Tuberculosis and Diabetes: another perfect storm? By César Augusto Ugarte Gil, MD MSc A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland December 2016 © 2016 César Augusto Ugarte Gil All Rights Reserved 1. Abstract Objective Tuberculosis is one of the most prevalent diseases worldwide, and is the most frequent infectious cause of death. Diabetes is also one of the most common non-communicable diseases worldwide, with substantial increases in low-and-middle income countries in recent years. Due to the synergy between these two diseases, low-and-middle income countries are facing difficulties to control both diseases, largely because there is no adequate information on tuberculosis-diabetes comorbidity. This study sought to improve the understanding of the co-occurrence of tuberculosis and diabetes in Peru, with the overarching aim to provide critical evidence to inform Peruvian disease control and health prevention programs. Methods First, we conducted a systematic review and meta-analysis in double high burden tuberculosis and diabetes countries was done to evaluate the role of Diabetes on Tuberculosis treatment outcomes. Second, to evaluate the epidemiology of diabetes in Peruvian tuberculosis patients, we conducted a cross-sectional study of 484 tuberculosis patients in Lima, evaluating diabetes prevalence and risk factors for the co-occurrence of tuberculosis and diabetes. Finally, mortality and factors associated with diabetes among tuberculosis multi-drug resistant (MDR-TB) patients in Lima was done using the information on the 1999 MDR-TB patients at the National Tuberculosis Program in Peru. Results ii In the systematic review, diabetes was associated with an increased risk for poor treatment outcomes among tuberculosis patients. Among Peruvian tuberculosis patients, diabetes was associated with older age and higher body mass index (BMI). In the cohort study among MDR-TB patients enrolled in Lima between 2010 and 2013, higher mortality was found among patients with diabetes, and MDR-TB patients with diabetes were associated with older age and higher BMI. Conclusions Tuberculosis-Diabetes comorbidity is more common in low-and-middle income countries like Peru than HIV. The presence of diabetes is associated with poor tuberculosis treatment outcomes and may put in jeopardy the advances in tuberculosis control in high burden countries. Considering the increasing incidence of diabetes in low-and-middle income countries, an adequate programmatic management involving both health programs (tuberculosis and diabetes) is required to reduce the burden of this comorbidity. Challenges at the health system level involving an adequate screening, including glucose test at Tuberculosis diagnosis and during the treatment may also be needed. iii 2. Committee of Thesis Readers Thesis Readers: Elizabeth Selvin, PhD; Committee Chair Professor, Department of Epidemiology Jonathan E. Golub, PhD; Advisor Associate Professor, Department of International Health Lawrence H. Moulton, PhD Professor, Department of International Health Amita Gupta, MD Associate Professor, School of Medicine Alternates: Andrea Ruff, MD Associate Professor, Department of International Health Kelly E. Dooley, MD PhD Associate Professor, School of Medicine Tianjing Li, MD PhD Assistant Professor, Department of Epidemiology iv 3. Acknowledgements These almost 5 years of my PhD was, in several ways, an incredible period, professionally, but most important, at personal level. I had the opportunity to meet several outstanding professionals, who challenge and teach me with a lot of generosity. First, I would like to thank my advisor, Dr. Jonathan Golub, who has a lot of patience and make a lot of effort to support and guide me through a new setting for him (Lima, Peru), always with the honesty required at this training level, pushing me to make my best effort. Also, I want to thanks to Professor Robert Gilman, who push and help me to apply to this PhD, after that was my first advisor and the first friendly face at JHSPH. When I decide to change the topic and advisor, Bob was very supportive and he always demonstrated a special interest in my career, teaching me a lot about mentoring and science during our chats. At JHSPH I have the opportunity to interact with a great group of amazing public health students, who gave to me a friendly support in a new city and in an exciting (but very intense) new academic adventure. Andrés, Ricardo, Javier, Gabriele, Manuela, Afsan, Mariana, Nick, Emma, Jonathan, Jessica, Claudia, Ian among others friends, gave me the sense of family in Charm City. During my activities at JHSPH, I had to interact with several faculty members who, with their example, teach me several issues for my professional and personal career. At US Cochrane Center, Prof. Kay Dickersin and Dr. Tianjing Li were extremely supportive and always interested in my career development, gave me the opportunity to participate actively in a great research group. Dr. Darcy v