J Pediatr Adolesc Gynecol (2009) 22:197e204Mini-ReviewHuman Papilloma Virus Infection and Preventionin the Adolescent PopulationW. David Hager, MD, FACOGWomen’s Care Center, Central Baptist Hospital, Lexington, KY 40503Key Words. Human papillomavirus (HPV)— this is not a reportable infection, the ﬁgures of incidenceSexually transmitted infection (STI)—HPV screen- and prevalence are based on estimates. It is currentlying—HPV immunization—Vaccine implementation estimated that there are about 6.2 million new cases annually with about 20 million persons currently infected. Since there are an estimated 45 million persons currently infected with Herpes simplex virus,Introduction HPV is the STI of second highest prevalence. These data indicate that an estimated 74% of all new HPV in-With the recent availability of a quadrivalent vaccine fections occur among individuals 15e24 years of age,against human papillomavirus (HPV), there has been resulting in about 9.2 million adolescents and younga surge of published information about this infection adults being currently infected.1 The Centers for Dis-in both the scientiﬁc and lay press. Medical care pro- ease Control and Prevention (CDC) estimates that byviders desire more detailed information about HPV in 50 years of age, at least 80% of women will have or haveorder to answer the questions frequently being posed had genital HPV infection.2by their patients and their patient’s parents or guard- We are currently unable to culture HPV in the labo-ians. It is important to have a thorough and accurate ratory. Diagnosis of infection is made in women by do-understanding of the incidence/prevalence; risk fac- ing DNA-hybridization on Pap tests that show atypicaltors for infection; pathophysiology; disease conse- cells or dysplasia or by visualizing genital warts. Sincequences of infection; updated screening guidelines Pap tests are not routinely done in the male populationfor disease detection; and the latest information about (studies to evaluate the use of anal Pap tests in men haveHPV immunization including the Advisory Commit- been done), we do not have estimates of infection in thistee on Immunization Practices guidelines, efﬁcacy group that are as accurate as in the female population. Inin both viral-naıve and non-naıve populations, persis- ¨ ¨ research settings the diagnosis may also be made bytence of cross-neutralizing antibody levels, delayed doing polymerase chain reaction (PCR) testing or iden-anamnestic response to viral challenge and potential tifying neutralizing antibodies from blood. When an in-adverse events from vaccine. dividual tests positively for HPV there must be a viral In this article, the factors listed above are presented load signiﬁcant enough to detect. If a person tests neg-to give you a resource of information that will enable atively, there may nevertheless be virus present but justyou to diagnose, manage, and prevent HPV infection not enough to detect with our current technology. Wein your patient population. can currently identify various species of HPV as well. HPV SpeciationBackground The genus of the family human papilloma virus thatInfection with HPVis the sexually transmitted infection may be oncogenic in the genital tract is Alpha papil-(STI) of highest incidence in the United States. Since lomavirus. More than 100 species of HPV have beenAddress correspondence to: W. David Hager, MD, FACOG, identiﬁed, with some being non-genital and about 40Women’s Care Center, Central Baptist Hospital, 1720 Nicholas- occurring primarily in the ano-genital tract. Fifteenville Road, Suite 506, Lexington, KY 40503; E-mail: wdhager@ are considered ‘‘high-risk’’ types and the remainderwomenscarecenter.com ‘‘low-risk’’ types. The signiﬁcance of the variousÓ 2009 North American Society for Pediatric and Adolescent Gynecology 1083-3188/09/$36.00Published by Elsevier Inc. doi:10.1016/j.jpag.2008.01.079
198 Hager: Human Papilloma Virus Infection and Preventionspecies regarding HPV-related disease is reviewed be- virus. Genital warts may be obvious and uncomfort-low in this paper. It is important to realize that the A7 able; but even with these lesions; most individualsand A9 species are the oncogenic species of greatest are completely asymptomatic when infected. Theysigniﬁcance. The prototype for the A7 species is have no idea that they have an infection and are trans-HPV-18 and for the A9 species is HPV-16. Munoz mitting the virus. Once the virus has been transmittedet al have found that HPV-16 and 18 cause 70% of to the damaged surface epithelium, it penetrates to theall cervical cancer, adenocarcinoma in-situ of the cer- basement membrane level and there may proliferatevix, cervical intraepithelial neoplasia- III (severe dys- or remain quiescent.plasia), as well as vulvar and vaginal intraepithelial Until three decades ago, HPVinfection was regardedneoplasia- II and III (moderate and severe dysplasia). as benign and self-limited, resulting in cutaneous andIn addition, about 50% of all cervical intraepithelial genital