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Isoniazid preventive therapy: evidence for

safety and efficacy

5th International Clinician’s course for TB/HIV in South

Prof Gavin Churchyard

Dr Liesl Page-Shipp

10 May 2013

Overview of presentation

� Meta-analysis

�TST

� Screening for TB

� Duration of IPT

� Adverse events

� INH Resistance

� IPT & ART

more people

living with HIV

dying of TBNO

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Isoniazid preventive therapy reduces the

risk of TB among PLWHIV

Akolo. 2010, Cochrane review

0.36

0.86

0.86

0.67

0.74

0.81

1.02

0.95

1.01.0

�RCTs demonstrated the efficacy of IPT in PLHIV infected with MTB as early as 1998Wilkinson D, Squire S B, Garner P. Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials. BMJ 1998; 317:625–629

Bucher HC, Griffith LE, Guyatt GH, Sudre P, Naef M, Sendi P, t al. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials. AIDS 1999;13:501–507

�Cochrane Systematic review (2004) of 11 trials (8130 participants)� Decreased risk of TB (33% overall) 64% (TST+ ve)

In 1998 the WHO and UNAIDS endorsed targeted IPT

Why IPT?

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� 12 trials, 8578 randomized participants

� IPT vs. placebo -lower incidence of active TB (RR 0.68, 95% CI

0.54-0.85)

� more pronounced in TST +ve (RR 0.38, 95% CI 0.25-0.57)

� Efficacy similar for all regimens (regardless of drug type, frequency or duration)� But short-course multi-drug regimens much more

likely to require discontinuation due to A/E than INH alone

� IPT reduces active TB esp. if TST +ve

Cochrane review 2010

Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection

in HIV infected persons. Cochrane Database of Systematic Reviews 2010, Issue 1

Art. No.: CD000171. DOI: 10.1002/14651858.CD000171.pub3.

Duration of IPT

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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

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

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Study design

� Cluster-randomised intervention study

� Cluster defined as all employees & contractors

at mine shaft(s) and associated hostels

� 15 clusters (1000-12000 miners)

� 8 intervention/ 7 controls

Hostels Mine shaft

Cluster

Intervention� Community education and mobilisation

� 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 & drug sensitivity

testing

� If eligible, 9 months of isoniazid preventive therapy

� Monthly follow-up visits for dispensing & screening for TB

(symptom) & possible side effects

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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

tiv

e %

of

clu

ste

r co

nse

nte

d

month from start of intervention

Uptake to the intervention

Uptake in first four clusters = 58.0%

Uptake in last four clusters = 78.7%

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TB Person years Rate/100 pyo

Intervention 887 29,352 3.02

Control 856 29,015 2.95

EffectivenessTB 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

Individual-level effect of isoniazid

preventive therapy on risk of

tuberculosis in the Thibela TB study

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Objective

� We investigate the effect of IPT on TB incidence in

� individuals starting IPT in intervention clusters vs.

� individuals in control clusters

Results – flow diagramBaseline 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(not on TB rx or IPT)

(n=6,263, 7 clusters)

IPT arm(Started IPT, regardless of HIV

Status/ CD4)

(n=4,646, 8 clusters)

Excluded

Did not start IPT

(n=2,963)

Excluded

TB / IPT

(n=134)

Excluded

Not employees

(n=1,604)

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Thibela TB: durability of IPT effect 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 arm

Interval Arm Adjusted IRR

(95% CI)

0-9mth

(IPT period)

IPT

Control

0.37 (0.19-0.72)

1

9-18mths IPT

Control

0.94 (0.57-1.54)

1

>18mths IPT

Control

0.79 (0.54-1.17)

1

Thibela TB: why didn't it improve TB

control?

Was it that: Results suggest:

Intervention coverage too low? yes, but even if

optimised, impact

would only be modest

IPT didn't protect individuals

against TB?

no

IPT effect didn't last long enough yes…..

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� plausible

� consistent with molecular epidemiological

data from mines and elsewhere in southern

Africa

� but very difficult to measure

Thibela TB: was IPT effect brief because

risk of reinfection very high?

