Human Papillomavirus: HPV Information for Clinicians

CS110004

• Transmission • Prevention • Detection • Clinical Management

Centers for Disease Control and Prevention April 2007 Contents

Section I: Genital HPV Infection...... 1 About HPV...... 1 Table 1: Types of HPV...... 2 Table 2: Factors Associated with HPV Infection...... 3 HPV Transmission...... 3 HPV Natural History...... 4 HPV-associated Outcomes...... 7 HPV Prevention...... 9 HPV Detection...... 13

Section II: Cervical Cancer Prevention...... 15 Table 3: Cervical Cancer Screening Guidelines...... 16 Screening with Cervical Cytology...... 18 HPV Testing for High-Risk Types...... 19 Cervical Cancer Screening Management Algorithms.....20

Section III: Genital Warts...... 23 Diagnosis...... 23 Treatment...... 24 Table 4: Recommended Treatment...... 24 Special Considerations for Women...... 25

Section IV: References...... 26 HPV Infection Section I: Genital HPV Infection that infects humans is called Why is it human papillomavirus, or HPV. HPV commonly causes epithelial Important proliferations at cutaneous and to Know mucosal surfaces. About HPV? Types of HPV There are more than 100 different Genital infection with human types of HPV. They differ in terms papillomavirus (HPV) is the most of the types of epithelium they common sexually transmitted infect. Some infect cutaneous infection (STI) in the United sites, whereas others infect States (U.S.) today.1 Over half of mucosal surfaces. sexually active women and men Over 40 types infect mucosal are infected with HPV at some surfaces, including the anogenital point in their lives.2 epithelium (e.g., cervix, vagina, In most cases, infections with vulva, rectum, urethra, penis, HPV are not serious. Most HPV and anus). For most of these infections are asymptomatic, HPV types, there are sufficient transient, and resolve without data to divide them into treatment. However, in some “high-risk” (e.g., oncogenic or individuals, HPV infections cancer-associated) types and result in genital warts, Pap test “low-risk” (e.g., non-oncogenic) abnormalities, or, rarely, cervical types (see Table 1 on page 2). cancer.3 How Common is HPV? The Pap test is useful in early detection of cervical cancer, one Approximately 20 million of the possible outcomes of an Americans 15 to 49 years of HPV infection. Early detection age (approximately 15% of the and treatment of pre-cancerous population) are currently infected lesions can prevent development with HPV.5 Others may have been of cervical cancer.4 infected in the past and may no longer have the virus. About What is HPV? half of those who are infected with HPV are sexually active Papillomaviruses are DNA tumor adolescents and young adults 15 viruses that are widely distributed to 24 years of age.5 Between 5% throughout animal species; and 30% of individuals infected these viruses are species- with HPV are infected with specific. The papillomavirus multiple types of HPV.6

PB • Each year, about 6.2 million caused by low-risk types of people in the U.S. become HPV are imprecise. About 1% newly infected.1 of sexually active adults have visible genital warts at any • Estimates for the incidence point in time.7 and prevalence of genital warts

Table 1: Types of HPV

High-risk Low-risk (oncogenic or cancer-associated) (non-oncogenic) types types

Common types: Common types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 6, 11, 40, 42, 43, 59, 68, 82 44, 54, 61, 72, 73, 81

These are considered high-risk because These can cause they can be found in association with benign or low- invasive cancers of the cervix, vulva, grade cervical cell penis, or anus (as well as other sites). changes and genital warts but are rarely, • HPV 16 is the most common high-risk if ever, found in type, found in almost half of all cervical association with cancers. It is also one of the most invasive cancers. common types found in women without cancer.8 • HPV 6 and HPV 11 are the • HPV 18 is another common high-risk low-risk viruses virus, found not only in squamous that are most lesions but also in glandular lesions of commonly found the cervix. HPV 18 accounts for 10% in genital warts.8 to 12% of cervical cancers.8 All of the other high-risk types can be associated with cervical cancer, but much less frequently than HPV 16 and 18. HPV types 31, 33, 45, 52, and 58 each account for between 2% to 4% of cancers. Each of the other high-risk types account for 1% or less of cancers.9

HPV Infection

Table 2: Factors Strongly Associated with Acquisition of HPV Infection in Women2, 10, 11, 12 A number of prospective studies conducted primarily in young women have defined the risk factors for HPV acquisition. • Young age (less than 25 years) • Increasing number of sex partners • Early age at first sexual intercourse (16 years or younger) • Male partner has (or has had) multiple sex partners

proportionately linked to the How is risk of HPV infection.10, 11, 13 Genital HPV Having sex with a new partner may be a stronger risk factor Transmitted? for initial HPV acquisition than having sex with a steady partner.13, 16 HPV is usually transmitted through direct skin-to-skin For women, the sexual activity of contact, most often during their partner(s) is also important penetrative genital contact for determining risk of HPV (vaginal or anal sex). Other acquisition. For adolescent types of genital contact in females and college students, the absence of penetration the risk of acquiring HPV is (oral-genital, manual-genital, increased if a woman’s partner and genital-genital contact) has had or currently has other can lead to HPV infection, but partners.16 those routes of transmission are much less common than HPV infections are also common sexual intercourse.13 in men who have sex with men (MSM) and women who have sex Genital HPV infections are with women.17 HPV DNA can be uncommon in women reporting detected in swabs from the anal no previous sexual intercourse, canal in over 50% of MSM.18 appearing in less than 2% of this population.13, 14, 15 HPV infection can be detected on inanimate objects, such Sexual behavior is the most as clothing or environmental constant predictor of acquiring surfaces. However, transmission infection. Most importantly, is not known to occur by the number of sex partners is this route.19, 20 duration of new infections is Natural typically eight months.10 History of HPV 16 infections tend to persist longer than infection with other Genital HPV HPV types, but most HPV 16 infections become undetectable Infections within two years.10 The gradual development of Most genital HPV infections are an effective immune response transient and asymptomatic. is thought to be the likely Approximately 70% of women mechanism for HPV DNA 4 with HPV infections become clearance. However, it is also HPV DNA negative within possible that the virus remains in one year, and as many as a non-detectable dormant state 91% of them become HPV and then reactivates many years DNA negative within two later. This may explain why HPV years.10, 16, 21, 22 The median may be newly detected in some

The Three Steps of Cervical Carcinogenesis

Transient Infection Persistent HPV Infection

Mild cytologic HPV abnormalities

Initial infection

Progression Normal HPV-infectied Pre-cancerous cervix cervix lesion Cancer Clearance Regression Invasion 1 2 3 The steps can be conceptualized as infection with specific high-risk types of human papillomavirus (HPV), progression to a precancerous lesion, and invasion. HPV infections are usually transient and are often associated with mild cytologic abnormalities. Persistent infection with high-risk types of HPV is uncommon and is required for progression.

Reprinted from “Adding a test for human papillomavirus DNA to cervical-cancer screening.” Wright TC and Schiffman M. New England Journal of Medicine 2003 Feb 6; 348(6): 489-490. Copyright 2003 Massachusetts Medical Society. All rights reserved.

