Human Papillomavirus: Proving and Using a Viral Cause for Cancer

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Human Papillomavirus: Proving and Using a Viral Cause for Cancer presents a steady and massive accumulation of evidence about the role of HPV and prevention of HPV-induced cancer, along with the role and personal commitment of many scientists of different backgrounds in establishing global relevance. This exercise involved years of personal commitment to proving or disproving an idea that aroused initial skepticism, and that still has difficult implications for some. It remains one of the big successes of medicine that exploited both established medical science dating back to the nineteenth century and new molecular genetic science during a time of transition in medicine. Presents a comprehensive, up-to-date review of the role of HPV in cancer from those involved in its studyIncludes the way evidence on the role and utility of HPV based prevention has been accumulated over almost 40 years Gives a series of vignettes of individual scientists involved in the development of the science of HPV and cancer at different stages and their experiences and reasons for involvement Cover Human Papillomavirus: Proving and Using a Viral Cause for Cance Copyright Contents List of Contributors Preface General Introduction—The Background to Human Papillomavirus and Cancer Research Why Worry About Human Papillomavirus? The Book First Class Medical Science Is Not the Only Issue Cervical Cancer Was the Driver of Human Papillomavirus Research Finding the Role of Human Papillomavirus in Cervical Cancer Proving the Causal Role of Human Papillomavirus in Cervical Cancer The Importance of Human Papillomavirus DNA Testing for Clinical Research Into Human Papillomavirus and Cancer and Its Preve... The Complex Interactions of Academic Science, Clinical Medicine, and the Corporate World Human Papillomavirus Beyond Cervical Cancer The Key Role of Human Papillomavirus in Preventing Cervical Cancer Cervical Screening Before Human Papillomavirus Redefining the Pathology of Precancer in the Light of Human Papillomavirus—The Bethesda System and Its Successors The Move to Change Cervical Screening Based on Human Papillomavirus Science Applying Human Papillomavirus Screening Globally Development of Biomarkers Natural and Artificial Immune Responses to Human Papillomavirus and Human Papillomavirus Vaccines Developing Human Papillomavirus Vaccines The Impact of Corporate Human Papillomavirus Vaccine Trials and Marketing Human Papillomavirus Vaccination in Practice Human Papillomavirus and Modern Medical Science The Future References Further Reading 1 A Brief History of Cervical Cancer Understanding Cervical Cancer—From Paleopathology to the 19th Century Transforming Western Medicine and the Rise of Medical Science The Idea of Prevention (Fig. 1.6) Cervical Cancer Prevention by Cervical Cytology Screening Encouraging Participation in Cervical Cancer Screening Evolution of Ideas on the Causes of Cervical Cancer, Male Role, and Transmission of a Causative Agent Further Reading Section 1: Proving the Role of Human Papillomavirus in Cervical Cancer: Studies in the Laboratory, Clinic, and Community Introduction 2 Linking Human Papillomavirus to Human Cancer and Understanding Its Carcinogenic Mechanisms Animal Papillomaviruses: From Papillomas to Cancers The Search for Infectious Agents Associated With Cervical Cancer The Failure of the Herpes Hypothesis Molecular Tools The Human Papillomavirus Hypothesis Southern Blotting Cloning Human Papillomavirus DNAs Epidermodysplasia Verruciformis Identifying HPV 11, HPV 16, and HPV 18 Extending the Range of HPV Types The Advent of PCR Studying HPV Gene Expression in Lesions HPV 16 and 18 in Neoplastic Transformation: E6 and E7 Genes Additional Pioneering Studies of Immortalization and Transformation Recapitulation of Three-Dimensional Epithelial Tissues in Raft Cultures as an Experimental Model for Investigations of HPV-... Conclusion A Vignette: Early Clinical Experience With Human Papillomavirus References 3 Demonstrating the Importance of Different HPVs in Cervical Cancer and Other HPV-Related Cancers* Introduction Human Papillomavirus as Etiological Agent of Cervical Cancer Human Papillomavirus Association With Cervical Cancer: Case-Control Studies Human Papillomavirus Prevalence and Distribution in Cervical Cancer and Other Human Papillomavirus-Associated Carcinomas Human Papillomavirus-Type Distribution of Oncogenic Human Papillomavirus Types Across the Full Spectrum of Cervical Disease Human Papillomavirus Classification and Its Association With Carcinogenicity Implications References 4 Finding How Human Papillomaviruses Alter the Biochemistry and Identity of Infected Epithelial Cells Parasitic Lifestyles The Enigmatic, Illogical Life Cycle of High-Risk Human Papillomaviruses Inhibition of Innate Immune Signaling Mechanisms That Minimize Human Papillomavirus Genome Loss During Cell Division High-Risk HPV E6 and E7 Trigger and Subvert Cell-Intrinsic Defense Mechanisms Human Papillomavirus Infections Render Host Cells Genomically Unstable Concluding Remarks References 5 Biology of the Human Papillomavirus Life Cycle: The Basis for Understanding the Pathology of PreCancer and Cancer Productive Infection Facilitates the Assembly and Release of Virus Particles Genome Maintenance and the Replication of HPV Genomes in the Epithelial Basal Layer Productive Infection and Virus Synthesis Occurs in the Differentiated Layers of the Epithelium Nonproductive Infection Leads to the Development of Neoplasia The Role of HPV Gene Products in the Progression From Neoplasia to Cancer Understanding the Cervix and Other Vulnerable Epithelial Site in the Development of Cancer Understanding HPV Biology in Relation to the Pathological Classification of HPV-Associated Cancers and Precancer, and the S... Conclusion Acknowledgement References 6 The Pathology of Cervical Precancer and Cancer and its importance in clinical practice Introduction: Framing the Problem Terminology: Historical Perspective Diagnostic Process and Specimen Types Cytologic Specimens (“Pap Smears”) Cervical Biopsy Cone Biopsy Hysterectomy Gross Morphology–Colposcopic Features Morphology (Histology and Cytology) Normal Squamous Epithelium Negative for Intraepithelial Lesion or Malignancy Cervical Cytology’s Special Case of Equivocal Morphology Atypical Squamous Cells Epithelial Glandular Cells Abnormalities Sampling of the Endocervical Epithelium Low-Grade Squamous Intraepithelial Lesions/CIN1 Low-Grade Squamous Intraepithelial Lesions: Histology High-Grade Intraepithelial Squamous Lesion: CIN2 HSIL/CIN2 Histology High-Grade Intraepithelial Squamous Lesion: CIN3 HSIL/CIN3: Histology High-Grade Intraepithelial Squamous Lesion Variants Thin High-Grade Intraepithelial Squamous Lesion Keratinizing High-Grade Intraepithelial Squamous Lesion Papillary High-Grade Intraepithelial Squamous Lesion Microscopic Mimics Squamous Cell Carcinoma Glandular Neoplasia Sampling of the Endocervical Epithelium Atypical Glandular Cells Endocervical Adenocarcinoma In Situ Adenocarcinoma Using Our Molecular Understanding of Disease Progression to Improve Diagnosis: Detection of HPV DNA and Biomarkers of Infection Biomarkers Ki67 Cytokeratin 7 and Other Squamocolumnar Junctional Markers In Situ Hybridization (ISH) HPV DNA In Situ Hybridization Biomarkers on Cytology Samples Triage of HPV-Positive Women p16/ki-67 Dual Stain Clinical Course and Management of Cervical Neoplasia Low-Grade Squamous Intraepithelial Lesions Behavior/Management High-Grade Intraepithelial Squamous Lesion Behavior/Management Further Reading 7 Developing and Standardizing Human Papillomavirus Tests Historical Development Discovery of Human Papillomavirus Cloning of Human Papillomavirus First Wave of Human Papillomavirus DNA Tests Spectrum of Anogenital Human Papillomavirus Types First Commercial Human Papillomavirus DNA Tests Target Amplification for Detection of Human Papillomavirus DNA Broad-Spectrum