TB prevention studies in PLHIV: recent updates and what can they tell us for the future?

Richard E. Chaisson, MD

Center for AIDS Research Center for TB Research

Johns Hopkins University

TB/HIV Working Group Meeting

Washington, DC

February 11-12, 2014

Preventive Interventions in TB/HIV

Prevent Infection Treat HIV Chemoprophylaxis

Population-level interventions to control TB/HIV The Consortium to Respond Effectively to the AIDS-TB Epidemic (CREATE)

Study Intervention(s) Design (N)

Mass TB preventive

therapy for S.A. gold

miners

Cluster randomized

trial

(~80,000)

Enhanced TB case

finding, contact

evaluations in

Zambia and S.A.

Community

randomized trial

(~1 million)

Preventive therapy

and ARVs for HIV

patients in Rio de

Janeiro

Phased

implementation trial

(18,000)

4

THRio Study Design and Timeline Cluster-Randomized, Stepped Wedge Trial

Sep 05 Jan 08

48 60

Aug 09

Intervention and

Follow-up Period

(for all clinics)

Adapted from Moulton LH, Golub JE, Durovni B et al.

Clinical Trials 2007;4:190

Time to TST and Time to INH Before and After THRio Intervention

0 50 100 150 200

0.0

0.2

0.4

0.6

0.8

1.0

Time to PPD

Weeks

Pro

port

ion w

ith n

o P

PD

Pre-intervention

Post-intervention

0 50 100 150

0.0

0.2

0.4

0.6

0.8

1.0

Time to IPT

Weeks

Pro

port

ion w

ith n

o I

PT

Pre-intervention

Post-intervention

Durovni et al., AIDS 2010, 24 (suppl 5):S49–S56

19/100 PYs

59/100 PYs

36/100 PYs

144/100 PYs

Time to TST Time to IPT for TST+

Rates and risks of TB after intervention in the THRio

Study

Outcome Cases Crude HR

(95% CI) p-value

Adjusted HR

(95% CI) p-value

Intent

To

Treat

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

Per-

protocol

(Stayers)

TB 399 0.43

(0.31-0.58)

<0.001

0.42

(0.31-0.58)

<0.001

TB or Death 1055 0.50

(0.41-0.60)

<0.001

0.50

(0.41-0.60)

<0.001

Stayers – per-protocol - Among those remaining in clinic contact (Patients censored after one year without a clinic contact)

Durovni et al., Lancet Infect Dis. 2013;10:852-8

Durability of INH Preventive Therapy Effectiveness in THRio

– All Patients

Golub et al, CROI 2013

Durability of INH Preventive Therapy Effectiveness in THRio

By Treatment Completion

Non-completers

Completers

Golub et al, CROI 2013

Thibela TB

• N=78,000, 8 intervention clusters, 7 control

• IPT arm: Community education and mobilization

• Intervention offered to entire workforce

– Screening for active TB: symptoms and chest X-ray

– if symptomatic / abnormal CXR, one sputum sent for

microscopy, culture, DST

• People with suspected TB referred for treatment

• If eligible, 9 months of IPT

– 300mg daily, self-administered, monthly follow-up

Churchyard et al. N Engl J Med 2014;370:301-10.

TB Person

years

Rate/100 py

Intervention 887 29,352 3.02

Control 856 29,014 2.95

Thibela TB: TB

Incidence

Among employees in the primary outcome measurement period:

Incidence rate ratio

Unadjusted 1.00 (95% CI 0.75-1.34)

Adjusted* 0.96 (95% CI 0.76-1.21)

*Adjusted for gender, age, place of work (at individual level) and silicosis, ART use, TB CNR

Churchyard et al. N Engl J Med 2014;370:301-10.

Thibela TB: TB Prevalence

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)

Churchyard et al. N Engl J Med 2014;370:301-10.

Thibela TB: IPT effective at individual

level, but effect short-lived

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

100 p

yrs

Controlarm

58% reduction in TB incidence

during 9m of intervention

0-9m 9-18m >18m

TB inc rate:

control

IPT

2.91

1.10

2.71

2.34

2.70

2.42

adjusted RR 0.42 0.93 0.95

Churchyard et al. N Engl J Med 2014;370:301-10.

TST-positive, 6 months IPT

TST-positive, 36 months IPT

TST-negative, 36 months IPT

TST- negative, 6 months IPT

Lancet. 2011;377:1588-1598.

Days after enrollment

Nu

mb

er

of ca

se

s/1

00,0

00/y

ea

r

(tru

e in

cid

en

ce)

0

1000

2000

3000

4000

Reduce treatment delay

Maximise ART coverage

Better diagnostics

Better preventive therapy

Thibela TB: what will it take to control

TB control in gold mines?

Churchyard, White, et al. SA TB Conf 2012

Short-course TB Preventive Regimens

vs Lifelong IPT in HIV+ Patients

Outcome Rifapentine/INH

Weekly x 12

wks

(n = 328)

RIF/INH Twice

Weekly x 12

wks

(n = 329)

INH daily

for up to 6

yrs

(n = 164)

INH daily for

6 months

(n = 327)

Median f/u 4.0 yrs 4.1 yrs 3.9 yrs 3.9 yrs

TB or death

(per 100

PY)

3.1 2.9 2.7 3.6

TB or death

Rate ratio

(95% CI)

0.87

(0.54-1.39)

0.80

(0.50-1.29)

0.75

(0.38-1.38)

1

(ref)

Martinson et al., NEJM 2011;365:11-20

Effectiveness of Life-long INH in TST+/HIV+ Patients

Intent-to-treat vs. “as-treated”

Martinson et al., NEJM 2011;365:11-20

Efficacy of IPT in Patients on ART

• Pragmatic RCT in Cape Town (Ubuntu

clinic in Khayelitsha)

• Eligibility = HIV+ starting ART or on

established ART, >18 years, no TB

• 1,329 participants, 3227 person-years

• Median CD4 = 216 (IQR 152-360)

• 662 on placebo and 667 on IPT for 12

months

Rangaka et al., Lancet, in press.

Rangaka et al., Lancet, in press.

Effect of IPT on TB by IGRA and TST Status

Placebo Isoniazid Effect

Rate/100

PY

Rate/100

PY

HRa

IGRA

Negative 3.3 1.3 0.43* (0.20 - 0.96)

Positive 3.9 3.0 0.55 (0.26 - 1.24)

TST

Negative 4.1 1.7 0.43* (0.21 - 0.86)

Positive 2.8 2.6 0.86 (0.37 - 2.0)

*P<0.05

Rangaka et al., Lancet, in press.

The impact of preventive therapy on

control of TB in high-burden areas

Implications

• IPT works for HIV+ patients in high- and low-

incidence areas

• IPT works in advanced HIV disease and in TST

negative patients

• In high-incidence areas, benefit may not be

durable and prolonged PT may be needed

• In medium- and low- incidence areas, short-

course PT appears to be effective

• Lack of long-term efficacy could be due to

reinfection or failure to sterilize latent infection

• Combination preventive interventions for TB and

HIV are essential