1. Stratified medicine in the treatment of TB
Patrick Phillips, PhD
Division of Pulmonary and Critical Care, Department of Medicine
Division of Biostatistics, Department of Epidemiology and Biostatistics

2. Treatment Stratification

3. Personalized medicine: “molecular profiling technologies for tailoring the right therapeutic strategy for the right person at the right time”.
Overambitious promise of individualized unique drug targeting and development.
Stratified medicine: reflects the effects of medicines at population level.
This population approach better aligns with the public health approach used in TB.
European Commission DR. Workshop report, Stratification biomarkers in personalized medicine,
2010

4. Bringing stratified medicine to TB – a paradigm shift in trial design and overall objectives
Cure all patients with TB
Not 90-95% of patients, but target cure >99%
Identify a pragmatic treatment strategy that is superior to standard of care
Pursue cure for all and keep markers simple.
Abandon “One Size Fits All” approach
Use baseline and/or on-treatment markers to stratify patients into risk groups
Patients in different risk groups receive different durations or compositions of regimens

5. Relapse rates in 2/3/4-month regimens in DS-TB
Total patients
HR throughout, with S&Z added (Fox, 1981)
NIRT (Jawahar, 2013)
Gati
Moxi
OFLOTUB (Merle, 2014)
RIFAQUIN (Jindani, 2014)
REMoxTB (Gillespie, 2014)
Moxi & INH
Moxi & EMB
(Johnson, 2009) Smear neg, no cavities
Daily SHRZ, Smear negative (Hong Kong, 1981, 1989)

6. Relapse rates in 2/3/4-month regimens in DS-TB
Total patients
Proportion of patients cured
HR throughout, with S&Z added (Fox, 1981)
NIRT (Jawahar, 2013)
Gati
Moxi
OFLOTUB (Merle, 2014)
RIFAQUIN (Jindani, 2014)
REMoxTB (Gillespie, 2014)
Moxi & INH
Moxi & EMB
(Johnson, 2009) Smear neg, no cavities
Daily SHRZ, Smear negative (Hong Kong, 1981, 1989)

7. Evaluating the same shorter regimen for all
Shorter novel regimen ‘one size fits all’
8.7% unfavorable
6-month HRZE, 8% unfavorable
Low risk 3% 2%
Moderate risk 8% 7%
Non-inferiority depends primarily on efficacy in the high risk patients
High risk
16%
20%

8. Evaluating a treatment stratification approach
Novel regimen with treatment stratification, 3-4% unfavorable
6-month HRZE, 8% unfavorable
Low risk 3%
Radically shorter duration 2%
Moderate risk 8%
Shorter duration 5%
High risk
16% 5%
Longer duration

9. Evaluating a treatment stratification approach
Novel regimen with treatment stratification, 3-4% unfavorable
6-month HRZE, 8% unfavorable
1. Target Treatment Shortening, with no reduction in efficacy in low risk group
Low risk 3%
Radically shorter duration 2%
Moderate risk 8%
Shorter duration 5%
2. Target Improved Efficacy, with a more potent regimen in high risk group
High risk
16% 5%
Longer duration

10. The CURE-TB Strategy – Stratified Medicine to Cure All in DS TB
Illustrative example using RPT at 1200mg
Randomise
Strata (risk of relapse)
Control
Treatment strategy 1 (Baseline factors only)
Treatment strategy 2
(On treatment biomarker to adjust duration)
Low
2HRZE/4HR
(6 months)
2HPZE
(2 months)
(2+ months)
Moderate
2HPZE/2HP
(4 months)
(4+ months)
High
2HPZE/4HP
(6+ months)
Low risk of relapse
Moderate risk of relapse
High risk of relapse
From the TBTC CURE-TB Working Group

11. Advantages of stratified medicine in TB
Each patient receives the therapy that gives them the best opportunity for cure
Phase III trials with superiority rather than non-inferiority designs.
Superiority more robust for interpretation and generalizability
Two-pronged attack to achieve cure for all
Shorter duration for those for which it is appropriate
Reducing health system costs, improving adherence
Longer duration for those that need it
Improving population-level outcomes, reducing onward transmission

12. Objections to stratified medicine in TB
We don’t have good enough stratification factors
TB-REFLECT analysis is providing robust evidence
Stratification algorithm can evolve over time as new data and markers emerge
Treatment stratification will lead to market fragmentation
Informal stratification is already practiced in many resource-rich settings
Formalization of an evidence-based treatment strategy allows for clear strategies for market access.
It’s too complex to implement in a resource poor setting
Begin with simple markers
Utilize readily available digital technology for stratification

13. Acknowledgements
Payam Nahid, Rada Savic, and the TBTC CURE TB Working Group
The CURE TB MDR-TB Consortium