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Human Papillomavirus Disease
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April 10, 2009
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From Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. National Institutes of Health, the Centers for Disease Control and Prevention, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Vol. 58, No. RR-4. April 10, 2009.
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Epidemiology

Human papillomavirus (HPV), a common sexually transmitted DNA virus (825Hildesheim A, Gravitt P, Schiffman MH, et al. Determinants of genital human papillomavirus infection in low-income women in Washington, D.C. Sex Transm Dis 1993;20:279-85., 830Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence of HPV infection among men: a systematic review of the literature. J Infect Dis 2006;194:1044-57.), is the most frequent cause of cervical cancer (831Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958-64., 832Bosch FX, Manos MM, Muoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87:796-802., 833Lorincz AT, Reid R, Jenson AB, et al. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 1992;79:328-37.). Most HPV infections, however, resolve or become latent and undetectable (828,834,835), whereas persistent infection with an oncogenic HPV type is required for tumorigenesis. Of more than 100 HPV types, more than 40 can infect the cervix, and at least 13 of these are considered oncogenic types, including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66 (836Cogliano V, Baan R, Straif K, et al. Carcinogenicity of human papillomaviruses. Lancet Oncol 2005;6:204.). HPV16 alone accounts for approximately 50% of cervical cancers in the general population and HPV18 for another 10%-15%, whereas the other oncogenic HPV types each individually account for <5% of tumors (832Bosch FX, Manos MM, Muoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87:796-802., 837Munoz N, Bosch FX, de Sanjos S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.). HPV types 6 and 11 cause 90% of genital warts (838Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol 1995;33:2058-63.).

Cervical cancer is the second most common cause of cancer in women worldwide, with almost twofold higher incidence in developing countries than in industrialized countries (839Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137-50.). In the United States and Western Europe, women with HIV/AIDS have several-fold higher rates of cervical cancer compared with the general population, according to studies linking population-based cancer registries with registries for HIV/AIDS (840Goedert JJ, Cot TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998;351:1833-9., 841Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;285:1736-45., 842Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92:1500-10., 843Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr 2003;32:527-33.). In Africa, findings have varied (844Orem J, Otieno MW, Remick SC. AIDS-associated cancer in developing nations. Curr Opin Oncol 2004;16:468-76.), but the only African study with a prospective registry-based design reported substantially increased risk for cervical cancer in women with HIV/AIDS, and cervical cancer represented 10% of all tumors detected (845Mbulaiteye SM, Katabira ET, Wabinga H, et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer 2006;118:985-90.). Furthermore, HIV seropositivity is associated with a high prevalence of HPV infection, low-grade cervical intraepithelial neoplasia (CIN), and the precursor to cervical cancer, CIN 3 (846Moscicki AB, Ellenberg JH, Crowley-Nowick P, et al. Risk of high-grade squamous intraepithelial lesion in HIV-infected adolescents. J Infect Dis 2004;190:1413-21., 847Schrager LK, Friedland GH, Maude D, et al. Cervical and vaginal squamous cell abnormalities in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr 1989;2:570-5., 848Maiman M, Fruchter RG, Serur E, et al. Human immunodeficiency virus infection and cervical neoplasia. Gynecol Oncol 1990;38:377-82., 849Feingold AR, Vermund SH, Burk RD, et al. Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr 1990;3:896-903., 850Vermund SH, Kelley KF, Klein RS, et al. High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. Am J Obstet Gynecol 1991;165:392-400., 851Laga M, Icenogle JP, Marsella R, et al. Genital papillomavirus infection and cervical dysplasia-opportunistic complications of HIV infection. Int J Cancer 1992;50:45-8., 852Spinillo A, Tenti P, Zappatore R, et al. Prevalence, diagnosis and treatment of lower genital neoplasia in women with human immunodeficiency virus infection. Eur J Obstet Gynecol Reprod Biol 1992;43:235-41., 853Wright TC, Koulos J, Schnoll F, et al. Cervical intraepithelial neoplasia in women infected with the human immunodeficiency virus: outcome after loop electrosurgical excision. Gynecol Oncol 1994;55:253-8., 854Klein RS, Ho GY, Vermund SH, Fleming I, Burk RD. Risk factors for squamous intraepithelial lesions on Pap smear in women at risk for human immunodeficiency virus infection. J Infect Dis 1994;170:1404-9., 855Ho GY, Burk RD, Fleming I, Klein RS. Risk of genital human papillomavirus infection in women with human immunodeficiency virus-induced immunosuppression. Int J Cancer 1994;56:788-92., 856Cappiello G, Garbuglia AR, Salvi R, et al. HIV infection increases the risk of squamous intra-epithelial lesions in women with HPV infection: an analysis of HPV genotypes. Int J Cancer 1997;72:982-6., 857Hankins C, Coutlee F, Lapointe N, et al. Prevalence of risk factors associated with human papillomavirus infection in women living with HIV. CMAJ 1999;160:185-91.,858Massad LS, Riester KA, Anastos KM, et al. Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. J Acquir Immune Defic Syndr 1999;21:33-41. ,859Cu-Uvin S, Hogan JW, Warren D, et al. Prevalence of lower genital tract infections among human immunodeficiency virus (HIV)-seropositive and high-risk HIV-seronegative women. Clin Infect Dis 1999;29:1145-50., 860Palefsky JM, Minkoff H, Kalish LA, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999;91:226-36., 861Branca M, Migliore G, Giuliani M, et al. Squamous intraepithelial lesions (SILs) and HPV associated changes in HIV infected women or at risk of HIV. Eur J Gynaecol Oncol 2000;21:155-9., 862Palefsky JM. Cervical human papillomavirus infection and cervical intraepithelial neoplasia in women positive for human immunodeficiency virus in the era of highly active antiretroviral therapy. Curr Opin Oncol 2003;15:382-8., 863Hawes SE, Critchlow CW, Faye Niang MA, et al. Increased risk of high-grade cervical squamous intraepithelial lesions and invasive cervical cancer among African women with human immunodeficiency virus type 1 and 2 infections. J Infect Dis 2003;188:555-63., 864Taylor G, Wolff T, Khanna N, Furth P, Langenberg P. Genital dysplasia in women infected with human immunodeficiency virus. J Am Board Fam Pract 2004;17:108-13., 865Wright TC, Ellerbrock TV, Chiasson MA, et al. Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. Obstet Gynecol 1994;84:591-7.). Among HIV-infected women, rates of oncogenic HPV and high-grade CIN increase with diminished CD4+ count and higher HIV RNA levels (858Massad LS, Riester KA, Anastos KM, et al. Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. J Acquir Immune Defic Syndr 1999;21:33-41., 860Palefsky JM, Minkoff H, Kalish LA, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst 1999;91:226-36., 866Schuman P, Ohmit SE, Klein RS, et al. Longitudinal study of cervical squamous intraepithelial lesions in human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis 2003;188:128-36., 876Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 2005;97:577-86.).

