TB prevention studies in PLHIV: recent updates and what ...Time to TST and Time to INH Before and...
Transcript of TB prevention studies in PLHIV: recent updates and what ...Time to TST and Time to INH Before and...
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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
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Preventive Interventions in TB/HIV
Prevent Infection Treat HIV Chemoprophylaxis
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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)
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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
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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+
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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
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Durability of INH Preventive Therapy Effectiveness in THRio
– All Patients
Golub et al, CROI 2013
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Durability of INH Preventive Therapy Effectiveness in THRio
By Treatment Completion
Non-completers
Completers
Golub et al, CROI 2013
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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.
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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.
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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.
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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.
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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
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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
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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
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Effectiveness of Life-long INH in TST+/HIV+ Patients
Intent-to-treat vs. “as-treated”
Martinson et al., NEJM 2011;365:11-20
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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.
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Rangaka et al., Lancet, in press.
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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.
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The impact of preventive therapy on
control of TB in high-burden areas
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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