Phelan-Emrick and Allyn Arnold gave me the opportunity to participate as teaching assistant with undergraduate students at Homewood, always encouraging me to improve my teaching skills and providing me the space to improve my English interaction with students. I would also like to thank these enthusiastic and very supportive administrative body at JHSPH, who always were very supportive during my PhD years, specially to Cristina Salazar, Ashley Simmons, Magdalena Nelson, Carol Buckley and Karla McCarthy. In addition, I would like to thank the members of my thesis dissertation committee: Prof. Lawrence Moulton, Prof. Elizabeth Selvin, Prof. David Moore and Dr. Jonathan Golub for their inputs and comments that help me to improve a lot this dissertation. Regardless all the incredible support through Hopkins, none of my PhD's activities would have been achieved without the fundamental support of great group of people in Peru. First at all, my colleagues and professors at Universidad Peruana Cayetano Heredia, specifically Dr. Eduardo Gotuzzo and Dr. Carlos Seas, who always were looking every step in my career since medical school, providing many opportunities for training and development. Also, I would want to thanks to Dr. Larissa Otero, Dr. Elsa Gonzalez and Dr. Carlos Zamudio to provide me the support though the TB Research Unit at Instituto de Medicina Tropical Alexander von Humboldt, but most important, to providing me their friendship. Special thanks to Dr. Kelika Konda, Dr. Julia Critchley and Dr. Gwenyth O'Neill Lee for their helpful comments in the drafts of this thesis. The second paper of this dissertation would not be possible without the awesome and important work of vi TANDEM team in Lima and Europe: Jorge, Walter S., Walter C., Sonia, Ruth, Betty, Katy, Jhomelin in Lima and Prof. Reinout van Crevel, Prof. Hazel Dockrell, Yoko Lawrence and Sarah Kerry, among others, who help me a lot during the research process. Also, to my friends and colleagues at St. George’s University of London (Fiona Pearson, Peijue Huangfu and Julia Critchley) for the support, patience and teaching lessons in the systematic review. One person very important in this endeavor (who invited me to participate in TANDEM, and because of that, providing me a new topic for my PhD thesis) is Prof. David Moore. Dave is not only the best mentor for a junior researcher like me, but his generosity and friendship for more than 10 years, help me not only when I did my Master in Epidemiology at London School of Hygiene and Tropical Medicine, but also during my Hopkins period, always asking me how is my PhD going on and providing important lessons with the aim to balance my academic life with my personal life, reason why I considering very fortunate to be his collaborator and (most important) his friend. None of my achievements in my life can be possible without lovely support from my family: my parents, always lovely and supportive, are the best example of an outstanding academic life, but most important, the most amazing parents I can dream. Manolo, my little brother, who always support me without ask me why, with Laurie (my sister-in-law) and Mariana (my goddaughter) continuing support and cheer me, make me feel very lucky. Finally, my lovely wife Cynthia, who help me through these arid times of writing, when everything seems blurry and tedious, providing support, time, patience and space with huge generosity to reach finally this milestone, always making our family time the vii best I ever dreamed. Cynthia, as the clever and loving soul as she is, brought to our family Lucas, our puppy, who join me during these mornings, afternoon and nights of writing, reading and meditation in this dissertation work, making this time unforgettable and with several smiles during the process. Now, after this PhD work is over, Cynthia and I are starting the most important adventure of our life: parenthood, reason why I dedicate this work with all my love to my boy, Nicolas, who will join our family next year. viii 4. Support Tuition and stipend support for this degree program were provided through by the Peru International Clinical, Operational, and Health Services Research and Training Award Network for AIDS/TB Research Training (National Institutes of Health Grant 1U2RTW007368-01A1 Fogarty International Center, Lima, Peru). The financial support for this dissertation research was provided through by the National Institutes of Health Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Center, National Heart, Blood, and Lung Institute, and the National Institutes of Health Office of Research for Women’s Health through the Fogarty Global Health Fellows Program Consortium comprised of the University of North Carolina, John Hopkins, Morehouse and Tulane (1R25TW009340-01) and the American Recovery and Reinvestment Act; the Program for Advanced Research Capacities for AIDS in Peru (PARACAS) at Universidad Peruana Cayetano Heredia (D43TW00976301) from Fogarty International Center at the U.S.