Advances in Prevention of Cervical Cancer and Other Human Papillomavirus-Related Diseases

In theory, recognition that a pandemic infection is responsible for more than half a million cancer cases each year would attract huge media attention, and infection control would become the subject of preventative efforts from all global health agencies. Media attention would likely be particularly acute if the majority of deaths was among women rearing families in the developing world and if the disease were sexually transmitted. A vaccine capable of preventing the disease would be diligently pursued and, once available, promptly distributed for the health and welfare of humankind. Human papillomavirus (HPV) infection fits this scenario; however, HPV has yet to make an impact on either the media or public thinking as outlined in the previous paragraph, even though the link between HPV infection and cervical cancer has been recognized for more than 20 years. It is possible that the delay between acquisition of HPV infection and death, on average 20 years, or the asymptomatic nature of acute infection, greatly diminishes the immediacy of the public impact of this epidemic. Although apparently safe vaccines capable of preventing >90% of HPV infections are in the offing, focus on prevention of HPV associated deaths is being diverted by debates about the morality of vaccination against a sexually transmitted infection and its hypothesized impact on human sexual behavior. A roundtable discussion was held in Vancouver, British Columbia to consider and develop a consensus statement among informed clinicians about HPV infection, the role of HPV in cervical cancer, the role of HPV in other anogenital malignancies, the role of HPV in genital warts and the prospects for control of the global HPV pandemic through vaccination. The consensus statements outlined within have been agreed upon and represent the informed opinions of this expert working group. CONSENSUS 1: GENITAL HPV-ASSOCIATED DISEASE IS A MAJOR HEALTH CARE BURDEN HPV infection is the cause of genital warts and most preinvasive and invasive cancers of the lower anogenital tract. Clinically or histologically recognized genital warts, abnormal cervical cytology and preinvasive or invasive cancer are major causes of physical and psychologic morbidity and of treatment-related cost. The Causal Relationship Between HPV and HPV-Associated Diseases Papillomaviruses are small, nonenveloped viruses that infect cutaneous and mucosal epithelial tissues. More than 100 types of HPV have been identified, of which more than 40 infect the genital mucosa (Fig. 1). 1 The life cycle of HPV is dependent on active cellular replication and subsequent cellular division. Because the uppermost layers of the squamous epithelium have undergone terminal differentiation and are no longer dividing, HPV requires access to the undifferentiated basal layer of the epithelium to initiate a productive infection cycle. Current hypotheses suggest that HPV accesses the underlying basal layer through naturally thin epithelial layers, such as those found in the transformation zones of the cervix or anus, or through microabrasions in the epithelium produced during sexual activity.2 Once infection has been established, the virus uses host cell machinery to replicate viral genetic material and express viral proteins. Because viral replication is dependent on continued cellular division, the virus has evolved to express proteins that inhibit cellular differentiation and stimulate continued cellular proliferation (Fig. 2) (for an in-depth review of HPV pathology, see Reference 3). Therefore, unrestricted cell growth is the hallmark of HPV infection, and many HPV-associated clinical manifestations can be explained by these molecular mechanisms.FIGURE 1.: Phylogenetic tree containing the sequences of 118 papillomavirus types.1FIGURE 2.: Natural history of HPV infection of mucosal epithelial layers. A, HPV infects the basal layer of the epithelium. B, The virus uses host cell machinery to replicate viral DNA and express virally encoded proteins. C, Viral particles are formed and released.3High Risk HPV Infections Genital HPV types have been separated into high and low risk groups depending on the observed risk of malignant progression (Table 1). The distinction between high and low risk HPV types has been made primarily because clinical diseases caused by infection with low risk HPV types are usually clinically benign and rarely progress to neoplasia. High risk HPV types are responsible for most high grade, precancerous lesions and >99.7% of cervical cancers.4 HPV is the cause of more than half of all invasive the of HPV HPV and HPV have that HPV and are responsible for of all cervical cancers and the majority of precancerous during cervical cancer cytology The for of HPV in cervical cancer is that the for on of the and the have high risk HPV as a human The has recognized HPV as a human and and the in 1: of Genital HPV the of cervical