TB DIAGNOSIS: THE BIG PICTURE

Madhukar Pai, MD, PhD

McGill University, Montreal

DISCLOSURES

No financial or industry conflicts

I serve as a consultant or advisor to:

FIND, Geneva

TB Alliance, New York

Stop TB Partnership, Geneva

THE PROBLEM

CRITICAL TIME FOR TB

Source: WHO 4

CRITICAL TIME FOR TB

5

2019

DIAGNOSIS: A WEAK LINK IN TB CONTROL

6

MANY TB PATIENTS STRUGGLE TO GET QUALITY DX

Missing patients and major access issues

Long, complex pathways to TB care & diagnostic delays

Broken care cascades

Challenges in getting decentralized care

Limited access to new tools

MISSING PATIENTS AND POOR ACCESS TO CARE

Reaching the 40 million target will require finding all the missing people with TB, as well as maintaining progress in the TB response

Source: WHO

Source: WHO 9

13 country patient-pathways

analysis

Multiple providers are seen before TB is detected

~2 months diagnostic delay in most HBCs

Kapoor et al. PLoS ONE 2012 Mistry et al. PLoS ONE 2016 Veesa et al. PLoS ONE 2018

DELHI MUMBAI TAMIL NADU

Much longer pathway for EPTB

Purohit M et al. Tuberculosis Research & Treatment, 2019

India - EPTB

Bhattacharya Chakravarty A, Rangan S, Dholakia Y, Rai S, Kamble S, et al. (2019) Such a long journey: What health seeking

pathways of patients with drug resistant tuberculosis in Mumbai tell us. PLOS ONE 14(1): e0209924.

https://doi.org/10.1371/journal.pone.0209924

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209924

Much longer pathway for DR-TB

India – DR-TB 134 days

7 providers

167 km

Slide courtesy of Guy Stallworthy 14

In 6 of the 7 countries

with most missing cases

(65% of the global total)

private providers account

for 65%-85% of initial

care-seeking …

Percent private primary care

Striking correlation between private/informal care seeking & ‘missing patients’

EVEN WHEN PATIENTS SEEK CARE, WHAT QUALITY DO THEY GET?

30 HBCs

Cascade of care

http://www.jogh.org/documents/issue201901/jogh-09-010423.htm

Global

Cascade of care: DR-TB

Kendall E et al. Int J Tuberc Lung Dis 2019

Cascade of care: Children

https://www.sciencedirect.com/science/article/pii/S2405579417300360

Uganda & Kenya

Cascade of care: Latent TB Infection

Alsdurf H et al. Lancet Infect Dis 2016

Simulated patient studies in 4 countries show that most primary care providers do not manage TB well

www.qutubproject.org 20

SIMULATED PATIENT: CLASSIC CASE OF SUSPECTED TB

(2-3 WEEKS OF PRODUCTIVE COUGH, FEVER, WEIGHT LOSS – “PRESUMED TB”)

www.qutubproject.org 21

RESULTS FROM 4 COUNTRIES

www.qutubproject.org 22Das et al. (2015); Kwan et al. (under review); Daniels et al. (2017); Sylvia et al. (2017); Christian et al. (2018); Daftary A et al. unpublished

Setting - Sector % Correctly Managed % Referred

Delhi, India – private sector 21% 10%

Mumbai, India – private sector 37% 15%

Patna, India – private sector 33% 10%

Nairobi, Kenya – public & private

33 – 40%

Public: 79% asked for sputum test

Private: 36% asked for sputum test

4% - 10%

Rural China (3 provinces) - public

28%, village clinics

38%, township centers

90%, county hospitals

28%, village clinics

18%, township centers

5%, county hospitals

South Africa – public

(Western & Eastern Cape)

43% got TB and HIV tests

84% got sputum TB tests

South Africa – private

(KZN)35% 26%

DOTS coverage What about quality?

MOST TB PROGRAMS STILL FOCUS ON COVERAGE, NOT QUALITY!

24https://naturemicrobiologycommunity.nature.com/users/20892-madhukar-pai/posts/32859-science-of-improvement-tb-cannot-afford-to-lag-behind

TB DX: ACCESS

25

ACCESS TO NEW TOOLS: XPERT MTB/RIF

Cazabon D, Pande T, et al. Gates Open Res 2018

ACCESS TO NEW TOOLS: URINE LAM RAPID TEST

DRC

Nig

eria

4 of 21

countries

are

currently

using LF-

LAM*

DRC

Nig

eria

9 of 21

countries

include

LF-LAM in

a national

policy

DRC

Nig

eria

13 of 21

countries

plan on

using LF-

LAM in the

near

future

*Irrespective of inclusion in national policy

Does your

country’s national

policy include

LF-LAM test in its

TB or HIV

program?

Is your country

currently using the

LF-LAM test?

Do you plan on

using the LF-

LAM test in the

near future?

Singhroy D, et al. Unpublished

TB DX: WHAT ARE THE NEEDS?

