HPV病毒分类、型别（高危、低位）、产生原因、预防、诊断及治疗方式-+CDC+Clinicians.pdf

1!m$n$(illom$,i-./!0 1n2o-m$3ion 2o-4linici$n.6 7-$n.mi.ion6-e,en3ion6 9e3ec3ion6 4linic$l:$n$gemen3Centers for Disease Control and PreventionNovember 20062ContentsSection I:Genital HPV Infection.1About HPV.1Table 1:Types of HPV.2Table 2:Factors Associated with HPV Infection.3HPV Transmission.3HPV Natural History.4HPV-associated Outcomes.7HPV Prevention.9HPV Detection.13Section II:Cervical Cancer Prevention.15Table 3:Cervical Cancer Screening Guidelines.16Screening with Cervical Cytology.18 HPV Testing for High-Risk Types.19Cervical Cancer Screening Management Algorithms.20Section III:Genital Warts.23Diagnosis.23Treatment.24 Table 4:Recommended Treatment.24Special Considerations for Women.25 Section IV:References.261 i.i3 1m(o-3$n3 3o?now Abo3!0CGenital infection with human papillomavirus(HPV)is the most common sexually transmitted infection(STI)in the United States(U.S.)today.1 Over half of sexually active women and men are infected with HPV at some point in their lives.2In most cases,infections with HPV are not serious.Most HPV infections are asymptomatic,transient,and resolve without treatment.However,in some individuals,HPV infections result in genital warts,Pap test abnormalities,or,rarely,cervical cancer.3 The Pap test is useful in early detection of cervical cancer,one of the possible outcomes of an HPV infection.Early detection and treatment of pre-cancerous lesions can prevent development of cervical cancer.4What is HPV?Papillomaviruses are DNA tumor viruses that are widely distributed throughout animal species;these viruses are species-specifi c.The papillomavirus that infects humans is called human papillomavirus,or HPV.HPV commonly causes epithelial proliferations at cutaneous and mucosal surfaces.Types of HPVThere are more than 100 different types of HPV.They differ in terms of the types of epithelium they infect.Some infect cutaneous sites,whereas others infect mucosal surfaces.Over 40 types infect mucosal surfaces,including the anogenital epithelium(e.g.,cervix,vagina,vulva,rectum,urethra,penis,and anus).For most of these HPV types,there are suffi cient data to divide them into“high-risk”(e.g.,oncogenic or cancer-associated)types and“low-risk”(e.g.,non-oncogenic)types(see Table 1 on page 2).How Common is HPV?Approximately 20 million Americans 15 to 49 years of age(approximately 15%of the population)are currently infected with HPV.5 Others may have been infected in the past and may no longer have the virus.About half of those who are infected with HPV are sexually active adolescents and young adults 15 to 24 years of age.5 Between 5%and 30%of individuals infected with HPV are infected with multiple types of HPV.6HPV InfectionDec3ion 1/Eeni3$l!0 1n2ec3ion2 Each year,about 6.2 million people in the U.S.become newly infected.1 Estimates for the incidence and prevalence of genital warts caused by low-risk types of HPV are imprecise.About 1%of sexually active adults have visible genital warts at any point in time.7Table 1:Types of HPVHigh-risk(oncogenic or cancer-associated)types Low-risk(non-oncogenic)types Common types:16,18,31,33,35,39,45,51,52,56,58,59,68,82Common types:6,11,40,42,43,44,54,61,72,73,81These are considered high-risk because they can be found in association with invasive cancers of the cervix,vulva,penis,or anus(as well as other sites).HPV 16 is the most common high-risk type,found in almost half of all cervical cancers.It is also one of the most common types found in women without cancer.8 HPV 18 is another common high-risk virus,found not only in squamous lesions but also in glandular lesions of the cervix.HPV 18 accounts for 10%to 12%of cervical cancers.8All 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.9These can cause benign or low-grade cervical cell changes and genital warts but are rarely,if ever,found in association with invasive cancers.HPV 6 and HPV 11 are the low-risk viruses that are most commonly found in genital warts.83!ow i.Eeni3$l!0 7-$n.mi33edCHPV is usually transmitted through direct skin-to-skin contact,most often during penetrative genital contact(vaginal or anal sex).Other types of genital contact in the absence of penetration(oral-genital,manual-genital,and genital-genital contact)can lead to HPV infection,but those routes of transmission are much less common than sexual intercourse.13 Genital HPV infections are uncommon in women reporting no previous sexual intercourse,appearing in less than 2%of this population.13,14,15Sexual behavior is the most constant predictor of acquiring infection.Most importantly,the number of sex partners is proportionately linked to the risk of HPV infection.10,11,13Having sex with a new partner may be a stronger risk factor for initial HPV acquisition than having sex with a steady partner.13,16For women,the sexual activity of their partner(s)is also important for determining risk of HPV acquisition.For adolescent females and college students,the risk of acquiring HPV is increased if a womans partner has had or currently has other partners.16HPV infections are also common in men who have sex with men(MSM)and women who have sex with women.17 HPV DNA can be detected in swabs from the anal canal in over 50%of MSM.18HPV infection can be detected on inanimate objects,such as clothing or environmental surfaces.However,transmission is not known to occur by this route.19,20Table 2:Factors Strongly Associated with Acquisition of HPV Infection in Women2,10,11,12A number of prospective studies conducted primarily in young women have defi ned the risk factors for HPV acquisition.Young age(less than 25 years)Increasing number of sex partners Early age at fi rst sexual intercourse(16 years or younger)Male partner has(or has had)multiple sex partnersHPV Infection4G$3-$l!i.3o-o2 Eeni3$l!0 1n2ec3ion.Most genital HPV infections are transient and asymptomatic.Approximately 70%of women with HPV infections become HPV DNA negative within one year,and as many as 91%of them become HPV DNA negative within two years.10,16,21,22 The median duration of new infections is typically eight months.10 HPV 16 infections tend to persist longer than infection with other HPV types,but most HPV 16 infections become undetectable within two years.10The gradual development of an effective immune response is thought to be the