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The human papillomavirus (HPV) vaccine, HPV related diseases and cervical cancer in the post-reproductive years
Maturitas 65 (2010) 205–209
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
The human papillomavirus (HPV) vaccine, HPV related diseases and cervical cancer in the post-reproductive years Gerard Wain ∗ Gynaecological Oncology, Westmead Hospital, Hawksbury Road, Westmead, NSW 2145, Australia
a r t i c l e
i n f o
Article history: Received 14 November 2009 Received in revised form 3 December 2009 Accepted 3 December 2009
Keywords: Human papillomavirus HPV vaccine Cervical cancer HPV related neoplasia Cervical screening
a b s t r a c t Prophylactic HPV vaccines have demonstrated high efficacy against a range of HPV related diseases. They have been widely adopted as population health interventions in many jurisdictions and their routine use has been endorsed by the WHO. The development of these vaccines comes after an increased understanding of the natural history and epidemiology of HPV infection and disease in both males and females. Persistent HPV infection with oncogenic types induces malignant transformation in a range of epithelia including the cervix, anogenital regions, the penis and a number of head and neck sites. In relation to HPV disease prevention in the post-reproductive years, most infections occur soon after commencement of sexual activity but new infections do occur throughout the age spectrum. This reduces the likely impact of prophylactic vaccines in this population. The major impact on HPV related disease in this age group will come from advances in screening and early detection of HPV and neoplastic precursors. The most appropriate prevention for any individual man or women in this age group will be an individualised combination of vaccination, screening and early detection depending on the individual’s own circumstances. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural history of HPV related neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPV epidemiology in older men and women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sexual behaviour and transmission studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for HPV related diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPV vaccines including therapeutic vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction The introduction of HPV vaccines has been widely greeted as a triumph for science and medicine, but the promise of these vaccines appears to be largely a promise for future generations. Large numbers of adult men and women will have already been in contact with the virus and so the discussion is not about preventing these diseases with prophylactic vaccines, but of managing the consequences of pre-existing infection. While the vaccine itself may have
∗ Corresponding author. Tel.: +61 2 9845 6801; fax: +61 2 9845 8311. E-mail address: [email protected]. 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.12.002
limited value to the population already in post-reproductive years, it is worthwhile to explore what new dimensions the understanding of HPV viral carcinogenesis, epidemiology and prevention can bring to this population. Since the recognition of human papillomavirus (HPV) as a necessary cause of cervical cancer in the mid-80s, its role in a range of other human conditions has been increasingly recognised. HPV DNA has been associated with several different anogenital cancers other than cervical including the vulva, vagina, anus and penis. It has also been identified with an increasing proportion of head and neck cancers, including those of the oral cavity, oropharynx and larynx in both sexes.
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This review will aim to update the natural history of HPV infection in relation to the adult population and discuss new findings on the epidemiology of HPV in both the male and female population. New observations from the vaccine trials and new screening approaches are now available which will help to clarify and consider the optimal management and prevention of HPV related disease in this population. 2. Natural history of HPV related neoplasia HPVs are a very large family comprising >130 genotypes that have been cloned from different clinical lesions, numbered consecutively according to the timing of their discovery [1]. They classically infect either cutaneous or mucosal surfaces and approximately 40 genotypes have been associated with genital tract infections. They are classified according to their potential association with malignancy into those with high associations with malignant disease, known as high risk types and those less commonly associated with malignancy or low risk types. There are approximately 15 oncogenic types that infect the genital tract, but the two most frequently associated with malignancy are types 16 and 18, associated with at least 70% of cervical cancers. The two most common low risk types are types 6 and 11, responsible for more than 90% of anogenital warts. The natural history of genital tract HPV infection and the consequent risk of developing cervical cancer in women are well documented. HPV infection, replication and particle maturation occurs in the stratified squamous epithelia of skin and mucous membranes, with virus spread occurring by skin-to-skin contact. The absorption of HPV into the basal layer of stratified epithelia has now been well described and relies on a complex interaction between intact virions and basal keratinocytes probably via microabrasions of the epithelial surface that leave the basal lamina intact [2]. All subsequent events in the viral life-cycle are tightly linked to the differentiation of the keratinocyte [3]. Low risk viruses proceed to complete differentiation and production of mature viral particles. Oncogenic viruses produce viral proteins that induce neoplasia and there is evidence that these proteins alter the immune tolerance of the infection and the neoplastic process. Most people encounter genital HPV soon after the onset of sexual activity with the highest risk of contracting the infection in the first 5–10 years after commencing sexual activity, but the risk of new infection continues throughout a person’s life, particularly with exposure to new sexual partners or other means of contracting a sexually transmitted infection. The clinical consequences of infection will vary according to the type of HPV encountered. Most infections resolve spontaneously, presumably relying on the host’s immune system to clear the infection. The immune response to HPV infection has been recently summarised by Stanley [4]. Most individuals with HPV infections eventually mount an effective cell mediated immune response (CMI) so that infections and their associated lesions regress. Failure to develop an effective CMI response to clear or control infection results in persistence and in the case of oncogenic viruses, an increased probability of dysplasia or intraepithelial neoplasia and subsequent invasive carcinomas. For whatever reason, some individuals do not clear their infections, and if they are caused by oncogenic varieties of HPV, this persistence will lead to overexpression of oncogenic viral proteins, the loss of cellular control mechanisms and the potential for malignant transformation. Factors contributing to the delay between HPV infection and clearance relate to the minimal disturbance and cellular injury of the infected epithelial cells, lack of dendritic cell activation and the capacity of viral proteins to evade innate immune recognition by specially inhibiting and suppressing components of the innate immune system.
