Epilogue: Looking forward to cervical cancer elimination

Epilogue: Looking forward to cervical cancer elimination

Epilogue: Looking forward to cervical cancer elimination David Jenkins1,2 and F. Xavier Bosch3,4,5 1 Emeritus Professor of pathology, University of N...

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Epilogue: Looking forward to cervical cancer elimination David Jenkins1,2 and F. Xavier Bosch3,4,5 1

Emeritus Professor of pathology, University of Nottingham, United Kingdom 2Consultant in Pathology to DDL Diagnostic laboratories, Rijswijk, The Netherlands 3Catalan institute of Oncology (ICO), Barcelona, Spain 4Bellvitge Research Institute (IDIBELL), Barcelona, Spain 5Open University of Catalonia (UOC), Barcelona, Spain

In the field of human papillomavirus (HPV) and cancer, the beginning of the 21st century is characterized by the bold proposal to eliminate cervical cancer globally as a public health problem. The field seems to be ripe to attempt an effort at the level of the one deployed in the past to eradicate small pox or to dramatically reduce (to the level of elimination) polio, measles, and several other communicable diseases caused by infectious agents. As shown in this book a wealth of scientific documentation on HPV is available to substantiate the objectives, the monitoring as well as the technological and financial aspects of a cervical cancer elimination campaign which in turn should achieve a significant preventive impact on other HPVinduced cancers. The backbone of the project is generalized (gender neutral) vaccination with broad spectrum vaccines and at least one/two HPV-based screening events followed by adequate treatment of invasive cancer, including advanced cancer and the provision of palliative care whenever other options fail. The development and validation of the required tools are the results that the scientific community has provided and evaluated in the last three decades. In 2018, WHO launched the cervical cancer elimination campaign and is currently generating the guidelines and basic documents to provide the theoretical framework for the elements of the strategy and the intermediate monitoring endpoints. Other aspects of the campaign will be developed such as the provision of funds, guidance on vaccine access and procurement, appropriate use of the HPV screening technologies and the educational efforts that need to be put in place and coordinated to cement the operation [1]. With this call and recommendations, the countries will have to match these objectives to their local situation and formulate their national prevention plans. The intermediate objectives are being defined in such a way as to achieve by 2030 a reduction of 30% of the cervical cancer mortality. Model-based predictions for short-term evaluation include: 1. Achieving sustained HPV vaccination of at least 90% of all cohorts of girls under 15 years, 2. Providing two HPV screening episodes to at least 70% of women at ages 35 and 45 years, and 3. Treating adequately 90% of all “cases”—whether screen positive preneoplastic lesions or invasive cancer at any stage including access to diagnosis and palliative care. In most circumstances, intensive vaccine coverage would achieve the elimination level towards the end of the 21st century. The time to achieving this level of control solely with vaccination is

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strongly dependent on the baseline levels of cervical cancer incidence. In the higher-risk countries, vaccination only is predicted not to achieve elimination rates within the century. However, the addition of the HPV screening component of the campaign at a high level of coverage and followup is predicted to accelerate the time to elimination by two or three decades [2]. The coming years will witness the application of different versions of this general strategy, the deployment of the relevant indicators and the monitoring of progress towards the general goal of having populations largely free of cervical cancer. Developed countries will certainly build upon these objectives and in many instances vaccination and screening plans include the extension of the vaccine indications to boys (23 countries in 2018), a broader age range for vaccination among women, specific ancillary programs to vaccinate high-risk groups, and repeated HPV screening on a 5-year interval. This book has reviewed in considerable detail the historical perspective the landmarks and the state of the art in HPV research and its clinical applications. The review has also identified gaps in knowledge in which more research is still needed and critical issues that need to be scientifically resolved. Some of the salient points are hereby summarized.

