GJ Churchyard

20th November 2013

Aeras

Thaler lecture

Preventing TB in high burden countries: lessons learnt from treatment of latent

TB infection

Overview

Background

TB preventive therapy Impact on TB control

Durability

MDR TB

Test of cure

Mechanisms of protection

Implications for TB vaccines

Conclusion

Background

• Burden of disease

• Strategies for TB elimination

• Treatment of LTBI

Estimated TB incidence, 2012

Global trends in TB

Incidence Prevalence Mortality

(Global TB report, 2013)

Potential impact of new TB vaccines, diagnostics and drugs in SE Asia

Sou

rce:

L. A

bu

Rad

da

d e

t al, P

NA

S 2

009

William Osler A Canadian Physician in the 1800

“All who mix with tuberculosis patients got infected, but remained

well so long as they took care of themselves and kept the soil in a

condition unfavourable for the growth of the seed.”

Efficacy of IPT

Akolo. 2010, Cochrane review

0.36

0.86

0.86

0.67

0.74

0.81

1.02

0.95

1.0 1.0

TB prevention: Achieving population level impact

• Treatment of latent TB infection

o Community-wide

o HIV clinics

Churchyard GJ, Lewis JJ, Fielding KL,

Vynnycky E, White RG, Grant AD

on behalf of the Thibela TB team

Community-wide isoniazid preventive therapy among gold miners in South

Africa: the Thibela TB study

TB case notification rates <5%/yr by 2001

Driven by silicosis, exacerbated by HIV (~30% in 2000)

Not contained by conventional control measures

Year

1000

2000

3000

4000

5000 HIV Pos HIV Neg

0

Epidemic TB in SA gold mines

TB rate / 100,000 pop

Extraordinary

problem, needing

an extraordinary

intervention

Effectiveness of IPT among HIV-infected miners

(Grant AD, JAMA, 2005)

Time to recurrence by HIV status

3.5 / 100 pyo

8.7 / 100 pyo

• Re-infection accounted for 68% of recurrence

• ARI ~ 10% / year

(N=609, FU = 1.02 years)

(S Charalambous. Int J TUBERC Lung Dis. 2008;12(8):942–948

0.45

0.3

Haller (1999)

Fitzgerald (2000)

Churchyard (2002)

Reference

(Incidence Rate Ratios & 95% CI)

Efficacy of secondary preventive therapy among HIV+ individuals

1.0

0.18

(Churchyard GJ. Infect Dis. 2007;196 (Suppl. 1): S52-62.)

0

500

1000

1500

2000

2500

3000

1954 1957 1960 1963 1966 1969 1972

Community-wide IPT was effective in controlling epidemic TB in Alaska

TB

in

cid

en

ce p

er

100,0

00 p

op

Comstock. Am Rev Respir Dis. 1979;119:827

Thibela TB: interrupting TB transmission

2.5% prevalence of active TB:

89% prevalence of latent TB

Screen entire

population for

active TB

Active disease:

treatment for

active disease

No active

disease:

treatment for

latent infection

Aim

To compare the

effectiveness of

isoniazid preventive therapy (IPT) given on a community-wide basis

to current standard of care on TB among gold miners in South Africa

Methods

Study design

Cluster-randomised intervention study

Cluster defined as all employees & contractors at mine shaft(s) and associated hostels

Hostels Mine shaft

Cluster

Study design Cluster-randomised intervention study

15 clusters:

5,366 11,892

3,025

6,124 6,586 3,665 8,756 6,091 2,279

1,266 5,187 3,200 3,296 9,173 2,690

Study design Cluster-randomised intervention study

15 clusters: 8 intervention and 7 control

5,366 11,892

3,025

6,124 6,586 3,665 8,756 6,091 2,279

1,266 5,187 3,200 3,296 9,173 2,690

Intervention

Intervention offered to entire workforce

TB screening: symptoms and chest X-ray

Persons with suspected TB investigated by

collecting one sputum specimen for microscopy,

culture, speciation & DST

If eligible, 9 months of isoniazid preventive

therapy. Monthly follow-up visits for

dispensing & screening for TB (symptom) &

possible side effects

Intervention follow-up 9 months

Intervention enrolment 3-16 months

Primary outcome measurement 12 months

Final Survey

Baseline Survey

TB episodes: data collection

Study activity timeline Intervention clusters

Nominal follow-up time

Primary outcome measurement 12 months

Final Survey

Baseline Survey

Study activity timeline Control clusters

TB episodes: data collection

Primary endpoint TB incidence (all cases) among employees

measured over 12 months from last person enrolled completing therapy

Fielding et al Contemporary Clinical Trials 2011 32:382-92

Intervention follow-up 9 months

Intervention enrolment 3-16 months

Primary outcome measurement 12 months

Final Survey

Baseline Survey

Nominal follow-up time

Primary outcome measurement 12 months

Intervention

Control

Secondary endpoints: TB prevalence TB prevalence (sputum culture) among a sample of

employees at the end of the study

Fielding et al Contemporary Clinical Trials 2011 32:382-92

Intervention follow-up 9 months

Intervention enrolment 3-16 months

Primary outcome measurement 12 months

Final Survey

Baseline Survey

Nominal follow-up time

Primary outcome measurement 12 months

Intervention

Control

Results

Participant flow Total population

78,744

Intervention clusters 40,981

Control clusters 37,763

Consented 27,126 (66.2%)

