Review

Impact of HPV immunization on the detection of cervical disease Expert Review of Vaccines Downloaded from informahealthcare.com by Nyu Medical Center on 07/14/15 For personal use only.

Expert Rev. Vaccines 13(4), 533–544 (2014)

Ami J Munro* and Margaret E Cruickshank Department of Obstetrics and Gynecology, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen, AB25 2ZD, UK *Author for correspondence: Tel.: +44 012 2443 8434 [email protected]

Human papillomavirus (HPV) is the primary cause of cervical cancer and genital warts. The development of HPV vaccines has been a major advance in the prevention of these diseases. Recent studies have shown promising early effects of HPV immunization programs on cervical abnormalities and genital warts, with evidence of herd immunity against genital warts also emerging in Australia. Further studies are required to not only continue monitoring the effect of the HPV immunization on the incidence of these diseases, but also to establish the effect the immunization will have on cervical screening programs and the performance of colposcopy. KEYWORDS: cervical screening • CIN • colposcopy • genital warts • HPV • HPV vaccine

Aims

To review emerging evidence on the impact of HPV vaccination on HPV prevalence and cervical disease and to discuss the potential impacts on cervical screening programs. The review was conducted using papers from the past 5 years (2008–2013). Papers older than this were excluded unless for an overriding purpose. Article

HPV is a sexually transmitted infection that can cause anogenital and oropharyngeal cancers as well as genital warts [1,2]. The virus is relatively common: it is estimated that sexually active adults have a 75% lifetime risk of acquiring an HPV infection [3]. Skin-to-skin and mucosa-to-mucosa contact are the two main modes of transmission for HPV infections. This means that condoms are not entirely effective at preventing transmission as it can still be transmitted via the surrounding skin [4]. HPV is responsible for 99.7% of cases of invasive cervical cancer [5]. The discovery that HPV was the principal cause of this disease made the virus the first necessary cause of a cancer to be discovered [2–4,6]. There is sufficient evidence to meet a causality criterion, which has been approved by the International Agency for Research on Cancer [1,7,8]. informahealthcare.com

10.1586/14760584.2014.894468

Worldwide, cervical cancer is the second most common cancer in women and is a major healthcare issue [4,7,9,10]. It is estimated that 500,000 cases of cervical cancer develop every year and over 250,000 women die as a result of the disease [4]. In contrast to most other malignancies, cervical cancer has a peak incidence in younger women aged 35–55 years old, making it a significant cause of death in women during their age of highest productivity. Primarily a disease of the developing world, where 80% of cases occur, the incidence and mortality of cervical cancer are lower in developed countries where advances have been made in both treatment and screening programs for the disease [1,4,9]. Cervical intraepithelial neoplasia (CIN) is the term used to describe histological changes in premalignant lesions. CIN can be classified as grade 1, 2 or 3 according to the proportion of the epithelial thickness occupied by abnormal undifferentiated cells. If untreated, then it is estimated that at least 40% of CIN3 would progress to invasive cancer [5]. Routine cervical screening by cytology, which aims to detect CIN before any progression to cancer, could prevent 80% of cases of cervical cancer occurring [6]. Cervical cancer prevention programs vary considerably between countries, but countries with established national cervical screening programs with high population-based

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uptake and systematic call and recall for screening have been shown to have lower incidence and mortality rates for cervical cancer. Cervical screening was introduced to Scotland in 1987 and is offered to all women aged between 20 and 60 years old. The program successfully reduced the incidence of cervical cancer by over 40% between 1986 and 2003 [11]. In the rest of the UK, women are invited to attend for screening every 3 years from the age of 25–50 years and every 5 years from the age of 50–64 years. The impact of organized screening has been reported from other countries too. For example, in Australia, women are screened using a cervical cytology test every 2 years from the age of 18 until the age of 69 years. Since the National Cervical Screening Program was established in 1991, the incidence and mortality of cervical cancer have halved [12]. At present, liquid-based cytology (LBC) is used in the UK for cervical sampling. This involves the use of a brush-like device to collect exfoliated cells from the transformation zone of the cervix. These cells are stained and examined for nuclear changes associated with CIN. The introduction of LBC has led to a significant decrease in the number of unsatisfactory test results [11]. Women who are identified by the screening test as having cervical changes are invited to attend for colposcopy, a procedure in which the cervix is magnified and illuminated in order to examine it in greater detail, allowing biopsies to be taken and treatment to be administered [13]. Colposcopy is a somewhat subjective investigation, with studies reporting the sensitivity as ranging from 52 to 98% [6,14]. Despite this, colposcopy has established itself as a core component of the cervical screening program and is essential for both the diagnosis and treatment of CIN.

