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Cancer risk among women living with HIV: Implications for care in the modern cART era by Kate A. Salters Master of Public Health, Simon Fraser University, 2012 Bachelor of Arts, Brock University, 2008 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Doctor of Philosophy Program Faculty of Health Sciences © Kate A. Salters SIMON FRASER UNIVERSITY Summer 2017 Copyright in this work rests with the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Approval Name: Kate A. Salters Degree: Doctor of Philosophy Title: Cancer risk among women living with HIV: Implications for care in the modern cART era Examining Committee: Chair: Charlotte Waddell Professor Robert S. Hogg Senior Supervisor Professor Angela Kaida Supervisor Associate Professor Neora Pick Supervisor Associate Professor Department of Medicine University of British Columbia Mark Brockman Internal Examiner Associate Professor Helen Trottier External Examiner Associate Professor Preventive and Social Medicine University of Montreal Date Defended/Approved: June 28 2017 ii Ethics Statement iii Abstract Following the advent of modern combination antiretroviral therapy (cART) in 1996, a temporal decline was widely observed in AIDS-related morbidity and mortality. In the province of British Columbia (BC), universal provision of cART free-of-charge for people living with HIV (PLHW) has contributed in part to a significant demographic shift, with individuals over 50 years of age comprising over half of all PLHW. In this context there is a need to understand how comorbidities, such as cancer, impact this aging cohort. Within this line of inquiry, it is imperative to look at cancer risk specifically amongst women living with HIV (WLWH). The majority of studies looking at cancer as a co-morbid condition among PLWH fail to conduct sex-stratified analyses, which may obscure the burden of cancer risk specific to WLWH. Using a Life Course Epidemiology framework, the objectives of this PhD dissertation were to: 1) measure cancer incidence among WLWH in BC compared to a general population sample of women; 2) identify the role of early cART initiation in mitigating excess risk of cancer observed among WLWH; and 3) estimate the burden of cancer-related mortality among PLWH. This research utilized administrative health data from Population Data BC (which included data from the BC Cancer Agency and Vital Statistics) and clinical HIV data from the BC Centre for Excellence in HIV/AIDS. Findings suggest WLWH experience an increased risk of certain cancers, notably for certain viral-related malignancies, in comparison to HIV- negative women in the modern cART era. A protective effect of early initiation of cART therapy was found for some types of cancer, suggesting oncological health benefits might be associated with timely initiation of cART after HIV diagnosis for WLWH. Finally, sex stratified age-adjusted cancer-related mortality rates promisingly suggest there may not be significantly different cancer-related mortality outcomes between PLWH and the general population. This dissertation demonstrates that cancer-related morbidity is a healthcare priority for the growing aging demographic of WLWH and subsequently highlights the importance of appropriate and effective routine cancer screening measures as well as comprehensive HIV care inclusive of timely diagnosis and cART initiation. Keywords: Women living with HIV; combination antiretroviral therapy; HIV; cancer; co-morbidity; mortality iv Dedication “[I think] being smart is cooler than anything in the world” –Michelle Obama For women and those fighting for women. Those who came before me are the reason I have the opportunity to write this dissertation. I hope to always act in service of this. v Acknowledgements I would like to extend my thanks to my PhD committee. Dr. Bob Hogg has been a constant source of support and encouragement. He has instilled in me the desire to “do good research and work with good people” and has truly led by example. Dr. Angela Kaida has been a mentor in the truest sense of the word and has helped guide and shape me as a researcher far beyond what lies within these pages. Dr. Neora Pick has provided enthusiastic support and has granted me the opportunity to learn from her passionate clinical experience. Drs. Brockman and Trottier were extremely thoughtful and fair examiners who significantly helped to refine this work. I also thank Dr. Waddell for Chairing my defence and providing structure and guidance in that process. The COAST team, under the guidance of Dr. Hogg, has provided me with a wealth of data as well as ongoing support. I could not have finished this dissertation without the help of colleagues and friends at the BC Centre for Excellence in HIV/AIDS. Special thanks to Dr. Jeannie Shoveller, Paul Sereda, Michelle Lu, Monica Ye, Alexandra Collins, Allison Carter, Oghenowede Eyawo, Shahab Jabbari, Dr. Aranka Anema, and Wendy Zhang. I would like to state that I am forever indebted to Angela Cescon, Dr. Surita Parashar and Dr. Alexis Palmer for their guidance and friendship. I am the Ringo Starr in this rock star band of women. I am so appreciative that they have let me hang around them for so many years and learn from them. I would like to acknowledge my doctoral funding support from the Canadian Institutes of Health Research (CIHR) and the Canadian Association for HIV Research (CAHR) as well as support from the BC Centre for Excellence in HIV/AIDS and the Soroptimist Foundation of Canada. I would also like to thank Population Data BC including Monique Gagne, who greatly supported this student work as well as the COAST study overall. Finally, graduate student awards from Simon Fraser University as well as the incredible support from all those in the Faculty of Health Sciences including Margaret Van Soest, Jen Van Rassel and many others. I want to thank my dear friends – those in Vancouver and those far away. Your faith in me means everything. Special thanks to Greg, Alison, Meghan, Jill, Kim, Tristan, and Jillian for being there for me throughout this entire process and keeping me sane. I vi also have to give a shout-out to the CFBC family who have put up with me complaining about graduate student life every morning for the past 4 years and cheered for me regardless. Matthew, thank you for caring for me, encouraging me to be proud of myself and for reminding me, when need be, that I “haven’t cried that much” during this process. Most of all, thanks for making me happy. Finally, I want to thank my family for instilling in me the drive and dedication needed to complete this PhD. Anything good in me comes from you. Thanks for your unwavering support Mom, Dad, Leigh and Oma. I sincerely mean it when