INTEGRATING CERVICAL CANCER PREVENTION IN THE FRAME OF OTHER NATIONAL HEALTH PRIORITIES Achieving elimination of cervical cancer as a public health problem will require in many instances making choices within the health systems of the countries, when competing for resources with other major health problems. Fig. A.1 shows the relative impact (mortality in thousands of cases in 2017) of all major causes including three major infectious diseases TB/HIV/MALARIA as well as the number of deaths at the major cancer sites including cervical cancer. In the graph, cervical cancer appears as relatively minor condition (1% of the total mortality among women worldwide). However, in the decade 2007 17, the number of cases of cervical cancer has increased by close to 19%, whereas the number of deaths to some selected infectious diseases has significantly decreased by 15% for TBC; 50% for HIV/AIDS and 30% for malaria [3]. Interpretation of time trends for cervical cancer strongly suggests the dominant effect of population growth and longevity. Predictions under current preventive practices are that the number of cases of cervical cancer will double to triple in developing countries by the turn of the century. This somber prognosis is counterbalanced by the options offered by the arrival of HPV vaccines and HPV screening technologies and by the definite commitment of the major public health institutions in the world to focus on the control of HPV and its related diseases. Other than the crude number of cases or the incidence and mortality rates, social and political issues may be relevant at the time of making decisions to deploy the cervical cancer elimination campaign and on the intensity with which the campaigns will be implemented and sustained over time. Some of these issues (by no means an exhaustive account) could include the following: 1. Cervical cancer mortality clusters dramatically in countries without established screening opportunities and in poor populations of the world including low and marginalized social groups in developed countries. 2. Cervical cancer is a long-term consequence of a sexually transmitted infection and thus is a cancer with a stigma in many populations.

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FIGURE A.1 Global causes of death in 2017 (both sexes, all ages, n 5 55,945,700).

3. Cervical cancer is a women’s disease and the priority of the intervention reflects also the social role of women in the decision making process and their access to preventive care in every country and culture. 4. Children’s sexual abuse, adolescent sexual behavior, and sexual patterns along adult lifetime are all relevant to calibrate the amplitude of the HPV preventive programs. However, many of these parameters and social trends are still perceived as taboo and in practice their characteristics and impact remain largely unseen by the decision makers, the health professionals, and the population at large. 5. In developed countries, HPV vaccination and screening practices are implemented and highly supported by the population and the public and private health programs. Modification of the current status of the preventive campaigns may create some transition periods of confusion and will require careful local organization. 6. The early milestones on cancer reduction will occur and be measured in the countries in the developed world that pioneered HPV-based preventive interventions (i.e., cervical cancer reduction in Finland/Australia/Scotland/and others). In all these populations, the information systems and cancer registries are operational and record linkage is feasible. Extrapolation of results and protocols to developing countries may require careful attention and in many instances calibrated algorithms for diagnostics and management will have to recognize and adapt to the socioeconomic variability. It is important that accurate diagnosis of invasive cancers is widespread globally as wrong diagnoses particularly of adenocarcinomas arising in

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vaccinated individuals can cause issues in understanding the role of HPV in cervical cancer and apparent failures of HPV screening and vaccination.

NATURAL HISTORY AND SPECTRUM OF DISEASE RELATED TO HUMAN PAPILLOMAVIRUS While cervical cancer is the most frequent cancer linked to HPV infection and dominated the clinical and epidemiological research in the 1980s and 1990s, progress in the understanding of the etiological role of HPV in other conditions has provided estimates of the other cancer sites affected by the oncogenic capacity of HPV. As a group, these malignancies amount to an expected number of new cases per year worldwide of 630,000 of which 29,000 correspond to oropharyngeal cancer; 556,000 to female genital cancers (cervical, vulvar, and vaginal) and 48,000 to penile and anal cancer [4]. Fig. A.2 provides a numerical estimate of the HPV-linked pathology for 30 countries in the European Union. The graph also displays the relevance of the preneoplastic lesions linked to HPV in countries where cervical screening is in place. Notice that related to an estimate of cervical cancer incidence generated by reliable cancer registries (estimated at some 35,000 cases) the equivalent

FIGURE A.2 European Union (30 countries) HPV-related disease burden.

