1. Do we need to test for isoniazid resistance? No conflict of interest Claudia Denkinger, MD PhD McGill University, Montreal Foundation for Innovative New Diagnostics

2. 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 1 st line drugs is associated with increase failure/relapse rates and increased development of MDR Niemz Exp Rev Mol Diag 2012 Menzies PLOS Med 2009 Jacobson CID 2011 Smith IJTLD 2012

3. ??? 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

4. 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 Secondary progression Secondary progression Failing on therapy Cured Default/Relaps e Cured Cured with 2 nd line or DST guided treatment Failing on 2 nd line or DST- guided treatment Reinfection

5. 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 1 st line Rx WHO Global report 2012 EquilibriumYear 0Implementation of tests

6. Input parameters WHO Global report 2012 Menzies PLOS Med 2009 Jacobson CID 2011

7. Scenarios with molecular test 1.TB detection only 2.Rif detection 3.INH +RIF detection  Low coverage: 15%, 25%, 30% > new, relapse/default, failure  High coverage: 50%, 80%, 100% > new, relapse/default, failure WHO Global report 2012

9. A B C D

10. Sensitivity analysis TB+RIF/INH vs TB+RIF 0.2 0

11. 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

12. 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 2012 Balcells EID 2006 WHO Report 2012 RNTCP 2011

13. Supplementary Figures

14. A B C D Figure S1

15. A B C D Figure S3

16. Figure S5 A B C D

17. Thank you! Questions???

18. Acknowledgement David Dowdy Madhu Pai Dick Menzies