warts. The pioneering work of zur Hansen andneoplasia-II (moderate dysplasia) is caused by these colleagues in the 1970s showed that cancer of the cervixtwo species. HPV-16 is responsible for about 58.7% was most likely attributable to infection with a subset ofand HPV-18 about 12.2% of all cervical cancer.3 genital HPVs rather than to other sexually transmitted With these species as the prototypes for speciation, pathogens.5types 39, 45, and 59 have been characterized as A7 Most infections occur soon after the onset of inti-types like HPV-18 due to their genetic homology mate contact with an infected sexual partner. Onceand types 31, 33, 35, 52, and 58 are A9 types like infected, the majority of persons will clear their infec-HPV-16. This categorization will be important when tion within 24 months via their host-immune defensewe discuss the issue of cross-protection with vaccine. mechanisms with type-speciﬁc immunity. It has been HPV-6 and HPV-11 are the prototypes for species that estimated that this occurs in about 90% of all womenare the primary causes of benign disease such as genital infected. Of those who have persistent infection, theywarts. Although these types may cause atypical cells and may have progression over time to cervical dysplasiacervical intraepithelial neoplasia-I (mild dysplasia), (pre-cancer) or invasive cancer. Most early infectionsthere is seldom progression to higher grade lesions. aside from warts are detected by the reading of atypical cells on a Pap test of the cervix. If there is progression toRisk Factors for HPV Infection low-grade squamous intraepithelial lesions (LGSIL), about 65% of these will spontaneously resolve. ThusThe risk factors for infection with the sexually trans- the majority of infections and low-grade changes ofmitted virus HPV are similar to those of any STI. the cervix will resolve to a level that HPV DNA cannotEarly sexual debut is a signiﬁcant risk factor for the be detected by current methods. Of those whose infec-acquisition of any STI, because most persons who tion persists, the HPV DNA is incorporated into the hostinitiate intercourse at an early age will likely have cell genome and begins to control cellular proliferationmultiple partners during their adolescent and young and the ability to repair damaged cells, resulting inadult years.4 Unwanted sex has also become a major a dysplastic process. Even some higher-grade lesionsrisk factor. Blythe et al found that 40.9% of 14 to may resolve with only biopsy as therapy.617 years olds surveyed reported unwanted sex. Hav- Current estimates are that it takes about 12e24ing multiple partners or a partner who has had multi- months of persistence for atypia to develop. From thisple partners are also signiﬁcant risk factors for degree of cellular change it may then take 3e5 yearsacquiring an infection. Because of this, about 45% for cervical intraepithelial neoplasms (CIN-I) toof female college students will acquire HPV during develop; 5e8 years for CIN-II/III to develop and uptheir college careers. The use of oral contraceptives to 20 years for invasive cancer to occur. We know thathas been mentioned as a risk factor but may have in some situations, rapid progression from infectionmore to do with those women being more sexually ac- to high-grade dysplasia can occur.6tive than non-users. The association of sex with drugs/ Although infection with types other than the higher-alcohol and cigarette smoking have also been reported risk type 16 is most common, when infection occursas risk factors for HPV infection.4 with type 16 in particular, but the other oncogenic types as well, there is a greater probability that there will bePersistence of Infection progression to cervical dysplasia and/or cancer. Most cervical cancers are caused by a single type of HPV,Human papilloma virus infections are easily transmit- with type 16 being the most prevalent. Low and high-ted, presumably through microscopic tears in the sur- grade dysplasia are more frequently caused by multipleface epithelium that may occur with sexually intimate types. Thus, HPV-16 is involved as a causative agent inbehavior. Since HPV is so prevalent in the population 58.7% of all cervical cancers, but in 54.6% of all cases itof sexually active persons, any contact resulting in is a sole isolate. Together, types 16 and 18 are involvedmicroabrasions may allow for transmission of the in 70.9% of all cervical cancers.3