I say I could not have done it without you. vii Table of Contents Approval ............................................................................................................................. ii Ethics Statement ............................................................................................................... iii Abstract ............................................................................................................................. iv Dedication ......................................................................................................................... v Acknowledgements ........................................................................................................... vi Table of Contents ............................................................................................................ viii List of Tables ..................................................................................................................... xi List of Figures .................................................................................................................. xii List of Acronyms ............................................................................................................. xiii Preface ............................................................................................................................ xiv Chapter 1. Introduction ............................................................................................... 1 1.1. Abstract ................................................................................................................... 1 1.2. Background ............................................................................................................. 1 1.2.1. Cancer comorbidity in the modern cART era ................................................... 1 1.2.2. Relationship between HIV and cancer ............................................................. 2 1.2.3. Cancer-related mortality ................................................................................... 5 1.2.4. Cancer among Women living with HIV ............................................................. 6 1.3. Guiding framework .................................................................................................. 8 1.3.1. Life Course Epidemiology ................................................................................. 8 1.4. Gaps in the Literature ............................................................................................. 9 1.5. Relevance ............................................................................................................. 10 1.6. Study Setting and Design ..................................................................................... 11 1.6.1. BC Cancer Agency (objective 1) .................................................................... 11 1.6.2. BC Centre for Excellence in HIV/AIDS Drug Treatment Program (objectives 1, 2 and 3) ....................................................................................................................... 12 1.6.3. COAST study (objectives 2 and 3) ................................................................. 12 1.7. Ethical Approval .................................................................................................... 14 1.7.1. Potential Risks and Benefits ........................................................................... 15 1.8. Study Objectives, Hypotheses, and Summaries ................................................... 15 1.9. Summary ............................................................................................................... 17 Chapter 2. All-type, AIDS-defining and non-AIDS-defining malignancy risk among women living with HIV: A scoping review ........................................... 18 2.1. Abstract ................................................................................................................. 18 2.2. Background ........................................................................................................... 19 2.3. Methods ................................................................................................................ 21 2.3.1. Definition of cancer ......................................................................................... 21 2.3.2. Search terms .................................................................................................. 22 2.3.3. Inclusion and exclusion criteria ....................................................................... 22 2.4. Results .................................................................................................................. 23 viii 2.4.1. Literature review results ................................................................................. 23 2.4.2. All-type cancer incidence among WLWH ....................................................... 24 2.4.3. AIDS-defining malignancies among WLWH ................................................... 25 2.4.4. Non-AIDS-defining malignancies among WLWH ........................................... 26 Lung cancer ............................................................................................................. 28 Breast Cancer .......................................................................................................... 28 Virus-related non-AIDS-defining malignancies among WLWH ............................... 29 HPV-related cervical cancer .................................................................................... 30 HPV-related anal cancer ......................................................................................... 30 EBV-related Hodgkin’s lymphoma ........................................................................... 31 Hepatitis-related liver cancer ................................................................................... 31 H pylori-related stomach cancer .............................................................................. 31 2.5. Discussion ............................................................................................................. 32 2.6. Summary ............................................................................................................... 33 Chapter 3. Cancer incidence among women living with HIV in British Columbia, Canada: A heightened risk of virus-related malignancies .............................. 35 3.1. Abstract ................................................................................................................. 35 3.2. Background ........................................................................................................... 