Infect Dis Obstet Gynecol 2001;9:149–154 Female genital warts: global trends and treatments Stanley A. Gall Department of Obstetrics and Gynecology, University of Louisville, Louisville, KY The increasingincidence of human papillomavirus (HPV)infection and HPV-associated conditions such as genital wartsin women isa global concern.Genital wartsare a clinical manifestation of HPVtypes 6 and11, andare estimated toaffect 1% of sexually active adultsaged between 15 and49. HPVinfection is also stronglyassociated with cervical cancer,and is prevalent in as many as99% of cases.The psychological stressof having genital wartsis oftengreater than the morbidity of the disease,and therefore successful treatment is crucial. Current treatments arepatient-applied andprovider-administered therapies. Imiquimod 5%cream, apatient-applied therapy,is an efficacious treatmentwith tolerable side-effectsand a low recurrencerate, and has the potential tobe an effective strategy for the management of genital warts. Key words: H UMAN PAPILLOMAVIRUS ; ANOGENITAL CANCER; PATIENT-APPLIED THERAPY; IMIQUIMOD PREVALENCE OF Table 1 Humanpapillomavirus (HPV) types and HUMAN PAPILLOMAVIRUS AND related oncogenic risk of cervical squamous carcinoma 4 GENITAL WARTS Oncogenic Human papillomavirus (HPV) infectionis oneof HPV type potential thethree most commonsexually transmitted 16, 18 High risk diseases (STDs) inthe United States, alongwith 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 Intermediate risk gonorrheaand chlamydia 1.Itis estimated thatas 6, 11, 26, 40, 42 –44, 53–55, 62, 66 Low risk many as 20–40% of sexually active womenare infectedwith HPV 2.Inthe US, theestimated aid their diagnosis. Theirmost commonlocation numberof new HPV infectionseach year is in women is the vulva (Figure 1) 7. 5.5 million, withan estimated totalprevalence of Theannual incidence of genital warts has 20 million3. increased steadily amongwomen since theearly Over 100different types of HPV exist, andthey 1950s, whenthe estimated incidencein the USwas canbe grouped according to their oncogenic only13 per 100 000 for the female population 8. potential(Table 1) 4.HPV 6and11 are termed ‘low Duringthe late 1970s genital wartprevalence risk’, as theyare rarely associated withcarcinomas 5 increased to106 per 100 000, andat present1% of andmost commonlymanifest as external genital sexually active adultsaged 15– 49 are estimated to warts6.Genital warts, however, have beenfound have genital warts 6.Theincidence of genital warts tobeinducedby other‘ high’or ‘intermediate’risk has also increased inEurope, with an approxi - HPVs5.Genital warts are exophytic,confluent, mately five-fold increase forfemales inthe United cauliflowertumors and their typicalmorphologies Kingdombetween 1971 and 1994 9,wherethey are Correspondenceto: StanleyA. Gall, MD, Departmentof Obstetricsand Gynecology, University of Louisville, 550South Jackson Street, Louisville, KY 40202, USA. Email: [email protected] Review 149 Genital warts in females Gall Furthermore, thehost’ s immune status is also a factorthat is importantin controlling HPV infec- tionsand the development of HPV lesions suchas genital warts. Thisis supportedby theobservation thatpatients whoare immunosuppressedhave an increased incidenceof HPV-associated lesions 17. Activationof the specific humoraland cellular immunity pathwaysis reportedto be importantin HPV-infectedindividuals forspontaneous regres- sion of genital warts 18. Figure 1 Location of genital warts in women HUMAN PAPILLOMAVIRUS AND ANOGENITAL CANCER nowthe most commonlydiagnosed STD in Althoughgenital warts are consideredto be a genitourinary medicine clinics 10. benigncondition, an association betweenHPV infectionand squamous cell carcinoma(SCC) of theanogenital tract has beenidentified 15. Cervical RISK FACTORS ASSOCIATED WITH canceris themost commontype of anogenital HUMAN PAPILLOMAVIRUS INFECTIONS cancer;however, vulvar, vaginal andanal cancer are also associated withHPV 19.HPV prevalence, Twofactors that clearly influencethe incidence of inparticular ‘ highrisk’ HPV types 16and 18, is genital HPV infectionare age andsexual behavior. greater than99% in cervical carcinomas 20. Other Asis thecase withother sexually transmitted infec- HPV types thatare associated withanogenital tions, prevalence is reportedto be highest in cancer are HPV 31, 33, 35 and 45 (Table 1) 21. sexually active youngadults between 18 and 25 Theincreasing incidenceof cervical intra- years of age8.Sexual behavioralso has aninfluence epithelial neoplasias (CIN) inyounger women 22 is onthepotential risk ofbeinginfected with HPV. ofconcern because oftheir malignant potential. Womenwith five ormore partnersin the previous Forexample, over 30%of CIN3 lesions progress to 5years are over seven times more likely