Sexually Transmitted Diseases:
Reassessing the Epidemiology of Human Papillomavirus Infection: Back to Basics
Franco, Eduardo L. MPH, DrPH; Trottier, Helen MSc, PhD
From the Division of Cancer Epidemiology, Department of Oncology and Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada
Correspondence: Eduardo L. Franco, Division of Cancer Epidemiology, McGill University, 546 Pine Ave. West, Montreal, QC, Canada H2W 1S6. E-mail: firstname.lastname@example.org.
Received for publication December 6, 2007, and accepted December 22, 2007.
Once upon a time, when the evidence in support of a carcinogenic role for human papillomaviruses (HPVs) was still in its infancy, studies of HPV infection prevalence in different populations were in vogue.1–3 Throughout the 1980s, there was increasing realization that not only most cervical carcinomas harbored HPV DNA but also that cervical HPV infection was common in women without cervical abnormalities, with prevalences in the range of 10% to 40%.4 The consistency of the sexually transmitted disease model for cervical neoplasia provided the rationale for a solid research base of mechanistic molecular investigations and epidemiologic studies that emerged in the 1980s and matured in the 1990s, and finally implicated HPV as the causal agent of this disease.5 This era witnessed the application of molecular epidemiology to elucidate the etiology of one of the most important cancers worldwide. It culminated with the publication in 1995 of a landmark monograph by the International Agency for Research on Cancer (IARC) implicating HPVs, particularly genotypes 16 and 18, as bonafide human carcinogens, with additional types classified as “probable” carcinogens.6
The IARC monograph had an enormous impact on subsequent prevention research and policy. The biotechnology sector began to develop HPV tests with the aim of improving secondary prevention approaches via screening and management.7 Likewise, the IARC monograph6 gave pharmaceutical companies the scientific leverage to take on the financial risks in developing candidate HPV vaccines. The result, about 10 years later, is 2 new exciting fronts for cervical cancer prevention: HPV vaccination and improved screening with HPV tests.
The licensing in 2006 of a first prophylactic HPV vaccine (Gardasil, Merck, Inc., Whitehouse Station, NJ) against types 16 and 18 has ushered a new era in cervical cancer prevention. A second vaccine (Cervarix; GlaxoSmithKline Inc., Research Triangle Park, NC) also targets these types and will be available in 2007 to 2008. In clinical trials, these vaccines have been nearly 100% efficacious in preventing incident persistent infection with the target types and the ensuing precancerous high-grade lesions in women without prior exposure to HPVs 16 and 18.8–11 Mathematical models of the impact of these vaccines project a substantial public health benefit.12–14
Screening will continue after vaccination, most likely as a reformulated strategy that incorporates the emerging evidence concerning HPV testing. The above vaccines protect only against HPVs 16 and 18, which account for a little more than 70% of all cervical cancers.15 Although some cross-protection against phylogenetically related HPVs may be expected,8 there is a theoretical possibility that the distribution of HPV types may gradually change in vaccinated populations to fill the vacated ecologic niches after the elimination of HPVs 16 and 18. This yet unproven phenomenon is known as type replacement and would elicit concerns similar to those in influenza and pneumococcal vaccination surveillance. It is also possible that the immunity conferred by vaccination may wane over time. The deployment of vaccination will thus require surveillance mechanisms to determine the effectiveness of vaccination against HPVs 16 and 18-associated cervical cancer, the duration of that protection, the effectiveness and duration of crossprotection against nonvaccine-targeted types, and the potential for other oncogenic types of HPV to replace HPVs 16 and 18 as primary drivers of cancer risk. Such surveillance mechanisms imply continued monitoring of both virological and lesion endpoints in the population, which can be achieved with a concerted effort of combining screening to HPV prevalence surveys.16
We are thus back to basics in HPV epidemiology. Surveys of the distribution of HPV types before large-scale vaccination provide the foundation on which to base an effective postvaccination surveillance. The study by Nielsen et al. in this issue17 is a good example of the necessary first step in establishing a well-functioning surveillance system. Denmark and Scandinavian countries stand to get an early start in reaping the benefits from HPV vaccination. They enjoy integrated health services that effectively permit close monitoring of the population impact of vaccination. The authors report the findings on cervical HPV prevalence and its determinants in 2 large population-based surveys in Denmark.17 These surveys targeted different age groups, thus providing valuable baseline information to inform future policies concerning catch-up vaccination of young women, as well as to permit monitoring the effects of off-label, opportunistic vaccination of women who are older than the upper age limit set by national immunization advisory committee recommendations. The sheer size of the study and the fact that it is population-based bolster the generalizability of its findings. This point cannot be overemphasized; most previous HPV prevalence surveys have resorted to convenience samples of women attending screening or maternal and child health clinics, hospital outpatients, or volunteer university students. Although internally valid, such studies are prone to selection biases, which diminish their value as the foundation of an HPV surveillance system.
