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The lifestyles and socio-economic status that are prevalent in regions of the world with limited resources form the background for the unique features of neoplastic diseases in these areas, where the majority of the world population lives. The predominance of the world’s retroviral burden of in these areas further compounds the nature and challenges of the cancer there. Much of the international cancer literature covers the nature and challenges of the disease as seen in high-income regions of the world, thereby giving a skewed view of the global cancer challenges. As the low- and middle-income regions of the world transition from communicable to non communicable disease patterns, there is a need for a corresponding paradigm shift, with increased emphasis on what the world needs to know about non communicable diseases, including cancer, where the disease is hitherto poorly documented. The main goal of the proposed book is to contribute to this outcomes.

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Christopher Kwesi O. Williams

Cancer and AIDS

Part II: Cancer Pathogenesis and Epidemiology

Cancer and AIDS

Christopher Kwesi O. Williams

Cancer and AIDS Part II: Cancer Pathogenesis and Epidemiology

Christopher Kwesi O. Williams Hematology Oncology Consultancy Port Angeles, WA, USA

ISBN 978-3-319-99234-1 ISBN 978-3-319-99235-8 (eBook) https://doi.org/10.1007/978-3-319-99235-8 Library of Congress Control Number: 2018959099 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

The reader will find in the pages of this book an extensive and thought-provoking review by an experienced oncologist, with a long and deep experience in Africa, Europe, and North America, and an astute observer of the international scene. The focus is on two very different disease complexes: HIV/AIDS and cancer. However, although they have different pathogenesis, epidemiology, and therapy, they share many similarities in the problems, which they pose to health systems in low- and middle-income countries (LMIC). The author reminds of the difficulty of providing affordable health care in those parts of the world subsumed by the label of “LMICs” (and indeed of the fact that, within this group, incomes and resources also vary enormously). The fact that, within the health sector alone, the governments of these countries are facing the double burden of an increasing load of noncommunicable disease, while the traditional problems on infections/maternal and child mortality, remain. Basically, the issue is how low-income countries can address these challenges with the resources available. Of course, addressing the root cause (of inequalities of opportunity and wealth around the world) might be the logical approach; in this book, we cannot expect solutions to redressing the world economic order (where primary producers are rewarded less than manufacturers and they in turn less than “service providers”), rather, how to make do within this framework. Low income (exacerbated by gross inequalities in its distribution) results in poor health-care provision from public sources (government or social security schemes), with correspondingly poor results. Time and again, the author makes reference to the standards and guidelines developed in high-income countries (especially the USA) and asks how can they be made relevant to low-income settings. Of course, almost always they cannot.

What to Do? Currently, the focus is upon action plans for NCDs, as sparked by the Declaration the United Nations General Assembly on the Prevention and Control of Non communicable Diseases [1], which the WHO followed up with its global v

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Foreword

monitoring framework on NCDs [2]. The latter urges the establishment of multisectoral national NCO plans. Is this a sensible idea from the point of view of implementation? In fact, although NCDs have some commonalities (for instance, they are not communicable), from a diagnosis and management point of view, there is nothing in common between, for example, diabetes, hypertension, and cancer. It is true that in high-income settings, some NCDs share common risk factors (tobacco for some cancers and heart disease and obesity for diabetes and some cancers), but in low-income settings, there is in reality little overlap. Indeed, as extensively documented in Chaps. 3 and 6 of Part II, the most important cause of cancer in LMICs is infection (especially with HPV, hepatitis viruses, Helicobacter pylori, and HIV itself). The reality is that the control strategies for cancers (embracing surveillance, prevention, early detection treatment, and palliation) are generally quite different from those for other NCDs. How to develop some sort of plan to “control” cancer, given limited infrastructure and resources? There are many clues and suggestions throughout the book. The author writes in Chap. 9 of Part III: “The complexity of modern cancer management could be so overwhelming, especially for cancer caregivers of low-income countries, that the practice of cancer control tends to promote its prevention in preference to its management. However, a reasonable balance between the various aspects of cancer control is probably more reasonable.” This is surely correct. A previous director of the Cancer Unit of WHO used to castigate hospitals providing cancer care as “white elephants,” a charge that was grossly unfair to their staff. Care of the sick is an unavoidable minimum for any health-care system. Prevention may well be more logical, and cheaper, but this is of little comfort to those struck down with disease. And, the author reminds us in Chap. 7 of Part II, of the most important factor in determining who will get cancer-chance. Rediscovered, recently [3], in antiquity, Job discovered that a blameless past will not protect one from disaster (brought on by the unknowable will of a divinity or by a sequence of random mutations), although it is of course possible to change one’s odds of disease through appropriate preventive action. Cancer control, then, involves a balance of prevention, early detection and care (curative and palliative), with the balance determined by needs, resources, and the efficacy of different interventions. And, intervention is needed – some of the epidemiological transitions described in the book (such as the decline in incidence of cancers of the cervix and lung) are not natural phenomena, like the seasons, but the result of active interventions. Looking at priorities for cancer prevention, it is tempting to look to the guidelines of prestigious bodies, especially in the USA (see Chap. 8 of Part III). These will almost always be quite inappropriate to the task in hand. Each unit (country) will need to examine its own cancer profile, and the prevalence of risk factors, to quantify the fractions of cancer that is preventable, before weighing up the feasibility of doing so. The author points out the bizarre fact that many countries are contemplating the more costly (and difficult) proposition of vaccination against HPV (and being urged to vaccinate boys as well as girls), while incorporation of the HBV vaccine into infant immunization schedules is incomplete.

Foreword

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The head of the UK Screening Evaluation Unit began a lecture by noting that, among the strategies for controlling cancer, screening was the least important. She was surely correct. The logic of screening and the technological wizardry involved make it almost irresistible to cancer experts. Yet, as the author points out, in Chap. 8 of Part III, “for screening to be effective, it has to be population-based, whereby each person in the eligible population is invited to attend each round of screening.... this involves the establishment of a national public policy documented in a law, or an official regulation decision directive or recommendation. Although standard in resource-rich countries, this is not practicable in countries of limited resources, for economic reasons.” As a result, cancer screening in low-income settings has generally been limited to local, opportunistic projects (e.g., detection of preinvasive cervical lesions, using VIA), with unknown, but surely very limited, impact on the population. There are much more compelling reasons to work out how to improve stage at presentation of cancer, which, as the discussion in Chap. 8 of Part III documents, means acting at the individual, community, and system (health service) levels. Dealing with the most appropriate treatment services to offer is perhaps the most difficult part of cancer control, but it cannot be avoided, and the issues are fully discussed in Chap. 9 of Part III. Radiotherapy, the most expensive of interventions (in terms of equipment, trained personnel, maintenance, and management), is paradoxically the most required in low-income settings where patients present with advanced disease and palliative care is essential. The cost of drugs, especially the newer targeted immunotherapeutic drugs, is a huge concern. There is no alternative but to fall back on some sort of cost-per-life-year approach, which is implicitly the basis of the essential medicines program and more explicitly of some national regulatory agencies. Palliative services get appropriate recognition as an essential component of cancer control. Really, no one should die in pain when the remedy is so cheap, making it always available must be a top priority for any “care” service. What of research and science, a field the author knows well? As he points out, it is another area of inequality; not only have the brain drain but also the lack of resources hampered research in the health sciences in LMICs. There is a lack of even the most fundamental research into health service need and performance. Look at the evidence the author could assemble of basic measures of cancer prognosis and outcome – for the USA, the SEER survey allows precise information on cancer stage and prognosis, their distribution and trends; for lower-income countries, the author must fall back on miscellaneous clinical series from local journals, with who-knows-what relevance to the population scenario. Too many of the articles cited seem to be commentary or diagnosis (“look at the problems” with far too little practical basis and providing no investment in legacy for the future). The Bill & Melinda Gates Foundation (impatient optimists working to reduce inequity) has given $279 million to the University of Washington study disease patterns worldwide. How much of this will be spent in improving the means to collect and analyze such important data in LMICs, where they are sorely lacking?

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Foreword

It is appropriate, given this excess of hand-wringing articles that the author in his final chapter provides some ideas for moving forward. The situation is unlikely to improve spontaneously; for every Singapore, there is a Somalia. His prescription of international action is surely the best hope of allowing the transfer of wealth and expertise from rich to poor. Just as climate change has forced reluctant international coordinated action, we must aim for the same in health. Sporadic efforts by a myriad of self-appointed NGOs are likely to be as effective as their efforts in conflict zones, where lack of coordination leads to as much effort going into interagency completion as to the task in hand. The model of focused partnerships in the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GF) seems highly relevant. Global Health System strengthing? One can only hope that the UN and its specialist agencies can seize the opportunity; action is surely overdue! United Nations General Assembly: Political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases, UN New York, 2011 [available at http://www.un.org/en/ga/ ncdmeeting2011/]. Honorary Senior Research Fellow CTSU, Richard Doll Building Old Road Campus Roosevelt Drive Oxford OX3 7LK, UK

Donald Maxwell Parkin

References 1. World Health Organization. Global action plan for the prevention and control of noncommunicable diseases 2013–2020. 2013. Available at: http://apps.who.int/iris/bitstream/ l0665/94384/1/9789241506236_eng.pdf. 2. Tomasetti C, Vogelstein B. Cancer etiology. The number of stem cell divisions can explain variation in cancer risk among tissues. Science. 2015; 347:78–81. 3. http://www.washington.edu/news/2017/01/25/bill-melinda-gates-foundation-boosts-vitalwork-of the-uws-institute-for-health-metrics-and-evaluation/.

Preface

The world can be subdivided into different categories, depending on the nature of the characterization. Perhaps, the best instrument of characterization of the populations of the world is the United Nations Human Development index (HDI), which classifies countries into “very high,” “high,” “medium,” and “low” ranks of development, based on a variety of criteria. The topmost 49 of about 170 countries with the highest HDI scores are classified as being “very highly” developed. Many countries in this category are of almost unlimited human and financial resources. They contain less than 20% of the world population. Not only do the less-developed parts of the world harbor the greater burden of cancer, because, partly, that is where the majority of the world population lives. The predominance of the world’s retroviral infectious burden, including HIV/AIDS and HTLV-1/HTLV-2, in these areas further compounds the nature and challenges of health care there. Much of the international literature on cancer covers the nature and challenges of the disease and its control from the point of view of the high-income regions of the world. This is because of the presence in this region of mature and well-structured health-care systems. Doing so, however, gives a skewed view of cancer for the whole world. As the low- and middle-income regions of the world transition from communicable to noncommunicable disease patterns, however, there is a need for a corresponding paradigm shift. Cancer control measures of the high-income countries are largely impracticable in low-income countries, because they are simply not affordable there. The questions then arise as to whether cancer control should be a prerogative of high-income regions of the world or how this can be accomplished in the low- and middle-income settings as well. These are some of the questions that need to be addressed if a reduction of the sufferings caused by premature death from cancer and HIV/AIDS in the prime of life in much of the world is to be curtailed. This is the goal that this book aims to achieve. The book provides a description of the epidemiology of cancer and retroviral diseases, including HIV/AIDS, with special reference to resource-poor settings, based on the author’s own observations. For example, even though the author’s background is adult medical oncology, he was preoccupied while working in the 1980s in Nigeria with childhood malignancies, especially Burkitt lymphoma, ix

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Preface

because adult malignancies were much less common in the hospital settings. Childhood acute lymphoblastic leukemia, which he encountered very frequently during his medical training and practice in high-income countries, was much less frequent in Nigeria, while cases of childhood acute myelogenous leukemia were, to his astonishment, commonly associated with mass formation (chloromas) at presentation. These observations were among the reasons for the author’s interest in the role of lifestyle and environmental factors in pathogenesis of various childhood and adult cancers as outlined in the book. Furthermore, the difficulties that he encountered in providing appropriate care to a vulnerable segment of the community provoked in him a passion to find ways to address health-care system deficiencies in cancer control. The author of this book is uniquely positioned to address the global challenges in the control of cancer and retroviral diseases, because of his global education and academic medical practice. Born and raised in Nigeria, he had his medical education in Munich, Germany. He subsequently underwent postgraduate education in Canada and the United States, followed by academic medical practice in Africa, Europe, and the Middle East, including extensive research-related travels in India, Brazil, and Argentina. Decades of practice of hematology and medical oncology in the United States and Canada, including years of service as a principal investigator of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) have given him a rich experience of the world’s leading health-care systems. The beginning of his training in medical oncology in New York City under the tutelage of some of the authors of the blueprint of the United States “National Cancer Act,” which President Nixon signed into law in 1971, a few years earlier, places him at a vantage point of observing the evolution of cancer control in the many decades of unprecedented advances that have followed. Similarly, his early involvement in human retroviral research in Africa, through his collaboration with leading scientists of the National Cancer Institute, in Bethesda, MD, USA, beginning at a point in time prior to the recognition of the human immunodeficiency virus (HIV) as the causative agent of the acquired immunodeficiency disease (AIDS), has also given him the opportunity to follow the evolving human tragedy of HIV/AIDS pandemic and its impending end. International exposures through his over 35-year membership of prestigious cancer control organizations, including the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) have given him the opportunity to follow the evolution of the science of oncology and virology. His commitment to the elucidation of cancer control challenges in Africa and other developing parts of the world is what drove him to join others as a co-founder in 1982 of the African Organisation for Research and Training in Cancer (AORTIC). In an era, in which there is a genuine concern for global equity in access to health, this book hopes to serve those who seek to understand the forces that shape global health-care systems, what needs to be done in the LMICs, where help is needed. These include health-care practitioners of all health-care systems, especially those in the “very developed” countries who are interested in global health care as a career. It will prove useful for funding agencies in the “very developed”

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countries providing assistance to health-care providers, researchers and others in the less developed world. It will hopefully also be a valuable resource for health-care providers and health care policy-makers in resource-poor settings of the world, who seek to understand the dynamics of health-care provision in all health-care systems. Port Angeles, WA, USA

Christopher Kwesi O. Williams

Contents

Part II Pathogenesis and Epidemiology 3 Cancer, Retroviral Diseases and Global Economy�� 3 3.1 Economic Indices and the Human Development Index�� 4 3.2 Quantifying Inequalities�� 7 3.3 Inequality and Health�� 7 3.3.1 Inequality and Health in Early Life�� 7 3.3.2 Inequality and HIV/AIDS�� 8 3.3.3 Inequality and Cancer Burden�� 9 3.4 Changing Trend of Global Burden of Non-communicable Diseases�� 16 3.5 Epidemiological Transition and Health Care Funding �� 17 3.6 Inequality in Science�� 17 References�� 18 4 Global HTLV-1/2 Burden and Associated Diseases�� 21 4.1 The Discovery of the Human T-Lymphotropic Virus Type 1 (HTLV-1)�� 22 4.2 Virology of HTLV-1�� 23 4.3 Diagnosis of HTLV-1 Infection�� 23 4.4 Modes of Transmission of HTLV-1�� 24 4.4.1 Mother-to-Child Mode of Transmission�� 24 4.4.2 Sexual Transmission of HTLV-1�� 25 4.4.3 Parenteral Transmission of HTLV-1 �� 26 4.4.4 Prevention of HTLV-1/2 Transmission �� 26 4.5 HTLV Infection and Lifestyle of Nigerians�� 27 4.6 Origin, Spread and Global Prevalence of HTLV-1/2�� 31 4.7 HTLV-1 Associated Diseases�� 34 4.7.1 Adult T-Cell Leukemia/Lymphoma (ATL) �� 36 4.7.2 HTLV-1 Associated Myelopathy and Tropical Spastic Paraparesis (HAM/TSP)�� 38

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4.7.3 HTLV-1 Associated Infective Dermatitis�� 39 4.7.4 Other Infectious Complications of HTLV-1 �� 41 4.7.5 Other Inflammatory Complications of HTLV-1 Infection�� 42 4.7.6 The Role of HTLV-I in Health and Disease�� 43 References�� 44 5 Global HIV/AIDS Burden and Associated Diseases �� 59 5.1 Discovery of the Causative Agent of HIV/AIDS�� 60 5.1.1 Retroviruses�� 60 5.1.2 Human Lentiviruses and Subtypes of HIV-1�� 61 5.1.3 Diversities in HIV Types and Subtypes and Implications for Disease Control �� 62 5.2 Early Phase of AIDS Epidemic in Africa: The Nigerian Experience�� 63 5.3 Global HIV/AIDS Burden�� 64 5.4 Global Trends in HIV/AIDS DALY�� 66 5.5 Financial Resources for Global Campaign Against HIV/AIDS �� 67 5.6 Sustainable Financing of HIV/AIDS Control: External Resources�� 69 5.7 Sustainable Financing of HIV/AIDS Control: The Challenge of Local Funding�� 71 5.8 HIV/AIDS and Global and Universal Health Care�� 72 5.8.1 Global Status of Antiretroviral Coverage �� 73 5.9 HIV/AIDS in Eastern Europe and Central Asia�� 74 5.10 Non-malignant Complications of HIV/AIDS �� 75 5.10.1 HIV/AIDS Associated Infectious Complications�� 75 5.10.2 HIV-Associated Rheumatic Diseases �� 78 5.10.3 HIV/AIDS Associated Neurologic Disorders�� 78 5.10.4 HIVAIDS Associated Neuropsychiatric Disorders�� 79 5.10.5 HIV/AIDS Associated Nephropathy�� 79 5.10.6 HIV/AIDS Associated Anemia�� 80 5.10.7 HIV/AIDS Associated Gastrointestinal Complications�� 80 5.10.8 HIV/AIDS Associated Metabolic Disorders�� 81 5.10.9 HIV/AIDS Associated Cardiovascular Disorders�� 81 5.10.10 HIV-AIDS Associated Pulmonary Hypertension �� 82 5.11 HIV/AIDS Associated AIDS Cancers�� 82 5.11.1 HIV/AIDS Associated Non-AIDS-Defining Malignancies�� 83 5.11.2 HIV/AIDS Associated Cancers�� 83 References�� 86

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6 Cancer and Infection �� 97 6.1 Cancer Associated Infectious Agents�� 98 6.2 Viral Infections (Other Than Retroviruses) and Associated Cancers�� 98 6.2.1 Hepatitis B and C Viruses and Associated Cancers�� 99 6.2.2 Epstein-Barr Virus and the Associated Cancers �� 100 6.2.3 Human Papilloma Virus and the Associated Cancers�� 100 6.2.4 Kaposi’s Sarcoma Herpesvirus and Kaposi’s Sarcoma�� 101 6.2.5 Human T-cell Lymphotropic Virus Type 1 (HTLV-1) and the Adult T-cell Leukemia/Lymphoma (ATL) �� 103 6.3 Helicobacter Pylori Bacterium and Associated Cancers�� 103 6.4 Macroparasite Infections and Cancers�� 104 6.5 Microbiota and Cancer�� 105 6.6 Microbial Oncometabolite and Cancer �� 106 6.7 Microbiota and Cancer Pharmacotherapy�� 106 6.8 Inflammation and Cancer�� 106 6.9 Chronic Inflammation and Obesity�� 108 6.10 Microbiome and Human Development�� 108 6.11 Microbiome, Infections and Childhood Leukemia �� 108 References�� 109 7 Risk Factors for Cancer�� 115 7.1 Cancer Risk Among Tissues �� 116 7.1.1 Cancer Risk and the Concept of the “External Risk Score”�� 116 7.1.2 Cancer Risk Factors and Cancer Prevention�� 117 7.1.3 Interaction of Cancer Risk Factors �� 118 7.2 Cancer Risk and Chemical Agents�� 118 7.2.1 Alcohol Consumption and Cancer�� 122 7.2.2 Occupational Chemical Agents and Cancer �� 125 7.2.3 Polycyclic Aromatic Hydrocarbons and Cancer�� 126 7.2.4 Obesity and Cancer�� 127 7.2.5 History of the Origin of Tobacco�� 130 7.2.6 Aflatoxins and Food Contaminants�� 133 7.2.7 Plant Based Chemicals and Cancer�� 135 7.3 Genetic Susceptibility, Ethnicity and Cancer�� 136 7.3.1 International Genomic Research and Cancer �� 137 7.3.2 Genetic Ancestry and Rare Mutations�� 139 7.3.3 Origins of Racial Diversity and Disparities�� 140 7.4 Epigenetics and Cancer�� 140 7.4.1 Epigenome and Cancer�� 141 7.4.2 Epigenome and Environmental Factors�� 141 7.4.3 Epigenome and Cancer Therapy/Prevention�� 142

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7.5 Geographical Epidemiology of Cancer, with Emphasis on the Third World�� 143 7.5.1 Global Cancer Epidemiology and Lifestyles of Affluence�� 144 7.5.2 Global Cancer Epidemiology and Lifestyles of Poverty �� 146 7.6 Impact of HIV/AIDS Pandemic and Global Cancer Epidemiology�� 150 7.6.1 Global Epidemiology of Endemic and Epidemic Kaposi’s Sarcoma �� 152 7.6.2 Global Epidemiology of Non Hodgkin Lymphoma in the Era of HIV/AIDS Pandemic �� 157 7.6.3 Global Epidemiology of Hodgkin Lymphoma in the Era of HIV/AIDS Pandemic �� 157 7.6.4 Global Epidemiology of HPV-Associated Cancers in the Era of HIV/AIDS Pandemic �� 159 7.6.5 Epidemiology of Non-AIDS Defining Cancers in the Era of HIV/AIDS Pandemic �� 160 7.6.6 AIDS Associated Cancers in the Era of HAART �� 160 7.6.7 Global Epidemiology of the Leukemias�� 160 7.6.8 Risk Factors for Childhood Hematological and Non-hematological Cancers�� 162 References�� 166 Index�� 179

Part II

Pathogenesis and Epidemiology

Chapter 3

Cancer, Retroviral Diseases and Global Economy

Abstract The Human Development Index (HDI), a concept of global socioeconomic subdivision developed by the United Nations based on three characteristics – life expectancy at birth, education and means of decent living – yields four socioeconomic categories: very high, high, medium and low HDI countries. The Gini coefficient, another index used by economists, reflects the distribution of wealth within national boundaries. HDI and Gini indices elucidate the role of poverty in the epidemiology of HIV/AIDS and cancer and other non-communicable diseases, including the consequences of adoption of affluent lifestyles in low- and middle-income countries. High incidence especially of the cancers of the colon, breast, prostate and stomach characterize cancer epidemiology of the high/very high HDI countries, constituting the so-called “cancers of industrialization.” The concept of “double burden” relates to the persistence of high prevalence of communicable diseases in low and middle HDI countries in addition to acquisition of diseases of affluence characteristic of the high/very HDI countries, including obesity and the related diseases like diabetes and cardiovascular disorders and “cancers of industrialization”. Transition in global cancer epidemiology is illustrated by the inverse relationship between the incidence of breast cancer and that of cervical cancer in high/very high and medium HDI countries. In Uganda, a low HDI country, however, the incidences of both cancers are increasing. External funding of health care is discordant with disease burden in recipient countries of medium and low HDI, indicating the need for reappraisal by both local and external sources in the management of health priorities. Keywords Great divergence · HDI · World Bank · Gini · Mathew effect · DAH · Australia · China · Colombia · Costa Rica · Denmark · India · Japan · Slovakia · Spain · USA · Uganda