Other cancers caused by oncogenic HPV infection include most anal cancers and a subset of tumors of the vulva, vagina, penis, oral cavity, and oropharynx (836Cogliano V, Baan R, Straif K, et al. Carcinogenicity of human papillomaviruses. Lancet Oncol 2005;6:204., 877D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944-56.). HPV16 is the type present in the majority of these HPV-positive noncervical cancers. As with cervical cancer, the incidence of anal cancer and the other HPV-associated tumors is substantially higher in patients with HIV/AIDS than in the general population (841Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;285:1736-45., 842Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 2000;92:1500-10., 878Sitas F, Pacella-Norman R, Carrara H, et al. The spectrum of HIV-1 related cancers in South Africa. Int J Cancer 2000;88:489-92.). Furthermore, high-grade anal intraepithelial neoplasia (AIN), the likely anal cancer precursor lesion, is more common in HIV-seropositive adults than in HIV-seronegative adults (879Mathews WC, Sitapati A, Caperna JC, Barber RE, Tugend A, Go U. Measurement characteristics of anal cytology, histopathology, and high-resolution anoscopic visual impression in an anal dysplasia screening program. J Acquir Immune Defic Syndr 2004;37:1610-5., 880Wilkin TJ, Palmer S, Brudney KF, et al. Anal intraepithelial neoplasia in heterosexual and homosexual HIV-positive men with access to antiretroviral therapy. J Infect Dis 2004;190:1685-91., 881Kreuter A, Brockmeyer NH, Hochdorfer B, et al. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005;52:603-8., 882Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005;19:1407-14., 883Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis 2006;43:223-33.) as are anal and genital warts and, in women, vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VAIN) (884Massad LS, Silverberg MJ, Springer G, et al. Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus. Am J Obstet Gynecol 2004;190:1241-8., 886Jamieson DJ, Paramsothy P, Cu-Uvin S, Duerr A. Vulvar, vaginal, and perianal intraepithelial neoplasia in women with or at risk for human immunodeficiency virus. Obstet Gynecol 2006;107:1023-8.).

Although ART has altered HIV natural history, its effect on HPV and HPV-associated neoplasia is less clear. Certain studies have found reduced persistence/progression of cervical intralepithelial neoplasia (CIN) with use of ART. Conversely, most studies have not reported reduced persistence/progression of high-grade anal intraepithelial neoplasia (AIN) (AIN 2 or AIN 3) among men using ART (882Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005;19:1407-14., 892Heard I, Palefsky JM, Kazatchkine MD. The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and HPV-related diseases. Antivir Ther 2004;9:13-22., 893Palefsky J, Holly EA, Ralston ML, et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr 2001;28:422-8., 894Piketty C, Darragh TM, Heard I, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis 2004;31:96-9.), and most studies of cancer incidence have failed to document decreases in either cervical or anal cancer incidence since the widespread introduction of ART (882Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005;19:1407-14., 892Heard I, Palefsky JM, Kazatchkine MD. The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and HPV-related diseases. Antivir Ther 2004;9:13-22., 894Piketty C, Darragh TM, Heard I, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis 2004;31:96-9., 895Bower M, Powles T, Newsom-Davis T, et al. HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr 2004;37:1563-5., 896Clarke CA, Glaser SL. Population-based surveillance of HIV-associated cancers: utility of cancer registry data. J Acquir Immune Defic Syndr 2004;36:1083-91., 897Clifford GM, Polesel J, Rickenbach M, et al. Swiss HIV Cohort. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005;97:425-32., 898Diamond C, Taylor TH, Aboumrad T, Bringman D, Anton-Culver H. Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy. Sex Transm Dis 2005;32:314-20., 899Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol 2007;165:1143-53.). Similarly, the incidence of high-grade vulvar neoplasia was not reduced with ART use (884Massad LS, Silverberg MJ, Springer G, et al. Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus. Am J Obstet Gynecol 2004;190:1241-8.), even though rates of low-grade vulvar lesions and anal or genital warts did decrease with ART (884Massad LS, Silverberg MJ, Springer G, et al. Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus. Am J Obstet Gynecol 2004;190:1241-8., 900Birnbaum W, Hodgson TA, Reichart PA, et al. Prognostic significance of HIV-associated oral lesions and their relation to therapy. Oral Dis 2002;8(Suppl 2):110-4.). Whether ART has an effect on warts among HIV-infected persons is unclear (884Massad LS, Silverberg MJ, Springer G, et al. Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus. Am J Obstet Gynecol 2004;190:1241-8., 888Orlando G, Fasolo MM, Signori R, et al. Impact of highly active antiretroviral therapy on clinical evolution of genital warts in HIV-infected patients. AIDS 1999;13:291-3., 900Birnbaum W, Hodgson TA, Reichart PA, et al. Prognostic significance of HIV-associated oral lesions and their relation to therapy. Oral Dis 2002;8(Suppl 2):110-4.). With ART having limited or no effect on HPV-associated cancers, and HIV-seropositive persons living longer, HIV-seropositive women and men will increasingly enter middle age, when the incidence of cervical and other HPV-associated cancers typically increases (901Frisch M, Melbye M, Moller H. Trends in incidence of anal cancer in Denmark. BMJ 1993;306:419-22., 902Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018-22., 903Saraiya M, Ahmed F, Krishnan S, et al. Cervical cancer incidence in a prevaccine era in the United States, 1998-2002. Obstet Gynecol 2007;109:360-70.). Future increases in HPV-associated cancer rates among these patients are possible, particularly for cancers for which no routine screening, such as anal cancer is available. Continued careful monitoring of cancer rates in HIV-positive patients during the highly aggressive antiretroviral therapy (HAART) era is warranted.

Clinical Manifestations

The principal clinical manifestations of mucosal HPV infection are genital, anal, and oral warts; CIN; VIN; VAIN; AIN; squamous cell cancers; and cervical adenocarcinomas. A subset of oropharyngeal cancers are caused by HPV (877D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944-56.). HPV6 and 11 also cause recurrent respiratory papillomatosis, a rare condition in which papillomas grow in the respiratory tract.