cancer was about the of cervical cancer disease however, the history of cervical cancer is in because of cervical cancer and Although cervical is HPV infections are to cause low which progress to high lesions and to in and cervical cancer (for an in-depth review of the history of cervical cancer, see Reference associated with cervical cancer has the of the and of cervical cancer in most an million are in the a each year million women are with squamous million with low squamous lesions with high squamous lesions and with cervical an women in the of cervical cancer The associated with HPV infection is the of cervical cancer and of preinvasive and invasive for the from 1 to HPV the most sexually transmitted infection to human virus associated with HPV infection cervical of low and high of cervical cancer and to of (Fig. 3). 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warts among and women are with for women between 20 and of and for between and of among between the groups of and years. as with HPV infections and the of cervical genital warts are most among and The of in the of HPV and the of HPV-Associated Diseases It has been hypothesized that HPV rarely infects the cervix in the of sexual that HPV can be transmitted to the or in the of sexual women in sexual most likely for cervical and women most likely for anogenital In of this HPV DNA was the in of no HPV DNA was observed in these women on the cervical infection, infection, most likely requires from the the cervix and many to and during A of 20 was to is against HPV infection or of HPV-associated The from the were that against HPV infection that of against the of HPV-associated In a that HPV infection among women were likely to have of cervical HPV infection than those HPV infects that are of those by a be informed that of against infection of the however, against infection of other anogenital is of many and most be to and during all of sexual have that the of HPV-associated diseases and in were likely to develop genital warts than those In a and women were likely to be with genital have been for cervical In a by and women were likely to have high lesions than those women were to have a risk of developing has that of HPV infection and in In this women with cervical were to a of for women The by which are however, the of virus viral the of other that be in the of in and the of HPV-associated CONSENSUS IS A HPV HPV-ASSOCIATED DISEASE women become with high risk HPV in the of develop precancerous lesions that progress to infection with high risk HPV types is a major for developing high preinvasive cervical High Risk HPV are the Infections It is that HPV is and that most sexually active become to HPV in many have that high risk HPV types are the most HPV infections develop or malignant anogenital the of of HPV is of for clinicians and health for women of all In a of high risk 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are risk for HPV infection and developing HPV-associated be in are risk for HPV infection and developing and have of with have of all in were with Therefore, the risk of HPV infection and developing is for the Because is associated with an risk of HPV infection, have with are an risk for HPV In of for HPV cervical HPV infection, for HPV infection with In a of sexually active of HPV infection between and for all groups (Fig. in are with to of for HPV to cervical HPV high risk HPV infections are the most infections in of HPV infection and squamous in have with squamous are a risk of developing precancerous and lesions than are have with women or those in The of low and high is high in as with HPV infection, of and high in all groups of (Fig. those with are an even risk of developing HPV-associated than a of were with high with of are to those observed for the of of were with high with of risk associated with the of high disease lower cell and infection with with a risk of developing high disease between and than those were The of high disease among with HPV infection was with of no HPV (Fig. to cervical infection, these the of HPV infection in the progression of for the of in with and HPV the in the was observed that of cancer than women for cervical cancer in the suggest that women develop cervical cancer and that as many as develop is to be in of develop cancer found that a risk of developing cancer with the It be that all are risk for developing all with the risk of developing squamous cell cancer among of is than for for cancer in has been and has that in life would be with other clinical preventative CONSENSUS HPV A GENITAL HPV vaccines for HPV are to anogenital HPV infection in women and are likely to greatly the HPV-associated health HPV vaccines be particularly to women have sexual however, sexually active are to vaccine HPV types from vaccination HPV vaccines to be and in preventing infection in be for vaccination and are likely to the public health and be as vaccines become HPV vaccination has to be an to morbidity and vaccination has the of