HPV Infection

older women who have been in a long-term mutually monogamous relationship.1 Many women with transient HPV infections may develop atypical squamous cells of undetermined significance (ASC-US) or low- grade squamous intraepithelial lesions (LSIL), as detected on a Pap test. These are mild cytologic abnormalities that represent the cytopathic effect caused by HPV infection, and they may spontaneously regress. Only about 10% of women infected with HPV develop persistent HPV infections.23 Women with persistent high-risk HPV infection are at greatest risk for developing high-grade cervical cancer precursors and cancer. The risk of developing moderate to severe dysplasia, or grades 2 or 3 cervical intraepithelial neoplasia (CIN 2, 3) lesions, for women with persistent high-risk HPV infection is not well defined. However, the risk is greater than that of Top: The epithelium of the CIN 1 lesion is thickened and the upper layers contain women whose infections clear cells characterized by perinuclear halos, spontaneously.24, 25 multinucleation, and significant nuclear atypia. Such cells are referred to as “koilocytes.” Currently, there are no data Bottom: This high-powered magnification of available on the natural history a CIN 1 lesion shows the nuclear irregularities of HPV infection in men. typically seen in “koilocytes.”

Factors Influencing Cigarette smoking has been HPV Persistence associated with HPV persistence and risk of cervical cancer. and Progression to Multiple case-control studies Cervical Cancer show a moderate and statistically significant association between Several risk factors have been smoking and cervical cancer, identified that appear to be even after adjusting for the associated with HPV persistence effects of HPV.27 as well as progression to cervical cancer. The single most Other epidemiologic factors important factor associated associated with risk of cervical with invasive cervical cancer cancer include long-term is the factor of never or rarely use of oral contraceptives,27 being screened for cervical co-infections such as cancer. The National Institutes Chlamydia,28 parity, and of Health (NIH) estimates that nutritional factors.29, 30, 31, 32 half of the women who receive cervical cancer diagnoses have However, in populations that are never been screened for cervical screened regularly, as is typical cancer and that an additional in the U.S., cervical cancer 10% have not been screened in develops rarely in women, even the previous five years.4 with persistent HPV infection. This is because women with Immunosuppression from any high-grade precursor lesions cause, including HIV infection, are usually identified through is recognized to increase HPV cytologic screening, and the persistence and to be associated development of cancer can with increased risk of invasive be prevented through early cervical cancer.22, 26 detection and treatment.

HPV Infection What are Potential Outcomes Associated with Genital HPV Infection?

Most HPV infections are An exophytic invasive cervical cancer of the cervix. asymptomatic, and they resolve without treatment. However, some infections result in changes comparison, the age-adjusted to the epithelium—or cancer. incidence rates for anal, vulvar, and vaginal cancers were 1.5, Women 2.3, and 0.7 per 100,000 women, respectively.33 Genital infection with low-risk types of HPV is associated with While infection with high- genital warts in women. risk HPV is necessary for the development of cervical cancer, Persistent infection with high- most infections do not result in risk types of HPV is associated cancer. with almost all cervical cancers and many cancers of the vulva, Women with HPV infection vagina, and anal regions. who spontaneously clear their However, the risk for anal, infection and continue to be HPV vulvar, and vaginal cancers is DNA negative appear to be at considerably less than the risk very low risk for subsequently for cervical cancer. developing cervical cancer. In 2002 (most recent year for which data are available), the Men age-adjusted incidence rate* Genital infection with low-risk for invasive cervical cancer in types of HPV is associated with the U.S. was 8.7 per 100,000 genital warts in men. women (12,085 new cases). In Infection with high-risk types of HPV is associated with * The number of new cases of a disease that occur in a population in a given year, a proportion of preinvasive accounting for the age differences squamous lesions of the penis between populations.

(penile intraepithelial neoplasia history of AIN, the reliability of or PIN) and with penile cancer, screening methods, the safety as well as with preinvasive and response to treatments, and squamous lesions of the anus the programmatic considerations (anal intraepithelial neoplasia or that would support this screening AIN) and with anal cancer. approach. Until more data are generated on screening for AIN, Invasive penile cancer is quite this screening approach is not uncommon, especially in recommended.36 circumcised men. In 2002, the age-adjusted incidence rate for penile cancer in the U.S. Children was 0.8 per 100,000 men Very rarely, genital HPV (985 new cases). infections can be transmitted from mother to baby during The age-adjusted incidence delivery.37 Perinatally transmitted rate for anal cancer was 1.2 per infections with low-risk HPV 100,000 men (1,453 new cases). types can result in respiratory However, the risk of anal tract warts in children, a cancer for MSM is significantly condition known as recurrent higher.34, 35 Because of the respiratory papillomatosis (RRP). increased incidence of anal RRP is very rare. Estimates of cancer in MSM, especially the incidence rate for RRP are HIV-infected MSM, some imprecise but range from 0.4 specialists recommend screening to 1.1 cases per 100,000 live for AIN by cytology in this births to women with a history of population. However, there genital warts.38 are limited data on the natural It is unclear whether cesarean delivery prevents RRP in infants and children; thus, cesarean delivery should not be performed solely to prevent HPV infection in the newborn. Cesarean delivery may be indicated for women with genital warts if the pelvic outlet is obstructed or if vaginal delivery would result in excessive bleeding.

Multiple condylomata acuminate on penis. Included with permission from the Cincinnati STD/HIV Prevention Training Center.

HPV Infection

• On June 29, 2006, the Prevention Advisory Committee on Immunization Practices (ACIP) of Genital voted to recommend use of the quadrivalent vaccine in HPV Infection females, ages 9 to 26 years of age. Prevention of genital HPV infection is important in reducing ACIP Recommendations the prevalence of genital warts, for HPV Vaccine abnormal Pap tests, and cancer. The vaccine should be administered to 11- to HPV Vaccines 12-year-old girls and can be Quadrivalent HPV Vaccine administered to girls as young as 9 years of age. The vaccine also • A new quadrivalent vaccine, is recommended for 13- Gardasil®, protects against to 26-year-old females who have four HPV types (6, 11, 16, 18), not yet received or completed which are responsible for 70% the vaccine series. of cervical cancers and 90% of genital warts. • Ideally, the vaccine should be administered before onset • This prophylactic vaccine is of sexual activity. However, made from non-infectious females who are sexually HPV-like particles (or virus- active also may benefit from like particles, VLP); it does not vaccination. Females who contain thimerosal or mercury. already have been infected with one or more HPV type would • The vaccine is administered only get protection from the through a series of three intra- vaccine type(s) they have muscular injections over a not acquired. six-month period (at 0, 2, and 6 months). • For more information about the ACIP recommendations, • On June 8, 2006, this vaccine including indications and was licensed by the Food and contraindications for use, see Drug Administration (FDA), MMWR 56(RR02);1-24, or becoming the first licensed www.cdc.gov/mmwr/preview/ vaccine developed to prevent mmwrhtml/rr5602a1.htm. cervical cancer and other diseases in females caused by genital HPV infection.