Hager: Human Papilloma Virus Infection and Prevention 199 Persistence of infection at the transformation zone conventional or liquid-based cytology could be per-(TMZ) of the cervix is key to the development of formed every 3 years.8 Although there are occasionaldisease. The cervical transformation zone is the area women who will have rapid progression of an abnor-of immature metaplasia between the squamous cells mality to high-grade dysplasia, since this is unusual,that line the vagina and lower cervix and the columnar it is best not to initiate screening until after the adoles-cells that line the endocervix and the endometrium of cent or young woman is sexually active. Aggressivethe uterus. This zone or squamo-columnar junction is management of cervical abnormalities in adolescentsfurther out on the cervix in younger girls. This puts and teens is discouraged.the individual at greater risk for acquisition of HPVwhen abraded or irritated areas of the cervix are Decreasing the Risk for HPV Infectionexposed to the virus. Age, childbirth, and invasive pro-cedures all tend to cause the TMZ to move further up Abstinence is obviously the best way to prevent the ac-the endocervical canal. Thus, an adolescent may be ex- quisition of any sexually transmitted infection, includ-posed to HPV with a vulnerable squamo-columnar ing HPV, by acting as a primary prevention method.junction, be infected, and if the virus persists and is Encouraging young people to delay their sexual debutnot eradicated by the host, may over months to years is beneﬁcial not only in decreasing the risk of STIsprogress to dysplasia and eventually to cancer if not but also of non-marital pregnancy and the emotionaldetected and treated. sequelae of adolescent sexual involvement. If an adolescent or teen is sexually active it isScreening for Cervical Disease in Females important for them to understand their boundaries so that they will not be manipulated into having inter-Since the Papanicolaou smear was introduced into the course before they are ready. The use of appropriatepractice of medicine in the late 1940s, there have been contraceptive methods should be discussed at home,dramatic reductions in the rates of invasive cervical in church or synagogue youth groups, and in schoolcancer in the countries where this tool is used routinely. health classes. Birth control pills do not offer any pro-Unfortunately, because many developing nations do not tection from HPV infection. Although it would seemhave such screening readily available, there are an esti- intuitive that condoms might offer protection frommated 580,000 cases of cervical cancer worldwide with transmission of infection, the NIH Condom Effective-about 230,000 deaths annually. This makes cervical ness Panel determined that there were not sufﬁcientcancer the second leading cancer in women younger data to indicate that condoms are protective againstthan 45 years.7 HPV.10 Since the conclusions of this panel were In the United States there are approximately 50 published, others have indicated that there is somemillion Pap tests done annually to screen for cervical reduction in the risk of acquisition of HPV by usingdisease. There are no reliable screening tests for men. condoms.11 Unfortunately, continued and consistentRecent efforts to increase the sensitivity of cervical use of condoms frequently does not last even with ap-cytological tests in women have resulted in a move to propriate condom-use counseling.12liquid-based testing with thin-layer cytology. When Thus it was very important to attempt to developcontrolled for sample order (whether the conventional a vaccine that would serve as a primary preventionPap was obtained before or after the liquid-based test), method for this infection. Research over the pastthe sensitivity of thin-layer cytology for detecting CIN two decades has focused on immunization with bothII/III was signiﬁcantly higher than that of conventional a bivalent and a quadrivalent vaccine. If successful,smears in patients with previous abnormal cytology, but over time, this may help to minimize the need forthis was at the expense of speciﬁcity.8 There will be ap- secondary prevention methods such as condoms, andproximately 2.0 million specimens read as atypical tertiary prevention methods that include biopsy ofcells of undetermined signiﬁcance; 1.4 million read lesions, various types of conization or excision proce-as LGSIL; 330,000 high-grade lesions (HGSIL); and dures of the cervix, and even hysterectomy in more11,150 cervical cancers resulting in an estimated advanced cases of cervical disease.3,670 deaths in 2007.9 The American Cancer Society recommends that HPV Immunization As a Primary Preventioncervical screening with a Pap test should begin approx- Methodimately 3 years after a woman begins having vaginalintercourse, but no later than 21 years of age. Screening In evaluating the efﬁcacy of a vaccine against HPVshould be done every year until age 30. At or after age infection it is important for the primary end points30, women who have had 3 normal test results in a row to be appropriate. One might think that cervical can-may get screened every 2 to 3 years. Alternatively, cer- cer should be the primary end point to evaluate suchvical cancer screening with HPV DNA testing and a vaccine. There are two reasons why this is not