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estimate for preneoplastic lesions is close to 160-fold higher for atypical or borderline abnormal cytology or worse (ASCUS 1 ) (5.6M) and 11-fold higher for high grade lesions (389,000 cases of CIN2 1 ). These are conditions requiring further diagnostic procedures and eventually treatment. One of the consequences of using a screening test with low sensitivity and poor reproducibility (i.e. cytology) followed by decision to treat based on colposcopy and biopsies also limited by low sensitivity and repeatability is the undesired overtreatment of lesions that may otherwise regress spontaneously with high frequency (i.e., a significant fraction of the CIN 2 cases). In many developed countries, the costs and health services requirements are strongly determined by the burden of preneoplastic conditions. This is likely to be an important driver in the decisions to transition screening programs from the cytology-based current situation to the HPV-based programs that are being recommended by most updated guidelines and national programs. The burden created in the health system by the preneoplastic diagnoses is a hidden cost, rarely perceived and evaluated as a side effect of screening programs. The unwanted side effects include not only in the worst case scenario, some obstetric consequences but also the psychological stress related to the diagnosis and treatment as well as the costs to the system and the expense to the women involved. Better triage tests to determine more accurately and reproducibly the need for treatment of HPVpositive women are an important approach as detailed in this book. All preneoplastic lesions of the other HPV-related cancer sites (anogenital and oropharyngeal) do not follow the same patterns as in the cervix and have not been fully described. Neither has any screening methodology been validated. Limited information from Phase III clinical trials indicates that protection afforded by the HPV prophylactic vaccines can include the HPV infections and preneoplastic lesions of the anal canal, the vulva, and the vagina. It can thus be speculated that vaccinated cohorts will be protected against the relevant fraction of oncogenic HPV-driven cancer cases in all locations. Understanding the burden of disease linked to HPV infections has greatly benefited from the existence of an IARC-lead international network of cancer registries and a long-term sustained research program that standardizes methodology, assists novel cancer registries in developing countries and reports regularly on cancer incidence, mortality, and time trends [4,5]. Moreover, this program has also developed methodology to produce estimates of cancer incidence for regions where cancer registration is limited or nonexisting [4]. The HPV field has in addition supported the organization and maintenance of a specific information resource named ICO/IARC HPV Information Center that compiles and offers in user-friendly and free-access format summaries of published documentation on HPV, HPV-related cancers, and status of preventive programs. The information is retrievable for each one of the 192 countries in the world or any combination of countries in regions or continents [6]. These resources and the coordination of the health statistical unit at WHO are currently devising the appropriate tools to monitor the deployment of the cervical cancer elimination campaign.

RESEARCH AREAS IN THE SCREENING AND TREATMENT FIELDS Some of the relevant issues that may be addressed by research projects in the coming years include the development and validation of low cost and point-of-care screening technologies. These alternatives may alleviate the difficulties to adequately follow up women with screen-detected abnormalities, a proven major barrier in most developing countries. Research on screen-and-treat protocols is

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of importance to ensure that the participants at any screening event are properly managed on time with a significant reduction of the numbers of individuals lost to follow-up [7]. It is important to reach international agreements to accelerate the acceptance of promising new technologies for screening. Currently, academic researchers have generated a relatively rapid validation procedure comparing HPV test performance on predefined sample sets (i.e., the Valgent project) [8] and generating sound summaries of the testing and vaccine literature (i.e., the Cochrane reviews, the IARC monographs or the ICO/IARC HPV information Center) [6,9,10]. The prequalification procedures organized by WHO as well as other major reviews need to join forces with the academic community to accelerate the arrival of critically important technology. Self-sampling for HPV testing has been extensively proposed and evaluated in many different settings. The efficacy, acceptance and safety of these approaches are important in improving screening coverage in both developing and developed countries. Self-sampling appears to be useful not only among the nonparticipants in current screening programs but is progressively proposed as a generalized alternative for all participants in screening programs. Remarkable examples of high rates of self-sampling coverage and participation have been achieved in environments such as Malaysia and Turkey as well as in developed countries like The Netherlands and Sweden [6,11 13]. In the understanding of the natural history from HPV infection to cancer, biomarkers are useful intermediate diagnostic resources that can serve the purpose of screening and early diagnosis or be part of the triage strategies for HPV-positive individuals to decide on management. The closer to invasive cancer and the higher the consistency of the molecular change the better the predictive value. P16 (p16INK4a) is the longest established biomarker as a surrogate of HR HPV E7 gene activity but is limited on its own as it is also expressed physiologically in cervical metaplasia and is expressed in productive HPV lesions as well as high-grade preneoplasia and cancer (cross-reference to fb-nonchapter 2). The immunohistochemical stain for Ki 67 is a useful addition to cytology and additional biomarkers under study including E4 to identify productive HPV lesions, mRNA tests, and methylation of viral and host genes to define progression of HPV infection to neoplasia. Panels of molecular markers (over 100 studied) are being investigated to achieve discrimination between HPV infections with high risk of progression and transient infections with limited clinical consequences. It is important to consider any increase in complexity of management and cost resulting from the introduction of new biomarkers. While the adoption of protocols including these markers is likely to be feasible and acceptable in developed countries, they may be more difficult to use in developing countries raising additional barriers in situations where simplicity and reduced follow-up visits seems to be of critical importance. Imaging of the surface of the cervix using mobile technology, artificial intelligence, and large image banking with rapid access in the internet may provide an alternative for screening and triage in some settings [14]. Nonsurgical treatments for HPV infections/early cervical lesions are the long-term missing link in the chain of options for cervical cancer control. The introduction of HPV testing in primary screening will generate a significant fraction of the screening population (expected average of 10% 12%) with normal cytology and HPV test positive. For these women, the current recommendations are condom use (to prevent transmission) and monitoring (6 12 months repeated visits) without any effective treatment. This is clearly unsatisfactory for both the patient and the healthcare provider. Moreover, HPV positive women remain the most important high-risk group for HPV transmission, contributing to the incidence and high prevalence of HPV infections in the

