Can TB Be Eliminated?

Richard E. Chaisson, MDCenter for AIDS ResearchCenter for TB Research

Johns Hopkins University

Estimated number of cases

Estimated number of deaths

1.8 million*(1.5-2.1)

10.4 million(8.7–12.2 million)(IR=142/100,000)

All forms of TB

MDR TB / RR TB

HIV-associated TB 1.2 million (11%)(1.0–1.3 million)

390,000 (22%)(320,000-460,000)

WHO Global Tuberculosis Report 2016

The Global Burden of TB -2015

580,000(520,000-640,000)

250,000(160,000–340,000)

*1.4 million among HIV negative

WHO Global Tuberculosis Report 2016

TB is now leading infectious cause of death

WHO Global Tuberculosis Report 2016

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

Eradication, elimination or control?

• Eradication – complete absence of the disease from the planet.

• Elimination – ending the disease as a public health problem. • Defined as TB incidence of <1 per million and TB deaths <1 per 10 million

• Control – making it a much smaller problem than it currently is.

Tools to Control of TuberculosisWhy hasn’t TB already been eliminated?

• Global failure to apply biomedical tools effectively– Weaknesses in health systems– Lack of political will and commitment

• Inadequacies of most widely used tools– Smear detection of cases ~50%– Adherence to regimens is poor and MDR TB regimens are toxic and weak – BCG vaccine does not prevent adult TB

• Changing epidemiological situation– HIV epidemic– MDR– Migration

• Global policies that lack understanding of best epidemiologic approaches

Primary

TB (~2-3 million/year)

Uninfected/Susceptible

(5 billion)

Case finding and treatment of active TB

TB Preventive Rx

Latent TB(Global ~ 2 billion)

Active TB(Global ~6-7 million/year)

Vaccination

Reduce and treat individual drivers (HIV)

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– 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

TB Case Detection: Missed Cases Drive Transmission and Mortality

WHO Global Tuberculosis Report 2013

• 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

New Tools for Diagnosing TB

Xpert MTB/RIF UltraOmni Xpert Platform

BD MaxAbbott

New tools are exciting and attractive, but do they make a difference in incidence of disease or death?

Southern Africa Zambia

Western Cape

Western Cape 0 3

0 Km

15

Zambia

0 400 K

200

ZAMSTAR Interventions:Enhanced Case finding vs. Household Contact Screening

• Enhanced case finding (ECF)– Community Mobilization and sputum collection– School intervention– Open Access at the clinic

• Household intervention (HH)– Visit all households of new TB patients– Offer TB screening, HIV testing and referral to appropriate care to entire

household

0.82

0.45

1.09

1.36

0.13 0.25 0.50 1.00 2.00 4.00 8.00 16.00

Household Evaluations: Impact on TB prevalence

ECF impact on TB prevalence

ECF impact on transmission in children

Risk ratios (for prevalence) and Rate ratios (for transmission)

Impact of Household Contact Evaluations for New TB Patients or Community Active TB Case (ECF) Finding in High Burden Areas

Household Evaluations: impact on transmission in children

H. Ayles, et al., Lancet, 2013

18%

55%

Impact of Improving Case Finding and Treatment on Tuberculosis Control: A Mathematical Model

0

5

10

15

0 2 4 6 8 10Years After Stabilization of Case Detection Rate

Ann

ual D

eclin

e in

TB

Inci

denc

e (%

)

20%40%60%70%80%

Case Detection Rate:

Dowdy and Chaisson, Bull WHO 2009, 87:296–304

Effect of case-finding plateaus eventually

PERÚ: TASA DE MORBILIDAD E INCIDENCIA DE TUBERCULOSIS. 1990 – 2014*

* Información preliminarFuente: ESNPCT /DGSP /MINSA /PERUFecha de Elaboración.: 17-MAR-2015

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014*

MORBILIDAD 198. 202. 256. 248. 227. 208. 198. 193. 186. 165. 155. 146. 140. 123. 124. 129. 129. 125. 120. 118. 109. 109. 105. 101. 100.INCID TBC 183. 192. 243. 233. 215. 196. 161. 158. 156. 141. 133. 126. 121. 107. 107. 109. 109. 106. 103. 102. 95.7 97.4 93.0 90.3 87.5INCID TBP FP 116. 109. 148. 161. 150. 139. 111. 112. 111. 97.1 87.9 83.1 77.4 68.8 66.4 67.1 67.9 64.5 63.9 61.9 58.3 59.7 58.6 55.3 54.7

