Active approaches to latent tuberculosis: modelling public health strategies towards eliminating tuberculosis in Australia Justin Timothy Denholm Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy March 2013 Department of Medicine (RMH/WH) The University of Melbourne 1 2 Declaration This is to certify that: (i) the thesis comprises only my original work towards the PhD except where indicated, (ii) due acknowledgement has been made in the text to all other material used, (iii) the thesis is fewer than 100,000 words in length, exclusive of tables, maps, bibliographies and appendices. ……………………………………………. Justin Timothy Denholm 3 4 Acknowledgements I would like to thank the National Health and Medical Research Council for supporting this work through a postgraduate scholarship. I would also like to thank Dennis and Eileen Bakke and the Mustard Seed Foundation for generous financial support and invaluable personal encouragement through the Harvey Fellowship program during my doctoral candidacy. A number of individuals and organisations have provided assistance and support without which this work would not have been possible. I would especially like to acknowledge the Peter Doherty Institute, Nossal Institute for Global Health, Victorian Infectious Diseases Service, Department of Health Victoria and the Victorian Infectious Diseases Reference Laboratory. Most substantial thanks must be given to my doctoral supervisors, Associate Professor Emma McBryde and Professor Graham Brown. Their expertise, insight and enthusiasm have both encouraged and restrained me periodically throughout this process, and I am very thankful for them. Finally, I would like to thank my family, who have, I think, enjoyed this period of doctoral study despite having to sustain me through it periodically! My parents, Carey and Laura, have provided me with tools and models over a lifetime. My wife Gina and my children William, Charlie and Susannah are a delight and blessing in every way – thank you all. Soli deo gloria 5 Table of contents Declaration ......................................................................................................................... 3 Acknowledgements ............................................................................................................ 5 Table of contents ................................................................................................................ 6 Publications arising from this thesis ................................................................................ 11 List of Tables ................................................................................................................... 12 List of Figures .................................................................................................................. 13 Abstract ............................................................................................................................ 15 1.1 What is latent tuberculosis? .............................................................................. 17 1.1.1 Biology ………………………………………………………… 17 1.1.2 Public health ......................................................................................... 18 1.2 How is LTBI managed? ................................................................................... 20 1.2.1 Diagnosis .............................................................................................. 20 1.2.2 Individual treatment strategies ............................................................. 21 1.2.3 Regimens for treatment of LTBI .......................................................... 24 1.3 Population-based strategies relating to LTBI ................................................... 36 1.3.1 Theoretic value and examples of use ................................................... 36 1.3.2 Limitations in development and assessment of public health strategies38 1.4 Estimating population prevalence of LTBI ...................................................... 38 1.4.1 Population surveys ............................................................................... 39 1.4.2 Improving estimates of LTBI with alternative study methods ............. 43 1.4.3 Mathematical approaches to improving experimentally-derived LTBI prevalence ............................................................................................. 44 1.4.4 Theoretical mathematical approaches .................................................. 46 1.4.5 Need for improved methods ................................................................. 48 1.5 Estimating reactivation rates ............................................................................ 48 1.5.1 Basis for current estimates ................................................................... 48 1.5.2 Limitations in current understanding and possibilities for improvement51 6 1.6 Summary of the limits of current understanding of LTBI and implications for evaluation of public health strategies ......................................................... 52 2. Estimating latent TB prevalence and TB risk in immigrant cohorts ......................... 54 2.1 Estimating tuberculin test reactivity in Chinese immigrants ........................... 55 2.1.1 Background .......................................................................................... 55 2.1.2 Aim ……………………………………………………………………58 2.1.3 Methods ………………………………………………………………..58 2.1.4 Results ………………………………………………………………..58 2.1.5 Discussion ............................................................................................ 61 2.2 Adjusting LTBI prevalence estimates using a latent-class, random effects approach ........................................................................................................... 62 2.2.1 Aims ……………………………………………………………….63 2.2.2 Methods ……………………………………………………………….63 2.2.3 Results ……………………………………………………………….63 2.2.4 Discussion ............................................................................................ 65 2.3 Estimating risk of tuberculosis reactivation in Australian immigration cohorts. ............................................................................................................. 66 2.3.1 Aims ……………………………………………………………….66 2.3.2 Methods ……………………………………………………………….66 2.3.3 Results ………………………………………………………….……68 2.3.4 Discussion ............................................................................................ 74 2.4 Summary of approach to estimating TB risk for public health evaluation ...... 76 3. Current approaches to management of LTBI in Australasia ..................................... 78 3.1 Existing guidelines for the management of LTBI ............................................ 78 3.1.1 Aim ……………………………………………………………….79 3.1.2 Methods …………………………………………………………….…79 3.1.3 Results …………………………………………………………….…80 3.1.4 Discussion ............................................................................................ 81 3.2 LTBI management survey ................................................................................ 83 3.3 Treatment of suspected multidrug resistant LTBI ............................................ 93 7 3.4 Potential impact of optimizing current management practices on public health ................................................................................................................ 93 3.4.1 Limiting drug resistance in TB ............................................................. 94 3.4.2 Improved cost-effectiveness ................................................................. 94 3.5 Conclusions ...................................................................................................... 95 4. Multidrug resistant LTBI in Victoria, Australia ........................................................ 97 4.1 Aims ................................................................................................................. 98 4.2 Methods ............................................................................................................ 98 4.3 Results ............................................................................................................ 102 4.4 Discussion ...................................................................................................... 108 4.5 Summary and implications for public health evaluation ................................ 110 5. Risk factors for tuberculosis reactivation ................................................................ 112 5.1 HIV ................................................................................................................. 113 5.2 Diabetes mellitus ............................................................................................ 114 5.3 Tobacco smoke ............................................................................................... 115 5.4 Vitamin D deficiency ..................................................................................... 116 5.5 Genetic factors ................................................................................................ 117 5.5.1 Human leukocyte antigens (HLA) ..................................................... 119 5.5.2 Vitamin D receptor (VDR) ................................................................. 119 5.5.3 SLC11A1 ............................................................................................ 120 5.6 Novel meta-analysis of mannose-binding lectin gene (MBL2) polymorphisms and TB susceptibility