Vaccine Safety, Efficacy, There is no evidence of waning and Duration of Protection immunity during that time period. • In studies of over 11,000 females (9 to 26 years of age), HPV Vaccine Cost and Coverage the vaccine has been found • The private-sector list price of to be safe and to cause no the vaccine is $119.75 per dose serious side effects. Adverse (about $360 for the full series). events were mainly mild injection site pain. • The federal Vaccines for Children (VFC) Program will • Clinical trials have provide free vaccines to demonstrated 100% efficacy in children and adolescents preventing cervical precancers under 19 years of age who are caused by the targeted HPV uninsured, Medicaid-eligible, types and nearly 100% efficacy American Indian, or Alaska in preventing vulvar and vaginal Native. The VFC Program precancers and genital warts also allows children and caused by the targeted HPV adolescents to receive VFC types among women ages 16 to vaccines through Federally 26 years, who were naive to the Qualified Health Centers or specific HPV vaccine types.39 Rural Health Centers, if their private health insurance does • Data do not indicate that the not cover the vaccine. vaccine has any therapeutic effect on HPV infection or HPV- • Some states also provide associated disease, including free or low-cost vaccines existing Pap test abnormalities at public health department or genital warts. clinics to people without health insurance coverage for • While it is possible that vaccines. vaccination of males with the quadrivalent vaccine may offer • While some insurance direct health benefits to males companies may cover and indirect health benefits to the vaccine and cost of females, there are currently administration, others may not. no efficacy data available to Most large group insurance support use of HPV vaccine plans usually cover the cost in males. Efficacy studies in of recommended vaccines. males are ongoing. However, there is often a short lag-time after a vaccine is • The duration of vaccine recommended and before protection is unclear.40 Current it is available and covered by studies (with five-year followup) health plans. indicate that the vaccine is effective for at least five years.

10 11 HPV Infection

Although this vaccine offers Counseling messages for a promising new approach prospective vaccine recipients to the prevention of HPV and are provided in an insert at the associated conditions, this end of this booklet. vaccine will not replace other prevention strategies, such as Other Vaccines in cervical cancer screening or Development protective sexual behaviors, • A bivalent HPV vaccine was because the vaccine will submitted to FDA in March not protect against all types 2007 and may be licensed in 41 of genital HPV infection. the next year. This vaccine Cervical cancer screening would protect against the two recommendations have not types of HPV (16, 18) that changed for females who receive cause 70% of cervical cancers. the HPV vaccine. • Therapeutic HPV vaccines— vaccines that prevent Vaccine providers should notify development of pre-cancerous vaccinated females that: cells in women already infected with HPV—are not as far along • They will need regular in clinical trials. cervical cancer screening as the vaccine will not provide For updates on HPV protection against all types of vaccines, please visit: HPV that cause cervical cancer. Centers for Disease Control • They should practice protective and Prevention (CDC) Division of sexual behaviors (e.g., STD Prevention’s HPV website, abstinence, monogamy, limiting www.cdc.gov/std/hpv their number of sex partners, CDC’s National Immunization and using condoms), as the Program website, vaccine will not prevent all www.cdc.gov/nip cases of genital warts—nor will it prevent other STIs. ACIP’s website, www.cdc.gov/nip/ACIP • They may not receive the full benefits of the vaccine if they VFC website, receive the vaccine after they www.cdc.gov/nip/vfc have become sexually active (and may have acquired a vaccine HPV type) or if they do not complete the full vaccine series.

10 11 Other Strategies to • It is unclear what proportion Prevent HPV Infection of HPV-infected persons who spontaneously become Other strategies to prevent HPV DNA negative truly clear HPV transmission may include HPV, and in what proportion (a) reducing the duration of of such individuals HPV infectiousness, (b) decreasing simply becomes dormant or the efficiency (likelihood) of undetectable. transmission, and (c) reducing the number of sex partners. (b) Decrease the Efficiency of Transmission (a) Reduce the Duration of Infectiousness The most common approach to decreasing the efficiency The most common approach to of transmission of an STI is reducing infectiousness of an STI to use physical barriers, is treatment. However, there is such as condoms. no effective systemic treatment for genital HPV, and treatment is As reported in CDC’s Sexually not recommended for subclinical Transmitted Diseases (STD) 36 genital HPV infection (diagnosed Treatment Guidelines, 2006: by colposcopy, biopsy, or acetic • Condom use might reduce acid application or detected by the risk for HPV-associated laboratory tests) in the absence diseases (e.g., genital warts and of squamous intraepithelial cervical cancer44) and mitigate 36 lesions (SIL). There is minimal the adverse consequences of evidence that treatment of HPV- infection with HPV. The use of associated lesions can prevent condoms has been associated HPV transmission. with higher rates of regression • Treatment for genital HPV may of CIN and clearance of HPV 45 be applied to lesions, such infection in women and with as genital warts (see Genital regression of HPV-associated 46 Warts section, page 23), or penile lesions in men. cervical cancer precursors • A limited number of (using treatments, such as prospective studies have cryotherapy, electrocautery, demonstrated a protective 42 or surgical excision). effect of condoms on the • Some evidence suggests that acquisition of genital HPV. treatment of genital warts One recent prospective study reduces the amount of HPV among newly sexually active DNA that can be found in the college women demonstrated tissue. However, it is unknown that consistent condom use whether treatment reduces infectivity of partners.41, 43

12 13 HPV Infection

was associated with a 70% less likely to be HPV-infected reduction in risk for HPV (e.g., a partner with no or transmission.47 few previous sex partners) may help reduce the risk of • However, HPV infection can acquiring genital HPV.13 occur in areas that are not covered or protected by a condom (e.g., scrotum, vulva, or perianus). (c) Reduce the Number of Detection of Sex Partners Genital HPV • The surest way to prevent HPV infection is to abstain from any Infection genital contact, including non- penetrative intimate contact of the genital area.13 HPV DNA Test • For those who choose to be Molecular tests can be used to sexually active, long-term detect HPV DNA. The only such mutual monogamy with a test that is currently approved single uninfected partner is by the FDA is Digene’s Hybrid ® likely to be the next most Capture II HPV Test, a solution effective approach to prevent hybridization method to test for infection.48 However, it is high-risk HPV DNA. Samples usually impossible to determine that can be tested with this whether a partner who was technology include exfoliated sexually active in the past is cervical cells collected with a currently infected with HPV, specially designed brush and as most infected people placed into a liquid medium are asymptomatic and have or in residual fluid left over never had evidence of HPV- from liquid-based cytology related conditions, such as specimens. This HPV DNA test genital warts or Pap test is designed to detect high-risk abnormalities.2 types of HPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, • For those choosing to be 59, and 68). The HPV DNA test sexually active, but who are detects whether one or more not in long-term mutually types of HPV are present; it does monogamous relationships, not identify individual HPV types. reducing the number of sex partners is another effective The FDA has approved this strategy to avoid acquisition high-risk HPV DNA assay for of genital HPV infection. use in some women in the Choosing a partner who is context of cervical cancer

12 13 screening (see FDA-Approved HPV DNA testing should not Indications for High-Risk HPV be used: DNA section, page 19). The principal utility of the test is in • for men; identifying women with high-risk • to check the HPV status of HPV who are at risk for having patients with genital warts or or developing pre-cancerous or other STIs; cancerous changes (CIN 2, 3 lesion) in the 36 months following • to check the HPV status of initial testing. partners of patients with genital warts or other STIs; Another test is available to detect • to check the HPV status of low-risk types of HPV, but this partners of women with cervical test is not FDA-approved and cancer abnormalities; or there are no clinical indications for this test.1, 28, 29, 49 • to check the HPV status of pregnant women.