0.0

50.0

100.0

150.0

200.0

250.0

300.0

TASA

PO

R 1

00 0

00 H

ABIT

ANTE

S

CDC, 2016

Contact evaluation: combining TB case finding and TB preventive therapy: DOTS Ampliado (Enhanced DOTS)

• Cluster-randomized trial in 8 neighborhoods in central Rio de Janeiro comparing standard DOTS to DOTS Ampliado

• DOTS Ampliado:– Identification of all household contacts (household visits)– Evaluation with PPD, x-ray and clinical exam– 4% of contacts had active TB– 72% of contacts had latent TB– ~70% of contacts treated with preventive therapy

Cavalcante et al., Int J TB Lung Dis 2010:14:203-9

Community-Randomized Trial of Household Contact Evaulation and Preventive Therapy (DOTS-A) vs DOTS in Rio de Janeiro

0

50

100

150

200

250

300

350

400

450

1999 2000 2001 2002 2003 2004

Year

TB

Inci

denc

e/10

0,00

0

DOTSDOTS-A

p=0.04, 1999 vs. 2004

Cavalcante et al., Int J TB Lung Dis 2010:14:203-9

15% difference

Preventive Interventions in TB

Prevent Infection Reduce ChemoprophylaxisSusceptibility

TB and HIV vaccines obvious additional strategies, but not currently available

Prevalence of latent tuberculosis infection in rural China

Gao, et al. Lancet Infect Dis 2015:15;310-9

Tuberculin Skin Test >10 mm

Tuberculin Skin Test >10 mm

Quantiferon test positive

Quantiferon test positive

Preventive Interventions in TB:Impact of ART on TB Incidence in HIV+ People

ReduceSusceptibility

A.B Suthar, et al. PLoS Medicine, 2012

Intervention

Control

Month1 2 3 4 5 30 36 42

TB-HIV in Rio (THRio): Improving the uptake of TB screening and INH preventive therapy (IPT) in people receiving care of HIV infection in Rio

de Janeiro

28

Intervention• Training for 2 clinics every other month• Implementation of TB screening and TST policy for

all HIV-infected patients• TST to be done for all eligible clinic patients

– No prior TB history– No prior IPT– No prior +TST

• IPT x 6 months for all TST+ without active TB and all contacts of active TB cases

Clinic-level Outcome Cases Crude HR

(95% CI) p-value Adjusted HR* (95% CI) p-value

TB 475 0.87 (0.69-1.10) 0.24

0.73 (0.54-0.99) 0.04

TB or Death

1313 0.76 (0.66-0.87) <0.001

0.69 (0.57-0.83) <0.001

*Adjusted for age, sex, ART and CD4 count at enrollment

Lancet Infect Dis. 2013;10:852-8

Long term efficacy of IPT in HIV-infected persons in a medium TB burden setting: Rio de Janeiro

Golub, et al. CID, 2015

0.00

0.05

0.10

0.15

0.20

0.25

Cum

ulat

ive

prob

abili

ty o

f tub

ercu

losi

s

732 1470(7) 1506(12) 1437(12) 1149(2) 790(5) 414(3) 189(0)Started IPT1222 400(58) 318(14) 241(9) 168(1) 123(2) 84(2) 62(0)Did not start IPT

Number at risk (events)

1 mo 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr 7 yrYears since PPD+

Did not start IPTStarted IPT

TEMPRANO: Immediate vs Deferred ART Initiation and IPT Delivery for African Patients Not ‘Eligible’ for ART

TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015

Mos From Randomization

Cum

ulat

ive

Prob

abilit

y of

D

eath

or S

ever

e H

IV-R

elat

ed Il

lnes

s (%

) 25

20

15

10

5

00 6 12 18 24 30

Deferred ARTDeferred ART + IPTImmediate ARTImmediate ART + IPT

30-Mo Probability, %14.18.87.45.7

Poor Global Uptake of IPT for People with HIV

WHO. Global TB Report, 2016

The Cascade of Care for Latent TB

Alsdurf et al., Lancet ID, 2016

31% start PT

18.8% complete PT

Valid Result Obtained903 (76%)

