Integrating Human Papillomavirus Vaccination in ...

Public Health Genomics 2009;12:352–361 DOI: 10.1159/000214925

Published online: August 11, 2009

Integrating Human Papillomavirus Vaccination in Cervical Cancer Control Programmes Eduardo L. Franco a, b François Coutlée a, f Alex Ferenczy c–e Departments of a Oncology, b Epidemiology and Biostatistics, c Pathology, and d Obstetrics and Gynecology, McGill University, e Jewish General Hospital, and f Département de Microbiologie et Infectiologie, Centre Hospitalier de l’Université de Montréal, Montréal, Qué., Canada

Key Words Cervical cancer ⴢ Human papillomavirus ⴢ Screening ⴢ Vaccination ⴢ Pap cytology

Abstract Screening with Pap cytology has substantially reduced cervical cancer morbidity and mortality during the last 50 years in high-income countries. Unfortunately, in resource-poor countries, Pap screening has either not been effectively implemented or has failed to reduce cervical cancer rates. Cervical cancer in these countries thus remains a major public health problem. Infection with certain human papillomavirus (HPV) types is now recognized as a necessary cause of this disease and has led to new preventive strategies for cervical cancer. Testing for HPV DNA of oncogenic types is gaining increasing interest and application in cervical cancer screening. It has much greater sensitivity and only slightly lower specificity than Pap cytology. Molecular-based screening will be of particular clinical value in the post-vaccine era in which cervical disease will be a rare event and may escape cytology-based detection. As a primary screening test followed by Pap triage of HPV-positive cases, HPV testing has the potential to improve the overall quality of screening programmes, thus allowing for increased testing intervals, which would lower program costs with acceptable safety. Prophylactic vaccines against the 2 leading oncogenic HPV

© 2009 S. Karger AG, Basel 1662–4246/09/0126–0352$26.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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types (16 and 18) have been recently licensed. In large clinical trials, they have shown excellent safety and nearly 100% efficacy in preventing persistent infections and the cervical pre-cancers due to vaccine HPV types 16 and 18. Combining modern screening techniques and universal prophylactic HPV vaccination is likely to produce the most advanced and cost-effective preventive strategy to fight cervical cancer worldwide. Copyright © 2009 S. Karger AG, Basel

Introduction

Cervical cancer is an invasive neoplastic disease for which preventive measures have been among the most successful in the Western industrialized world. Indeed, in high-income countries, screening with the Pap test, whether organized or opportunistic, has resulted in a 70– 80% reduction in cervical cancer incidence and mortality during the last 50 years. By analogy with other cancer prevention goals, we are still far from reaching the expected equivalent target of 80% reduction in lung cancer incidence via tobacco cessation. Likewise, public health efforts in screening for other male or female neoplasms represent much less ambitious targets for cancer control. Unfortunately, in most developing countries cervical cancer screening has not been implemented or has had Prof. Eduardo Franco McGill University, Division of Cancer Epidemiology 546 Pine Avenue West Montreal, Qué., H2W 1S6 (Canada) Tel. +1 514 398 6032, Fax +1 514 398 5002, E-Mail [email protected]

Eastern Africa Southern Africa Melanesia Caribbean Central America Western Africa South America Polynesia Middle Africa South Central Asia South-Eastern Asia Eastern Europe Northern Africa Southern Europe Western Europe Micronesia Northern Europe North America Incidence Mortality

Eastern Asia Australia/New Zealand

Fig. 1. Average annual incidence and mor-

Western Asia

tality rates for cervical cancer by region. Standardization according to the age structure of world population of 1960. Source: GLOBOCAN, 2002 [1].

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limited impact and, as a result, cervical cancer remains an important public health problem in these countries. It is, in fact, the second most common malignant neoplasm affecting women worldwide, with nearly 500,000 new cases diagnosed in 2002, about 80% of which were in developing countries [1]. As shown in figure 1, the highest risk areas for cervical cancer are in Southern and Eastern Africa, Melanesia, the Caribbean, and Central and South America, with average incidence rates well above 30 per 100,000 women per year. These regions and others in the developing world also experience a disproportionately high mortality compared with that of developed countries. The relatively recent understanding of the necessary causal connection between infection with certain types (the so-called high-risk, or oncogenic types) of human papillomavirus (HPV) and cervical cancer [2–4] has paved the way for initiating new approaches to cervical cancer prevention. The advent of testing for DNA of oncogenic HPVs has considerably improved the potential for detecting pre-cancerous lesions and early intervention in screening programmes (i.e. secondary preven-

tion). Prophylactic HPV vaccination will likely prove to be the ultimate solution in primary prevention of cervical cancer. In this overview we summarize the key developments in this field and examine the opportunity for efficient integration of these 2 preventive fronts in cervical cancer control.