Direct-to-consumer advertising Other HPV Tests may prompt demand for the HPV test. However, while patients There are no routine methods may request an HPV test, use for culturing HPV. Serology tests of this test should be limited are available for HPV, but these to the uses recommended by tests are used only in research professional organizations (see settings. Many persons with FDA-Approved Indications for detectable HPV DNA do not have High-Risk HPV DNA Testing, antibodies, so these tests are page 19). not a good method to indicate infection with HPV.50

There is currently no FDA- approved HPV DNA test for Although primary prevention males, nor is HPV testing of and detection are generally males recommended. There is no clinical objectives for STI care, clinical utility in testing men for HPV infection offers unique HPV; infection does not indicate challenges. Infection is both increased risk of disease for the very common in sexually active man or his partner. While HPV is individuals, and it is generally common in men, HPV-associated asymptomatic. The ubiquitous cancers are rare. nature of the virus, coupled with a relative rarity of clinical signs and symptoms, suggests focusing on the detection, prevention, and treatment of the potential consequences of HPV infection. 14 15 Section II: Prevention of Cervical Cancer

Cervical cancer once claimed 70% of cervical cancer cases the lives of more American through primary prevention. women than any other type However, regular cervical cancer of cancer. But over the last screening will still be necessary Cervical Cancer Prevention 40 years, widespread cervical for vaccinated women because: cancer screening using the Pap test and treatment 1. The vaccine will NOT provide of pre-cancerous cervical protection against all types abnormalities have resulted of HPV that cause cervical in a marked reduction in the cancer. incidence of and mortality due 2. Women may not receive the to cervical cancer in the U.S.3 full benefits of the vaccine The American Cancer Society if they do not complete the (ACS) estimates that in 2006, vaccine series. approximately 9,710 cases of invasive cervical cancer will be 3. Women may not receive the diagnosed, and 3,700 women full benefits of the vaccine if will die from this disease in they receive the vaccine after the U.S. they have already acquired a vaccine HPV type. The advent of an HPV vaccine (see HPV Vaccines, page 9) now Key Public Health offers an additional, promising method of preventing up to Message Approximately half of all cervical cancers occur in women who have never been screened.31 Therefore, screening is particularly important in women who have never or rarely been screened.

The following section focuses on secondary prevention of cervical cancer through cytology and HPV DNA testing. For an overview of primary An exophytic invasive cervical cancer of the cervix is present. When cancers are not prevention through vaccines, necrotic they can sometimes be mistaken for a please see the HPV Prevention large cervical condyloma. section on page 9. 14 15 Table 3: Cervical Cancer Screening Guidelines

When to start Approximately 3 years after Within 3 years of onset of Approximately 3 years after onset of vaginal intercourse, sexual activity or age 21, onset of sexual intercourse, but no later than age 21 whichever comes first but no later than age 21

Intervals • Conventional Pap test • Annually; every 2-3 years for • At least every 3 years • Annually; every 2-3 years for women ≥30 with 3 negative women ≥30 with 3 negative cytology tests* cytology tests*

• If liquid-based cytology used** • Every 2 years; every 2-3 years • Insufficient evidence • Annually; every 2-3 years for for women ≥30 with 3 negative women ≥30 with 3 negative cytology tests* cytology tests*

• If HPV testing used** • Every 3 years if HPV negative, • Insufficient evidence • Every 3 years if HPV negative, cytology negative cytology negative

When to stop Women >70 years with >3 Women >65 years with negative Inconclusive evidence to recent, consecutive negative tests, who are not otherwise at establish upper age limit tests & no abnormal tests in high risk for cervical cancer prior 10 years*

Post total hysterectomy Discontinue if for benign reasons Discontinue if for benign reasons Discontinue if for benign reasons & no prior history of high-grade & no prior history of high-grade CIN* CIN*

* Some exceptions apply (e.g., women who are immunocompromised, have a history of prenatal exposure to DES). See guidelines for details. ** See Table 2 at www.cdc.gov/std/hpv/screening (entitled, “Recommendations for Liquid-Based Cytology and HPV Testing”) for recommended use.

16 17 Table 3: Cervical Cancer Screening Guidelines

American Cancer Society1 U.S. Preventive American College www.cancer.org Services Task Force2 of Obstetricians and (ACS, Nov 2002) www.ahrq.gov/clinic/uspstfix.htm Gynecologists3 (USPSTF, Jan 2003) www.acog.org (ACOG, Aug 2003) Cervical Cancer Prevention When to start Approximately 3 years after Within 3 years of onset of Approximately 3 years after onset of vaginal intercourse, sexual activity or age 21, onset of sexual intercourse, but no later than age 21 whichever comes first but no later than age 21

• If HPV testing used** • Every 3 years if HPV negative, • Insufficient evidence • Every 3 years if HPV negative, cytology negative cytology negative

1. Saslow D, et al. American Cancer Society Guideline for the Early Detection of Cervical Neoplasia and Cancer. CA Cancer J Clin 2002; 52: 342-362. Available at http://caonline.amcancersoc.org/cgi/content/full/52/6/342 2. USPSTF. Screening for Cervical Cancer. Jan 2003. Available at: http://www.ahcpr. gov/clinic/uspstf/uspscerv.htm 3. ACOG. Cervical Cytology Screening. ACOG Practice Bulletin No. 45. ACOG 2003;102: 417-427. See also: http://www.acog.org/from_home/publications/press_ releases/nr07-31-03-1.cfm

16 17 Screening with Cervical Cytology

The purpose of cervical cancer screening is to identify cervical cancer precursors that can be treated before they progress to cervical cancer. There are three major professional organizations that issue cervical cancer screening guidelines: the U.S. Preventive Services Task Force† (USPSTF); the American College of Obstetricians and Gynecologists (ACOG); and the ACS. Their screening recommendations are summarized in Table 3 on page 16. Both conventional Pap tests (smear and slide) and a new liquid-based cytology Top: There is a cluster of cells with enlarged, hyperchromatic nuclei present. Several (a method in which cervical binucleated cells are present in this cluster. cells are collected into a liquid However, very few atypical cells were present on medium) can be used to screen slide and although the cells are suggestive of SIL, for cervical cancer. they are not diagnostic of SIL. Bottom: This cervix has a well-circumscribed • The sensitivity of the area of acetowhitening that appears low-grade. conventional Pap test ranges However, cervical biopsy was diagnosed as CIN 2,3. from 30% to 87%, and the specificity ranges from 86% to 100%53 † The U.S. Preventive Services Task Force is • The sensitivity of liquid-based an independent panel of experts in primary cytology ranges from 61% to care and prevention that systematically reviews the evidence of effectiveness and 95%, and the specificity ranges develops recommendations for clinical from 78% to 82%52, 53 preventive services.