Prophylactic HPV vaccines generate high levels of neutralising antibody and prevent incorporation of the infectious virion into the basal keratinocytes. The available vaccines have shown no therapeutic benefit on existing infections or lesions [5] and it is unlikely that vaccines influence the CMI response to existing infections. This highlights the importance of vaccine administration prior to exposure for any potential benefit. The maximum efficacy demonstrated with the prophylactic vaccines has been in HPV naïve populations prior to exposure [6,7]. Efficacy of the quadrivalent vaccine in women aged 24–45 years has been reported [8]. The reported reduced efficacy of the vaccines in older sexually active populations almost certainly reflects infection prior to the administration of the vaccine with the neoplastic process already underway, rather than reduced activity or immunogenicity of the vaccine. There have been no reported studies of vaccine efficacy in women older than 45 years and there are unlikely to be population benefits for mass vaccination programs in this age group.
3. HPV epidemiology in older men and women Most of the worldwide burden of HPV related disease is attributable to HPV infections acquired during the reproductive years although the long time frame from infection to clinical disease means that some neoplastic manifestations of the infection do not appear till beyond the reproductive years. Control of HPV disease therefore needs to take into account the long time frame from infection, when prophylactic vaccines will have a role in prevention, and then screening and early detection at a later point in the course of the disease. The incidence of cervical cancer peaks in mid-adult life and continues to rise with advancing years. The peak incidence of vulva cancer, of which approximately 50% are HPV related, is well beyond menopause, although recent evidence suggests a decline in the median age of those vulval cancers related to HPV. Most HPV related neoplasias in males reach peak incidence in later years, although the age incidence will be lower in immunocompromised populations. The time from infection to clinical disease with low risk types such as 6 and 11 is usually much shorter than for oncogenic varieties. Although most genital warts are seen soon after the commencement of sexual activity new presentations of warts are reported across the age spectrum, indicating that new infections continue to occur in older age groups. In a study of teenage university students, the median time between detection of incident HPV 6 or 11 infection and detection of genital warts was 2.9 months compared to the median time for detection of CIN 2–3 from detection of HPV was 14.1 months [9]. In studies of Columbian women, all age groups followed in the study demonstrated new infections over a 5-year period, even though these new infections were less frequent in the older women [10]. Data from health insurance funds in the US show that new presentations of genital warts occur throughout the age spectrum into the post-reproductive years [11]. Overall HPV prevalence in women has been reported in multiple populations, but estimates will vary according to previous screening practices and sexual activities of the population. Studying a population of Costa Rican women who had previously been unscreened, Herrero et al. reported an overall prevalence of 26.4%: 18.2% of the women were infected with a single type and 8.2% of the women were infected with at least 2 HPV types [12]. Oncogenic types and non-oncogenic types were detected in 13.7% and 17.5% of the women, respectively. The age-specific prevalence of oncogenic HPV types decreased from 24.4% in the women aged <25 years to 9.7% and 9.8% in the women aged 35–44 and 45–54 years, respectively. A second peak in the prevalence of oncogenic types reached a maximum of 12.6% in the women aged more than 65 years.
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This second peak in older women has been widely observed in many populations but is notably absent in others, raising the question of its significance in relation to the rising incidence of cervical cancer in most older populations. Whether it reflects longstanding persistence from earlier infection, with technical failure of detection due to presumed low viral load not reaching detection threshold, some manifestation of diminished immune tolerance or the acquisition of new infections from recent sexual activity remains unresolved. Resolution of this uncertainty will underlie any potential benefit from prophylactic vaccines in this older population and clarify the relative roles of prevention and detection in relation to disease in this age group. In a study of HPV prevalence among cytologically normal middle-aged women in Spain, Colombia, and Brazil, the prevalence of HPV DNA was positively associated with the number of lifetime sexual partners and inversely associated with the levels of family income and with age at first sexual intercourse [13]. HPV infection in the external genital tract of men has been detected in a range of 1.8–73% of healthy men [14]. The wide range of reported incidence reflects different sampling methods and anatomical sites sampled. In general the age range of men in whom infection is detected is higher than in women and serological evidence of infection appears later in men than in women. Population studies of HPV serology demonstrate different age-specific patterns of positivity in male and female patients peak prevalence occurring later in males than in females [15]. One infection is detected, viral persistence of oncogenic infections in men, compared to women, appears to be shorter with higher clearance rates. Differences in prevalence by age are not as significant in men as in women suggesting a difference in immunological tolerance and response between the sexes. A serologic response to HPV infection is not entirely protective against disease, and the quadrivalent vaccine trials indicated a statistically significant benefit in disease protection for serologically positive, DNA negative women who received the vaccine [16]. The vaccine appeared to prevent reinfection or reactivation of disease with vaccine HPV types compared to women in the placebo arm who continued to develop disease.