than those used for cytology-based screening programs. A recent follow-up of four randomized trials has provided evidence that supports the initiation of HPV-based screening from the age of 30 and extending screening intervals to 5 years or more. These studies involved a total of 176,464 women aged 20–64 and were conducted in the UK, Sweden, the Netherlands and Italy. The women were randomly assigned to HPV- or cytology-based screening, and the efficacy of each test for prevention of invasive cancer was compared. The studies found that HPV-based screening provides 60–70% greater protection against invasive cervical carcinomas compared with cytology [18]. In 2008, a joint European cohort study investigating the long-term predictive values of cytology and HPV testing in cervical cancer screening recommended that screening intervals could be safely increased to every 6 years in women who tested negative for HPV. This study involved 24,295 women and was conducted in seven centers across Europe. It found that the cumulative incidence rate of CIN3+ after 6 years was considerably lower in women who tested negative for HPV compared with those who had negative cytology results [19]. Although the role of colposcopy is unlikely to change, the characteristics and size of the population attending for colposcopy would be altered by the introduction of primary HPV testing. Colposcopists would no longer be seeing HPVnegative lesions that are not at risk of progressing to cervical cancer, but would be seeing a large number of patients with carcinogenic HPV infections that may have been detected at an early stage and would therefore have lesions that are difficult to detect by colposcopy. At present, there are no indications that the use of HPV testing will improve the performance of colposcopy [17].

Primary HPV testing

HPV & cervical cancer

In recent years, the role of HPV testing as part of cervical screening has been widely investigated. Testing for carcinogenic types of HPV has been shown to be more sensitive than cytology [15,16]. However, in younger women, in whom the presence of transient HPV infection is very common, the specificity of HPV testing is inadequate. There are many possibilities for the role of primary HPV testing: in the UK, it has been proposed that LBC may be replaced by HPV triage testing, whereby only patients who test positive for high-risk HPV would receive a cytology-based test [15]. This would identify the patients who are most at risk of developing cervical abnormalities, as well as decreasing the anxiety caused by repeated inadequate or borderline cytology tests. Given the low specificity in young women, it is also possible that potential screening programs using primary HPV testing will be restricted to women past the peak of sexual transmission, such as in the USA, where HPV testing is used in conjunction with cytology for women aged 30 years and older [17]. Given the high negative predictive value of HPV testing, it has been recommended that longer intervals should be used

The majority of HPV infections are cleared spontaneously. In approximately 10% of cases, however, the infection persists and may lead to precancerous or cancerous lesions of the cervix [4]. It is not known exactly why these 10% of cases progress, but various cofactors have been implicated. These cofactors amplify the risk of developing cervical cancer or CIN when present in women with a concurrent carcinogenic HPV infection [4]. Sexual risk factors, such as age at first intercourse and lifetime number of sexual partners, are cofactors that were associated with cervical cancer before the association with HPV was established. These risk factors are known as surrogate factors as they increase the risk of contracting HPV. Other cofactors such as multiparity, smoking and long-term use of oral contraceptives increase the risk of developing cervical cancer, but the exact mechanism by which this happens is unknown [4,20]. Women who are immunosuppressed, such as those who are HIV positive or have received an organ transplant, are at a much greater risk of persistent HPV infection and thus developing a precancerous or cancerous lesion. This is because their immune systems have a decreased ability to clear infections including HPV [4].

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Human papillomavirus

HPVs belong to the Papilloviridae family. Over 100 different genotypes of HPV have been identified and described, but only 40 are known to infect the lower genital tract [12]. HPV can be classified as a high-risk, probably high-risk or low-risk type [9], and almost all cases of cervical cancer are caused by one or more of 12 high-risk genotypes [4]. HPV16 and 18 carry the highest risk of HPV and are responsible for 70% of cervical cancer cases [21–23]. These genotypes are found in half of high-grade cervical abnormalities and a quarter of low-grade abnormalities [12]. It is harder to assign causality of low-grade abnormalities as infection with multiple HPV types is common in these cases [24]. Other known highrisk HPV types are 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Genital warts, or condylomata acuminata, are the most common sexually transmitted viral disease [25]. An estimated 30 million cases of genital warts occur worldwide each year [24]. HPV6 and 11 are two low-risk genotypes that are responsible for 90% of genital warts [12,26,27]. Although in 90% of cases, the virus is cleared by the immune system within 1 or 2 years of exposure, persistent infection with high-risk HPV can lead to precancerous or cancerous changes of the cervix. HPV16 is known to both demonstrate persistence and be identified in cancers more than other HPV genotypes, and therefore carries a higher rate of progression to precancerous cervical lesions [4,28]. A study of 599 women over the age of 18 years in Costa Rica found that HPV infections that persisted for longer than 12 months resulted in a 21% risk (95% CI: 15–28) of CIN2+ by 30 months. In women under the age of 30 years, this risk increased to 53% (95% CI: 29–76) if they were infected with HPV16 [28]. The shared mode of transmission means that women can be infected with multiple HPV types at once. It has been shown that women who have multiple HPV infections take longer to clear the infections, resulting in an increased risk of persistence and therefore CIN [4]. Women can be infected with the same type of HPV infection multiple times throughout their life. There are two theories for why this may be: one is that antibodies naturally developed after infection with HPV are not always formed in sufficient concentrations to confer protection against future infections with the virus [29], and the other is that the virus may be maintained in a latent state and can reemerge later in life [4]. Mechanism of HPV disease development