HPV Vaccination in Cervical Cancer Control

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Shortcomings of Pap Cytology Screening

Although universal deployment of organized or opportunistic screening with the Pap test in high-income countries has led to substantial reductions in cervical cancer morbidity and mortality, the necessary economic burden imposed by cervical cancer screening with cytology is substantial. In most Western countries, for each new case of invasive cancer found by the Pap test, there are between 50 and 100 cases of abnormal smears consistent with squamous intra-epithelial lesions (SIL) of the low-grade (LSIL) and high-grade (HSIL) variants. These require clinical management [5]. Additionally, there are 353

at least twice as many cases of equivocal or borderline atypias, also known as ‘atypical squamous cells of undetermined significance’ (ASC-US). Altogether, ASC-US and SIL cytological abnormalities can account for 5–10% of all Pap smears that are processed in screening programs in Western countries [6]. Overall, their triage and management impose a great financial burden on the healthcare system of countries that can afford to maintain opportunistic or organized cervical cancer screening programs. Pap cytology has other important limitations. First, the quality of collected samples is critical to obtain accurate readings of cellular alterations. The unsatisfactory rate may be as high as 10% in routine practice and thus a substantial proportion of tests have to be repeated. Poorquality samples may not contain diagnostic cells and may lead to false-negative tests (absence of cells in smears from women who have lesions). Second, cytology is based on subjective interpretation of morphological alterations of exfoliated cervical cells and is, therefore, associated with interpretative and screening errors. For example, one cytologist’s HSIL may be another’s LSIL or yet another’s negative test. The highly repetitive nature of screening smears, most of which are negative, leads to fatigue that invariably causes screening errors in interpretation and missed lesions (laboratory false negatives). A meta-analysis that included only studies unaffected by verification bias indicated that the average sensitivity of Pap cytology to detect histologically verified cervical intra-epithelial neoplasia or invasive cervical cancer was 51% and its average specificity was 98% [7]. Therefore, the Pap test’s high false-negative rate has been its most critical limitation. False-negative diagnoses have important medical, financial and legal implications; the latter being a particularly acute problem in North America where false-negative smears are among the most frequent reasons for malpractice litigation in gynaecology [5]. The advent of liquid-based cytology as opposed to the traditional glass-slide cytological smear has improved the efficiency in processing cervical samples in screening programs, but the limitations of interpretative cytology remain the same [8]. This low sensitivity for an individual testing opportunity must be compensated via heightened surveillance: women entering screening age with an initially negative Pap test must repeat it at least twice over the next 2–3 years before they can be safely followed as part of a routine screening schedule [9, 10]. This effectively brings the screening program sensitivity to acceptable levels, but safeguards must be in place to ensure compliance, coverage and quality, which are costly undertakings that have worked well only in 354


Western industrialized countries. However, in practice, physicians mindful of the sensitivity limitation or simply following ‘clinical reflex’ tend to take annual Pap tests, which make cytology screening an inefficient and costly process. Many developing countries that have invested in screening programs have yet to witness a reduction in cervical cancer burden. In these countries, failure to reach and follow women at high risk of cervical cancer has been the greatest limitation of screening cytology. Finally, the reductions in cervical cancer incidence seen in many Western countries have reached levels that cannot be further decreased, which brings a sense of diminishing returns in light of the costs.

HPV Testing in Cervical Cancer Screening

In view of the above shortcomings of Pap testing and the discovery of the connection between HPV and cervical cancer, there has been great enthusiasm for the adoption of new molecular-based technologies to improve the accuracy and efficiency of cervical cancer screening. Among these, HPV DNA testing has been the one eliciting the greatest interest in most Western countries. There are primarily 2 technologies for this purpose. The hybrid capture assay (Qiagen Inc.) is currently the only FDA-approved and clinically validated cervical screening test worldwide. It combines nucleic acid hybridization and an enzyme-linked immunoassay, resulting in signal amplification and detection of 13 high-risk HPV DNA genotypes in cervical specimens. HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 are associated with the vast majority of all cervical cancers. As a parallel technology, different PCR protocols have been used in research settings. PCR protocols are based on target (HPV DNA) amplification using type-specific or consensus or general primers followed by hybridization with specific oligoprobes. PCR techniques to detect HPV DNA as well as other target amplification assay types are currently under validation for clinical licensing and are expected to be commercially available [see related article in this issue: ‘Detection and typing of human papillomavirus nucleic acids in biological fluids’ by Coutlée et al., pp 308–318). In North America, the AmplicorTM PCR HPV DNA assay (Roche Inc.) has been approved for clinical use in Canada and regulatory approval is expected in the USA. HPV testing found its first application niche in triaging equivocal (ASC-US) Pap tests [10, 11]. It is a suitable and cost-effective option in deciding whether or not such cases need to be referred for colposcopy [12]. However, Franco /Coutlée /Ferenczy