Polymerase Chain Reaction Type-Specific Polymerase Chain Reaction Detection of Human Papillomavirus mRNA Polymerase Chain Reaction Read-Out Methods Design and Performance Assessment of Human Papillomavirus Tests Intended Use Clinical Specimen, Collection, and Processing Target Selection and Amplification Human Papillomavirus DNA Detection Tests With Partial and Full Spectrum Genotyping Performance Assessment of HPV Tests and Requirements for Ongoing Quality Assurance Analytical Versus Clinical Performance Proficiency Panels Internal/Endogenous Control Brief Summary of Selected Commercial Human Papillomavirus Tests The Hybrid Capture 2 Human Papillomavirus DNA Test GP5+/6+ System SPF10/DEIA/LiPA25 System The LINEAR ARRAY Human Papillomavirus Genotyping System The Cobas 4800 Human Papillomavirus Test (Roche Cobas) The APTIMA Human Papillomavirus assay The BD Onclarity Human Papillomavirus Assay The Xpert Human Papillomavirus Assay Future Perspectives Vaccinology Human Papillomavirus Surveillance Human Papillomavirus-Based Screening Cervical Screening in Vaccinated Women Full Molecular-Based Screening Next Generation Sequencing Overview and Summary References 8 Proving the Causal Role of Human Papillomavirus in Cervical Cancer: A Tale of Multidisciplinary Science* Avoiding a Clash Between Different Lines of Scientific Evidence Learning From Errors A New Beginning for Molecular Epidemiology The Birth of a New Paradigm in Cancer Prevention Moving From Understanding Etiology to Improving Cervical Cancer Screening The Opportunity to Prevent Cervical Cancer With a Vaccine From Discovery to a Nobel Prize References 9 The Natural History of Human Papillomavirus Infection in Relation to Cervical Cancer Key Bullet Points Transmission of Human Papillomavirus Lack of Strong Epidemiologic Indicators for Human Papillomavirus Persistence (or Clearance) Roles of Parity, Female Hormones and Tobacco References Section 2: Human Papillomavirus Beyond Cervical Cancer Introduction Reference 10 Low-risk Human Papillomavirus: genital warts, cancer and respiratory papillomatosis The Problem: Genital Warts and Laryngeal Papillomatosis Historical Aspects of Genital Warts and Laryngeal Papillomatosis Risk Factors, Natural History, and Treatment of Genital Warts and Laryngeal Papillomatosis Pathology of Genital Warts and Laryngeal Papillomatosis Human Papillomavirus in Genital Warts and Laryngeal Papillomatosis Low-Risk Human Papillomavirus Types and Cancer Therapeutic and Prophylactic Vaccines Against Genital Warts and Laryngeal Papillomatosis Past, Present, and Future Epidemiology of Genital Warts and Laryngeal Papillomatosis Conclusion Acknowledgements References 11 Human Papillomavirus Infection and Related Diseases Among Men Where the Story of Male Human Papillomavirus Infection Among Heterosexual Men Began: The Male Factor in Cervical Carcinogenesis Human Papillomavirus Natural History in Heterosexual Men—Past and Current Understanding The HIM Study: Population and Procedures Genital Human Papillomavirus Infection Anal Human Papillomavirus Infection Oral Human Papillomavirus Infection Human Papillomavirus Serology Heterosexual Human Papillomavirus Transmission References 12 Anal HPV Infection and HPV-Associated Disease Studies of Anal HPV Infection: Their Origins and Inspirations Development of Tools to Study Anal HPV Infection and HPV-associated Diseases Anal Cancer and Immune Suppression Anal Cancer in HIV-infected Men and Women in the era of Antiretroviral Therapy The Future: An Emerging Field, and Potential for Contributions to Understanding the Overall Biology of HPV Infection Summary References 13 Oropharyngeal Human Papillomavirus and Head and Neck Cancer Introduction Epidemiology Molecular Pathophysiology of Human Papillomavirus Carcinogenesis Prognosis of Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma Trends in Human Papillomavirus Oropharyngeal Squamous Cell Carcinoma Staging Prevention Conclusion Financial Disclosures Conflicts of Interest References 14 Vulvar, Penile, and