global tb elimination: tilting at windmills? · cluster-randomized trial of xpert vs. led...

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)

TB Case Fatality Rates, 2018


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


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


• 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


positive AFB smear


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

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