Thibela TB: was IPT effect brief because

IPT does not cure latent infection?

� plausible

� consistent with data from mouse models

� no good clinical trial data from HIV+

populations

� model suggests this is important

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Targeted IPT Community-wide

IPT

Yes please! No thanks!

What was the duration of

the benefit of six months IPT?

200 days

after 6H

Start of coded medication

All participants analyzed in this graph received 6 months of IPT prior to day 0 in this graph

The Botswana IPT Trial: 36 months vs. 6mnths INH for

TB prevention in HIV-Infected adults 2004-2009

Samandari et al.

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Author Location Intention

to treat

Per

Protocol

Martinson Soweto 19% 69%

Samandari Botswana

All 54% 65%

TST+ 93%

TST- 19%

(Martinson et al. Union conference, 2008, CROI 2009)

(Samandari et al. Union Conference. 2009)

Continuous IPT effective if adherent

TST

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TST status & cumulative TB incidence

TST –0.9% per yr

The Botswana IPT Trial: 36 months vs.

6mnths INH for TB prevention in HIV-

Infected adults 2004-2009 Samandari et

al.

Requiring tuberculin skin tests before

implementing IPT leads to avoidable and

substantial number of TB cases

� Golub JE et al. 18th International AIDS Conference, abstract

MOAB0305, Vienna, 2010.

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IPT in PEPFAR assisted sites: 2010-2011

Bristow CC et al. Scale-up of isoniazid preventive therapy in PEPFAR-assisted clinical sites in South Africa. INT J TUBERC LUNG DIS 16(8):1020–1022. 2012

TB screening

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Proportion of TB detected by symptom and

CXR screening

All TB

n (%)

Smear

positive

n (%)

Smear

negative

n (%)

(n=281) (n=132) (n=149)

Symptoms

Symptom trio * 113 (40.2) 64 (48.5) 49 (32.9)

Abnormal CXR 233 (82.9) 119 (90.2) 114 (76.5)

Symptom trio and CXR

The addition of CXR to symptom screening increased the

number of TB cases detected by 2.5 fold (113 to 281)

* Cough>2 weeks, night sweats and weight loss

Proportion of TB detected by symptom and

CXR screening

All TB

n (%)

Smear

positive

n (%)

Smear

negative

n (%)

(n=281) (n=132) (n=149)

Symptoms

Symptom trio * 113 (40.2) 64 (48.5) 49 (32.9)

Abnormal CXR 233 (82.9) 119 (90.2) 114 (76.5)

Symptom trio and CXR

The addition of CXR to symptom screening increased the

number of TB cases detected by 2.5 fold (113 to 281)

* Cough>2 weeks, night sweats and weight loss

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TB missed at screeningB/w July 2006 and December 2008

� 23,299 participants completed screening

� 19,609 included in analysis of TB missed at screening

Prevalence

� 0.2% (definite, probable and possible TB)

� 0.12% (definite, probable TB)

Risk factors: unadjusted analysis

� age: aOR: 1.66/10yr (1.07-2.56)

� In HIV care: aOR 4.80 (1.63-14.1)

� Lower weight: aOR 2.07/10Kg (1.23-3.49)

� Alcohol use: aOR 2.52 (1.31-4.86)

Adverse events

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Methods: study-defined AEs

� AE reporting included

� hepatitis

� hypersensitivity

� peripheral neuropathy

� convulsions

� Occurring between

� first IPT dispensing date

� two months after last IPT dispensing date

AEs: results

� 24221 participants started IPT

� 95% male, median age 40 years

� 130 individuals experienced 132 possible study

defined AEs (0.54%)

� Suspected hypersensitivity rash 61

� Peripheral neuropathy 50

� Convulsions 4

� Hepatotoxicity 17

� INH non-related 2

� One AE resulted in death: overall risk of death of 4

per 100,000 (0.004%)

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Risk factors for hepatotoxicityVariable Category Hepatotoxicity/total (%) Odds ratio (95% CI)

Sex Male

Female

14/23038 (0.06%)

1/1168 (0.09%)

1

1.4 (0.2-10.7)