the most promising application of HPV testing is in primary cervical cancer screening. There have been several studies assessing the value of HPV testing compared to the Pap test as a cervical cancer screening tool in European, African, Asian, Latin American and North American populations, many of which are randomized controlled trials [13–19]. HPV testing has been shown to have 30–40% higher sensitivity than cytology but somewhat lower (5–10%) specificity for detecting high-grade lesions [20–23]. Screening women older than 30 years tends to improve the performance of HPV testing because cervical HPV infections in this age group are less likely to be of a transient nature than those in younger women. Of note is the fact that the combination of cytology and HPV DNA testing (dual or co-testing) attains very high sensitivity and negative predictive values (approaching 100%). This could potentially allow increasing screening intervals safely, for example from 1–3 years to 3–5 years, depending on the population. The drawback of this approach, however, is the excessive number of patients who would need to be referred for colposcopy initially, many of whom would turn out to be lesion free. Despite the extra costs related to the secondary triage of these cases, resource-rich and risk-averse countries such as the USA find this strategy cost-saving over time. This is because of the extension in the screening interval for women who are cytology and HPV negative [10]. As a result, co-testing with Pap and HPV has become popular in the USA following its approval in screening guidelines by the American Cancer Society and professional societies [24– 26]. However, a caveat to this approach is that the Pap test adds little to the already very high sensitivity of the HPV test and increases screening costs. A more sensible way to screen is to use the highly sensitive HPV DNA test as a first-line screen and the highly specific Pap test as a second-line screen (triage) in women who test HPV DNA positive (HPV/Pap triage). This approach, similar to that in use for syphilis and HIV, is theoretically appealing also for screening of women vaccinated against HPV (see below) [27–29]. Despite its much greater accuracy and efficiency in detecting existing high-grade cervical lesions, the HPV/Pap triage paradigm has not yet been adopted for primary screening because of lack of long-term follow-up studies on the safety of extended screening intervals. However, a recent pooled analysis of European studies has shown that the risk of interval pre-cancer in women with negative HPV DNA tests is, in fact, much lower than that conferred by a negative Pap test. In other words, a negative HPV DNA test provides more reassurance to a woman HPV Vaccination in Cervical Cancer Control

that she is at a low risk while she awaits the next screening opportunity [30]. This new line of evidence will eventually assist policymakers in defining acceptable screening intervals based on HPV testing.

Cervical Cancer Prevention via HPV Vaccination

Two prophylactic vaccines (Gardasil쏐 or SilgardTM, Merck Inc., and Cervarix쏐, GlaxoSmithKline Inc.) have been licensed in the past 2 years. Both contain the 2 most important oncogenic genotypes (16 and 18). Gardasil also contains HPV-6 and -11 immunogens. The latter HPV types are responsible for most external anogenital warts and between a quarter and half of low-grade vulvo-vaginal lesions. In randomized, double-blind, placebo-controlled clinical trials, these vaccines have been nearly 100% efficacious in preventing incident persistent infections with the target types as well as precancerous highgrade lesions that are caused by these viruses in young women aged 16–26 years who had no prior exposure to HPVs 6, 11, 16, 18 [31–34] (see the review ‘Prevention of human papillomavirus infections and associated diseases by vaccination: a new hope for public health’ by Harper, this issue, pp 319–330). Mathematical models of the impact of these vaccines have projected a substantial public health benefit in most geographical areas [35–38]. The licensure of HPV vaccines have prompted a broad discussion regarding the most appropriate public health policy for whether and how to implement these vaccines in many countries throughout the world. The key issues are cost, target age for vaccination, and concerns regarding vaccination for a sexually-transmitted infection [39]. Currently, the very high cost of HPV vaccines would impose an unacceptable burden on the health care budgets of developing countries and most middle-income countries, which have the highest rates of cervical cancer globally. International agencies such as the Global Alliance of Vaccines and Immunization (GAVI), the Pan American Health Organization Revolving Fund and UNICEF could play an important role in easing the introduction and implementation of vaccines to developing countries [40]. This occurred with the hepatitis B vaccine in early 2001, following funding by GAVI. Centralized, large stock procurement via these international mechanisms could result in far more affordable prices. Furthermore, by analogy with other vaccines, the cost per HPV vaccination dose will decline gradually during the first decade after implementation, presumably to levels that will permit cost-effective deployment to developing countries. Public Health Genomics 2009;12:352–361