The HPV genome consists of 8 kbp single-stranded circular DNA and codes for eight genes. These genes are classified as either early (E) or late (L), depending on whether they are expressed in E or L stage of epithelial differentiation. E1, 2, 3, 5, 6 and 7 are expressed early, E4 is expressed throughout and L1 and 2 are expressed toward the end of differentiation [4,30]. E6 and E7 are the primary HPV oncogenes: they code for the proteins E6 and E7 both of which have multiple cellular targets. The most important of these targets are p53 and retinoblastoma tumor suppression protein (pRB). E6 inhibits informahealthcare.com

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p53, thus preventing apoptosis and allowing mutations to accumulate; and E7 inhibits pRB, which abrogates cell cycle arrest [4,7,31]. Throughout the infectious process, both of these proteins are expressed at low levels. At some point, however, their expression is dysregulated, which leads to their overexpression, disruption of the cell cycle and ultimately progression to CIN. The exact mechanism by which their expression is dysregulated is not known although it is thought that it could be as a result of either genetic or epigenetic changes [4]. In most cervical carcinomas, HPV genomes are found to be integrated into the cellular DNA. The changes that occur during viral DNA integration favor the maintenance and enhancement of E6 and E7 expression. Upon integration, the viral DNA is disrupted and recombination often occurs, resulting in focal deletions within the viral genes E1 or E2 [7,31]. As a consequence of these deletions, E6 and E7 are left coupled to the viral enhancer and promoter sequences in the HPV upstream regulatory region, allowing their expression to continue after integration. In addition, the expression of these oncogenes is enhanced as E2 disruption leads to derepression of the viral promoter [7,31]. HPV immunization

Until recently, health education programs promoting abstinence or condom use were the mainstay of primary HPV infection prevention [4]. The development of prophylactic HPV vaccines has been a major advance in the prevention of HPV infections and CIN. The vaccines were developed using HPV L1 virus-like particles. L1 proteins are the main components of the HPV virus capsid [1]. The recombinant L1 proteins are self-assembled into noninfectious capsids that do not contain any genetic material, but have sufficient resemblance to the viral capsid to induce antibodies when administered as an immunogen [30,32]. The vaccine is administered intramuscularly and induces titers of neutralizing antibodies that peak at least 100-times higher, then plateau at levels over 10-times higher, than the titers produced by natural infection [29,32]. To date, two virus-like particle vaccines have been commercialized: CervarixÒ and GardasilÒ. Cervarix, manufactured by GlaxoSmithKline, is a bivalent vaccine that protects against HPV16 and 18; whereas Gardasil, manufactured by Merck & Co., is a quadrivalent vaccine that offers protection against HPV6, 11, 16 and 18 [30,32]. The first of these vaccines was licensed in 2006, and it has received regulatory approval in over 100 countries worldwide [12,24]. In 2012, 51 countries worldwide had implemented either the bivalent or quadrivalent vaccine as part of their national immunization programs and a further 26 countries had implemented pilot programs [33]. In 2013, the Global Alliance for Vaccines and Immunisation (GAVI) announced that it had secured a deal to provide a sustainable supply of HPV vaccines to developing countries. By 2020, GAVI hopes to have vaccinated over 30 million girls in more than 40 developing countries [34]. 535

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The HPV vaccines were not designed to be therapeutic, and there is no evidence to show that HPV vaccines treat existing infections [4,35]. Because of this, they should ideally be administered before girls have become sexually active. This needs to be balanced against early administration as it needs to offer protection throughout the ages of 19–25 years, when girls have the highest risk of being exposed to HPV infection, and the duration of protection is only known to be at least 8 years at present [29,36].

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HPV vaccine efficacy

Although long-term data are not yet available for the HPV vaccines, a study published in 2012 by Roteli-Martins et al. [37] reported bivalent vaccine efficacy and immunogenicity up to 8.4 years, which is the longest analysis to date. The study found that the vaccine had a 95.1% (95% CI: 84.6–99.0) efficacy for preventing incident infection and 100% (95% CI: 79.8–100.0) efficacy against 6 months persistent infection. In addition, the study participants remained seropositive to HPV16/18 and were found to have antibody titers that were several times higher than those produced by natural infection [37]. Although the efficacy of the vaccine beyond 8.4 years is not yet known, mathematical calculations have predicted that increased antibody titers will remain present for at least 20 years [29]. These findings are similar to other studies, which have found the efficacy of the vaccine against HPV infection and HPV-associated diseases to range between 90 and 100% [35]. A long-term follow-up study of the quadrivalent vaccine in 1360 women aged 24–45 years has recently presented interim analysis showing that the vaccine is generally well tolerated and that the anti-HPV 6,11,16 and 18 responses have been maintained over 6.3 years. Further analyses will be conducted at years 8 and 10 [38]. Evidence of cross protection against other high-risk HPV types has also been recorded. Studies have found that the bivalent vaccine offers significant protection against HPV31, 33 and 52 and relatively strong protection against HPV45. The quadrivalent vaccine, however, only demonstrated significant cross protection against HPV31 [32]. It has been calculated that the quadrivalent vaccine has the potential to prevent about 70% of cervical cancers and 90% of genital warts [24,39]. The FUTURE I study is a Phase III trial, which was conducted to evaluate the efficacy of the quadrivalent HPV vaccine in preventing anogenital diseases (including genital warts and CIN). The randomized, placebo-controlled, double-blind trial enrolled 5455 women aged 16–24 years from 62 study sites worldwide. A total of 2723 women were assigned to receive the vaccine and 2732 received a placebo. For the primary analysis, intention to treat analysis was conducted including all participants, and analysis was also conducted in the ‘per protocol’ population (which only included women who tested negative for HPV6, 11, 16 and 18 at baseline: 2241 women in the vaccine group and 2258 in the 536

