do we need to test for isoniazid resistance? no conflict of interest claudia denkinger, md phd...
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Do we need to test for isoniazid resistance?
No conflict of interest
Claudia Denkinger, MD PhD
McGill University, Montreal Foundation for Innovative New Diagnostics
Context
• Xpert rapidly being rolled• Xpert includes RIF but not INH resistance testing• INH resistance is much more common than MDR• Treatment of INH resistant MTB with 1st line
drugs is associated with increase failure/relapse rates and increased development of MDR
Niemz Exp Rev Mol Diag 2012Menzies PLOS Med 2009Jacobson CID 2011Smith IJTLD 2012
???
Should the next generation of molecular tests include detection of
isoniazid resistance to prevent- A further increase in INH resistance
- INH resistance driving MDR resistance
Latent TB Infection
New active TB - Access to diagnostics
Susceptible
Treated/Cured
Previously treated active TB –
Access to diagnostics
New active TB – No access to diagnostics
Failure
Self cure
Primary progression
Primary progression
Secondaryprogression
Secondaryprogression
Failing on therapy CuredDefault/
Relapse
Default/Relapse
Cured
Cured with 2nd line or DST guided treatment
Failing on 2nd line or DST- guided treatment
Reinfection
Model
• Steady state (60 years ago)
• Rise of MDR and INH over 60 years to levels reported today (2.1%, 15%) for epidemiological setting like India
• Standard diagnostic, calibrated to CDR (~75%)• Molecular testing: 95% sensitivity• MDR Rx at baseline only for pts failing 1st line Rx
WHO Global report 2012
Equilibrium Year 0 Implementation of tests
Input parameters
WHO Global report 2012Menzies PLOS Med 2009Jacobson CID 2011
Scenarios with molecular test
1. TB detection only2. Rif detection3. INH +RIF detection
Low coverage: 15%, 25%, 30% > new, relapse/default, failureHigh coverage: 50%, 80%, 100% > new, relapse/default, failure
WHO Global report 2012
A B
C D
Sensitivity analysis TB+RIF/INH vs TB+RIF
0.2 0 0.2
Conclusions
• INH testing in addition to rifampin resistance detection does not have a substantial effect – on INH resistance– or MDR-TB
• Testing for rifampin resistance in contrast has a sizeable effect on MDR– Idealized scenario– Reduction in prevalent (chronic) cases early on– Reduction in time to diagnosis as MDR
Limitations
• Simplified model• Not including HIV limits generalizability• Not considering IPT > limited use, unclear
impact on resistance• Not considering different health sectors• Not accounting for possible beneficial effects
of detection of rifampin monoresistance
Smith IJTLD 2012Balcells EID 2006WHO Report 2012RNTCP 2011
Supplementary Figures
A B
C D
Figure S1
A B
C D
Figure S3
Figure S5 A B
C D
Thank you!
Questions???
Acknowledgement
• David Dowdy
• Madhu Pai
• Dick Menzies