Age group (years) <35

35-44

45+

3/7763 (0.04%)

7/8203 (0.09%)

5/8201 (0.06%)

1

2.2 (0.6-8.5)

1.6 (0.4-6.6)

Ethnic group Black

Other

14/23794 (0.06%)

1/425 (0.24%)

1

4.0 (0.5-30.5)

Baseline weight (kg) <60

61-80

81+

2/4234 (0.05%)

8/14700 (0.05%)

5/5275 (0.09%)

1

1.2 (0.2-5.4)

2.0 (0.4-10.4)

History suggesting HIV care No

Yes

15/23584 (0.06%)

0/618 (0%)

1

-

Antiretroviral therapy No

Yes

15/23654 (0.06%)

0/544 (0%)

1

-

Alcohol use (units/week) 0

1-14

15+

4/14139 (0.03%)

10/7760 (0.13%)

1/2321 (0.04%)

1

4.6 (1.4-14.5)

1.5 (0.2-13.6)

Risk factors for hepatotoxicityVariable Category Hepatotoxicity/total (%) Odds ratio (95% CI)

Sex Male

Female

14/23038 (0.06%)

1/1168 (0.09%)

1

1.4 (0.2-10.7)

Age group (years) <35

35-44

45+

3/7763 (0.04%)

7/8203 (0.09%)

5/8201 (0.06%)

1

2.2 (0.6-8.5)

1.6 (0.4-6.6)

Ethnic group Black

Other

14/23794 (0.06%)

1/425 (0.24%)

1

4.0 (0.5-30.5)

Baseline weight (kg) <60

61-80

81+

2/4234 (0.05%)

8/14700 (0.05%)

5/5275 (0.09%)

1

1.2 (0.2-5.4)

2.0 (0.4-10.4)

History suggesting HIV care No

Yes

15/23584 (0.06%)

0/618 (0%)

1

-

Antiretroviral therapy No

Yes

15/23654 (0.06%)

0/544 (0%)

1

-

Alcohol use (units/week) 0

1-14

15+

4/14139 (0.03%)

10/7760 (0.13%)

1/2321 (0.04%)

1

4.6 (1.4-14.5)

1.5 (0.2-13.6)

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INH resistance

INH resistance

Balcells Emerg Infect Dis 2006;12:744-51

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0 5 10 15 20 25 30 35 40

Percentage

TB after IPT

TB after IPT

Laboratory sub-study

First

episodes

Retreatment

episodes

Any INH resistance: Mean (95% CI)

TB after IPT (n=126)

AIDS. 2010 Apr 24;24(7):1051-5.Tuberculosis outcomes and drug susceptibility in individuals exposed to isoniazid preventive therapy in a high HIV prevalence setting.van Halsema CL, Fielding KL, Chihota VN, Russell EC, Lewis JJ, Churchyard GJ, Grant AD.

INH resistance by treatment arm

Botswana background = 9% INH resistance new TB patients;

18% INH-R expected in Trial if no additional contribution by IPT

2 (14%)4 (17%)Any INH resistance >36 mo # (%)

11MDR (INH + RIF)

13INH-mono-resistant

1424Drug susceptibility test available

36H (n=1006)6H (n=989)

The Botswana IPT Trial: 36 months vs. 6mnths INH for TB

prevention in HIV-Infected adults 2004-2009 Samandari

et al.

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IPT and ART

�We know TB� remains the leading cause of death on ART

� rates are significantly reduced on ART vs. no ART

� annual risk decreases, the longer effective ART

BUT

�TB rates on effective ART still much higher than HIV-neg, possibly due to� Incomplete TB-specific immune restoration

� Poor adherence

� Nosocomial transmission (ART visits)

IPT and ART

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RCT of IPT in HIV-infected persons on

antiretroviral therapy

� Khayelitsha Ubuntu ART clinic

� Pragmatic randomized double-blind placebo-

controlled

� Efficacy of IPT on ART (established or newly

starting)

