Elsevier

Vaccine

Volume 31, Supplement 8, 22 November 2013, Pages I1-I31
Vaccine

Review
Comprehensive Control of Human Papillomavirus Infections and Related Diseases

https://doi.org/10.1016/j.vaccine.2013.07.026Get rights and content

Highlights

  • HPV is globally prevalent and related to at least 6 different cancer sites in women and men

  • Prevention of HPV infections and its consequences is now technologically feasible

  • Novel options for prevention include HPV vaccination and the use of HPV screening methods

  • Vaccination is cost-effective with high efficacy for HPV infection and disease

  • International major efforts are needed to extend HPV-related cancer prevention to developing countries

Abstract

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries.

This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

Section snippets

HPV and cervical cancer: natural history and prevention opportunities

Cervical cancer is the rare end stage of an unresolved HPV infection, currently defined as a persistent presence of the HPV DNA in repeated testing of cervical specimens. In many industrialised countries the prevalence of HPV infections in young adult females is as high as 40–80% and the lifetime probability of ever encountering HPV is as high as 80–90%. Most of these infections clear spontaneously without clinical signs or symptoms. The fraction of persistent carriers of HPV in the middle ages

HPV prevalence

The global prevalence of HPV infection in women with normal cytology is around 11–12%, with the highest prevalences in sub-Saharan Africa (24%), Eastern Europe (21%) and Latin America (16%) (Fig. 2). Maximum rates of HPV prevalence are observed in women less than 25 years, declining in older ages in many populations, some of which have a secondary peak in peri-menopausal or early menopausal women. In other populations, like in China, the prevalence of HPV is relatively age independent. The

Natural history of cervical HPV

Cervical infections are the best understood HPV infections. Cervical HPV persistence is the known necessary event for the development of cervical precancer and cervical cancer. New infections appearing at any age are benign unless they persist. The early natural history of HPV infection and first steps of cervical carcinogenesis have been directly observed in prospective studies of the kind illustrated in Fig. 5.

A negative HPV test implies low risk of CIN3+ and a positive HPV test implies a

HPV and diseases of the upper airway: head and neck cancer and respiratory papillomatosis [5]

HPV infection is causally associated with benign and malignant diseases of the upper airway, including RRP and oropharyngeal cancer.

Biology and life cycle of HPVs

The interaction between papillomaviruses and their hosts is very ancient. This has lead to a balance between viral replication and immune tolerance. HPVs belong to one of five genera within the family Papillomaviridae. During evolution, HPVs have adapted to specific niches, and different papillomavirus types have different disease association and disease prevalence.

Normal productive life cycle

Our knowledge of the viral life cycle refers mainly to high-risk mucosotropic HPVs and is commonly extrapolated to all HPVs.

Current treatment of HPV-related disease

Standard treatment for HPV-associated anogenital lesions has primarily been by surgical excision. The current treatment of chronic and neoplastic HPV-associated conditions is summarized below:

High-grade CIN: Treatment strategies focus on eliminating the abnormal HPV-infected precancerous cells while minimizing harm to the cervical integrity. Common procedures include a loop electrosurgical excision procedure, cold knife cone biopsy, electrofulgaration, cold-coagulation and cryotherapy. Due to

Evidence regarding HPV testing in secondary prevention of cervical cancer [8]

Regularly updated reviews of the full validity of screening tests have been a major benefit to clinicians as they facilitate the understanding of the continuously increasing amounts of new information regarding innovative cervical cancer prevention methods. Meta-analyses and systematic reviews have been performed on three possible clinical applications of HPV testing. These include triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after

Nucleic acid tests for the detection of alpha HPVs [9]

A comprehensive inventory of commercial tests for detection of alpha-HPV has identified at least 125 distinct HPV tests and at least 84 variants of the original tests (Table 6). However, only a small subset of HPV tests has documented clinical performance for any of the standard HPV testing indications. For more than 75% of HPV tests currently on the market, no single publication in peer-reviewed literature can be identified.

HPV tests that have not been validated and lack proof of reliability,

New technologies and procedures for cervical cancer screening [10]

The clearly higher sensitivity and reproducibility of HPV DNA testing for high-grade CIN has led to widespread calls to introduce it as the primary screening test. The main concern has been its lower specificity, due to the fact that it cannot separate transient from persistent infections; only the latter are associated with an increased risk of high-grade CIN and cancer. Thus, even proponents of HPV testing generally only recommend it for women over the age of 30 years. If HPV testing is to

Introduction of HPV DNA screening in the world: 15 years of experience [11]

The discovery of the necessary cause of cervical cancer, HPV, has led to important technological advances, including the development of molecular tests for HPV to identify women with cervical precancerous lesions. HPV testing has proven to be more sensitive and more reliable, albeit cross-sectionally less specific, for detection of cervical precancer than cytologic methods of detection. As the result, HPV testing can reduce the incidence of cervical cancer within 4–5 years and reduce the

HPV vaccines - immune responses [12]

Immune mechanisms for protection against infection and for recovery from infection are not necessarily the same; the latter is almost invariably the result of cell-mediated immunity and the recruitment and activation of cytotoxic effector cells. These may be irrelevant to the prevention of infection and disease afforded by the vaccine which, like most of the successful prophylactic vaccines used at the present, appears to be via antibody.