likely mechanism for HPV DNA clearance.4 However,it is also possible that the virus remains in a non-detectable dormant state and then reactivates many years later.This may explain why HPV may be newly detected in some ClearanceHPVMild cytologic abnormalitiesNormal cervixHPV-infectied cervixInitial infectionPre-cancerous lesionCancerInvasionThe steps can be conceptualized as infection with specifi c 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.Transient InfectionPersistent HPV InfectionThe Three Steps of Cervical Carcinogenesis123ProgressionRegression5older women who have been in a long-term mutually monogamous relationship.1Many women with transient HPV infections may develop atypical squamous cells of undetermined signifi cance(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 defi ned.However,the risk is greater than that of women whose infections clear spontaneously.24,25 Currently,there are no data available on the natural history of HPV infection in men.Top:The epithelium of the CIN 1 lesion is thickened and the upper layers contain cells characterized by perinuclear halos,multinucleation,and signifi cant nuclear atypia.Such cells are referred to as“koilocytes.”Bottom:This high-powered magnifi cation of a CIN 1 lesion shows the nuclear irregularities typically seen in“koilocytes.”HPV Infection6Factors Infl uencing HPV Persistence and Progression to Cervical CancerSeveral risk factors have been identifi ed that appear to be associated with HPV persistence as well as progression to cervical cancer.The single most important factor associated with invasive cervical cancer is the factor of never or rarely being screened for cervical cancer.The National Institutes of Health(NIH)estimates that half of the women who receive cervical cancer diagnoses have never been screened for cervical cancer and that an additional 10%have not been screened in the previous fi ve years.4 Immunosuppression from any cause,including HIV infection,is recognized to increase HPV persistence and to be associated with increased risk of invasive cervical cancer.22,26 Cigarette smoking has been associated with HPV persistence and risk of cervical cancer.Multiple case-control studies show a moderate and statistically signifi cant association between smoking and cervical cancer,even after adjusting for the effects of HPV.27Other epidemiologic factors associated with risk of cervical cancer include long-term use of oral contraceptives,27 co-infections such as Chlamydia,28 parity,and nutritional factors.29,30,31,32 However,in populations that are screened regularly,as is typical in the U.S.,cervical cancer develops rarely in women,even with persistent HPV infection.This is because women with high-grade precursor lesions are usually identifi ed through cytologic screening,and the development of cancer can be prevented through early detection and treatment.770 years with 3 recent,consecutive negative tests&no abnormal tests in prior 10 years*Post total hysterectomyDiscontinue if for benign reasons&no prior history of high-grade CIN*16*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.U.S.Preventive Services Task Force2www.ahrq.gov/clinic/uspstfi x.htm(USPSTF,Jan 2003)American College of Obstetricians and Gynecologists3www.acog.org(ACOG,Aug 2003)Within 3 years of onset of sexual activity or age 21,whichever comes fi rstApproximately 3 years after onset of sexual intercourse,but no later than age 21 At least every 3 years Insuffi cient evidence Insuffi cient evidence Annually;every 2-3 years for women 30 with 3 negative cytology tests*Annually;every 2-3 years for women 30 with 3 negative cytology tests*Every 3 years if HPV negative,cytology negativeWomen 65 years with negativetests,who are not otherwise at high risk for cervical cancerInconclusive evidence to establish upper age limitDiscontinue if for benign reasonsDiscontinue if for benign reasons&no prior history of high-grade CIN*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/52/6/3422.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.cfmCervical Cancer Prevention1718Dc-eening wi3=4e-,ic$l 43ologThe 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(a method in which cervical cells are collected into a liquid medium)can be used to screen for cervical cancer.The sensitivity of the conventional Pap test ranges from 30%to 87%,and the specifi city ranges from 86%to 100%53 The sensitivity of liquid-based cytology ranges from 61%to 95%,and the specifi city ranges from 78%to 82%52,53 The U.S.Preventive Services Task Force is an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services.Top:There is a cluster of cells with enlarged,hyperchromatic nuclei present.Several binucleated cells are present in this cluster.However,very few atypical cells were present on slide and although the cells are suggestive of SIL,they are not diagnostic of SIL.Bottom:This cervix has a well-circumscribed area of acetowhitening that appears low-grade.However,cervical biopsy was diagnosed as CIN 2,3.Cervical Cancer Prevention!0 9GA 7e.3ing 2o-!ig=IJi.K 7(e.A high-risk HPV DNA test is commercially available and approved for use in women in the setting of cervical cancer screening and management.Use of HPV DNA Testing in Managing Women with ASC-US55Borderline cytologic abnormalities referred to as ASC-US are quite common in the U.S.Approximately 4%to 5%of all cervical cytology results are reported as ASC-US.Use of the HPV DNA test in the management of women with ASC-US Pap test results is recommended as an option by the American Society for Colposcopy and Cervical Pathology(ASCCP,www.asccp.org/index.html),ACS,and ACOG.The USPSTF found the evidence insuffi cient in its last review(2003)to recommend for or against the use of HPV DNA testing in this setting.56FDA-Approved Indications for High-Risk HPV DNA TestingTesting is approved for:Use in the management of women with ASC-US cervical cytology results.This test can be used to help determine which women(of any age)with ASC-US cervical cytology results should be referred for colposcopy and which can be followed up with cytological screening in 12 months.54 Routine adjunctive screening with cervical cytology screening for women ages 30 and older(e.g.,use in conjunction with a Pap test for primary screening).This test is not approved for use with cervical cytology