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Table 1 Areas of Research Where Relevant Changes are Likely to Occur in the Coming Years. HPV and Cancer. Natural History

HPV Screening/Treatment

HPV Vaccination

Natural history of HPV-related head and neck cancers HPV in the etiology of cancers of the skin/anal canal/penis/vulva/vagina, and scrotum HPV/HIV interactions

Self-sampling as the routine practice in screening programs Screen-and-treat protocols in low/middle resource settings

Impact of one dose protocols in adolescents Vaccination of adult women (with one/two doses) Generalized male vaccination

HPV transmission, sexual dynamics of the populations, and social groups (i.e., MSM, commercial sex workers) International surveys on trends in sexual behavior and in sub populations

Point-of-care/low-cost HPV screening technologies Imaging technologies for screening in low/middle resource settings Triage of screen-positives in low/middle resource settings

Spontaneous HPV exposures as natural boosters

Screening other HPV-sensible organ sites (i.e., anal canal)

Development of the methodology to monitor intervention impact under suboptimal conditions of data collection Maintenance of the health statistics systems to monitor time trends in vaccination and screening coverage and cancer incidence

Treatments of HPV 1 individuals

Improving herd protection by vaccination HPV 1 and prevention of transmission Therapeutic/mixed vaccines. Natural boosting of vaccinated individuals by HPV infections Include HPV vaccines into the EPI vaccination schedule/multiple antigen combined vaccines Selective vaccination of high-risk groups

Modeling screening requirements in vaccinated cohorts

Low-cost HPV vaccines

Monitoring screening programs in low/middle income countries Educational programs on the reshaping of screening protocols in developed countries

Compliance and COI regulations

Educational efforts on HPV vaccine safety

Antivax positioning

populations, on average close to 12% in women with normal cytology [15]. Finding effective treatments to resolve the infection/early lesions and to interrupt/decrease transmission is an urgent need to accelerate control of the infection. Several trials using immunological treatments are underway as well as trials using small molecules [16]. In this respect, the opportunity to reduce transmission by vaccinating adult women is an important alternative to explore following the observations of a reduced risk of recurrence of HPV infections at the time of treatment for CIN 2 1 cases [17] or the anecdotal observation of reduced clinical symptoms of recurrent respiratory papillomatosis following immunization with a vaccine including antigens of HPV 6/11 [18] (Table 1).