200 Hager: Human Papilloma Virus Infection and Preventionpractical. In a placebo-controlled trial, it is not ethical published in the past two years. Seven of these trials haveto assign young women to the placebo arm and wait to evaluated the quadrivalent vaccine,15 16, 17, 18 and twosee if they will develop cervical cancer. In addition, evaluated the bivalent vaccine.19, 20 The quadrivalent tri-since it may take up to 20 years after initial infection als have evaluated 28,691 study participants vs 28,694to develop cancer, it is not practical. Using infection controls. The bivalent trials evaluated 8,269 study partic-itself as a primary end point is also not ideal because ipants vs 8,208 controls. The primary end points in the90% of all infections resolve spontaneously without trials referenced 15 and 16 were CIN 2/3 and AIS. Intherapeutic intervention. Thus, the primary end points Garland et al,17 the endpoints were CIN 2/3, AIS, VINfor efﬁcacy to allow licensure, as developed by the 1-3, VaIN 1-3, and genital warts. In Joura et al,18 the end-Vaccines and Related Biological Products Advisory points were VIN 2/3 and VaIN 2/3. In the bivalent vac-Committee of the Center for Biologics Evaluation cine trials the endpoints were CIN 1-3.19,20and Research were high-grade dysplasia of the cervix In Ault’s Future II study group paper,16 there 2,409(CIN II/III), or adenocarcinoma-in-situ (AIS) of the subjects entered into a Phase IIa, HPV-16 trial; 552cervix or endocervix which are immediate and neces- entered into a Phase IIb, quadrivalent portion; andsary precursors to cervical cancer; high-grade dyspla- 17,622 entered into Phase III, quadrivalent vaccinesia of the vulva or vagina (VIN II/III, VaIN II/III); and studies. In each study, vaccine was administered atgenital warts.13 A secondary end point was low-grade day 1 and months 2 and 6. Subjects were from thedysplasia of the cervix (CIN I). Remember that as pre- Americas, Europe, and the Asia-Paciﬁc areas. Meanviously mentioned, 60e70% of CIN I will resolve follow-up was 3.0 years from the ﬁrst dose. At enroll-spontaneously. The Advisory Committee also recom- ment, women underwent a complete gynecologicalmended that trials of such vaccines should enroll examination in which cervical samples for Pap testingparticipants irrespective of baseline HPV status or and cervicovaginal swabs for detection of HPV DNAPap test results, so that trial results would indicate were obtained. Serum samples were tested for anti-the efﬁcacy and safety of the vaccine in a general pop- body to HPV 6/11/16/18.ulation that includes women who have already been In women naıve to vaccine types 6, 11, 16, and 18 ¨infected with the virus.13 during the vaccination regimen, vaccine efﬁcacy was The FDA allowed end points that meet the follow- 99% (CI 93e100%) for the primary endpoints. In aning criteria: it is a necessary step in the development intention-to-treat analysis of all randomized womenof invasive cervical cancer; it is sequentially close to (including those who were vaccine-type naıve or ¨invasive cervical cancer; it confers a high risk for vaccine-type infected at day 1), efﬁcacy was 44%development of invasive cervical cancer; and preven- with all but one case in vaccine recipients occurringtion of the pathologic state or subsequent treatment in women infected with HPV16 or HPV 18 beforehas been shown to reduce cervical cancer mortality.13 vaccination. There was an 18% reduction againstPap tests alone are not good end points because the any HPV type in a separate intention-to-treat analysis.diagnosis is conﬁrmed by biopsy of the involved tis- A sub-population follow up has shown statisticallysue. However, conﬁrmation of HPV infection utilizing signiﬁcant cross-protection against CIN 2/3 and AISPap test results as well as DNA hybridization identiﬁ- of 45% for types 31, 33, 35, 52 and 58.16cation of HPV species and PCR testing is considered In the Future II study group trial published inconﬁrmatory of the diagnosis. 2007,15 there were 6,087 women who received quad- Since infection with HPV can occur as soon as sex- rivalent vaccine and 6,080 controls. Ages ranged fromual activity begins, it was important to evaluate 15e26 years and mean follow-up was 3.0 years.adolescents. Rather than enroll girls and young adoles- Among women naıve to HPV types contained in the ¨cents into these trials, the FDA allowed bridging to be vaccine, the per-protocol efﬁcacy for those vaccineused to demonstrate safety and immunogenicity. A types was 98% (CI 86e100%). In the intention-to-population of girls and boys, 9e15 years of age, were treat analysis including women who were HPV in-given the vaccine to evaluate their ability to achieve an fected at day 1, the efﬁcacy was 44% for the vaccineimmune response and to ensure that the vaccine was as types and 17% against all types.15safe in them as in an older group of females. The re- Garland et al17 and Joura et al18 have reported per-sults of these trials indicate that younger adolescents protocol efﬁcacy for vaccine-type HPV, VIN andachieve a more robust immune response than older VaIN of 100% and 100% respectively; intention-to-subjects and have no increase in adverse events.14 treat efﬁcacy for vaccine-type HPV, VIN and VaIN of 73% and 71% respectively and intention-to-treatHPV Vaccine Trial Results efﬁcacy for any HPV type, VIN, and VaIN of 34% and 49% respectively.We have found six major publications of nine Phase IIb/ In their international, bivalent, L1, virus-like particleIII vaccine trials (some have pooled data) that have been vaccine trial with types 16 and 18 in women ages
