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Global TB Elimination: Tilting at Windmills?
Richard E. Chaisson, MDCenter for TB Research and Center for AIDS Research
Johns Hopkins University
Pablo Picasso, Don Quixote
Estimated number of cases
Estimated number of deaths
1.45 million(1.32-1.59 million)
10.0 million(9.0–11.1 million)
All forms of TB
MDR/RR TB
HIV-associated TB 862,000 (9%)(776,000-952,000)
251,000 (29% HIV+/17% total)(223,000-281,0000)
Source: WHO Global Tuberculosis Report 2019
The Global Burden of TB -2018
487,000 (4.9%)(420,000-560,000)
214,000 (44% MDR/15% total)
(133,000-295,000)
Source: WHO Global Tuberculosis Report 2019
TB Case Fatality Rates, 2018
Source: WHO Global Tuberculosis Report 2019
TB is the leading infectious cause of death globally
WHO Global Tuberculosis Report 2019
Vision: A world free of TB Zero TB deaths, Zero TB disease, and Zero TB suffering
Goal: End the Global TB epidemic
Vision, goal, targets, milestones
Progress towards 2020 targets
Source: WHO Global Tuberculosis Report 2019
End TB targets: Aspirations or delusions?
Salvador Dali, Tilting at Windmills
Global ART Scale-Up – A Delusion Being Realized
UNAIDS 2018.
Number of people living with HIV accessing antiretroviral therapy, global, 2000–2017 and 2020 target
35
30
20
15
10
5
0
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2020
2017
2018
2019
Num
ber
of
people
on a
nitre
troviral
thera
py
(mill
ion)
Number of people living with HIV on antiretroviral therapy Target
Nelson Mandela calls for action on TB at the Bangkok AIDS Conference
“The world has made defeating
AIDS a top priority… But TB
remains ignored. Today we are
calling on the world to recognize
that we can't fight AIDS unless we
do much more to fight TB as well.”
July 15, 2004!
Modeled approaches to reaching TB elimination
Dye, et al., Ann Rev Publ Health 2013
A Platform for Controlling Global Tuberculosis
• FIND the TB that is there– Passive case detection is not sufficient
– Improved diagnostic technologies very important
– Better case finding strategies essential
• TREAT the TB that is found– Improved treatment outcomes essential
– Shorter duration of treatment
– M/XDR is abysmal
– New drugs and treatment strategies urgently needed
• PREVENT the TB that hasn’t occurred yet– Preventive therapy essential for high risk populations
– Infection (transmission) control critical
– Control susceptibility (antiretrovirals, diabetes control)
– New vaccine
Gaps in TB Diagnosis
Source: WHO Global Tuberculosis Report 2019
• Adults dying at home, no
specific diagnosis
• (18% excluded, known to
have TB)
• Consent from family
• Bilateral axillary Tru-Cut
biopsy
• Modified bronchoalveolar
lavage
Tuberculosis found at limited autopsy in adults dying
at home from ‘natural causes’
Post-Mortem Diagnosis N=85 (%)
TB on ≥1 lab test 27 (32)
TB on ≥2 lab tests 18 (21)
Biopsy with TB (N=20)
Histology 14/20 (70)
AFB positive (ZN) 7/20 (35)
Xpert 17/20 (63)
MGIT 18/29 (62.1)
BAL with TB (N=22)
AFB+ (Auramine) 9/22 (41)
Xpert 20/22 (91)
MGIT 19/29 (86)
Omar et al., Int J Tuberc Lung Dis 2015,19:1320-5
Can private doctors in India diagnose TB? (Hint: no!)
Outcomes of Simulated Patients visiting private doctors
Kwan, et al. PLoS Med, 2018;15(9):e1002653.
Case 1: Classic TB
symptoms
Case 2: Classic TB +
failed antibiotics +
abnormal CXR
Case 3: Classic TB +
positive AFB smear
Case 4: Classic TB +
prior incomplete TB Rx
New Tools for Diagnosing TB
Xpert MTB/RIF Ultra
Omni Xpert Platform
BD Max
AbbottLAM
Adapted from: Dowdy et al., PLoS Medicine 2011:8(7): e1001063
Patient with TB symptoms
presents to clinic
TB morbidity averted, after
diagnostic delay
Test result positive?
Test sensitivityDiagnosis Delayed
Patient suffers from
untreated TB
No
No
Outcomes with TB Diagnostic
Tests
Yes
Yes
Adapted from: Dowdy et al., PLoS Medicine 2011:8(7): e1001063
Patient with TB symptoms
presents to clinic
TB morbidity averted, after
diagnostic delay
Patient initiates and
completes treatment?
Patient returns and is
offered treatment?
Results made available to
clinician and patient?
Test result positive?
Test sensitivity
Diagnostic test performed
properly?
Physician orders diagnostic
test?
Physician suspects TB?
