TB prevention: new data, new approaches, new challenges

Improving health worldwide

www.lshtm.ac.uk

Alison GrantLondon School of Hygiene & Tropical Medicine

TB prevention: breaking the cycle

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HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

HIV-

HIV+

slide courtesy Peter Godfrey-Faussett

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HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

Prevent infection

TB prevention: breaking the cycle

HIV-

HIV+

--_-_--_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

Prevent disease

TB prevention: breaking the cycle

HIV-

HIV+

TB prevention: low transmission settings

TB prevention: low transmission settings

_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

Prevent reactivation

HIV-

HIV+

0.67

0.36

0.86

Overall

TST+

TST-

Placebo

Relative risk, 95% CI

Akolo 2010, Cochrane review

Effect of isoniazid preventive therapy (IPT) on TB for HIV+:meta-analysis of clinical trials

1.0

Low TB transmission settings• most TB disease arises from latent infection• treatment of latent TB is central to TB elimination• INH x 9 months is long, completion rates are poor• shorter regimens preferable if effective, safe

Rifapentine+INH vs. INH

N=7731 (MITT)

Rp/INH weekly (DOT) x3m

N=398689% US/Canada

2% HIV+72% TB contacts

82% completion

INH daily (self) x 9m

N=374589% US/Canada

2% HIV+70% TB contacts

69% completion

Sterling NEJM 2011;365:2155

Rifapentine+INH vs. INH: results to 33 months

Sterling NEJM 2011;365:2155

non-inferior

9H: 15 TB cases0.16/100pyrs

3RpH: 7 TB cases0.07/100pyrs

Rifapentine+INH vs. INH in HIV+

N=394 (MITT)

Rp/INH weekly x3m (N=201)

Median CD4 493US/Canada 44%

Permanent d/c, any 11%Permanent d/c 2⁰ AE 4%

Hepatotoxicity, drug-related 2%

INH daily x 9m (N=193)

Median CD4 514US/Canada 50%

Permanent d/c, any 35%Permanent d/c 2⁰ AE 4%

Hepatotoxicity, drug-related 6%

Sterling AIDS 2012

Shorter preventive regimens under investigation

• rifampicin x 4m vs. INH x9m– adults, TST+ or IGRA+ (excluding HIV+ on incompatible

ART)– currently recruiting, high and low burden settings

• rifapentine/INH daily x1m vs. INH daily x 9m– HIV+, TST≥5mm OR IGRA+ OR resident in high burden

country – self-administered– started recruitment 2012

TB prevention: high transmission settings

TB prevention: high transmission settings

--_-_--_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

HIV-

HIV+

TB prevention: high transmission settings

--_-_--_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

HIV-

HIV+

TB prevention: high transmission settings

--_-_--_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

HIV-

HIV+

TB infection control is TB prevention

MSF South Africa, Gilles van Cutsem and Colin Brown

Earlier TB treatment is TB prevention

morbidity

infectiousness

asymptomatic

symptomatic, does not seek care

symptomatic, seeks care

smear neg, culture neg

smear neg, culture pos

smear pos, culture pos

The long and winding road to TB treatment

TB curedHassymptoms

Attends health centre

TB test sent

TB test result

Treatment start

Infectious

infectiousness

Earlier test result is TB prevention……..

TB curedHassymptoms

Attends health centre

TB test sent

TB test result

Treatment start

Infectious

infectiousness

…providing positive test results lead to treatment

TB curedHassymptoms

Attends health centre

TB test sent

TB test result

Treatment start

Infectious

infectiousness

mind the gap…..

Initial default and time to treatment: Thibela TB

S-C-

S-C+

S+C+

0.00

0.25

0.50

0.75

1.00

pro

po

rtio

n n

ot o

n R

x

0 3 6 9 12follow-up time (months)

median = 5.1 months

median = 12 days

Smear neg, culture neg

Smear neg, culture pos

Smear pos

Churchyard et al, SA TB conference 2012

Earlier testing is TB prevention

TB curedHassymptoms

Attends health centre

TB test sent

TB test result

Treatment start

Infectious

infectiousness

P. Godfrey-Faussett, H. Ayles, N. Beyers

Southern Africa

Map Source: Google Earth October 2007

Zambia

Western Cape

Western Cape0 30 Km15

Zambia

0 400 Km

200

A community randomized trial of two interventions delivered to ~1,200,000 people while strengthening the existing health systems