Started IPT 23,659 (87.2%)

Ineligible 1,455 TB suspect 2,012 Ineligible for IPT

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

cum

ula

tive

% o

f cl

ust

er

con

sen

ted

month from start of intervention

Uptake to the intervention

Uptake in first four clusters = 58.0%

Uptake in last four clusters = 78.7%

% population taking IPT by study month

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

% o

f cl

ust

er

dis

pe

nse

d IP

T p

er

mo

nth

month from start of intervention

TB Person years Rate/100 pyo

Intervention 887 29,352 3.02

Control 856 29,015 2.95

Effectiveness TB incidence

Among employees in the primary outcome measurement

Incidence rate ratio Unadjusted 1.00 (95% CI 0.75-1.34) Adjusted* 0.96 (95% CI 0.76-1.21) *Adjusted for individual level variables gender, age, surface/underground work, and cluster level variables of silicosis and ART prevalences TB case notification rate 12-months prior to cluster enrolment and pre-randomisation strata

TB prevalence: no effect

Among a sample of employees at study end

TB (n) Total (N) Prevalence (%)

Intervention 166 7,049 2.35

Control 119 5,557 2.14

Prevalence rate ratio Unadjusted 1.05 (95% CI 0.60-1.82) Adjusted* 0.98 (95% CI 0.65-1.48) *Adjusted for gender, age, place of work (individual level); silicosis, ART use, TB CNR (cluster level)

TB case notification rates control clusters

TB case notification rates Intervention clusters

Individual-level effect of isoniazid preventive therapy on risk of

tuberculosis in the Thibela TB study

Objective

We investigate the effect of IPT on TB incidence in individuals starting IPT in intervention clusters vs.

individuals in control clusters

Results – flow diagram Baseline survey

(n=15,609, 15 clusters)

Employees

(n=14,005, 15 clusters)

Control clusters

(n=6,397, 7 clusters)

Intervention clusters

(n=7,608, 8 clusters)

Control arm

(n=6,263, 7 clusters)

IPT arm

(Started IPT)

(n=4,646, 8 clusters)

Excluded

Did not start IPT

(n=2,963)

Excluded

TB / IPT

(n=134)

Excluded

Not employees

(n=1,604)

Thibela TB: duration of IPT effect after at least 6 months of IPT at individual level

0

0.5

1

1.5

2

2.5

3

3.5

0-9 m 9-18m >18m

TB in

cid

en

ce p

er

10

0 p

yrs

IPT arm

Control arm86% reduction in TB

incidence during 9m of IPT

(Fielding CROI 2012)

Reactivation vs. reinfection

Cure, no reinfection Reactivation, no reinfection

Reactivation & reinfection Cure, reinfection

Placebo

6H

Cu

mu

lati

ve in

cid

en

ce

Impact of TB screening on TB incidence among 480 HIV-infected SA gold miners TB screen

Symptoms

CXR

Sputum microscopy and culture (x2)

TB prevalence: 3.3%

TB incidence: 2.6 per 100 pyo

IRR: 1.1

-12 months 12 months Prospective FU Retrospective FU

(Corbett et al. Am J Respir Crit Care Med. 2004,

Lewis et al. Am J Respir Crit Care Med. 2010)

TB Incidence rates following screening

Rates/100py 95% CI

HIV negative < 6 months 0.87 0.34 – 1.96

>6 months 1.83 0.87 – 3.83

HIV positive < 6 months 5.68 3.36 – 9.58

> 6 months 6.70 3.61 – 12.45

Thibela TB: duration of IPT effect after at least 6 months of IPT at individual level

0

0.5

1

1.5

2

2.5

3

3.5

0-9 m 9-18m >18m

TB in

cid

en

ce p

er

10

0 p

yrs

IPT arm

Control arm86% reduction in TB

incidence during 9m of IPT

(Fielding CROI 2012)

Reactivation

Thibela TB: duration of IPT effect after at least 6 months of IPT at individual level

0

0.5

1

1.5

2

2.5

3

3.5

0-9 m 9-18m >18m

TB in

cid

en

ce p

er

10

0 p

yrs

IPT arm

Control arm86% reduction in TB

incidence during 9m of IPT

(Fielding CROI 2012)