4. Sexual behaviour and transmission studies As a sexually transmitted disease, considerations of risk of acquiring new HPV infections needs to be considered in the context of the sexual behaviour of the individual and their partner or partners and the transmissibility of the infection. Both of these aspects are relevant to the consideration of new HPV infections in the post-reproductive years. Doherty et al. have discussed the question of sexual networks and their consequences in relation to the spread of STIs in a review [17]. Sexual networks are made up of individuals who are sexually connected either directly or indirectly. Social network analysis entails the study of ties among people and how the structure and quality of such ties affect individuals and overall group dynamics. Social determinants of sexual networks pertain to the underlying social, economic, cultural and political forces at play in a particular society or region. Clearly social norms in one society may be vastly different in another and so generalisations about specific groups can be misleading when applied to another population. They may also evolve with time introducing cohort differences among specific populations. The impact of the introduction of contraception during the last 50 years has vastly changed the nature of sexual behaviour in most populations. The concept of sexual mixing is also relevant to HPV transmission. Sexual mixing provides an assessment of the types of contact patterns within and across groups. Assortative mixing (like with
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like) relates to sexual contact between groups with similar risk of infection based on recognised risk factors such as age. Dissortative mixing (like with unlike) occurs when people from different risk groups, for example different age groups, participate in sexual contact. Dissortative mixing has been shown repeatedly to increase the odds of acquiring any STI. Most sexual networks conform to assortative mixings, but with changing social norms such behaviour cannot be assumed on an individual basis. The timing of specific sexual relationships also has implications for HPV transmission. For example, multiple concurrent partnerships will increase the exposure to active HPV infections and increase the risk of transmission. Even serial monogamy or nonoverlapping partnerships may not be protective given the relatively long duration of infection within individuals. In studying female university students, Winer et al. showed that among sexually active women who were HPV negative at enrolment to the study, current smoking, current oral contraceptive use, increasing cumulative number of sexual partners and male partners’ number of prior sex partners, and knowing a partner for less than 8 months before engaging in sexual intercourse were all significant predictors for contracting new HPV infection [18]. It is likely that similar risks would likely apply in older men and women. When considering an individual, the characteristic sexual behaviour of both the individual and their partner, and whether either may be exposed to new infection, will determine the overall risk of new acquisition HPV infection. Such calculations will be very difficult on an individual basis due to the nature of the information required to fully inform such an assessment. In relation to HPV transmission, the data on transmissibility is limited but available evidence suggests high degrees of transmissibility. In studying acquisition of HPV after first penetrative sexual intercourse in women aged 18–24 years, Winer et al. reported a 12month cumulative incidence of HPV infection after reporting a first sex partner of 28.5%, which increased to 39.2% at 24 months and 49.1% at 36 months [19]. In univariate analysis, women reporting partners with 2, ≥3 or an unknown number of previous partners and women whose partners were aged 22–42 years were more likely to acquire HPV than women reporting partners with no previous partners or women whose partners were aged 16–19 years. Age at first intercourse was not statistically associated with the risk of HPV acquisition. In multivariate analysis, the only variable that remained statistically significant was partner’s number of previous partners. In a recent Danish study, the major risk factor for acquisition of new HPV was the number of recent partners not the number of lifetime number of partners, suggesting that recent sexual history is more important than lifetime history [20]. When assessing the incidence of HPV infection in men, the same research group found a 24-month cumulative incidence of genital HPV infection in 240 19–20-year-old college students was 62.4% for any type of HPV, 47.9% for high risk HPV types, 19.5% for HPV-16 and 8% for HPV-6 and HPV-11 [21]. A report of a new sex partner 0–4 months and 5–8 months before assessment and a history of cigarette smoking were statistically significant on multivariate analysis.
5. Screening for HPV related diseases Cervical HPV disease represents the most prevalent HPV disease and organised screening for cervical cancer with conventional cervical cytology has been one of the great public health success stories. Screening for other HPV related disease in either men or women has not been established as cost effective and is not routinely applied. Well-organised population based screening programs have demonstrated dramatic reductions in incidence and mortality from
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cervical cancer [22]. The integration of new technology and understanding of the viral nature of this disease introduce new challenges for the prevention of disease. In a recent editorial, Schiffman and Solomon commented that “it is a challenging time to be a clinician or health planner dedicated to cervical cancer prevention” [23]. They went on to comment that “even though an increasingly powerful set of prevention tools is available, no combination of vaccination, cytology, HPV testing, colposcopy, and novel methods will be suitable for all settings” and this comment most particularly applies to the older population who may have been previously exposed to HPV infection. Numerous studies have looked at various combinations of conventional cytology, liquid based (LBC) and automated cytology and HPV based screening programs. The limitations of population coverage with conventional cytology in relation to recruitment and participation in screening and to the technical issues related to sensitivity and specificity of cytology have been widely discussed. The addition of newer technology such as liquid based and automated cytology have produced conflicting results in terms of sensitivity although well conducted independent meta-analyses have failed to demonstrate any convincing or cost effective advantage from this technology despite continuing commercial pressures and wide adoption in several jurisdictions [24]. With the viral aetiology of cervical cancer well established, interest in using HPV detection methods in screening has been widely explored. Application of automated molecular techniques potentially overcomes many of the quality and workforce issues associated with cytology. Population screening with HPV has demonstrated a significant reduction in mortality in an unscreened Indian population [25]. The major problem with HPV based screening is a loss of specificity and high false positive rates, but this usually reflects the higher point prevalence of transient HPV infections in the younger population. It is more reliable in the older population. One approach is to incorporate detection of persistent infections into the screening algorithms but such approaches are difficult to promote in a cancer screening paradigm. Population based longitudinal data confirm that detection of oncogenic HPV types is extremely common on a cross-sectional screening but that the large majority of infections clear quickly regardless of age. With greater duration of persistence, the chance for subsequent clearance declined and the risk of CIN 2+ diagnosis among persisting infections rose [26]. When applied to an older population, HPV testing is more sensitive, more specific and has a very reliable positive and negative predictive value. A further way of minimising false positive screening results is to apply a further triage to women who test positive to HPV. When HPV testing is used with cytology triage, as demonstrated in a recent very large randomised Finnish study, this approach is more sensitive and more specific than conventional cytology and these results were more pronounced in women over the age of 35 years [27]. Such an approach could introduce efficiencies to the screening program, allowing reductions in frequency of screening for screen negative women and would address the productivity and workforce issues that are features of all cytology based screening programs [28]. As the evidence from more population studies are presented, each expected to show similar results, the pressure to modify existing cytology based screening programs to incorporate molecular virological techniques will be very strong.