Hager: Human Papilloma Virus Infection and Prevention 20115e25 years, Paavonen et al20 reported a vaccine-type, Current recommendations for cervical cancermodiﬁed-intention-to-treat efﬁcacy against types 16 screening have not changed for females who re-and 18 to be 90% (CI 53e99%). The efﬁcacy estimates ceive quadrivalent HPV vaccine.were not statistically signiﬁcant for HPV 18 only, how- Females who have an equivocal or abnormal Pap test,ever. Efﬁcacy for prevention of persistent infections at a positive Hybrid Capture II high-risk test, or genital12 months with HPV 16 and 18 was 76%. They did not warts can receive the quadrivalent HPV vaccine.report crossover efﬁcacy for CIN, AIS, VIN, or VaIN, o Recipients should be advised that the vaccinebut did report efﬁcacy for 12-month persistent infec- will not have therapeutic effect on existing Paptions with all non-vaccine, oncogenic types to be test abnormalities, HPV infection, or genital27%. Cross-over protection against infection at 12 warts. Vaccination would provide protectionmonths with types 31, 33, 45, 52, and 58 had conﬁdence against infection with vaccine HPV types notintervals that crossed one and were not signiﬁcant. Only already acquired.12% of their subjects were included in the immunoge- Lactating women can receive quadrivalent HPVnicity analyses that were done. vaccine. Harper et al19 followed up on their multi-center, Immunocompromised females can receive quadri-double-blind, randomized, placebo-controlled trial that valent HPV vaccine.was reported in 2004 and found that the HPV-16/18 L1, o However the immune response to vaccinationvirus-like particle vaccine using aluminum sulfate as an and vaccine effectiveness might be less than inadjuvant, was immunogenic and safe for up to 4.5 years females who are immunocompetent.in preventing infection. The conﬁdence interval did notconﬁrm statistical signiﬁcance against type-18. They Quadrivalent HPV vaccine is contraindicated inalso showed evidence of cross-protection against infec- people with a history of immediate hypersensitivitytion with types 45 and 31. to yeast or to any vaccine component. Kjaer et al21 have recently reported data to suggest Quadrivalent HPV vaccine is not recommended forthat approximately 10% of women in the Nordic use in pregnancy.countries experience genital warts before the age of o (Category B)45 years. This emphasizes the need to attempt to de- Individuals should report any exposure to the vaccinecrease HPV infection resulting in genital warts of during pregnancy to the vaccine pregnancy registry.which 90% are caused by HPV types 6 and 11. Quadrivalent HPV vaccine can be administered to females with minor acute illnesses.ACIP Recommendations o Vaccination of people with moderate or severe acute illnesses shold be deferred until after theFollowing the FDA approval of the quadrivalent vac- illness improves.cine, Gardasil [Merck Co., Inc. (Vaccine Division),Lansdale, PA], the Advisory Committee on Immuni- Implementation of HPV Vaccinezation Practices formulated their recommendationsfor implementation.22 Having reviewed the previous information, it seems prudent to strongly recommend HPV immunization Routine vaccination with 3 doses of quadrivalent for young women in an attempt to decrease infection HPV vaccine for females 11e12 years of age. and the possible development of disease conse- o Can be started in females as young as 9 years of age. quences such as cervical, vaginal, and vulvar dyspla- Catch-up vaccination for females 13e26 years of sia and genital warts. Since there is diminished age not previously vaccinated or who have not efﬁcacy among girls and women who have already completed the full vaccine series. been exposed to HPV vaccine types, it is important o Ideally, vaccine should be administered before to attempt to immunize adolescent females before potential exposure to HPV. they are exposed and when their immune response is more robust. Even if a young woman remains absti- Each dose of quadrivalent HPV vaccine is 0.5 mL, nent until marriage she may still marry a male who administered intramuscularly. has previously contracted HPV, placing her at risk Quadrivalent HPV vaccine is administered in a for infection. 3-dose schedule. Once the vaccine regimen is implemented, every o The second and third doses should be adminis- effort should be made to complete the three-dose sched- tered 2 and 6 months after the ﬁrst dose. ule. If a woman becomes pregnant, the regimen would Quadrivalent HPV vaccine can be administered at be interrupted and completed after delivery. The ACIP the same visit at which other age-appropriate vac- currently recommends completing the schedule regard- cines are provided, such as Tdap, Td and MCV4. less of the time interval between doses.