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The most appropriate age for vaccination must be balanced between the greatest expected health impact and the most feasible existing public health infrastructures. Currently, there is agreement that vaccination should occur prior to sexual initiation, or soon afterwards (i.e. preadolescent and adolescent girls) [41]. This strategy is feasible in countries that already have successful schoolbased vaccination programs for this age group (e.g. for the hepatitis B vaccine), but in other countries an adolescent program would be a considerable challenge. Conversely, infant vaccination programs are universal and could have far greater impact for HPV and cervical cancer prevention, should immunity induced by these vaccines prove to be long-lasting [42]. Although the efficacy of prophylactic HPV vaccination is very high, it is generally accepted that cervical cancer screening will have to continue after vaccination. Both vaccines are highly effective as pre-exposure prophylaxis for disease caused by HPV types 16 and 18, when used before the onset of infection; however, women currently infected with these viruses may derive little or no benefit [43]. Moreover, the target types included in the 2 vaccines are causally linked only to 70% of all cervical cancers [44]. Although some degree of cross-protection against lesions caused by phylogenetically-related HPVs (e.g. HPVs 18–45 and 16–31, 33, 35, 52, 58) may exist, little is known about the potential long-term benefit of this cross-type immunization response [45]. In addition, an increase in prevalence of other HPV types could occur in vaccinated populations as a result of the vacated ecologic niches following the progressive elimination of HPVs 16 and 18 (a yet unproven phenomenon known as type replacement). There is also the possibility that the type-specific immunity conferred by vaccination may wane over periods extending beyond 10 years, the maximum observation period in clinical trials until now. Despite these caveats, it is expected that a vaccinated woman will be at much lower risk of developing cervical pre-cancerous lesions over a period that may extend for a decade or longer. Thus, intensive screening of vaccinated women with annual or biennial Pap cytology would waste resources while providing only marginal additional benefit. While much is yet to be learned about the above issues, it is obvious that the incorporation of HPV vaccination will impose a substantial burden to the public health budgets of most countries. Even resource-rich countries will be hard pressed to absorb the high costs of vaccination without some form of restructuring of their cervical cancer screening programs and risk-management practices. In the next sections, we discuss changes in screen356


ing paradigms by taking advantage of the value of HPV DNA testing and the likely impact of vaccination on lowering disease incidence. These are likely to lead to more efficient use of health care resources to be used for cervical cancer control. Implementation of HPV vaccination follows specific health policy environments. Many resource-rich Western countries with centrally managed health care systems, such as Canada, Australia, and the UK, have adopted vaccination as universal policy for all adolescents and young women. In the USA, there is wide variation because of differences in legislation across states, but HPV vaccination is covered under Medicaid and by many managed care organizations. In other settings, where decisions about publicly funded vaccination have been postponed, the costs of vaccination may be borne by individuals, with or without reimbursement via supplemental health insurance. As of this writing, the majority of countries in which at least 1 of the aforementioned HPV vaccines had been licensed had not yet established specific policies concerning publicly-funded vaccination. A recent document by the World Health Organization has been strongly supportive of publicly funded HPV vaccination in countries that consider cervical cancer control a priority and have the infrastructure and funds for sustainable vaccination programs [41]. While such a recommendation for adopting HPV vaccination in national immunization programmes awaits implementation, decisions concerning vaccination will be left to health care providers and their patients. They are likely to be influenced by individual perception about the importance of risk avoidance and ability to pay for the vaccine.