6. HPV vaccines including therapeutic vaccines Prophylactic HPV vaccines against the L1 viral proteins of HPV have demonstrated high efficacy and have been widely adopted in many jurisdictions. The WHO has recommended routine vaccina-
tion of sexually naïve adolescents [29]. The role of these vaccines in previously exposed individuals is more uncertain but is likely to offer protection against future infections. For the sexually active individual therefore, it will always be a personal risk assessment regarding the likelihood of acquiring new infections based on the issues discussed above. Unfortunately the available prophylactic HPV vaccines have shown little or no therapeutic efficacy against established HPV neoplasia. This probably reflects the fact that papillomavirus is a non-lytic virus that divides only in epithelial keratinocytes. The major oncogenic proteins (E6 and E7) are expressed early in the basal layer and thrive within an immune protected milieu. E6 binds to p53 and E7 binds to pRb preventing exit from the cell cycle. Cells continue to divide permitting ongoing replication of the virus genome. E7 has been shown to be more highly expressed in cancer cells and is more immunogenic than E6. This molecular environment makes intervention with therapeutic vaccines a major challenge. Therapeutic vaccines directed against E6 and E7 have been a common theme in clinical trials, but none have so far demonstrated consistent therapeutic efficacy [30]. All vaccines face formidable obstacles in the need to break immunological tolerance by vaccination, antigen loss on tumour cells and local secretion of immunosuppressive cytokines by neoplastic cells. A recent report however, using long peptide vaccine against HPV 16 oncoproteins E6 and E7, did show clinical responses against HPV 16-positive vulvar intraepithelial neoplasia related to induction of HPV 16-related immunity [31]. This latter study suggests that clinical research with these newer vaccines should be pursued. 7. Summary In general men and women in the post-reproductive years will fail to benefit from the development of the current prophylactic HPV vaccines. They remain at risk for a range of HPV related disease however. Significant advances in the understanding of the transmission of HPV, its role in the natural history of many diseases and developments in the detection of HPV infection and neoplasia, particularly in relation to cervical cancer have major implications for the prevention of HPV disease in this age group. Contributor Dr. Gerard Wain, Director of Gynaecological Oncology, Westmead Hospital, Westmead, NSW 2145, Australia. Competing interests The author has participated in research studies of HPV vaccines and received travel support and speakers fees from Merck and CSL Ltd. Provenance Commissioned and externally peer reviewed. References [1] de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004;324:17–27. [2] Stanley M. Immune responses to human papillomavirus. Vaccine 2006;(Suppl. 1):S16–22. [3] Doorbar J. The papillomavirus life cycle. J Clin Virol 2005;32(Suppl. 1):S7–15. [4] Stanley M. A practitioner’s guide to understanding immunity to human papillomavirus. US Obstet Gynecol 2009;4:2–7. [5] Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 virus like particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007;298:743–53.
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[18] Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218–26. [19] Winer RL, Feng Q, Hughes JP, O’Reilly S, Kiviat NB, Koutsky LA. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis 2008;197:279–82. [20] Nielsen A, Iftner T, Munk C, Kjaer S. Acquisition of high-risk human papillomavirus infection in a population-based cohort of Danish women. Sex Transm Dis 2009;36:609–15. [21] Partridge JM, Hughes JP, Feng Q, et al. Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students. J Infect Dis 2007;196:1128–36. [22] IARC. IARC handbooks of cancer prevention. Cervix cancer screening, vol. 10. Lyon, France: International Agency for Research on Cancer Press; 2005. [23] Schiffman M, Solomon D. Screening and prevention methods for cervical cancer. JAMA 2009;302:1809–10. [24] Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared to conventional cervical cytology: a systematic review and metaanalysis. Obstet Gynecol 2008;111:167–77. [25] Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Eng J Med 2009;360:1385–94. [26] Rodriguez AC, Sciffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008;100:513–7. [27] Leinonen M, Nieminen P, Kotaniemi-Talonen L, et al. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst 2009;101:1–12, doi:10.1093/jnci/djp367. [28] Franco EL. A new generation of studies of human papillomavirus: DNA testing in cervical cancer screening. J Natl Cancer Inst 2009;101:1–2, doi:10.1093/jnci/djp392. [29] World Health Organisation. Human papillomavirus vaccines: WHO position paper. Weekly epidemiological record, vol. 84. WHO; 2009 [http://www.who.int/wer] pp. 117–132. [30] Ruutu M, Frazer I, Liu X. Therapeutic vaccination against cervical cancer—are we near? Cancer Forum 2008;32:98–103. [31] Kenter G, Welters M, Valentijn A, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. NEJM 2009;361:1838–47.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
The human papillomavirus (HPV) vaccine, HPV related diseases and cervical cancer in the post-reproductive years Gerard Wain ∗ Gynaecological Oncology, Westmead Hospital, Hawksbury Road, Westmead, NSW 2145, Australia
a r t i c l e
i n f o
Article history: Received 14 November 2009 Received in revised form 3 December 2009 Accepted 3 December 2009
Keywords: Human papillomavirus HPV vaccine Cervical cancer HPV related neoplasia Cervical screening
