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.

Stefan H.E. Kaufmann is the Director of the Department of Immunology at the Max Planck Institute for Infection Biology in Berlin, Germany. Having obtained his academic degrees from the Johannes Gutenberg University in Mainz he spent his time as post-doc at the Max Planck Institute for Immunobiology and later became full Professor for Microbiology and Immunology at the University of Ulm. Professor Kaufmann has authored over 600 scientific publications and has received numerous scientific awards including the Aronson Prize of the State of Berlin, the Smith Kline Beecham Science Prize for Medical Research, the Merckle Research Prize, The Robert Pfleger Prize, The Pettenkofer Prize, The Research Prize of the German Society for Hygiene and Microbiology and the Alfred Krupp Prize for Young Professors. He is also member of the Berlin-Brandenburg Academy of Sciences and the Leopoldina Academy of Natural Sciences and a long-time Editor-in-Chief of the Journal Microbes and Infection.

Dr. Walker is Professor of Medicine at Harvard Medical School and Director of the Center for AIDS Research at Harvard University; Director of the Partners AIDS Research Center at Massachusetts General Hospital; and a Howard Hughes Medical Institute Investigator. He obtained his undergraduate training at the University of Colorado and the Swiss Federal Technical Institute, and graduated from Case Western Reserve University School of Medicine. Following an internship and residency in Internal Medicine at Massachusetts General Hospital and Harvard Medical School, he completed a postdoctoral fellowship in infectious diseases in the laboratory of Dr. Robert T. Schooley, studying the cellular immune response to HIV in infected persons. He now spends the majority of his time in the laboratory studying immune responses in chronic viral infections. His basic science research focuses on cellular immune responses to HIV and hepatitis C virus (HCV). Dr. Walker also continues his work as a clinician with a specialty is infectious disease, focusing on the treatment of persons with HIV/AIDS. In addition, he has been involved in collaborative research in Africa at the University of KwaZulu-Natal in Durban, South Africa, where he helped to establish a state of the art AIDS Research Center to serve sub-Saharan Africa.

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 HIVTB 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 DrugDrug and DrugDisease 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 DrugDisease 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