Diagnosis Delayed
Patient suffers from
untreated TB
No
No
No
No
No
No
No
Cascade of Opportunities for Poor
Outcomes with TB Diagnostic
Tests
No
Cluster-randomized Trial of Xpert vs. LED Fluorescent Microscopy as Point of Care Test in HIV Clinics
Rate ratio for all-cause mortality at 1 year
0.83 (0.65, 1.06)
0.86 (0.47, 1.58)
0.73 (0.48, 1.11)
0.49 (0.28, 0.87)
1.19 (0.79, 1.78)
1.07 (0.55, 2.07)
0.46 (0.25, 0.84)
Ngwira et al., CID 2018
Favors Xpert Favors Microscopy
POC Tools for Diagnosing TB
Sputum-based Urine-based
Xpert MTB/RIF Ultra
Omni Xpert Platform
LAM
Can we treat our way out of the TB epidemic?
Modeling the impact of optimizing new treatments for DS and DR TB
Kendall et al., PLoS Medicine,
2017,14(1): e1002202.
Drug-susceptible TB Drug-resistant TB
Impact on 10-year DS incidence
-12% (95% CI 6-22%)
Impact on 10-year DR incidence
-32% (95% CI 18-46%)
https://www.who.int/tb/cHILD3.jpg
Universal antiretroviral therapy
TB preventive therapy
High impact strategies to treat and prevent HIV and TB are needed
START: Immediate vs Deferred ART for HIV+ People with CD4 >500
Endpoint
Immediate ART
(n = 2326)
Deferred ART
(n = 2359) HR (95% CI)
P Value
N Rate/100 PY N Rate/100 PY
Serious AIDS-related event 14 0.20 50 0.720.28
(0.15-0.50)< .001
Serious non-AIDS–related event 29 0.42 47 0.670.61
(0.38-0.97).04
All-cause death 12 0.17 21 0.300.58
(0.28-1.17).13
Tuberculosis 6 0.09 20 0.280.29
(0.12-0.73).008
Kaposi’s sarcoma 1 0.01 11 0.160.09
(0.01-0.71).02
Malignant lymphoma 3 0.04 10 0.140.30
(0.08-1.10).07
Non-AIDS–defining cancer 9 0.13 18 0.260.50
(0.22-1.11).09
CVD 12 0.17 14 0.200.84
(0.39-1.81).65
INSIGHT START Group. N Engl J Med. 2015; 373:795-807].
Does universal ART reduce TBincidence?
SEARCH
Ya Tsie
PopART
ANRS 12249
Iwuji et al. Lancet HIV 2018J Makhema et al. NEJM 2019;230-243RJ Hayes et al. NEJM 2019;381:207-218DV Havlir et al. N Engl J Med 2019;381:219-229
Does universal ART reduce TB incidence?
DV Havlir et al. N Engl J Med 2019;381:219-229.
59% lower rate of TB in Treat All
communities
Lancet Infect Dis. 2013;10:852-8
Clinic-level
OutcomeCases
Crude HR
(95% CI)p-value
Adjusted HR*
(95% CI)p-value
TB 475 0.87
(0.69-1.10) 0.240.73
(0.54-0.99)0.04
TB or
Death
1313 0.76
(0.66-0.87) <0.0010.69
(0.57-0.83)<0.001
Temprano Study of early ART + IPTIPT reduces risk of death by 37% - independent of ART
Badje et al., Lancet Global Health, 2017
Global uptake of TB preventive therapy is abysmal
WHO Global TB Report 2019
1.8 million PLWH received TB preventive therapy in 2018
Less than 6% of those eligible
0
100
200
300
400
500
600
700
800
900
Estimated Identified Screened Initiated Completed
99%
39%37%
Nu
mb
er
of
Ho
use
ho
ld C
hild
Co
nta
cts
60%49%
60%52%
94%
All proportions are cluster adjusted
55%
56%
96%37%
Overall: 9% of estimated household child contacts complete IPTp=0.39 p=0.12 p=0.79 p=0.87
Symptom Arm
TST Arm
Salazar-Austin, et al., CID 2019, epub ahead of print
Poor Uptake of TB Preventive Treatment for Child Contacts <5 yo
by Symptom or TST Screening, North West Province, South Africa
Uptake of TB Preventive Therapy (TPT) in PEPFAR Programs, 2018
Godfrey et al., IAS MOPDD0106LB Mexico City, 2019
TB Preventive Therapy Denialism
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000
2009 2010 2011 2012 2013 2014 2015 2016
AIDS deaths
• 11.1 million deaths
since 2009 (when
WHO recommends
IPT for all PLWH)
• ~37% preventable
with IPT?
• 4.1 million
preventable deaths?
