Providing the latest information on preventive, diagnostic and therapeutic aspects of tuberculosis and AIDS, this is the only book to place a major emphasis on the increasing coexistence of these two life-threatening diseases in individuals. Edited by outstanding scientists in the field, this ready reference is divided into three main sections covering immunology and vaccination strategies, drugs, and clinical issues. Timely reading for microbiologists, virologists, bacteriologists, immunologists, and pathophysiologists, as well as for the pharmaceutical and biotechnological industries.

Table of Contents:
Preface XIII List of Contributors XVII Part One Immunology and Vaccination Strategies for AIDS and TB 1 1 HIV Immunology and Prospects for Vaccines 3 Boris Julg and Bruce D. Walker 1.1 Introduction 3 1.2 Challenges for HIV Vaccine Design 3 1.3 What Immune Responses will be Required for an Effective AIDS Vaccine? 5 1.3.1 Cytotoxic T Lymphocytes 6 1.3.2 Neutralizing Antibodies 8 1.3.3 CD4þ T Helper Cells 9 1.3.4 Natural Killer Cells 10 1.4 Models of Successful Vaccination? 10 1.5 Human Trials of AIDS Vaccines 11 1.5.1 Antibody-Based Vaccination 12 1.5.1.1 VaxGen Trial of AIDSVax 12 1.5.2 T Cell-Based Vaccination 12 1.5.2.1 The STEP Study 12 1.6 Recent Advances in Animal Models: Reasons for Optimism 13 1.6.1 Success against Heterologous Challenge 14 1.6.2 Heterologous rAd26 Prime/rAd5 Boost Vaccine Regimen 14 1.6.3 Induction of Effector Memory T-Cell Responses at Viral Entry Sites 15 1.7 The Current Vaccine Pipeline 15 1.7.1 DNA 15 1.7.2 Adenovirus 16 1.7.3 Peptides 16 1.7.4 Bacillus Calmette-Guérin 17 1.7.5 Listeria and Other Bacterial Vectors 17 1.7.5.1 Listeria monocytogenes 17 1.7.5.2 Salmonella enterica 18 1.7.5.3 Shigella 18 1.7.6 Canarypox 18 1.7.7 Adeno-Associated Virus 19 1.8 Conclusions and Future Directions 19 References 20 2 Immune Response to Tuberculosis as a Basis for Rational Vaccination Strategies 31 Stefan H.E Kaufmann and Steffen Stenger 2.1 Introduction 32 2.2 Clinical Aspects of TB 32 2.3 Immune Response to TB: Innate Immunity 34 2.4 Adaptive Immunity 36 2.4.1 T-Cell Subsets 36 2.4.2 T-Cell Activation 38 2.5 Cytokines as Mediators of Immune Function 38 2.5.1 IL-12 Family of Cytokines 38 2.5.2 Tumor Necrosis Factor 40 2.6 Vaccines against TB 40 2.6.1 From the Past to the Present 40 2.6.2 The Future 42 2.6.2.1 Goals of Vaccination 42 2.6.2.2 Vaccination Strategies 44 2.6.2.3 Targets for Vaccination 46 2.7 Biomarkers 46 2.7.1 Immunologic 48 2.7.2 Transcriptomics 48 2.7.3 Proteomics 49 2.7.4 Metabolomics 49 2.8 Concluding Remarks 49 References 50 3 BCG Vaccination in the HIVþNewborn 55 Willem A. Hanekom and Gregory D. Hussey 3.1 Bacillus Calmette-Guérin (BCG) and its Efficacy in Healthy Infants 55 3.2 Adverse Events Caused by BCG in Healthy Infants 56 3.3 Specific Immunity Induced by BCG in Healthy Infants 58 3.4 Efficacy of BCG to Prevent TB in HIV-Infected Infants 60 3.5 Adverse Effects Caused by BCG in HIV-Infected Infants not Receiving Antiretroviral Therapy 61 3.6 BCG Immune Reconstitution Inflammatory Syndrome (BCG-IRIS) 62 3.7 Management of BCG Disease in HIV-Infected Infants 63 3.8 Specific Immunity Induced by BCG in HIV-Infected Infants 64 3.9 Weighing up the Evidence: Should BCG be given to HIV-Infected or HIV-Exposed Infants? 65 3.10 How Can We Protect HIV-Infected Infants Against TB, if BCG is Not Given? 