Eligible1214 (76%)

Enrolledn = 1169 (96%)

IGRA Clinics

Valid Result Obtained83 (6%)

Eligible990 (78%)

Enrolledn = 933 (94%)

Standard-of-Care (TST)

Martinson and Golub, IUATLD 2016

TEKO Study – Interferon Gamma Release Assay Blood Test vs Tuberculin Skin Test to Screen HIV+ People for TB

Cluster-Randomized Trial of Nurse-initiated IPT based on symptom screening vs TST-based screening

Restricted Randomization

-Mean No. TB cases/month-Distance from

Hospital • Koombi fare

16 Matlosana Sub-district Primary Care Clinics

8 clinics: TST-based

Screening

Symptom-based

ScreeningEndpoint:Proportion of child contacts started on IPT

Salazar-Austin, CROI 2017

Screening and provision of INH preventive therapy to child contacts in Matlosana Health District, October 2015 – March 2016

# TB In

d e x Ca s e s

# Es t im

a ted C o n ta

c ts <

5 y

r

# Ide n t if

ied C o n ta

c ts <

5

# Sc re

e n e d C o n tac ts

< 5

# Co n ta

c ts In

it ia te

d Tre

a tme n t

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

1 4 0 0

C a s c a d e o f C h ild C o n ta c t E v a lu a tio n

1 1 7 3

8 2 1

4 0 8

2 0 2 1 8 5

Salazar-Austin, CROI 2017

Estimated INH Coverage for Child Household Contacts

= 22%

1 month of daily rifapentine/INH (HP) vs 9 months of daily INHACTG A5279 Study

Design: Multicenter, randomized, open-label, phase III clinical trial

Study Population: 3000 HIV-infected participants >12 years old in 13 countries

Stratification 1) CD4+ cell count at entry (<100, 100-250, and >250 cells/mm3) 2) ART use at entry (Yes/No – 50% on ART at entry)

Duration: 3 years (156 weeks) after the last participant is enrolled

R. Chaisson and S. Swindells, Co-Chairs

Target Populations for TB Control in Developed CountriesActive case finding and preventive therapy

• Immigrants and refugees from high-burden countries• Immunosuppressed patients

– HIV– TNF and cytokine inhibitors– Transplant and chemotherapy

• Injection drug users• Prisoners • Homeless• Comorbidities: smoking, diabetes, end-stage renal disease

Understanding Local Drivers of TBRisk Factors in Patients with Culture-Confirmed Pulmonary TB in Baltimore

Characteristic No. (Total = 139) %

Foreign born 12 9%

HIV Infection 31 24%IDU 28 20%

Diabetes 18 14%Renal Failure 12 9%Recent Cancer 8 6%

Steroid Use 7 6%

Oursler et al., CID 2002;34:729-9

How to improve TB control globally

• Increase case finding• Better diagnostic tests• Active case finding, especially in household contacts

• Initiate treatment early and improve outcomes• Reduce early losses to follow up• Better regimens

• Prevent TB in high-risk populations• Preventive therapy for those at increased risk

• Better regimens – sterilizing regimens in high-burden settings• Reduce susceptibility, e.g., ART

Can TB be eliminated? Probably not by 2035 or even 2050.

Can TB be controlled? Yes, with investment in epidemiologically sound strategies and tools

and greatly improved delivery.

AcknowledgementsJHU/PHRUJonathan GolubNeil MartinsonDavid DowdyLarry MoultonNicole Salazar-AustinSilvia CohnBonnie KingGrace Link BarnesAnne EfronSusan DormanJenny HoffmannChris Hoffmann

Funders:Fogarty Int’l CenterNIDANIAID/NIHCDCFDABill and Melinda Gates Foundation

ZAMSTARPeter Godfrey-FaussettHelen AylesNulda BeyersRichard HayesTHRioSolange CavalcanteBetina DurovniValeria SaraceniACTGSue SwindellsTBTCTim SterlingElsa VillarinoMarcus Conde