Genital, Anal, and Oral Warts

Warts (condyloma acuminata) are usually flat, papular, or pedunculated growths on the mucosa or epithelium. The lesions might be a few millimeters to 1-2 centimeters in diameter; multiple lesions might be present. Certain persons with warts are asymptomatic although some have genital itching or discomfort.

CIN, VIN, and Squamous Cell Cancers

No characteristic symptoms are associated with CIN. These lesions are often asymptomatic but might manifest with bleeding. Cervical cancer also might be asymptomatic or might manifest with bleeding, pain, or a palpable mass.

AIN, VAIN, VIN and Oral HPV-Related Disease

No characteristic symptoms are associated with VAIN, VIN, and AIN. These lesions are often asymptomatic but might manifest with bleeding or itching, and external lesions might be visible or palpable. Similarly, squamous cell cancers at these sites also might be asymptomatic or they might manifest with bleeding, pain, or a visible/palpable mass.

Diagnosis
Genital, Anal, and Oral Warts

Diagnosis of genital and oral warts is made by visual inspection and can be confirmed by biopsy, although biopsy is needed only under certain circumstances (e.g., if the diagnosis is uncertain; the lesions do not respond to standard therapy; the disease worsens during therapy; or warts are pigmented, indurated, fixed, bleeding, or ulcerated). No data support the use of HPV tests in the routine diagnosis or management of visible genital or oral warts (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).).

CIN, VIN, and Squamous Cell Cancers

The same cytology (Papanicolaou or Pap test) and colposcopic techniques used to detect CIN among HIV-seronegative women should be used in HIV-seropositive patients (904Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-9.). Clinicians should be aware of such cytology and histology terms (Table 11). The entire genitalia and anal canal should be inspected carefully for visual signs of warts, intraepithelial neoplasia, or invasive cancer. Cervical cytology, tissue histology, or both should be performed according to the schedule described in the following sections.

After the Pap test, a digital examination of the vaginal, vulvar, and perianal regions and the anal canal should be performed as part of routine evaluation to feel for masses.

After an abnormal Pap test, a colposcopically directed cervical biopsy is the principal means of identifying CIN so that the lesion can be treated to prevent development of cervical cancer and to determine appropriate follow-up. For further details, see the section on prevention of cervical cancer.

AIN, VAIN, VIN and Oral HPV-Related Disease

AIN might first be recognized using a combination of visual inspection and anal cytology (termed anal SIL or ASIL), but as with CIN the diagnosis of AIN is principally made using anoscopically directed biopsy. Similarly, VAIN, VIN, and oral dysplasia are recognized through visual inspection and biopsy as needed. See the section on prevention of anal cancer.

Role of HPV Testing

Although a clinical test is available to detect 13 types of oncogenic HPV infection, no recommendations exist for use of this test in HIV-seropositive women. HIV-seropositive women should be referred for colposcopy if their cervical Pap test is interpreted as ASC US, ASC-H (or atypical glandular cells [ACG]), low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL) (368CDC. Guidelines for the investigation of contracts or persons with infectious tuberculosis: recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005;54(No. RR-15)., 904Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-9., 905Ferris DG. The 2001 ASCCP management guidelines for cervical cytology. Am Fam Physician 2004;70:1866-1868.). HPV testing may be used in the management of HIV-seronegative women with a cytologic diagnosis of ASC-US. "This practice has been recommended for similar use in HIV-seropositive women in American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines (906Wright TC, Jr., Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346-55.), but at present, insufficient data are available to support this practice. Unlike for HIV-seronegative women, no recommendations exist for the use of HPV testing for triage of HIV-seropositive women aged >30 years with normal cervical cytology (e.g., to less or more frequent Pap tests based on a hybrid capture test) or in follow-up of CIN after treatment. No recommendations are available for HPV testing of anal specimens or other noncervical specimens.

Preventing Exposure

onsistent and correct use of male latex condoms has been associated with 72% reduction in risk for acquisition of genital HPV infection among sexually active college age women (907Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354:2645-54.). Evidence confirms that condom use might reduce the risk for HPV-associated disease, including warts, cervical cancer, and CIN in women (908Vaccarella S, Franceschi S, Herrero R, et al. Sexual behavior, condom use, and human papillomavirus: pooled analysis of the IARC human papillomavirus prevalence surveys. Cancer Epidemiol Biomarkers Prev 2006;15:326-33., 909Manhart LE, Koutsky LA. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sex Transm Dis 2002;29:725-35.). Fewer data are available on prevention of HPV infection and HPV-associated conditions among HIV-seropositive patients. Laboratory studies have indicated that latex condoms provide a sufficient barrier to prevent passage of particles the size of HPV (908Vaccarella S, Franceschi S, Herrero R, et al. Sexual behavior, condom use, and human papillomavirus: pooled analysis of the IARC human papillomavirus prevalence surveys. Cancer Epidemiol Biomarkers Prev 2006;15:326-33., 910Kish LS, McMahon JT, Bergfeld WF, Pelachyk JM. An ancient method and a modern scourge: the condom as a barrier against herpes. J Am Acad Dermatol 1983;9:769-70.). Although condoms might not prevent transmission of HPV from skin outside the area of condom coverage, they should be used by sexually active HIV-seropositive patients to reduce the risk for transmission or acquisition of sexually transmitted infections (AII).

A vaccine targeted against HPV16 and HPV18 (the two HPV types responsible for 60%-70% of cervical cancers) and HPV6 and HPV11 (which cause most anogenital warts) was licensed and recommended for use in 2006 (911Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007;56(No. RR-2)., 912Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7-28.). This quadrivalent HPV vaccine was efficacious in preventing HPV infection and high-grade CIN associated with vaccine-related HPV types among young HIV-seronegative women (913Koutsky LA, Koutsky LA, Ault KA, et al. Proof of principle study investigators: a controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:1645-51., 914Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271-8., 915Koutsky LA, Harper DM. Current findings from prophylactic HPV vaccine trials. Vaccine 2006;24(Suppl 3):114-21., 916Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion 2006;73(Suppl 1):86-93.). A second vaccine targeting HPV16 and 18 has had similar efficacy. No data are available regarding the safety, tolerability, immunogenicity, or efficacy in HIV-infected women, and specific recommendations for HIV-seropositive women await data from ongoing studies. However, given the safety of other noninfectious vaccines in HIV-seropositive patients, the HPV vaccine is not absolutely contraindicated in HIV-seropositive women, and it may be used in circumstances when the clinician believes clinical benefit can be derived. The HPV vaccine has not demonstrated therapeutic benefit to treat existing HPV-related lesions in either HIV-seropositive or HIV-seronegative women, and women who have already acquired one sexually transmitted infection (e.g., HIV infection) are presumably more likely to have acquired others (e.g., infections with various HPV types). No published studies support using the HPV vaccine to prevent HPV infection and associated lesions of the anus, penis, or oral cavity; the vaccine is not currently approved for use in men in the United States. As in HIV-seropositive women, no data on the safety or efficacy of the HPV vaccine in HIV-positive men are available.