202 Hager: Human Papilloma Virus Infection and Prevention It is important to continue cervical Pap test screen- cervical and other anogenital cancers? This infor-ing for women who have been immunized with an ini- mation will be forthcoming from both nationaltial Pap test by age 21 or within 3 years of the onset of and international tracking data.sexual activity. The vaccine is not a therapeutic inter- Will there be an increase in the prevalence of non-vention but rather intended to be preventive. vaccine HPV types as a result of widespread immu- nization? Certainly the early data on cross-protectionGardasil Adverse Events would seem to cast doubt on this assertion. What is the titer of neutralizing antibody necessary toAdverse events will occur with any medication that is obtain immunity to HPV? The vaccine is intended toprescribed frequently enough. With over 30 million prevent disease consequences of HPV infection. Theuses of the quadrivalent vaccine worldwide we should speciﬁc titer is not known; however, after 5 years theexpect reports of some un-toward events. In the eval- geometric mean titers are stable.uation of the prospective trials; pain (83.7%), swelling How long will the immune response last and will(25.4%), erythema at the injection site (24%), and booster doses be necessary? Since the immuno-pruritis (3.1%) were the most frequent early adverse genic response to vaccine is more robust than natu-events. Fever in the ﬁrst two weeks occurred in ral infection and since early data indicate a brisk10.3% of subjects but also occurred in 8.6% of pla- anamnestic response to re-exposure to the vaccine,cebo subjects. Approximately 10% of younger sub- it would appear that this vaccine will behave muchjects have been reported to have a syncopal episode like tetanus toxoid and will not require frequentafter immunization with Gardasil; however, this is boosters if at all.no greater than syncope reported in this age range Will the data from large volume use of HPV vac-with any vaccine. cine continue to reveal good tolerability and safety? Gardasil is rated as Pregnancy Category B by the The FDA has not changed its approval status for theFDA with no increased rate of fetal loss among recip- quadrivalent vaccine and ACIP has not revised itsients and no speciﬁc congenital anomalies resulting. recommendations. The safety proﬁle is good in Due to concerns about the Vaccine Adverse Event all age groups studied.Reporting System(VAERS), the Centers for Disease Will implementation of immunization in youngControl and Prevention established the Vaccine Safety women discourage them from having routine cervi-Datalink(CDC VSD) in 1990. This network tests hy- cal cancer screening tests? Types 16 and 18 arepotheses suggested by VAERS reports and prelicen- responsible for approximately 70% of high-gradesure trials. The VSD did not ﬁnd any statistically cervical dysplasia and cancer. Even with cross-signiﬁcant risk for any of the prespeciﬁed adverse protection of other types this will prevent 80e85%events after vaccination with Gardasil for any age of disease. Thus there will still be HPV-related cervi-group. These prespeciﬁed events included: Guillain- cal, vaginal, vulvar, and anal disease as well as soft-Barre’ syndrome, seizures, syncope, appendicitis, tissue disease of the head and neck, so screening isstroke, venous thromboembolism, or allergic reac- essential. The ACIP along with other professionaltions. Because syncope can lead to serious adverse organizations continue to recommend no change inoutcomes they recommended that preventive mea- Pap test screening for women regardless of immuni-sures be taken such as having the subject sit or lie zation status. Since there are no readily availabledown and be observed for a short time after the screening tests for HPV in males, early detection willinjection.23,24 continue to occur in females. If a woman has already been exposed to HPV and has had an abnormal high-risk Pap test, is she a can-Unanswered Questions About HPV didate for immunization? Because she may haveImmunization been exposed to only one of the HPV vaccine types and now because we have data to support cross-pro-As use of the quadrivalent HPV vaccine completes its tection, women with prior exposure are still candi-third year, there are several questions that have been dates for immunization.raised related to use, safety, and effectiveness in the Will HPV immunization encourage increased