66 3.11 BCG Vaccination of HIV-Exposed, Uninfected Infants 67 3.12 Conclusions 69 References 69 Part Two Drugs 75 4 HIV/AIDS Drugs 77 Roy M. Gulick 4.1 Introduction 77 4.2 Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs) 81 4.3 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 84 4.4 HIV Protease Inhibitors 86 4.5 Newer Classes: Entry Inhibitors and Integrase Inhibitors 90 4.5.1 Entry Inhibitors 90 4.5.2 Integrase Inhibitors 91 4.6 Newer Strategies 93 4.7 Concomitant Treatment of HIV Infection and Tuberculosis 94 4.8 Conclusions 95 References 95 5 Mycobacterium tuberculosis: Drug Resistance and Genetic Mechanisms – Facts, Artifacts, and Fallacies 103 Erik C. Böttger and Burkhard Springer 5.1 Introduction 103 5.2 Genetic Aspects of Drug Resistance 104 5.3 Principles of Drug Susceptibility Testing in the Laboratory 108 5.4 Clinical Implications of Drug Resistance 111 5.5 Outlook and Perspectives 114 References 115 6 HIV–TB Drug Interactions 123 Tolu Oni, Dominique J. Pepper, and Robert J. Wilkinson 6.1 Important Concepts and Definitions 123 6.2 Background 124 6.3 Current Therapy for TB and AIDS 124 6.4 Potential Drug–Drug and Drug–Disease Interactions 125 6.5 Treatment of Tuberculosis 126 6.5.1 Rifampin 127 6.5.2 Rifapentine 130 6.5.3 Rifabutin 130 6.5.4 Isoniazid 130 6.5.5 Pyrazinamide and Ethambutol 131 6.5.6 Ethionamide 131 6.5.7 Fluoroquinolones 131 6.5.8 Streptomycin/Amikacin/Kanamycin/Capreomycin 132 6.5.9 Terizidone/Cycloserine 132 6.5.10 Linezolid 133 6.5.11 Co-Amoxyclav 133 6.5.12 PAS 133 6.5.13 Clarithromycin 133 6.6 Treatment of HIV Infection 133 6.6.1 Fusion Inhibitors 134 6.6.2 Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 134 6.6.3 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and Protease Inhibitors (PIs) 134 6.6.3.1 Oral Bioavailability of Delavirdine and PIs 134 6.6.3.2 CYP Interactions in PIs 137 6.7 Treatment Issues in Coinfection 137 6.7.1 Shared Toxicities 137 6.7.2 TB/Antiretroviral Drug Interactions 137 6.7.2.1 Rifamycins 137 6.8 Drug–Disease Interactions 141 6.8.1 TB Drugs in Development, and Potential Interactions 141 6.8.2 AIDS Drugs in Development, and Potential Interactions 142 6.8.3 Other Interactions of Note 142 6.8.3.1 Antituberculosis Drugs and Oral Hypoglycemic Agents 142 6.8.3.2 Antituberculosis Agents and Prednisolone 143 6.9 Conclusions 144 References 144 Part Three Clinical Issues 155 7 Clinical Issues in the Diagnosis and Management of HIV Infection 157 Scott Dryden-Peterson, Henry Sunpath, and Rajesh T. Gandhi 7.1 Introduction 157 7.2 Diagnosis 158 7.2.1 Rationale for Testing 158 7.2.1.1 HIV Testing for Prevention 158 7.2.1.2 Earlier Entry to Care 159 7.2.2 Recommendations for Testing 160 7.3 Methods of Testing 160 7.3.1 ELISA 162 7.3.2 Rapid Tests 163 7.3.3 Western Blot 163 7.3.4 Nucleic Acid Amplification 164 7.4 Management of the Newly Diagnosed HIV-Infected Patient 164 7.4.1 Assessment of Baseline HIV Parameters 164 7.4.2 Concurrent Infection 165 7.4.2.1 Tuberculosis 165 7.4.2.2 Sexually Transmitted Infections 167 7.4.2.3 Viral Hepatitis 167 7.4.2.4 Other Infections 168 7.4.3 Comorbid Conditions 170 7.4.4 Adherence Assessment 170 7.4.5 Prophylaxis 171 7.5 Antiretroviral Therapy 171 7.5.1 When to Start 171 7.5.1.1 Asymptomatic Patients 171 7.5.1.2 Patients with Tuberculosis 172 7.5.1.3 Patients with an Opportunistic Infection 173 7.5.1.4 Primary HIV Infection 173 7.5.2 Choice of Initial Therapy 174 7.5.2.1 Backbone: Nucleoside Reverse Transcriptase Inhibitors 174 7.5.2.2 Anchor: Non-Nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors 177 7.5.3 Monitoring 178 7.6 Summary and Conclusions 179 