Preventing Disease
Preventing Cervical Cancer

See the guidelines for the use of cytology and biopsy to diagnose CIN. Also see section regarding treatment of CIN.

After obtaining a complete medical history, including the history of previous cervical disease, HIV-seropositive women should have a pelvic examination and a Pap test. The Pap test should be obtained twice during the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter (AII). If the results of the Pap test are abnormal, care should be provided according to the Guidelines for Management of Women with Abnormal Cervical Cancer Screening Tests by ASCCP (904Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-9.).

Regardless of CD4+ count, plasma HIV viral load, or antiretroviral treatment status, colposcopy and appropriate directed biopsy are recommended for HIV-seropositive women with cytological reports of "atypical squamous cells, cannot exclude high grade SIL" (ASC-H), (BII), LSIL (AII), HSIL (AII), or squamous cell carcinoma (AII) (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). HPV testing may be used in the management of HIV-seronegative women with a cytologic diagnosis of ASC-US. This has been recommended for similar use in HIV-seropositive women in recent ASCCP guidelines (904Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-9.). However, published data are limited, conflicting, and insufficient to support the use of HPV DNA testing in triage of ASC-US among HIV-seropositive women (DIII). A prudent plan is to perform routine colposcopy for HIV-seropositive women with ASC-US (CIII).

Among women with ASC-US on a Pap test, if a biopsy-confirmed CIN is absent and the colposcopic exam was adequate, follow-up with cervical cytology in 12 months is recommended (BIII), with referral back to colposcopy if results of ASC-US or greater are obtained. After two repeated results negative for intraepithelial lesion or malignancy, an affected woman can return to routine annual cytological screening (AII). ASCCP guidelines should be followed if the colposcopic exam is not adequate or when CIN is found.

If no CIN 2 or 3 lesion is identified at colposcopy among women with ASC-H, and a review of the results confirms the reading of ASC-H, cytological follow-up is recommended at 6 and 12 months (CIII). Women with ASC-US or greater on repeat cytology should again be referred for repeat colposcopy (BII).

For women referred to colposcopy for LSIL, if the colposcopy is satisfactory (entire squamocolumnar junction can be visualized with the colposcope) and no lesion or CIN is identified, follow-up with repeat cytological testing at 6 and 12 months is recommended (BII). ASCCP guidelines should be followed if the colposcopy is unsatisfactory or CIN is found.

A cytological result of HSIL identifies a woman at high risk for high-grade CIN or invasive cervical cancer. An immediate loop electrosurgical excision or colposcopy with endocervical assessment is an acceptable method for managing women with HSIL (BII). ASCCP guidelines should be followed if the colposcopy is satisfactory and no lesion or only CIN 1 is identified, or the colposcopy is unsatisfactory, or CIN 2 or 3 is found.

AGC on cytology is associated with greater risk for CIN and glandular neoplasia than ASC-US or LSIL. The Bethesda system has classified AGC into three categories: AGC, either endocervical, endometrial, or glandular cells not otherwise specified ("AGC NOS"); AGC, either endocervical or glandular cells favor neoplasia ("AGC favor neoplasia"); and endocervical adenocarcinoma in situ (AIS). Colposcopy with endocervical sampling is recommended for all the subcategories of AGC and AIS (AII). Endometrial sampling is recommended in conjunction with colposcopy and endocervical sampling in women 35 years of age and older (BII). ASCCP guidelines should be followed for women under the age of 35 and for subsequent evaluation of AGC.

For women with "AGC favor neoplasia" or AIS, those with normal colposcopy should undergo a diagnostic excisional procedure (e.g., cold knife excision, loop electrosurgical excision) (BII). If the initial colposcopy is normal in a woman with "AGC NOS," repeat cytology is recommended at 4-6-month intervals until four consecutive tests negative for intraepithelial neoplasia are obtained before returning to routine cytological screening (BIII). If abnormal cytology, including ASC, is obtained on follow-up cytology, repeat colposcopic examination or referral to a specialist is recommended (BIII).

Preventing Vaginal and Vulvar Cancer

In keeping with recommendations for HIV-seronegative women, routine screening of HIV-seropositive women for vaginal cancer following a hysterectomy for benign disease is not recommended, but women with a history of high-grade CIN or invasive cervical cancer are at increased risk and should be followed with a regular vaginal cuff Pap test (AIII) (917Kalogirou D, Antoniou G, Karakitsos P, et al. Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix. Eur J Gynaecol Oncol 1997;18:188-91., 918Paramsothy P, Duerr A, Heilig CM, et al. Abnormal vaginal cytology in HIV-infected and at-risk women after hysterectomy. J Acquir Immune Defic Syndr 2004;35:484-91.). For patients with abnormal vaginal cuff Pap tests with no visible vaginal colposcopic abnormalities, vaginal colposcopy and use of Lugol's iodine to stain the vagina are recommended (AIII). Vaginal colposcopy is also indicated in the presence of concomitant cervical and vulvar lesions (919Petry KU, Kchel H, Bode U, et al. Human papillomavirus is associated with the frequent detection of warty and basaloid high-grade neoplasia of the vulva and cervical neoplasia among immunocompromised women. Gynecol Oncol 1996;60:30-4., 920Chiasson MA, Ellerbrock TV, Bush TJ, Sun XW, Wright TC, Jr. Increased prevalence of vulvovaginal condyloma and vulvar intraepithelial neoplasia in women infected with the human immunodeficiency virus. Obstet Gynecol 1997;89:690-4.). Classification of VAIN parallels that of the cervix (i.e., VAIN 1, VAIN 2, and VAIN 3).

No screening procedure is available for vulvar cancer. However, for HIV-seropositive women with a past history of cervical or VAIN/cancer, an inspection of the vulva with or without colposcopy should be encouraged as part of their regular follow-up (CIII). Diagnosis of VIN/cancer should be confirmed with a biopsy (AII). A wedge biopsy under local anesthesia is usually done.