placebo group). Follow-up was conducted for an average of 3 years, and vaccine efficacy was found to be 100% (95% CI: 94–100) against cervical disease and in the per protocol population. In this same population, the vaccine efficacy was 100% (95% CI: 94–100) against vaginal, vulvar, perineal and perianal intraepithelial lesions or warts. In the intention-to-treat analysis, vaccine efficacy was found to be 55% (95% CI: 40–66) against cervical lesions. This reinforces the need to vaccinate girls prior to exposure to vaccinetype HPV infections [40]. The FUTURE II study is a larger randomized, double-blind trial involving 12,167 women aged 15–26 years from 90 study sites in 13 countries. In this study, 6087 women received the vaccine and 6080 received the placebo. Similarly, to FUTURE I, the subjects were followed for an average of 3 years, and analysis was conducted on both the per protocol and intention-to-treat basis. In the per protocol population, vaccine efficacy was 98% (95% CI: 86–100) against CIN2+. In the intention-to-treat population, efficacy was 44% (95% CI: 26–58) [41]. A combined analysis of these studies looking at the 4 years efficacy against low-grade cervical, vulvar and vaginal intraepithelial neoplasia and anogenital warts was published in 2010. The study found that in the per protocol population, the vaccine had 96% (95% CI: 91–98) efficacy for CIN1 and 99% (95% CI: 96–100) efficacy for genital warts [24]. The first country to implement a funded national HPV vaccination program was Australia. The quadrivalent vaccine has been given to girls in schools aged 12–13 years since April 2007. When the vaccine was first introduced, catch-up campaigns were launched and ran from July 2007 until December 2009: females aged 13–26 years were eligible to receive the vaccine either in schools (for those aged 13–17 years) or in the community (for those aged 18–26 years) [12]. The bivalent HPV vaccine was introduced in the UK as part of the school-based immunization program in September 2008 [22]. The vaccine was administered in three doses over 6 months (day 1, months 1 and 6) to girls aged 12–13 years [42,43]. The uptake rates for the HPV vaccine in the UK have been high: 90% of girls eligible for the vaccine in 2010/2011 received all three doses [44]. When the vaccine was initially introduced, a catch-up program to provide the vaccine for girls aged 14–17 (born after 1 September 1990) was also launched [21]. This campaign ended on 31 August 2011 [44]. In Autumn 2012, the bivalent vaccine was replaced with the quadrivalent vaccine in the UK school-based immunization program [45]. Impact of HPV on colposcopic features

It has been suggested that there is a link between HPV genotypes and colposcopic features in women with cervical abnormalities. To date, three studies have been conducted which examine this hypothesis. None of these studies was commenced with the aim of investigating the impact of HPV genotypes on Expert Rev. Vaccines 13(4), (2014)

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Impact of HPV immunization on the detection of cervical disease

colposcopic features and was instead substudies of larger studies as a result of incidental findings. In 2007, a substudy of the ASCUS–LSIL Triage study was conducted to examine the correlation between HPV genotypes and visual appearance of the cervix [46]. The study was conducted in the USA and involved 939 women aged 18–73 years (mean age 26.2 years) who had been referred for colposcopy with ASCUS or LSIL. This study found that HPV16 was more likely to produce lesions with clinically identifiable features than other HPV types, regardless of the histology result. This led them to suggest that women with HPV16-positive lesions were more likely to be detected, regardless of severity and that lesions associated with other HPV types may be more likely to be missed. This study was the first to hypothesize that the introduction of the HPV vaccination may alter the performance of colposcopy if fewer women were infected with HPV16. In 2010, a prospective multicenter comparative clinical trial was conducted to validate the use of the dynamic spectral imaging (DSI) colposcope [47]. This study, which took place in the Netherlands, involved 275 women with a mean age of 36.7 years (18.8–62.6 years). The majority of participants were referred for colposcopy with abnormal cytology (91.6%) and the remainder attended colposcopy for CIN follow-up. The study found that the sensitivity of the DSI colposcope for the detection of high-grade lesions was significantly improved when HPV16 was present and hypothesized that HPV16 may be associated with a greater degree of acetowhitening, upon which a diagnosis using DSI colposcopy is heavily based. A sub study of this validation trial, involving 177 women, took place in 2012 to further explore the relationship between high-risk HPV infections and colposcopic appearance [48]. This study also found that HPV16-positive lesions were significantly more likely to be detected than HPV16-negative lesions using a DSI colposcope. However, it found that conventional colposcopy had a higher sensitivity in non-HPV 16 lesions compared with HPV16 lesions. These findings were not of statistical significance, so the study concluded that the presence of HPV16 did not affect the colposcopic opinion using conventional colposcopy. This study also found that the effect of HPV16 has on the definition of clinical features is dependent on the final histology results, contradicting the findings of the first study examining the relationship between HPV genotypes and colposcopic appearance [46,48]. If the findings from ASCUS–LSIL Triage study are valid, then the introduction of the HPV vaccination may have a significant impact on the performance of colposcopy [46]. It would be expected that the prevalence of HPV16 and 18 would be significantly reduced in vaccinated women, and thus characteristic features may not be visible during colposcopy despite the presence of abnormal histology, making CIN harder to identify and treat. The findings of these studies should be treated with caution as it is possible that they may be influenced by the low informahealthcare.com