a b s t r a c t Prophylactic HPV vaccines have demonstrated high efficacy against a range of HPV related diseases. They have been widely adopted as population health interventions in many jurisdictions and their routine use has been endorsed by the WHO. The development of these vaccines comes after an increased understanding of the natural history and epidemiology of HPV infection and disease in both males and females. Persistent HPV infection with oncogenic types induces malignant transformation in a range of epithelia including the cervix, anogenital regions, the penis and a number of head and neck sites. In relation to HPV disease prevention in the post-reproductive years, most infections occur soon after commencement of sexual activity but new infections do occur throughout the age spectrum. This reduces the likely impact of prophylactic vaccines in this population. The major impact on HPV related disease in this age group will come from advances in screening and early detection of HPV and neoplastic precursors. The most appropriate prevention for any individual man or women in this age group will be an individualised combination of vaccination, screening and early detection depending on the individual’s own circumstances. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural history of HPV related neoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPV epidemiology in older men and women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sexual behaviour and transmission studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for HPV related diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HPV vaccines including therapeutic vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction The introduction of HPV vaccines has been widely greeted as a triumph for science and medicine, but the promise of these vaccines appears to be largely a promise for future generations. Large numbers of adult men and women will have already been in contact with the virus and so the discussion is not about preventing these diseases with prophylactic vaccines, but of managing the consequences of pre-existing infection. While the vaccine itself may have
∗ Corresponding author. Tel.: +61 2 9845 6801; fax: +61 2 9845 8311. E-mail address: [email protected]. 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.12.002
limited value to the population already in post-reproductive years, it is worthwhile to explore what new dimensions the understanding of HPV viral carcinogenesis, epidemiology and prevention can bring to this population. Since the recognition of human papillomavirus (HPV) as a necessary cause of cervical cancer in the mid-80s, its role in a range of other human conditions has been increasingly recognised. HPV DNA has been associated with several different anogenital cancers other than cervical including the vulva, vagina, anus and penis. It has also been identified with an increasing proportion of head and neck cancers, including those of the oral cavity, oropharynx and larynx in both sexes.
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This review will aim to update the natural history of HPV infection in relation to the adult population and discuss new findings on the epidemiology of HPV in both the male and female population. New observations from the vaccine trials and new screening approaches are now available which will help to clarify and consider the optimal management and prevention of HPV related disease in this population. 2. Natural history of HPV related neoplasia HPVs are a very large family comprising >130 genotypes that have been cloned from different clinical lesions, numbered consecutively according to the timing of their discovery [1]. They classically infect either cutaneous or mucosal surfaces and approximately 40 genotypes have been associated with genital tract infections. They are classified according to their potential association with malignancy into those with high associations with malignant disease, known as high risk types and those less commonly associated with malignancy or low risk types. There are approximately 15 oncogenic types that infect the genital tract, but the two most frequently associated with malignancy are types 16 and 18, associated with at least 70% of cervical cancers. The two most common low risk types are types 6 and 11, responsible for more than 90% of anogenital warts. The natural history of genital tract HPV infection and the consequent risk of developing cervical cancer in women are well documented. HPV infection, replication and particle maturation occurs in the stratified squamous epithelia of skin and mucous membranes, with virus spread occurring by skin-to-skin contact. The absorption of HPV into the basal layer of stratified epithelia has now been well described and relies on a complex interaction between intact virions and basal keratinocytes probably via microabrasions of the epithelial surface that leave the basal lamina intact [2]. All subsequent events in the viral life-cycle are tightly linked to the differentiation of the keratinocyte [3]. Low risk viruses proceed to complete differentiation and production of mature viral particles. Oncogenic viruses produce viral proteins that induce neoplasia and there is evidence that these proteins alter the immune tolerance of the infection and the neoplastic process. Most people encounter genital HPV soon after the onset of sexual activity with the highest risk of contracting the infection in the first 5–10 years after commencing sexual activity, but the risk of new infection continues throughout a person’s life, particularly with exposure to new sexual partners or other means of contracting a sexually transmitted infection. The clinical consequences of infection will vary according to the type of HPV encountered. Most infections resolve spontaneously, presumably relying on the host’s immune system to clear the infection. The immune response to HPV infection has been recently summarised by Stanley [4]. Most individuals with HPV infections eventually mount an effective cell mediated immune response (CMI) so that infections and their associated lesions regress. Failure to develop an effective CMI response to clear or control infection results in persistence and in the case of oncogenic viruses, an increased probability of dysplasia or intraepithelial neoplasia and subsequent invasive carcinomas. For whatever reason, some individuals do not clear their infections, and if they are caused by oncogenic varieties of HPV, this persistence will lead to overexpression of oncogenic viral proteins, the loss of cellular control mechanisms and the potential for malignant transformation. Factors contributing to the delay between HPV infection and clearance relate to the minimal disturbance and cellular injury of the infected epithelial cells, lack of dendritic cell activation and the capacity of viral proteins to evade innate immune recognition by specially inhibiting and suppressing components of the innate immune system.