Preventing Anal Cancer

High-grade AIN (AIN 2 or 3) has the potential to progress to invasive anal cancer (921Marfing TE, Abel ME, Gallagher DM. Perianal Bowen's disease and associated malignancies: results of a survey. Dis Colon Rectum 1987;30:782-5., 922Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Perianal Bowen's disease and anal intraepithelial neoplasia: review of the literature. Dis Colon Rectum 1999;42:945-51.). Evidence from multiple studies demonstrates that HIV-seropositive MSM and HIV-seropositive women are at increased risk for AIN 2 or 3 and are at increased risk for anal cancer compared with the general population. The incidence of anal cancer has not declined since the widespread introduction of ART (899Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol 2007;165:1143-53.). This evidence and a cost-effectiveness analysis projecting that screening and treatment for anal precancerous lesions detected by Pap tests provide clinical benefits comparable to other OI prevention measures for HIV-seropositive persons (923Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999;281:1822-9.), anal cytology screening of HIV-seropositive MSM and of women might be useful preventive strategies. However, studies of screening and treatment programs for AIN 2 or 3 should be implemented before definitive recommendations for anal cytology screening can be made. No national recommendations exist for routine screening for anal cancer (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Until such time, certain specialists recommend an annual digital rectal examination as an important procedure to detect masses on palpation that might be anal cancer (BIII) (924Chin-Hong PV, Palefsky JM. Human papillomavirus anogenital disease in HIV-infected individuals. Dermatol Ther 2005;18:67-76.). In addition, certain specialists recommend anal cytologic screening for HIV-seropositive men and women (CIII). If anal cytology is performed and indicates ASC-US or ASC-H, LSIL, or HSIL (BIII), then it should be followed by high-resolution anoscopy (HRA). Visible lesions should be biopsied to determine the level of histologic changes and to rule out invasive cancer (BIII). See section on treatment for details of treatment of AIN.

Preventing Other HPV-Associated Cancers Among HIV-Seropositive Men and Woman

Other cancers that have been associated with HPV infection among HIV-seropositive men and women include oropharyngeal squamous cell and penile cancers (841Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001;285:1736-45., 897Clifford GM, Polesel J, Rickenbach M, et al. Swiss HIV Cohort. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005;97:425-32., 925Herida M, Mary-Krause M, Kaphan R, et al. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 2003;21:3447-53.). Prevention options for these cancers are unclear. Circumcision might reduce the risk for penile cancer as documented in one study (926Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of health benefits and risks. Sex Transm Infect 1998;74:368-73.); however, the benefits of circumcision to prevent HPV infection and penile cancer have not been studied in a randomized clinical trial or among HIV-seropositive men. No national recommendations exist for screening for oropharyngeal or penile cancer or precancerous lesions among those with HIV infection.

Treatment of HPV-Associated Genital and Anal Lesions
Treatment of Genital and Oral Warts

Treatments are available for genital warts, but none is uniformly effective (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). No single treatment has been demonstrated to be superior to any other, and no single treatment is ideal for all patients or all warts. Recurrences are common regardless of the modality (927Beutner KR, Wiley DJ, Douglas JM, et al. Genital warts and their treatment. Clin Infect Dis 1999;(Suppl 1):37-56.). Data are limited on the response of HIV-seropositive patients to the available treatments for genital warts. In the absence of data specific to the HIV-seropositive population, guidelines for the treatment of STDs for HIV-seronegative patients should be followed (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Data are insufficient to recommend a single treatment modality for all patients, and more than one treatment option might be required for refractory or recurrent lesions among patients with HIV infection.

Patient-applied treatments are generally recommended for uncomplicated external warts that can be easily identified by the patient and consist of the following options:

Podophyllotoxin (e.g., podofilox [0.5% solution or gel]) is an antimitotic agent that should be applied topically to warts twice daily for 3 days, followed by 4 days of no therapy. Treatment can be repeated weekly for up to four cycles (BIII). The efficacy is 40%-60% in immunocompetent subjects (928Bonnez W, Elswick RK, Jr., Bailey-Farchione A, et al. Efficacy and safety of 0.5% podofilox solution in the treatment and suppression of anogenital warts. Am J Med 1994;96:420-5., 929Tyring S, Edwards L, Cherry LK, et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol 1998;134:33-8.).

Imiquimod (5% cream) is a topical cytokine inducer that recruits an inflammatory response to the site of the wart. Patients should apply the cream once daily at bedtime three times a week for up to 16 weeks. The treatment area should be washed with soap and water 6-10 hours after the application (BII). The efficacy of imiquimod in immunocompetent persons is 30%-70%; the overall response in HIV-seropositive persons might be lower than in immunocompetent persons (930Beutner KR, Tyring SK, Trofatter KF, Jr., et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998;42:789-94., 931Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25-30., 932Gilson RJ, Shupack JL, Friedman-Kien AE, et al. A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. AIDS 1999;13:2397-404.).

Provider-applied treatments are typically recommended for complex or multicentric lesions or those lesions inaccessible to patient-applied treatments. These include intra-anal and vaginal warts. Options are summarized as follows:

Cryotherapy (liquid nitrogen or cryoprobe) destroys lesions by thermal-induced cytolysis. Liquid nitrogen should be applied until each lesion is thoroughly frozen and repeated every 1-2 weeks. Certain specialists recommend allowing the lesion to thaw and freezing a second time in each session (BIII). The efficacy of cryotherapy is 60%-80%.

Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) (80%-90%) act as caustic agents to kill wart tissue. Providers should apply a small amount to warts only and allow them to dry, at which time 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 to remove unreacted acid. The treatment can be repeated weekly for 3-6 weeks (BIII). The expected efficacy is 60%-80%.

Surgical treatments (tangential scissor excision, tangential shave excision, curettage, electrosurgery, electrocautery, infrared coagulation) can be used for external genital and anal warts (BIII). Laser surgery also can be used, but is usually more expensive (CIII). The efficacy of surgical removal can approach 100%, depending on the location of the lesions.

Podophyllin resin is a crude extract that contains podophyllotoxin and other cytotoxins and induces wart necrosis after topical application. It is prepared as a 10%-25% suspension in tincture of benzoin. It is applied to all lesions by the provider (up to 10 cm2 of skin area) and then removed by washing a few hours later. Applications can be repeated weekly for 3-6 weeks (CIII). Efficacy is 20%-80%. It is usually only applied to external lesions and use of podophyllotoxin is preferred over podophyllin resin.