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prevalence of HPV16-negative CIN or differences in the natural history of HPV16 lesions compared with other HPV types. Impact of HPV immunization

To date, limited data are available on the impact of HPV immunization. Given that the aim of the immunization is to reduce deaths from cervical cancer, it could be 30 years before this can be measured. The long lead time between infection with HPV and development of malignancy means that highgrade CIN is often used as a surrogate marker of disease and can be used as an indication of vaccine efficacy [12]. In contrast to precancerous cervical lesions, genital warts develop over a few months. Because of this, many ecological studies have been conducted to examine the early impact of the quadrivalent vaccine on genital warts. It is hoped that the vaccine will have a similar effect on precancerous cervical lesions as it does on genital warts, and therefore examining the impact on genital warts provides an early indication of vaccine efficacy. Impact on genital warts

National surveillance data have been published recently on the impact of the HPV vaccine on genital warts in young Australians [49]. Australia successfully achieved high coverage of the quadrivalent vaccination, with 2010 rates showing that 73% of 12–13 year olds in schools received the full three doses of the vaccine. The coverage rates for the vaccine were lower in older age groups and lowest in those who were eligible for the vaccine in the community catch-up program [49]. Data from 2004 to 2011 were collected from eight sexual health services in Australia regarding the patients’ demographics and behavior as well as clinical diagnosis of genital warts. The data were divided into prevaccination period (January 2004 until June 2007) and postvaccination period (July 2007 until December 2011), and the proportion of patients with genital warts in each period was compared. The study found a significant decline in the proportion of young Australian women with genital warts in the postvaccination period. The largest decline was of 92.6% (from 11.5% in 2007 to 0.85% in 2011) in women under 21 years (p < 0.001). Indeed, in this same age category, no women who reported prior vaccination were found to have genital warts in 2011. A decline in genital warts was also found in women aged 21–30 years. The proportion of women diagnosed with genital warts in this age category fell by 72.6% from 11.3% in 2007 to 3.1% in 2011 (p < 0.001). No significant trend in the proportion of women diagnosed with genital warts was seen in women over the age of 30 years. The study also examined the impact of the HPV vaccination on genital warts in men. In the prevaccination period, the proportion of heterosexual men under the age of 21 years being diagnosed with genital warts had increased by 68% (p < 0.01). Following the introduction of the HPV vaccination, however, the proportion of men in this category being diagnosed with genital warts significantly decreased by 81.8% from 12.2 to 2.2% in 2011 (p < 0.001). This trend was also present in 537

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heterosexual men aged 21–30 years: the proportion of these men diagnosed with genital warts decreased by 51.1–8.9% in 2011 (p < 0.001). Similar to women over 30 years, no significant trend was seen in the proportion of men over 30 years being diagnosed with genital warts after the vaccine was introduced. The results of this study are very promising as they have shown that the introduction of the quadrivalent vaccine has successfully reduced the proportion of young women, who would have been offered vaccination, being diagnosed with genital warts. In addition, the decline in the proportion of young heterosexual men being diagnosed with genital warts indicates that the vaccination may offer a degree of herd immunity against genital warts. Although these data cannot be linked to an individual’s vaccination status, the fact that no cases of genital warts were detected in young women in the last year of the study, who reported that they had received the quadrivalent vaccine, is a very important finding and indicates that the eradication of genital warts may be possible in the future through cross protection against other HPV types that cause genital warts and herd immunity. In 2013, it was announced that Australia’s HPV school-based immunization program would be extended to include boys. The vaccine will now be offered to boys aged 12–13 years, and a catch-up campaign will be run for boys aged 14–15 years until the end of 2014 [50]. In Sweden, the quadrivalent HPV vaccine was made available in May 2007 to girls aged 13–17 years at a subsidized cost, and women outwith this age range had to pay a substantially higher price. There was no school-based immunization program, so the vaccination had to be requested from physicians or a vaccination center. As a result of this, the coverage was lower than other countries with school-based immunization programs: as of August 2011, 25% of Swedish girls aged 13–20 years were thought to have received at least one dose of the quadrivalent vaccine. Since then, a national school-based immunization program has been approved for girls aged 11–12 years, and a catch-up campaign will also be launched for girls aged 13–18 years. A study was conducted in Sweden to investigate the impact the quadrivalent vaccine had on the incidence of genital warts [27]. This study included the entire population aged 10–44 resident in Sweden between 2006 and 2010 and calculated the incidence of genital warts using the Prescribed Drug Register and the National Patient Register. Patients were considered to have had a case of genital warts if they had a diagnosis recorded in the National Patient Record, or if they had podophyllotoxin or imiquimod (the recommended primary treatments for genital warts) prescribed to them in the absence of any genital wart episode in the previous 6 months. The study found that the age-stratified incidence proportion of genital warts in 2010 was highest for women aged 20 years and for men aged 24 years. Between 2006 and 2010, there was a significant downward trend in genital warts in females aged 538

