Abstract
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HPV is the most common cause of STIs. At least 40 different HPV types have been detected in the genital tract mucosa. HPV is a stable DNA virus, and therefore an excellent target for primary prevention by vaccination.
The link between HPV and cervical cancer was discovered in the early 1980s by Harald zur Hausen and others [1]. zur Hausen received the Nobel Prize in 2008 for this discovery. High-risk types HPV 16/18 cause approximately 70% of all cervical cancer cases worldwide [2]. Closely related high-risk HPV types cause most of the remaining cancer cases. These high-risk HPV types also cause a large proportion of other malignancies.
Virus-like particles (VLP) were discovered in the early 90s. This discover rapidly led to the development of prophylactic HPV vaccines. VLPs are manufactured in yeast cells or insect cells and are DNA-free. Quadrivalent vaccine includes VLPs of HPV types 16/18 and HPV 6/11 [3]. The latter cause 90% of genital condylomas. The bivalent vaccine includes VLP's of HPV 16/18 [4].
These vaccines turned out to be extremely immunogenic and safe. Global Phase III efficacy trials started in 2002 (FUTURE) and 2004 (PATRICIA), in which almost 40,000 15–26-year-old women were enrolled from four continents and 14 countries [3,4]. The vaccines were strikingly effective against the best surrogate marker for cervical cancer, CIN3, among HPV-naive women not exposed to the high-risk HPV types [5]. The bivalent vaccine was more effective than the quadrivalent vaccine against CIN3 caused by any HPV type. This suggests that the bivalent vaccine has better cross-protection against HPV16/18-related high-risk HPV types.
No significant adverse effects were discovered during the active follow-up of the Phase III efficacy trials. Both vaccines were licensed 2006 and 2007 based on the results of the Phase III efficacy trials. Soon, the vaccines were included in national vaccination programs in many countries. Community randomized Phase IV trial was started in Finland in 2007 in which more than 32,000 adolescent women and men were enrolled, in order to define the best vaccination strategy [6,7]. The key questions of the Phase IV trial are the vaccination coverage in relation to herd immunity and the added value of vaccinating males.
Phase III and Phase IV vaccination trials are continued by passive follow-up based on health registry linkages. This is particularly feasible in Finland in which large numbers of individuals have been enrolled in the HPV vaccination trials. The cohorts followed by registry linkages include both vaccinated individuals and nonvaccinated control individuals of the same age range [8]. Cancer registry linkage will soon reveal real-life vaccine efficacy against invasive cervical cancer. Health registry linkage will also add data on safety aspects, particularly in relation to autoimmune diseases.
Recent HPV vaccination trials in men have shown equally high efficacy against persistent HPV infection and related anogenital disease [9]. This is important evidence since most genital infections in men are symptomless and subclinical, and appropriate screening tests available in clinical practice do not exist. Women-only vaccination programs for HPV have been introduced in many countries aiming to prevent cervical neoplasia. However, HPV-associated cancers in men are rising and by not vaccinating adolescent boys we certainly fail to gain maximum health benefit of the vaccines. Furthermore, each year almost 650,000 cases globally receive the diagnosis of head and neck cancer. HPV is the main contributor to cancers of the head and neck in both genders [10]. HPV also causes genital warts, the most common sexually transmitted viral disease in both genders. Management of genital warts is extremely frustrating and mutilating since effective treatment modality does not exist and recurrences are common.
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Most previous health economic studies conclude that when vaccination coverage in adolescent women is high, vaccination of men may not be cost effective [11]. Accordingly, comprehensive cost-effectiveness analysis of including boys in an HPV vaccination program have not shown good value for resources compared with vaccinating adolescent girls only. However, such health economic analysis should be revisited as new data of the disease burden emerge [12].
A school-based vaccination program was started in Australia already in 2007. Recent reports have already demonstrated the major health impact of the vaccination program. Genital warts have almost disappeared [13]. Similarly abnormal Pap smear findings and CIN have also rapidly decreased among young women [14]. HPV vaccination is now included in the vaccination programs of most EU countries. In Finland this happened as recently as in November 2013. The vaccination coverage is generally high in countries in which the vaccination program is school-based. The vaccination program in Finland will be carefully followed and scrutinized particularly in relation to the vaccination coverage. We anticipate high compliance and high coverage since the program is school-based. Assuming the ongoing Phase IV trial will demonstrate a significant overall added value by vaccinating boys as well, the program will be revisited and revised accordingly. High vaccine cost is no longer a major barrier since the vaccine manufacturers now offer vaccines at a reasonable price.
Pap smear was discovered almost 100 years ago. Pap smear is specific but not very sensitive. Pap smear organized screening performance largely depends on repeat testing. Mass screening based on Pap smears started in Finland in 1963 after which the cervical cancer rates dropped by approximately 80%. Finland has a population of 5.5 million, and in most communities Pap screening starts at age 30 years with repeat testing every 5 years. In Finland, the total annual number of Pap smears obtained is approximately half a million but only less than 200,000 Pap smears are obtained within the screening program. Thus, opportunistic screening is strikingly common and not well targeted. Overtreatment of mild cytologic atypia and lesions such as CIN1 is another common problem among young women. This is because cervical procedures are associated with short- and long-term complications such as bleeding and pain, and also increase the risk for preterm birth at least twofold [15,16]. This is important to emphasize since most such patients are young and therefore all procedures which increase adverse pregnancy outcome are problematic and overtreatment should be avoided. Secondary prevention by Pap screening does not really decrease the HPV disease burden, but simply transfers the disease burden from cancer to pre-cancer and in fact increases the overall costs.
Some countries have already revised the screening programs by moving from Pap screening to more sensitive HPV DNA screening [17]. This makes sense since HPV is the proven cause of cervical neoplasia. Italy, The Netherlands and Sweden are examples of countries moving to HPV primary screening. The goal is to detect persistent infections. Therefore, such HPV screening programs should not start before age 30. Most HPV infections in young women are transient. Active screening of young women may lead to overdiagnosis and also over-treatment and increase the overall healthcare costs.
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Primary prevention by HPV vaccination is now available. Emerging new data from multiple countries have already demonstrated rapid decrease in overall HPV disease burden. The key question now is how to organize screening among HPV-vaccinated populations. HPV vaccines are extremely effective against CIN3 caused by HPV16/18 and also any CIN3 regardless of HPV type. This suggests that the current vaccines have significant cross-protection against 16/18-related high-risk HPV types. Studies utilizing mathematical modeling suggest that in the future once-in-a-lifetime or twice-in-a-lifetime HPV DNA testing may be a valid screening strategy. Ongoing studies are currently looking into this. Undoubtedly newer generation, more multivalent prophylactic HPV vaccines could prevent up to 100% of cervical cancer cases worldwide if effectively implemented.
Financial & competing interests disclosure
The authors have received research funding from Merck Co. and GSK through the Helsinki University Hospital Research Institute to conduct clinical trials on HPV vaccination. The authors have no other 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 apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.