Other treatments might be options, but because of limited available data, difficult administration, or possible side effects these treatments should be considered only if the treatments described above are ineffective. In limited, uncontrolled studies, topical application of cidofovir has reported activity against genital warts (CIII) (933Matteelli A, Beltrame A, Graifemberghi S, et al. Efficacy and tolerability of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected persons. Sex Transm Dis 2001;28:343-6., 934Snoeck R, Bossens M, Parent D, et al. Phase II double-blind, placebo-controlled study of the safety and efficacy of cidofovir topical gel for the treatment of patients with human papillomavirus infection. Clin Infect Dis 2001;33:597-602.). No topical formulation is commercially available. Intralesional interferon has been used for the treatment of genital warts but because of cost, difficult administration, and potential for systemic side effects (i.e., fever, fatigue, myalgias, and leukopenia) it is not recommended for first-line treatment (DIII). Among non-HIV-infected persons, the overall efficacy of interferon in treating genital warts is not superior to other therapies and it has not been specifically studied for efficacy among HIV-infected persons.

Oral warts can be located on various surfaces in the mouth. In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in patients on ART has been reported from the United States and the United Kingdom (935King MD, Reznik DA, O'Daniels CM, et al. Human papillomavirus-associated oral warts among human immunodeficiency virus-seropositive patients in the era of highly active antiretroviral therapy: an emerging infection. Clin Infect Dis 2002;34:641-8., 936Hodgson TA, Greenspan D, Greenspan JS. Oral lesions of HIV disease and HAART in industrialized countries. Adv Dent Res 2006;19:57-62.). No randomized trials of treatment of oral warts exist. Treatments include surgical excision and cryotherapy; some topical modalities have had success (937Baccaglini L, Atkinson JC, Patton LL, et al. Management of oral lesions in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(Suppl S50):e1-23.).

Treatment of CIN and Cervical Cancer

HIV-infected women with CIN should be managed by a specialist. Women having undergone satisfactory colposcopy with biopsy-confirmed CIN 1 preceded by ASC-US, ASC-H, or LSIL cytology can be followed with repeat cytological assessment at 6 and 12 months (BII). Referral to colposcopy is indicated if follow-up shows ASC or greater (AII). After two consecutive negative cytology tests, annual cytologic screening can be resumed (AII). If CIN 1 persists for at least 2 years, either continued follow-up or treatment with excision or ablation is acceptable (AI). ASCCP guidelines should be followed if the colposcopy is unsatisfactory, the endocervical sampling contains CIN, or the patient has been previously treated (AIII) (938Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:340-5.). A diagnostic excisional procedure or observation with colposcopy and cytology at 6- month intervals for 1 year is acceptable for CIN 1, preceded by HSIL or AGC-NOS (BIII). Women with satisfactory colposcopy and biopsy-confirmed high-grade CIN can be treated with either ablation (cryotherapy, laser vaporization, electrocautery, diathermy, and cold coagulation) or excisional methods (loop electrosurgical excision procedure [LEEP], laser conization, cold knife conization) (AI). In patients with recurrent high-grade CIN, diagnostic excisional methods are recommended (AII). Hysterectomy is acceptable for treatment of recurrent/persistent biopsy-confirmed high-grade CIN (BII). ASCCP guidelines should be followed if colposcopy is unsatisfactory (938Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:340-5.).

After treatment of high-grade CIN, follow-up with cervical cytology or combination of cervical cytology and colposcopy at 6-month intervals with at least two cytologic results of "negative for squamous intraepithelial lesion or malignancy" is acceptable (AI). Annual cytology can be done thereafter. Any ASC or greater requires colposcopy (AII).

Invasive cervical cancer is usually treated by radical hysterectomy with lymph node dissection or by radiation therapy for advanced disease. If cone biopsy or loop excision reveals microinvasive cervical cancer with clear margins, a simple hysterectomy can be done. An alternative for women with microinvasive lesions who want to preserve their fertility is local surgical procedure such as LEEP or cone biopsy with careful follow-up.

Treatment of VIN and Vulvar Cancer and of VAIN and Vaginal Cancer

Various treatment modalities for VIN are available, including local excision, laser vaporization, or ablation. Management of vulvar cancer must be individualized in consultation with a specialist. The cornerstone of the treatment of vulvar cancer is surgery. There is no standard operation and the emphasis is on the most conservative operation consistent with curing the disease. Radical vulvectomy with "en bloc" inguinofemoral lymphadenectomy has led to a favorable prognosis but with substantial morbidity (939Hacker NF. Vulvar Cancer. Practical Gynecologic Oncology. Edition 4, Lippincott Willimans & Wilkins 2005:543-83., 940de Hullu JA, van der Zee AG. Surgery and radiotherapy in vulvar cancer. Crit Rev Oncol Hematol 2006;60:38-58.). Further studies are needed to determine the optimal combined modality treatments. Radiation is also an option for some patients. The optimal treatment recommendations for HIV-seropositive women with advanced vulvar cancer remain unclear.

Similarly, treatment of VAIN is individualized in consultation with a specialist and depends on the patient's medical condition and the location and extent of the disease. Various methods of local tissue ablation to more extensive surgery have been used to treat VAIN. Treatment options include topical 5-fluorouracil, 5% imiquimod cream, laser vaporization with CO2 laser, and excisional procedures with electrosurgical loops or a scalpel excision. On occasion, total vaginectomy may be necessary. Radiation therapy is the treatment of choice for vaginal cancer.