15–25 years (p < 0.0001). However, in this same time period, there was no significant trend in genital warts among men in Sweden (p = 0.71). Between 2006 and 2010, there was a decrease of over 25% in the incidence proportion of genital warts among 17- to 18-year old females (p < 0.001). Given that the vaccine coverage in Sweden was considerably lower than in Australia (25–30% compared with over 80% in Australia), it is not surprising that any decline in genital warts would be lower than in Australia. In addition with lower vaccine coverage, there was no indication of herd immunity offering protection to men. In the USA, the quadrivalent vaccine has been available since 2006 and, as of 2011, 35% of females aged 13–17 years had received all three doses [51]. A study was conducted in California to analyze trends in genital wart diagnoses using clinical encounter claims data from the California Family Planning Access Care and Treatment program [52]. In this group of lowincome individuals, it was found that the incidence of genital wart diagnoses decreased by 34.8% (Ptrend < 0.001) among women younger than 21 years. The incidence of genital warts also significantly decreased in women and men aged 21–25 years and men under the age of 21 years. Although vaccination status for the study subjects was not obtained, this study provided promising evidence of herd immunity against genital warts among young men and women in the USA. Although multiple ecological studies have been conducted, Denmark was the first country to assess the population effect of the HPV vaccine on the incidence of genital warts by using personal identification numbers to link vaccine status with genital wart diagnoses on the National Patient Register, which contains information on hospital admissions and outpatient visits. The quadrivalent HPV vaccine was introduced to the national childhood vaccination program in January 2009 and is given to girls aged 12 years. A catch-up vaccination was available for girls aged 13–15 years, and women born before 1993 were also offered the vaccination although they had to pay for it. Coverage rates for Denmark are exceptionally high, with 80% of girls born between 1993 and 1999 having received all three doses by February 2013. A total of 248,403 vaccinated and 151,367 unvaccinated women born between 1989 and 1999 were included in the study, and the median follow-up was 3.1 years for vaccinated and 3.5 years for unvaccinated women. The study found that the relative risk of genital warts among vaccinated girls was significantly lower compared with unvaccinated girls. The risk varied with age and was lower in the younger age groups in whom vaccine coverage was higher. In girls born between 1995 and 1996, the risk was 0.12 (95% CI: 0.04–0.36; p < 0.001). The risk could not be calculated for the youngest cohort (1997–1999) as there were no cases of genital warts identified. Impact on cervical abnormalities

A study investigating the early effect of the HPV vaccination on cervical abnormalities was conducted in Victoria, Australia [12]. This study used data from the Victorian Cervical Cytology Expert Rev. Vaccines 13(4), (2014)

Impact of HPV immunization on the detection of cervical disease

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Percentage of women positive for any HPV

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* 30 Non-vaccinated 3 doses

25

20

15

10

* *

5

0 6

11 16 18 26 31

33 35 39

42 43 44 45 51 52 53 56 58 59 66

68 70 73 82

HPCV type

Figure 1. 2012 surveillance data from 20-year old women in Scotland. A comparison of the prevalence of 24 genotypes between unvaccinated women and women who had received the full three doses of the bivalent vaccine. *p < 0.05. Data provided by Kevin Pollock and John Love, Health Protection Scotland (2013) [59].

Register between 2003 and 2009 and found that there had been a significant decrease (0.38%; p = 0.003) in high-grade cervical abnormalities in girls under the age of 18 years following the introduction of the HPV vaccine. There was no significant decrease in the incidence low-grade cervical abnormalities in this same age category or in women aged 18–20 years. This was expected as low-grade abnormalities can be caused by any one of the 40 genital HPV types, whereas HPV16 and 18 are strongly associated with highgrade abnormalities. No significant decrease in high-grade cervical abnormalities was detected in women aged over 18 years who would have received the vaccine in the catchup program. This reinforces the importance of vaccinating girls before they become sexually active. Further research on the impact of the quadrivalent vaccine on cervical abnormalities has since been conducted in Victoria, Australia by linking data from the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register. This included 14,085 unvaccinated and 24,871 vaccinated women attending cervical screening. The study observed a significant reduction in detection of high-grade cervical abnormalities in women who received the vaccine as part of the school-based immunization program compared with unvaccinated program: hazard ratio 0.72 (95% CI: 0.58–0.91) [53]. In the USA, where vaccine coverage is relatively low, a project has been set-up to monitor the impact of the HPV vaccine (HPV-IMPACT). Between 2008 and 2010, a pilot study was informahealthcare.com

conducted to provide baseline data on CIN2+ incidence and associated HPV genotypes. It is anticipated that the study will take place over 10 years and provide information on the early impact of the HPV vaccine on precancerous cervical lesions and associated HPV genotypes [54]. Impact on HPV prevalence