© Springer Nature Switzerland AG 2019 C. K. O. Williams, Cancer and AIDS, https://doi.org/10.1007/978-3-319-99235-8_1

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3 Cancer, Retroviral Diseases and Global Economy

3.1 Economic Indices and the Human Development Index The role that societal inequalities play in cancer and HIV/AIDS has been alluded to earlier (see Sect. 3.6, [1, 2]). According to Angus Deaton, Professor of Economics and International Affairs at Princeton University, Princeton, NJ, USA: “The world is unequal in many dimensions: even life itself is unequally distributed. For instance, while 2–6 children out of every 1000 die before the age of one in the United States, in 25 countries, 60 out of 1000 do so. There are ten countries, all in Africa, where per-capita gross domestic product (GDP) is less than 10% of U.S. per-capita GDP [3]”. These gaps, which manifest in the sub-categorization of the world, has been attributed to “the legacy of the Great Divergence that began 250 years ago, in which sustained progress in health and wealth in Europe spread to the rest of the world” [3]. The Great Divergence [4–7], coupled with the numerous historic events of several centuries [8], has contributed largely to the inequalities of today’s world, which are described in sub-categorization of parts of the world according to various economic indices and spectrum of human development. The concept of Human Development Index (HDI), and its relationship to the global state of health emerged through the United Nations Development Program and first published in 1990 [9, 10]. It is a composite index of three basic dimensions of human development – a long and healthy life, education, and decent standard of living – combined into a unit-free index with a value between 0 and 1. The first dimension is measured by life expectancy at birth. This component is calculated using a minimum value of 20 years and a maximum of 83.57 years, these being the extremes of this determination for countries over the period 1980–2012. Access to knowledge, the educational component, is indicated by the average duration of schooling that has been provided to adults aged 25 years and the expected years of schooling for children of school- entry age. The third component, a decent standard of living, is measured by the gross national income per capita (in purchasing power parity in United States dollars) [10]. These three characteristics of human development as they are ascertained in countries are provided in Table 3.1. As previously reviewed in 3.6, Hans Rosling, a former head of the Division of Global Health at the Karolinska Institute in Stockholm, laments that the term “developing world” blurs the differences between middle-income countries, like Turkey, and those dominated by extreme poverty such as Somalia. In his view, the world population can be divided into three categories: 1.5 billion people who have a light bulb and a washing machine, 4 billion who have only the light bulb, and about 1.5 billion who have neither. “The population of Liberia, Guinea and Sierra Leone mostly fall into the last category...and that is the reason we can have such a huge Ebola outbreak there” [12]. Figure 3.1 illustrates the dichotomous division of the world into the classical concept of “developed” and “developing” countries. Using the HDI estimates for 2012, the world can be roughly divided dichotomously into low/medium HDI and high/very high HDI (Fig. 3.2). The categorization can be further enhanced by dividing the 2012 HDI into quartiles to indicate “very high”,

39%

817 million $1099

Bangladesh, Cambodia, Kenya

35

90%

64%

Guatemala, India, Nigeria

56

$8731

Secondary school enrolment rate, 2010b 100%

$3287

2.5 billion

Brazil, China, Russia

54

2.5 billion

Total population 1.1 billion

Number of Country countries examples 70 Canada, Poland, U.S.

Average income in 2010 (constant PPP 2005 international $) $33,232

57.5

64.8

71.5

Life expectancy at birth (years, 2009) 79.8

76.5

51.7

17.5

Infant mortality rate (per 1000 live births, 2009) 5.8

a

The World Bank calculates gross national income using the Atlas conversion factor, which reduces the impact of exchange fluctuations when comparing national incomes across different countries b Ratio of enrolment in secondary school (regardless of age) to the population of the age group that corresponds to that level of education Source: World Bank, World Development Indicators. Reproduced with permission of the Conference Board of Canada [11]

Income categories High-income countries (rich countries) Upper-middle- $3976 to $12,275 income countries $1006 to $3975 Lower- middle- income countries $1005 or less Low-income countries (poor countries)

Income classification criteria: gross national income per capita in 2009 (US$)a Higher than $12,276

Table 3.1 Profiles of countries by World Bank income categories

3.1 Economic Indices and the Human Development Index 5

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Fig. 3.1 Global map of development of individual countries: the historical division into “developing” and “developed” countries [10]

Fig. 3.2 Global map of development of individual countries: countries with low/medium HDI, and those with high/very high HDI [10]

“high”, “medium” and “low” levels of human development [10], as shown in Fig. 3.3. Assignment to a particular HDI category is not static, but may change from one period to the other. Thus, several African countries have transitioned from low to medium HDI category, so also many Asian countries, including India and China, while many Latin American and Central Asian countries have moved from medium to high HDI category [10]. Figures 3.1, 3.2 and 3.3 are reproduced with permission from Stewart and Wild [13]. Data compiled from the United Nations Development Programme [10].

3.3 Inequality and Health

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Fig. 3.3 Global map of development of individual countries: subdivision by quartiles into low, medium, high and very high HDI

3.2 Quantifying Inequalities The HDI-based sub-categorization of countries provides only a rough idea about wealth and human development. In the United States, new information suggests a wide rift between top and bottom income earnings [14, 15]. As disturbing as the wealth distribution in the United States may seem to be, the chasm between the super-rich and the poor is much worse in several countries of the world. This is revealed by the application of the Gini coefficient, which economists use to quantify inequality. It ranges between 0, at which point everyone has equal incomes, and 1, in which a single person takes all the income and the rest get nothing. The U.S. Gini, at 0.40 in 2010, seems relatively high compared with, for example Japan at 0.32 [15]. The Gini coefficient of Canada, a high-income country like the US and Japan, is somewhere between those of its economic partners. South Africa, a middle-income country, has a “sky-high” Gini of 0.7 [15]. Countries with very high inequality are clustered in South America and southern Africa. Countries with low inequality are mostly in Europe, corresponding to the concentration there of high income countries (see Table 3.2). Canada and the U.S. have medium income inequality, although increase in inequality has been greater in Canada than in the U.S. in more recent years [11].

3.3 Inequality and Health 3.3.1 Inequality and Health in Early Life Research has established a base of knowledge about the harmful effects of disadvantageous circumstances on education and health. The deleterious influences on health reach as far back as early stages of life, as outlined by Aizer and Currie [16]. These include maternal disadvantage leading to worse health at birth through poor

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Table 3.2 Distribution of levels of income inequality by country income level

Low inequality (Gini 0.200–0.299) Medium inequality (Gini 0.300–0.399) High inequality (Gini 0.400–0.499) Very high inequality (Gini above 0.500) Total

High-income countries Share # (percent) 17 53

Upper-middle- income countries Share # (percent) 3 9

Lower-middle- income countries Share # (percent) 1 3

Low-income countries Share # (percent) 1 3

14

44

8

23

12

35

15

52

1

3

16

46

11

32

10

34

0

0

8

23

10

29

3

10

32

100

35

100

34

100

29

100

Source: The World Bank, World Development Indicators; The Conference Board of Canada. In keeping with Simon Kuznet’s hypothesis that as countries become more developed, they first experience more inequality and then progressively less inequality, high-income countries are more likely to have lower inequality. The income groupings most likely to have high inequality are middle-income countries – in other words, countries moving up the economic development ladder. Source: World Bank, World Development Indicators. Reproduced with the permission of the Conference Board of Canada [11]

health behaviors, exposure to harmful environmental factors, and worse access to medical care, including family planning, and worse underlying maternal health. While it is well known that the fetus is vulnerable to myriad health insults, resulting in prenatal health issues, it is unclear how much these are contributory to health outcomes in adult life, especially since postnatal interventions can be effective in promoting or reversing the adverse effects of early life health insults [16].

3.3.2 Inequality and HIV/AIDS AIDS has been described as a disease positioned at the core of a “vicious cycle”, whereby its impacts increase poverty and social deprivation while poverty and social deprivation increase the vulnerability to HIV infection [1]. The close association between the Gini coefficients of various African countries and HIV prevalence is illustrated in Fig. 3.6.1, indicating the possible influence of abnormal income distribution and HIV pandemic in parts of the world. Just as in cancer control, social inequality is a major driving force in the evolution of the multi-headed hydra that AIDS represent. Its negative impacts range from those on individuals families to disruption of national economies and threat to international security, thus, explaining the emergence of several international strategies to control it. These include the

3.3 Inequality and Health

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creation of the Global Fund in 2002 for a 5-year plan to provide anti-retroviral drugs for 1.6 million people, counseling and testing for more 62 million people, and care for more than a million orphans [17]. In 2003, the US President’s Emergency Plan For AIDS Relief (PEPFAR), through which $15 billion was to be spent over 5 years, representing what was believed to be the “largest commitment ever by any nation for an international health initiative dedicated to a single disease” [17]. Given the role of governance in the management of AIDS control, it is not surprising that it is the only health issue ever to have become the subject of United Nations Security Council debate [1]. It was also in 2011 the subject of the first of a number of special meetings of the UN General Assembly dedicated to global health issues, including Non Communicable Diseases. These measures have had the salutary effect of global trend in the reduction of HIV prevalence. At the end of 2013, 12.9 million people with HIV were receiving ART globally, up from less than 1 million a decade earlier. This represents approximately 37% of the estimated 35.0 million people living with HIV [18]. “Fifteen years after antiretroviral therapy was first provided in developing countries in the public sector, 15 million people are receiving treatment (as of March 2015) – a significant global accomplishment that meets the goal of the 2011 UN High Level Meeting on HIV/AIDS agreed upon by all member states” [19]. Given the complexity of the AIDS problem, it seems that the solution will require varied innovative strategies incorporating the socioeconomic factors of poverty and inequalities peculiar to different locales and regions, thereby avoiding the “silos” approach of facilitating only the access to HAART, but rather exploring ways and means of integrating this with other workplace, lifestyle, political and legislative measures.

3.3.3 Inequality and Cancer Burden The most common cancers in terms of new cases and deaths according to two levels of HDI – high/very high HDI versus low and medium HDI – are shown in Fig. 3.4 for 2012. After lung cancer, breast, prostate, and colorectal cancers are the most frequent cancers I the countries with high or very high HDI. Whereas colorectal, breast and lung cancers have also become more frequent in countries with low or medium HID, there remains a large excess of poverty- and infection-related cancers in these countries, notably cancers of the stomach, liver, cervix and esophagus [10]. Lung cancer is the major cause of cancer death in both HDI areas, and colorectal cancer ranks a clear second in countries with high or very high HDI. Liver and stomach cancers remain as major causes of cancer death in areas with low or medium HDI, a result of high incidence of these cancers in these areas as well as an extremely poor prognosis for patients after diagnosis. Colorectal, breast and prostate cancer constitute more than 30% of the 7.9 million new cancers annually in high HDI countries, while cancers of the cervix, liver, stomach and Kaposi’s sarcoma constitute less than 10%. In low- and medium-income countries, however,

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Fig. 3.4 ‘Total burden of the 27 most common cancers in 2012: (a) incidence and (b) mortality according to two-level human development index (HDI)” (Reproduced with permission from Stewart and Wild [13]. Data from Ferlay et al. [20]

about 25% of the 6.2 million new cancers per annum are due to infectious agents, while about 20% are due to cancers of the colorectum, breast and prostate. Examination of incidence, mortality and 5-year prevalence of the five most common cancers by the four-level HDI is depicted in Fig. 3.5. This shows that for countries of very high and high HDI, these are made up of lung and stomach cancers along with the “so-called cancers of affluence: breast, prostate and colorectal cancer”. This group of cancers apparently constitute the cancers of “industrial lifestyle” as shown for countries of “high/very high HDI” and countries of “low/medium HDI” (Fig. 3.6) [10]. “Lung cancer occupies a high rank in terms of incidence and is the most frequent cause of death in all HDI categories except low HDI. The disease has a lesser rank in terms of prevalence, however, because of poor survival after diagnosis”, according to Freddie Bray [10]. Freddie Bray, furthermore uses the incidence of breast, prostate, and colorectal cancers in 2012 to illustrate the function of the level of development, and risk of developing these cancers increases as countries transition to higher HDI levels, while the risk of mortality varies considerably less, because of proportionately

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11

Fig. 3.5 “The five most frequent cancers in terms of incident cases, cancer deaths, and 5-year cancer prevalence in 2012 (ages 15 years and older), according to four-level human development index (HDI).” Excerpt from: Bernard W. Stewart; Christopher P. Wild. World Cancer Report 2014.” iBooks. (Reproduced with permission from Stewart and Wild [13]. Data from Ferlay et al. [20], Available at http://globocan.iarc.fr. [10])

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A

High/Very High HDI: 7.9 million new cases

Other cancer types 53.8%

Infection-related cancers

B

9.6% 36.6%

Cancers related to industrialized lifestyles

Low/Medium HDI: 6.2 million new cases

Other cancer types 54.7%

25.0%

Infection-related cancers

20.3%

Cancers related to industrialized lifestyles

Fig. 3.6 “Percentage of cancers related to industrialized lifestyles (colorectal cancer, female breast cancer, and prostate cancer), infection-related cancers (cervical, liver, and stomach cancers and Kaposi sarcoma), and all other cancers (a) in countries with high or very high Human Development Index (HDI) and (b) in countries with low or medium HDI, 2012” Excerpt From: Bernard W. Stewart; Christopher P. Wild. “World Cancer Report 2014.” iBooks. (Reproduced with permission from Stewart and Wild [13]. Data from Ferlay et al. [20]. Available at http://globocan. iarc.fr. [10])

higher case fatality in countries with lower HDI (Fig. 3.7, panel C), apparently more convincingly so than breast cancer (Fig. 3.7, panel A), and prostate cancer (Fig. 3.7, panel B) [10], thus confirming colorectal cancer as a marker of development. Figure 3.8 shows that the correlation of colorectal incidence rates with rising HDI is demonstrable in a spectrum of countries ranging from those of the high/very high, such as Australia, Denmark, Japan, Slovakia, Spain and the US (Black and White) to the low HDI, such as Uganda. Freddie Bray’s analysis, appears to document a transitional pattern of low to rising incidence of colorectal cancer in the medium/

3.3 Inequality and Health

A

13

Female breast cancer

Very High HDI

8.4

1.5

4.9

High HDI

1.6 1.0

2.7

Medium HDI

3.4

Low HDI 8

B

Mortality

Incidence

Prostate cancer

4

1.8

0 4 Cumulative risk, 0-74 yrs, percent

Incidence

Mortality 0.8

Very High HDI 9.3

4.5

High HDI

1.3

0.3

0.7

Medium HDI

1.1

1.8

Low HDI 8

C

8

Colorectal cancer

Very High HDI

4

0 4 Cumulative risk, 0-74 yrs, percent Mortality

Incidence 1.2

3.6

High HDI

1.2

2.1

Medium HDI

1.3

Low HDI

0.7

0.6 8

4

8

0.4 0

4

8

Fig. 3.7 “Cumulative risk of (a) female breast cancer, (b) prostate cancer, and (c) colorectal cancer incidence and mortality (ages 0–74 years) in 2012, according to four-level human development index (HDI). Excerpt From: Bernard W. Stewart; Christopher P. Wild. World Cancer Report 2014”. iBooks (Reproduced with permission from Stewart and Wild [13]. Data from Ferlay et al. [20]. Available at http://globocan.iarc.fr. [10])

low HDI countries of India and Uganda, it also describes the interesting phenomenon of stabilization of the increasing incidence to a level, after which a decline occurs, in the very high HDI countries of Australia, Japan and the U.S. (Black and White). Temporal changes in the incidence of breast and cervix cancer (Fig. 3.9) strikingly illustrates the epidemiological transitions of these cancers, the former of

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Fig. 3.8 “Trends in age-standardized (World) incidence rates [21] for colon cancer in men in 1978–2010 in 12 countries versus concomitant trends in human development index (HDI) in 1980–2012. Incidence is smoothed using Loess regression.” Excerpt From: Bernard W. Stewart; Christopher P. Wild. “World Cancer Report 2014.” iBooks (Reproduced with permission from Stewart and Wild [13]. Data compiled from Ferlay et al. [20]. Available at htt//globocan.iarc.fr and the United Nations Development Programme [10])

3.3 Inequality and Health

15

Fig. 3.9 “Trends in age-standardized (World) incidence rates [21] for breast cancer versus cervical cancer in 1978–2010 in 12 countries. Incidence is smoothed using Loess regression.” Excerpt From: Bernard W. Stewart; Christopher P. Wild. “World Cancer Report 2014.” iBooks (Reproduced with permission from Stewart and Wild [13]. Data compiled from Ferlay et al. [22]. Available at http://globocan.iarc.fr and the United Nations Development Programme [10])

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which has earlier been shown to be an example of a cancer of high/very high HDI (Figs. 3.5 and 3.6) and the other with low HDI (Fig. 3.5). In Australia, China, Colombia, Costa Rica, Denmark, India, Japan, Spain, and USA (Black and White), a rapid decline in the incidence of cervix cancer correlates with increasing incidence of breast cancer. The year in which both cancers are equally common, with the incidence of one trending upwards, and of the other downwards, such as is observed in Colombia, Costa Rica and India, marks the time of epidemiological transition in the country. Such transition apparently occurred in the distant past in Australia, China, Denmark, Japan, Slovakia, Spain and the USA, but not in Uganda [10]. There, the incidence of cervical cancer and breast cancer are rising, indicating that the transitional time is yet in the future.

3.4 C hanging Trend of Global Burden of Non-communicable Diseases The rising trend of morbidity and mortality from noncommunicable diseases (NCD) in the developing world was brought to the attention of global leaders by the United Nations following the observation in 2008 that 36 of the 57 million deaths around the world were due to noncommunicable diseases, with 80% of the deaths occurring in the developing countries. This recognition apparently led to the 2011 Political Declaration of the High-Level Meeting of the United Nations General Assembly on the Prevention and Control of Noncommunicable Diseases (including cancer) [23]. The “double-jeopardy” nature that this observation connoted for the developing world that was emerging from the chronic state of communicable diseases, and the related maternal and child health deficiencies [24, 25], was reviewed by Jaime Selpulveda and Christopher Murray in their analysis of the state of global health in 2014. They also pointed out the need for donor countries to readjust the development assistance for health (DAH) accordingly [26]. In 2013, more than two-thirds of global deaths were attributable to noncommunicable diseases, including 8 million, 17.3 million, and 1.3 million due to cancer, cardiovascular/circulatory diseases and diabetes mellitus respectively, a trend that is attributable to globally increasing life expectancy of 1970–2010 [27]. There was marked regional variability in the pattern of increases in the incidence of noncommunicable diseases, with cancer and cardiovascular diseases being most prominent in Central Asia and Eastern and Central Europe. Obesity is rapidly emerging as an epidemic among noncommunicable diseases. Of the 671 million obese individuals worldwide, 62% live in the developing countries, especially in the countries of Latin America, Oceania, North Africa and the Middle East) [26]. While this epidemic is fuelling the challenges of metabolic disorders, like diabetes, obesity is also emerging as a carcinogenic factor [28, 29]. The evolving epidemiologic pattern gives much concern for the concept of “double burden” of communicable and noncommunicable disease in countries of low and middle-income countries through the acquisition of the cancer patterns of affluent societies.

3.6 Inequality in Science

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Table 3.3 Disease burden in YLL as compared with DAH. Country income levels are classified by the World Bank on the basis of estimates of gross national income, whereas DAH data are from 2010 [31] Low income YLL DAH HIV/AIDS 7.6% 41.6% Malaria 11.2% 14.3% Tuberculosis 3.1% 3.3% Maternal, newborn, and child health 37.8% 17.1% Noncommunicable diseases 20.7% 0.2% Other 19.7% 23.5%

Lower middle income YLL DAH 3.7% 32.0% 4.8% 9.6% 3.5% 6.6% 32.1% 23.7% 34.0% 1.0% 21.9% 27.1%

Upper middle income YLL DAH 4.8% 41.1% 0.0% 2.2% 1.0% 70% 8.1% 7.0% 65.3% 2.9% 20.8% 39.8%

Reproduced with permission from Lu et al. [31]

3.5 Epidemiological Transition and Health Care Funding The developing world is undergoing epidemiological transition as a result of changing traditional lifestyles to those of more affluent societies, with significant implication for the future of healthcare for future generations in countries affected. While it is estimated, for instance, that nearly a quarter of children and adolescents in developed countries are overweight or obese, in developing countries the corresponding proportion has increased from 8.2% to 13% since 1980 [30]. Table 3.3 suggests a discrepancy between disease burden in YLL and external funding by development assistance for health (DAH), perhaps signifying insufficient awareness of the ongoing transition. It could also be a reflection of the attitude and perception of priorities of the external funding agencies. Some reasons that could explain this discordance between the need at the local level and proffered external support have been discussed in Sect. 1.8 in Part I. The challenges arising from the epidemiological transition will require significant intervention of governments of the developing countries, in addition to the adjustments that need to be effected in DAH mechanisms.

3.6 Inequality in Science According to Yu Xie, inequalities in science manifest in three domains: resources, research outcomes and monetary or nonmonetary rewards, thus, easily manifesting in form of Matthew effect: “For to all those who have, more will be given, and they will have an abundance; but from those who have nothing, even what they have will be taken away” (Matthew 25:29) [32]. The socio-economic development of recent decades has revolutionized intercontinental communication and collaboration. In the 1950s and 1960s, international cancer scientists travelled to Africa and lived for years there to study the childhood cancer, Burkitt lymphoma, because of the emerging evidence that demonstrable environmental influences were causing cancer. That

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is less necessary today, given the Internet technology, and globalized economy, in addition to ‘“inexpensive air transportation and relatively peaceful world politics”, which has created an interconnected world [32, 33]. “In this new global environment, a successful scientist filled with ideas at a prestigious university in America or Europe can design studies and have them carried out by dependent collaborators in less developed countries…..where labor-intensive scientific work can be conducted at a lower cost” [32]. Given the poor governance that characterize countries of low HDI, characterized by poor appreciation of science and unsatisfactory promotion of intellectual activities, it is understandable that well funded and enterprising scientists of high/very high HDI countries would have little difficulty in invading academic territories of medium/low HDI countries with scientific proposals, which need not be appropriate for the recipient academic groups in low/medium HDI countries. This, in fact, is a well known, if poorly documented, source of friction between academics from these socioeconomic backgrounds. While the improved interaction of scientists of high/ very high HDI countries and those of lower HDI is a welcome development, there is a need for strategies to be developed to protect the scientific institutions of lowand medium HDI countries from misguided tendencies of high/very high HDI countries in scientific collaborations.