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RESEARCH IN THE VACCINATION FIELD After first licensing in 2006, HPV vaccines are now entering the second decade of follow-up of large populations. Likewise, participants in the early Phase I/II trials already have accumulated 15 1 years of observation. The record of vaccine effectiveness and safety is extraordinary and reductions of cervical cancer incidence have already been suggested in some early analysis of the participants in the vaccine trials in the Nordic countries in Europe [19]. Ongoing systematic timetrend analyses of cervical cancer incidence are being conducted and preliminary results are strongly suggestive of a consistent reduction of cervical cancer incidence in the cohorts that have been offered vaccination in their adolescent years. It is worth remembering the progress made from the early HPV vaccine indications in 2006/07 (girls only, single cohorts, age below 15 years/before sexual initiation, three doses required, etc.) to the gradually expanding indications based on either results of formal trials (male vaccination, widening of the age range, HIV cohorts, MSM, other high-risk groups, etc.) or based on clinical observations and educated interpretation of the evidence outside formal RCT (vaccination as adjuvant to treatments for CIN2 1 or as part of the management of recurrent respiratory papillomatosis) [20]. These novel indications translate the underlying observations that: 1. HPV vaccines are highly effective also in adult individuals. 2. HPV-vaccinated women are predicted to reduce dramatically their lifetime screening requirements increasing the cost effectiveness of the programs. 3. HPV vaccines are safe and do not have any formal contraindications. Further, their safety record now includes all special populations examined including, for example, groups of HIV 1 , HPV 1 , pregnant and lactating women, individuals with immunosuppression or with autoimmune diseases, and patients with RRP or CIN2 1 lesions. 4. Reaching vaccination coverage levels above 50% of the female population generates a very powerful herd protection effect and significant reductions in HPV prevalence and of genital warts has been documented among nonvaccinated females as well as in nonvaccinated males in the community. The nature of the herd protection needs to be further investigated and notably the opportunities to boosting it by reducing the transmission rates of the HPV carriers to their partners by vaccination. 5. Getting prepared for an effective and rapid investigation of any apparent breakthrough cases in vaccinated individulas and possible vaccine side effects can minimize the opportunity for “false-news” supporting antivaccine beliefs. 6. Finally, HPV vaccines are not therapeutic for prevalent infections. Therefore HPV 1 women, even if they receive some benefit from vaccination (protection against HPV types not prevalent at the time of vaccination) will remain at high risk and should be offered a closer follow-up algorithm. This continuously expanding panel of plausible indications has been socially encouraged by at least three components: 1. The reduction in the number of doses required (i.e., recommended two doses for girls below age 15 years) with some studies suggesting that two doses may be equally effective at least to age 18 years [21].

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2. The important reduction in vaccine prices notably for GAVI countries and large procurements afforded by public national programs of procurement consortiums such as the revolving fund lead by OPS/PAHO. 3. The overwhelming evidence of the efficacy and effectiveness of HPV vaccines that prompted decisions at all levels to generalize promotion of the vaccination programs. The use of two-dose regimes with 6 12 months interval between doses as opposed to the original indication of three-dose regimes was first suggested in Quebec, Canada and rapidly adopted in Mexico and other countries in public programs with a research component to ensure that third doses would be administered if the interim analyses showed the need to booster the immune response. These exploratory population-based programs were initially inspired by previous examples of dosage reduction in other vaccines and the early findings of the immune response assessment of the HPV vaccines. Further, Phase III and IV trials and unscheduled findings from population vaccination programs provided an ancillary result from groups of women that received one or two doses for a variety of reasons instead of the three doses scheduled. Upon completion of 7 1 years of observations of these spontaneously formed subgroups it seems clear than the antibody levels plateau and that no cases of persistent infections/CIN lesions have occurred after receiving one single dose of vaccine. The results attracted enough interest to launch formal trials to compare the value of one dose in terms of protection from infection and disease as well as to allow modeling the potential duration of protection [22]. Increasing indications by expert advisory groups in many countries reflect the recognized value of the HPV vaccines and is creating at present some shortage in the production and supply, a circumstance that may delay introduction and generalization. While efforts to increase the offer are underway, novel vaccines produced in cheaper and more efficient systems are being developed and tested. The expected arrival to the market of these new products from China and India will alleviate the shortage and allow faster deployment of the programs in low- and middle-income countries [23].

COMPREHENSIVE RESEARCH ON COMBINATIONS OF HUMAN PAPILLOMAVIRUS SCREENING AND HUMAN PAPILLOMAVIRUS VACCINATION Another area of great interest refers to the age range of vaccine indication and particularly how to articulate the extended vaccination indications with the rapidly expanding HPV-based screening protocols. One of such proposals is the HPV FASTER project which has recently been modeled using extensive data sets from population-based programs [2,24]. The proposal of the HPV-FASTER protocol is to offer HPV vaccination to women in a broad age range of 9 45 years (exact limits to be further refined and locally calibrated) irrespective of HPV-infection status. Women of any age above 25/30 years would, in addition to the vaccination, be screened using a validated HPV test as part of their initial visit; women who test HPV-positive would be offered triage and follow-up diagnostic tests and treatment in accordance with recommended guidelines. Screen-and-treat protocols would be useful in many environments working towards the concept of a single visit for the prevention of cervical cancer. The rationale of this project is that women properly diagnosed as HPV-negative at screening ages and receiving a broad spectrum vaccine should have a subsequent lifetime risk of cervical