The prevalence of HPV genotypes following the introduction of the HPV immunization provides another measure of vaccine efficacy, as well indicating any cross protection that the vaccine offers. In addition, through surveillance data, it may be possible to monitor any nonvaccine types that are increasing in prevalence in women who have received the HPV immunization. Postvaccine surveillance has been conducted in Australia to investigate the impact of the quadrivalent vaccine on HPV prevalence. The study was conducted 5 years after the vaccination program was introduced and compared HPV genoprevalence in 1199 women aged 18–24 years attending for cervical screening in a prevaccine period (2005–2007) with a postvaccine period (2010–2011). The study found that the prevalence of all vaccine genotypes was significantly lower in the postvaccine period (7.0%) compared with the prevaccine period (28.7%, p < 0.001). This was found to be significantly associated with vaccination status (p < 0.001) [55]. FIGURE 1 is the 2012 surveillance data from Scotland, which are collected by Health Protection Scotland. Residual samples from cervical screening of women attending for first screen at 539

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once the impact this genotype had on cervical abnormalities can be measured. 2012 unvaccinated 2012 vaccinated At present, HPV56 accounts for less than HPV HPV Percentage of HPV HPV Percentage of 1% of cervical cancer cases [8]. The data type A type B total samples type A type B total samples from Australia currently indicate significant decline in high-grade cytology, but 52 66 1.46 52 66 1.95 it will be a number of years before we 66 1.07 56 66 1.95 16 can ascertain the full impact of disease 66 1.66 16 53 0.97 42 decline. The change in HPV types seen may explain the apparent lack of impact 16 59 0.97 51 56 1.66 on low-grade cytology, as HPV16 and 16 52 0.78 52 56 1.66 18 are rarer in low grade compared with high-grade disease. It is therefore very 16 31 0.68 42 51 1.46 important for surveillance data to be 16 42 0.68 42 56 1.46 collected as more women who would 16 45 0.68 51 59 1.46 have been offered the vaccination enter national screening programs. 16 58 0.68 53 56 1.46 The impact of these nonvaccine HPV 33 42 0.68 39 59 1.36 genotypes that are being identified also A comparison of the most common HPV genotype pairings present in unvaccinated women and women who needs to be examined. A study is curhad received the full three doses of the bivalent vaccine. Bold denotes vaccine type; Italic denotes low-risk type; Underlined denotes putative high risk. rently underway in the UK, Colposcopy Data provided by Kevin Pollock and John Love, Health Protection Scotland (2013) [59]. and HPV Genotypes Study, that is invesage 20 years are tested for HPV genotypes and linked to tigating which HPV genotypes are present in women who national data from the immunization program. This compares would have been offered the immunization and who have certhe prevalence of 24 HPV genotypes between unvaccinated vical abnormalities. This should provide an indication of which women and women who had received the full three doses of HPV genotypes are causing cervical abnormalities in vaccinated the bivalent HPV vaccine. It provides a clear indication women. This study is also investigating whether the HPV genthat the prevalence of HPV16 and 18 has declined in the vacci- otypes have an impact on colposcopic features in these women, nated population, as expected. In addition, the prevalence of in order to ascertain whether the findings of Jeronimo et al. HPV45 has also declined. This supports the data from the vac- will have an effect on the performance of colposcopy in vaccicine trials of the bivalent vaccine [2]. Interestingly, HPV56 nated women [46,56]. appears to have increased in prevalence and seems to be emerging as the most common high-risk HPV genotype in women Impact on cervical cancer screening programs who have received the bivalent immunization. This could relate The introduction of the HPV vaccine will not eliminate the to a genuine increase in prevalence or to ‘unmasking’ where need for cervical screening as 30% of cervical cancers are elimination of HPV16/18 allows detection by current HPV caused by HPV types that are not covered by the vaccine [35]. tests. The data collection is ongoing, and it is likely that the In addition, although protection against HPV16 and 18 by prevalence of HPV genotypes will continue to change over the the vaccine is shown to be high, it cannot be expected to be next few years as more vaccinated women enter the cervical absolute, and long-term protection remains unknown. screening program. It has been predicted that when vaccinated cohorts of young In Scotland, the Scottish Call Recall System provides an women enter screening programs, there will be a 40–60% accurate record of girls’ HPV vaccination status, allowing decrease in rates of colposcopic referrals as a result of a reducsurveillance data such as this to be collected and analyzed. tion in cervical lesions in these women [57]. Data have also been collected regarding the most common Cervical screening programs in countries that have intropairings of HPV genotypes that were present in women in duced the vaccine will need to be re-evaluated and possibly 2012 and are shown in TABLE 1. HPV52/66 remains the most changed over the coming years as the current method of highcommon pairing in this cohort of young women, regardless frequency cytology testing will most likely be too costly to run of vaccination status. It is evident that the prevalence alongside HPV vaccination programs. A reduction in the prevaof HPV16 has decreased, and HPV56 has increased in lence of cervical abnormalities will also lead to a consequent women who completed the three dose course of the bivalent reduction in the positive predictive value (PPV) of cytologyvaccine. based testing, further supporting the role of HPV-based screenThe prevalence of HPV genotypes in vaccinated women is a ing tests [17,57]. very important aspect of the impact of the HPV immunization. Some countries have already begun to change their screening The emergence of HPV56 as one of the most prevalent geno- programs as a result of the introduction of the HPV vaccinatypes is a finding that could have implications in the future tion. In Scotland, for example, the age of entry into the cervical

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Table 1. 2012 surveillance data from 20-year old women in Scotland.

