EVALUATION OF METHODS FOR MEASUREMENT OF FACIAL FAT IN HIV INFECTED PATIENTS WITH LIPOATROPHY YANG YONG NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGMENTS I would like to express my deepest thanks and appreciation to my great supervisor, Associate Professor Nicholas Paton, for his expert, consistent and invaluable guidance, advice, supervision as well as encouragement and patience both during and outside the course, especially for awakening my interest in the clinical research study The way of research that I have learned from him will greatly benefit my career and life in the future I would also like to express my sincere thanks to Associate Professor Vincent TK Chow for his expert and invaluable supervision and encouragement during my study I would like to thank Dr Yih-Yian Sitoh, and Mrs Lynn Ho from the National Neuroscience Institute (NNI) for all their kind support and practical contributions to the MRI facial fat and muscle volume measurement described in this thesis I am also indebted to Dr Chen Pu Chong from INUS Technology Inc., Seoul, Korea, for his expert technical support in the development of the method of volume estimation by superimposition and cheek surface point displacement using laser scanning and indebted to Dr Chan Yiong Huak, Clinical research centre, Faculty of Medicine, National University of Singapore, for his guidance in the data analysis during this study ii I also thank Ms Ravathi Subramanaiam, Ms Naing Oo Tha, Ms Estelle Foo, Ms Anushia Panchalinghm, Ms Marline Yap, Ms Nora Amin, Ms Margaret Lee, Ms Katherine Lee, Ms Lian Fong Teo, Mr Elliot Lim, Dr Annelies Wilder-Smith, Dr Jason Zhu and all other colleagues of Department of Infectious Disease Research Centre (IDRC) in Tan Tock Seng Hospital (TTSH), Singapore for their assistance in assisting with recruiting study patients, DEXA scan, laser scanning, MRI image analysis and assistance in one way or another I wish to thank the numerous patients who participated in these often-laborious studies, in the knowledge that there would likely be no direct benefit to them Without their cooperation, the studies described in this thesis would not have been possible I would also like to thank Biomedical Research Council (BMRC), Singapore, for the support at the course of my research and study (Grant: 01/1/28/18/026) Finally, I am grateful to my wife, Hao QiaoYing, and my son, Yang Bo Chao, for their love and understanding This work could not have been completed without their support (A declaration of work done by the candidate in provided in Appendix 1) iii ACKNOWLEDGMENTS ii CONTENTS iv SUMMARY xii LIST OF TABLES I LIST OF FIGURES III LIST OF ABBREVIATIONS V AIMS OF THE THESIS VII CHAPTER 1 1.1 INTRODUCTION Human immunodeficiency virus (HIV) infection 1.1.1 Prevalence and transmission of HIV infection 1.1.2 Pathogenesis of HIV infection 1.1.3 Clinical course of HIV infection 1.1.4 1.2 Treatment of HIV infection HIV-related lipodystrophy 10 1.2.1 Clinical features and definition of terms 10 1.2.2 Prevalence of HIV-related lipodystrophy 12 1.2.3 Impact of HIV-related lipodystrophy 15 1.2.4 Risk factors and pathogenesis of HIV-related lipodystrophy 16 1.2.4.1 16 Risk factors of HIV-related lipodystrophy 1.2.4.2 Pathogenesis of HIV-related lipodystrophy 1.2.5 26 Methods of assessing HIV-related lipodystrophy 32 1.2.5.1 Subjective clinical assessment 32 1.2.5.2 Objective assessment methods 33 1.2.5.3 Lipodystrophy syndrome case definition model 36 1.2.5.4 Limitation of lipodystrophy case definition model 39 iv 1.3 41 1.3.1 Diet adjustment and physical exercise 41 1.3.2 Recombinant human growth hormone (rhGH) 41 1.3.3 NRTI switching strategy 42 1.3.4 Structured treatment interruption (STI) 43 1.3.5 Thiazolidinediones and leptin treatment 44 1.3.6 1.4 Treatment of HIV-related lipoatrophy Plastic surgical intervention 45 Summary 46 CHAPTER CHANGE MRI FACIAL FAT AND BODY COMPOSITION IN HIV-INFECTED PATIENTS WITH LIPOATROPHY 47 2.1 Introduction 47 2.2 Methods 48 2.2.1 Patients 48 2.2.2 Clinical characteristics 49 2.2.3 MRI measurements 50 2.2.4 DEXA measurements 53 2.2.5 Statistical analysis 53 2.3 Results 54 2.3.1 Demographic characteristics and clinical data 54 2.3.2 MRI facial fat and muscle volume 56 2.3.3 DEXA body composition 59 2.3.4 Correlation between facial fat volume and DEXA body composition