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
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