Prophylactic HPV vaccines generate high levels of neutralising antibody and prevent incorporation of the infectious virion into the basal keratinocytes. The available vaccines have shown no therapeutic benefit on existing infections or lesions [5] and it is unlikely that vaccines influence the CMI response to existing infections. This highlights the importance of vaccine administration prior to exposure for any potential benefit. The maximum efficacy demonstrated with the prophylactic vaccines has been in HPV naïve populations prior to exposure [6,7]. Efficacy of the quadrivalent vaccine in women aged 24–45 years has been reported [8]. The reported reduced efficacy of the vaccines in older sexually active populations almost certainly reflects infection prior to the administration of the vaccine with the neoplastic process already underway, rather than reduced activity or immunogenicity of the vaccine. There have been no reported studies of vaccine efficacy in women older than 45 years and there are unlikely to be population benefits for mass vaccination programs in this age group.
3. HPV epidemiology in older men and women Most of the worldwide burden of HPV related disease is attributable to HPV infections acquired during the reproductive years although the long time frame from infection to clinical disease means that some neoplastic manifestations of the infection do not appear till beyond the reproductive years. Control of HPV disease therefore needs to take into account the long time frame from infection, when prophylactic vaccines will have a role in prevention, and then screening and early detection at a later point in the course of the disease. The incidence of cervical cancer peaks in mid-adult life and continues to rise with advancing years. The peak incidence of vulva cancer, of which approximately 50% are HPV related, is well beyond menopause, although recent evidence suggests a decline in the median age of those vulval cancers related to HPV. Most HPV related neoplasias in males reach peak incidence in later years, although the age incidence will be lower in immunocompromised populations. The time from infection to clinical disease with low risk types such as 6 and 11 is usually much shorter than for oncogenic varieties. Although most genital warts are seen soon after the commencement of sexual activity new presentations of warts are reported across the age spectrum, indicating that new infections continue to occur in older age groups. In a study of teenage university students, the median time between detection of incident HPV 6 or 11 infection and detection of genital warts was 2.9 months compared to the median time for detection of CIN 2–3 from detection of HPV was 14.1 months [9]. In studies of Columbian women, all age groups followed in the study demonstrated new infections over a 5-year period, even though these new infections were less frequent in the older women [10]. Data from health insurance funds in the US show that new presentations of genital warts occur throughout the age spectrum into the post-reproductive years [11]. Overall HPV prevalence in women has been reported in multiple populations, but estimates will vary according to previous screening practices and sexual activities of the population. Studying a population of Costa Rican women who had previously been unscreened, Herrero et al. reported an overall prevalence of 26.4%: 18.2% of the women were infected with a single type and 8.2% of the women were infected with at least 2 HPV types [12]. Oncogenic types and non-oncogenic types were detected in 13.7% and 17.5% of the women, respectively. The age-specific prevalence of oncogenic HPV types decreased from 24.4% in the women aged <25 years to 9.7% and 9.8% in the women aged 35–44 and 45–54 years, respectively. A second peak in the prevalence of oncogenic types reached a maximum of 12.6% in the women aged more than 65 years.
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This second peak in older women has been widely observed in many populations but is notably absent in others, raising the question of its significance in relation to the rising incidence of cervical cancer in most older populations. Whether it reflects longstanding persistence from earlier infection, with technical failure of detection due to presumed low viral load not reaching detection threshold, some manifestation of diminished immune tolerance or the acquisition of new infections from recent sexual activity remains unresolved. Resolution of this uncertainty will underlie any potential benefit from prophylactic vaccines in this older population and clarify the relative roles of prevention and detection in relation to disease in this age group. In a study of HPV prevalence among cytologically normal middle-aged women in Spain, Colombia, and Brazil, the prevalence of HPV DNA was positively associated with the number of lifetime sexual partners and inversely associated with the levels of family income and with age at first sexual intercourse [13]. HPV infection in the external genital tract of men has been detected in a range of 1.8–73% of healthy men [14]. The wide range of reported incidence reflects different sampling methods and anatomical sites sampled. In general the age range of men in whom infection is detected is higher than in women and serological evidence of infection appears later in men than in women. Population studies of HPV serology demonstrate different age-specific patterns of positivity in male and female patients peak prevalence occurring later in males than in females [15]. One infection is detected, viral persistence of oncogenic infections in men, compared to women, appears to be shorter with higher clearance rates. Differences in prevalence by age are not as significant in men as in women suggesting a difference in immunological tolerance and response between the sexes. A serologic response to HPV infection is not entirely protective against disease, and the quadrivalent vaccine trials indicated a statistically significant benefit in disease protection for serologically positive, DNA negative women who received the vaccine [16]. The vaccine appeared to prevent reinfection or reactivation of disease with vaccine HPV types compared to women in the placebo arm who continued to develop disease.