A review of clinical trials of HPV prophylactic vaccines [13]

End of study analyses of the phase III trials of prophylactic HPV VLP vaccines in young women are now largely completed. Two distinct vaccines were evaluated, Gardasil® (Merck & Co., Whitehouse Station, NJ USA), a quadrivalent vaccine containing VLPs of types 6, 11, 16 and 18, and Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), a bivalent vaccine containing VLPs of types 16 and 18 (Table 8).

HPV vaccine introduction

The availability of prophylactic HPV vaccines has provided a powerful tool for primary prevention of cervical cancer and other HPV-associated diseases. Since 2006, the quadrivalent and bivalent vaccines have each been licensed in over 100 countries. By the beginning of 2012, HPV vaccine has been introduced into national immunization programs in at least 40 countries (Table 17). Australia, the United Kingdom (UK), the United States (US), and Canada were among the first countries to introduce HPV

Understanding HPV vaccine uptake [15]

Factors that influence HPV vaccine uptake may be viewed from the perspective of an Information—Motivation—Behavioral Skills (IMB) model analysis. The IMB model suggests that HPV vaccination information, HPV vaccination motivation, and HPV vaccine behavioral skills are fundamental determinants of HPV vaccine uptake. According to the IMB model, individuals who are well-informed about HPV vaccination, motivated to act on what they know about it, and who possess the behavioral skills required to

Overview of mathematical models for decision making

A comprehensive approach to the evaluation of HPV prevention raises a number of technical challenges. These include accurate modeling of HPV transmission within a population, the natural history of progression to cervical preneoplastic and neoplastic disease and other HPV-associated cancers, the efficacy of vaccination against different HPV types, cervical screening test performance for various screening and triage test technologies, diagnostic and treatment processes, and screening and

HPV, HIV and immunosuppression [17]

The vast majority of women infected with HIV will be co-infected with HPV. Linkage studies of HIV/AIDS and cancer registries have indicated a 2- to 22-fold increase in cervical cancer in HIV-positive women compared to HIV-negative women. In addition, it has been observed that immunocompromised individuals, such as those with HIV, are also resistant to treatment of HPV-related diseases and prone to accelerated development of HPV-associated cancers.

HPV and cancer prevention: gaps in knowledge and prospects for research, policy and advocacy [18]

The recognition that HPV infection is the central, necessary cause of cervical cancer paved the way to new fronts of prevention via improved screening methods and HPV vaccination.

Much has been learned in all fronts, from the molecular basis of our understanding of how HPV causes disease to the health economics of preventive strategies at the individual and population levels. Progress in other areas of cancer control has yet to show the same multi- and trans-disciplinary gains seen in research

Upgrading public health programs for HPV prevention and control is possible in low- and middle-income countries [19]

Cancer is an important cause of premature death in low- and middle-income countries (LMIC). Two preventive tools are available that have the potential together to sharply decrease the impact of cervical cancer in LMIC. The combination of HPV vaccination and cervical cancer screening within existing programs is possible. Although there is a great deal of concern about introducing and strengthening HPV prevention efforts in LMIC, recent projects have demonstrated feasibility. Thus, with

Burden of disease from HPV-related cancers in GAVI countries

Cervical cancer is the second leading cause of cancer death in women in less developed regions of the world and the leading cause of cancer deaths in GAVI-eligible countries, where 54% of worldwide cervical cancer deaths occur. If prevention is not implemented in these countries, population growth alone will lead to a 63% increase in deaths by 2025. Of the 530,232 new cervical cancer cases diagnosed in 2008 (9% of all female cancers), 48% of cases (254,374) occurred in GAVI-eligible countries.

Conclusion

When closing the ICO monograph (Vaccine Volume 30, Supplement 5, 2012) the International HPV Expert Group of editors and authors reached a consensus statement that aimed to summarize the evidence and the ways to move forward in relation to prevention of the HPV related diseases. The declaration serves us as a concluding remark of this article:

The available HPV vaccines will prevent cervical cancer and other HPV related diseases. All countries are encouraged to introduce routine HPV vaccination

Acknowledgments

Authors of the ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Vol. 30 Suppl. 5: Ginesa Albero (Spain), Laia Alemany (Spain), Ahti Anttila (Finland), Marc Arbyn (Belgium), Lawrence Banks (Italy), Christine Bergeron (France), Jerome L. Belinson (USA), Johannes Berkhof (The Netherlands), F. Xavier Bosch (Spain), Ignacio G. Bravo (Spain), Freddie Bray (France), Thomas R. Broker (USA), Julia M.L. Brotherton (Australia), Laia Bruni (Spain), Ann Burchell (Canada),

Glossary

According to Protocol (ATP) cohorts
Also designated Per Protocol Efficacy (PPE). ATP analyses are restricted to individuals who adhere to all aspects of the study protocol: for example, they received the three vaccine doses within specified intervals, and events are not counted until after receiving all three doses. Importantly, individuals included in ATP cohorts have no evidence of exposure to the vaccine-targeted type under analysis. Thus ATP analyses can be viewed as the best-case scenario

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