Impact of HPV Vaccination on Cervical Cancer Screening Practices

Assuming that HPV vaccination of young women will become the cornerstone for primary prevention of cervical cancer, it becomes essential to consider what will happen with screening practices. As the successive cohorts of vaccinated young women reach screening age, there will be a gradual reduction in cervical lesion prevalence. The expected short-term impact of HPV vaccination on screening practices will be seen in the management of pre-cancerous lesions. If the mainstay of cervical cancer screening will continue to be Pap test cytology, laboratories will be the first to experience the impact of vaccination. The reduced rates of abnormal Pap tests will also reflect on the rates of colposcopical referral. They will Franco /Coutlée /Ferenczy

decrease to about 50–60% of the existing case loads in most Western countries, to judge from the proportion of today’s lesions that are caused by the vaccine-targeted HPV types [46]. A small, but not insignificant, proportion of currently referred cases are associated with HPVs of low oncogenic risk, such as HPVs 6 and 11. Gardasil, which includes the latter 2 types as immunogens, may thus lead to a more pronounced reduction in abnormalities than Cervarix, perhaps by an extra 10% in absolute terms. Such reductions will no doubt translate into initial savings to the health care system or to individuals but may entail untoward consequences related to personnel training and degradation of performance standards in Pap cytology, as discussed below. The above reductions in case loads will be a function primarily of 2 factors: (1) the overall uptake of HPV vaccination by the successive cohorts of adolescents and young women targeted by vaccination, and (2) the time it will take for protected women to reach the age when they become participants in screening programmes. In countries without a centrally managed health care system, uptake of vaccination will require much effort in educating the public and health care providers. While women may welcome HPV vaccines, there may be dissent as well, mostly stemming from the parental perception that vaccination causes diseases such as autism or may foster permissive behaviour among adolescents [39]. Vaccinated adolescents will reach the traditional age of cervical cancer screening within 3 years after the onset of sexual activity. Therefore, the impact on screening and management case loads will be initially minimal for women vaccinated between the ages of 10 and 18 years. On the other hand, the benefits in risk reduction among young adult women receiving the vaccine will be realized almost immediately because of the short latency between the averted acquisition of HPV infection and the appearance of low-grade or equivocal cervical abnormalities. On the other hand, for countries where screening starts at age 30 or even 25 years (as happens in most of Europe), the effect on screening will be delayed [29]. In terms of long-term impact, even with high uptake it is unlikely that a statistically noticeable reduction in cervical cancer incidence will be observed for at least 10– 15 years following the adoption of HPV vaccination because of the latency required for averted high-grade lesions to have had the time to progress to invasive disease. A paradoxical situation may arise if high vaccine uptake occurs primarily among women who will eventually be compliant with screening recommendations. If adolescents and young women who are more likely to be vac-

cinated are also those who become screening-compliant, the reduction in cervical pre-cancers will be observed nearly exclusively among such women. The reduction in triaging and managing women consequent to the fewer abnormalities identified on screening will be well received. However, because of their high compliance with screening, these women would not be those destined to develop cervical cancer. On the other hand, unprotected women may be less likely to be screened and their cervical lesions may progress undetected until invasion occurs. No pre-cancerous lesions will be averted among the latter group and cytology surveillance will be oblivious to their existence until symptomatic invasive cancers are diagnosed [28]. This scenario of compounded inequity in resource allocation for cervical cancer prevention (double protection with vaccination and screening for some and no protection for others) can be avoided if countries implement well-managed universal immunization policies that ensure high and socially equitable coverage of HPV vaccination while providing similarly universal coverage for screening services.



Quantitative and Qualitative Changes in Screening Efficiency due to Vaccination

The positive predictive value (PPV) of a screening test is the indicator that best reflects the efficiency of an initial screen for a cancer or its precancerous lesion. Specifically for cervical cancer, the PPV estimates the proportion of cases with identified abnormalities that will truly benefit from clinical management to arrest cervical carcinogenesis by ablative or excisional therapies. Figure 2 illustrates the expected impact of changes in cervical lesion prevalence that will result from HPV vaccination on the PPV of a test such as Pap cytology. As shown, irrespective of test accuracy, the PPV will decline in populations with high vaccine uptake because clinically relevant abnormalities will become less common. Typical prevalence rates of low-grade abnormalities (the threshold that triggers clinical action) before vaccination in most urban centres in the Western world are in the 5–10% range, whereas high-risk areas have rates of 10–20%. In settings with stringent quality assurance for cytology, the Pap test has adequate sensitivity (approaching 70%) and excellent specificity (95% or higher), as represented by the uppermost curve in the graph (solid line with square symbols). More realistically, however, the average performance of the Pap test is represented by a sensitivity slightly higher than 50% [7, 16, 22], which is shown in the graph 357

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0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0 0

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Fig. 2. Positive predictive value of a screening test as a function of

lesion prevalence and according to varying levels of test accuracy. The PPV measures the proportion of positive test results that truly represent lesions that require management. Curves with solid lines represent the performance of a test with 95% specificity (the proportion of results that are negative among women without lesions); broken lines represent a test with 90% specificity. Variations in sensitivity (the proportion of results that are positive among women with lesions) are represented in the curves by different symbols: square = 70%; diamond = 50%; circle = 30%.