ZAMSTAR: two interventions

• Total population 962,655• 24 communities• Enhanced case finding (12 vs. 12):

community mobilisation open access to sputum microscopy TB/HIV at the

clinic: 257,698 Enhanced case

Finding: 148,090

Household: 257,729

ECF & household: 299,138

ZAMSTAR: two interventions

• Total population 962,655• 6 communities per arm• Enhanced case finding (12 vs. 12):

community mobilisation open access to sputum microscopy

• Household intervention (12. vs. 12) TB patient as entry point to household Screening for TB and HIV Referral for treatment and care

TB/HIV at the clinic: 257,698

Enhanced case Finding: 148,090

Household: 257,729

ECF & household: 299,138

000 000 001 001 002 004 008 016

1.36

1.09

0.45

0.82 HH impact on prevalence

HH impact on transmission

ECF impact on prevalence

ECF impact on transmission

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

Household intervention reduced TB prevalence and transmission

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HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

Prevent reactivation

TB preventive therapy in high transmission settings

HIV-

HIV+

TB preventive therapy: high TB transmission settings

• shorter regimens desirable• but is longer better?

Botswana: IPT 36 vs. 6m

N=1995 HIV+

INHx36m N=1006

71% female25% TST>5mm

Median CD4 30748% started ART

INHx6m N=989

73% female22% TST>5mm

Median CD4 28847% started ART

Samandari Lancet 2011;377:1588

36m vs. 6m IPT: 43% less TB during trial

0tan28a566028

0tan21a566021

0tan14a566114

0tan7a56617

0tan1a56621

0tan24a5662240%1%2%3%4%

Days after enrolment

Cum

ulati

ve T

B in

cide

nce

6H 36H

In trial n=1995

6H36H

Samandari Lancet 2011;377:1588

43% reduction in TB p=0.047

0tan28a566028

0tan21a566021

0tan14a566114

0tan7a56617

0tan1a56621

0tan24a566224

0tan17a5663170%1%2%3%4%

Days after trial end

Post-trial (no IPT) n=1678

6H36H

TB incidence post-trial: no difference for 36m vs. 6m INH arm

0tan28a566028

0tan21a566021

0tan14a566114

0tan7a56617

0tan1a56621

0tan24a5662240%1%2%3%4%

Days after enrolment

Cum

ulati

ve T

B in

cide

nce

6H 36H

In trial n=1995

6H36H

Samandari CROI 2012

43% reduction in TB p=0.047

Hazard ratio 0.82 p=0.52

Soweto: novel TB preventive therapy regimens

Martinson NEJM 2011;365:11

N=1148 HIV+, TST>5mm, not needing ART

RPT/INH wkly x3m

RIF/INH twice wkly x3m

INH continuous INH x6m

N=32885% female

median CD4 471median FU 4.0y

N=32981% female

median CD4 498median FU 4.1y

N=16485% female

median CD4 476median FU 3.9y

N=32784% female

median CD4 490median FU 3.9y

Soweto study: HIV+, TST+

Martinson NEJM 2011;365:11

Soweto study: HIV+, TST+

Martinson NEJM 2011;365:11

as treated analysis

Thibela TB• South African gold mines: TB case notifications

<5000 per 100,000 per year• Novel TB control strategies needed• Thibela TB: cluster-randomised trial of community-

wide IPT

Hostels + Mine shaft

Cluster =

Targeted vs. community-wide IPT

High TB risk: TB contactHIV+

Offered IPT:

High TB risk: everyoneOffered IPT: everyone

Thibela TB

• Cluster-randomised trial of community-wide IPT x 9m in 15 gold mines in South Africa (approx 80,000 people)• No impact on TB incidence or prevalence at population level

Churchyard CROI 2012; Fielding CROI 2012

Thibela TB: individual analysisBaseline 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)

ExcludedDid not start IPT

(n=2,963)

ExcludedTB / IPT(n=134)

ExcludedNot employees

(n=1,604)

Fielding CROI 2012

Thibela TB: duration of IPT effect at individual level

0-9 m 9-18m >18m0tan28a566028

0tan29a566029

0tan1a56601

0tan2a56602

0tan3a56603

Control armIPT arm

TB in

cide

nce

per 1

00 p

yrs

63% reduction in TB incidence during 9m of intervention

Fielding CROI 2012

0-9m 9-18m >18m

TB inc rate: control

IPT

2.911.10

2.712.34

2.702.42

adjusted RR 0.37 0.94 0.79

Why is IPT not durable in southern Africa?