References 1. Piot P, Greener R, Russell S. Squaring the circle: AIDS, poverty, and human development. PLoS Med. 2007;4(10):1571–5. 2. Connexion. Hollande declares new war on cancer. 2014. Available from: http://www.connexionfrance.com 3. Deaton A. Inevitable inequality? Science. 2014;344(6186):783. 4. Pomeranz K. The great divergence. Princeton: Princeton University Press; 2000. 5. King C. The great divergence. Munich: GRIN Verlag; 2013. 6. Allen RC. The great divergence in European wages and prices from the Middle Ages to the First World War. Explor Econ Hist. 2001;38(4):411–47. 7. Parthasarathi P. The great divergence. Past Present. 2002:275–93. 8. Pringle H. The ancient roots of the 1%. Science. 2014;344(6186):822–5. 9. United Nations Development Programme. Human development report 1990. Concept and measurement of human development. New York: UNDP; 1990. Available from: http://hdr. undp.org/en/reports/global/hdr1990/ 10. Bray F. Transitions in human development and the global cancer burden. In: Stewart B, Wild C, editors. World cancer report. Lyon: International Agency for Research on Cancer, World Health Organization; 2014. p. 54–68. 11. Anonymous. World income inequality. Is the world becoming more unequal?. The Conference Board of Canada. 2016. Available from: http://www.conferenceboard.ca 12. Kupferschmidt K. The old man and the disease. Science. 2014;346(6214):1164–5. 13. Stewart BW, Wild CP, editors. World cancer report. Lyon: IARC; 2014. Available from: http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-CancerReport-2014 14. Alvaredo F, Atkinson AB, Piketty T, Saez E. The world top incomes database. 2011 15. Chin G, Culotta E. What the numbers tell us. Science. 2014;344(6186):818–21.

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16. Aizer A, Currie J. The intergenerational transmission of inequality: maternal disadvantage and health at birth. Science. 2014;344(6186):856–61. 17. Greene WC. A history of AIDS: looking back to see ahead. Eur J Immunol. 2007;37(S1):S94–S102. 18. Evans T, Kieny M-P. Tracking universal health coverage – first global monitoring report. France: World Health Organization and The World Bank; 2015. 19. Anonymous. Decision around HIV treatment in 2015: seven ways to fail, derail or prevail. Issue Brief Of Medecins Sans Frontieres. 2015. 20. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide, IARC Cancer Base No. 11 – Internet. Lyon: IARC; 2013. 21. Mwanahamuntu MH, Sahasrabuddhe VV, Kapambwe S, Pfaendler KS, Chibwesha C, Mkumba G, et al. Advancing cervical cancer prevention initiatives in resource-constrained settings: insights from the Cervical Cancer Prevention Program in Zambia. PLoS Med. 2011;8(5):e1001032. 22. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBO. Lyon: IARC; 2013. 23. Anonymous. United nations feneral assembly 2011: political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. New York: UN; 2011. 24. Murray CJ, Frenk J, Piot P, Mundel T. GBD 2.0: a continuously updated global resource. Lancet. 2013;382(9886):9–11. 25. Murray CJ. GBD 2013: open call for collaborators. Lancet. 2013;382(9891):491–2. 26. Sepúlveda J, Murray C. The state of global health in 2014. Science. 2014;345(6202):1275–8. 27. Wang H, Dwyer-Lindgren L, Lofgren KT, Rajaratnam JK, Marcus JR, Levin-Rector A, et al. Age-specific and sex-specific mortality in 187 countries, 1970–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2013;380(9859):2071–94. 28. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev. 2009;18(10):2569–78. 29. Hsieh P-S. Obesity and carcinogenesis. J Cancer Res Pract. 2011;27(6):242–56. 30. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81. 31. Lu C, Schneider MT, Gubbins P, Leach-Kemon K, Jamison D, Murray CJ. Public financing of health in developing countries: a cross-national systematic analysis. Lancet. 2010;375(9723):1375–87. 32. Xie Y. Inequalities in science. Science. 2014;344(6186):809. 33. Friedman TL. The world is flat [updated and expanded]: a brief history of the twenty-first century. New York: Macmillan; 2006.

Chapter 4

Global HTLV-1/2 Burden and Associated Diseases

Abstract The human T-lymphotropic virus type 1 (HTLV-1) was the first retrovirus to be associated with human diseases. It shares serological features with HTLV- 2. Its epidemiology is global and complex, with the endemic regions including Japan and the less developed countries of Africa, Asia, the Caribbean region, South America and Oceania. The global burden, estimated as 5–10 million, is probably grossly conservative, as vast areas of remain unexplored. It is transmitted mainly by breast-feeding, heterosexual activities, and transfusion of infected blood products. Associated diseases include the neoplastic disease adult T-lymphoma/leukemia (ATL), and infectious complications including infective dermatitis, strongyloidiasis, tuberculosis, leprosy, and Norwegian scabies. Others are inflammatory diseases, including tropical spastic paraparesis (HAM/TSP), arthritis, uveitis and Sjörgren syndrome. The diagnosis of these diseases requires specialized laboratory, manpower and technological facilities that are usually unavailable in developing countries. Sporadic cases are therefore usually diagnosed in migrant populations from endemic areas of the developing world in specialized centers in developed countries with specialized facilities. Much of what is known of these diseases come from reports of itinerant scientific and healthcare workers of developed countries with interest in global diseases. The only exceptions are in the endemic areas of Japan, Australia, and Brazil. Public health measures for control of the global burden of the virus, including safe practices of breast-feeding and blood product transfusion, are in place only in a few countries. Addressing challenges of HTLV-1 infection would involve the academia, national governments and regional international institutions of endemic areas in developing countries. Keywords HTLV · ATL · HAM/TSP · Jamaica · Japan · Trinidad · Brazil · HDI · Nigeria · Retroviral

© Springer Nature Switzerland AG 2019 C. K. O. Williams, Cancer and AIDS, https://doi.org/10.1007/978-3-319-99235-8_2

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4.1 T he Discovery of the Human T-Lymphotropic Virus Type 1 (HTLV-1) Viral oncology has its foundations in scientific observations made at the turn of the century leading to the discovery of the first two retroviruses, namely the avian leukemia virus in 1908 by Ellermann and Bang [1], and the avian sarcoma virus in 1910 by Peyton Rous [2]. Subsequent discoveries by Ludwig Gross in the 1950s [3–5], and by William Jarrett in the 1960s [6] led to the awareness of the role of retroviruses in tumors of mice and cats respectively, thus augmenting the expectation that similar agents might be the causative agents of human cancer. The studies of the late 1960s and 1970s that looked for a human retrovirus in human blood disorders relied heavily on the electron microscope and were by and large futile. A dramatic era in human retrovirology was however to be ushered in by the Nobel Prize-winning experiments of Howard Temin [7–9] and David Baltimore [9–11]. Working independently, they showed that the known retroviruses contained enzymes called reverse transcriptase that were involved in transcribing the single stranded RNA copy of the input viral RNA into DNA. This enzymatic activity is associated with retrovirus particles and can be readily assayed in infected cells. Assays for reverse transcriptase activities unique to retroviruses, thus, provided an alternative and sensitive assay for the retroviruses. About the same time as Temin and Baltimore were making their revolutionary observation, Gallo and his co-workers discovered the T-cell growth factor, which later became known as interleukin-2. The availability of TCGF for induction of in vitro T-cell proliferation and the assay for reverse transcriptase which might be expressed by retroviruses in such cells set the stage for the discovery of the first human retrovirus, 70 years after Peyton Rous had discovered the avian sarcoma virus. After listening to a talk by David Baltimore and learning of the work of Howard Temin from the virologist Robert Ting, Robert Gallo (Fig. 2.8 in Part I) became interested in the study of retroviruses and made their study the primary activity of his laboratory [12]. Under his supervision, Doris Morgan, a post-doctoral fellow in his laboratory succeeded in growing T lymphocytes using the T cell growth factor (TCGF) [13], which was later to be renamed interleukin-2 (IL-2) by the Interlaken cytokine nomenclature committee. The availability of IL-2 enabled researchers to grow T-cells and study the viruses that they harbour, such as the human T-cell leukemia virus, HTLV-I, which was first isolated in 1980 in the laboratory of Robert C. Gallo from the leukemic cells of an African-American man who presented with a Sezary syndrome-like disease [14]. A similar disease had earlier been described in Japan and was known to be endemic in the most southern Japanese island of Kyushu and Shikoku [15]. The retrovirus was later recognized as endemic in the islands of the West Indies, especially among people of African ancestry [16], the northern regions of South America, the South-eastern states of the US, Japan and parts of Sub-Saharan Africa [17]. The discovery of HTLV-1 of HTV-1 was the proof that retroviruses exist in humans and suggested their role in human cancer as Peyton Rous and others had done for other vertebrates several decades earlier [18].

4.3 Diagnosis of HTLV-1 Infection

23

4.2 Virology of HTLV-1 HTLV-1 belongs to the family of retroviridae, and the genus of deltaretrovirus. It is a type C virus and a single-stranded RNA, which is converted to double-stranded DNA and inserted into the DNA of an infected host cell as a provirus [19], as a result of which it causes a lifelong infection. The virus preferentially infects CD4+ T-cells, but also CD 8+ T-cells, which serves as an important reservoir for the virus [20, 21]. Unlike HIV, HTLV-1 exists as cell-associated provirus and is transmitted as such [22]. It is presumed that early during infection, most new HTLV-1-infected cells are produced by cell-to-cell spread, resulting in polyclonal infection of both CD4+ and CD8+ T-cells. In a later stage, when equilibrium between viral replication and immune response is reached, HTLV-1 mainly multiplies by clonal expansion dependent on mitosis of host cells [20, 23].

4.3 Diagnosis of HTLV-1 Infection According to Angela Manns,“when infection is established, antibodies to core, envelope, and tax proteins (Fig. 4.1) appear in serum. In the first 2 months after primary HTLV-1 infection, antibodies to gag proteins, predominates with anti-p24 appearing before anti-p19. Antibody to recombinant gp21 is the earliest appearing envelope reactivity with native anti-gp46 appearing later. Anti-tax appears much later” [24, 25]. The viral genes and their products that serve for infection detection in serological screening are depicted in Fig. 4.1. Serological screening for the presence of HTLV-1 antibodies was done historically using whole-virus lysates in enzyme-linked immunoassay technique [26], which frequently yielded false positive results [27]. Confirmatory tests were subsequently introduced, as required by the US Public Health Service, and the World Health Organization, among other international agencies, [28] including commercially available Western blot and line immunoassays (Fig. 4.2) [24]. Some of the laboratory diagnostic challenges were addressed in Sect. 2.3.4.7 in Part I. In the ELISA procedure, samples giving OD ratios of ≥2.0 in HTLV-I ELISA were tested for confirmation by an immunocompetition assay [26]. These and other samples giving OD rations of ≥5.0 in the HTLV- III ELISA were further investigated by Western blot (Biotec Research, Inc., Rockville, MD, USA). Results were classified as ‘seropositive’ if the Western blot had unequivocal multi-band reactivity to viral gag, gag-precursor and envelope proteins, as ‘reactive indeterminant (RI) if there were only single or multiple gag or gag-precursors present, and ‘negative’ if the Western blot was devoid of reactivity (Fig. 4.2). In Japan, particle agglutination assay is most commonly used for screening. One particularly diagnostic problem for HTLV-1 screening is the need to distinguish between HTLV-1 and HTLV-II. The latter shares 60% genomic homology with HTLV-1 [29], while being less pathogenic than the former [30]. This is only possible with the use of virus-specific reagents as shown in Fig. 4.2. Polymerase

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4 Global HTLV-1/2 Burden and Associated Diseases

Fig. 4.1 “Structure of HTLV-1 genome” “Major coding domains include structural genes gag, pro (protease), pol (reverse transcriptase), and env. Regulatory genes tax and rex are encoded in regions joined by RNA spicing (horizontal line). These genes are flanked by two long-terminal repeat sequences (LTRs). Terminal noncoding sequences include two direct repeats (R) and a U5 (5′ unique) and U3 (3′ unique) sequence. Redrawn with permission, from figure 2B in Retroviruses (Coffin JM, Hughes SH, Varmus HE, eds., published by Cold Spring Harbor Laboratory Press).” Reproduced with permission from: Manns et al. [24].

chain reaction (PCR) is another technique that can be used to differentiate between the two viruses by studying their DNA in infected biological specimens [31–33].

4.4 Modes of Transmission of HTLV-1 The modes of transmission of HTLV-1 include mother-to-child mechanisms, including prolonged breast-feeding and other maternal factors including prolonged ruptured membranes during child-birth, low socioeconomic status; heterosexual activities, parenteral transmission by transfusion of blood products, sharing of contaminated needles and syringes by injecting drug users.

4.4.1 Mother-to-Child Mode of Transmission Mother-to-child transmission was postulated early in the investigation of ATL because of clustering of HTLV-1 in mothers and their offspring [34, 35]. Transmission of HTLV-1 was subsequently demonstrated experimentally in marmoset model [36], thus indicating the possibility of a similar transmission mode in humans. The latter was confirmed in prospective studies in Japan [37]and Jamaica [38]. The probability of mother-to-child transmission is 18–30% [24], and depends on maternal factors, including breast-feeding for more than 6 months [39–42].

4.4 Modes of Transmission of HTLV-1

25

Fig. 4.2 Confirmatory western blotting. “(a) = seropositive ATL; (b) = HTLV-II seropositive, (c) = HTLV seropositive with undefined subtype in ATL, subtype determined by PCR DNA typing; (d) = negative. Seropositivity is indicated by band reactivities to gag (p24 or p19) and env (GD21); additional env to rgp46I and rgp46II required in distinguishing HTLV-I from HTLV-II. An “indeterminate” western blot has specific bands but does not meet criteria for seropositivity. A negative blot has no reactivity to HTLV specific band reactivity. (Genelabs Diagnostics Pte Ltd., Singapore.).” (Reproduced with permission from: Manns et al. [24])

4.4.2 Sexual Transmission of HTLV-1 HTLV-1 can be transmitted though sexual intercourse as the provirus is present in genital secretions of infected people [43], and a rate of 0.9 per 100 person-years has been documented [20, 44]. The virus is transmitted four times more effectively from men to women at a rate of 4.9 per 100 person-years among women married to infected men, compared to the rate of 1.2 per 100 person-years among men married

26

4 Global HTLV-1/2 Burden and Associated Diseases

to infected women [45]. Higher transmission efficiency from men to women than women to men has also been suggested [46, 47]. The male-to-female transmission risk is greater if the male has high antibody titres or antibody to tax proteins, while the risk of female-to-male transmission is associated with the presence of penile ulcers or sores and the diagnosis of syphilis among males [20, 48].

4.4.3 Parenteral Transmission of HTLV-1 Transfusion of blood products is the most efficient mode of HTLV-1, with the risk of seroconversion through this modality being 40–60%, and the median time to seroconversion being about 51 days [20, 49, 50]. Blood products containing white blood cells, such as whole blood, packed red blood cells and platelet concentrates, are implicated in this transmission, apparently because white blood cells serve as reservoir for the virus. Both neoplastic as well as non-malignant complication of HTLV-1 transmission, namely adult T-cell leukemia lymphoma (ATL) [51], and the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) [52, 53] respectively, have been described as complications of HTLV-1 contaminated blood products. Another mode of transmission of both HTLV-1 and HTLV-2 is through the use of unclean needles and syringes among injecting drug users. HTLV-1 transmission is said to be frequent among such individuals in New York and Brazil, while HTLV-2 transmission is more prevalent among drug users in other North American and European injecting drug users [20, 54–56].

4.4.4 Prevention of HTLV-1/2 Transmission Screening of pregnant women for HTLV-1 infection with a view to counselling about breast feeding has been advocated by Shigeo [36]. This can either be omitted entirely [34, 35], or its duration could be limited, based on the observation of Takahashi et al. [39] who observed transmission rates of short-term (≤6 months) and long-term (>6 months) breast-feeders as 4.4% (4/90) vs. 14.4% (20/139) (p = 0.018). Perinatal interventions to prevention to avoid prolonged ruptured membrane would seem to be another feasible strategy to limit the risk of transmission in infected mothers, although intrauterine and peripartum transmission of HTLV-1 has been described as unlikely, infrequent or occurring in less than 5% of children of infected mothers [20, 40, 57, 58]. Nutritional strategies for reducing the risk of transmission through the breast milk include a combination of artificial feeding, while others being explored include experimental use of prophylactic immunoglobulin, antiretroviral therapy and HTLV-1 vaccine [24, 59]. In Japan, the only high/very high Human Development Index (HDI) country, where HTLV-1 is endemic, has developed various infection prevention strategies,

4.5 HTLV Infection and Lifestyle of Nigerians

27

apart from breast-feeding measures described earlier for infected mothers. Others include screening of blood donor candidates for HTLV-1 antibodies, a strategy that was first introduced in Southern Japan, and which has led to a decrease in the number of new infections in the general population [60]. In the United States of America, a low endemicity area of the world, screening for HTLV-1 was commenced in December 1988 [24]. At that time, the seroprevalence of HTLV-1 among the volunteer candidate donors was 0.014–0.21 for HTLV-1/2 [61]. The risk of transfusion- transmitted HTLV-1 is estimated as 1 in 641,000 compared to 1 in 677,000 for HIV [62]. Given the fact that transfusion of cell free blood products, such as fresh frozen plasma, has not been associated with HTLV-1 transmission, and that blood units stored for more than 7 days were less likely to transmit the virus [24],leucocyte depletion of blood products should reduce the risk of transfusion related transmission of the virus. Strategies for prevention of infection in high-risk individuals include advocacy of condom use among sex workers such as has been reported in Peru [63, 64].

4.5 HTLV Infection and Lifestyle of Nigerians From 1985 to 1986, a study of the prevalence of retroviral infections was carried out in three regions of Nigeria, with a view to determining risk factors for infection in the country. The study was co-sponsored by the World Health Organization and has been published in brief communications elsewhere [65, 66]. The purpose of this study was to evaluate the prevalence and distribution of HTLV among five different population groups representing the three major geographic regions of Nigeria using the more sensitive second-generation assays. Much of the controversy surrounding the prevalence of HTLV-I infection in Africa results from inadequacies of early assays for detecting true seropositivity (see Sect. 4.3). The recent availability of second-generation assays such as the HTLV 2.3 Western blot provides a more reliable serologic marker for detecting HTLV infection. In addition, the changing criteria for seropositivity and small numbers of tests in previous Nigerian surveys [67] have added to inability to establish the true prevalence of the infection. The high prevalence of indeterminate Western blot reactivity and low prevalence of ATL in the portion of the study evaluating a cohort of healthy subjects and patients with various lymphoproliferative and hematological disorders [68] also suggested some reactivity due to a variant HTLV-like virus. The study was carried out between September 1985 and March 1986 in three Nigerian cities – Ibadan (West), Calabar (East) and Zaria (North). The study sites are approximately 1000 km from one another and are located in areas that are culturally and ecologically distinct from one another. The study subjects were recruited from five population groups including normal adult blood donors, STD clinic attendees, female sex workers, and obligate celibate clergymen and women living in religious institutions. They are referred to as obligate celibates because they were required to abstain from sexual intercourse as a requirement of their religious voca-

28

4 Global HTLV-1/2 Burden and Associated Diseases

tion. The subjects were invited to participate following a discussion of the aims and objectives of the study. The lifestyle and sexual habits of each subject were assessed with a questionnaire after which the subjects were invited to donate 10 ml of blood. Sera were frozen at -20C for several weeks prior to shipment to the National Cancer Institutes for antibody studies. The sera were tested by commercial ELISA (Genetic Systems, Seattle, Washington and Cambridge Biotech, Rockville, MD). Serological confirmation was by WB assay (HTLV-2.3 blot; Singapore Biotechnology, Singapore) that incorporates the HTLV-I viral lysate and type-specific recombinant env proteins of HTLV-I and HTLV-II. This WB assay allows simultaneous confirmation and differentiation between HTLV-I and HTLV-II [69]. To confirm the HTLV type, samples showing a positive band for recombinant gp46 (rgp46) protein of either HTLV-I or -II were judged as HTLV-I or -II seropositive, respectively. There were a total of 396 subjects, 217 (55%) were males and 179 (45%) were females. Ages ranged from 13 to 60 years (median, 24 years). The median age of males was 25 years (range, 15–60 years) while that of females was 22 years (range 13–60 years). Subjects were recruited from the three major geographic regions of Nigeria – West (38%), East (29%) and North (16%). The subjects were stratified among five population groups – blood donors (60%), STD clinic attendees (11%), female sex workers (12%), male clergy (13%) and female clergy (4%). Ninety percent of all subjects had a history of formal education and 54% had never been married. Only 4% of subjects had a history of blood transfusion. Of the 396 samples, 20 (5%) were HTLV seropositive including 12 (3%) blood donors, 3 (0.8%) STD clinic attendees, 2 (0.5%) sex workers and 3 (0.8%) male clergy. Analysis of the 20 HTLV-positive specimens on modified WB (Fig. 4.1) demonstrated that 6 (1.6%) reacted with rgp46I and, hence, were typed as HTLV-I, 3 (0.8%) reacted with rgp46II and were classified as HTLV-II, 1 reacted with both rgp46I and rgp46II and were classified as dual (HTLV-I/II); and 10 specimens could not be typed. Analysis of the demographic and risk factors showed that of the 217 men 9 (4%) were HTLV seropositive and 11 (6%) of 179 were women. The sex-specific ratio for HTLV seropositivity was approximately 1:1 for the different types (Table 4.1). There was no demonstrated age-trend. Only 1 of the 20 HTLV seropositives had a history of blood transfusion. Among the 114 subjects from the eastern region of Nigeria, 12 (11%) were HTLV seropositive. Among the 276 subjects from all other Table 4.1 HTLV-1 seroprevalence rates in normal blood donors, female commercial sex workers (CSW), Sexually Transmitted Diseases (STD) Clinic patients, and religious celebates, including seminarians and novitiate nuns Study Groups Normal blood donors Female CSW STD clinic patients Seminarians (male) Noviciate nuns