Treatment of AIN and Anal Cancer

For AIN, no randomized, controlled therapeutic trials have been reported and data are insufficient to recommend a specific treatment approach. Treatment decisions are based on assessment of the size and location of the lesion and the grade of histology. The least aggressive approaches should be tried first whenever possible (CIII): for example, several different treatments, including topical 5-fluorouracil, photodynamic therapy, infrared coagulation, cryotherapy, laser therapy, and surgical excision, have been described in small open-label studies (881Kreuter A, Brockmeyer NH, Hochdorfer B, et al. Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005;52:603-8., 922Cleary RK, Schaldenbrand JD, Fowler JJ, Schuler JM, Lampman RM. Perianal Bowen's disease and anal intraepithelial neoplasia: review of the literature. Dis Colon Rectum 1999;42:945-51., 941Webber J, Fromm D. Photodynamic therapy for carcinoma in situ of the anus. Arch Surg 2004;139:259-61., 942Scholefield JH. Treatment of grade III anal intraepithelial neoplasia with photodynamic therapy: report of a case. Dis Colon Rectum 2003;46:1555-9., 942Scholefield JH. Treatment of grade III anal intraepithelial neoplasia with photodynamic therapy: report of a case. Dis Colon Rectum 2003;46:1555-9., 944Graham BD, Jetmore AB, Foote JE, Arnold LK. Topical 5-fluorouracil in the management of extensive anal Bowen's disease: a preferred approach. Dis Colon Rectum 2005;48:444-50.). In retrospective analysis, infrared coagulation has been proven to have moderate efficacy to treat AIN 2 or 3 in HIV-seropositive patients (CIII) (943Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator: a useful tool for treating anal squamous intraepithelial lesions. Dis Colon Rectum 2005;48:1042-54.) and was safe and well tolerated in this population in a recent AIDS Malignancy Consortium study. No indications exist for radiation therapy for patients with AIN in the absence of evidence of invasive cancer (EIII).

The results of studies do not indicate that treatment for AIN should be modified for patients receiving ART. Conversely, no evidence indicates that ART should be instituted or modified for the purpose of treating AIN (CIII).

Treatment of anal cancer must be individualized in consultation with a specialist.

Treatment of HPV-Associated Disease at Other Sites, Including the Penis and Mouth

Penile and some oral cancers are associated with HPV infection. Treatment options do not differ between HIV-seropositive and HIV-seronegative men and women. Data suggest a more favorable prognosis among HPV-associated oropharyngeal cancers compared with non-HPV associated oropharyngeal cancers (945Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630-6.).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Monitoring is required during and after treatment of genital warts because each of the treatments has associated toxicity and recurrences are common after treatment. Patients can be monitored by physical examination for evidence of recurrence. The major toxicity of podophylloxotin and topical podophyllin resin is local skin irritation. Also, if podophyllin is applied to a large treatment area, systemic absorption can cause nausea, vomiting, and CNS effects. The major toxicity of imiquimod is inflammation at the application site. The major toxicity of cryotherapy is local pain. The major side effects of surgical treatment for genital warts are local pain, bleeding, and secondary infection. The major adverse events associated with acid cauterization are local pain and irritation or ulceration of adjacent normal skin. Intralesional interferon can be associated with systemic toxicities of interferon, including fever, fatigue, myalgia, malaise, depression, and other influenza-like symptoms. Infrared coagulation might lead to bleeding and abscess formation.

Because risk for recurrence of CIN and cervical cancer after conventional therapy is increased among HIV-seropositive persons, patients should be followed after treatment with frequent cytologic screening and colposcopic examination according to published guidelines (AII) (853Wright TC, Koulos J, Schnoll F, et al. Cervical intraepithelial neoplasia in women infected with the human immunodeficiency virus: outcome after loop electrosurgical excision. Gynecol Oncol 1994;55:253-8., 946Fruchter RG, Maiman M, Sedlis A, et al. Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus. Obstet Gynecol 1996;87:338-44.). Treatment of CIN with ablative and excisional modalities can be associated with several adverse events such as pain and discomfort, intraoperative hemorrhage, postoperative hemorrhage, infection, and cervical stenosis.

Each of the treatment modalities for AIN described above is associated with adverse events, primarily pain, bleeding, ulceration, and, rarely, development of abscesses, fissures, or fistulas. Patients may be monitored for adverse events using the methods described above. Treatment of anal cancer is associated with a high rate of morbidity, even when the treatment is successful. Adverse events associated with anal cancer treatment include short-term side effects commonly associated with chemotherapy, such as neutropenia, and longer-term toxicities associated with radiation therapy, such as radiation proctitis.

IRIS has not been described in association with HPV infections.

Management of Treatment Failure

Treatment failure is defined as the persistence or recurrence of lesions after appropriate therapy. For persistent or recurrent genital warts, retreatment with any of the modalities previously described should be considered, preferably with an alternative modality to the one that previously failed (AIII). Genital warts often require more than one course of treatment. A repeat diagnostic excision or hysterectomy is acceptable for women with histological diagnosis or recurrent or persistent CIN 2 or 3 (BII) (853Wright TC, Koulos J, Schnoll F, et al. Cervical intraepithelial neoplasia in women infected with the human immunodeficiency virus: outcome after loop electrosurgical excision. Gynecol Oncol 1994;55:253-8.). Lesion persistence and recurrences after treatment of AIN are common. No data exist to guide the choice of treatment for recurrence of AIN, but either the original therapeutic modality or a different one may be used. Treatment of anal cancer that recurs after standard chemoradiation therapy often consists of abdominoperineal resection of the tumor.

Preventing Recurrence

HIV-seropositive women are at high risk for recurrent CIN after therapy, and HIV-seropositive men and women are at high risk for recurrent AIN. Preventing recurrence requires careful follow-up of patients after treatment. Patients should be monitored with cytologic screening according to published guidelines and, when indicated, colposcopic examination for recurrent lesions (AI) (923Goldie SJ, Kuntz KM, Weinstein MC, et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999;281:1822-9., 947Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. JAMA 1994;271:1866-9.). In one study of HIV-seropositive women treated for high-grade CIN, low-dose intravaginal 5-fluorouracil (i.e., 2 grams twice weekly for 6 months) reduced the short-term risk for recurrence (948Maiman M, Watts DH, Andersen J, et al. Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial. Obstet Gynecol 1999;94:954-61.). However, clinical experience with this therapy is too limited to provide a recommendation for use and no follow-up study to confirm these observations has been reported. One study documented that women receiving ART are less likely to have recurrence of CIN compared with women who are not receiving treatment (949Heard I, Potard V, Foulot H, et al. High rate of recurrence of cervical intraepithelial neoplasia after surgery in HIV-positive women. J Acquir Immune Defic Syndr 2005;39:412-8.), but treatment for CIN should not be considered an indication for ART.

No guidelines exist regarding frequency of monitoring after therapy and the monitoring intervals will vary depending on the treatment approach, extent of disease, and other factors. Patients with AIN can be monitored by anal cytology, standard anoscopy, HRA, and biopsy as indicated. Patients with perianal intraepithelial neoplasia can be monitored by visual inspection and biopsy as indicated. Recommendations for monitoring patients for recurrence of anal cancer after completion of therapy are the same for HIV-seropositive and HIV-seronegative persons.

No indication exists for secondary prophylaxis (chronic maintenance therapy) with any of the conventional modalities to prevent recurrence of genital warts, CIN, or AIN.