parameters 2.4 61 Discussion 64 2.4.1 64 Facial fat loss in lipoatrophy v 2.4.2 65 2.4.3 Facial fat and muscle change in lipoatrophy 66 2.4.4 2.5 Deep facial fat loss in lipoatrophy Whole body and regional fat changes in lipoatrophy 67 Summary CHAPTER 69 LONGITUDINAL CHANGES IN FACIAL FAT IN HIV-INFECTED PATIENTS WITH LIPOATROPHY 71 3.1 Introduction 71 3.2 Methods 73 3.2.1 Patients 73 3.2.2 Clinical characteristics 73 3.2.3 MRI measurements 74 3.2.4 DEXA measurements 74 3.2.5 Statistical analysis 74 3.3 Results 76 3.3.1 Patients 76 3.3.2 Longitudinal facial fat changes in patients with lipoatrophy 77 3.3.3 Comparison of compartmental changes between patients with lipoatrophy and patients undergoing weight change 3.4 83 Discussion 86 3.4.1 Facial fat changes over time in lipoatrophy patients 86 3.4.2 MRI as a tool in assessment of facial fat changes over time 87 3.4.3 Facial soft tissue changes in lipoatrophy and weight change patients 3.5 Summary 88 90 vi CHAPTER EVALUATION OF DEXA IN ASSESSMENT OF LIPODYSTROPHY IN HIV INFECTED PATIENTS 91 4.1 Introduction 91 4.2 Methods 93 4.2.1 Patients 93 4.2.2 Clinical lipodystrophy assessment 93 4.2.3 Clinical characteristics 93 4.2.4 DEXA measurements 94 4.2.5 Statistical analysis 96 4.3 Results 97 4.3.1 Patients demographic and clinical characteristics 4.3.2 Comparison of body composition results between DEXA machines 4.3.3 Discussion 4.4.1 99 Comparison of two machines for detection of lipodystrophy changes 4.4 97 103 106 Comparison of two machines for detection of lipodystrophy changes 106 4.4.2 Differences between Lunar and Hologic DEXA 107 4.4.3 Difference in contribution to the lipodystrophy diagnosis score by the two DEXA machines 4.4.4 Calibration of different machines with standard soft tissue phantom 4.5 108 Summary 109 110 vii CHAPTER EVALUATION OF REPRODUCIBILITY AND ACCURACY OF 3-DIMENSIONAL LASER SCANNING FOR ESTIMATING FACIAL VOLUME CHANGE 111 5.1 Introduction 111 5.2 Methods 113 5.2.1 Accuracy of the volume simulation method 113 5.2.2 Reproducibility of the volume change simulation in mannequin and healthy subjects 5.2.3 LS procedure 114 5.2.4 Analysis of paired laser scans 116 5.2.5 5.3 113 Statistical analysis 119 Results 120 5.3.1 120 5.3.2 Reproducibility of volume changes 122 5.3.3 5.4 Accuracy of volume changes Reproducibility of measurements in healthy subjects 124 Discussion 127 5.4.1 Accuracy of the LS volume estimation method 127 5.4.2 Reproducibility of the LS volume estimation method 128 5.4.3 Comparison with other measurement methods for facial fat change over time 5.5 Summary 129 131 viii CHAPTER VALIDATION OF LASER SCANNING FOR DETECTING FACIAL FAT CHANGES IN PATIENTS UNDERGOING FACIAL FAT CHANGE 132 6.1 Introduction 132 6.2 Methods 133 6.2.1 Patients 133 6.2.2 Laser scanning procedure and analysis 133 6.2.3 Superficial fat volume measurement by MRI method 137 6.2.4 Statistical analysis 137 6.3 Results 138 6.3.1 Patients 138 6.3.2 Estimated CSV changes by LS and their relationships with MRI cheek fat changes 6.3.3 CPD changes and their relationships with MRI cheek fat changes 6.4 138 141 Discussion 143 6.4.1 Surface volume change in patients with facial lipoatrophy 143 6.4.2 Cheek surface contour change and facial fat compartment change 144 6.4.3 CPD as a measurement of facial fat change 6.5 145 Summary 146 ix CHAPTER LONGITUDINAL CHANGES IN FACIAL FAT AND WHOLE BODY FAT IN A COHORT OF PATIENTS RECEIVING COMBINATION ANTIRETROVIRAL THERAPY 148 7.1 Introduction 148 7.2 Methods 149 7.2.1 Patients 149 7.2.2 Clinical characteristics 149 7.2.3 Laser scanning procedure and analysis 151 7.2.4 DEXA measurements 151 7.2.5 Statistical analysis 152 7.3 Results 153 7.3.1 153 7.3.2 Clinical facial lipoatrophy both at baseline and follow up 155 7.3.3 CSV and CPD at baseline and changes over time 157 7.3.4 CSV and CPD change over time 160 7.3.5 7.4 Demographic and clinical characteristics of study patients Factors contributed to the facial fat change over time 164 166 7.4.1 LS as methods for measurement of facial fat loss 166 7.4.2 Comparison between CSV and CPD 167 7.4.3 Comparison with other study results 168 7.4.4 7.5 Discussion Limitation of the LS methodology 170 Summary 171 x Y Yang et al contribution was significantly lower with Hologic DXA than with Lunar DXA both for patients with LD (–6.30 vs 2.59, P