# Studied 237 46 42 54 17

Mean Age 28.6 21.2 23.7 25.0 22.5

% Seropositive 4.6 13.0 16.7 1.85 11.8

Reproduced with permission from a conference poster presentation: Williams [205]

4.5 HTLV Infection and Lifestyle of Nigerians

29

regions, only 8 (3%) were seropositive. The association between region of origin and HTLV seropositivity was significant (p = 0.002; OR = 3.9, 95% CI = 1.4, 10.9). Stratified by HTLV-type and region, seropositivity was 100% (3/3) for HTLV-II, 100% (1/1) for HTLV-I/II, 60% (6/10) for HTLV-Untypable and 33% (2/6) for HTLV-I among study subjects from the eastern region of Nigeria. The sex-specific prevalence was 13% among females and 7% among males (OR = 2.1; 95% CI = 0.5, 12.7). Eighty-three percent of HTLV seropositives resided in urban areas. Ten of the twelve HTLV seropositives from the eastern region were heterosexual while the remaining two were celibate. None had a history of blood transfusion. There was no significant difference in seroprevalence between residence in urban and rural areas (5% vs. 3%). Of the 396 subjects tested, 20 were confirmed to be HTLV positive and 16 were HTLV indeterminates (Table 4.1). HTLV seroindeterminate patterns ranged from Gag only (3 were p24+/p19+, 2 were p19+ and 3 were p24+) and env only (3 were r21+ and 1 was rgp46+) reactivities. Other patterns observed included one case of p19+ and 3 cases of other bands. These data indicate that both HTLV-I and HTLV-II infections were prevalent in the mid-1980s in Nigeria. Thus, Nigeria can be added to the list of African countries including Ghana, Zaire, Gabon, Ethiopia, Somalia, Ivory Coast, Cameroon and Guinea where HTLV-II has previously been detected [70–73]. As shown in Table 4.1, the HTLV sex-specific prevalence is consistent with previously reported data showing a higher rate of seropositivity in females over males in the Caribbean population [48]. The strongest risk factor for HTLV-seropositivity was origination from the eastern region of Nigeria (Tables 4.2 and 4.3), which likely points to a focus of activity there. It is unclear why the eastern region of Nigeria may have a higher prevalence of HTLV infection compared to surrounding regions of Nigeria. One hypothesis could be its proximity to an area of high endemicity in Central Africa. Wiktor and his colleagues observed a similar region of high HTLV-I seroprevalence in the province of Equateur of the former republic of Zaire, whereby the strongest risk factor for seropositivity among Kinshasha sex workers was originating from that province [38]. Goubau and his colleagues observed a similar geographical clustering in the former republic of Zaire and identified an epicenter in Lisala [74]. According to Wiktor and colleagues, remoteness and rural nature could account for clustering of HTLV-I infection [38]. However, in the light of lack of association between seropTable 4.2 Survey of HTLV-1 seroprevalence by geographical region in Nigeria Region Eastern Western Northern

Statesa Cross River, Anambra, Rivers Lagos, Ogun, Oyo, Ondo, Bendel, Kwara Niger, Benue, Plateau, Kaduna, Kano, Bauchi, Borno

# Positive/# tested %Positive 17/114 14.9 8/189 4.23 0/70 0.00

Reproduced with permission from a conference poster: Williams [205] Some of these States have been further split into newer entities since this study was completed. These include: Cross River (Cross River and Akwa Ibom); Anambra (Anambra and Enugu); Oyo (Oyo and Oshun); Bendel (Delta and Edo); Kwara (Kwara and Kogi); Kaduna (Kaduna and Katsina); Kano (Kano and Jigawa); and Borno (Borno and Yobe)

a

30

4 Global HTLV-1/2 Burden and Associated Diseases

Table 4.3 Independent Risk Factors for HTLV-I Infection among Nigerians

Risk factors Female sex Eastern origin Female of Eastern origin Female CSW of Eastern origin Non-CSW female of Eastern origin Frequency of male heterosexual activity STD with genital herpes Male of Eastern origin Rural versus urban residence Age group STD with gonorrhoea Polygamy Ethnic group

P-value 0.037 0.0000095 0.0006 0.0058 0.009 0.024 0.067 0.116 0.216 0.48–0.92 0.488 4.32 2.15

Reproduced with permission from a conference poster: Williams [205]

revalence and urban/rural residential environment in our study (Table 4.3), it would seem that other unknown environmental influences might be responsible for the observation. A direct comparison between the results of our study and those of others done in neighboring Central African countries may not be valid because of technical variations. However, it is pertinent to note that the overall seropositivity rate of 5% observed in this study is higher than that reported in Southern Chad and Northern Cameroon (0.5–2.0%), and the savannah region of Cameroon (4.2%). It is, however, lower than that in Equatorial Guinea (6.5%) [75] and in Gabon (Western Equatorial Africa) [72]. Thus, the high seroprevalence rate on the southeastern border of Nigeria may be due to its proximity to an area of high endemicity in Central Africa. Investigators have recently identified this region as being of interest for research into human and animal retroviruses. The high prevalence of HTLV-seroindeterminate patterns ranged from gag-only and env-only reactivities. Previous studies have shown that such isolated gag reactivities detect immune reactivity to cross-reactive antigenic determinants rather than true HTLV-I/II antigens [70]. Whether these isolated band patterns represent true HTLV infection could not be tested because mononuclear cells necessary for PCR were unavailable. Thus, the finding in the previous study of a lower than expected occurrence of ATL and high rate of Western blot reactivity but with aberrant profiles (i.e., weak reactivity and sparse banding) [68] suggests the possibility that a mixture of true HTLV-I positivity and cross-reactivity with a related virus may explain this paradox. Our earlier suggestion that HTLV-II might be this related virus [76] has been confirmed, at least in part, by Olaleye and his colleagues [77], who used Western blot and PCR-based techniques to evaluate the role of retroviral infection in hematological malignancies or sexually transmitted diseases among Nigerians.

4.6 Origin, Spread and Global Prevalence of HTLV-1/2

31

4.6 Origin, Spread and Global Prevalence of HTLV-1/2 HTLV-1 is found in all parts of the world, but at widely variable prevalence rates even in neighboring regions. The virus is characterized by a remarkable phylogenetic stability, which is attributed to its mode of viral amplification and transmission via clonal expansion of infected cells, rather than by reverse transcription, a characteristic that differentiates it from HIV [22]. Because it is only in Africa, where all types of HTLV-1 and their simian counters are found, it is assumed that the common ancestors for these viruses, the primate T-lymphotropic viruses (PTLV), originated in Africa, while phylogenetic studies have identified Central Africa as the cradle of PTLV [78]. The low sequence variation of HTLV-1 has been useful in gaining insight into the origin, evolution and global spread of the virus. Thus, at least four geographic subtype of the virus are known: the Cosmopolitan subtype A, the Central African subtype B, the Central African/Pygmies subtype D, and the Australo- Melanesian subtype C. Other subtypes include the E, F, and G, which are confined to Central Africa. The Cosmopolitan subtype A, on the other hand, consists of geographical subgroups including Japanese, West African, North African and Transcontinental (Fig. 4.3) [79] While the divergence of HTLV-1 subtypes is dated back to between 5300 and 21,100 [20, 80], the very low sequence variability within subtype A reflects its relatively “recent” dissemination of some centuries to a few millennia [79]. The Australo-Melanesian subtype C is the most divergent, apparently signifying a long period of evolution of several millennia. Phylogenetic variations within the Cosmopolitan A and the Australo-Melanesian subtypes are indicative of interspecies transmission between STLV-1 infected monkeys and humans, followed by periods of adaptation in the human hosts [78, 81–85]. There is no evidence of any association between the viral genotype and disease pathogenesis. As illustrated in Fig. 4.3, the origin and mode of global spread of HTLV-1 is puzzling. HTLV-1 is highly endemic southwestern Japan, sub-Sahara Africa, South America and the Caribbean region, with foci of high endemicity in the Middle East, and Australo-Melanesia. This pattern of global distribution has been linked to founder effect in population groups in sub-Sahara Africa, which is the most endemic region for HTLV-1 [79], and where the spread of PTLV-1 occurred 27,300 years ago [80], Southwestern Japan, where it has its highest prevalence [86–88], and Oceania [89, 90]. Ancient Mongoloid migration across the Bering Strait is believed to have led to the introduction of HTLV-1 into the First Nations population of Canada and the Amerindians [91, 92], and of the Japanese Ainu and Ryukyans, both direct descendants of Mongoloid populations [20, 93]. However, more recent slave trade associated human trafficking from sub-Sahara Africa to the New World would explain the endemicity of HTLV-1 in places like the Caribbean basin and Brazil, Colombia, and the United States of America [94], while its presence in European countries like United Kingdom and France is related to colonialism associated migration. Unexplainable is the relatively high HTLV-1 prevalence status in Romania, a European country [95, 96] without evidence of migration from typical HTLV-1 endemic regions. The high prevalence in Japan and its association with

32

4 Global HTLV-1/2 Burden and Associated Diseases

Fig. 4.3 Map of the geographical distribution of HTLV-1 subtypes (a–g), and the main modes of viral dissemination by migration of infected populations (large arrows). Small arrows indicate the probable interspecies transmission of STLV-1 from non-human primates (NHP) to humans. The Cosmopolitan subtype (a) consists of the following subgroups: Transcontinental (TC), Japanese (Ajp), West African (Awa), and North African. The (b) is the most frequent subtype in this large endemic area of Central Africa. The C subtype is limited to Australasia and Oceania, while subtypes (d, e, f, g) are limited to Central Africa. (Reproduced from: Gessain and Cassar [79])

HTLV-1a, an African subtype, which has been linked to “adventures” such as those of Portuguese sailors, [20, 97] remains puzzling. Table 4.4 provides the global seroprevalence of HTLV-1 and the association with ATL and/or HAM/TSP by regions countries, and/or cities. The estimation of the global HTLV-1 burden is hampered by a number of circumstances, some of which have been alluded to earlier in this chapter (see Sect. 4.3). Apart from diagnostic challenges, some of which had resulted in overestimation of HTLV-1 seroprevalence in earlier studies, the unusual distribution pattern of the viral infection, whereby areas of high endemicity are located next to those of low or absent viral prevalence. Furthermore, several large areas or regions have not been investigated for HTLV-1 infection, including highly populated regions of Asia and North Africa [79]. Most studies of HTLV-1 seroprevalence are based on studies of blood donors, pregnant women, or hospitalized patients. Population based studies are lacking even in regions, where HTLV-1 constitutes a public health challenge of significance. An estimate of global HTLV-1 burden of 10–20 million infected people reported over 20 years ago by de Thé and Bomford [98] is considered as an overestimation due to the use of less specific diagnostic serology, while the more

4.6 Origin, Spread and Global Prevalence of HTLV-1/2

33

Table 4.4 HTLV-1/2 seroprevalence rates in selected regions and cities correlated to occurrence of adult T-cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy and tropical spastic paraparesis (HAM/TSP) Continent, Country (CITY) Africa Nigeria (Ibadan)

Study population

Rates (%) ATL HAM/TSP

Nigeria (Ibadan) Nigeria (Ibadan) Nigeria (Ibadan) Nigeria (Lagos)

School Children Blood donors General Antenatal Blood donors

Nigeria (Zaria/Kaduna)

Blood donors 2.0

Ghana/Rural Ghana/Urban Cote d’Ivorie

General General General

4.0 3.6 1.8

Gabon, Equatorial Guinea, Southern Cameroon Gabon North Africa

General

8.6–11.6

General General

≥25 6.0 1.66

India Europe United Kingdom

Antenatal

France

Antenatal

Romania Caribbean Region Jamaica, Haiti, Dominican Republic Trinidad

Blood donors 0.05

Tobago Cuba

Blood donors 0.14

General Selected

0.03– 0.04f 0.1f

6.1

0h, 0.2i, 3.2j Survey 11.4 Blood donors 0.0

Infection literature

Yes [140, 206]/Yesa [68] [207] [68] [68] [77] Yes [140, 206]/Yes [208] a [207] [209] Yes [209]/Yesa [207] Yes [79]/Yes [79] [210] Yes [79]/Yes [79] [210] Yesb [211]/Yesb [131] [211] Yes [212]/Yes [212] [75] Unk. /Unk. Yesc [213, 214]/ Yesc [213, 214]

[143] [215] [215]

Yes [216]/unk. Yes [139]/Yes [218] Yes [139]/Yes [218] Yesd [220, 221]/ Yese [222] Yes [224]/Yes [225]

[217] [139, 219] [139, 219] [223] [226]

Yesf [227]/Yesf [229] [228] Yesf [211]/Yesf [52, [230] 211] [231] Yesg [95] Yes [79, 232]/Yes [79, 234] [79, 233] Yes [201]/Yes [201] [201] Yes [201]/Yes [201] [201] Unk. /Unk. [235] (continued)

34

4 Global HTLV-1/2 Burden and Associated Diseases

Table 4.4 (continued) Continent, Country (CITY) North America United States Mexico (Yucata) Central and South America Brazil Peru Guyana Oceania Australia, Coastal (non- aboriginal area) Australia, Central (aboriginal area) Vanuatu archipelago Hawaiian archipelago

Study population

Rates (%) ATL HAM/TSP

Blood donors 0.009– 0.025 Antenatal 0.0

Yes [14, 236]/Yes [237] Unkn. /Unkn

Blood donors 0.04–2.1 Blood donors 1.2–3.8

Yes [240]/Yes [241] Yes [245, 246]/Yes [166] 0.0k, 10.3l Yes [249]/Yes [249]

Blood donors 0.001– 0.032 Survey 7.2–13.9 General 0.62 Blood donors 0m-9.3n

Unkn/Unkn.

Infection literature [61, 238] [239] [242–244] [245, 247, 248] [249] [250, 251]

Yes [252]/Yes [253] [254, 255] Unkn./Unkn. Yesn [257]/Yesn [257]

[256] [258]

A case of HAM/TSP was described by Olaleye et al. Expatriate patients receiving medical care in France; DRC = Democratic Republic of the Congo c ATL, HAM/TSP diagnosed either locally or in migrant population in Europe d Reported in three Israeli citizens, all descendants of Iran (Mashad region) e Reported in Israeli citizens of Iran/Mashad region (Mashadi Jews) f Immigrants from former colonies and dependent territories in Africa and the Caribbean region g Migrant patients of Romanian descent h People of European descent i People of Asian descent j People of African descent k Wayana Indians l Noir-Marrons, an ethnic group of African ancestry m Among Caucasian, Chinese, Filipino and Pacific islander members of the survey n Individuals of Japanese descent Unkn = Unknown a

b

recent estimate of 5–10 million, based on an approximately 1.5 billion individuals originating in HTLV-1 endemic area (Table 4.4) may well be an underestimation, given the absence of data from regions of the world with large populations [79].

4.7 HTLV-1 Associated Diseases HTLV-1 has been associated with a spectrum of diseases, which have been classified as: 1. malignant, 2. inflammatory, and 3. infectious complications (see Table 4.5) [20]. Of the 15 diseases listed, the evidence of association is most convincing for the adult T-cell leukemia/lymphoma (ATL), a neoplastic condition, and the HTLV-1

4.7 HTLV-1 Associated Diseases

35

Table 4.5 Estimates of the number of HTLV-1 infected carriers in countries of various parts of the world Continent/Country Africa Senegal Gambia Guinea-Bissau Guinea Sierra Leone/Liberia Cote d’lvoire Ghana Togo/Benin Burkina Fasso Mali Nigeria Cameroon Eq. Guinea Gabon CAR DRC Republic of The Congo Mozambique South Africa Asia China (Fujian Province) Japana Iran (Mashad area) Taiwan Europe United Kingdom** France Spain Romania Caribbean Region Haiti/Dominican Republic Jamaica Guadeloupea Martiniquea Trindad and Tobago North America United States Central and South America Panama Colombia (Turnaco area)

Population! 12,969,606 1,840,454 1,628,603 10,884,958 5,485,998/3,887,886 21,952,093 25,241,998 6,961,049/9,598,787 17,275,115 14,533,511 170,123,740 20,129,878 685,991 1,608,321 5,057,208 73,599,190 4,366,266 23,515,934 48,810,427 35,110,000 127,368,088 78,868,711 23,113,901 63,047,162 65,630,692 47,042,984 21,848,504 9,801,664/10,088,598 2,889,187 401,730 395,953 1,226,383 313,847,465 3,510,045 45,594 (est. 1988)

HTLV-1 range 30,000 2500 12,000 75,000 50,000 130,000 125,000 80,000 42,000 32,000 850,000 80,000 1500 16,000 15,000 600,000 12,000 120,000 180,000

105,000 13,000 28,000 150,000 100,000 250,000 375,000 160,000 125,000 95,000 1,700,000 180,000 4500 30,000 30,000 1,300,000 36,000 360,000 540,000

2000 1,080,000 10,000 10,000

20,000 1,300,000 40,000 30,000

20,000 15,000 1000 3000

30,000 25,000 8000 15,000

150,000 100,000 3000 3000 9000

350,000 140,000 6000 6000 18,000

90,000

100,000

3500 1000

25,000 1500 (continued)

36

4 Global HTLV-1/2 Burden and Associated Diseases

Table 4.5 (continued) Continent/Country Venezuela Suriname French Guyana Guyana Peru Brazil Chile Australo-Melanesia Australia (Aboriginal Australians) Solomon Islands Vanuatu Total

Population! 28,047,936 560,157 217,000 741,908 29,549,517 205,716,890 17,067,369

HTLV-1 range 14,000 3000 2000 2000 150,000 300,000 90,000

463,900 584,578 227,574 1,567,570,505

2500 3000 250 4,520,250

70,000 7000 5000 5000 450,000 800,000 250,000 5000 6000 1000 9,295,000

Reproduced from: Gessain and Cassar [79] !: Population according to the CIA World Factbook 2012 [259] a According to Satake et al.

associated myelopathy and the tropical spastic paraparesis (HAM/TSP), which are listed among inflammatory syndromes. These two diseases have been reported in virtually all parts of the world, where the virus is endemic (Table 4.5). The evidence linking HTLV-1 with other syndromes, such as arthropathies [99–106], uveitis [107, 108], thyroiditis [108], Sjorgren’s syndrome [109–112], pulmonary disorders [113, 114], infective dermatitis [115–121], Norwegian scabies [122, 123], strongylodiasis [124–127] and tuberculosis [128, 129], and leprosy [130–133], several of which are frequently encountered in countries of medium to low Human Development Index (HDI), signifies the significant impact on the health of populations in these areas.

4.7.1 Adult T-Cell Leukemia/Lymphoma (ATL) Adult T-cell leukemia/lymphoma (ATL) was the disease that led to the discovery of HTLV-1 as the first human retrovirus (see Chap. 2, Sect. 2.3.4.3 in Part I). The disease is a malignancy of CD 4+ post-thymic T cells in which the provirus is integrated (Fig. 4.1). The mechanism of carcinogenesis by animal retroviruses differs from that of HTLV-1 in ATL: the former is by the activity of transforming genes, which are lacking in HTLV-1. The regulatory protein produced by the tax possesses pleotropic functions that not only enable the gene product act as a key regulator of viral replication, but also other activities ultimately resulting in cell transformation and leukemogenesis [15, 134]. Early life exposure to HTLV-1 apparently by breastfeeding is essential in the development of ATL [135]. The infection is followed by a protracted period of incu-

4.7 HTLV-1 Associated Diseases

37

bation lasting a few decades. Studies in the West Indies have yielded an estimated lifetime risk of about 5% in individuals infected before the age of 20 years [136], more specifically 4.0% for males and 4.2% for females [137], with an incidence rate of 2–4 per 100,000 person-years [136, 138]. The average age of onset varies from 40 years in series from the Caribbean region [136] and Brazil [138] as compared to 60 years in Japan [139]. In a small series of nonHodgkin lymphoma of Nigerian patients who were seropositive for HTLV-1, 4 patients presenting with features of ATL were aged between 12 and 47 [140]. The index case of ATL in the country was aged 19 [141] (Fig. 2.10 in Part I). The median age of ATL cases diagnosed in the 1980s in Nigeria, including 2 females and 3 males was 22 years, thus, making them the youngest of any published series. The reason for the geographical variation in age of onset of ATL is unknown, but may be related to the fact that the outcome of HTLV-1 infection depends on a complex interaction between the virus and the host genetics and immunologic factors [142] as well as age and mode of infection [135]. The pattern of HTLV-1 infection in Nigerians (Sect. 4.5, Tables 4.1 and 4.3) is consistent with early exposure through breast-feeding. The clinical presentation of the disease, which ranges from acute to chronic and smouldering, also varies on geographical basis. In Japan, 57% of cases are classified as acute ATL on presentation, compared to 47% in Jamaica. In Nigeria, two of 5 cases, including the index case (Fig. 2.10 in Part I) presented with acute features. In a region of the world, where B-cell malignancies predominate, ATL constituted four of 30 (13.3%) non-B cell non-Hodgkin lymphoma cases [140], in sharp contrast to the 50–60% rate observed I the HTLV-1 endemic areas of Jamaica and Japan. A similar situation has been reported from other parts of Africa [72, 143]. Possible reasons for this discrepancy could include: early death of African cases prior to presentation for medical attention due to poor health care facilities in the area, reduced recognition as a clinical entity, and death in early life from HTLV-1 related pathologies, other than ATL. Such pathologies could include complications from immunodeficiency as described in the HTLV-1 associated pediatric syndrome of infective dermatitis [120, 144]. Most T-cell malignancies are poorly responsive to therapy compared to B-cell malignancies. The acute forms of ATL are no exceptions in their responses to standard treatment regimens, such as the combination of cyclophosphamide, doxorubicin, oncovin and prednisone (also known as CHOP regimen). Investigative approaches include high-dose chemotherapy followed by hemopoietic stem cell transplantation, interferon-alpha plus zidovudine combination following CHOP etc. [145–150]. On the whole, the prognosis for the acute form of the disease is poor. Patients with the chronic form of ATL, including the smouldering variant survive longer. The experience with the interferon-alpha plus zidovudine is interesting because of the response, though limited, in both acute and chronic forms of the disease [148, 149]. Clinical trials are indicated for the management of all forms of ATL.