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screening program will increase to 25 years in 2015. This is because it is anticipated that fewer abnormalities will be present in women who received the HPV vaccine as part of the routine school-based immunization program, in whom the coverage of immunization was very high [13,15,44]. As well as deciding on appropriate intervals and tests for vaccinated women, it is also important to maintain screening programs that are appropriate for unvaccinated women, particularly older women who are unlikely to benefit from herd immunity.

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Expert commentary

The development of HPV immunizations has been a major advance in cervical cancer prevention, as well as in the prevention of other anogenital cancers, oropharyngeal cancers and genital warts. The vaccines have consistently been shown to be highly effective in clinical trials and early published data, in particular regarding genital wart incidence and HPV prevalence, indicating that they are also effective in practice. Given the time delay between infection with the virus and the detection of cervical abnormalities, it will be many years before the full impact of the HPV immunization can be determined. The results from the recent study in Australia regarding the impact of the immunization on genital warts were very promising. Indeed, not only did the results show evidence of herd immunity, but they also indicated that the eradication of genital warts may be possible in the future in countries with successful HPV immunization programs. The suggestion that a reduction in HPV16-positive cervical lesions will have an impact on the performance of colposcopy should also be considered [46]. If this is the case, then it is possible that cervical abnormalities caused by nonvaccine types of HPV in vaccinated women may be more likely to be missed, thus creating the impression that there are less abnormalities in women who have received the HPV immunization. Further studies regarding the association between HPV genotypes and colposcopic appearance should be conducted in order to predict the impact the immunization will have on the performance of colposcopy. Given that the HPV vaccine was first launched in 2006, any women attending for routine cervical screening at present who have been vaccinated will have received the vaccine as part of a catch-up program. The uptake rates in catch-up programs were generally significantly lower than school-based immunization programs. This means that although it may be possible to detect the early effects of the vaccine on cervical abnormalities in these women at present, further studies should be conducted when women who received the vaccine as part of routine school-based immunization programs reach the age for routine cervical screening.

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Review

Five-year view

As girls who received the HPV immunization as part of school-based programs, in whom the coverage rates are very high, enter cervical screening programs, further studies regarding the impact of the immunization will emerge. The likely reduction in high-grade abnormalities in these women may result in changes to national cervical screening programs, to both the age and type of test that is performed. The emerging data, which shows a reduction in high-grade cytological changes but no difference in low-grade changes, may be accounted for by the increased prevalence of other HPV genotypes that are not associated with cervical cancer. This could mean that continuing to use cytology as the primary test for screening produces a low-PPV with large number of unnecessary referrals for colposcopy. It may take many years to identify the effect on high-grade CIN and indeed decades to determine the long-term effect of the HPV vaccine on cervical cancer mortality. During this time, new vaccines are likely to be developed such as the nonavalent vaccine that covers nine HPV types [58]. In countries where the quadrivalent immunization is used, there is likely to be a dramatic reduction in incidence of genital warts in both young females and heterosexual males, hopefully lowering the burden on sexual healthcare services. In Australia, the inclusion of boys in the vaccination program should also lead to reduction of genital warts and oropharyngeal cancers in men who have sex with men. Given that 80% of cases of cervical cancer occur in the developing world, it is hoped that the establishment of effective HPV immunization programs in these countries will have an even greater impact on the disease there. If the GAVI HPV immunization program is successful in the initial countries, then it is likely that the program will expand to cover even more developing countries. While the study of women who would have been offered HPV immunization is crucial, it is also important to maintain standards of prevention and treatment of cervical cancer in older women who were not eligible to receive the HPV immunization and do not appear to be benefiting from herd immunity. Vaccine efficacy beyond 8.4 years has not been determined, and for that reason, it is vital to establish or maintain effective cervical screening programs. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Key issues • HPV is the primary cause of cervical cancer, as well as other anogenital cancers, oropharyngeal cancers and genital warts. • The introduction of a vaccination against HPV6, 11, 16 and 18 has been a major advance in the prevention of these diseases. • Both the quadrivalent and bivalent vaccines have been shown to be highly effective in Phase III clinical trials. • Early data indicate that the introduction of the quadrivalent immunization has led to a decrease in incidence of genital warts in young women who have received the vaccine. • Incidence of genital warts has also decreased in young heterosexual men and unvaccinated young women, indicating that herd immunity may be created with high uptake rates. • The incidence of high-grade cervical abnormalities has decreased in women under the age of 18 years following the introduction of the

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immunization [12]. • The decrease of HPV16-positive cervical lesions may have an impact on the performance of colposcopy in cervical screening programs beyond that expected with lower disease prevalence. • Further studies are required in the future to determine the long-term effect of the HPV immunization on genital warts, cervical abnormalities, anogenital and oropharyngeal cancers.

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