28

TOOLS WE HAVE TODAY?

Tuberculin IGRAs

Conventional

microscopyLED/FM

microscopy

Solid cultures Liquid cultures

Conventional

PCR

Xpert MTB/RIF & Ultra

Molecular DST (LPAs)Conventional,

phenotypic

DST

29

TB LAMP

Urine LAM

Included in

1st WHO

Essential

Diagnostics

List

NEEDS ASSESSMENT AND TPPS

Priority needs TPPs

30Kik S et al. ERJ 2014

NEED FOR NEW TOOLS SPANS THE HEALTHCARE SYSTEM, BUT

CONCENTRATED AT LOWER LEVELS OF THE SYSTEM

31

Reference

center

District

hospital

Microscopy

center

Health

post

Community

health worker

Passive & active case detection

Rule out test or triage test

Latent to active progression

Drug susceptibility testing

Treatment monitoring

A

B

D

E

F

eHealth and connectivity solutions

Courtesy: FIND, Geneva

WE NEED BETTER TOOLS FOR LATENT TB

Pai M, et al. Nature Rev Dis Primer 2016 32

© Bill & Melinda Gates Foundation | 33

TB DX: WHAT IS THE CRITICAL PATHWAY?

34

THE IDEAL: SINGLE, LINEAR VALUE CHAIN

REAL, MESSY VALUE CHAIN

Source: http://www.tbdxpathway.org/

VALLEYS OF DEATH!

http://gbchealth.org/crossing-the-valleys-of-death-in-tb-from-development-to-roll-out/

UPSTREAM CHALLENGES: BIOMARKER DISCOVERY AND VALIDATION

38

https://www.bm2dx.org/

DOWNSTREAM CHALLENGES: PRODUCTS TO IMPACT

39Schumacher S et al. PLOS ONE 2016.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151073

IN MONTREAL, XPERT MTB/RIF HAD LITTLE IMPACT

“Limited potential impact of Xpert testing in high-

resource, low-incidence ambulatory settings due to

lower sensitivity in the context of less extensive

disease, and limited potential to expedite diagnosis

beyond what is achieved with the existing, well-

performing diagnostic algorithm.”

CID 2014:58 (1 April)

40

IN IQALUIT, XPERT MTB/RIF HAD A POSITIVE IMPACT

“In a predominantly Inuit population …where the burden of TB

is high and no TB testing facilities are available, on-site Xpert

was feasible, accurate and shortened time to TB treatment

initiation.”

Alvarez G et al. CHEST 2015 41

SO, OUR MONTREAL GENEXPERT MACHINE IS NOW SERVING PATIENTS IN RURAL INDIA!

CAN WE RE-IMAGINE TB CARE*?

*ONGOING WORK WITH STOP TB PARTNERSHIP43

44https://www.huffingtonpost.ca/dr-madhukar-pai/tuberculosis-cure-treatment-research_a_23449596/?utm_hp_ref=ca-blogs

ACTIVE TB CARE: REIMAGINED

Presumed TB

Rapid Triage Rapid Dx & DST Sequencing

confirmation

Short drug regimensPatient support & benefits,

adverse event management

Test for treatment

response & cure

eTB ICT

& dashboardNew vaccine

Early care

seeking &

clinical

assessment

Systematic

screening

CHILDHOOD TB CARE: REIMAGINED

Possible TB

Rapid Triage Sputum and non-sputum

based rapid Dx & DST for

PTB and EPTB

Sequencing

confirmation

Short drug regimens

Child-friendly formulationsAdherence, nutritional & family supportTest for treatment

response & cure

eTB ICT

& dashboardNew vaccine

Early care

seeking &

clinical

assessment

Contact & systematic

screening

LATENT TB CARE: REIMAGINED

At risk for infection

&/or progression Diagnosis of infection Rule out disease

Short drug regimens

eTB ICT

& dashboardVaccine to

prevent infection

Risk & clinical assessment

1HP

3HP

4R

Risk/benefit

assessment

Vaccine to

stop

progressionPredictive

correlate of

risk signature

Test for treatment

response & cureClient support & benefits,

adverse event management

VaccinationEarly care seeking

TriageSample

transport & diagnostics

SequencingNew drug regimens

Adherence

Patient Support &

Direct Benefits

ICT, dashboard

& AI

PRODUCT ECOSYSTEM

TB CARE TODAY IS DESIGNED FROM A

PUBLIC HEALTH APPROACH & IS

AIMED AT ‘DISEASE CONTROL’

HUMAN-CENTERED DESIGN TO IMPROVE

TB CARE

PATIENTS’ WISH LIST FOR TB CARE

Active side effects

monitoring

High quality clinical care

Short & sweet

regimen

Targeted information

Peer based counselling

Treated with dignity

Access to mental

health care

Family involvement

Skills building activities

Legal and social

protection

1-stop shop services

Post survival support

11 YEARS TO 2030!

52