Source: UNAIDS
HIV Deaths By Year
Global LTBI guidelines – massive scale-up of TB Preventive Therapy
• LTBI testing is not a requirement for initiating
preventive therapy in PLWH
• Treat all HIV+ people after active TB excluded
• Treat all household contacts <5
• Treat older household contacts with +LTBI test
IMPAACT4TBScaling up 3HP for TB Prevention
Problem
Consortium Partners
Low income countries Zimbabwe, Tanzania, Mozambique, Ethiopia, Malawi
Low Middle Income Countries Indonesia, Kenya, Ghana, India, Cambodia
High Middle Income Countries South Africa, Brazil
Project countries
UN High-Level Meeting, September 26, 2018General Assembly Declaration Commitments
• End the TB epidemic globally by 2030
• Treat 40 million people with TB from 2018-2022, including:• 3.5 million children• 1.5 million people with MDR-TB (including 115,000 children)
• Provide TB preventive therapy to 30 million people by 2022, including:• 4 million children <5• 20 million household contacts• 6 million PLHIV
• Increase global investments in TB prevention and care to $13 billion/year by 2022
• Increase global investment in TB research to $2 billion/year• Close $1.3 billion funding gap
http://www.un.org/en/ga/73/resolutions.shtml
Lancet Commission on TB Recommendations
• Scale up proven strategies• Ensure person- and family- centered care for all
• Reach high-risk populations with targeted screening, testing, and care
• Provide preventive therapy to those most at risk• People with HIV, household contacts, prisoners, others
• Prioritize private sector engagement
• Make diagnostic testing for drug resistance universally available
• Invest in TB Research and Development• Invest in R&D for diagnostics, drug regimens, and vaccines
• Invest in R&D for implementation science
• Implement existing tools and prepare for new advances
• Advocate with LMIC and industry to finance discover and uptake
Lancet Commission on TB Recommendations
• Ensure sustainable funding• Boost domestic funding for TB
• Reduce reliance on private sector funding
• Increase donor funding for TB as public good
• Develop new models of financing accountable to public
• Create an enabling environment• Accelerate progress towards Universal Health Coverage
• Fortify leadership and engagement of civil society
• Establish accountability mechanisms, e.g., report cards
Zero TB in Tibetan Kids:Implementing comprehensive TB control in a high-risk population
• Tibetan refugees have amongst the world’s highest rates of TB
– 400-1,000/100,000 in various settings1
• MDR TB is highly prevalent
– 14% in new cases, 31% in retreatment cases2
• TB control is limited by political persecution, lack of access, living in congregate settings (schools, monasteries), and distrust of outside health systems
1 Dierberg et al., EID 22:463, 2016, 2 Salvo et al., Int J Tuberc Lung Dis, 18:655–662,2014
Zero TB Kids: Comprehensive mobile community-based screening and
treatment program for active and latent TB that brings TB care to doorsteps of
the schools and monasteries
Active Case Finding &
Treatment
Reduction in Adult TB
cases under National
Program
Elimination in
Children
LTBI Screening and
Preventive Therapy
Community Mobilization
Zero TB Kids Framework for TB Control and
Elimination in Children
Community Mobilization
Zero TB Kids: 2017–2019
5726 students and staff
screened for active and
latent TB
2017
907 (655 new) students
and staff screened for
active and latent TB
2018 2019
4484 (987 new) students
and staff screened for
active and latent TB
11,119 people (10,141 students & 978 staff) screened over 3 years.
Year-wise Prevalence of Active TB in Schoolchildren
Year Students population
TB Disease Incidence
2017 5013 42 838/100,000
Year Students screened
Latent TBI Prevalence
2017 4860 913 19%
Year-wise Prevalence of Latent TBI in Schoolchildren
“Unlike many…diseases, TB is curable so it must be eliminated.… We should never let down our guard in the goal to eliminate TB.” - His Holiness The 14th Dalai Lama
Achieving TB Control: Our Duty as Medical and Public Health ‘Knights Errant’
“It is not the responsibility of knights errant to discover whether the afflicted, the enchained and the oppressed… suffer...for their vices, or for their virtues: the knight's sole responsibility is to succour them as people in need, having eyes only for their sufferings...”Miguel de Cervantes, “Don Quixote”
Pablo Picasso, Ciencia y caridad
AcknowledgementsJHU/PHRU
Eric Nuermberger
Amita Gupta
Kelly Dooley
Neil Martinson
Jacques Grosset
Kunchok Dorjee
Nicole Ammerman
Jonathan Golub
David Dowdy
Grace Link Barnes
Liz Bonomo
Funders:
NIAID/NICHD/NIH
CDC
UNITAID
FDA
USAID
STOP TB Partnership
Bill and Melinda Gates Foundation
JHU Alliance for a Healthier World
ACTG
Sue Swindells
Ritesh Ramchandani
Constance Benson
TBTC
Tim Sterling
Elsa Villarino
Marcus Conde
Aurum Institute
Gavin Churchyard
Zero TB in Tibetan Kids
Zorba Paster
Tsetan Sadutshang
Sonam Topgyal
Dawa Phunkyi
Gracias
Alice Neel, T.B. Harlem, 1940