Scrotal Human Papillomavirus and Non–Human Papillomavirus Cancer Pathways History of Vulvar, Penile, and Scrotal Cancer Reflects Both Human Papillomavirus–related and Non–Human Papillomavirus–relat... Burden of Vulvar, Penile, and Scrotal Cancer Pathology of Vulvar, Penile, and Scrotal Neoplasia Cancer Pathways of Vulvar, Penile, and Scrotal Cancer: Human Papillomavirus and Non–Human Papillomavirus Related Common Characteristics Between Vulva, Penile, and Scrotal Carcinoma Clinical Management of Vulvar, Penile, and Scrotal Neoplasia Conclusion References Section 3: Using Human Papillomavirus Knowledge to Prevent Cervical and Other Cancers Introduction References 15 Triage of Women With ASCUS and LSIL Abnormal Cytology: The ALTS Experience and Beyond Evidence That Human Papillomavirus Testing May Be Useful for Triage of Some Abnormal Cytology Origin and Development of the ALTS Study Main Results of the ALTS Study Impact of the ALTS Study in Changing Medical Practice in the United States and Worldwide Metaanalyses on the Clinical Accuracy of Human Papillomavirus DNA Testing to Triage Women With ASCUS Future of Cytology and Human Papillomavirus Triage References Further Reading 16 Primary Screening by Human Papillomavirus Testing: Development, Implementation, and Perspectives Development of HPV-Based Screening HPV Testing Versus Cytology Sole HPV Testing or HPV Testing Combined With Cytology? Screening Intervals, Follow-up of HPV Positive Women, and Age to Start Screening Triage of HPV Positive Women Microscopy-Based Triage Strategies Cytology P16/Ki-67 Dual Staining Molecular Triage Strategies HPV Testing With HPV Genotyping Viral or Host Methylation Markers Validation of HPV Tests for Cervical Screening Self-Sampling The New HPV Based Program in the Netherlands Colposcopy Triage of HPV Positive Women Screening Intervals Self-Sampling HPV Negative and Low-Risk HPV Positive CIN3 and Carcinomas Future Perspectives for Cervical Screening Conflicts of Interest Disclaimer References 17 Infection to Cancer—Finding Useful Biomarkers for Predicting Risk of Progression to Cancer Introduction Biomarkers for Transforming Human Papillomavirus -Infections: p16INK4a and Ki-67 Biomarkers for productive human papillomavirus -infections: HPV E4, L1 Biomarkers for Transforming Human Papillomavirus -Infections: Methylation of Cellular Genes Biomarkers for Transforming HPV-Infections: Methylation of Viral Genes References 18 Immune Responses to Human Papillomavirus and the Development of Human Papillomavirus Vaccines Introduction Innate Immunity Adaptive Immunity Immunity to Human Papillomavirus: A Successful Infectious Agent Human Papillomavirus Infectious Cycle Human Papillomavirus Evades Innate Immune Defenses HRHPVs Downregulate Interferon Responses Human Papillomavirus Interactions With Dendritic Cells Professional Antigen Presenting Cells The Immune Response to Human Papillomavirus in Natural Infections Immune Responses Are Deregulated During Human Papillomavirus-Associated Neoplastic Progression The Mucosal Environment Humoral Immunity to Human Papillomavirus and the Development of Human Papillomavirus Vaccines What Animal Papillomavirus Infections Told Us Generation of Virus-Like Particles Did the Antibodies Generated by L1 Virus-Like Particles Protect—Preclinical Animal Studies Human Papillomavirus Virus-Like Particle Vaccines A Vignette: The Story of jian zhou References 19 Clinical Trials of Human Papillomavirus Vaccines Introduction Limitations of Secondary Prevention Primary Prevention Timeline of HPV Vaccine Success Story Designing Clinical Trials of Preventive HPV Vaccines Clinical Trial Endpoints HPV Vaccination Phase II/III Clinical Efficacy Trials in Women With Active Follow-Up Early Clinical Trials Phase 3 Efficacy Trials Quadrivalent HPV Vaccine Phase 3 Trial (FUTURE* I/II) Phase 3 Studies of the Bivalent HPV16/18 Vaccine Comparison of Quadrivalent and Bivalent Vaccine Efficacy Against Cervical HSIL Based on Clinical Trials The Overall Implementation of