Impact of tuberculosis screening and
isoniazid preventive therapy on incidence of
TB and death in the TB/HIV in Rio de Janeiro
(THRio) study
B. Durovni1,2, V. Saraceni1, A. Pacheco3, S. Cavalcante1,3, S. Cohn4,
B. King4, L. Moulton4, R. Chaisson4, J. Golub4, THRio study group
1Rio
de Janeiro City Health Secretariat, Rio de Janeiro, Brazil,
2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,
3Fiocruz, Rio de Janeiro, Brazil,
4Johns Hopkins University, Baltimore, United States
THRio Objectives
• To determine if implementation of a policy of widespread use
of isoniazid preventive therapy (IPT) in HIV-infected patients
with access to ARV therapy reduces the incidence of active TB
and death in the HIV clinic population
• Scale up of tuberculin skin testing (TST) and IPT among HIVinfected patients in public primary health units in Rio de
Janeiro within the current HIV clinic infrastructure
– In an effort to reduce:
• TB Incidence
• Mortality
THRio Study Design and Timeline
Cluster-Randomized, Step-Wedge Trial
Intervention and
Follow-up Period
(for all clinics)
48
Sep 05
Jan 08
60
Aug 09
4
Intervention
• Training clinics to properly implement TB screening and
adhere to TST/IPT policy for all HIV-infected patients
• TST to be done for all eligible
clinic patients
– No prior TB history
– No prior IPT
– No prior +TST
• IPT x 6 months for all TST+ without active TB and all contacts
of active TB cases
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TST and IPT
• 69% had at least one TST placed and read
• 83% started IPT
• 0.84% had an adverse event
• 84% completed IPT
Time to TST and Time to IPT Before and After
THRio Intervention
• Time to TST and time to IPT are both markedly improved
post-intervention
Time to IPT
1.0
Time to PPD
0.2
0.4
Proportion with no IPT
0.6
0.8
1.0
0.8
0.6
0.4
0.0
0.2
0.0
Proportion with no PPD
Pre-intervention
Post-intervention
Pre-intervention
Post-intervention
0
50
100
150
200
Weeks
Durovni et al., AIDS 2010, 24 (suppl 5):S49–S56
0
50
100
Weeks
150
Methods for Current Analysis
Primary endpoints: Incidence of TB and TB or death at the clinic level before
and after the intervention
Eligible patients who made > 1 visit after 1 Sept 2003
• ‘Eligible’ = no prior TB or IPT
• ‘Prevalent’ TB and deaths (within 60 days of enrollment) excluded
• Patients remain in the denominator until TB or Death
Intent-to-treat Analysis – includes all eligibles
“Stayers” Analysis -- among those remaining in clinic contact, censoring
those missing for >1 year (mITT)
Statistical analysis: Crude hazard ratios (HR) obtained from frailty-adjusted
Cox models are presented
CONSORT Diagram (modified for stepped
wedge cluster-randomized trial)
Clinics Eligible for
Inclusion (n=29)
Clinics Receiving
Intervention
(n=29)
Patients in Clinics
Eligible for
Intervention
(n=12,815)
Eligible patients
contributing to
control phase
(n=9,853 )
Patients in Clinics
Ineligible for
Intervention
(n=4,480)
Eligible patients
contributing to
intervention phase
(n= 10,840)
THRio cohort characteristics (n=12,815)
• Median age: 37 years old
• Male: 61%
• Median years since HIV diagnosis: 2.4 years
• HAART at entry: 60%
• Median CD4 cell count at entry: 403 cells/mm3
THRio Results
TB cases, total contribution time, incidence per 100pyrs
Control Phase
Cases
Person years
Rate/100pyrs
Intervention Phase
221
254
16,834
23,126
1.31
1.10
TB/Death cases, total contribution time, incidence per 100pyrs
Control Phase
Cases
Person years
Rate/100pyrs
Intervention Phase
617
696
16,834
23,126
3.67
3.01
THRio Results: Unadjusted Cox Models
Intent
To
Treat
Outcome
Cases
HR (95% CI)
p-value
TB
475
0.233
TB or Death
1313
0.87
(0.68-1.10)
0.72
(0.62-0.82)
• Intent-to-treat – Among all eligibles
<0.001
THRio Results: Unadjusted Cox Models
Intent
To
Treat
Modified
Intent
To Treat
(Stayers)
Outcome
Cases
HR (95% CI)
p-value
TB
475
0.233
TB or Death
1313
TB
403
TB or Death
1073
0.87
(0.68-1.10)
0.72
(0.62-0.82)
0.57
(0.44-0.76)
0.56
(0.47-0.66)
<0.001
<0.001
<0.001
• Intent-to-treat – Among all eligibles
• Stayers – mITT - Among those remaining in clinic contact
(Patients censored at the moment they go one year without a clinic contact)
Conclusions
• Overall, the THRio intervention had a modest impact (13%
reduction) on TB, but showed an important and statistically
significant impact on TB and death (28% reduction) in the
primary intent-to-treat analysis;
• The “Stayers” analysis, including those who were more likely to
be exposed to the intervention (mITT), showed an even larger
and highly significant impact on reduction of TB incidence (43%)
and TB incidence and death (44%)
• TST screening and provision of IPT to HIV-infected patients with
access to highly active antiretroviral therapy significantly
reduces the risk of TB and death and should be widely
implemented
Rio de Janeiro
• Betina Durovni
• Solange Cavalcante
• Valeria Saraceni
• Antonio Pacheco
• Giselle Israel
• Vitoria Vellozo
• Rita Ferreira
• Lilian Lauria
• THRio Study Team
THRio Study Team
JHU
• Richard Chaisson
• Jonathan Golub
• Larry Moulton
• Silvia Cohn
• Bonnie King
• Anne Efron
• Susan Dorman
Funding: Bill and Melinda Gates Foundation
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