36 3.3. Methods ................................................................................................................ 37 3.3.1. Study Population ............................................................................................ 37 3.3.2. Inclusion and Exclusion Criteria ..................................................................... 38 3.3.3. Outcome Variable ........................................................................................... 38 3.3.4. Explanatory Variables ..................................................................................... 39 3.3.5. General Population Comparison .................................................................... 39 3.3.6. Statistical Analyses ......................................................................................... 39 3.4. Results .................................................................................................................. 40 3.5. Discussion ............................................................................................................. 44 3.6. Summary ............................................................................................................... 47 Chapter 4. Timing of cART initiation influences cancer risk among women living with HIV ................................................................................................................ 48 4.1. Abstract ................................................................................................................. 48 4.2. Background ........................................................................................................... 49 4.3. Methods ................................................................................................................ 51 4.3.1. Study population ............................................................................................. 51 4.3.2. Inclusion and exclusion criteria ....................................................................... 52 4.3.3. Outcome variable ........................................................................................... 53 4.3.4. Primary explanatory variable .......................................................................... 53 4.3.5. Covariates ...................................................................................................... 53 4.3.6. Statistical methods ......................................................................................... 54 4.4. Results .................................................................................................................. 54 4.4.1. Sample characteristics ................................................................................... 54 4.4.2. Bivariate comparison of WLWH with and without cancer diagnosis ............... 55 4.4.3. Immune suppression at cART initiation among WLWH ................................. 57 ix 4.4.4. Cancer incidence by CD4 cell count at cART initiation .................................. 58 4.4.5. Predictors of cancer risk among women living with HIV ................................. 60 4.5. Discussion ............................................................................................................. 61 4.6. Summary ............................................................................................................... 64 Chapter 5. Cancer-related mortality among women and men living with HIV in the modern cART era ................................................................................................ 65 5.1. Abstract ................................................................................................................. 65 5.2. Introduction ........................................................................................................... 66 5.3. Methods ................................................................................................................ 69 5.3.1. Study population ............................................................................................. 69 5.3.2. Inclusion criteria .............................................................................................. 70 5.3.3. Outcome variable ........................................................................................... 70 5.3.4. Covariates ...................................................................................................... 71 5.3.5. Statistical methods ......................................................................................... 71 5.4. Results .................................................................................................................. 72 5.4.1. Sample characteristics ................................................................................... 72 5.4.2. Cancer mortality among PLWH and the general population with cancer ....... 75 5.4.3. Cancer mortality rates .................................................................................... 76 5.4.4. Temporal trends in cancer mortality among PLWH ........................................ 78 5.4.5. Predictors of cancer-related mortality ............................................................. 79 5.5. Discussion ............................................................................................................. 80 5.6. Summary ............................................................................................................... 83 Chapter 6. Summary and Recommendations ......................................................... 84 6.1. Abstract ................................................................................................................. 84 6.2. Summary of findings ............................................................................................. 84 6.3. Significance and contribution ................................................................................ 87 6.4. Consideration of limitations ................................................................................... 88 6.5. Implications for clinical care .................................................................................. 90 6.6. Recommendations ................................................................................................ 92 6.7. Future research directions .................................................................................... 94 6.8. Conclusions .......................................................................................................... 96 References ..................................................................................................................... 98 x

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