� Daily INH or matching placebo x 1 yr

� Followed for up to four years

� Tuberculosis excluded by sputum culture

MX Rangaka et al. Randomized controlled trial of isoniazid preventive therapy in HIV-infected persons on antiretroviral therapy. Nineteenth International AIDS Conference, Washington DC, abstract THLBB03, 2012

RCT continued: Results

� 1,329 : 662 on placebo/ 667 on IPT

� Comparable CD4/ proportion starting ART

� 95 developed TB

� 3.6/100py in placebo vs 2.3/100py in IPT

� Study drug discontinued

� 2.5% in placebo vs 4.1% in IPT

� Deaths was similar

� 3.0% in placebo vs 2.1 in IPT

� Apparently effect waned slower than Thibela/Botusa

MX Rangaka et al. Randomized controlled trial of isoniazid preventive therapy in HIV-infected persons

on antiretroviral therapy. Nineteenth International AIDS Conference, Washington DC, abstract THLBB03,

2012

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RCT continued: Conclusion� Under field conditions

� 12 months of IPT

�Reduced the incidence of TB

�Did not cause excess harm in HIV-infected

individuals established on ART or newly

starting ART.

� IPT feasible in busy ART clinics

MX Rangaka et al. Randomized controlled trial of isoniazid preventive therapy in HIV-infected persons on antiretroviral therapy. Nineteenth International AIDS Conference, Washington DC, abstract THLBB03, 2012

Effect of IPT and ART on TB incidence

Golub. AIDS.2009 TB Incidence

/100py

aHR (95% CI)

No IPT/ART 7.1 1

ART 4.6 0.36 (0.25-0.5)

ART/IPT 1.1 0.11 (0.02-0.8)

Golub et al. Isoniazid preventive therapy, HAART and tuberculosis risk in

HIV-infected adults in South Africa: a prospective cohort.. AIDS 2009,

23:631–636

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Death after IPT & ART

Deaths PYRS RATE/100 95% CI

Never started 227 2,047 11.08 (9.74-12.63)

Started INH 32 863 3.71 (2.62-5.24)

Golub et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS 2009, 23:631–636

Results – Multivariable analysis

Unadjusted analysis

(N=3270)

Adjusted analysis*

(N=3094)

INH Death

Rate

/100py

Hazard

Ratio (HR)

95% CI

(P value)

Hazard

Ratio

(HR)

95% CI

(P value)

No

Yes

11.10

3.71

1

0.34

(P<0.001)

0.24 – 0.49

1

0.51

P=0.002

0.32 – 0.80

*Adjusted for age group, baseline WHO stage, baseline CD4 count,

year started on ART and previous TB

Innes C et al. Effectiveness of isoniazid preventive therapy inreducing mortality in patients on ART. Seventeenth CROI abstract 102, 2010

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Influence of ART and 36H by TST status

TST negative TST positive

HR (%

reduction)

95%CI HR (%

reduction)

95%CI

ART alone* 0.44 (56%) 0.2,0.9 0.44 (56%) 0.2,0.9

36H alone 0.92 (8%) 0.4,2.0 0.07 (93%) 0.01,0.6

Both 0.40 (60%) 0.1,1.2 0.03 (97%) 0.0,0.3

* 300 days of ARTThe Botswana IPT Trial: 36 months vs. 6mnths INH for TB prevention in HIV-

Infected adults 2004-2009 Samandari et al.

NEW IPT Guidelines

Pre-ART (CD4 > 350) On ART

TST not

done

6 months 6 months

TST

negative

6 months 12 months

TST

positive

36 months 36 months

The South African Antiretroviral Treatment Guidelines 2013. Version 14Mar2013

Same guidelines for pregnant women except those on

FDC (CD4>350)- IPT for 12 months

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TST cont.

� Although new guidelines “require” TST

�Do not delay IPT while awaiting TST

�Provision is made for “TST not done”

Conclusion of evidence

� Feasible to implement IPT at scale

� IPT can be delivered safely with clinical

monitoring by trained nursing staff

� IPT not associated with increased INH resistance

� IPT with ART reduces TB incidence and mortality

� IPT reduces TB in HIV clinics

� TST required to determine duration of IPT

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Questions?