To serve as the keystone of HPV surveillance a survey must use validated molecular methods to assess HPV infection. Nielsen et al.17 used the Hybrid Capture 2 (HC2) assay (Digene, Inc., Gaithersburg, MD), the only commercially available HPV DNA test currently approved by the US Food and Drug Administration for clinical use. This assay has been designed and validated for detecting cervical lesions. As such, by necessity, it targets the most common oncogenic types associated with cervical cancer and its precursors (HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). It does so in probe-cocktail format, which precludes the identification of individual types. The HC2 assay has been calibrated to achieve acceptable screening specificity, which translates into a higher threshold of viral load detection than the polymerase chain reaction (PCR) protocols that have been widely used in epidemiologic studies and permit HPV typing.18–21 Nielsen et al.17 determined the presence of HPV by HC2 followed by typing of positive cases via PCR. The authors were quick in recognizing this caveat. Because they did not test all specimens with the more sensitive PCR method, the actual HPV prevalence is likely higher than what they found. On the other hand, this limitation turns out to be an advantage because a postvaccination surveillance system for HPV infection should be integrated with cervical cancer screening, and at present, HC2 is the most extensively validated test for this purpose. One could argue that using PCR would permit more thorough surveillance of all endemic mucosotropic HPV types. However, the transient nature of HPV infection and the qualitative differences among types would make such approach inappropriate for screening cervical lesions. Transient HPV infections are not suitable endpoints for monitoring the effects of vaccination, including epiphenomena such as type replacement. Therefore, a system that relies on an initial virological screen for relevant infections and identifies types only in cases that are found to be positive is better suited to monitor relevant endpoints in cervical carcinogenesis.
Nielsen et al.17 also conducted a thorough analysis of determinants of HPV infection. Again, this is a useful return to the basics of HPV epidemiology. Although their findings were not entirely novel they unveiled useful information by comparing the 2 age-stratified surveys. They explained the monotonic, negative association with age, without an increase in prevalence among older women, as a possible consequence of Denmark’s screening program, which effectively seeks and treats all clinically relevant cervical lesions, thus decreasing the pool of HPV-positive women reaching the age of 50 years.17 Although proof is lacking that ablative treatment of cervical precancers eliminates the underlying HPV infection, this tentative explanation is plausible and would help explain the differences in patterns of age-specific prevalence around the world.22,23 Also noteworthy is the finding that recent sexual activity explains HPV infection risk in young but not in older women, which is in line with the often-stated belief that infections in the latter may have been established earlier thus reflecting persistent infections, whereas those in young women represent mostly transient, recent episodes.24 Those who reached menopause and beyond and are HPV-negative may have benefited from accrued immunity developed over their sexually active years. The authors found that, independently of age and sexual partners, a woman’s HPV infection risk decreases with time since onset of sexual activity.17
Studies such as that of Nielsen et al. represent a new generation of epidemiologic surveys based on the fundamental premise of understanding the distribution of HPV types in the population that motivated similar studies in the 1980s and 1990s. The ultimate goal now—setting the baseline for postvaccination surveillance—is different than that of yesteryear, which was to gain insights into a candidate etiological relation. Whatever their historical context, epidemiologic studies continue to serve as the scientific cornerstone of progress in cervical cancer prevention.
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6. IARC Working Group. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 64: Human Papillomaviruses. Lyon, France: International Agency for Research on Cancer, 1995.
7. IARC Working Group. IARC Handbooks of Cancer Prevention, vol. 10: Cervix Cancer Screening. Lyon, France: International Agency for Research on Cancer, World Health Organization, IARC Press, 2005.
8. Harper DM, Franco EL, Wheeler CM, et al.; HPV Vaccine Study Group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: Follow-up from a randomized control trial. Lancet 2006; 367:1247–1255.
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11. Paavonen J, Jenkins D, Bosch FX, et al.; HPV PATRICIA Study Group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: An interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369:2161–2170.
12. Kulasingam SL, Myers ER. Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA 2003; 290:781–789.
13. Goldie SJ, Kohli M, Grima D, et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst 2004; 96:604–615.
14. Taira AV, Neukermans CP, Sanders GD. Evaluating human papillomavirus vaccination programs. Emerg Infect Dis 2004; 10:1915–1923.
15. Muñoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004; 111:278–285.
16. 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.
17. Nielsen A, Krüger-Kjaer S, Munk C, Iftner T. Type specific HPV infection and multiple HPV types—Prevalence and risk factor profile in nearly 12,000 younger and older Danish women. Sex Transm Dis 2008; 35:276–282.
18. Jacobs MV, Snijders PJ, van den Brule AJ, Helmerhorst TJ, Meijer CJ, Walboomers JM. A general primer GP5+/GP6(+)-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J Clin Microbiol 1997; 35:791–795.
19. Coutlée F, Gravitt P, Kornegay J, et al. Use of PGMY primers in L1 consensus PCR improves detection of human papillomavirus DNA in genital samples. J Clin Microbiol 2002; 40:902–907.
20. van Doorn LJ, Quint W, Kleter B, et al. Genotyping of human papillomavirus in liquid cytology cervical specimens by the PGMY line blot assay and the SPF(10) line probe assay. J Clin Microbiol 2002; 40:979–983.
21. Iftner T, Villa LL. Chapter 12: Human papillomavirus technologies. J Natl Cancer Inst Monogr 2003; 31:80–88.
22. Franceschi S, Herrero R, Clifford GM, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer 2006; 119:2677–2684.
23. de Sanjosé S, Diaz M, Castellsagué X, et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: A meta-analysis. Lancet Infect Dis 2007; 7:453–459.
24. Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine 2006; 24(suppl 1):S1–S15.
© Copyright 2008 American Sexually Transmitted Diseases Association
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