Evidence for use of urinary LAM Dr Tom Boyles University of the Witwatersrand, Johannesburg, South Africa With thanks to Ankur Gupta-Wright for slides from STAMP trial The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Conflicts of interest Alere now Abbott- Speaker fees for academic meetings Donation of LAM strips Lending of equipment for studies The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Significant morbidity and mortality from HIV/TB 0.4 million deaths in 20161 TB causes 32-67% deaths in HIV+ adults admitted to hospital in Africa2 Half undiagnosed at time of death2 Urine-diagnostics have good diagnostic yield3 Urine easily obtained Disseminated TB common in advanced HIV Global Tuberculosis Report 2017 Gupta et al, AIDS 2015. Systematic Review and Meta-Analysis of PM studies Lawn et al, BMC Med 2015 & BMC Med 2017. Observational study The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

We don’t do If no one does it skip The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Costs and training Costs Cost savings Training $3 per test Less other investigations e.g. ultrasound scans Training Debate regarding use at bedside or by referral to laboratory services The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

How to test a test Diagnostic intervention research Test research Diagnostic research Diagnostic intervention research The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

P = Adults suspected of having TB I = Urine LAM C = Xpert/nothing O = Morbidity and mortality The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Pooled sensitivity 44% Pooled specificity 92% All patients with HIV Pooled sensitivity 44% Pooled specificity 92% The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Pooled sensitivity 54% Pooled specificity 90% Inpatients with HIV Pooled sensitivity 54% Pooled specificity 90% The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Pooled sensitivity 21% Pooled specificity 97% Outpatients with HIV Pooled sensitivity 21% Pooled specificity 97% The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Pooled sensitivity 49% Pooled specificity 90% CD4 <200 Pooled sensitivity 49% Pooled specificity 90% The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Pooled sensitivity 56% Pooled specificity 90% CD4 <100 Pooled sensitivity 56% Pooled specificity 90% The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

A note on specificity Possible cross reactivity with NTM Higher specificity with more reference samples and composite reference standards Nel 19/21 patients with confirmed NTM but no evidence of TB were LAM +ve Low cross reactivity found in patients with CF who had NTM of the lung Lawn >99% specificity when using multiple samples and composite reference standard Nel et al CID 2017 Lawn et al BMC Med 2017 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Current WHO guidance 1- LAM not to be used except as below 2- LAM may be use in HIV positive adult inpatients with Signs and symptoms of TB with CD4 count <100 If seriously ill regardless of CD4 count With unknown CD4 count (conditional recommendation, low quality evidence) WHO consolidated guideline 2016 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

What’s new since 2016 ? Nel 19/21 patients with confirmed NTM but no evidence of TB were LAM +ve Low cross reactivity found in patients with CF who had NTM of the lung Lawn >99% specificity when using multiple samples and composite reference standard The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

We identified 10 studies eligible for inclusion in this systematic review, reporting on a total of 1172 HIV-TB cases. Of these, 512 patients (44 %) tested positive for urinary LAM Detectable LAM in the urine is an independent risk factor for mortality among patients receiving treatment for HIV-TB. The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

How to test a test Diagnostic intervention research Test research Diagnostic research Diagnostic intervention research The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Patients with HIV needing admission Randomised to routine diagnostics +/- LAM 2500 patients in 4 countries Median CD4– 84 Primary outcomes = 8 week mortality The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

NNT 25 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

on behalf of the STAMP trial team Rapid urine-based screening for TB to reduce AIDS-related mortality in hospitalized patients in Africa (STAMP) trial Ankur Gupta-Wright, Elizabeth L Corbett, Joep J van Oosterhout, Doug Wilson, Daniel Grint, Melanie Alufandika, Jurgens A Peters, Lingstone Chiume, Stephen D Lawn & Katherine Fielding on behalf of the STAMP trial team CROI 2018 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

2600 UNSELECTED adult HIV+ admissions Edendale, KZN, South Africa 2600 UNSELECTED adult HIV+ admissions Irrespective of TB symptoms Exclude: <18 years old TB treatment in last 12 months IPT in last 6 months Outside follow-up area Admitted >48 hours Unable to provide consent Zomba, Malawi Standard of care arm Sputum Xpert MTB/RIF Intervention arm Sputum Xpert MTB/RIF + Urine TB-LAM and Xpert MTB/RIF + CROI 2018 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Unselected HIV +ve admissions 90% at least 1 TB symptom 85% on ART CD4 215 11.5% had TB CROI 2018 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

CROI 2018 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Microbiologically confirmed TB, intervention arm (n=210) Samples submitted for TB testing: 99.0% produced urine 56.9% produced sputum 14.3% (n=30) Sputum Xpert (n=85) 8.6% (n=18) 13.8% (n=29) 3.8% (n=8) 41.4% (n=87) Urine LAM (n=158) 6.2% (n=13) 11.4% (n=24) Urine Xpert (n= 74) Note: 1 patient was negative on all Xpert and LAM tests but was sputum TB culture positive The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Diagnostic accuracy, incremental yield and cost of determine TB-LAM and sputum induction for in seriously ill adults with HIV, cough and WHO danger signs Tom H Boyles1, Rulan Griesel2, Annemie Stewart2, Marc Mendelson1, Gary Maartens2 1Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, South Africa 2 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Cough and WHO danger signs CD4 107 50% had TB 325 HIV +ve admissions Cough and WHO danger signs CD4 107 50% had TB The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

$50 $42 The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018

Summary Cheap Point of care Identifies sick patients with TB 2 RCTs show mortality benefit May be cost saving The Global Action Fund for Fungal Infections meeting Kampala 10-12 April 2018