References 180 8 HIV-Associated Tuberculosis: Clinical Challenges 191 Neil W. Schluger 8.1 Introduction 191 8.2 Epidemiology of Tuberculosis in HIV-Infected Persons 191 8.3 Clinical Issues in the Care of HIV-Infected Patients with Tuberculosis 192 8.3.1 Latent Tuberculosis Infection (LTBI) 192 8.3.1.1 LTBI Diagnosis 193 8.3.1.2 LTBI Treatment 195 8.3.2 Active Tuberculosis 196 8.3.2.1 Active Tuberculosis Diagnosis 196 8.3.2.2 Active Tuberculosis Treatment 198 8.4 Conclusions 203 References 203 9 TB/AIDS Coinfection: An Integrated Clinical and Research Response 209 Anne E. Goldfeld and Elizabeth L. Corbett 9.1 Introduction 209 9.2 TB/HIV Epidemiology 215 9.2.1 Global Epidemiology of HIV/TB Coinfection and Disease: Estimates and Regional Time Trends 215 9.2.1.1 Trends in the Global HIV/TB Epidemic Since 2000 216 9.2.2 HIV as a Risk Factor for TB in the Pre- and Post-ART Era 218 9.2.3 The Secondary Impact of HIV-Related TB on Global TB Transmission Rates and Population Genetics of M. tuberculosis 219 9.2.3.1 HIV and TB Transmission Rates at the Community Level 220 9.2.3.2 HIV and Institutional TB Transmission 222 9.2.3.3 HIV and TB Population Genetics and the Coinfected Individual 223 9.2.4 The Impact of Pathogen and Host Genetics on Disease Outcome in TB/HIV Coinfection 223 9.2.4.1 The Impact of HIV Subtype Specificity on HIV Regulation and Disease Outcome in TB/HIV Coinfection 224 9.2.4.2 The Impact of TB Strain Variability on HIV Regulation and Disease Outcome in TB/HIV Coinfection 225 9.2.4.3 The Impact of Host Variability and Disease Outcome on TB/HIV Coinfection 225 9.3 Clinical Aspects of TB Disease in the HIV-Infected Patient 226 9.3.1 Chronic Cough and other Common Clinical Presentations of HIV/TB 227 9.3.2 Diagnosis of HIV-Related TB Infection and Disease 229 9.3.3 Excluding TB in the Context of HIV Care 229 9.3.4 Treatment of Latent TB, and Preventive Therapy 230 9.4 Treatment of HIV-Infected TB Patients 231 9.4.1 Reducing Mortality in HIV-Infected TB Patients 232 9.4.2 Antituberculosis Regimens 232 9.4.3 Choice of Antiretrovirals in the Context of Treating TB 233 9.4.4 When to Start ART? 234 9.4.5 Immune Reconstitution in TB/HIV Coinfection 235 9.5 Critical Issues in the Delivery of Coordinated TB and HIV Prevention and Care 239 9.5.1 An Example of Linking TB and HIV/AIDS Care at the Community Level 239 9.6 Conclusions 241 References 242 10 Extensively Drug-Resistant Tuberculosis and HIV/AIDS 253 Megan Murray and Ted Cohen 10.1 Introduction 253 10.2 The Burden of XDR TB and HIV 254 10.3 Evidence of a Causal Association Between HIV and Drug-Resistant TB 255 10.4 Mechanisms by which HIV may Lead to Drug Resistance in TB 255 10.4.1 Acquired Resistance 257 10.4.2 Primary Resistance 259 10.5 Role of HIV on the Infectiousness of XDR TB 261 10.6 Community Level Impact of HIV on Population Increases in Drug-Resistant TB 262 10.7 Effect of HIV on the Diagnosis and Treatment of MDR and XDR TB 262 10.7.1 Diagnosis 262 10.7.2 Treatment 263 10.8 Future Directions 267 References 267 11 Clinical Issues (Including Diagnosis): Immune Reconstitution Inflammatory Syndrome (IRIS) 277 Martin P. Grobusch, Colin N. Menezes, and Melanie-Anne John 11.1 The Problem of IRIS: An Overview 277 11.1.1 Introduction 277 11.1.2 Pathogenesis 278 11.1.3 Defining IRIS 280 11.2 Tuberculosis-Related IRIS 280 11.2.1 Case Definitions and Diagnostic Criteria 280 11.2.2 Epidemiology 281 11.2.3 Clinical Manifestations 283 11.2.4 Management 284 11.2.5 Prevention 285 References 286 Index 291