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4 Global HTLV-1/2 Burden and Associated Diseases

4.7.2 H TLV-1 Associated Myelopathy and Tropical Spastic Paraparesis (HAM/TSP) HTLV-1 associated myelopathy and tropical spastic paraparesis HAM/TSP occurs globally, primarily in areas of the world where HTLV-1 is endemic, but also sporadically in countries of low endemicity among migrant populations from endemic areas (Table 4.4). In spite of the fact that sub-Sahara Africa harbours several millions of HTLV-1 infected individuals, epidemiological information is scarce from this region for various reasons. Although this, like other parts of the developing world, continues to be inundated with communicable diseases, it does have a long tradition of studies myeloneuropathies, which are primarily related toxic, nutritional and infectious causes. Among these are the chronic cyanide intoxication of dietary origin and a degenerative neuropathy in Nigerians [151], toxic ataxic neuropathy [152], lathyrism due to excessive consumption of peas of the Lathyrus family [153, 154], konzo [155] and other non-specific neurological syndromes [156]. While differences in the clinical manifestations of these tropical myeloneuropathies and those of HAM/TSP have been documented [151, 157], factors limiting the recognition of the global burden of the latter are largely related to the general state of healthcare in much of the parts of the world where the virus is endemic, with the exception of Japan and the West Indies. In the nineteenth century, Henry Strachan made the first description of a form of polyneuropathy that was prevalent in the West Indies [158] and is now believed to have been the earliest cases of was later to be recognized as HAM/TSP. In 1956, Eric Cruickshank described 100 cases of a neurologic disorder that “differs in essentials from all the neurological disorders known in European medicine” [159], the clinical features of which are consistent with those of HAM/TSP. Following the discovery of HTLV-1 in 1979 [14] (see Sect. 4.1), neurological disorders similar to those of the West Indies were linked to the virus in Japan and named HTLV- 1associated myelopathy (HAM) [160]. On the other hand, antibodies to HTLV-1 had been found in the serum and cerebrospinal fluid of patients with progressive neurologic disease, thus suggesting the association of the virus with cases of tropical spastic paraparesis (TSP) [161]. The World Health Organization subsequently decided that the HAM and TSP were the same disease, hence the terminology HAM/TSP. The main pathologic feature of HAM/TSP is chronic inflammation of the spinal cord characterized at the early stages by perivascular cuffing of mononuclear cells accompanied by lymphocytic infiltration [162]. At later stages of the disease, the cellular infiltrates yield a process of atrophy involving mainly the white mater of the low thoracic spinal cord, hence the evolution of spastic paraparesis. Although the exact mechanism of the pathogenesis of HAM/TSP remains to be elucidated, it appears to bear some relationship to the proviral load of the infiltrating mononuclear cells and the production of cytokines. The damage to the central nervous system tissue appears to be related to the “bystander damage” resulting from CD8+ HTLV- 1-specific cytotoxic T lymphocytes attack HTLV-1 infected CD4+ T lymphocytes

4.7 HTLV-1 Associated Diseases

39

trafficking into the CNS tissue [162]. A process of autoimmunity resulting from cross-reactivity between HTLV-1 antigens and a tissue antigen has also been suggested. The product of the HTLV-1 gene, tax, which has been implicated in the pathogenesis of ATL [134] (see Sect. 4.7.1) has also been associated with an autoimmune process leading to HAM/TSP. Thus, a cross-reactive immune response between HTLV-I tax and neuronal hnRNP A1 contained within the human immunodominant epitope of tax suggests that molecular mimicry plays a role in the pathogenesis of HAM/TSP [163, 164]. The average age at diagnosis is 40 years, following acquisition of the infection as adult [24], specifically through sexual transmission [165]. The disease is uncommon in children, although it could co-exist with infective dermatitis, which is a more common HTLV-1 associated disorder of childhood. The clinical features of the disease include gradually progressive symmetrical paraparesis of the lower extremities with signs of pyramidal involvement [117, 161, 166], as well as symptoms of dysuria and frequent urinary tract infection [167] as well as sexual dysfunction [117, 145, 166, 168]. Chronic back pain back pain, constipation and sensory symptoms are also frequent symptoms and signs of HTLV-1/TSP. The suggested pathogenesis of HTLV-1/TSP would tend to indicate that strategies directed towards immunologic processes, autoimmunity, cytokine production and proviral load reduction should be beneficial at earlier stages of the disease. Thus, there are reports of the value of corticosteroids [169], interferon-α [170], interferon-β1a [171], and anti-retroviral nucleoside analogues (zidovudine and lamivudine) [172]. The treatment responses so far have been limited, thus, indicating the need for large clinical trials in addressing the therapeutic interventions for HAM/TSP (Table 4.6).

4.7.3 HTLV-1 Associated Infective Dermatitis The recognition of infective dermatitis as a clinical entity developed from the observation of the high incidence of the skin disorder in children of West Indian immigrants in the United Kingdom in the 1960s. The disorder was subsequently found to be highly prevalent in Jamaican children in 1966 [121], and was subsequently associated with HTLV-1 infection in 1990 [120]. Infective dermatitis has been reported in populations of countries, where the virus is endemic, such as those of the West Indies [120, 144, 173, 174], Brazil [116–118, 175–182], Columbia [178, 183–185] and Japan [186]. In Africa, which is probably the largest endemic area for HTLV-1 [79], and which is the ancestral home of populations of the West Indies and Bahia, Brazil, where large number of cases of infective dermatitis have been reported from, there have been only sporadic reported cases of the disease [115, 187]. This situation is highly suggestive of under-diagnosis of infective dermatitis in the region. Consistent with this suggestion is the report by George Henry Vernon Clarke, writing on skin diseases of Africans in 1959, that skin diseases constitute about 16% of

40

4 Global HTLV-1/2 Burden and Associated Diseases

Table 4.6 Diseases reported in association with HTLV-1 and basis for the association Epidemiological evidence Case reports Case control or series studies Inflammatory syndromes HAM/TSP Yes Yes Uveitis Yes Yes Arthropathy Yes Yes Sjögren’s syndrome Yes .. Polymyositis Yes .. Thyroiditis Yes .. Pneumopathy Yes .. Yes .. T lymphocyte alveolitis Malignant diseases ATL Yes Yes Cutaneous T-cell Yes .. lymphoma Infectious complications Yes Yes Strongyloides stercoralis Crusted scabies Yes .. Infective dermatitis Yes .. Tuberculosis Yes Yes Leprosy Yes Yes

Cohort studies

Biological evidence HTLV-1 in Animal lesions model

Yes .. .. .. .. .. .. ..

Yes Yes Yes Yes Yes Yes .. ..

Yes Yes Yes Yes Yes .. .. ..

Yes ..

Yes Yes

Yes ..

Yes

..

..

.. .. .. ..

.. .. .. ..

.. .. .. ..

Reproduced with permission from: Verdonck et al. [20] .. = unknown

all diseases in the African, “an incidence slightly greater than that met with in European countries. In contrast to dermatological practice in a European country it was found that the infective conditions accounted for more than half of all the cases seen in West Africa, whereas only 3.1% of patients were suffering from dermatitis and only 1.4% from eczema” [188]. The clinical and laboratory features of infective dermatitis are outlined in Table 4.7 The association of the disease with severe exudative infection of the scalp, external ear and retroauricular areas as well as other areas of cutaneous folds, coupled with the involvement of staphylococcus aureus and/or β-hemolytic streptococci [24] gives a picture of a life threatening illness. This is particularly so because of the average age of onset of the disease in the Jamaican series is about 2 years [24], when the immune system is fragile. The disease clusters in the family, thus suggesting the contribution of the host genetics and environmental factors. The epidemiology of HTLV-1 in Nigeria (Sect. 4.5, Table 4.1), including HTLV-1 seroprevalence rate of 21.2 among school children of Ibadan [140], Nigeria suggests that the virus may be playing a role in in the under-5 (U-5) mortality, whereby the country is the second largest contributor to the world U-5 mortality, attributed

4.7 HTLV-1 Associated Diseases

41

Table 4.7 aFour major criteria required for the diagnosis with mandatory inclusion of 1,2, and 5; to meet criterion 1, at least two of the sites must be affected [173] Criteria for diagnosis of Infective dermatitis Major criteriaa (1) Eczema of scalp, axillae, and groin, external ear and retroauricular areas, eyelid margins, paranasal skin, and/or neck (2) Chronic watery nasal discharge without other signs of rhinitis and/or crusting of anterior nares (3) Chronic relapsing dermatitis with prompt response to (but prompt recurrence on withdrawal of) antibiotics (4) Usual onset in early childhood (5) HTLV-I seropositivity Minor or less specific criteria Positive cultures for S aureus and/or β-haemolytic streptococci from skin or anterior nares Generalised fine papular rash (in most severe cases) Generalised lymphadenopathy with dermatopathic lymphadenitis Anaemia Raised erythrocyte sedimentation rate Hyperimmunoglobulinaemia (IgD and IgE) Raised CD4 count, CD8 count, and CD4/CD8ratio Reproduced with permission from: Manns et al. [24]

by UNICEF Nigeria to preventable causes (Christopher Williams, unpublished). Given the epidemiological data that suggest that infective dermatitis is a harbinger of later development of ATL, it conceivable that U-5 mortality from an HTLV-1 devastating pediatric disease could explain the reduced frequency of ATL compared to Jamaica and Japan (see Sect. 4.7.1).

4.7.4 Other Infectious Complications of HTLV-1 These include strongyloidiasis, tuberculosis, crusted scabies, and leprosy. These conditions are highly prevalent in the tropical areas, where HTLV-1 is highly endemic (Fig. 4.4) [79]. While most people with strongyloidiasis would experience nonspecific symptoms, including mild diarrhea, and would remain largely asymptomatic, those with HTLV-1 could develop a systemic dissemination of the helminthic infection with a high risk of fatality through the evolution of the infestation into a hyperinfection syndrome [189–191]. Japanese workers have estimated that the risk of developing systemic strongyloidiasis is twice as high among HTLV-1 infected individuals as compared to healthy controls [126]. This appears to be due to the effect of HTLV-1 infection on the immune response to the helminthic infestation [192], leading to a decrease in the rate of parasite killing, an increase in the rate of autoinfection [193], and diminished response to standard treatment regimen, including ivermectin, tiabendazole and albendazole [124, 126, 194].

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4 Global HTLV-1/2 Burden and Associated Diseases

Fig. 4.4 Geographical distribution of the main foci of HTLV-1. (Reproduced from: Gessain and Cassar [79])

HTLV-1 is associated with suppression of the delayed-type hypersensitivity reaction. The mechanism appears to be related to altered cytokine production in infected individuals and concomitant changes in cell populations involved in delayed-type hypersensitivity, thus indicating that HTLV-1, like HIV, could increase the risk of developing tuberculosis [195]. Other epidemiological evidence linking HTLV-1 infection and tuberculosis is that the virus infection is more prevalent among tuberculosis patients, while tuberculosis is more prevalent in HTLV-1 infected individuals [86, 196]. The causative agent of leprosy is mycobacterium leprae, an acid-fast bacillus. It is therefore intriguing to think that the relationship described earlier between HTLV-1 and tuberculosis could be applicable to leprosy. In a survey of HTLV-1 infection in Ivory Coast, highest prevalence of HTLV-1 infection (13.7%), was observed in an isolated colony of lepers, compared to 1.8% in the general population [131]. In Ethiopia, where HTLV-1 seroprevalence is low (0.0–0.8%) in the general population, the seroprevalence among 250 leprosy patients was also low (0.0–0.4%) [132]. HTLV-1 infection was associated with reduced survival of infected leprosy patients compared to HTLV-1 seronegative patients in a 20-year old retrospective study, indicating additional complications in infected leprosy patients [197].

4.7.5 Other Inflammatory Complications of HTLV-1 Infection The association between arthritis and HTLV-1, first made in 1989 [100], has been controversial. More recent studies have established a higher prevalence and incidence of arthritis between HTLV-1 infected individuals compared to uninfected

4.7 HTLV-1 Associated Diseases

43

individuals. The tax protein, which has previously been linked to the pathogenesis of ATL and HAM.TSP, has also proposed as being involved in the HTLV-1 rheumatoid arthritis like joint disorder of HTLV-1 infection. This is supported by the observation that Tax transgenic mice develop a rheumatoid arthritis like disorder [103, 104]. Frequent unexplained occurrence of uveitis among HTLV-1 individuals in the endemic areas of Japan (Kyushu, Shikoku) is what led to the association of this ocular ailment with HTLV-1 infection. It is probably akin to other visual complications of systemic infection. The disorder begins with blurry vision and sensation of “floaters” in the visual fields. The prognosis of the condition is favorable, and spontaneous regression is not uncommon.

4.7.6 The Role of HTLV-I in Health and Disease The role of HTLV-1 in health and disease and the impact of the viral infection in public health are probably grossly under-appreciated. This is particularly so because of the global distribution of the infection (Fig. 4.4). With the exception of Japan, HTLV-1 poses few challenges to the public health of the very high/high HDI countries. The parts of the world most affected are in the categories of medium to low HDI, areas of the world that are just about emerging from centuries of inundation by more mundane communicable diseases, and diseases of neglect, like malaria, schizostomiasis, malnutrition, kwashiorkor, etc., areas of epidemic emergencies like Ebola, and Zika virus. The public health challenges have been addressed by international health experts that have worked in the areas [198]. These are precisely the countries least able to foot the evolving challenges of yet another class of retroviral diseases, separate from those of the pandemic of HIV/AIDS. Much of what we know of the emerging HTLV-1/2 science is attributable to the efforts of Japanese clinicians and scientists. However, other countries in the developing world, where the virus is endemic, such as Jamaica, Trinidad and Tobago, and Brazil have also made significant contributions, especially with the aid of international research institutes, including the National Institutes of Health of the United States in cases of the West Indies [16, 24, 50, 120, 135–137, 165, 173, 199–201] and Nigeria [66, 140, 141, 202, 203], and Institute Pasteur of Paris, France in the case of Francophone Africa and the West Indies [72, 79, 81, 143, 204]. One cannot help lamenting the fact that we are yet to see the tip of the iceberg of the problems of HTLV1/2 in a place like Africa, which probably harbor the lion share of the infection. The public health challenges needing to be addressed are probably of the magnitude posed by HIV/AIDS, with the exception of the fact that HTLV-I/2 infections do not constitute pandemics. The nature of the challenges are, otherwise, wide-ranging and include those of regional HTLV-1 epidemiology, assessment of the prevention of the mode of transmission of the virus, prevention of transmission in perinatal care, and assurance of safety of transfusion of blood products, diagnosis and care of associated non-communicable diseases, including cancers, infectious and inflam-

44

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Table 4.8 HTLV 1/2 in health and disease in endemic areas correlated with Human Development Index

Health

Disease

Public Health Initiatives

Countries Adults Children ATL HAM/TSP Infectious complications Inflammatory complications Breast feeding Blood product transfusion

Seroprevalence (%) by HDI Categories Medium Low Low High High/Very High DRC Nigeria Jamaica Japan (Kyushu) 5–20 0.7–11 6.1 >6.0 Unknown 21.3 5a 1.8b Frequency of occurrence (%) Sporadic 13c 50–60d 50–60d,e Sporadic Sporadicf 1.9g Incidence: 3.1 × 10−5 cases/yearh UND UND WDC WDC UND

UND

WDC

WDC

UND UND

UND UND

UND UND

WDC WDC

DRC Democratic Republic of the Congo, UND: Undocumented, WDC Well documented Children with atopic dermatitis (as compared to those with infective dermatitis) [173] b In Okinawa prior to infection prevention [260] c Of case of non-B non-Hodgkin lymphoma [140] d Of all lymphoma cases [140] e Incidence 3.5 × 10−6 for HTLV-1 carriers older than 40 years f A case report [207] g Lifetime risk [165] h among infected individuals per year [261] a

matory complications of the virus. Table 4.8 illustrates to what degree these challenges are being addressed in countries of varying levels of development. While Japan, the only developed country, where HTVL-1 is endemic, leads the way in confronting the challenges posed by HTLV-1, developing countries, especially those of Africa, where the largest number of infected people live, are yet to show signs of awareness of dangers of the virus. Addressing challenges of HTLV-1 infection would involve the academia, national governments and regional international institutions, with the assistance of international organizations, such as the World Health Organization and its regional headquarters, and transcontinental organizations like the Africa Union.

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Chapter 5

Global HIV/AIDS Burden and Associated Diseases

Abstract The last three to four decades have witnessed the emergence of HIV/ AIDS as a global health challenge, impacting virtually every aspect of human existence and revealing gaps in global health care. In spite of the fortuitous early recognition of the causative agent as a retrovirus, the most devastating of the emerging zoonotics threatening the global health system, but one that has proven to be controllable by a cocktail of anti-retroviral agents, a plethora of diseases are emerging, both as the complications of the viral infection itself, and those of its treatment. Although essentially a pandemic, the burden of the disease in terms of the disability- associated life years is not uniformly shared, with the greatest impact being in historically economically marginalized parts of the world. HIV/AIDS impacts virtually every aspect of human biology, ranging from rare infections, to neurologic, nephrologic, gastroenterologic, pulmonic, cardiovascular, metabolic, and rheumatic complications, as well as a wide spectrum of neoplastic disorders. Some of the latter are referred to as “AIDS–defining” and mimick the prevalent virus-associated cancers of sub-Saharan Africa, including Kaposi’s sarcoma and Burkitt lymphoma, and immunodeficiency-associated cancers, either heritable, such as Wiskott-Aldrich syndrome, or acquirable through organ transplantation. Others are “non-AIDS related”, involving pathogenic viruses notably associated with “AIDS-defining cancers,” such as Epstein-Barr virus (Arrieta et al., Sci Transl Med 7(307):307ra152– 307ra152, 2015), but manifesting in new settings, such as the EBV-associated soft tissue sarcoma of children. HIV/AIDS is, indeed, producing new health scenarios that signal a need for paradigm changes in disease mechanisms and health care provision. Keywords Transcriptase · DALY · PEPFAR · Vancouver consensus statement · HPV · ART · HAART · AIDS-defining · Phylogeny · Celibate · Communicable

© Springer Nature Switzerland AG 2019 C. K. O. Williams, Cancer and AIDS, https://doi.org/10.1007/978-3-319-99235-8_3

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5.1 Discovery of the Causative Agent of HIV/AIDS The history of the discovery of the discovery of the human retroviruses and the associated diseases has been discussed in Sect. 2.6.1 in Part I. The dramatic manner with which the first cases of the disease presented 1981, invariably with unusual infections and uncommon neoplastic diseases [2–4], led to wild speculations about its etiology, especially because it was affecting exclusive otherwise healthy young men, who practiced homosexuality. Etiological agents considered included recreational drugs that were used for “sexual enhancement”, such as inhaled amyl or butyl nitrate [5]. However, by the second or third year of the epidemic, the spectrum of individuals affected by the disease had changed to include female sex partners of men, who were bisexual, hemophiliacs, intravenous recreational drug users, and infants of women who used intravenous drugs, thus, raising the suspicion of an infectious microorganism. Attention soon turned to viruses, including HTLV-1, the first human retrovirus, which had been discovered only a few years earlier in association with cutaneous lymphoma [6]. The likelihood of the role of this organism was buttressed by the fact that it is, at least mildly, immunosuppressive apart from being associated with a neoplasm. In fact, a number of reports indicated a role for HTLV-1 [7–9]. Workers at the Institut Pasteur in Paris, France, led by Françoise Barré-Sinoussi subsequently isolated a virus from a French patient with lymphadenopathy, and named it “the lymphadenopathy associated virus” [10]. A similar virus was isolated by Robert Gallo and his colleagues at the Laboratory of Cell Biology of the National Cancer Institute in Bethesda, Maryland, USA, and was named HTLV-III [11–13]. In 1985, a second immunodeficiency virus, HTLV-IV was isolated in sex workers in Senegal by Max Essex of Harvard University and his colleagues [14, 15], while a similar virus was isolated by Montagnier and his colleagues and named it LAV-2. Both viruses were proved to be less pathogenic as HTLV-III/ LAV. In 1986, the name HIV was proposed by a committee of the International Committee on Taxonomy of Virus to designate the human immunosuppressive viruses, which prior to then carried a variety of names [16].

5.1.1 Retroviruses Retroviruses are unique for their content of reverse transcriptase, which enables them to transcribe RNA template to DNA [17–19]. It is this unique characteristic that marks them out for identification among other viruses. While this type of viruses had been known to cause disease in animals, it is only in 1980 that the first of these viruses was reported to have been identified in humans, with the identification of HTLV-1 [6] (also see Sect. 2.6.1 in Part I). They are also unique by the diversity and changeability of their genetic genomes, apparently resulting from their ability to transduce, or acquire genetic materials from the cells that they invade,

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which has given rise to oncogenes [20], to viral oncology [21, 22], and a new concept in our understanding of the pathogenesis of cancer. It is also this unique characteristic that led to the emerge of HIV-1 from the primate virus SIVcpz (see Sect. 2.6.4 in Part I, Fig. 2.11) [23]. The characteristics of HIV and AIDS reflect the general features of retroviruses [24], including: [25] their mutation rate, which is much higher than DNA viruses, such as pox viruses or herpes [26, 27], which underlies its ability to generate drug resistant variants, evade neutralizing antibodies and other immune responses, or change their affinity for cell receptors or co-receptors; ability to stabilize such mutations through reverse transcription of RNA template into proviral DNA, which is integrated into host chromosomal DNA [28, 3] the diploid nature of retroviruses, which provides the opportunity of recombination of different parental genomes in the same viral particle, since the assembly and release would not be able to be selected against in parental viruses that affected functions other than virus assembly [29]. Another feature of retroviruses is their ability to adapt in a process referred to as “latency.” Latency is characterized by the lack of expression of viral proteins, leading to protection fro attack by immune cells and antibodies, as well as from elimination during drug therapy, since proviral DNA components, which these agents target are not expressed in the state of latency. The inability to eliminate proviral DNA in long living infected cells is responsible for the incurability of HIV-infected individuals [24].