• ? High rates of TB reinfection– very difficult to measure– consistent with molecular epidemiology data

from mines and elsewhere in southern Africa

Why is IPT not durable in southern Africa?• ? high rate of reinfection

– would explain why RH/RpH no better than IPT in Soweto

Why is IPT not durable in southern Africa?• ? but if most TB in HIV+ is reinfection, why does TB

incidence remain low among those TST neg at enrolment?

Samandari Lancet 2011; 377:1588

Why is IPT not durable in southern Africa?• ? but if most TB in HIV+ is reinfection, why does TB incidence

remain low among those TST neg at enrolment?

Samandari Lancet 2011; 377:1588

Why is IPT not durable in southern Africa?

• ? High rates of TB reinfection– consistent with molecular epi data from mines

and elsewhere in southern Africa– very difficult to measure

• ?IPT does not cure latent infection– very difficult to measure– consistent with data from mouse models

Activity of TMC207 (J) in a mouse model of treatment for latent TB infection

Rx duration to prevent 50% relapse

H, isoniazid; R, rifampin; P, rifapentine; J, TMC207

H

Months1 2 3 4 5 60

R

RH

PH1/7

J

Zhang et al, Am J Respir Crit Care Med 2011; 184:732thanks to Eric Neurmberger for this slide

Untreated CFU

0

2

4

6

Months post-infection

Lung

log 10

CFU

Disease course in untreated mice

• If reinfection, priority is to reduce transmission– find and treat people with infectious TB– (which we need to do anyway)

• If lack of cure with IPT alone, need better "preventive" regimens – particularly where TB transmission is low– shorter regimens operationally much easier to implement

• probably a bit of both• either way, data support continuous IPT for HIV+

Implications of limited IPT durability

TB prevention: addressing susceptibility

--_-_--_-

HIV-HIV- TB

Infectious TB

Latent TB infection

HIV+HIV+

TBNon-infectious TB

Improve CD4 count

HIV-

HIV+

ART for TB prevention

Suthar PLoS Medicine 2012;9:e1001270

ART for TB prevention: necessary but not sufficient

Gupta PLoS ONE 2012;7:e34156

IPT plus ART: Brazil• Retrospective cohort, N=11,026 HIV+ clinic attendees, Brazil

pyrs TB cases IR IRR (95% CI)

Neither 3865 155 4.01 1.0

ART only 11627 221 1.90 0.48 (0.39-0.59)

IPT only 395 5 1.27 0.32 (0.10-0.76)

ART+IPT 1253 10 0.80 0.20 (0.09- 0.91)

Golub AIDS 2007;21:1441

pyrs TB cases IR* IRR (95% CI)

Neither 3865 155 4.01 1.0

ART only 11627 221 1.90 0.48 (0.39-0.59)

IPT only 395 5 1.27 0.32 (0.10-0.76)

ART+IPT 1253 10 0.80 0.20 (0.09-0.91)

*per 100 pyrs

RCT of IPT plus ART: Cape Town

Rangaka AIDS 2012 late breaker

Thibela TB• Community-wide IPT did not improve TB control in

South African gold mines• What will it take?

Hostels Mine shaft

Cluster

TB prevention in gold mines: what will it take?•

a) IPT for 9 monthsb) continuous IPTc) ARTd) reducing treatment delaye) more sensitive diagnosticsf) none of the aboveg) all of the above

0

1000

2000

3000

4000

Num

ber o

f cas

es/1

00,0

00/y

ear

(tru

e in

cide

nce) Reduce treatment delay

Maximise ART coverage

Better diagnostics

Better preventive therapy

Thibela TB modelling: needcombination TB prevention

Vynnycky, Sumner, Cox, White SA TB conference

• Know your TB epidemic, know your TB response

Conclusions

Low transmission settings

• Rifapentine / INH: simpler, shorter – awaiting data on effectiveness for HIV positive people

High TB transmission settings

• IPT has limited durability in Southern Africa• continuous IPT for HIV+ people

• Combination TB prevention• earlier treatment via better diagnostics• improving systems to minimise treatment delay• maximising ART coverage• optimising TB preventive therapy

Thank you• Gavin Churchyard, Violet Chihota, Aurum Institute• Katherine Fielding, James Lewis, Peter Godfrey-Faussett, Emilia

Vynnycky, Tom Sumner, Andy Cox, Richard White, LSHTM• Chris Dye, WHO• Taraz Samandari, CDC• Dick Chaisson, Jonathan Golub, Neil Martinson, Johns Hopkins• Tim Sterling, Vanderbilt University

Funders: • Bill and Melinda Gates Foundation• Global Health Trials (UK MRC / Wellcome Trust / Department for

International Development)

• No conflicts of interest to declare