infection. Factors associated with persistence include age younger than 21 years at first intercourse, four or more sexual partners during their lifetime, and most importantly, the presence of genital warts.25 Consequently, one cannot regard HPV infection as a transient infection. 3. Perhaps, the main controversial question is whether treatment by itself is effective in clearing the infection. Anogenital HPV infection is inherently multifocal (one or more lesions on one anatomic site), or multicentric (lesions on disparate anatomic sites, eg, vulva, perineum, anal, and cervical). Thus, cell-destructive therapies that have been the standard of treatment for several decades, with the goal of removing all HPV infected epithelial cells from the patient, might not do so. Keratinocytes surrounding visible lesions may be infected in a latent manner, harboring viral DNA. Such epithelial cells present the source of relapsing infections and stimulate the growth of new lesions. Indeed, in a well-designed study performed 2 decades ago, a strong association was found between the presence of HPV-16 genomes and histologically normal tissue within 2 to 5 cm of the tumors,26 thus indicating the existence of viruses in the surrounding of the visible tumor or wart. Israeli researchers3 showed with sophisticated methods that most
548 patients treated with loop electrosurgical excision have no viruses 20 mm from the center of the lesion, which could indicate complete eradication of HPV genomes with this method. Some have argued that treatment or eradication of visible genital warts might reduce (although not erase) infectivity, transmission to partners, and ping-pong transmission27,28; however, evidence-based data to support this argument are lacking.
Conclusions Many unknowns, uncertainties, and controversies remain with regard to the value of treatment of genital warts in terms of clearing or curing the disease, that is, eradicating the viruses, preventing cancer, and reducing infectivity. There is no consensus at present whether treatment of men with evidence of genital HPV infection influences the natural history of their female sex partner's cervical disease.
References 1. Skerlev M, Grce M, Sirotkoviae-Skerlev M, Husnjak K, Lpozencic J. Human papillomavirus male genital infections: clinical variations and the significance of DNA typing. Clin Dermatol 2002;20:173-8. 2. Mlakar B. Anoscopy could be beneficial for women with external anogenital condyloma. Eur J Obstet Gynecol Reprod Biol 2007;133: 121-2. 3. Schoenfeld A, Ziv E, Levavi H, Samra Z, Oadia J. Laser versus loop electrosurgical excision in vulvar condyloma for eradication of subclinical reservoir demonstrated by assay for 2′5′ oligosynthetase human papillomavirus. Gynecol Obstet Invest 1995;40:46-51. 4. Syed TA, Lndin S. Topical treatment of penile condylomata acuminata with podophyllotoxin 0.3% solution, 0.3% cream and 0.15% cream. A comparative open study. Dermatology 1993;187:30-3. 5. Padilla-Ailhaud A. Carbon dioxide laser vaporization of condyloma acuminata. J Low Genit Tract Dis 2006;10:238-41. 6. Mayeaux Jr EJ, Harper MB, Barksdale W, Pope JB. Noncervical human papillomavirus genital infections. Am Fam Physician 1995;52:1137-50. 7. Savoca S, Nardo LG, Rosano TF, D'Agosta S, Nrdo F. CO(2) laser vaporization as primary therapy for human papillomavirus lesions. A prospective observational study. Acta Obstet Gynecol Scand 2001;80: 1121-4. 8. Lacey CJ, Goodall RL, Tennvall GR, et al. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Transm Infect 2003;79:270-5. 9. Ault KA. Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol 2006; 14:40470.
R. Wolf, B. Davidovici 10. Lacey CJ. Therapy for genital human papillomavirus-related disease. J Clin Virol 2005;32(Suppl 1):S82-S90. 11. Lacey CJ, Lowndes CM, Sah KV. Chapter 4: burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 2006;24(Suppl 3):S35-S41. 12. Gross G, Ikenberg H, Gissmann L, Hgedorn M. Papillomavirus infection of the anogenital region: correlation between histology, clinical picture, and virus type. Proposal of a new nomenclature. J Invest Dermatol 1985;85:147-52. 13. Vandepapeliere P, Barrasso R, Meijer CJ, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005;192: 2099-107. 14. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Ffe KH. Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol 1999;37:3316-22. 15. Sheary B, Dyan L. Cervical screening and human papillomavirus. Aust Fam Physician 2005;34:578-80. 16. Mao C, Hughes JP, Kiviat N, et al. Clinical findings among young women with genital human papillomavirus infection. Am J Obstet Gynecol 2003;188:677-84. 17. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 1997;102:3-8. 18. Koutsky LA, Galloway DA, Hlmes KK. Epidemiology of genital human papillomavirus infection. Epidemiol Rev 1988;10:122-63. 19. Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005;191:1796-807. 20. Moscicki AB, Shiboski S, Broering J, et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr 1998;132:277-84. 21. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423-8. 22. Franco EL, Villa LL, Sobrinho JP, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis 1999;180: 1415-23. 23. Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis 1995;171:1026-30. 24. Rosa MI, Fachel JM, Rosa DD, Medeiros LR, Igansi CN, Bozzetti MC. Persistence and clearance of human papillomavirus infection: a prospective cohort study. Am J Obstet Gynecol 2008;199:617.e1-7. 25. Sycuro LK, Xi LF, Hughes JP, et al. Persistence of genital human papillomavirus infection in a long-term follow-up study of female university students. J Infect Dis 2008;198:971-8. 26. Macnab JC, Walkinshaw SA, Cordiner JW, Clements JB. Human papillomavirus in clinically and histologically normal tissue of patients with genital cancer. N Engl J Med 1986;315:1052-8. 27. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55:1-94. 28. Centers for Disease Control and Prevention. Report to Congress: prevention of genital human papillomavirus infection (Jan 2004). Atlanta (Ga): CDC; 2004.