as the solid line with diamond symbols. Therefore, if we assume that the Pap test performance parameters are held constant within a given screening setting, the PPV will decline by 50% or more in relative terms for reductions in lesion prevalence of 50%. This is expected irrespective of baseline prevalence (i.e. whether in a low-risk or high-risk population). Reductions of lesion prevalence to 1% or less will lead to very low PPVs, regardless of underlying screening performance. The above discussion illustrates the quantitative effects of the impact of vaccination, assuming that test performance is unaffected (sensitivity and specificity held constant in a given setting) by the changes in lesion prevalence. In reality, this scenario is likely to be too conservative. Vaccination also is likely to lead to an increase in false-negative cases because the low abnormality rate will lead to fatigue, boredom and less meticulous reading of negative smears. Consequently, with more false-negative results, the already low sensitivity of the Pap test will further decline. On top of this, a decline in specificity is also likely to occur because of a decrease in the relative proportion of squamous abnormalities including koilocytosis (signal) to inflammation and reactive atypias (noise) in most smears. This will lead to more false-positive re358


sults in overcalling benign abnormalities (noise), particularly if the cytotechnician is fearful of missing any relevant abnormalities [28, 29]. Figure 2 also serves to illustrate the compounded problem of concomitant quantitative and qualitative effects of the decrease in lesion prevalence on the PPV of Pap cytology. As lesion prevalence decreases over time, it is more plausible to assume that the declines in PPV will not occur along the same continuum as shown by the 2 upper solid curves in the graph. As the qualitative effects take place, the shift to the left in lesion prevalence will entail reductions in PPV that will occur in parallel to downward shifts in sensitivity and specificity [i.e. a move from the solid to the broken lines (loss in specificity) and from the curves with squares to those with circles (loss in sensitivity)]. Consequently, there will be a far more pronounced decline in PPV as a function of the vaccineinduced reduction in lesion prevalence over time. The lower PPV for cytology will require vigorous quality assurance, which may be achieved by centralizing screening in larger laboratories. Use of liquid-based cytology may offset some of the problems only if combined with optical artificial intelligence to recognize cellular abnormalities. However, because of the rarity of relevant lesions, the altered signal-to-noise ratio described above that is expected after vaccination may require recalibration of the computer-assisted recognition algorithms. Therefore, the negative impact on the PPV can be expected even with heightened quality control and improved cytology systems [29]. Finally, figure 2 also shows a sufficiently wide range of lesion prevalence scenarios to include also relatively high rates (above 20%) that are not typical of the primary screening conditions of any population. The graph purposefully includes such atypically high lesion prevalence rates to illustrate the expected scenario to be found in triage of initially positive HPV tests. If instead of Pap cytology we assume that HPV DNA testing will serve for the primary screen, we may expect that in any group of HPVpositive cases the prevalence of cytological abnormalities will be considerably greater, exceeding 20% or more. It can be seen that cytology will have its highest PPV and thus greatest clinical utility if lesion prevalence can be maintained at a high level. This situation is ‘artificially’ created in women who are screened first with the HPV test and then triaged by cytology. Also contributing to the improvement in screening work conditions is that the cytotechnician will be fully aware that the Pap smears to be read are ‘flagged’ for they come from women who are HPV-positive and thus more likely to have lesions. This Franco /Coutlée /Ferenczy

in turn will make for less tedious work and greater accuracy in identifying lesions [28, 29, 47]. Moreover, if HPV testing alone is used for primary screen, there will be a substantial reduction in smear reading workload for cytotechnicians. This, in addition to reducing costs, will improve the attention and thoroughness with which each smear will be read.