5.1.2 Human Lentiviruses and Subtypes of HIV-1 Following the identification of HIV-1 as the first lentivirus, related viruses were soon identified in monkeys, including the first simian immunodeficiency viruses (SIVs) of experimental colonies of Asian macaques that had an immunodeficiency syndrome similar to human AIDS [30, 31], and similar findings in several species of African monkeys [32–35]. HIV-2, which was subsequently identified in populations of female commercial sex workers, was serologically indistinguishable from the SIVs identified in Macaques, whereas it was clearly distinguishable from HIV [36, 37], thus, indicating possible entry of HIV-2s in to human species [24] through Mangabey SIVs (Fig. 5.1). Fig. 5.1 Possible entry of HIV-2s into human species. (Reproduced with permission from: Essex and Mboup [24])

Mangabey SIVs

SIVmac Colonized Asian monkeys

HIV-2 Humans

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5.1.3 D iversities in HIV Types and Subtypes and Implications for Disease Control The disease resulting in HIV-2 infection of humans, was clinically identical but less virulent than HIV-1. Furthermore, HIV-2 did not spread as efficiently between people, either by sexual transmission [38], or from infected mother to their infants as observed with HIV-1 [39, 40], thus, probably, explaining its relative geographical confinement to the West African region. “In retrospect, it seems likely that HIV-2 had moved into the human population before HIV-1, yet it has not expanded beyond West Africa, except perhaps for small number of infections in a few sites that were linked to West Africa by frequent travel [41]” M. Essex and S. M’Boup [24]. Genotypic characterization of HIVs through nucleotide sequencing has revealed an evolving complexity in the family tree of HIVs as shown in Fig. 5.2, ranging between outlier subtype groups of HIV-1 Group 0 [42, 43] and HIV-1 Group N [44] bordering the main or major subtypes A-K group. The viruses subtypes of Group 0 and Group N seem to be rare in people, occurring primarily in individuals around Cameroon, where isolation of viruses closely related to IV-1 “0” has been made in subhuman apes [45], “allowing for the interpretation that such viruses entered the human species even more recently than other HIV-1s and HIV-2 (Fig. 5.2)” [24]. Some of the genotypic subtypes of HIV-1 are known to be recombinant forms: for instance, one end of viral genome E, a distinct subtype, recombining with another distinct subtype A, yields an HIV-1 subtype A/E, which is known to be circulating in Central African Republic. Similarly, other recombinant forms, such as C/D and A/G are known to be circulating in Tanzania and West Africa, respectively as illustrated in Fig. 5.2 [24]. The phenotypic expression of these genotypic alterations could be mapped to various portions of the virus, e.g. a few amino acid changes in the V3 region of the gp120 protein [46], resulting in changes in viral properties, including tropism and attachment to chemokine co-receptors during infection [47, 48].

Chimpanzee SIVs

A

HIV-1 Group N

HIV-1 Progenitor A-K

HIV-1 Group O B

A/E

C D E F

Central African Republic

G H I

C/D

Tanzania

J

K

A/G

West Africa

Examples of Circulating Recombinant Forms (CRFs) in Africa

Fig. 5.2 Possible entry of HIV1s into human species. (Reproduced with permission from: Essex and Mboup [24]. See also Fig. 2.11 in Part I for connection to Chimpanzee SIVs [23])

5.2 Early Phase of AIDS Epidemic in Africa: The Nigerian Experience

63

HIV-1B, which is a common subtype in “the West” that has provided the vast majority of clinical isolates analyzed in the laboratory [49], is known to have phenotypic characteristics [50], as well as clinical and epidemiological features that differentiate it from subtypes found predominantly [51–53] elsewhere, including Sub-Sahara Africa. Thus, it is unclear whether the natural history of HIV infection in western populations infected with HIV-IB, where viral transmission is mainly through homosexual activities and injection drug users, is the same as in other parts of the world, like Sub-Sahara Africa, where transmission is predominantly by heterosexual activities. This may explain differences in rates of progression from infection to clinical AIDS, as observed in Senegalese women [54], or differences in mother-to-infant transmission in Tanzania [55]. “Many more studies must be done in African populations to determine whether significant differences in the natural history may be present in different regions” (Max Essex and Souleymane M’boup [24].

5.2 E arly Phase of AIDS Epidemic in Africa: The Nigerian Experience The history of HIV pandemic has been discussed in Sect. 2.6.4 in Part I, while the process, whereby research on HTLV-1 epidemiology had virtually inadvertently led to the earliest observation of AIDS epidemic in Nigeria has been reviewed in Sect. 2.6.4 in Part I. The discovery of the first case of HTLV-1 associated disease in the African region in Nigeria, only a few years after the virus was discovered in the US, marked the onset of interest in human retrovirology in the country. The country therefore had the opportunity to make observations of the earliest phase of the emergence of the epidemic [56], unlike elsewhere in Africa, where the pandemic was manifesting as new clinical syndromes, such as “slim disease” in Uganda [57], or aggressive Kaposi’s sarcoma in Zambia [58, 59]. As shown in Table 5.1, the seroprevalence of HIV-1 in Nigerians was low in the early years of the pandemic, even in individuals at high-risk for infection, including commercial sex workers. The observations were similar to those of Senegal, unlike Uganda, where the onset of AIDS epidemic was like a bolt from the blue (Table 5.2) [60]. HIV seroprevalence, however, changed dramatically between 1985 and 2000 in all subgroups studied, with the exception of celibates, where data are lacking. The country-specific chronological changes in HIV seroprevalence show remarkable differences. The marked rise in HIV seroprevalence in Nigeria between 1985 and 2011 (Table 5.2) is in contrast to the stability seen in Senegal and the apparent reversal in Uganda. Botswana and South Africa, both with high seroprevalence rates, also appear to show reducing trends between 1996 and 2011. The observed variation in the trends of HIV seroprevalence among African countries probably relate to cultural differences and the response to the pandemic by the governments of the countries. Similar factors are probably driving the global trends in HIV-AIDS burden from country to country, whereby HIV/AIDS contribution to global disease burden has evolved since 1980 [61] Fig. 5.3.

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Table 5.1 HIV-Seroprevalence rates (%) in subpopulations of Nigerians 1983–2000 Period General 1983–1985a ≈0.5–1.0 1/184–1/93 1985–1990e 2.0 1791 1987–1990g 1.8 1991–1995 NA 1996–2000 5.0j

NBD Celebates GOPD 0.84 1/237b 0.0 0/74 1.9 1/53c

STD 0.0 0/42

CSW 0.0 0/46d

1.2 1640 NA NA 7.7k

0–4.1610 3.6 31g,h–65g,i 21.2k

0–10.0 60f 0.0 0.0–74.0 60.6k

NA NA NA NA

0–61.6 1253 NA NA NA

Number studied, NA not available, NBD Normal blood donors, GOPD General Outpatient Department patients, STD Sexually Transmitted Disease patients, CSW Commercial Sex Workers a See Sect. 2.6.5 in Part I, [62, 63] b Ibadan and Zaria c Teaching Hospital, Calabar d based in brothels of Ibadan and Calabar e [64] f All 6 of 10 samples tested positive: [65] g [66] h HIV rate in patients with dermatoses (1992) [66] i HIV rate in patients with dermatoses (1994) [66] j National Security Adviser’s Office, CIA World Factbook k [67] Table 5.2 HIV-1 seroprevalence rates (%) in five selected countries (1983–2011) Periods 1983–1985 1985–1987 1985–1990 1991–1995 1996–2000 2001–2011

Nigeria ≈0.5–1.0a 0.25d–1.1e 2.0e NA 5.0g 3.6h

Senegal 0.4b 0.8f 0.8f 0.8f 0.9f 0.9h

Botswana NA NA NA NA 35.8g 24.8h

S. Africa NA NA NA NA 19.9g 17.8h

Uganda ?14.0c NA NA NA 6.1h 6.6h

See Sect. 2.6.5 in Part I, [62, 63] [68] c [60] d [69] e [64] f UNAIDS/WHO Epidemiological Fact Sheet (Senegal) g [65] h US National Security Adviser’s Office; CIA World Factbook. a

b

5.3 Global HIV/AIDS Burden A glance at the current state of global health at the different stages of life is helpful in placing the global HIV/AIDS burden in perspectives (Fig. 5.3) [70]. Furthermore, the global and country-level burden of HIV/AIDS relative to 291 other causes of burden from 1980 to 2010 has been evaluated using the Global Burden of Disease

Number of DALYS

10 000 000 20 000 000 30 000 000 40 000 000

5.3 Global HIV/AIDS Burden

65

44.6%

20.0% 14.8% 8.2% 4.9%

2.7%

0

0.8%

1

2

3

4

5

10

>10

Fig. 5.3 Summation of country-level HIV/AIDS disability-adjusted life years (DALY) by rank for 2010. The figure illustrates the summation of HIV/AIDS DALYs for countries with similar HIV/ AIDS DALY ranks in 2010. The HIV/AIDS DALY ranks are listed at the bottom. The percentages on top of each bar indicate the proportion of global HIV/AIDS DALYs attributable to the summation of DALYs from all countries with that rank. (Reproduced with permission from: Lozano et al. [61])

Study 2010 (GBD 2010) as the vehicle of exploration by Katrina F. Ortblad and her colleagues [71]. They observed that HIV/AIDS, which used to be the 33rd most important cause of disease burden globally in 1990, increased dramatically to be the fifth leading cause of disease burden in 2010, a 354% increase in absolute terms [71], but that its impact on global disability–adjusted life years (DALYs) varied in distribution across demographics and regions. In the age-group 30–44 years in both sexes, HIV/AIDS was ranked as the leading DALY cause in 2010 for 21 countries that fell into four distinct blocks: Eastern and Southern Africa, Central Africa, the Caribbean and Thailand. They also observed that although the majority of the DALYs caused by HIV/AIDS were in countries of high-burden, 20% of the global HIV/AIDS burden in 2010 was in countries, where HIV/AIDS did not feature among the top 10 leading causes of disease burden (Fig. 5.3). Although HIV/AIDS is a pandemic, the burden of the disease is not equally shared. Sub Sahara Africa, in particular, shows the impact of the disease, whereby 47 countries in this region contributed to 70.9% of global DALYs attributable to HIV/AIDS in 2010. The pandemic, on the other hand, is showing signs of transition, as the burden disease attributable to HIV/AIDS is decreasing in high-burden countries and shifting to a greater number of countries that have not historically had large epidemics and are struggling with other leading causes of disease burden. Thus, in 2010, 20.0% of HIV/AIDS burden was in countries, where HIV/AIDS ranked higher than 10 compared to only 15.5% 5 years earlier. Furthermore, although global HIV/AIDS mortality has been steadily decreasing since 2006 (Fig. 5.3), it has actually been increasing for 98 countries during the same period of time [71].

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5.4 Global Trends in HIV/AIDS DALY

1 500 000 1 000 000 500 000 0

HIV death number

2 000 000

The dynamics of HIV/AIDS DALYs vary substantially around the world. In 2010, HIV/AIDS became the leading cause of DALY in southern sub-Saharan, having increased 1065% since 1990. At the same time, however, it ranked 17th in South Asia despite the fact that the percentage increase in HIV/AIDS associated DALY between 1990 and 2010 was 4761% (almost fivefold of the southern sub-Saharan African rate) [71]. Dramatic changes were probably occurring elsewhere in sub- Saharan Africa. Nigeria, where low HIV-1 seroprevalence was demonstrable between 1983 and 1987 in the various subgroups of the population, including high- risk individuals, (Tables 5.1 and 5.2), HIV/AIDS DALY had become the second cause of DALY by 2010, unlike the observation in Senegal, where HIV-1 seroprevalence was comparable to that of Nigeria in the 1983–1987 period, and remained below 1.0 by 2011 (Table 5.2), the HIV/AIDS DALY in 2010 was ranked 10th [71]. Uganda in East Africa, where HIV-1 seroprevalence declined from about 14.0 in early 1980s to 6.6 in 2011, as well as Botwana and South Africa, both in the southern sub-Saharan Africa, HIV/AIDS constituted the leading DALY in 2010 [71]. A decline in global HIV/AIDS DALY against the general trend of falling infectious disease burden became apparent [71] around 2004 (Fig. 5.4). This occurred, apparently, due to a combination of declines in incidence of HIV-1 infection, significant global increase in anti-retroviral coverage (see Introduction, Sect. 1.8 in Part I), [72– 74] (Fig. 5.5). This is attributable to the emergence of substantial global action, including the creation of new institutions such as UNAIDS in 1996 [75], the Global Fund To Fight AIDS, Tuberculosis, and Malaria in 2002 (GFATM) [76] and the US President’s

1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

Year

Fig. 5.4 Global HIV/AIDS mortality, 1980–2010. (Reproduced from: Ortblad et al. [71] an open access publication)

5.5 Financial Resources for Global Campaign Against HIV/AIDS

67

9 8 7

Millions

6 5 4 3 2 1 0 End 2002 End 2003 End 2004 End 2005 End 2006 End 2007 End 2008 End 2009 End 2010 End 2011

North Africa and the middle East

Latin America and the Caribbean

Europe and Central Asia

Sub-Saharan Africa

East, South and South-East Asia

Fig. 5.5 Number of people receiving antiretroviral therapy in low and middle-income countries by regions, 2002–2011. (Reproduced with permission from: UNAIDS Report on the Global AIDS Epidemic: HIV/AIDS JUNPo. [72])

Emergency Plan For AIDS Relief in 2003 (PEPFAR) [77, 78], through the action of which access to retroviral therapies was scaled up. In 2011, eight million HIV-infected people received antiretroviral therapy, a 20-fold increase since 2003, translating into 54% of all eligible people in low and middle-income countries [72]. The resulting reversal in the global trend of HIV/AIDS mortality (Fig. 5.4) has unleashed enthusiasm about ambitious goals of the control of the pandemic, including such goals as “Getting to Zero” campaign, which aims at achieving “zero new infections”, “zero discrimination”, and “zero AIDS-related deaths” in foreseeable future [71, 79, 80] as well as “90-90-90” in reference to the UNAIDS year 2020 goal of “90% of people living with HIV will know their status; 90% of all people diagnosed with HIV will receive antiretroviral therapy (ART); and 90% of all people receiving ART will reach and maintain viral suppression” [81].

5.5 F inancial Resources for Global Campaign Against HIV/AIDS The role of the international organization in AIDS control has been alluded to in Sect. 1.8 in Part I. Between 2002 and 2010, development assistance for health targeted for HI/AIDS increased from US$1.4 billion to US$6.8 billon (387.7%) [71,

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82]. International funding of health in poor and middle-income countries began growing in the 1990s and exploded after 2000 [83]. Much of funding was channeled through new public-private partnerships like the Global Fund To Fight AIDS, Tuberculosis, and Malaria (GFAFM), GAVI, the Vaccine Alliance, and the Bill and Melinda Gates Foundation. Other contributors included regional development banks, the World Bank, international non-government organizations (NGOs), US NGOs, European Commission, UNICEF, World Health Organization (WHO), and bilateral organizations of the United Kingdom and the US [83], also see Fig. 5.6. The money was spent distributing drugs, vaccine, and bed nests as well as in fighting malnutrition. Many political, historical, and economic factors influenced how much aid lowand middle-income countries received during this period [84]. Of 140 countries that received public health aid in the years 2009–2011, the top beneficiaries included (US$ in billions) – India: 2.53; Nigeria: 2.32; Ethiopia: 2.09; Tanzania: 1.97; Kenya: 1.93; South Africa: 1.90; Uganda: 1.31; Mozambique: 1.3; Democratic Republic of the Congo 1.17 and Mexico: 1.05. The amount received did not always match the burden of the disease for which it was given. Thus, in terms of the “expected” aid – based on disease burden and gross domestic product – Botswana, South Africa and Namibia were the “biggest winners”, receiving 13.96x, 6.77x, and 8.02x respectively what should have been received. Countries like Iran (0.17x), Venezuela (0.08x), Malaysia (0.04x), Algeria (0.08x) and Chile (0.13x) were “short-changed” in the process [83]. Furthermore, the targeting of the funds did not always correspond to the disease burden of the low- and middle-income countries. As shown in Table 5.3 [70], Figs. 5.7 and 5.8, HIV/AIDS received a disproportionately large amount of fund in development assistance for health, while much less went to noncommunicable diseases, whose burden is large and growing in the countries [83].

Fig. 5.6 International assistance funding for HIV in 2012: 48.7% – United States President’s emergency plan for AIDS relief; 19.7% – global fund to fight AIDS, Tuberculosis, and Malaria; 16.3% – European governments; 7.8% – other multilateral agencies; 5.4% – philanthropies; 1.9% – the other Organisation for Economic Cooperation and Development (OECD) governments; 0.1% – Brazil, Russian Federation, India, China, South Africa, non-OECD Development Assistance Committee (DAC) governments. (Source: UNAIDS estimates) (Reproduced with permission from: UNAIDS [87])

5.6 Sustainable Financing of HIV/AIDS Control: External Resources

69

Table 5.3 Disease burden in potential years of life lost (YLL) as compared with developmental assistance for health (DAH) Low income YLL DAH HIV/AIDS 7.6% 41.6% Malaria 11.2% 14.3% Tuberculosis 3.1% 3.3% Maternal, newborn, and child health 37.8% 17.1% Noncommunicable diseases 20.7% 0.2% Other 19.7% 23.5%

Lower middle income YLL DAH 3.7% 32.0% 4.8% 9.6% 3.5% 6.6% 32.1% 23.7% 34.0% 1.0% 21.9% 27.1%

Upper middle income YLL DAH 4.8% 41.1% 0.0% 2.2% 1.0% 7.0% 8.1% 7.0% 65.3% 2.9% 20.8% 39.8%

The country income levels are classified by the World Bank on the basis of estimates of gross national income, whereas DAH date are from 2010. (Reproduced with permission from: Lu et al. [86])

The Global AIDS Response Progress Reporting (GARPR) as shown in Fig. 5.8 has documented the degree to which low- and middle-income countries supplement the international support. The domestic public spending as a percentage of total domestic public and international spending in low- and middle-income countries varies widely, ranging between 19% and 21% in the countries of Central and Western Africa and 88% and 94% in those of East Asia and Latin America, respectively. The reasons for this pattern of response HIV/AIDS health challenges from various countries are many and complex. It has been suggested that the relationship between HIV/AIDS and socioeconomic status, which varies from country to country, reflecting differences in culture and traditions, as well the various forms of societal inequalities play a role [85].

5.6 S ustainable Financing of HIV/AIDS Control: External Resources The massive investment that HIV/AIDS research has enjoyed within the US financial system has recently come under attack. The US Congress had earmarked 10% of the National Institute of Health annual budget to combating HIV/AIDS in response to the pressure from AIDS activist groups, such as ACT UP (see Sect. 1.5 in Part I). A string of new drugs have meanwhile emerged, which have been making HIV/AIDS a manageable, if not entirely curable disease. The number of deaths in the US directly attributable to HIV dropped from the staggering 45,000 per year in 1995–7000 in 2013 [89]. The prudence of continuing to devote so much funds to one single disease entity in the face of competing health priorities has become a matter of concern in academia and among activists for other health issues. The NIH is therefore refocusing the AIDS research subvention on ending the pandemic.

70 Fig. 5.7 Skewed funding between disease burden and developmental assistance for health. The diseases that cause the highest burden – expressed in disability-adjusted life years (DALYs) – don’t get most of the international financial support. In 2010, HIV/AIDS received the biggest chunk, while little went to noncommunicable diseases like diabetes, whose burden is large and growing (Source: Reproduced with permission: from Institute for Metrics and Evaluation [82])

5 Global HIV/AIDS Burden and Associated Diseases

100%

80%

60%

40%

20%

0% Aid

Disease burden Malaria HIV/AIDS Tuberculosis

Noncommunicable diseases Other

Maternal, newborn, and child health

Fig. 5.8 Regional distribution of domestic public spending as a percentage of total domestic public and international spending in low- and middle-income countries, according to the Global AIDS Response Progress Reporting (GARPR) 2013 [88]. (Reproduced with permission from: UNAIDS [87])

5.7 Sustainable Financing of HIV/AIDS Control: The Challenge of Local Funding

71

Since the 2008 global financial crisis, the rich donor countries that have financed much of HIV/AIDS care globally have had to reorder their own financial priorities. Increasingly, demands are being made for evidence of return on the investment being made in HIV/AIDS control. While the demand of donor countries for evidence of impact of the billions of dollars spent so far, the world is facing the dilemma as to what will have to remaining HIV/AIDS burden of the poor countries, which have so far failed to match the effort of DAH. As the decade long surge in health funding plateaus out, some believe this is happening too soon. The $31.3 billion spent on global health in 2013 has been estimated as being less than 1% of what rich countries spent on their own health the year before [83]. Ending AIDS globally, which is the vision of the ambitious programs such as the UNAIDS 90–90–90 requires the development of strategies for sustainable financing of care. This can only be achieved by increasing the domestic input into national HIV/AIDS care (Figure 5.8). There is a need to promote the participation of recipient countries and persuading the national health care authorities about the need to adopt the ambitious programs of international institutions like UNAIDS in working towards a world without HIV/AIDS. The report about AIDS death rates beginning to drop dramatically about two decades ago has come under criticism as being “only part of the truth” [90]. The Center For Disease Control (CDC) of the United States has reported that the number of new infections in the country has been steady at about 45,000 annually for at least 20 years [91]. Commenting on this controversy, Neal Nathanson, Emeritus Professor, Department of Microbiology, University of Pennsylvania, Philadelphia remarked that HIV being an infectious disease, which could be controlled by reduction of transmission, and that this could be achieved even in the absence of a vaccine. To achieve reduction of transmission, he urged “a major investment in implementation science (with participation of social, political, and economics experts) and coordinate these initiatives with the CDC. This is no time to turn our back on the research required to end the epidemic of HIV/AIDS in the United States” [90]. A large international study of prevention of transmission of HIV among discordant partners has shown that HIV transmission is preventable with early as opposed to delayed ART [92] and lends support for making ART for pre-exposure prophylaxis available worldwide, and especially in countries with high retention in care and high ART coverage among infected MSM [93].