18 19 Cervical Cancer Prevention 19 55

), ACS, ACS, ), 56 If the woman is found to be be to found is woman the If repeat negative, DNA HPV months. 12 in cytology If the woman is found to to found is woman the If refer positive, DNA HPV be colposcopy. to www.asccp.org/index.html found USPSTF The ACOG. and last its in insufficient evidence the for recommend to (2003) review DNA HPV of use the against or setting. this in testing Women with ASC-US Women abnormalities cytologic Borderline quite are ASC-US as to referred Approximately U.S. the in common cytology cervical all of 5% to 4% ASC-US. as reported are results the in test DNA HPV the of Use with women of management is results test Pap ASC-US the by option an as recommended Colposcopy for Society American (ASCCP, Pathology Cervical and Use of HPV DNA DNA of HPV Use in Managing Testing According to ACOG, ACS, and and ACS, ACOG, to According guidelines: ASCCP • • Management of Women Management of Women with ASC-US Using HPV DNA Testing

54 This test test This

0 and older (e.g., use in in use (e.g., older and 0

Routine adjunctive screening screening adjunctive Routine prevalence of cervical cancer cancer cervical of prevalence to compared low, relatively is women. older infection is highly prevalent prevalent highly is infection women in transient usually and the while ages, younger at use with cervical cytology cytology cervical with use younger women in screening HPV because 30 age than conjunction with a Pap Pap a with conjunction screening). primary for test for approved not is test This with cervical cytology cytology cervical with ages women for screening 3 Use in the management of of management the in Use followed up with cytological cytological with up followed months. 12 in screening which women (of any age) age) any (of women which cytology cervical ASC-US with for referred be should results be can which and colposcopy women with ASC-US cervical cervical ASC-US with women results. cytology determine help to used be can screening and management. management. and screening commercially available and and available commercially in women in use for approved cancer cervical of setting the High-Risk Types Types High-Risk is test DNA HPV high-risk A Testing for for Testing HPV DNA DNA HPV • • Testing is approved for: approved is Testing • FDA-Approved FDA-Approved High-Risk for Indications Testing DNA HPV 18 Management of Women with Atypical Squamous Cells of Undetermined Signiﬁ cance (ASC-US)

HPV DNA Testing Preferred if liquid-based cytology or co-collection available

HPV Positive HPV Negative (for high-risk types) (for high-risk types)

Repeat Cytology Colposcopy @ 12 months

Manage per No CIN/Cancer CIN/Cancer ASCCP Guideline

Cytology @ 6 & 12 mos ≥ ASC or HPV (+) Repeat Colposcopy OR HPV DNA testing Negative Routine Screening @ 12 mos

Reprinted from The Journal of Lower Genital Tract Disease Vol. 6 Issue 2 with the permission of the ASCCP© American Society for Colposcopy and Cervical Pathology 2002.

Management of Women Ages 30 and Older, Based on Cytology and HPV DNA Testing Results

Cytology Cytology Cytology Cytology Cytology > negative negative ASC-US ASC-US ASC-US HPV negative HPV positive HPV negative HPV Positive any HPV result

Routine Repeat both Repeat Screening at tests at Cytology at Colposcopy Colposcopy 3 years 6 - 12 months 12 months

Both Cytology Cytology > Any cytology negative ASC-US ASC-US result HPV negative HPV negative HPV positive

Routine Rescreen with Colposcopy Colposcopy screening cytology and at 3 years HPV at 12 months

Reprinted from “Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening.” Wright TC, Schiffman M, Solomon D, et al. Obstetrics and Gynecology 2004; 103(2): 304-309 ﬁ g. 1.

These algorithms can also be found as tear-outs at the end of this booklet. 20 High-risk HPV DNA testing may be a practical approach to Patient Followup Based managing women with ASC-US on Cytology and HPV whenever liquid-based cytology is used for screening or when DNA Testing co-collection of a sample According to ACS and ACOG for HPV DNA testing can be guidelines: performed. This is because HPV DNA testing may be more • Women with negative results Cervical Cancer Prevention convenient for patients than their on both tests should not be returning for a repeat cytology; re-screened for at least three approximately half of women years. with ASC-US will be high-risk HPV DNA negative and will not • Women who are HPV DNA require colposcopy.57 HPV DNA positive, but cytology negative, testing in this setting has been should not be referred for shown to be more cost-effective colposcopy. Instead, they than the other management should be re-tested with both strategies.54, 58 tests in 6 to 12 months.

Use of HPV DNA Testing for Routine Re-screening for women found Adjunctive Screening to be both cytology negative and high-risk HPV DNA negative can with a Pap Test for be done at three years.54 This is Women Age 30 and because women with negative Older52 results by both cytology and HPV DNA testing have a very low The combination of molecular risk of having a CIN 3 lesion or testing for high-risk types of of developing a CIN 3 over the HPV together with a Pap test next three years.54, 61, 62, 63 The is considered by the ACS and extended testing interval of three ACOG to be an acceptable years in women who are both approach to cervical cancer cytology negative and HPV DNA screening of women age 30 negative is a benefit of HPV DNA 54, 59, 60 and older. However, the testing. USPSTF found the evidence insufficient to recommend for Please see the 2001 Consensus or against the routine use of Guidelines for Managing Women HPV DNA testing as a primary with Cytological Abnormalities screening test for cervical and Interim Guidance for Use cancer.58 of HPV DNA Testing as an Adjunct to Cervical Cytology for Screening for more information.54, 55

20 21 HPV DNA testing should test to conventional cytology not be used: increased the sensitivity to 87% to 100%). • in women <30 years of age with any Pap test result other • The specificity of a single than ASC-US; Pap test ranged from 87% to 98%. Adding the HPV DNA • as an adjunct to Pap for test to conventional cytology primary screening of women decreased the specificity to <30 years of age; 69% to 95%. • as an adjunct to Pap for women who are immuno– Published studies have found compromised for any reason, that colposcopy is more sensitive including infection with HIV; than HPV DNA testing or repeat and cytology for detection of cervical cancer precursor lesions; HPV • as an adjunct to Pap for DNA testing is more sensitive women who have had total than repeat cytology.57, 64 hysterectomy for benign gynecologic disease. Other Uses of HPV DNA Remember: Testing for High-Risk Types • Women who are HPV DNA One professional organization negative and cytology negative also recommends use of the are at very low risk for having HPV DNA test for followup CIN 2, 3 or for developing it of cervical abnormalities within the next three years and (www.asccp.org); however there can be re-screened at three is no FDA-approved indication years. for this use. • The risk that women who Performance of HPV DNA are HPV DNA positive, but Testing Combined with cytology negative, will have Cytology for Women Over CIN 2, 3 or cancer is very low. 30 Years of Age Therefore, colposcopy should not be performed routinely in In international cross-sectional this circumstance. HPV DNA studies that examined both testing along with cervical cytology and the HPV DNA test cytology should be repeated 54 result: at 6 to 12 months. If the • The sensitivity of a single Pap woman is persistently high-risk test for identifying CIN 2, 3 or HPV DNA positive, then she cancer ranged from 33% to should receive a colposcopic 94% (adding the HPV DNA examination.