HPV Vaccination Subsequent Additional Phase 3 Trials Broad Spectrum Nonavalent HPV Vaccine Trial HPV Vaccine Trials in Women Older Than 25 years Phase 4 Trials to Evaluate Vaccine Performance in Populations HPV Vaccine Efficacy Against External Genital Lesions Genital Warts High Grade Vulvar and Vaginal Intraepithelial Neoplasia (VIN2-3, VaIN2-3) Cross-Protective Efficacy Against Nonvaccine High Risk HPV Types Quadrivalent HPV6/11/16/18 (4vHPV) Vaccine Bivalent HPV16/18 (2vHPV) Vaccine HPV Vaccination Phase III Clinical Efficacy Trials in Men With Active Follow-Up Viral and Disease Endpoints Used in Trials Among Men Prior HPV Vaccination Prevents Recurrent HPV Related High Grade Disease HPV Vaccination After Treatment for CIN Prevents Recurrent HPV Related High Grade Disease HPV Vaccine Safety Clinical Trial Safety Data Health Registry Based Safety Data Conclusion A vignette: joining the dark side: a pathology academic joins a vaccine manufacturer References Further Reading Section 4: Accumulating Long-Term Evidence for Global Control and Elimination of Human Papillomavirus Induced Cancers Introduction A Complex Issue Compiling Evidence Introducing Human Papillomavirus Vaccination in Practice The Importance of Vaccine Safety The Mixed History of the Medical Profession and the Pharmaceutical Industry Good Evidence or Belief? Cancer Prevention Meets Politics Globally References 20 The Key Role of Mathematical Modeling and Health Economics in the Public Health Transitions in Cervical Cancer Prevention Introduction General Background to Mathematical Models in Population Health History of the Early Development of Cervical Cancer Models: The 1980s and 1990s The 2000s: A New Field Emerges Recent Developments in Cervical Cancer Modeling: 2010–2019 Conclusions Acknowledgments Conflict of Interest List of Abbreviations A Vignette: The Story Behind the First Cost-Effectiveness Evaluations of Human Papillomavirus Vaccination (Told by Shalini ... References 21 Twelve Years of Vaccine Registration and the Consequences HPV Vaccines and Their Introduction Registered HPV Vaccines Introduction Into National Immunization Programs Measures of Vaccination Programs Vaccine Coverage Vaccine Impact and Effectiveness HPV DNA Genoprevalence Genital Warts Cervical Disease Juvenile Onset Recurrent Respiratory Papillomatosis Cervical Cancer Evolving Policy Issues Male Vaccination Two Dose Schedules Nonavalent Vaccine [9vHPV] Other Vaccines on the Horizon Challenges Impact on Current Cervical Screening Programmes Conclusion References 22 Political and Public Responses to Human Papillomavirus Vaccination Introduction Case Studies Case Study: Slow and Uneven Progress; Human Papillomavirus Vaccination in the United States Case Study: Recovery; Human Papillomavirus Vaccination in Austria, Denmark, and Ireland Case Study: No Recovery; Human Papillomavirus Vaccination in Japan Case Study: Successful and Sustained Implementation; Human Papillomavirus Vaccination in Australia and the United Kingdom Case Study: False Start; Human Papillomavirus Vaccination in India Case Study: Introduction of Human Papillomavirus Vaccination Programs in Low-/Middle-Income Countries Discussion References 23 Expanding Prevention of Cervical Cancer in Low- and Middle-Income Countries Case Study Nkhoma “Screen and Treat” Program Cervical Screening Using Human Papillomavirus Testing Perspective From Asia Global Perspective References Further Reading Epilogue: Looking forward to cervical cancer elimination Integrating Cervical Cancer Prevention in the Frame of Other National Health Priorities Natural History and Spectrum of Disease Related to Human Papillomavirus Research Areas in the Screening and Treatment Fields Research in the Vaccination Field Comprehensive Research on Combinations of Human Papillomavirus Screening and Human Papillomavirus Vaccination Antivaccines and Antivaccination Campaigns Compliance Regulations and Public and Private Partnerships Acknowledgements Competing Interests References Index Back Cover