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cancer very low, tending to zero. Likewise HPV-positive women at the time of vaccination adequately followed-up (including treatment of CIN2 1 cases) will also have a significantly reduced risk of disease. In both instances, the subsequent needs for screening may be dramatically reduced to one or two in a lifetime, thus increasing sustainability and compliance as well as alleviation of the burden and workload at the health centers, typically overloaded already with patient care. Vaccinated cohorts will increasingly enjoy a significant reduction in viral circulation, in abnormal pap smears including high-grade lesions and within a few decades, significant reductions in cervical cancer and all other HPV-caused cancers. These changing estimations of disease burden will also reduce the frequency of screening events and drive the replacement of the pap smear method by HPV-based screening technologies. However, for several cohorts that could not benefit from early vaccination, screening will remain their only alternative for prevention. As a consequence and for a number of years the two interventions will need to be combined and the challenge is to accomplish it in the most cost-effective way.

ANTIVACCINES AND ANTIVACCINATION CAMPAIGNS Vaccines have generated over the years an intriguing effect currently embraced by the concept of “anti-vaxers” and “vaccine skeptics.” Among a list of mechanically repeated and unproven arguments (i.e., natural alternatives to vaccination, low number of cancer cases when screening is in place, etc.) vaccine safety concerns are consistently presented, typically claiming that all adverse events occurring soon after a vaccination episode are causally related to the vaccine or the vaccine components such as the adjuvants. Antivaccine movements are being identified as a significant barrier to achieve universal coverage. Examples are available where cases of diseases that were considered eliminated in given populations reemerged either as isolated cases (i.e., one case of diphtheria in Spain) or full outbreaks (i.e., measles in Europe or the United States). WHO has identified vaccine hesitancy as one of ten most relevant public health problems, deserving understanding and attention [25]. These attitudes include occasionally health professionals that are hesitant or reluctant to recommend HPV vaccines to their patients or display openly defiance to the scientific international consensus on vaccine recommendations. These positions ignore the wealth of scientific evidence accumulated over decades and the many examples in which unvaccinated individuals develop the disease in environments that have been disease-free for many years. Social scientists investigating the phenomena describe a hysteresis-like effect in which a fake narrative (i.e., measles vaccine causes autism) installs itself in the collective mindset after a clinical anecdotal episode, an alarming publication or simply a reiterated front page in the media. The fakestory strongly influences the time of persistency of the doubts about vaccine, generates hesitancy in a fraction of the population and has the potential to dramatically reduce the vaccine coverage rates for some time [26]. Examples of vaccine crisis for HPV have been experienced in Japan, Colombia, Denmark, and Ireland, countries in different parts of the world with very different cultural and socioeconomic status and with different access to information and to publically supported vaccination programs. Furthermore, the confidence and credibility crisis has hit some of the most prestigious review bodies, such as the Cochrane collaboration, and remains virulent even if a full audit including

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scientific reanalysis of the data and inclusion of additional trials are conclusive on the safety of the vaccines. Any initial scientific skepticism concerning evidence of effectiveness and safety are nowadays resolved by the overwhelming evidence generated by public programs including literally tens of millions individuals who have been vaccinated in countries that benefit from careful scientific scrutiny and independent evaluation of any suspicion of a deleterious secondary effects of any clinical significance [9].

COMPLIANCE REGULATIONS AND PUBLIC AND PRIVATE PARTNERSHIPS Other than safety, an increasingly important issue in HPV research and prevention interventions will be the management of the collaboration between academic scientists, clinical practitioners and the relevant industry either in the diagnostic or vaccine fields or eventually in the promotion of treatments whenever available. Issues of potential conflicts of interest and increasing compliance restrictions to participate in public forums are often aired as arguments to restrict vaccination programs and deserve an in depth discussion in the academic and public health fields. Close collaboration of academic research and industry support in the HPV field has had a critical impact on the progress towards the call for elimination of HPV-related cancers in at least the following aspects: 1. Providing the basic etiological evidence and HPV type specific attributable fractions worldwide to support the development and evaluation of HPV screening and vaccination alternatives. 2. Helping define the HPV types to be included as probes in diagnostic tests and as antigens in vaccine composition. 3. Describe the international consistency and the limited variability in the HPV types in related cancers. One part of this is ensuring access to high-quality pathology providing consistent accurate diagnosis of cancers studied. 4. Validating HPV diagnostic technologies in large ASCUS triage trials and in very large primary screening trials literally involving millions of women. 5. Recruiting over 100,000 participants in RCT of HPV vaccines and driving a significant number of ancillary studies on HPV natural history. 6. Providing cost reductions and tiered pricing in diagnostic tests and HPV vaccines for GAVI countries and national public programs. 7. Supporting educational and communication programs and events worldwide. 8. Coordinate with the public health communities and institutions the production and distribution of the hundreds of millions doses of HPV vaccines that will be required over time to sustain the cervical cancer elimination campaign. Despite the importance of close collaboration between academic research and industry in the development of preventive approaches to HPV-associated cancers described in this book, it is no secret that the interactions between industry, health institutions, and health professionals have experienced significant storms and ethical and scientific challenges worldwide. However, there are substantial differences in the nature of public and private collaborations in relation to the product being promoted by the specific aspects of the product under consideration.