22 23 The use of the HPV DNA test among women (58%), it is may introduce new psychological unclear whether knowledge of its and interpersonal components association with cervical cancer to cervical cancer screening is increasing.67 and management. Women may experience anxiety, distress, fear, Qualitative surveys indicate that anger, and guilt in response to women want more information an HPV diagnosis.65 Providers about HPV, specifically with should provide patients respect to transmission, information and counseling when prevention, progression, and administering the test and when treatment, as well as risk of 3 delivering HPV DNA test results. cancer. Counseling messages for women The provision of patient receiving the HPV DNA test with information and counseling Pap for cervical cancer screening must be considered both when are provided in an insert at the administering the HPV DNA end of this booklet. test and when delivering test results. The manner in which this information is communicated Counseling Women to patients can influence the Infected with psychological effect of this Genital HPV diagnosis, as well as a woman’s likelihood of following Genital Warts According to a national survey up with necessary testing or conducted in 2005, less than treatment.68, 69, 70 half of American women had heard of HPV, and only 23% of Counseling messages for women were able to identify HPV patients with a high-risk HPV as the primary cause of cervical DNA test result are included in an cancer.66 While HPV awareness insert at the end of this booklet. levels seem to be increasing

Section III: Genital Warts

Diagnosis

• Diagnosis of genital warts is • The use of HPV tests is not made by visual inspection. indicated for the routine diagnosis or management of • A genital warts diagnosis visible genital warts. may be confirmed by biopsy, although biopsy is needed only in certain circumstances. 22 23 Treatment Treatment Regimens • A number of treatment options • If left untreated, genital warts are available for visible genital may resolve on their own, warts. There is no definitive remain unchanged, or increase evidence to suggest that any in size or number. one treatment is superior to others. Factors that may • The effect of treatment on influence the selection of future transmission of HPV treatment include patient infection is unclear. preference; available resources; provider experience; the size, • The primary goal of treating number, anatomic site, and visible genital warts is removal morphology of wart(s); and the for cosmetic reasons. cost, convenience, and adverse • In most patients, treatment effects of treatment. can remove warts. However, • Providers should be recurrences are frequent. knowledgeable about and have • Some patients may forego available at least one patient- treatment as genital warts may applied and one provider- resolve on their own. administered treatment.

Table 4: Recommended Treatment Regimens36 Patient-Applied Treatments Provider-Applied • Podofilox* 0.5% solution Treatments or gel • Cryotherapy • Imiquimod* 5% cream • Podophyllin resin* • Trichloroacetic Acid (TCA) or Bichloroacetic Acid (BCA) 80%–90% • Surgical Removal—by tangential scissor excision, tangential shave excision, curettage, or electrosurgery.

Note: If possible, the health care provider should apply initial treatment to demonstrate the proper application technique and identify which warts should be treated. Follow-up visits may be useful several weeks into therapy to determine appropriateness of medication use and patient response to treatment.

* These treatments should not be used during pregnancy, as their safety during pregnancy has not been established.

24 25 Patients may prefer the privacy Counseling messages for and convenience of patient- patients with genital warts are applied modalities. included in an insert at the end of this booklet. • Many patients require a course of therapy rather than a single treatment. • There is no evidence that the use of more than one therapy Special at a time will improve efficacy. Considerations • The response to treatment and treatment side effects should for Women be evaluated throughout the course of therapy. Treatment • Neither the presence of genital modality should be changed warts nor their treatment is if a patient has not improved associated with the development substantially. of cervical cancer in women. • The use of locally developed Therefore, the presence of and monitored treatment genital warts is not an indication algorithms has been associated for cervical colposcopy or a change in the frequency of Pap

with improved clinical Genital Warts outcomes and is encouraged. tests for women. Please refer to CDC’s Sexually • The presence of genital warts Transmitted Diseases alone is not an indication for Treatment Guidelines, 200636 cesarean delivery in expectant (www.cdc.gov/STD/treatment) women. Cesarean delivery for more information about these may be indicated for women treatments, including safety with genital warts if the pelvic indications, directions for use, outlet is obstructed or if benefits, adverse effects, and vaginal delivery would result in possible complications. excessive bleeding. • Pregnant women with genital Counseling Patients warts should be counseled with Genital Warts about the low risk of warts on the larynx (recurrent respiratory Information and counseling are papillomatosis) in their infants important aspects of managing or children. There are no patients with genital warts. controlled studies suggesting Counseling is most effective if that cesarean delivery prevents provided in a non-judgmental this condition. manner appropriate to the patient’s culture, language, sex, sexual orientation, age, and developmental level. 24 25 Section IV: References

1. Weinstock H, Berman S, Cates 10. Ho GY, Bierman R, Beardsley L, W, Jr. Sexually transmitted diseases et al. Natural history of cervicovaginal among American youth: incidence papillomavirus infection as measured and prevalence estimates, 2000. by repeated DNA testing in Perspect Sex Reprod Health. Jan-Feb adolescent and young women. N Engl 2004;36(1):6-10. J Med. 1998;338(7):423-428. 2. Koutsky LA. Epidemiology of 11. Sellors JW, Karwalajtys TL, genital human papillomavirus Kaczorowski J, et al. Incidence, infection. Am J Med. 1997;102(5A):3- clearance and predictors of human 8. papillomavirus infection in women. CMAJ. Feb 18, 2003;168(4):421-425. 3. Health and Sexuality. Association of Reproductive Health Professionals. 12. Baseman JG, Koutsky LA. Jan 2005;10(1). The epidemiology of human papillomavirus infections. J Clin Virol. 4. National Institutes of Health (NIH). 2005;32(Suppl 1):S16-24. NIH Consensus Statement: Cervical Cancer. 1996;14:1-38. 13. Winer RL, Lee SK, Hughes JP, et al. Genital human papillomavirus 5. Cates W, Jr. Estimates of the infection: incidence and risk factors incidence and prevalence of sexually in a cohort of female university transmitted diseases in the United students. Am J Epidemiol. States. American Social Health 2003;157(3):218-226. Association Panel. Sex Transm Dis. 1999;26(4):Suppl:S2-7. 14. Rylander E, Ruusuvaara L, Almstromer MW. The absence of 6. Revzina NV, Diclemente RJ. vaginal human papillomavirus 16 DNA Prevalence and incidence of human in women who have not experienced papillomavirus infection in women in sexual intercourse. Obstet Gynecol. the USA: a systematic review. Int J 1994;83(5 Pt 1):735-737. STD AIDS. 2005;16(8):528-537. 15. Kjaer S, Chackerian B, van de 7. Koutsky LA, Galloway DA, Holmes Brule A, et al. High-risk human KK. Epidemiology of genital human papillomavirus is sexually transmitted: papillomavirus infection. Epidemiol evidence from a follow-up study Rev. 1988;10:122-163. of virgins starting sexual activity. 8. Bosch FX, de Sanjose S. Chapter Cancer Epidemiol Biomarkers Prev. 1: Human papillomavirus and cervical 2001;10(2):101-106. cancer—burden and assessment of 16. Moscicki AB, Hills N, Shiboski causality. J Natl Cancer Inst Monogr. S, et al. Risks for incident human 2003;3:3-13. papillomavirus infection and low- 9. Clifford GM, Smith JS, Plummer M, grade squamous intraepithelial lesion et al. Human papillomavirus types in development in young females. invasive cervical cancer worldwide: JAMA. 2001;285(23):2995-3002. a meta-analysis. Br J Cancer. 2003;88(1):63-73.