A Paradigm Change in Screening to Prepare for the Impact of HPV Vaccination

Simply making traditional cytology screening less frequent may not be a viable strategy to achieve a cost-effective combination of vaccination and screening in light of the aforementioned problems that may plague Pap cytology performance in conditions of low lesion prevalence. As we discussed in preceding sections, the HPV/Pap triage paradigm has the screening performance characteristics that would make it an ideal primary cervical cancer screening test in such conditions. Although the quantitative effect discussed above will also adversely affect the PPV of HPV testing, the latter is unlikely to be affected by the qualitative effects that are inherent to cytology because of the subjective interpretation to define a positive result for the latter. Pap cytology should be reserved for triage settings, i.e. in assisting management of HPV positive cases because it is more likely to perform with sufficient accuracy in conditions in which lesion prevalence is high, a situation that is artificially created when the workload includes only Pap smears from women harbouring HPV infection. The advantages of using HPV testing as the primary screen and then triaging positive women with cytology have been described before [27–29] and are being clinically evaluated in Finland [14], northern Italy [19] and in British Columbia, Canada. Another major advantage of using HPV testing as the primary screening tool is the opportunity for extended screening intervals compared with a cytology-centred screening program, which inevitably will reduce costs. The safety afforded by a negative HPV test result after about 4 years is equivalent to that of a negative Pap test result after 1 year, in terms of the cumulative risk of high-grade lesions [30]. Even after vaccination it would not be prudent to space intervals for a Pap-based program because the lesions that are caused by oncogenic HPV types other than those covered by the vaccine will continue to occur. On the other hand, this requirement would not exist for HPV testing because lesions caused by any oncogenic HPV types would be equally detectable HPV Vaccination in Cervical Cancer Control

by either signal (hybrid capture) or target (PCR) amplification tests. The HPV/Pap triage strategy for cervical cancer screening can also play an important role in post-HPV vaccination surveillance. Countries that integrate administrative databases of prevention programs will have the opportunity to create HPV infection registries with the provision to link test results from the same women over time. This allows an efficient and low-cost strategy to monitor long-term protection among vaccinated women while providing a cervical cancer screening service to the population. Other advantages of this approach are the improved screening efficacy relatively to cytology in detecting glandular lesions and the opportunity to use selfcollected samples to increase the screening coverage of women in remote areas, such as aboriginal populations. At present, the main obstacle for this paradigm change is the high cost of HPV testing. The fact that the market is dominated by a single manufacturer of a clinically approved and validated HPV assay (Qiagen) is certainly a deterrent for achieving lower prices for HPV testing. Another problem comes from the current practice guidelines in most countries which at most approve HPV testing for the triage of ASC-US abnormalities, an admittedly restricted niche market that represents at most 5% of the total patient population that can benefit from this screening technology. It is expected that once HPV testing is deployed in the high volume of primary screening, there will be a reduction in the cost of individual tests because of the market expansion following an economy of scale. Governments and managed care organizations may be able to negotiate with the manufacturers lower prices conditioned to high-volume purchasing. Furthermore, a change in market size from simple ASC-US triage to wide-scale primary screening will inevitably bring other biotechnology companies to compete in the field by bringing their own molecular HPV tests for validation and regulatory approval [48]. Taken together, the combination of shifting trends in screening practices, economies of scale, and perception of new market opportunities for companies will further contribute to a reduction in the overall cost of the HPV screening followed by Pap triage approach.

Prospects for Further Research

Notwithstanding the promising opportunities for an integrated approach to cervical cancer prevention by adopting a new paradigm for screening to make efficient Public Health Genomics 2009;12:352–361

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use of resources in the era of HPV vaccination, several obstacles remain. Much research needs to be conducted to assist with evidence-based policy decisions concerning optimal age for initiation of screening, use of ancillary technologies based on HPV typing and detection of biomarkers of lesion progression, and appropriate algorithms to manage HPV-positive women [49]. The implementation of the technological changes discussed in this article also imply substantial modifications in skills and training of providers and raise concerns in respect of revenue generation for cytopathology laboratories and colposcopy clinics. In conclusion, much has been achieved during the last 10 years from research on screening and prevention of cervical cancer. Progress in this area has been grounded on the recognition that HPV infection is the central, necessary cause of this important neoplastic disease. How-

ever, it is imperative that screening and preventive strategies be adapted to one another to permit cost-effective reductions in the burden of cervical cancer. As research on the subject continues to provide acceptable evidence for public health action, the next 5–10 years will bring many changes in practice standards and guidelines. Primary care providers, gynaecologists and oncologists will do well to observe closely the unfolding story of cervical cancer prevention.

Acknowledgments Support for the authors’ research has been provided by a team grant on HPV and associated diseases by the Canadian Institutes of Health Research (grant 83320).

