An assessment of nucleic acid amplification testing for active mycobacterial infection

Executive summary 19

An assessment of nucleic acid amplification testing for active mycobacterial infection 19

Main issues for MSAC consideration 19

Rationale for assessment 19

Proposed medical service 20

Current funding arrangements 21

Proposal for public funding 21

Comparator details 21

Clinical use of the intervention 22

Key differences in the delivery of the proposed medical service and the main comparator 22

Clinical claim 23

Approach taken to the evidence assessment 23

Characteristics of the evidence base 24

Results of assessment 24

Other relevant considerations 29

Economic evaluation 30

Glossary and abbreviations 35

Introduction 37

Background 39

Approach to assessment 57

Objective 57

Clinical pathway 57

Comparator 63

The reference standard 63

Research questions 63

Diagnostic assessment framework 64

Review of literature 65

Expert advice: Health Expert Standing Panel (HESP) 78

Results of assessment and discussion 79

Is it safe? 79

Is it effective? 80

Direct evidence of the effectiveness of NAAT in the diagnosis of MTB 80

Linked evidence of effectiveness of NAAT in the diagnosis of MTB 85

Is it accurate? 85

Does it change patient management? 110

Does change in management improve patient outcomes? 118

Linked evidence of diagnostic effectiveness of NAAT in the diagnosis of NTM 135

Is it accurate? 136

Other relevant considerations 145

TB in the Australian Indigenous population 145

What are the economic considerations? 150

Economic evaluation 150

Population and setting for the economic evaluation 150

Structure and rationale of the economic evaluation 152

Inputs to the economic evaluation 160

Outputs from the economic evaluation 179

Financial implications 188

Data sources used in the financial analysis 188

Net financial implications to the MBS 189

Other Australian healthcare system costs 194

Conclusions 195

Is NAAT safe? 195

Is NAAT effective? 195

Is NAAT cost-effective? 205

Costing 206

Appendix A Health Expert Standing Panel and Assessment Group 207

Appendix B Search strategies 208

Appendix C Diagnostic accuracy 2x2 data from included studies 212

Appendix D Analysis of diagnostic accuracy data 241

Appendix E Meta-analysis of studies assessing the diagnostic accuracy of AFB compared with culture 257

Appendix F Study profiles of studies included in the assessment 263

Appendix G Excluded studies 313

Appendix H Economic literature search 333

Appendix I Additional information relating to the economic evaluation 334

Appendix J Alternative NAAT fees 341

References 342

Box 1 PICO criteria for studies assessing the safety of NAAT in patients suspected of TB where AFB microscopy is obtained 79

Box 2 PICO criteria for identification of studies relevant to an assessment of effectiveness of NAAT for patients where AFB microscopy is obtained 80

Box 3 PICO criteria for identification of studies relevant to an assessment of the accuracy of NAAT 88

Box 4 PICO criteria for identification of studies relevant to an assessment of change in management following NAAT in patients able to have an AFB microscopy test 111

Box 5 PICO criteria for direct evidence in patients with tissue biopsy consistent with NTM infection 137

Figure 1 Principles of the LAMP method 39

Figure 2 The 81-bp MTB-specific rifampicin-resistance determining region of the rpoB gene 41

Figure 3 Current clinical management of TB and proposed use of NAAT for active TB where AFB is obtained 52

Figure 4 Current clinical management and proposed algorithm with use of NAAT for active TB where AFB microscopy is not able to be obtained 53

Figure 5 Current clinical management algorithm and proposed algorithm with use of NAAT for patients who are suspected of having an NTM infection 54

Figure 6 Summary of the process used to identify and select studies investigating the use of NAAT to diagnose MTB (direct evidence, accuracy and change in management) 61

Figure 7 Summary of the process used to identify and select studies investigating the use of NAAT to diagnose NTM (direct evidence, accuracy and change in management) 61

Figure 8 Summary of the process used to identify and select studies for the impact of early identification of drug resistance and alternative treatment 62

Figure 9 Summary of the process used to identify and select studies for the impact of early versus delayed treatment for TB 62

Figure 10 Summary of the process used to identify and select studies for the impact of inappropriate antibiotic use 63

Figure 11 Forest plot showing the pooled sensitivity and specificity values for culture compared with NAAT, using a clinical reference standard, and for NAAT compared with culture in the same subset of studies 82

Figure 12 Forest plot showing the pooled sensitivity and specificity values for AFB plus NAAT compared with culture for studies grouped according to the NAAT comparator, specimen type and incidence of TB in the country in which the study was conducted 83

Figure 13 LR scattergram for diagnosis of MTB infection by AFB plus NAAT compared with culture in studies using either in-house NAAT or commercial Xpert NAAT 84

Figure 14 SROC curve for all studies investigating the sensitivity and specificity of AFB plus NAAT versus culture in the diagnosis of TB for all studies based on NAAT methodology (A), and for sputum (B) and non-sputum (C) specimens based on incidence of TB 86

Figure 15 Forest plot showing the pooled sensitivity and specificity values for NAAT compared with culture for studies grouped according to the NAAT comparator, specimen type and incidence of TB in the country in which the study was conducted 87

Figure 16 Deek’s Funnel plot asymmetry test to assess publication bias for the diagnostic accuracy of NAAT compared with culture 88

Figure 17 LR scattergram for diagnosis of MTB infection by NAAT compared with culture in studies using either in-house NAAT or commercial Xpert NAAT 89