5.7 S ustainable Financing of HIV/AIDS Control: The Challenge of Local Funding While the funding from external sources has plateaued, the needs have not. The relation between local and external funding varies between countries. As PEPFAR increasingly assumes a complementary role in the challenge of reaching ambitious goals, such as the 90-90-90, the need for a transition from external to local funding is stimulating efforts in for local funding resources. In Kenya, 73% of funding for HIV/AIDS IN 2012–2013 was from external sources compared to 26% of funding

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for health in general. The dwindling trend is apparently stimulating a search for new approaches to HIV/AIDS care financing in the country, including: improving efficiency; building stakeholders’ capacity to advocate for priority setting; advocating for more domestic resources; reforming the National Health Insurance Fund to include ART; and increasing the role of the private sector. Pressuring the national government to increase domestic spending on HIV/AIDS is not considered the answer to the present dilemma in HIV/AIDS funding in Kenya. The government is capable of funding about 20% of ART in the context of 90-90-90 [94]. The Caribbean, a region consisting of a multitude of small islands that are among the most desired tourist destinations, is largely an area of “monocrop” economies, which are highly susceptible to climate change and external forces. Most of the countries of this region are classified as middle/upper income countries (although much of the financial resources are concentrated in the hands of a few wealthy individuals), with the exception of Haiti. The area is heavily dependent on external resources for funding of ART (Fig. 5.8). Spending on HIV/AIDS as a percentage of GDP is highest in Haiti for the region [95]. Cuba, on the other hand, has a low prevalence of HIV/AIDS, and enjoys very low rate of external funding for its HIV/ AIDS program. Among options for the way forward are: exploring more public/ private partnership; exploring sustainability through recognition of the importance of addressing the social determinants, which impact adherence to treatment, access to treatment, HIV testing, and prevention of new infections; emphasizing the importance of linking HIV/AIDS control to the overall national health plan.

5.8 HIV/AIDS and Global and Universal Health Care Access to Universal Health, as proposed in the UN Sustainable Development Program [96] should be an opportunity to HIV/AIDS control, rather than a threat. As HIV programs are being increasingly integrated into national health systems, there are three decades of lessons learnt from HIV response, which may inform and advance global health goals. Externally funded programs, such as of PEFFAR in Africa, usually focus on delivery of complex procedures of HIV/AIDS care without adequate attention to the general health of the recipient populations, leading to neglect in such patients of conditions like cardiovascular and renal disorders [97, 98]. The concept of HIV/AIDS prevention at population level through the integration of testing and multi-disease care [99] appears to have a greater potential for early diagnosis and treatment, which in turn signals a greater opportunity of HIV/ AIDS control. In other words, the concept is not that of “treatment versus prevention, but rather that of “treatment is prevention” at the community level. A chronic disease approach, targeting common chronic ailments such as hypertension and diabetes, may provide a greater incentive for national health planning authorities in designing community-based approaches for HIV/AIDS control through testing and early treatment within the national universal health care programs. Uganda is already using HIV/AIDS care to addressing AIDS communicable diseases, such as

5.8 HIV/AIDS and Global and Universal Health Care

73

tuberculosis, as well as noncommunicable diseases, such as cancer and hypertension, in their communities [100–102]. The linkage to global health has been suggested to be a potential “game-changer” in HIV/AIDS care. The Vancouver Consensus statement (Fig. 5.10), which emerged at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention [103], signals the scientific affirmation that, rather than limiting access to those who are immune compromised, immediate access to antiretroviral medicines holds the power to rapidly advance the fight to end AIDS [104]. It has been suggested that “there will be no Global Health without the defeat of the AIDS pandemic” [103].

5.8.1 Global Status of Antiretroviral Coverage The global scale-up of access to antiretroviral therapy over the past decade has been one of the most dramatic and successful public health interventions of the Millennium Development Goal (MDG) era [96], and, together with improvements in treatment efficacy, has dramatically reduced AIDS mortality rates. ART is provided free of out-of-pocket expenses in many African countries. At the end of 2013, 12.9 million people living with HIV were receiving ART globally, up from less than one million a decade earlier. In sub-Sahara Africa, where 25 million HIV-infected people live, 9.1 million (37%) of people living with HIV received ART (Fig. 5.9), up from a negligible percentage a decade earlier [96]. ART coverage was highest in Botswana at 70%. The four countries with the largest numbers of people living with HIV worldwide include South Africa and Kenya, which had ART coverage of 42% and 41% respectively in 2013, India, which had 36% coverage, and Nigeria where the ART coverage was 20% [96]. There is age-related disparity in access to ART. While ART coverage number for children under 15 has increased during the past decade to more than 700,000 globally [105], only 23% of children living with HIV in low- and middle-income countries are on ART, compared with 37% of adults (Fig. 5.10).

Fig. 5.9 Percentage of people living with HIV who are currently on ART by region and globally, 2003 and 2013. (Reproduced with pending permission from: Evans and Kieny [96])

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Fig. 5.10 The Vancouver Consensus, displayed on a billboard at the International AIDS Society Conference, Vancouver, BC, Canada, July 2015. (Reproduced from personal archive of medical illustrations)

5.9 HIV/AIDS in Eastern Europe and Central Asia The HIV/AIDS epidemic is expanding in Eastern Europe and Central Asia (EECA), largely driven by intravenous drug abuse. Access to ART is low and HIV prevention effort is also low or non-existent. Russia and Ukraine account for 90% of cases of HIV in Eastern Europe. The key populations for infection in this region are intravenous drug users and their sexual partners, sex workers and men who have sex with men [1]. While access to ART is increasing, it still lags behind incidence of infection. Of the more than 3.5 million intravenous drug users in EECA, approximately 25% are HIV positive, including individuals who are co-infected with HBC and TB. The rapid growth of the HIV epidemic in the region is related to wrong healthcare policies, which persist in spite of availability of evidence of efficacy preventive measures. Much of the funds for HIV control in drug users, sex workers and MSM are from external sources, while less than 10% are of local sources [106].

5.10 Non-malignant Complications of HIV/AIDS

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5.10 Non-malignant Complications of HIV/AIDS The complications of HIV/AIDS are numerous and complex (Table 5.4), because some of them are directly related to the viral infection itself, while others are the consequences of the associated immunodeficiency, the complications of the antiretroviral agents, or the complications of the natural aging process. The complications include non-malignant conditions such as infections, inflammatory, neurologic, neuropsychiatric, nephrologic, hematologic, gastrointestinal, metabolic, cardiac and pulmonary disorders. Others are neoplastic disorders, including “non-AIDS” cancers, and the AIDS defining cancers.

5.10.1 HIV/AIDS Associated Infectious Complications 5.10.1.1 HIV/AIDS and Bacterial Infection Bacterial vaginosis plays a role in the risk of HIV infection, based on outcome of metaanalysis of 23 publications. It has, however, been suggested that prospective studies are needed to determine the role played by bacterial vaginosis in HIV infection risk [107]. Table 5.4 Complications of HIV/AIDS and its therapy Subclass Infection

Inflammation Neurologic

Neuropsychiatric

Nephropathy Hematologic Gastrointestinal Metabolic

Cardiac Pulmonary Cancer Non-AIDS defining AIDS- associated

Type Bacterial, parasitic (malaria, pneumocystis, toxoplasma), viral (herpes simplex, HPV, CMV, HCV), mycobacterial, fungal (candida, sporotrix) Rheumatic diseases Hearing loss, polyneuropathy, painful polyneuropathy HAND, drug-dependency, pain associated to psychosocial factors, leucoencephalopathies, catatonic disorders IgA immune complex; co-infection by HIV and HCV Anemia Secretory diarrhoea Lipodystrophy, diabetes, anorexia-cachexia, lipid abnormalities associated with protease inhibitors, infection associated endocrinopathies HIV associated acceleration of CAD Pulmonary hypertension EBV-associated smooth muscle tumor, infection and smoking associated cancers Kaposi’s sarcoma, lymphoma, conjunctival cancer

Site Blood, vagina, mucous membrane, skin, peripheral nerves, CNS, CSF, periodontal tissue Joints, muscles Auditory nerves, vestibules, peripheral nerves CNS

Kidney Blood Small intestine Adipose tissue, endocrine glands, gonads

Coronary arteries Lungs Smooth muscles, lungs, prostate Skin, lungs, conjunctiva

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5.10.1.2 HIV/AIDS and Parasitic Infection Given the high HIV/AIDS burden in the parts of the parts of the world, where malaria is highly endemic, the interaction of these two pathologies is highly pertinent. In a study reviewing the evidence of association between malaria and HIV/ AIDS co-infection showed that HIV-1 infection was associated with increased incidence of plasmodium falciparum parasitemia and the development of severe malaria, cerebral malaria and high parasite density. The efficacy of chloroquine and sulphadoxine-pyrimethamine in reducing placental malaria in HIV-1 pregnant women was impaired compared to HIV-1 negative pregnant women [108]. 5.10.1.3 HIV/AIDS Associated Fungal Infection Oral candidiasis occurs commonly and recurs frequently, and is often the initial manifestation of HIV/AIDS. The associated symptoms could be a major source of impairment of the patients’ quality of life, hence the importance of its successful prevention and management. In a review of 33 studies of interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection involving 3445 study subjects, including adults and children, the direction of the findings suggested that ketoconazole, fluconazole, itraconazole and clotrimazole improved treatment outcomes. The need for more research on the effectiveness of less expensive interventions in resource poor settings has been suggested [109]. The Collaborative Workgroup on the Oral Manifestations of Pediatric HIV infection reached a consensus, based on available data, as to the presumptive and definitive criteria to diagnose the oral manifestations of HIV infection in children. Orofacial lesions commonly associated with pediatric HIV infection include candidiasis, herpes simplex infection, linear gingival erythema, parotid enlargement, and recurrent aphthous stomatitis [110]. 5.10.1.4 HIV/AIDS Associated Viral Infections Genital ulcers and HSV-2 infection [111] as well as syphilis are associated with HIV acquisition. The exact role for these HIV co-factors is still unknown [112]. Thus, suppressive therapy of HSV is ineffective in reducing HIV acquisition [113], but male circumcision reduces HSV-2 acquisition [114] as well as HIV infection [115, 116]. While a few types of cancers, including Kaposi’s sarcoma, primary lymphoma of the central nervous system, non Hodgkin lymphoma and cervical cancer – were among the AIDS defining diagnosis by the United States Center for Disease Control (CDC) in 1982 [117], cancers have also been known, even in the pre-AIDS era, to complicate the process of solid organ transplantation [118–120]. Thus, the immunodeficiency shared by these two disease states seems to contribute to the risk of malignancy. Unlike the limited number of cancers associated with AIDS, the num-

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ber and spectrum of the cancers linked solid tumor transplantation is higher and wider [121]. A study comparing cancer incidence among people with AIDS and those immunosuppressed following solid organ transplantation showed that cancer incidence was increased in both populations. Most of these were cancers of known infectious cause, including the AIDS defining ones, all HPV-related cancers as well as Hodgkin lymphoma [121], those indicating a main role for immunodeficiency state rather than other risk factors for cancer risk in these populations. Questions that still need to be resolved include the biology of HPV infection among immunocompromised transplant individuals, compared with AIDS whether the biology of specific HPV type is the same in HIV-positive as in HIV-negative individuals [122]. Thus, the prevalence of HPV is higher among HIV-positive women and the range of HPV types in the population is broader than among HIV-negative women [123]. The question of co-infection by HIV and the hepatitis virus types B and C is of public health interest, especially given the epidemiology of these viruses, and the similarity of groups at risk for infection [124], especially in parts of Africa and Asia. In other parts of the world, where intravenous route is an important route of transmission of HIV, the biological and clinical implications of co-infection is of significant relevance [125]. It has been reported that people with AIDS often show evidence of current or past HBV infection, while HIV infection is known to lead to reactivation of latent HBV [126, 127]. These types of observation have led to the suggestion for longitudinal studies of HBV and HIV co-infection so as determine the impact of HIV on the natural history of HBV in Africa [124]. Of relevance to this are studies that have been carried out on the natural history of HBC infection in a situation of dual infection with HIV in the era of antiretroviral therapy (ART). Chronic hepatitis C outcomes are worse among individuals with dual infections of HIV and HCV, and it would seem that ART did not appear to fully correct the adverse effect of HIV infection on HCV prognosis [128]. The implication of dual infection of hepatitis virus subtypes with HIV for the chronicity of the former, and for the risk of hepatocellular cancer is another potential public health issue, giving the dominance of this cancer type in large populations of parts of Africa and Asia. 5.10.1.5 HIV/AIDS Associated Mycobacterial Infection HIV/AIDS associated tuberculosis (HIV-TB) has emerged a major challenge to global health, with 1.37 million of new cases of HIV-TB occurring in 2007, representing 15% of the total global burden of TB [129]. Sub-Sahara Africa is the worst affected region, with 79% of the disease burden being located in the region. The epicenter of the co-infection is in the south of the continent, with South Africa alone accounting for over 25% of all cases [129]. HIV is also associated with multidrug- resistant TB cases as well as with institutional outbreaks, especially in South Africa and Eastern Europe [130]. ART is proving to be beneficial in HIV-TB control both in low-income [131, 132] and high-income countries [133]. It is unclear whether HIV is driving a disproportionate increase in multi-drug resistant TB (MDR-TB) cases at a population level [130]. However, a systematic

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review and meta-analysis of the association of HIV and MDR-TB has demonstrated that there is an association between the two, thus, signifying the need to scale up the capacity of diagnosis of MDR-TB and ART in HIV-TB control [134]. HIV infection is the strongest risk factor for developing tuberculosis and has fuelled its resurgence in sub-Sahara Africa [135, 136]. Africa, home to 11% of the world’s population, which has the highest burden of HIV/AIDS (see Sect. 5.3), is also, carries 29% of the global burden of tuberculosis cases and 34% of related deaths. The rapid progression of tuberculosis in African countries has been estimated by the World Health Organization (WHO) as doubling between 1990 and 2005, whereby only Mali and Togo had an incidence of the disease of 300 per 100,000 in 1990, 25 countries had reached that incidence by 2005, while 8 countries had twice as high incidence [135]. The fact that meta-analytical studies suggest a positive effect of ART in reversing this trend underlines the need of public health strategies in combating tuberculosis in Africa.

5.10.2 HIV-Associated Rheumatic Diseases An infectious trigger for immune activation deriving from molecular mimicry has been postulated as one of the mechanisms for the intriguing association of HIV and rheumatic disorders. It has been suggested that during the loss of immunocompetence, autoimmune diseases that are predominantly CD8+ T-cell driven predominate. The list of reported autoimmune diseases in HIV/AIDS include systemic lupus erythematosus, anti-phospholipid syndrome, vasculitis, primary biliary cirrhosis, polymyosits, Graves’ disease, and idiopathic thrombocytopenic purpura. Paradoxically, highly active antiretroviral therapy (HAART) is contributing to a changing picture of autoimmune diseases, with the emergence of new disorders and clinical manifestations that are challenging the expertise of rheumatologists [137].

5.10.3 HIV/AIDS Associated Neurologic Disorders These disorders include hearing loss, polyneuropathy and painful neuropathy. Hearing changes can occur due to damage to the outer, middle and inner ear. An integrative review of the literature did not find any strong direct association between ART and hearing loss although there are indication of hearing loss in the populations studied, there associations and causes need to be investigated [138]. A number of reports have shown that HIV can affect both the peripheral and central vestibular system, irrespective of age and viral disease stage. Peripheral vestibular involvement may affect up to 50% of patients, and vestibular involvement may be even

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more prevalent, while opportunistic infections such as oto- and neurosyphilis and encephalitis cause secondary vestibular dysfunction resulting in vertigo, dizziness and imbalance. Patients with HIV/AIDS should be routinely be monitored for vestibular involvement, to minimize functional limitation of quality of life [139]. Peripheral neuropathy is a common and vexing symptom of people living with HIV/AIDS, and may occur in several different syndromes, including distal polyneuropathy and painful neuropathy. Its pathogenesis is diverse, and may include the direct effects of HIV, exposure to ART agents, particularly the nucleoside reverse transcriptase inhibitors, advanced immunosuppression, and comorbid TB infection and anti-TB medications. Assessment of neuropathy in people living with HIV/ AIDS must be incorporated into nursing practice for these patients [140].

5.10.4 HIVAIDS Associated Neuropsychiatric Disorders HIV-associated neurocognitive disorders (HAND) are among chronic co-morbidities of HIV/AIDS (see Table 5.4). Their causes and epidemiology remain unclear [141] but the majority of patients appear have multifactorial etiologies [142]. Among the diagnostic problems in this field appears to be a wide variation in criterion validity primarily due to non-standard definition of neurocognitive impairment [143]. Clinical and laboratory studies suggest that in some cases, HAND may the product of interaction of endogenous (critical parts of the brain) and exogenous (exposure to chemical agents either illicitly or inadvertently introduced into the body) [144]. Some of these agents have been shown in in vitro studies to potentiate HIV replication and enhance or synergize with HIV proteins, which in turn inflict pathophysiological damages to critical brain structures. Among the clinical sequels are pain syndromes of estimated prevalence of 54–83% among people living with HIV/ AIDS (PLWHA) [145], and dementia, which is said to be the most important “primary” neurologic complication of HIV infection in the United States identified dementia [146].

5.10.5 HIV/AIDS Associated Nephropathy A systematic study of kidney in deceased AIDS patients, using light and immunofluorescence microscopy revealed diffuse mesangial IgA deposits in 7.75% of 116 kidneys examined, thus, indicating that the association between IgA and HIV infection is not rare. Urinary abnormalities were mild in all cases [147]. Hepatitis C co- infection was found to be associated with a significant increase in the risk of HIV-related kidney disease [148].

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5.10.6 HIV/AIDS Associated Anemia Anemia is a commonly encountered hematological abnormality in HIV infected patients, with the prevalence in HIV/AIDS ranging between 1.3% and 95%, depending on several factors, including stage of the disease, sex, age, pregnancy status, and injection-drug use. A study in Nigerian adult HIV/AIDS patients reported anemia prevalence of 61% in HAART naïve patients, with a significant increase in males than females [149]. In general, the prevalence of anemia and its severity increases as the disease progresses. In HIV infected individuals, anemia has been shown to be a statistically significant predictor of progression to AIDS [150, 151], and is independently associated with an increased risk of death in patients with HIV [104]. The use of highly active antiretroviral therapy (HAART) has been associated with a significant increase in hemoglobin concentration and a decrease in the prevalence of anemia [152]. A study of the pathogenesis of anemia in HIV-infected children found that failure of erythropoiesis was the most important mechanism for anemia in HIV- infected children. However, a Cochrane review of six trials on the management of HIV- associated anemia with recombinant human erythropoietin found no benefit in terms of reduction of mortality or transfusion requirement, thus, leading to cautions against using this expensive treatment modality of anemia management in this scenario [153]. This caution is consistent with the challenge of the management of “anemia of chronic illness” in adults, and indicates the need to for more studies on the mechanism of the derangement of erythropoiesis in HIV-infected children.

5.10.7 HIV/AIDS Associated Gastrointestinal Complications A new disease, characterized by weight loss and diarrhea, and ravaging populations in rural Uganda, marked the advent of HIV/AIDS in the East African country in the early 1980s. It was known locally as “slim disease”, described as “strongly associated with HTLV-III infection (63 out of 71 patients)” and affecting “females nearly as frequently as males. The clinical features are similar to those of enteropathic acquired immunodeficiency syndrome as seen in neighbouring Zaire” [57]. Diarrhea is experienced by over 50% of AIDS patients during the course of their disease, and it is the cause of increased morbidity and mortality in them [154]. The standard of care is hydration and antibiotic management of the microbial gut infection. However, this approach has been compromised by the emergence of resistant strains of the microbial agents, leading to the loss of millions of AIDS patients. Intestinal channel blockers have played a significant role in procuring symptomatic relief in this form of secretory diarrhea [154]. Esophageal disease is a common complication and cause of morbidity in patients with HIV infection and may occur either as its initial manifestation or in patients with long-standing infection [155]. Infection either by candida (candida esophagi-

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tis), or viral agent (e.g. cytomegalovirus, herpes simplex) is the most etiological factor, leading to clinical presentation as dysphagia or odynophagia [155].

5.10.8 HIV/AIDS Associated Metabolic Disorders Lipodystrophy is a term used to describe fat loss, fat gain or a combination of both, which is associated with some antiretroviral agents. The side effects contributing to this syndrome are distracting from the success of ART to the extent that protease inhibitors are being regarded as having a greater life-threatening potential than AIDS itself [156]. The cosmetic impact aside, there is particular concern of possible increased risk of accelerated atherosclerosis through the biochemical pathways that lead to lipodystrophy [157]. The limited research on lipodystrophy in the low- and middle-income countries that bear 95% of HIV/AIDS burden is also a matter of concern [158]. At the beginning of the AIDS epidemic, severe malnutrition and weight loss were common. Wasting was once described as one of the three most common AIDS Defining Conditions (ADCs) [159, 160]. However, this manifestation of AIDS persists in the HAART era, thus, indicating the complexity of the etiology of weight loss and wasting syndrome of AIDS [161]. While megestrol acetate (MA) was approved in 1993 by the US Food and Drug Administration (FDA) for the treatment of anorexia, cachexia or unexplained weight loss in patients with AIDS [160], the thromboembolic frequently life-threatening complication of this agent should be a matter of concern for its use among populations with poor access to diagnostic facilities and care. Endocrine and metabolic disturbances occur in the course of HIV infection, and virtually every endocrine organ is involved through various processes, including infection (e.g. cytomegalovirus adrenalitis or other opportunistic organisms), neoplastic infiltration, or drug adverse effects [162]. The failure of these organs leads diverse clinical syndromes, such as hypogonadism in both sexes, amenorrhea, and hypothyroidism.

5.10.9 HIV/AIDS Associated Cardiovascular Disorders In the era of HAART, coronary artery disease (CAD) has emerged one of the most critical complications of HIV/AIDS, and a major cause of morbidity and mortality. While the side effects of ART include several metabolic disorders that predispose to CAD (see Sect. 5.10.8), epidemiological studies are in support of the fact that HIV infection itself contributes to CAD development, apparently through the activities of viral proteins of HIV [163]. A comprehensive review of the literature of HIV-associated coronary artery disease showed that 91% of the identified 129 cases were male aged between 23 and 77 years, who developed the disease in 72 (±60 SD) months after diagnosis. Acute

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myocardial infarct was the initial presentation associated with 3-vessel disease in 47%, 2-vessel disease in 18% and 1-vessel disease in 35% of the cases. The histologic characteristics unique to HIV-associated CAD were diffuse circumferential involvement of the vessel with an unusual proliferation of smooth muscle cells, mixed with abundant fibers, resulting in endoluminal protrusions [164].

5.10.10 HIV-AIDS Associated Pulmonary Hypertension The relationship between grade of pulmonary hypertension and factors associated with HIV infection is poorly documented [165]. Patients with AIDS, compared to non-AIDS patients, who present with primary pulmonary hypertension, have a higher degree of the disorder. This seems to be related to a cytokine-related stimulation and proliferation of endothelium. Thus, while high levels of cytokines present in AIDS patients can favor pulmonary hypertension, there may be a role for host factors in form of differences in the production of cytokines [165].