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compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol 2008;111:167–177. Miller AB, Nazeer S, Fonn S, BrandupLukanow A, Rehman R, Cronje H, Sankaranarayanan R, Koroltchouk V, Syrjanen K, Singer A, Onsrud M: Report on consensus conference on cervical cancer screening and management. Int J Cancer 2000; 86: 440– 447. Spitzer M: Screening and management of women and girls with human papillomavirus infection. Gynecol Oncol 2007;107(suppl 1):S14–S18. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346–355. Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J: Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004; 96:280–293. Sankaranarayanan R, Nene BM, Dinshaw KA, Mahe C, Jayant K, Shastri SS, Malvi SG, Chinoy R, Kelkar R, Budukh AM, Keskar V, Rajeshwarker R, Muwonge R, Kane S, Parkin DM, Chauhan MK, Desai S, Fontaniere B, Frappart L, Kothari A, Lucas E, Panse N; Osmanabad District Cervical Screening Study Group: A cluster randomized controlled tri-


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19 Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, GillioTos A, Minucci D, Naldoni C, Rizzolo R, Schincaglia P, Volante R, Zappa M, Zorzi M, Cuzick J, Segnan N; New technologies for Cervical Cancer Screening Working Group: Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst 2008; 100: 492–501. 20 Franco EL: Chapter 13: primary screening of cervical cancer with human papillomavirus tests. J Natl Cancer Inst Monogr 2003;31:89– 96. 21 IARC Working Group: Cervix Cancer Screening. IARC Handbooks of Cancer Prevention. Lyon, IARC Press, 2005. 22 Cuzick J, Clavel C, Petry KU, Meijer CJLM, Hoyer H, Ratnam S, et al: Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119:1095–1105. 23 Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J: Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006; 24(suppl 3): S78–S89. 24 Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, Cohen C; American Cancer Society: American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002;52:342–362. 25 Wright TC Jr, Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, Hatch K, Noller KL, Roach N, Runowicz C, Saslow D: Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004; 103:304–309. 26 Stoler MH, Castle PE, Solomon D, Schiffman M; American Society for Colposcopy and Cervical Pathology: The expanded use of HPV testing in gynecologic practice per ASCCP-guided management requires the use of well-validated assays. Am J Clin Pathol 2007;127:335–337. 27 Sasieni P, Cuzick J: Could HPV testing become the sole primary cervical screening test? J Med Screen 2002;9:49–51. 28 Franco EL, Cuzick J, Hildesheim A, de Sanjose S: Chapter 20: issues in planning cervical cancer screening in the era of HPV vaccination. Vaccine 2006;24(suppl 3):S171– S177. 29 Franco EL, Cuzick J: Cervical cancer screening following prophylactic human papillomavirus vaccination. Vaccine 2008; 26S: A16–A23. 30 Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, de Sanjose S, Naucler P, Lloveras B, Kjaer S, Cuzick J, van Balle-


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gies in an era of cervical cancer vaccination: a multi-regional health economic analysis. Vaccine 2008;26(suppl 5):F46–F58. Zimet GD: Understanding and overcoming barriers to human papillomavirus vaccine acceptance. Curr Opin Obstet Gynecol 2006; 18(suppl 1):s23–s28. Andrus JK, Lewis MJ, Goldie SJ, García PJ, Winkler JL, Ruiz-Matus C, de Quadros CA: Human papillomavirus vaccine policy and delivery in Latin America and the Caribbean. Vaccine 2008;26(suppl 11):L80–L87. World Health Organization: Weekly Epidemiological Record. Meeting of the Immunization Strategic Advisory Group of Experts, November 2008: Conclusions and Recommendations, No. 1–2, vol 84. Geneva, WHO, 2009, pp 1–16. Franco EL, Tsu V, Herrero R, Lazcano-Ponce E, Hildesheim A, Muñoz N, Murillo R, Sánchez GI, Andrus JK: Integration of human papillomavirus vaccination and cervical cancer screening in Latin America and the Caribbean. Vaccine 2008; 26(suppl 11):L88– L95. Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR; Costa Rican HPV Vaccine Trial Group: Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007; 298:743–753. Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004; 111:278–285. Stanley M: HPV vaccines. Best Pract Res Clin Obstet Gynaecol 2006; 20:1–15. Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM: Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005; 14:1157–1164. Depuydt CE, Arbyn M, Benoy IH, Vandepitte J, Vereecken AJ, Bogers JJ: Quality control for normal liquid based cytology: rescreening, high risk HPV targeted reviewing and/or high risk HPV detection? J Cell Mol Med 2008. Epub ahead of print. Meijer CJ, Berkhof J, Castle PE, Hesselink AT, Franco EL, Ronco G, Arbyn M, Bosch FX, Cuzick J, Dillner J, Heideman DA, Snijders PJ: Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older. Int J Cancer 2009; 124:516–520. Cuzick J, Mayrand MH, Ronco G, Snijders P, Wardle J: Chapter 10: new dimensions in cervical cancer screening. Vaccine 2006; 24(suppl 3):S90–S97.


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