26 27 17. Marrazzo JM, Koutsky LA, of human papillomavirus status to Kiviat NB, et al. Papanicolaou test cervical lesions and consequences screening and prevalence of genital for cervical cancer screening: human papillomavirus among women a prospective study. Lancet. who have sex with women. Am J 1999;354:20-25. Public Health. 2001;91(6):947-952. 26. Palefsky JM, Holly EA. Chapter 6: 18. Chin-Hong PV, Vittinghoff Immunosuppression and co-infection E, Cranston RD, et al. Age- with HIV. J Natl Cancer Inst Monogr. related prevalence of anal cancer 2003;(31):41-46. precursors in homosexual men: the 27. Castellsague X, Munoz N. EXPLORE study. J Natl Cancer Inst. Chapter 3: Cofactors in human 2005;97(12):896-905. papillomavirus carcinogenesis—role 19. Roden RB, Lowy DR, Schiller of parity, oral contraceptives, and JT, et al. Papillomavirus is tobacco smoking. J Natl Cancer Inst resistant to dessication. J Inf Dis. Monogr. 2003;(31):20-28. 1997;176(4):1076-1079. 28. Silins I, Ryd W, Strand A, et al. 20. Czegledy J. Sexual and non- Chlamydia trochomatis infection and sexual transmission of human persistence of human papillomavirus. papillomavirus. Acta Microbiol Int J Cancer. 2005;116(1):110-115. Immunol Hung. 2001;48(3-4):511-17. 29. Richardson H, Abrahamovicz 21. Woodman CB, Collins S, Rollason M, Tellier PP, et al. Modifiable risk TP, et al. Human papillomavirus type factors associated with clearance 18 and rapidly progressing cervical of type-specific cervical human intraepithelial neoplasia. Lancet. papillomavirus infections in a 2003;361(9351):40-43. cohort of university students. Cancer Epidemiol Biomarkers Prev. 22. Sun XW, Kuhn L, Ellerbrock TV, 2005;14(5):1149-1156. et al. Human papillomavirus infection in women infected with the human 30. Sedjo RL, Roe D, Abrahamsen immunodeficiency virus.N Engl J M, et al. Vitamin A, carotenoids, Med. 1997;337(19):1343-1349. and risk of persistent oncogenic human papillomavirus infection. 23. Genital HPV Infection—CDC Cancer Epidemiol Biomarkers Prev. Fact Sheet. Available from: U.S. References 2002;11(9):876-884. Department of Health and Human Services, Centers for Disease Control 31. Hildesheim A, Herrero R, Castle and Prevention, Atlanta, Ga. Available P, et al. HPV co-factors related to at: http://www.cdc.gov/std/HPV/ the development of cervical cancer: STDFact-HPV.htm#cancer. [Accessed results from a population-based July 14, 2005.] study in Costa Rica. Br J Cancer. 2001;84:1219-1226. 24. Schlect NF, Kulaga S, Robitaille J, et al. ��Persistent human papillomavirus 32. Franco EL, Schlecht NF, infection as a predictor of cervical Saslow D. The epidemiology of intraepithelial neoplasia. JAMA. cervical cancer. Cancer J. Sep-Oct 2001;286:3106-3114. 2003;9(5):348-359. 25. Nobbenhuis MA, Walboomers JM, Helmerhorst TJ, et al. Relation

26 27 33. U.S. Cancer Statistics Working phase II efficacy trial.Lancet Oncol. Group. United States Cancer 2005;6(5):271-278. Statistics: 1999–2002 Incidence 40. Villa LL, Ault KA, Giuliano AR, et and Mortality Web-based Report. al. Immunologic responses following Available from: U.S. Department of administration of a vaccine targeting Health and Human Services, Centers human papillomavirus Types 6, 11, for Disease Control and Prevention 16, and 18. Vaccine. 2006, Jul 7, and National Cancer Institute, 2006;24(27-28):5571-5583. Epub May Atlanta, Ga. Available at: www.cdc. 15, 2006. gov/cancer/npcr/uscs. Accessed December 6, 2005. 41. Tyring SK, Arany I , Stanley MA, et al. A randomized, controlled 34. Johnson LG, Madeleine molecular study of condyloma MM, Newcomer LM, et al. Anal acuminata clearance during treatment cancer incidence and survival: the with imiquimod. J Infect Dis. surveillance, epidemiology, and 1998;178(2):551-555. end results experience, 1973-2000. Cancer. 2004;101:281-288. 42. Beutner KR, Reitano MV, Richwald GA, et al. External genital warts: report 35. Daling JR, Madeleine MM, of the American Medical Association Johnson LG, et al. Human Consensus Conference. AMA Expert papillomavirus, smoking, and sexual Panel on External Genital Warts. Clin practices in the etiology of anal Infect Dis. 1998;27(4):796-806. cancer. Cancer. 2004;101:270-280. 43. Wilson J. Treatment of genital 36. Centers for Disease Control and warts—what’s the evidence? Int J Prevention (CDC). 2006. Sexually STD AIDS. 2002;13(4):216-220. Transmitted Diseases Treatment Guidelines. Morbidity and Mortality 44. Manhart LE, Koutsky LA. Do Weekly Report. 2006;55(RR-11). condoms prevent genital HPV Available at: www.cdc.gov/STD/ infection, external genital warts, or treatment/. cervical neoplasia?: A meta-analysis. Sex Trans Dis. 2002;29:725–735. 37. Syrjanen S, Puranen M. Human papillomavirus infections in children: 45. Hogenwoning CJA, Bleeker the potential role of maternal MCG, van den Brule AJC, et al. transmission. Crit Rev Oral Biol Med. Condom use promotes regression of 2000;11(2):259-274. cervical intraepithelial neoplasia and clearance of human papillomavirus: 38. Armstrong LR, Preston EJ, a randomized clinical trial. Int J Reichert M, et al. Incidence and Cancer. 2003;107:811–816. prevalence of recurrent respiratory papillomatosis among children in 46. Bleeker MCG, Hogewoning Atlanta and Seattle. Clin Infect Dis. CJA, Voorhorst FJ, et al. Condom 2000; 31(I):107-109. use promotes regression of human papillomavirus-associated penile 39. Villa LL, Costa RL, Petta CA, et lesions in male sexual partners of al. Prophylactic quadrivalent human women with cervical intraepithelial papillomavirus (types 6, 11, 16, and neoplasia. Int J Cancer. 18) L1 virus-like particle vaccine in 2003;107:804–810. young women: a randomised double- blind placebo-controlled multicentre