Reinfection

0

2000

4000

6000

8000

-1 0 1 2 3 4

Control

Intervention

Years since the introduction of IPT

Allowing model to assume 6m IPT might not cure

Nu

mb

er

of

cases/1

00,0

00 p

yrs

(measu

red

in

cid

en

ce)

Assuming 6m IPT cures latent infections

To match no effect observed, model needed to assume 6 months IPT did not cure latent infections

Best–fitting: % cured= 0%

0

2000

4000

6000

8000

-1 0 1 2 3 4

Dynamic Persistence of Antibiotic-Stressed Mycobacteria

(Wakamoto, Science, 2013))

Even if optimally implemented, community-wide IPT for 9 months would not be a long term solution to TB control in mines

Thibela TB: lack of IPT durability undermines intervention effect

Num

ber

of

ca

se

s/1

00

,000

/ye

ar

(tru

e in

cid

en

ce)

0

1000

2000

3000

4000

No intervention

Optimised IPT

implementation

Thibela TB: summary Community-wide IPT among gold miners

─ At the individual level reduced TB incidence

─ At the population level did not improve TB control

The effect of IPT was not durable due to ─ High rate of reinfection

─ Failure to cure latent infection

Continuous targeted IPT is required to durably reduce risk of TB in high transmission settings

%

reduction HR (95% CI) p-value

Primary Analysis

TB 475 0.87 (0.69-1.10) 0.24

TB/Death 1313 0.74 (0.64-0.85) < 0.001

IPT promotion in 29 HIV clinics in Rio de Janeiro,

Brazil reduced TB incidence/death at a clinic-level

TB incidence during and following IPT

CROI 2013; 190LB

CROI 2013; 190LB

TB incidence during and following IPT

non-completers

Completers

Results: 5-Year Durability

54

0

1

2

3

4

0

5

10

15

20

0 1 2 3 4 5

Po

pu

lati

on

TB

/HIV

Mo

rtal

ity,

pe

r 1

00

,00

0/y

r

Po

pu

lati

on

TB

/HIV

Inci

de

nce

, p

er

10

0,0

00

/yr

Year Since Initial Roll-Out

No IPT

IPT

IPT: 15.6% reduction

IPT: 14.3% reduction

Incidence

Mortality

(Annual rate of IPT delivery: 20%/year to fit study data)

(David Dowdy, Union Conference 2012)

TB preventive therapy

Durability

6-months IPT has limited durability in PWHIV in pre-ART era

6-months IPT has limited durability in PWHIV in pre-ART era

6 months IPT (6H)

36 months IPT (36H)

3 year randomized

controlled trial

Follow-up observation

average 2.7 years/pt

Isoniazid

ART

Increasing ART initiation Antiretroviral therapy

TB rates increase soon after stopping IPT 6H vs 36H in PWHIV in Botswana

0%

3%

6%

9%

0 200 400 600 800 1000

Days after enrolment

Cu

mu

lati

ve

TB

in

cid

en

ce

6H 36H

In-trial n=468

6H 36H

TB rates increase soon after stopping IPT 6H vs 36H in PWHIV in Botswana

TST positive participants

0%

3%

6%

9%

0 200 400 600 800 1000 1200

Days after trial end

Post-trial (no IPT) n=395

6H 36H

0%

3%

6%

9%

0 200 400 600 800 1000

Days after enrolment

Cu

mu

lati

ve

TB

in

cid

en

ce

6H 36H

In-trial n=468

6H 36H

TB rates increase soon after stopping IPT 6H vs 36H in PWHIV in Botswana

↑ 90%

TST positive participants

Time to TB or death: as treated

Martinson, NEJM 2011

6H

cIPT

TB preventive therapy

Latent TB infection with M/XDRTB

Household contacts of M(X)DR TB patients have increased risk of TB & death

Author Pop MDR TB XDR TB

/ Year Incidence 100 pyo

% DST same

% died

Incidence 100 pyo

% DST same

% died

Vella

/ 2011 a

KZN SA

4.0 43.8 14 3.3 59.4 52

Grandjean

/ 2011 b Lima Peru

2.4 72 - - - -

Becerra

/ 2011 c Lima Peru

1.5 59.7 - 2.9 - -

Households with secondary TB cases, % with≥2 TB cases: a=14.5%, b=26.3%, c=unknown

Author Pop MDR TB XDR TB

/ Year Incidence 100 pyo

% DST same

% died

Incidence 100 pyo

% DST same

% died

Vella

/ 2011 a

KZN SA

4.0 43.8 14 3.3 59.4 52

Grandjean

/ 2011 b Lima Peru

2.4 72 - - - -

Becerra

/ 2011 c Lima Peru

1.5 59.7 - 2.9 - -

Households with secondary TB cases, % with≥2 TB cases: a=14.5%, b=26.3%, c=unknown