4. Sexual behaviour and transmission studies As a sexually transmitted disease, considerations of risk of acquiring new HPV infections needs to be considered in the context of the sexual behaviour of the individual and their partner or partners and the transmissibility of the infection. Both of these aspects are relevant to the consideration of new HPV infections in the post-reproductive years. Doherty et al. have discussed the question of sexual networks and their consequences in relation to the spread of STIs in a review [17]. Sexual networks are made up of individuals who are sexually connected either directly or indirectly. Social network analysis entails the study of ties among people and how the structure and quality of such ties affect individuals and overall group dynamics. Social determinants of sexual networks pertain to the underlying social, economic, cultural and political forces at play in a particular society or region. Clearly social norms in one society may be vastly different in another and so generalisations about specific groups can be misleading when applied to another population. They may also evolve with time introducing cohort differences among specific populations. The impact of the introduction of contraception during the last 50 years has vastly changed the nature of sexual behaviour in most populations. The concept of sexual mixing is also relevant to HPV transmission. Sexual mixing provides an assessment of the types of contact patterns within and across groups. Assortative mixing (like with
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like) relates to sexual contact between groups with similar risk of infection based on recognised risk factors such as age. Dissortative mixing (like with unlike) occurs when people from different risk groups, for example different age groups, participate in sexual contact. Dissortative mixing has been shown repeatedly to increase the odds of acquiring any STI. Most sexual networks conform to assortative mixings, but with changing social norms such behaviour cannot be assumed on an individual basis. The timing of specific sexual relationships also has implications for HPV transmission. For example, multiple concurrent partnerships will increase the exposure to active HPV infections and increase the risk of transmission. Even serial monogamy or nonoverlapping partnerships may not be protective given the relatively long duration of infection within individuals. In studying female university students, Winer et al. showed that among sexually active women who were HPV negative at enrolment to the study, current smoking, current oral contraceptive use, increasing cumulative number of sexual partners and male partners’ number of prior sex partners, and knowing a partner for less than 8 months before engaging in sexual intercourse were all significant predictors for contracting new HPV infection [18]. It is likely that similar risks would likely apply in older men and women. When considering an individual, the characteristic sexual behaviour of both the individual and their partner, and whether either may be exposed to new infection, will determine the overall risk of new acquisition HPV infection. Such calculations will be very difficult on an individual basis due to the nature of the information required to fully inform such an assessment. In relation to HPV transmission, the data on transmissibility is limited but available evidence suggests high degrees of transmissibility. In studying acquisition of HPV after first penetrative sexual intercourse in women aged 18–24 years, Winer et al. reported a 12month cumulative incidence of HPV infection after reporting a first sex partner of 28.5%, which increased to 39.2% at 24 months and 49.1% at 36 months [19]. In univariate analysis, women reporting partners with 2, ≥3 or an unknown number of previous partners and women whose partners were aged 22–42 years were more likely to acquire HPV than women reporting partners with no previous partners or women whose partners were aged 16–19 years. Age at first intercourse was not statistically associated with the risk of HPV acquisition. In multivariate analysis, the only variable that remained statistically significant was partner’s number of previous partners. In a recent Danish study, the major risk factor for acquisition of new HPV was the number of recent partners not the number of lifetime number of partners, suggesting that recent sexual history is more important than lifetime history [20]. When assessing the incidence of HPV infection in men, the same research group found a 24-month cumulative incidence of genital HPV infection in 240 19–20-year-old college students was 62.4% for any type of HPV, 47.9% for high risk HPV types, 19.5% for HPV-16 and 8% for HPV-6 and HPV-11 [21]. A report of a new sex partner 0–4 months and 5–8 months before assessment and a history of cigarette smoking were statistically significant on multivariate analysis.
5. Screening for HPV related diseases Cervical HPV disease represents the most prevalent HPV disease and organised screening for cervical cancer with conventional cervical cytology has been one of the great public health success stories. Screening for other HPV related disease in either men or women has not been established as cost effective and is not routinely applied. Well-organised population based screening programs have demonstrated dramatic reductions in incidence and mortality from
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cervical cancer [22]. The integration of new technology and understanding of the viral nature of this disease introduce new challenges for the prevention of disease. In a recent editorial, Schiffman and Solomon commented that “it is a challenging time to be a clinician or health planner dedicated to cervical cancer prevention” [23]. They went on to comment that “even though an increasingly powerful set of prevention tools is available, no combination of vaccination, cytology, HPV testing, colposcopy, and novel methods will be suitable for all settings” and this comment most particularly applies to the older population who may have been previously exposed to HPV infection. Numerous studies have looked at various combinations of conventional cytology, liquid based (LBC) and automated cytology and HPV based screening programs. The limitations of population coverage with conventional cytology in relation to recruitment and participation in screening and to the technical issues related to sensitivity and specificity of cytology have been widely discussed. The addition of newer technology such as liquid based and automated cytology have produced conflicting results in terms of sensitivity although well conducted independent meta-analyses have failed to demonstrate any convincing or cost effective advantage from this technology despite continuing commercial pressures and wide adoption in several jurisdictions [24]. With the viral aetiology of cervical cancer well established, interest in using HPV detection methods in screening has been widely explored. Application of automated molecular techniques potentially overcomes many of the quality and workforce issues associated with cytology. Population screening with HPV has demonstrated a significant reduction in mortality in an unscreened Indian population [25]. The major problem with HPV based screening is a loss of specificity and high false positive rates, but this usually reflects the higher point prevalence of transient HPV infections in the younger population. It is more reliable in the older population. One approach is to incorporate detection of persistent infections into the screening algorithms but such approaches are difficult to promote in a cancer screening paradigm. Population based longitudinal data confirm that detection of oncogenic HPV types is extremely common on a cross-sectional screening but that the large majority of infections clear quickly regardless of age. With greater duration of persistence, the chance for subsequent clearance declined and the risk of CIN 2+ diagnosis among persisting infections rose [26]. When applied to an older population, HPV testing is more sensitive, more specific and has a very reliable positive and negative predictive value. A further way of minimising false positive screening results is to apply a further triage to women who test positive to HPV. When HPV testing is used with cytology triage, as demonstrated in a recent very large randomised Finnish study, this approach is more sensitive and more specific than conventional cytology and these results were more pronounced in women over the age of 35 years [27]. Such an approach could introduce efficiencies to the screening program, allowing reductions in frequency of screening for screen negative women and would address the productivity and workforce issues that are features of all cytology based screening programs [28]. As the evidence from more population studies are presented, each expected to show similar results, the pressure to modify existing cytology based screening programs to incorporate molecular virological techniques will be very strong.