tohave an SCC within1– 10 years 22.Theprogression from episodeof genital warts andare over 12times more low-gradelesion tohigh-grade lesion orSCC is likely tohave recurrentgenital warts, compared also reportedto occur in approximately a third withwomen with one sexual partnerin this time 11. of cases22.Theoutcome of low-grade cervical Otherrisk factorsreported in this studywere a neoplasia is influencedby a numberof factors, historyof anyother STDs, ahistoryof oral herpes includingthe oncogenicity of infecting HPV ora historyof allergies 11.Thereis conflicting type,sexual behavior, infectionof the cervical evidence aboutwhether smoking and use oforal epithelium withother viral/ bacterial agents, ciga- contraceptivesare also risk factorsfor genital rette smoking,oral contraceptiveusage andhost warts11–15. immunosuppression 22. Human immunodeficiencyvirus (HIV) infec- tionis anadditional determining factor for infec- tionwith other STDs, includinggenital warts. In onestudy,HIV-positive womenwere foundto be TRANSMISSION OF GENITAL WARTS over six times more likely tohave genital warts, Animportantissue forwomen with genital warts is andover three times more likely totest positive for theconcernabout transmission ofHPV andgenital oncogenicHPV thanHIV-negative women 16. warts totheir sexual partners. Transmission is Thisstudy reported an annual incidence rate for believed tobe predominantly through sexual genital warts inHIV-positive womenof 11.4%, intercourse, as genital HPV is absentin the major- compared with 1.4% in HIV-negative women 16. ity ofwomenwho have nothad sexual intercourse. 150 INFECTIOUSDISEASES IN OBSTETRICS AND GYNECOLOGY Genital warts in females Gall Therehave beenstudies, however, thathave anunspecified cancer. In terms oflifestyle, approx- detectedHPV DNAin cervical orvulva-vaginal imately 40%of women said thathaving genital samples fromwomen who have nothad sexual warts hadchanged their lifestyle. Sexual behavior intercourse 8. hadparticularly changed, resulting inan increase in Transmission ofHPV is enhancedwhen the condomusage duringsexual intercourse, absti- superficial epithelium is disrupted 6,as this is where nencefrom sexual intercourse, increased caution theinfectious agent resides 4.TheHPV life cycle aboutnew partners and a decrease inthe number begins withinfection of the basal cell layer of of sexual partners 25. theepithelium andprogresses withepithelial cell differentiation,resulting incomplete virions presentin the epithelial cells inthe superficial layer4.Thegreatest risk oftransmission is likely to TREATMENT OF GENITAL WARTS exist whengenital warts are present, as theyreflect Treatment ofgenital warts canbe a frustrating a productive HPV infection. experience forboth physician and patients 28. Therisk oftransmission ofHPV tooffspring is Thereare many currenttreatments forgenital also aconcern.The increasing frequencyof child- warts; however, noneare successful inall three hoodgenital warts has beenproposed to be the goals oftherapy: complete eradication of warts, result ofsexual abuse 5.However, anassociation maintaining clearance andeliminating thevirus. betweengenital warts andcutaneous HPV 2 23 has Recurrenceis asubstantial problem,as many also beenreported. There may also beanon-sexual therapies donot eradicate thereservoir ofHPV transmission ofgenital warts frommothers, as well DNAthat is present inthe tissue locatedadjacent as thepossibility oftransmission duringpassage to the genital wart. throughthe birth canal if mothers have external or Currenttherapies are composedof both abla- cervical genital warts 5.Additionaldata support a tive andcytodestructive modalities. Physically vertical (transplacental) transmission ofHPV ablative therapies includecryotherapy, laser DNA, as over50%of childrenborn to HPV 16- or therapy,electrosurgery andsurgical excision. 18-infectedmothers were positive forthese Manyof thephysicallyablative therapies have high HPVs24. initial success rates; however, recurrencerates are also high28.Cytotoxicagents thattreat genital warts destroythe affected tissue either bychemo- PSYCHOLOGICAL ASPECTS OF destructive orantiproliferative modes ofaction. GENITAL WARTS Cytotoxicagents includepodophyllin, podofilox Genital warts are notonly cosmetically unaccept- (podophyllotoxin),trichloroacetic acid (TCA) and able andassociated withdiscomfort and pain, but 5-fluorouracil. theyare also associated withemotional stress 25. It is Eradicationof genital warts bystimulation of reportedthat the psychological stress ofhaving theimmune system is analternative strategy for genital warts is oftengreater thanthe medical genital warttherapies. Interferon,an antiviral, effects ofthedisease 26.Some ofthe psychological immunomodulatoryagent is effective intreating outcomesof patients