5.11 HIV/AIDS Associated AIDS Cancers HIV/AIDS associated cancers include AIDS-associated cancers, which were among the AIDS defining conditions as outlined at the beginning of the pandemic. They are related immunodeficiency and similar to those found in other immunodeficiency states, such as post-transplant clinical status. These include Kaposi’s sarcoma (KS) and non-Hodgkin lymphoma (NHL), 2419 and 1030 cases respectively of which were reported to the Centers for Disease Control (CDC) in 1996 [166], thus, making them the prototypical AIDS-defining malignant diseases. However, many other neoplasms have been reported among people with AIDS, thus, prompting the need for establishment of causal relationship between such cancers and HIV/AIDS. A study of the AIDS-Cancer Match Registry, in which the cancer experience of people with AIDS was compared with those of the general population by matching by matching population-based cancer and AIDS registries in the USA and Puerto Rico [167]. This revealed 7028 cases of KS, 1793 of NHL, and 712 other cases of histologically defined cancer. This translated to 310-fold increase in the incidence of KS, 113-fold for NHL, and 1.9-fold among people with AIDS. Of 38 malignant disorders other than KS and NHL, only angiosarcoma (36.7-fold), Hodgkin disease (7.6-fold), multiple myeloma (4.5-fold), brain cancer (3.5-fold) and seminoma (2.9-fold) were raised and increasing significantly (p 10% Numerous chromosomal abnormalities, including breakages leading to DNA repair dysfunction; 11q22–23 [211] ++ Chromosomal rearrangements e.g. t(8:14) translocation [213–215]

Epithelial and mesenchymal neoplasias, including cholangiocarcinoma Adenocarcinoma of the stomach and colon; cervix, ovaries and vagina; lymphomas Hodgin and non- Hodgkin lymphomas (NHL)

Hodgkin and NHL, non-lymphocytic leukemias [178, 210]; malignancies of g.i. tract, pancreas, salivary glands, and mouth [180, 212] Clinically aggressive NHL occurring in unusual locations

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Chapter 6

Cancer and Infection

Abstract Chronic infections (CI) contribute disproportionately to cancer causation in resource poor (RP) compared to resource rich (RR) parts of the world, with 26% of cancer cases in the former and 8% in the latter being infection-related. IARC declared only 11 of 3.7 × 1030 microbes on earth as well-established human carcinogens (WEHC), the contributions of which to cancer burden are designated by their “population attributable fractions (PAF).” They include viruses, including EBV, linked with Burkitt lymphoma in Africa, and nasopharyngeal carcinoma in South- East Asia (SEA), hepatitis B and C causing hepatocellular carcinoma, HPV linked to cervical cancer and penile cancer, KSHS linked to endemic and epidemic Kaposi’s sarcoma (KS), HTLV-1 linked to the adult T cell lymphoma/leukemia, and HIV, which promotes carcinogenesis through immune deficiency (ID). Others WEHCs are bacterial, including helicobacter pylori, linked to stomach cancer, and macroparasites including schistosoma hematobium, linked to bladder cancer in Africa, opistorchis viverrini and clonorchis sinensis, which cause biliary cancers in SEA. Helminthic infections, like hookworm, facilitate carcinogenesis through ID, e.g. KS. Several other microbes absent in the IARC list include the oncomicrobes, which induce micrometabolites, and are linked to carcinogenesis and cancer drug toxicity or activation. Other CIs transform benign disorders like obesity or genetic disorders like Crohn’s disease to multiple forms of cancers and colo-rectal cancer respectively. Human development and intergeneration associated variations in microbiomes probably contribute to aspects of the global cancer burden disparities, especially on childhood leukemia/lymphoma, resulting from maternal microbiome impact on pre- and postnatal immune system. Keywords Population attributable fraction · PAF · South East Asia · Helicobacter pylori · IARC · Macroparasites · Schistosoma hematobium · Opistorchis viverrini · Clonorchis sinensis · Microbiota · Microbiomes

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6.1 Cancer Associated Infectious Agents In recent decades, the association of infectious agents and cancers has become better elucidated than in the past. In this connection, the association between Burkitt lymphoma and the Epstein Barr virus can be considered as a classic [1, 2], capturing the interest of cancer scientists of the 1960s in the role of a ubiquitous infectious agent and cancer. As of 1981, the only other infectious agent widely associated with cancer was the hepatitis B virus with its association with hepatocellular carcinoma [3]. Some 30 years later, eleven infectious agents are well established as carcinogenic [4]. Cancer sites and associated infectious agents include: stomach (helicobacter pylori); liver (HBV, HCV, opisthorchis viverrini, clonorchis sinensis); uterine cervix (HPV, with or without HIV); anogenital, including penis, vulva, vagina and anus (HPV, with or without HIV); nasopharynx [5]; oropharynx (HPV, with or without tobacco use/alcohol consumption); non-Hodgkin lymphoma (helicobacter pylori, EBV/with or without HIV, HCV, HTLV-1); Kaposi’s sarcoma (Kaposi’s sarcoma herpesvirus, with or without HIV); Hodgkin lymphoma (EBV with or without HIV) and bladder cancer (schistosoma haematobium) [4, 6]. The concept of “population attributable fraction” (PAF) has been developed by de Martel and her colleagues to reflect the global impact of various infectious agents on global cancer burden in eight geographical regions, using statistics on estimated cancer incidence in 2008 [6]. Using this statistical concept, about two million (16%) of the total of 12.7 million new cancers in 2008 were attributable to infections. This fraction varies ten-fold by regions; it was lowest in the developed countries, such as North America, Australia and New Zealand, which have 13 types), tobacco (>20 types) as well as industrial pollutants, such as asbestos (mesothelioma). Poverty associated practices in food preservation are associated with contamination with carcinogenic mycotoxins, e.g. aflatoxins (hepatocellular carcinoma – HCC) and carcinogenic plant-based agents in herbal preparations. As countries of less developed parts of the world transition economically towards the developed world, so also do their lifestyles, with concomitant acquisition of cancer risk factors of industrialization and a shift from predominating infection-associated cancers, including virus-associated cancers, e.g. human papilloma virus Clifford GM, Goncalves MAG, Franceschi S. Aids. 20(18):2337–2344, 2006 (cancer of the uterine cervix, anus, penis, conjunctiva), hepatitis B and C viruses (hepatocellular carcinoma), human herpes virus type 8 (HHV-8) (Kaposi’s sarcoma), and Epstein Barr virus (Burkitt and Hodgkin lymphomas), bacterial infection of Helicobacter pylori (gastric cancer) and parasitic infections, e.g. liver flukes (cholangiocarcinoma) and schistosoma hematobium (bladder cancer), to the cancers of industrialization. The immune deficiency of HIV/AIDS infection underlies the associated defining cancers of Kaposi’s sarcoma and aggressive non- Hodgkin lymphoma, as well as a residual cancer susceptibility and mortality even after the corrective effect of antiretroviral therapy. Genetic mutations are related to the “embryonal cancers” of childhood, while nutritional and/or hygienic factors probably play a role in the marked global differences in childhood leukemia and lymphoma epidemiology. Keywords Environment · Hereditary · Stochastic · Carcinogenesis · Lifestyle · Affluence · Poverty · Alcohol · Tobacco · Genetic · Epigenetic

© Springer Nature Switzerland AG 2019 C. K. O. Williams, Cancer and AIDS, https://doi.org/10.1007/978-3-319-99235-8_5

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7.1 Cancer Risk Among Tissues It is common knowledge that cancer occurs at markedly different frequencies in tissues, and that some tissue types give rise to human cancers million times more often than others. In the United States of America, the lifetime risk of lung cancer is 6.9% compared to that of the laryngeal cartilage, which is 0.000072% and childhood bone cancer [1–4]. Some of these differences are explainable by exposure to well recognized risk factors, like cigarette smoking, others are less so. For instance, cancers of the small intestine are three times less common than brain tumors [3], even though the former is exposed to much higher levels of environmental mutagens than the brain tissue, which is protected by the blood-brain-barrier [2]. Another well- studied risk factor is the hereditary factor, which is estimated to contribute about 5–10% in terms of heritable component of cancer risk [5, 6]. However, the role of the heritable risk factor is not clearly understood. Thus, the APC gene, which is responsible for the predisposition to colorectal cancer and small intestinal cancers in the familial adenomatous polyposis [7] syndrome, is linked much more differentially with cancer of the large bowel than those of the small intestine [2]. This may be due to the fact that the concentrations of environmental mutagens in the gastrointestinal content is much higher in the colon than in the small intestine [8], thus raising the possibility of an interaction between environmental heritable factors. The inadequacies of environmental and hereditary factors in explaining carcinogenesis has led to the consideration of a third factor, chance, otherwise known as “stochastic factor” [2].

7.1.1 C ancer Risk and the Concept of the “External Risk Score” In a study of 31 tissue types in which stem cells had been quantitatively assessed, there was a highly positive correlation between lifetime risk of cancer and the number of stem cell divisions, to the extent that had never been demonstrated for other environmental or inherited factors, thus confirming that the stochastic effects of DNA replication is the major contributor to cancer in humans [2]. The concept of the “external risk score” (ERS) has been developed to distinguish the effects of the stochastic replicative component from other causative factors of cancer, such as environmental and inherited mutations. ERS is defined as the product of the lifetime risk and the total number of stem cell divisions. Using the parameter of ERS, it was possible to segregate the 31 tissue types to two clusters: 9 tumor types with high ERS, and 22 tumor types with low ERS (Fig. 7.1) [2]. Tumors with relatively high ERS were those with known links to environmental or hereditary risk factors (Fig. 7.1 – right cluster). These were referred to as “D-tumors” (D for deterministic, because deterministic factors such as environmental mutagens or hereditary predispositions strongly affect their risk). Tumors of low ERS were referred to

7.1 Cancer Risk Among Tissues

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Fig. 7.1 “Stochastic (replicative) factors versus environmental and inherited factors:” “R-tumor versus D-tumor classification. The adjusted ERS (aERS) is indicated next to the name of each cancer type. R-tumors (cluster to the left) have negative aERS and appear to be mainly due to stochastic effects associated with DNA replication of the tissues’ stem cells, whereas D-tumors (cluster to the right) have positive aERS. Importantly, although the aERS was calculated without any knowledge of the influence of environmental or inherited factors, tumors with high aERS proved to be precisely those known to be associated with these factors”. (Reproduced and cited with permission from: Tomasetti and Vogelstein [2])

as R-tumors (R for replicative, because stochastic factors, presumably related to errors during DNA replication most strongly appear to affect their risk) (Fig. 7.1 – left cluster) [2]. Categorization of cancers according to their estimated ERS indicate that the three cancer risk factors, namely environment, inheritance and the replicative component, contribute differently to the two proposed tumor clusters: the classical determinants of inheritance and environment contribute much less to the R-tumors. On the other hand, however, replicative effects are essential, while environmental and hereditary factors simply add to the events leading to the D-tumors.

7.1.2 Cancer Risk Factors and Cancer Prevention Cancer prevention strategies can derive from assessment of the maximum fraction of tumors in a community that are preventable, especially non-hereditary D-tumors, which are highly prevalent in developing countries (see Chap. 6 – Sect. 6.1, Fig. 6.1). Such tumors should be amenable to control by primary prevention (vaccine against infectious agents, such as HBV, HCV, HPV, and change in altered lifestyle,

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such as smoking cessation). For R-tumors, primary prevention measures are not likely to be very effective, and secondary prevention, obtainable through early detection, should be the major focus [2].

7.1.3 Interaction of Cancer Risk Factors The concept that stochastic events, i.e. chance or luck, appears to be the major contributor to cancer in humans [2], has been difficult to accept not only in the lay media [8], but also in the academia [9–13]. In fact, the influences of the main components of cancer risk, namely heredity (HER), environment [6] and chance (C) overlap and interact [8]. In their contribution to the discussion, L. Luzzatto and P.P. Pandolfi have proposed a model of tumor formation, whereby each successive mutation confers onto a mutant cell a growth advantage over normal cells in a process that after the accumulation of a number n of causal mutations recapitulates the Darwinian concept through its aberrant grow in a given microenvironment [8]. The value of n varies in different tumors, but it probably small – six to eight in most cases [8, 14]. Somatic mutations are by their nature stochastic events [15], and therefore fall under C, chance. The number of somatic mutations that spontaneously accumulate in any set of cells is proportional to the number of cell divisions D. The relations between M and D is expressed by the equation: M = μ × D, where μ is the mutation rate [8]. The variability of D as described earlier [2] is the main determinant of the highly variable frequency of cancer in different tissues. Mutations occur by chance, and what genes they hit is also largely due to chance. In summary, the interplay between all components of cancer risk, environmental [6], heritable, (HER) and the stochastic (chance) (C) makes it difficult to separate the chance aspect of carcinogenesis from the heritable and environmental influences. Cancer control calls for intervention against all known risk factors, with the realization of the human limitations in the face of the unpredictable, namely chance, which could manifest as “bad luck” or, indeed, “good luck”.

7.2 Cancer Risk and Chemical Agents Exposures to a variety of chemical, physical, and metabolic agents, usually in the course of lifestyle and cultural practices play a significant role in global cancer epidemiology. Such agents could include alcohol (multiple cancers, including those of the liver, pancreas, and head and neck), asbestos (mesothelioma), obesity (multiple cancers), tobacco and other noxious chemicals (lung, and other cancers), gastric reflux, Barrett esophagus (esophageal cancer) [16], aflatoxins and plant-based chemicals (see Table 7.1). Lifestyle associated risk factors vary from society to society, depending on the state of development. In developed countries, such as the

Tobacco

Obesity

Asbestos

Agent Alcohol

Carcinogenic mechanism Genotoxic effect of aldehyde; increased estrogen concentration; solvent for tobacco carcinogens; changes in folate metabolism [17, 18] Oxidative stress and cytokine generation leading to chronic inflammation [21, 22] Depends on cancer site: chronic acid reflux and epithelial damaged; increased levels of circulating estradiol from precursor hormones in the adipose tissuee,; anovulation and reduced progesterone productionf; insulin resistanceg; [25–27]; chronic inflammatory state [28] Smoking Tobacco contains 60 carcinogens, while the smoke contains over 7000 (smokeless: over 3000) carcinogens [30], including polycyclic aromatic hydrocarbons, N-nitrosamines, volatile aldehydes; metabolic activation to DNA adducts leading to Smokeless miscoding and mutations in critical growth control genes [31] (Fig. 7.4); inflammation N/Ab [23], high-income countriesc [24]

Global impact by regions Mortality/DALY Highest Eastern Europe: 8.7i/242.5i [19]

N/Ab [23], low-income countriesc [24]

Lowest North Africa/Middle East: 0.6i/18.5i [19]

Lip, oral cavity, paranasal sinuses, esophagus, stomach, pancreas, larynx, trachea, bronchus, lungs, cervix, bladder, kidney and urinary tract, liver, colon, rectum, ovary (mucinous) acute myeloid leukemia [17, 32] Oral cavityn, esophagus, bladder and pancreas [33]

(continued)

Limited largely to South East Asia, but also in Indian and Papua New Guinea and Oceania and parts of Africa (Fig. 7.29)

Middle-income countries: Low-income countries: 29%k/m; 18.9%k/4.5%l m l High-income countries: /11.4%

High-income countries: 8.4h/6.5h Low-and Middle Esophagus (adenocarcinoma), colon, pancreas, kidney, breast [29] Income countries: (postmenopausal), endometrium 4.2h/2.0h [29]

Cancer type Oral cavity, pharynx, larynx, esophagus, colorectum, liver and hepatobiliary tract; female breast, stomacha, pancreasa, lunga [19, 20], melanoma [20] Larynx, lungs, mesothelioma, ovary

Table 7.1 Chemical, physical and metabolic agents of carcinogenesis

7.2 Cancer Risk and Chemical Agents 119

Cancer type Liver (hepatocellular carcinoma); skin, kidney, lung; urinary tract (Balkan endemic nephropathy) [35]

b

a

Global impact by regions Mortality/DALY Highest Lowest Aflatoxins are primarily, a cereal crop storage problem in the developing countries [36], mainly sub-Sahara Africa; food contaminants are a worldwide problem with no valid global epidemiological estimates

Aristolochia species have been linked to endemic Urothelium, bladder, kidney, Metabolism to DNA –reactive gastrointestinal tract, liver, lung, diseases of the kidney in the general population and in metabolites, e.g. nitrenium ion, research [34] leukemia [34] sulfo-oxy metabolites, dehydronecine, → DNA adducts → mutations [34] → molecular signature A:T → T:A inversions [37]; mutations in oncogenes etc. TP53, K-ras [38]

Carcinogenic mechanism DNA-reactive epoxide; interaction with DNA → TP53 mutations [34]; → disruption of lipid metabolism; → disruption of microtubule formation → mitosis inhibition

Insufficient causal evidence [19] Estimation not available due to controversy [23] c Related to volume of asbestos use according to the environmental Kuznets curve [24] d For adenocarcinoma of the esophagus [39] e For breast and endometrial cancer in postmenopausal women [39] f For endometrial cancer of premenopausal women [39] g For colon cancer in men, kidney and other cancers h Percentage of deaths and percentages of DALYs i Deaths and DALY’s per 100,000 people j Nicotine induces craving for tobacco, but it is not by itself a carcinogen [31]

Agent AflatoxinsmG-1K and food contaminants (including ochratoxin AmG-2BR ; fumonisin BmG-2B, fusarium miniliformemG-2B, sterigmatocystinmG-2B Plant-based chemicals (aristolochic acidmG-1, caffeic acidmG-2B, dihydrosafrolemG-2B and safrolemG-2B, riddelliinemG2-B

Table 7.1 (continued)

120 7 Risk Factors for Cancer

Represents percentage of total deaths from tobacco associated causes of death (including ischemic heart disease, chronic obstructive lung disease (COPD) and cancers of the trachea, bronchus, and lung) among ten leading causes of death projected for 2030 by baseline scenario; cancers of the trachea, bronchus and lung did not make the ten leading causes of death in low-income countries) [40] l Represents percentage of total disease-adjusted lifeyears lost (DALYs) from tobacco associated diseases (including ischemic heart disease, COPD and cancers of the trachea, bronchus, and lung) among ten leading causes of DALYs projected for 2030 by baseline scenario; cancers of the trachea, bronchus and lung did not make the ten leading causes of DALYs in middle and low-income countries, while COPD also did not make the ten leading causes of DALYs in low-income countries [40] m While the middle-income countries are projected to have the highest percentage of total deaths from tobacco associated causes of death among ten leading causes of death projected for 2030 by baseline scenario, the high-income countries are projected to have the highest DALYs from these disorders by 2030 [40] n IARC evaluation of carcinogenicity – Group 1 carcinogenic to human (G-1), Group 2B possibly carcinogenic to human (G-2B); US National Toxicology Program class – K known to be a human carcinogen, R reasonably anticipated to be a human carcinogen [34] o Gingiva-buccal cancer, due to tobacco-chewing is responsible for 30% of all cancer cases in India [41]

k

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United State of America, lifestyle associated risk factors include, in a declining order of importance, tobacco use, obesity/being overweight, infectious agents, unknown factors, physical inactivity, diet, occupational exposure, alcohol, reproductive factors, ultraviolet light, environmental pollutants and prescription drugs [42]. As countries of less developed parts of the world undergo economic evolutions towards those of the developed world, so also do their lifestyles undergo a transition, with concomitant acquisition of the associated cancer risk factors [29]. As a country develops, the types of diseases that affect a population shift from primarily infections, such as diarrhea and pneumonia, to primarily non-communicable, such as cardiovascular disease and cancer, a process that is referred to as “risk transition” [43]. This is because of improvement in medical care, ageing of the population and public health interventions, including vaccinations, provision of clean water, and sanitation [29].

7.2.1 Alcohol Consumption and Cancer Although an association of alcohol misuse and cancer of the aero-digestive system had been observed early in the twentieth century [44], alcohol beverages were identified as “carcinogenic to humans” much later by the International Agency for Research on Cancer (IARC) in 1988 [45], and again in 2007 [46] and in 2010 [47]. Most cultures of the world use alcoholic beverages, mostly brewed locally, using various traditional technologies. These include akpeteshi in parts of Ghana [48], palm wine in neighboring Nigeria [49–52], sochu and sake from Japan [53, 54]. Palm wine is described as “essentially a dense suspension of micro-organisms (yeast and bacteria) in fermenting sap…..obtained, usually, by tapping the inflorescence of two main palm species – Elaeis guinnensis and Raphia hookeri [49, 55, 56]” [57]. Only a small number of these traditional brews have made it up to level of large-scale commercialization, such as beer from barley, wine from grapes, and certain distilled beverages [19]. Studies of the Nigerian palm-wine revealed its content of dimethylnitrosamine and diethylnitrosamine, while the an average drinker was estimated to be consuming 48–180 μg of nitrosamines daily, thus, leading to speculations that this might be causing some cancers among the palm wine drinking population [57], such as had been linked with exposure to N-nitrosamines, including cancers of the esophagus, brain, pancreas, lung, stomach, tongue, liver, bladder, skin, kidney and bone [58]. Meta-analysis of numerous case-control and cohort studies subsequently established a dose-response association between alcohol consumption and cancers of the mouth, pharynx, esophagus, colo-rectum, liver, larynx, pancreas, female breast and prostate, while a negative association or no association have been observed for each of Hodgkin lymphoma [17, 59], non Hodgkin lymphoma [17, 59, 60], and renal cancer [17, 61]. Further epidemiological assessment has linked alcohol causally to cancers of the mouth, pharynx, esophagus, colo-rectum, liver, larynx and female

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breast (Table 7.1), while indicating the causal link to the cancers of the stomach, lung and prostate as insufficient [19]. Recent evidence has provided additional evidence of the link between alcohol and cancer. In August 2015, data were published from two large prospective ongoing cohort studies – the Nurses’ Health Study and the Health Professionals Follow-up Study [62] suggests that melanoma, as well as cancers of the stomach, lung, and prostate, may be associated with alcohol consumption, although only with high levels of consumption and to a moderate excess risk [20, 63]. During long-term followup (up to 30 years) of 88,084 women and 47,881 men, 19,269 and 7571 incident cancers were diagnosed, respectively (excluding nonadvanced prostate cancers). Alcohol consumption was significantly associated with increased risk for cancer, in both women (P trend

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