infection by for B, for and and has and (Fig. that against HPV infection are in the of clinical and have the to greatly the HPV-associated disease have the of HPV vaccines are of the major of the HPV is in a such as or into or that the of HPV in and have that of are and no genetic Because are have no or and are for as of in and that to HPV preventing into The vaccines were to in to the and of in the HPV and HPV a of women of with no history of abnormal cervical cytology and no history of genital warts were to between and 100 of or and and were for vaccines among women with high of by (Fig. in and of women with HPV and HPV were with the as the most HPV in women with HPV of the HPV as vaccines were in women of were to a of HPV vaccine or and were for a of the vaccination genital were to for HPV DNA and to the of HPV infection, as of HPV DNA or more the women the vaccine infection during the of the with cases of infection in the women the vaccine was in preventing of all women the vaccine and produced that were than those produced as a to HPV The vaccine was with no and in the vaccine of the with in the caused by a The from this the and of as vaccines and that vaccines can infection, the most risk for developing HPV-associated cervical Natural HPV infection to HPV are with HPV and of against infection with that HPV to other HPV to the public health HPV be to against the most HPV vaccines are in of clinical on a vaccine that is to against the most HPV HPV and would of all low cervical lesions and of high precancerous lesions and invasive HPV types would be to even more HPV-associated disease (Fig. A vaccine that against HPV types and as as low risk HPV types and would be to an of low cervical lesions and all cases of genital of these vaccines have and and have the to disease in cervical cancer with of HPV vaccine women of vaccine of 20 each of HPV and with or 1 and and women for to the 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longer the that against infection is of become an in be and of the be have been that have the and public health impact of with each focus on and because vaccination be most to the virus and sexual Although the average of sexual is in the many in of sexual many the become sexually active be into by and health for to In was to life by or life a of to a vaccination years. life have been for vaccination against and with each and The found that the of would HPV abnormal and cases of cervical A found that and cervical cancer of would in of in cervical cancer cases and in vaccination cervical cancer an in and an in this was more of the found that were into the cervical cancer of cervical cancer and of with of the most of and women was to be more in HPV infection and HPV-associated disease than that and women would in a in the of the women would by of and to be cervical cancer cases caused by HPV by a of and HPV-associated cancers by with a of and vaccine be by public health HPV vaccination to the of as as are HPV vaccines are to be in and vaccination vaccination of these groups to HPV in the vaccination of other such as women are with low or high cervical be is most and women be with each of the vaccine HPV vaccination would be to be vaccines are in is the consensus of this working that sexually active can from vaccination and be the to become CONSENSUS HEALTH CARE HPV and to be if are to be in cervical cancer and from health and be to vaccine an and Although vaccines debates among and other of vaccination against an infection transmitted through sexual and that are with other or because HPV vaccines are of vaccination be of sexual which the of disease prevention the of the vaccine with of risk of and health and to the disease and of the disease about vaccines and vaccine and such as vaccine are that were to be an would be In the of for vaccination because be as an of risk for an that be observed by health is that vaccination likely if the is a sexually active sexual or with that is risk for infection or be that of vaccination against HPV be as an of and an to be to vaccines for of the of and are and be It has been that vaccines against to a in and in sexual that are for or for sexual and these and to the most vaccination HPV and and It is that and women have a of the of the diseases HPV or the between genital HPV infection and genital warts, abnormal and cervical In 1 of women that of even women been with an abnormal or undergone the link between cervical and HPV have with of of HPV and of genital about HPV in was to be even of high that of the In than half of HPV as a of sexually active risk for an is that and be about the of HPV and the associated with have that many women are in about HPV and that efforts be on have sexual Although media of HPV has the of HPV DNA for cervical cancer of the is and HPV and to infection and Because and from health have been to be the most in to HPV and for and in and about to vaccination is of if the public health of 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