28 29 47. Winer R, Hughes JP, Feng Q, et 54. Wright TC, Schiffman M, Solomon al. Consistent condom use from time D, et al. Interim guidance for the use of first vaginal intercourse and the of human papillomavirus DNA testing risk of genital human papillomavirus as an adjunct to cervical cytology infection in young women. N Engl J for screening. Obstet Gynecol. Med. 2006;354:2645–2654. 2004;103:304-309. 48. Ley C, Bauer HM, Reingold 55. Wright TC, Cox JT, Massad LS, et A, et al. Determinants of human al. 2001 Consensus guidelines for the genital papillomavirus infection in management of women with cervical young women. J Natl Cancer Inst. cytological abnormalities. ASCCP- 1991;83(14):997-1003. Sponsored Consensus Conference. JAMA. 2002;287(16):2120-2129. 49. Smith JS, Green J, Berrington de Gonzales A, et al. Cervical cancer 56. U.S. Preventive Services Task and use of hormonal contraceptives: Force. Guide to clinical preventive a systematic review. Lancet. services. 3rd ed. Washington, D.C.: 2003;361(9364):1159-1167. U.S. Department of Health and Human Services; 2003. 50. Gerberding, JL. Report to Congress: Human Papillomavirus: 57. Solomon D, Schiffman M, Tarone Surveillance and Prevention R. For the ASCUS/LSIL Triage Study Research. Aug 2003. Available from: for Cervical Cancer (ALTS) Group. U.S. Department of Health and Comparison of three management Human Services, Centers for Disease strategies for patients with atypical Control and Prevention. Available squamous cells of undetermined at: http://www.cdc.gov/std/HPV/ significance. Baseline results from a 2004HPV%20Report.pdf. randomized trial. J Natl Cancer Inst. 2001;92(12):293-299. 51. Nanda K, McCrory DC, Myers Erea. Accuracy of the Papanicolaou 58. Kim JJ, Wright TC, Goldie SJ. test in screening for and follow-up Cost-effectiveness of alternative triage of cervical cytologic abnormalities: a strategies for atypical squamous cells systematic review. Ann Intern Med. of undetermined significance.JAMA . 2000;132:810-819. 2002;287:2382-2390. 52. Belinson J, Qiao YL, Pretorius 59. Cervical Cytology Screening: References Rea. Shanxi�� province cervical Testing Can Start Later and Occur cancer screening study: a cross- Less Often Under New ACOG sectional comparative trial of Recommendations. Available from: multiple techniques to detect American College of Obstetricians cervical neoplasia. Gynecol Oncol. and Gynecologists. ACOG Prac. 2001;83:439-444. Bul. 2003;45,102:417-427. 2005; 61. Available at: http://www.acog. 53. Kulasingam SL, Hughes JP, org/from_home/publications/press_ Kiviat NB, et al. Evaluation of human releases/nr07-31-03-1.cfm. papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288(14):1749-1757.

28 29 60. Saslow D, Runowicz CD, 66. Association of Reproductive Solomon D, et al. American Cancer Health Professionals. HPV Survey Society guideline for the early Executive Summary. Available detection of cervical neoplasia at www.arhp.org/HPVsurvey/ and cancer. CA Cancer J Clin. executivesummary.cfm. [Accessed 2002;52:342-362. October 13, 2006.] 61. Kjaer SK, van den Brule AJ, Paull 67. Harris Interactive Healthcare G, et al. Type specific persistence of Research. Health-Care Poll: Seventy high risk human papillomavirus (HPV) percent of US adults support use as an indicator of high grade cervical of the Human Papillomavirus (HPV) squamous intraepithelial lesions in vaccine. Available at: The Wall Street young women: population based Journal Online. 2006;5(13). http:// prospective follow up study. BMJ. www.harrisinteractive.com|news|news 2002;325(7364):572. letters|wsjhealthnews|WSJOnline_HI_ Health-Care Poll2006vol5_iss13.pdf. 62. Sherman ME, Lorincz AT, Scott [Accessed August 18, 2006.] DR, et al. Baseline cytology, human papillomavirus testing, and risk 68. McCaffery K, Waller J, Forrest for cervical neoplasia: a 10-year S, et al. Testing positive for cohort analysis. J Natl Cancer Inst. human papillomavirus in routine 2003;95:46-52. cervical screening: examination of psychosocial impact. BJOG. 63. Noller KL. Cervical cytology 2004;111(12):1437-1443. screening and evaluation. Obstet Gynecol. 2005;106(2):391-397. 69. Waller J, McCaffery K, Wardle J. Beliefs about the risk factors for 64. Arbyn M, Buntinx F, van Ranst M, cervical cancer in a British population et al. Virologic versus cytologic triage sample. Prev Med. 2004;38(6):745- of women with equivocal Pap smears: 753. a meta-analysis of the accuracy to detect high-grade intraepithelial 70. Waller J, McCaffery K, Nazroo J, neoplasia. J Natl Cancer Inst. et al. Making sense of information 2004;96:280-293. about HPV in cervical screening: a qualitative study. Br J Cancer. 65. McCaffery K, Forrest S, Waller J, 2005;92(2):265-270. et al. Attitudes towards HPV testing: a qualitative study of beliefs among Indian, Pakistani, African-Caribbean and White British women in the UK. Br J Cancer. 2003;88(1):42-46.

30 31 Management of Women with Atypical Squamous Cells of Undetermined Signiﬁ cance (ASC-US)

HPV DNA Testing Preferred if liquid-based cytology or co-collection available

HPV Positive HPV Negative (for high-risk types) (for high-risk types)

Repeat Cytology Colposcopy @ 12 months

Manage per No CIN/Cancer CIN/Cancer ASCCP Guideline

Cytology @ 6 & 12 mos ≥ ASC or HPV (+) Repeat Colposcopy OR HPV DNA testing Negative Routine Screening @ 12 mos

Reprinted from The Journal of Lower Genital Tract Disease Vol. 6 Issue 2 with the permission of the ASCCP© American Society for Colposcopy and Cervical Pathology 2002.

Management of Women Ages 30 and Older, Based on Cytology and HPV DNA Testing Results

Cytology Cytology Cytology Cytology Cytology > negative negative ASC-US ASC-US ASC-US HPV negative HPV positive HPV negative HPV Positive any HPV result

Routine Repeat both Repeat Screening at tests at Cytology at Colposcopy Colposcopy 3 years 6 - 12 months 12 months

Both Cytology Cytology > Any cytology negative ASC-US ASC-US result HPV negative HPV negative HPV positive

Routine Rescreen with Colposcopy Colposcopy screening cytology and at 3 years HPV at 12 months

CCDC_HPV_ClinicBro_v15.inddDC_HPV_ClinicBro_v15.indd 3131 44/2/07/2/07 2:53:572:53:57 PMPM From the Publication: Human Papillomavirus: HPV Information for Clinicians, November 2006

From the Publication: Human Papillomavirus: HPV Information for Clinicians, November 2006 Contents

Section III: Genital Warts...... 23 Diagnosis...... 23 Treatment...... 24 Table 4: Recommended Treatment...... 24 Special Considerations for Women...... 25

Section IV: References...... 26 CS110004

Human Papillomavirus: HPV Information for Clinicians

• Transmission • Prevention • Detection • Clinical Management

Centers for Disease Control and Prevention April 2007