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. Durovni.

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 HIV-infected patients in public primary health units in Rio de Janeiro within the current HIV clinic infrastructure

– In an effort to reduce:• TB Incidence• Mortality

4

THRio Study Design and TimelineCluster-Randomized, Step-Wedge Trial

Sep 05 Jan 08

48 60

Aug 09

Intervention and Follow-up Period (for all clinics)

5

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

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

0 50 100 150 200

0.0

0.2

0.4

0.6

0.8

1.0

Time to PPD

Weeks

Pro

port

ion

with

no

PP

D

Pre-interventionPost-intervention

0 50 100 150

0.0

0.2

0.4

0.6

0.8

1.0

Time to IPT

Weeks

Pro

port

ion

with

no

IPT

Pre-interventionPost-intervention

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

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 )

Eligible patients contributing to

intervention phase (n= 10,840)

Patients in Clinics Ineligible for Intervention (n=4,480)

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 Intervention Phase

Cases 221 254

Person years 16,834 23,126

Rate/100pyrs 1.31 1.10

TB/Death cases, total contribution time, incidence per 100pyrs

Control Phase Intervention Phase

Cases 617 696

Person years 16,834 23,126

Rate/100pyrs 3.67 3.01

THRio Results: Unadjusted Cox Models

Outcome Cases HR (95% CI) p-value

IntentTo

Treat

TB 475 0.87 (0.68-1.10)

0.233

TB or Death 1313 0.72 (0.62-0.82)

<0.001

• Intent-to-treat – Among all eligibles

THRio Results: Unadjusted Cox Models

Outcome Cases HR (95% CI) p-value

IntentTo

Treat

TB 475 0.87 (0.68-1.10)

0.233

TB or Death 1313 0.72 (0.62-0.82)

<0.001

Modified Intent

To Treat(Stayers)

TB 403 0.57 (0.44-0.76)

<0.001

TB or Death 1073 0.56 (0.47-0.66)

<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

16

Rio de Janeiro • Betina Durovni• Solange Cavalcante• Valeria Saraceni• Antonio Pacheco• Giselle Israel• Vitoria Vellozo• Rita Ferreira• Lilian Lauria• THRio Study Team

JHU• Richard Chaisson • Jonathan Golub• Larry Moulton• Silvia Cohn• Bonnie King• Anne Efron• Susan Dorman

THRio Study Team

Funding: Bill and Melinda Gates Foundation