Special Considerations During Pregnancy

HIV-infected pregnant women with genital warts or anogenital HPV-related neoplasia are best managed by an interdisciplinary team of specialists (e.g.,OB/GYN, infectious disease physician). Pregnancy might be associated with an increased frequency and rate of growth of genital warts (950Shah K, Kashima H, Polk BF, et al. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-9., 951Morrison EA, Gammon MD, Goldberg GL, Vermund SH, Burk RD. Pregnancy and cervical infection with human papillomaviruses. Int J Gynaecol Obstet 1996;54:125-30., 952Kjellberg L, Hallmans G, Ahren AM, et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer 2000;82:1332-8.). Podophyllin and podofilox should not be used during pregnancy (EIII). Use of podophyllin has been associated with an increased risk for fetal death in several animal models and case reports in humans, but not with congenital anomalies. No experience with imiquimod in human pregnancy has been reported; therefore, its use in pregnancy is not recommended (DIII). No anomalies have been observed among animals with use during pregnancy.

Other topical treatments (e.g., bichloroacetic and trichloroacetic acid) and ablative therapies (i.e., laser, cryotherapy, and excision) can be used during pregnancy.

Transmission of genital HPV6 and 11 from vaginal secretions at delivery is the presumed mechanism of early onset recurrent laryngeal papillomatosis in infants. This condition is rare but is more common among women who have genital warts at delivery (953Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet Gynecol 2003;101:645-52.). Cesarean delivery is not known to prevent this condition in infants and children (950Shah K, Kashima H, Polk BF, et al. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-9., 951Morrison EA, Gammon MD, Goldberg GL, Vermund SH, Burk RD. Pregnancy and cervical infection with human papillomaviruses. Int J Gynaecol Obstet 1996;54:125-30., 952Kjellberg L, Hallmans G, Ahren AM, et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer 2000;82:1332-8.) (954Fife KH, Katz BP, Brizendine EJ, Brown DR. Cervical human papillomavirus deoxyribonucleic acid persists throughout pregnancy and decreases in the postpartum period. Am J Obstet Gynecol 1999;180:1110-4.). No change in obstetrical management is indicated for women with HPV infection unless extensive condylomata are present that might impede vaginal delivery or cause extensive bleeding (955Puranen MH, Yliskoski MH, Saarikoski SV, Syrjanen KJ, Syrjanen SM. Exposure of an infant to cervical human papillomavirus infection of the mother is common. Am J Obstet Gynecol 1997;176:1039-45., 956Watts DH, Koutsky LA, Holmes KK, et al. Low risk of perinatal transmission of human papillomavirus: results from a prospective cohort study. Am J Obstet Gynecol 1998;178:365-73., 957Tseng CJ, Liang CC, Soong YK, Pao CC. Perinatal transmission of human papillomavirus in infants: relationship between infection rate and mode of delivery. Obstet Gynecol 1998;91:92-6., 958Tenti P, Zappatore R, Migliora P, et al. Perinatal transmission of human papillomavirus from gravidas with latent infections. Obstet Gynecol 1999;93:475-9.).

For evaluation of CIN, all pregnant women should have a Pap test at their initial prenatal visit unless a normal cervical cytology result has been obtained within the past year (80American College of Obstetricians and Gynecologists. Practice Bulletin: Antepartum fetal surveillance. No. 9; October 1999.). Cytobrush sampling can be done during pregnancy (959Orr JW, Jr., Barrett JM, Orr PF, Holloway RW, Holimon JL. The efficacy and safety of the cytobrush during pregnancy. Gynecol Oncol 1992;44:260-2.). Pregnant women with abnormal cervical cytology results should undergo colposcopy and cervical biopsy of lesions suspicious for high-grade disease or cancer (BIII). Endocervical curettage is unacceptable in pregnant women (EIII). Increased bleeding might occur with cervical biopsy during pregnancy.

Pregnant women with ASC-US can be managed the same as nonpregnant women, with the exception that it is acceptable to defer colposcopy until at least 6 weeks postpartum (CIII). In the absence of invasive disease, treatment of CIN is not recommended during pregnancy. Re-evaluation with cytology and colposcopy is recommended after 6 weeks postpartum. Women with CIN can deliver vaginally.

Pregnant women with suspected cervical cancer should be referred to a gynecologic oncologist for definitive diagnosis, treatment, and delivery planning. Vaginal delivery is not recommended for women with invasive cervical cancer.

The effects of treatment of AIN on pregnancy are not known. Most experts recommend deferral of diagnosis and treatment of AIN until after delivery unless a strong clinical suspicion of anal cancer exists.

Prophylaxis to prevent first episode of opportunistic disease: Human Papillomavirus (HPV) infection
IndicationFirst choiceAlternative
Women aged 15-26 yrs (CIII)HPV quadravalent vaccine 0.5 mL IM months 0, 2, and 6 (CIII)
Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Human papillomavirus disease
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Treatment of condyloma acuminata (genital warts)
Patient-applied therapy
transparent gifgrey bulletPodofilox 0.5% solution or 0.5% gel - apply to all lesions bid x 3 consecutive days, followed by 4 days of no therapy, repeat weekly for up to 4 cycles (BIII); or
transparent gif
transparent gifgrey bulletImiquimod 5% cream - apply to lesion at bedtime and remove in the morning on 3 nonconsecutive nights weekly for up to 16 weeks. Each treatment should be washed with soap and water 6-10 hours after application (BII)
transparent gif
Provider-applied therapy
transparent gifgrey bulletCryotherapy (liquid nitrogen or cryoprobe) -- apply until each lesion is thoroughly frozen; repeat every 1-2 weeks. Some providers allow the lesion to thaw, then freeze a 2nd time in each session (BIII).
transparent gif
transparent gifgrey bulletTrichloroacetic acid or bicloroacetic acid cauterization -- 80%-90% aqueous solution, apply to each lesion, repeat weekly for 3-6 weeks (BIII)
transparent gif
transparent gifgrey bulletSurgical excision (BIII) or laser surgery (CIII)
transparent gif
transparent gifgrey bulletPodophyllin resin 10%-25% suspen? sion in tincture of benzoin -- apply to all lesions, then wash off a few hours later, repeat weekly for 3-6 weeks (CIII)
transparent gif

Intralesional interferon-alpha is usually not recommended because of high cost, difficult administration, and potential for systemic side effects (DIII)

The rate of recurrence of genital warts is high, despite treatment

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