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As an example in a recognized oversimplified discussion, one can consider that the ethical/corruption issues are obvious if the product promoted is toxic and health damaging (i.e., tobacco, alcohol, added sugar, etc.). More difficult interpretations of the results and judgements about new interventions occur when considering clinical studies with uncertain and/or borderline results. This has happened most often with recommendations of expensive chemotherapies with very limited therapeutic benefit. Here the health economic impact is often used to make a judgement, but this uses arbitrary levels that are not necessarily matched to the values or desires of individuals. These situations are very different from the issues surrounding HPV vaccination where there is unanimous agreement that the vaccines are of great benefit to many different populations at large. While, at the time of completion of the phase 3 trials, it was possible to argue that even the large scale trials could not exclude the possibility of a very rare, but serious side effect in a very small number ( , 1/100,000) of vaccines. The accumulated data from the 12 years of follow-up and the large numbers vaccinated make this no longer scientifically tenable. The benefit of HPV vaccines should be promoted and openly defended. Global medicine, all biomedical science, and public health have to face the ethical and scientific challenges of ensuring that in its relations with relevant industries and within its own work, the quality and the analysis of the data and the interpretation lead to improved transparency of evidence and how it was obtained, analyzed and judgements made. It is important to progress beyond the current process of conflict of interest disclosures to facilitate and promote full, open discussion of results and their interpretation. If we fail to expand our understanding and address the consequences of conflicts of interest and develop a full ethical and scientific code of action we will continue to suffer from encountering very damaging situations in which relevant institutions and individuals are challenged and damaged in their scientific credibility by rumors, fake news or convoluted personal histories. It is important that researchers act ethically and are allowed to act responsibly and authoritatively, whether academic, public health, or industry based, in collaboration with regulatory agencies and recommending bodies to ensure that the highest standards of clinical research are followed and that no effort or contribution is bureaucratically dismissed. We are living in exciting times where the initial hypothesis of a sexually transmitted agent causing cervical cancer has evolved to a massive international campaign to eliminate several important cancers in both genders. The initiative will require multidisciplinary coordinated efforts across very different cultural and economic environments and face significant challenges.

ACKNOWLEDGEMENTS The work was partially supported by 1. The European Union Seventh Framework Programme (grant agreement #603019; CoheaHr); 2. Grants from the Instituto de Salud Carlos III-ISCIII (Spanish Government) cofunded by FEDER funds/ European Regional Development Fund (ERDF)—a way to build Europe (RD12/0036/0056, CIBERESP and CIBERONC) and 3. The Government of Catalonia via the Age`ncia de Gestio´ d’Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grant 2014SGR1077 and 2014SGR2016)

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The authors acknowledge the support of the Cancer Epidemiology and Research Program (PREC) at ICO and in particular of Dr. Marisa Mena in providing comments and literature reviews during the process of the preparation of the manuscript.

COMPETING INTERESTS F.X.B., received research funding via their institution from GlaxoSmithKline, Merck, Qiagen, Roche, and Sanofi Pasteur MSD. Personal grants for travel expenses, meetings and/or giving conferences from GlaxoSmithKline, Merck, Qiagen, Hologic, and Sanofi Pasteur MSD. D.J. has received research funding from GlaxoSmithKline and Merck and was Director of Clinical Research on the Cervarix (HPV16/18) research program. He is a consultant to DDL Diagnostic Laboratories, Rijswijk, The Netherlands.

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