6. HPV vaccines including therapeutic vaccines Prophylactic HPV vaccines against the L1 viral proteins of HPV have demonstrated high efficacy and have been widely adopted in many jurisdictions. The WHO has recommended routine vaccina-
tion of sexually naïve adolescents [29]. The role of these vaccines in previously exposed individuals is more uncertain but is likely to offer protection against future infections. For the sexually active individual therefore, it will always be a personal risk assessment regarding the likelihood of acquiring new infections based on the issues discussed above. Unfortunately the available prophylactic HPV vaccines have shown little or no therapeutic efficacy against established HPV neoplasia. This probably reflects the fact that papillomavirus is a non-lytic virus that divides only in epithelial keratinocytes. The major oncogenic proteins (E6 and E7) are expressed early in the basal layer and thrive within an immune protected milieu. E6 binds to p53 and E7 binds to pRb preventing exit from the cell cycle. Cells continue to divide permitting ongoing replication of the virus genome. E7 has been shown to be more highly expressed in cancer cells and is more immunogenic than E6. This molecular environment makes intervention with therapeutic vaccines a major challenge. Therapeutic vaccines directed against E6 and E7 have been a common theme in clinical trials, but none have so far demonstrated consistent therapeutic efficacy [30]. All vaccines face formidable obstacles in the need to break immunological tolerance by vaccination, antigen loss on tumour cells and local secretion of immunosuppressive cytokines by neoplastic cells. A recent report however, using long peptide vaccine against HPV 16 oncoproteins E6 and E7, did show clinical responses against HPV 16-positive vulvar intraepithelial neoplasia related to induction of HPV 16-related immunity [31]. This latter study suggests that clinical research with these newer vaccines should be pursued. 7. Summary In general men and women in the post-reproductive years will fail to benefit from the development of the current prophylactic HPV vaccines. They remain at risk for a range of HPV related disease however. Significant advances in the understanding of the transmission of HPV, its role in the natural history of many diseases and developments in the detection of HPV infection and neoplasia, particularly in relation to cervical cancer have major implications for the prevention of HPV disease in this age group. Contributor Dr. Gerard Wain, Director of Gynaecological Oncology, Westmead Hospital, Westmead, NSW 2145, Australia. Competing interests The author has participated in research studies of HPV vaccines and received travel support and speakers fees from Merck and CSL Ltd. Provenance Commissioned and externally peer reviewed. References [1] de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004;324:17–27. [2] Stanley M. Immune responses to human papillomavirus. Vaccine 2006;(Suppl. 1):S16–22. [3] Doorbar J. The papillomavirus life cycle. J Clin Virol 2005;32(Suppl. 1):S7–15. [4] Stanley M. A practitioner’s guide to understanding immunity to human papillomavirus. US Obstet Gynecol 2009;4:2–7. [5] Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 virus like particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007;298:743–53.
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[18] Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 2003;157:218–26. [19] Winer RL, Feng Q, Hughes JP, O’Reilly S, Kiviat NB, Koutsky LA. Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis 2008;197:279–82. [20] Nielsen A, Iftner T, Munk C, Kjaer S. Acquisition of high-risk human papillomavirus infection in a population-based cohort of Danish women. Sex Transm Dis 2009;36:609–15. [21] Partridge JM, Hughes JP, Feng Q, et al. Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students. J Infect Dis 2007;196:1128–36. [22] IARC. IARC handbooks of cancer prevention. Cervix cancer screening, vol. 10. Lyon, France: International Agency for Research on Cancer Press; 2005. [23] Schiffman M, Solomon D. Screening and prevention methods for cervical cancer. JAMA 2009;302:1809–10. [24] Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared to conventional cervical cytology: a systematic review and metaanalysis. Obstet Gynecol 2008;111:167–77. [25] Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Eng J Med 2009;360:1385–94. [26] Rodriguez AC, Sciffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008;100:513–7. [27] Leinonen M, Nieminen P, Kotaniemi-Talonen L, et al. Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting. J Natl Cancer Inst 2009;101:1–12, doi:10.1093/jnci/djp367. [28] Franco EL. A new generation of studies of human papillomavirus: DNA testing in cervical cancer screening. J Natl Cancer Inst 2009;101:1–2, doi:10.1093/jnci/djp392. [29] World Health Organisation. Human papillomavirus vaccines: WHO position paper. Weekly epidemiological record, vol. 84. WHO; 2009 [http://www.who.int/wer] pp. 117–132. [30] Ruutu M, Frazer I, Liu X. Therapeutic vaccination against cervical cancer—are we near? Cancer Forum 2008;32:98–103. [31] Kenter G, Welters M, Valentijn A, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. NEJM 2009;361:1838–47.