sex-future. Although this information is covered in the ual activity among teens and young adult women?text of this article, I would like to review these ques- There are no data to indicate that women who re-tions for the reader. These questions deal with a world ceive immunization perceive this to mean that theyview of implementation and not just use of the vac- can initiate sexual activity, be more sexually active,cine in the United States. or that it protects them from other STIs. As use of the vaccine is tracked will there be a Should sexually abstinent girls and women receive signiﬁcant reduction over time in the incidence of the vaccine? As mentioned in the text, many ﬁrst acts
Hager: Human Papilloma Virus Infection and Prevention 203 of intercourse are ‘‘unwanted.’’ If a young woman there is an excellent anamnestic response to subsequent remains sexually abstinent and then initiates sexual exposure. Cross-protection may enhance the effective- activity within or outside of marriage, she may be ness of the quadrivalent vaccine beyond the types in- exposed to a male who has previously been sexually cluded in the preparation. Family practitioners, active and transmits HPV to her. Thus, I would pediatricians, and gynecologists should be comfortable encourage all young women to be immunized. with diagnosing and treating HPV infection and its con- Is HPV vaccine safe in pregnancy? The vaccine, sequences, and should be well versed in counseling Gardasil, is classiﬁed as a Category B agent, but in about and administering the vaccine. Adolescent gyne- the Phase III trials mentioned there was no increase cologists will play a key role in educating adolescents in congenital anomalies or adverse pregnancy out- and their parents about HPV infection and the need comes. Actually, the time when a young woman is re- for immunization of younger adolescents as well as ceiving obstetrical care may be an ideal time to the catch-up population of older adolescents. This will immunize since they are being seen frequently also include the responsibility of insisting on routine, for clinical visits. The current ACIP recommendations appropriate cervical, cytologic screening. are to avoid use of quadrivalent vaccine in pregnancy. Should ‘‘mid-adult’’ women receive the vaccine? Cur- rently the ACIP recommendations are for ages 9e26 References years. Data are being gathered to evaluate the effects of immunization among women 27e45 years of 1. Weinstock H, Berman S, Cates W Jr: Sexually transmitted age. Since they have likely been exposed to HPV more diseases among American youth: incidence and prevalence frequently than a younger population, the vaccine may estimates, 2000. Perspect Sex Reprod Health 2004; 35:6 2. Centers for Disease Control and Prevention. MMWR not be as efﬁcacious, but there still may be beneﬁt. Morbid Mortal Wkly Rep. 2007;56(RR-2):1-24. Are there moral and/or ethical issues involved in ´ 3. Munoz N, Bosch FX, Castellsague X, et al: Against which choosing to utilize a bivalent vaccine rather than human papillomavirus types shall we vaccinate and screen? a quadrivalent vaccine? Since the bivalent vaccine The international perspective. Int J Cancer 2004; 111:278 does not protect against infection/disease from 4. Winer RL, Lee SK, Hughes JP, et al: Genital human types 6 and 11, it would be possible for a young papillomavirus infection: Incidence and risk factors in a cohort woman to be immunized and still develop genital of female university students. Am J Epidemiol 2003; 157:218 wart disease. This should be considered in making 5. Zur Hansen H, de Villiers EM, Gissmann L: Papillomavirus in- the choice of which agent to use. fections and human genital cancer. Gynecol Oncol 1981; 2:S124 Should men be immunized? Currently there are in- 6. Schiffman M, Castle PE: Human papillomavirus: epidemiol- sufﬁcient data to support immunizing males. Be- ogy and public health. Arch Pathol Lab Med 2003; 127:930 7. Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, cause we do not have screening tests available for 2002. CA Cancer J Clin 2005; 55:74 males except for serology, which is only available 8. Bergeron C, Bishop J, Lemarie A, et al: Accuracy of thin- in research settings, it is difﬁcult to establish layer cytology in patients undergoing cervical cone biopsy. cost-effectiveness for males. There are ongoing tri- Acta Cytol 2001; 45:519 als to evaluate efﬁcacy in young males. In order to 9. American Cancer Society: Cancer Facts and Figures 2007. achieve herd immunity, males will need to be im- Atlanta, American Cancer Society, 2007 munized as is being done in some other countries. 