Figure 18 SROC curve for all studies investigating the sensitivity and specificity of NAAT versus culture in the diagnosis of TB for studies based on NAAT methodology (A), specimen type (B) and incidence of TB (C) 91

Figure 19 Forest plot showing the pooled sensitivity and specificity values for NAAT compared with culture for AFB-positive (A) and AFB-negative (B) specimens grouped according to NAAT methodology, specimen type and incidence of TB in the country in which the study was conducted 94

Figure 20 LR scattergram for diagnosis of MTB infection by NAAT compared with culture for AFB-positive specimens according to NAAT methodology 95

Figure 21 LR scattergram for diagnosis of MTB infection by NAAT compared with culture for AFB-negative specimens according to NAAT methodology 96

Figure 22 SROC curve for all studies investigating the sensitivity and specificity of NAAT versus culture in the diagnosis of TB for AFB-positive specimens based on NAAT methodology 96

Figure 23 SROC curve for all studies investigating the sensitivity and specificity of NAAT versus culture in the diagnosis of TB for AFB-negative specimens based on NAAT methodology (A) and specimen type (B) 97

Figure 24 Forest plot showing the pooled sensitivity and specificity values for AFB, NAAT and AFB plus NAAT compared with culture according to specimen type 97

Figure 25 LR scattergram for diagnosis of MTB infection by AFB (A), NAAT (B) and AFB plus NAAT (C) compared with culture in studies using either in-house NAAT or the commercial Xpert NAAT 99

Figure 26 Forest plot showing the pooled sensitivity and specificity values for AFB and NAAT compared with culture according to HIV status 100

Figure 27 Forest plot comparing the pooled sensitivity and specificity values for NAAT versus culture according to AFB result and specimen type in HIV-positive specimens 101

Figure 28 Forest plot of the sensitivity and specificity of NAAT compared with culture-based DST to detect drug-resistant MTB infections 102

Figure 29 Percentage of patients initiating treatment based on smear (AFB microscopy) or NAAT results, by day 107

Figure 30 Forest plot showing the pooled sensitivity and specificity values for AFB and NAAT compared with culture or a clinical reference standard in diagnosing NTM infections in various types of specimens 132

Figure 31 LR scattergram for diagnosis of NTM infection by AFB microscopy (A) and NAAT (B) compared with culture 134

Figure 32 SROC curve for all studies investigating the sensitivity and specificity of AFB and NAAT versus culture in the diagnosis of NTM 135

Figure 33 Decision analytic structure of the economic evaluation, comparator (AFB) model arm 149

Figure 34 Decision analytic structure of the economic evaluation, intervention (AFB plus NAAT) model arm 150

Figure 35 Percentage of TB cases that exhibited multidrug resistance in Australia, 1995–2010 154

Figure 36 Tornado sensitivity analysis 177

Figure 37 Number of patients who accessed MC&S services, observed 2009–13 and projected 2014–19 182

Figure 38 Forest plot of the sensitivity and specificity of AFB microscopy compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with low and medium incidence of TB 235

Figure 39 Forest plot of the sensitivity and specificity of AFB microscopy compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with high incidence of TB 236

Figure 40 Forest plot showing the pooled sensitivity and specificity values for AFB, NAAT and AFB plus NAAT compared with culture, according to specimen type 238

Figure 41 Forest plot of the sensitivity and specificity of NAAT compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with low and medium incidence of TB 239

Figure 42 Forest plot of the sensitivity and specificity of NAAT compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with high incidence of TB 240

Figure 43 Forest plot of the sensitivity and specificity of AFB plus NAAT compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with low and medium incidence of TB 241

Figure 44 Forest plot of the sensitivity and specificity of AFB plus NAAT compared with culture, grouped according to use of in-house or commercial NAAT, for studies conducted in countries with high incidence of TB 242

Figure 45 Forest plot of the sensitivity and specificity of NAAT compared with culture in AFB-positive specimens, grouped according to type of NAAT and incidence of TB 243

Figure 46 Forest plot of the sensitivity and specificity of NAAT compared with culture in AFB-negative specimens, grouped according to use of in-house or commercial NAAT and incidence of TB 244

Figure 47 Forest plot of the sensitivity and specificity of AFB and/or NAAT compared with culture in HIV-positive patients suspected of having TB 245

Figure 48 Forest plot of the sensitivity and specificity of AFB and/or NAAT compared with culture in HIV-negative patients suspected of having TB 246

Figure 49 Forest plot of the sensitivity and specificity of AFB and NAAT compared with culture or a clinical reference standard in diagnosing NTM infections 247

Figure 50 Forest plot of the sensitivity and specificity of culture compared with a clinical reference standard and subgroup analysis of NAAT compared with culture, based on HIV and AFB status 248

Figure 51 Forest plot showing the pooled sensitivity and specificity values for AFB microscopy compared with culture for studies grouped according to NAAT comparator, AFB methodology and incidence of TB in the country in which the study was conducted 251

Figure 52 Deek’s Funnel plot asymmetry test to assess publication bias for the diagnostic accuracy of AFB microscopy compared with culture 251

Figure 53 LR scattergram for diagnosis of MTB infection by AFB microscopy compared with culture in studies using in-house NAAT or the Xpert NAAT 253

Figure 54 SROC curve for all studies investigating the sensitivity and specificity of AFB microscopy versus culture in the diagnosis of TB 254

Figure 55 Results of the economic evaluation, AFB model arm 327

Figure 56 Results of the economic evaluation, AFB plus NAAT model arm 328

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