Household contacts of M(X)DR TB patients have increased risk of TB & death

Author Pop MDR TB XDR TB

/ Year Incidence 100 pyo

% DST same

% died

Incidence 100 pyo

% DST same

% died

Vella

/ 2011 a

KZN SA

4.0 43.8 14 3.3 59.4 52

Grandjean

/ 2011 b Lima Peru

2.4 72 - - - -

Becerra

/ 2011 c Lima Peru

1.5 59.7 - 2.9 - -

Households with secondary TB cases, % with≥2 TB cases: a=14.5%, b=26.3%, c=unknown

Household contacts of M(X)DR TB patients have increased risk of TB & death

Author Pop MDR TB XDR TB

/ Year Incidence 100 pyo

% DST same

% died

Incidence 100 pyo

% DST same

% died

Vella

/ 2011 a

KZN SA

4.0 43.8 14 3.3 59.4 52

Grandjean

/ 2011 b Lima Peru

2.4 72 - - - -

Becerra

/ 2011 c Lima Peru

1.5 59.7 - 2.9 - -

Households with secondary TB cases, % with≥2 TB cases: a=14.5%, b=26.3%, c=unknown

Household contacts of M(X)DR TB patients have increased risk of TB & death

There is a lack of evidence to support use of existing TB drugs for treatment of LTBI with

MDR TB

Potential to use new TB drugs for treating DR LTBI

TB preventive therapy

Mechanisms of protection

Possible mechanisms of protection

Latently infected

person

Possible mechanisms of protection Reduce bacterial burden

Rapid rebound after stopping INH

Rapid rebound after stopping 6H in TST+ Botswanans

Reduced bacterial

burden

Possible mechanisms of protection Reduce bacterial burden

Rapid rebound after stopping INH

Cure, resulting in durable protection 12H in HIV-infected persons in America’s

Cured LTBI (Gordin JAMA 2000)

Possible mechanisms of protection Reduce bacterial burden

Rapid rebound after stopping INH

Cure, resulting in durable protection 12H in Alaskan households

12H in HIV-infected persons in America’s

Prevent reinfection Molecular epidemiology data and high

ARI suggests in high burden settings suggest that the risk of reinfection may be large

Continuous IPT provided durable protection in Botswana and South Africa

Protect against

reinfection

TB free survival in BCG vaccinated infants living with HIV

(Madhi, NEJM, 2011)

Durability post IPT high vs. low burden settings

High transmission settings Low transmission settings

Durability post IPT high vs. low burden settings

High transmission settings Low transmission settings

Durability post IPT high vs. low burden settings

High transmission settings Low transmission settings

High transmission settings Low transmission settings

Durability post IPT high vs. low burden settings

High transmission settings Low transmission settings

• Reduce transmission through

case finding and treatment

• Continuous IPT

• Better regimens

Durability post IPT high vs. low burden settings

High transmission settings Low transmission settings

• Reduce transmission through

case finding and treatment

• Continuous IPT

• Better regimens

• Better, shorter regimens

Durability post IPT high vs. low burden settings

TB preventive therapy

Test of cure

Test of LTBI treatment efficacy Tests for latent TB infection (LTBI) (TST & IGRAs) that are

predictive of future TB risk are available

Biomarkers of LTBI treatment efficacy are needed to identify

those cured

those inadequately treated & at high risk of reactivation

A test of LTBI treatment efficacy will be useful in

Managing patients treated for LTBI

Conducting shorter trials of novel LTBI regimens

therapeutic vaccines

Trial of interferon-g as a biomarker of LTBI treatment efficacy

1,659 HIV-uninfected, TST+, ELISPOT+ household contacts enrolled in the Gambia

IFN-g is not a useful biomarker of treatment efficacy in LTBI (Adetifa et al, Am J Respir Crit Care Med, 2013)

Trial of interferon-g as a biomarker of LTBI treatment efficacy

1,659 HIV-uninfected, TST+, ELISPOT+ household contacts enrolled in the Gambia

IFN-g is not a useful biomarker of treatment efficacy in LTBI (Adetifa et al, Am J Respir Crit Care Med, 2013)

Lessons learnt from treatment of LTBI: implication for TB vaccines

Implications for post exposure TB vaccine

? higher bacterial load in HBCs

May need both treatment of LTBI and vaccines

Need to cure existing infection and prevent reinfection

Needs to be effective in HIV-uninfected and infected persons

Need a test of cure of LTBI

reinfection

Conclusion

Conclusion

The risk of HIV associated TB can be reduced by TB preventive therapy

In high burden settings, TB after IPT is likely to be due to reactivation and reinfection

Continuous IPT can provide durable protection from TB regardless of the mechanism

Effective TB vaccines are required to achieve TB elimination