10. Fitch JT, Stine C, Hager WD, et al: Condom effectiveness: Will HPV vaccine be readily available in develop- Factors that inﬂuence risk reduction. Sex Trans Dis 2002; ing countries? The cost of the quadrivalent vaccine 29:811 to the medical care provider is $120 per dose.25 11. Holmes KK, Levine R, Weaver M: Effectiveness of con- This cost is prohibitive in developing nations and doms in preventing sexually transmitted infections. Bull WHO 2004; 82:454 programs to make the vaccine accessible will need 12. Wong EL, Roddy RE, Tucker H, et al: Use of male con- to be developed. Strategies to educate individuals doms during and after randomized, controlled trial partici- about HPV infection and the vaccine itself are pation in Cameroon. Sex Transm Dis 2005; 32:300 crucial as well as overcoming societal barriers to 13. Food and Drug Administration Center for Biologics Eval- immunization in order to effectively implement uation and Research: Summary minutes, vaccines and vaccine programs in these countries. related biological products advisory committee. Meeting #88 November 28e29, 2001, Bethesda, Maryland. HPV vaccine appears to exhibit high prophylactic 14. Block SL, Nolan T, Sattler C, et al: Comparison of theefﬁcacy against HPV diseases including CIN II/III, immunogenicity and reactogenicity of a prophylacticAIS, VIN, and VaIN as well as the occurrence of genital quadrivalent human papillomavirus (types 6, 11, 16 andwarts. Data indicate that the vaccine is safe and well tol- 18) L1 virus-like particle vaccine in male and female ad-erated. It now appears that the vaccine induces stable olescents and young adult women. Pediatrics 2006; 118:neutralizing antibody levels for at least 5 years and that 2135
204 Hager: Human Papilloma Virus Infection and Prevention15. The FUTURE II Study Group: Quadrivalent vaccine 20. Paavonen J, Jenkins D, Bosch FX: for the HPV PATRICIA against human papillomavirus to prevent high-grade cervi- study group: Efﬁcacy of a prophylactic adjuvanted bivalent cal lesions. N Engl J Med 2007; 356:1915 L1 virus-like-particle against infection with human papil-16. The FUTURE II Study Group: Effect of prophylactic hu- lomavirus types 16 and 18 in young women: an interim man papillomavirus L1 virus-like particle vaccine on risk analysis of a phase III double-blind, randomised controlled of cervical intraepithelial neoplasia grade 2, grade 3, and trial. Lancet 2007; 369:2161 adenocarcinoma in situ: a combined analysis of four ran- 21. Kjaer SK, Tran TN, Sparen P, et al: The burden of genital domized clinical trials. Lancet 2007; 369:1861 warts: a study of nearly 70,000 women from the general fe-17. Garland SM, Hernandez-Avila M, Wheeler CM, et al for male population in the 4 Nordic countries. J Infect Dis 2007; the Females United to Unilaterally Reduce Endo/Ectocer- 196:1447 vical Disease (FUTURE) I Investigators: Quadrivalent 22. ACIP: Recommendations for the use of quadrivalent vaccine against human papillomavirus to prevent anogen- HPV vaccine. Available at. http://www.cdc.gov/hip/tech/ ital diseases. N Engl J Med 2007; 356:1928 provisionalrecs/hpv.pdf. Accessed December 3, 200718. Joura EA, Leodolter S, Hernandez-Avila M, et al: Efﬁcacy 23. Gee J. Vaccine Safety Datalink Project: Monitoring the of a quadrivalent prophylactic human papillomavirus Safety of Quadrivalent Human Papillomavirus Vaccine (types 6, 11, 16, and 18) L1 virus-like-particle vaccine (HPV 4). Presented at Advisory Committee on Immuniza- against high-grade vulvar and vaginal lesions: a combined tion Practices Meeting, October 22, 2008. Atlanta, GA. analysis of three randomised clinical trials. Lancet 2007; 24. Calugar A. Quadrivalent Human Papillomavirus Vaccine 369:1693 (HPV 4): Post-licensure safety update, Vaccine Adverse19. Harper DM, Franco EI, Wheeler CM, et al: for the HPV Event Reporting System (VAERS), United States. Pre- Vaccine Study group: Sustained efﬁcacy up to 4.5 years sented at Advisory Committee on Immunization Practices of a bivalent L1 virus-like particle vaccine against human Meeting, October 22, 2008. Atlanta, GA papillomavirus types 16 and 18: follow-up from a rando- 25. Steinbrook R: The potential of human papillomavirus vac- mised control trial. Lancet 2006; 367:1247 cines. N Engl J Med 2006; 354:1109