Preserving Effective TB Treatment Study (PETTS )

1. Preserving Effective TB Treatment Study (PETTS) San Antonio, Texas 25 September 2012 Peter Cegielski, MD, MPH International Research and Programs Branch Division of Tuberculosis Elimination

2. Preview • Background and rationale • Objectives • Subjects, Methods • Results • Baseline • Follow up • Conclusions and next steps

3. Predicting the Growth of XDR TB Inadequate treatment of MDR TB results in growth of XDR TB XDR TB as % of MDR TB % of MDR TB cases detected and treated Blower S, Supervie V. Lancet Infectious Diseases 2007;7:443.

4. Increasing treatment of MDR TB • Increasing • resistance • to SLDs Can we preserve the effectiveness of second-line drug treatment of MDR TB?

5. Acquired resistance to second-line drugs: Can it be prevented? How often does it occur? How soon does it occur after starting treatment? Does it differ for different drugs? How does it affect patient outcomes?

6. PETTS Study Objectives • To determine the frequency, timing, and risk factors for acquired resistance to SLD • Program characteristics (GLC) • Patient characteristics • Mycobacterial characteristics • Treatment • To determine the effect of acquired SLD resistance on patient outcomes

7. PETTS Overview Prospective cohort study in 9 countries 5 GLC-approved: Estonia, Latvia, Russia, Peru, Philippines (11 sites) 4 non-GLC: S. Africa, S. Korea, Thailand, Taiwan (15 sites) Consecutive consenting adults with locally confirmed pulmonary MDR TB enrolled at start of MDR TB treatment, 2005-2008 Sputum culture at start of treatment and monthly sputum cultures shipped to CDC for testing Patients followed for 2 years, until treatment completed or end of study (30 June 2010)

8. PETTS Overview 2 First and last isolate from each patient tested at CDC for susceptibility to 12 drugs indirect proportion method on Middlebrook 7H10 agar plates If drug susceptibility test (DST) results differ  genotyping (spoligo, MIRU-24) Same genotype: ACQUIRED RESISTANCE Different genotypes: different strains

9. PETTS Study Design Pretreatment  Treatment  Acquired resistance Patient outcome Incidence of acquired resistance GLC-approved MDR TB treatment programs Non-GLC MDR TB treatment programs Incidence of acquired resistance = patient with acquired resistance

10. Baseline PETTS isolates

11. Prevalence of drug resistance in MDR baseline isolates, 8 countries, 2005-2008 (n=1278) * n=1270

12. Follow Up Data Clinical data Patient follow up ended - June 2010 Data checking and cleaning ongoing Interim database through November 2011 Microbiology Final shipments of cultures - September 2010 Final culture DST completed - October 2011 Genotyping to be completed – March 2012

13. Duration of Follow Up Duration of follow up on treatment (days) Mean: 579 (std. dev. 228) Median: 616 (1st-99th percentiles 48 – 1132) Mode: 728 Total: 2,623 person-years Duration of microbiological follow up Mean number cultures per patient: 14.7 Mean number positive cultures per patient: 3.5

14. Adherence to Treatment(% of days treatment received on schedule) • 87.8% of patients were ≥ 90% adherent • 12.2% of patients were < 90% adherent • 7.2% of patients were < 80% adherent • 1.9% of patients were < 50% adherent

15. Treatment Outcomes - Overall 961 (58.1%) Cured / treatment completed / continuing treatment 102 (6.2%) Treatment failure 227 (13.7%) Death 323 (19.5%) Default 1613 Sum of Above 41 (2.5%) Unknown

16. Treatment Outcome by Country (%)

17. Green Light Committee vs.Treatment Outcome [n (%)]

18. Green Light Committee vs.Treatment Outcome [n (%)]

19. Green Light Committee x Treatment Outcome, excluding HIV-infected patients

20. Use of Directly Observed Therapyx Treatment Outcome

21. Baseline Resistance to ≥ 1 Second-line Injectable Drug x Treatment Outcome

22. Baseline Resistance to Fluoroquinolones x Treatment Outcome

23. Baseline Extensive Drug Resistance (XDR) x Treatment Outcome

24. Emergence of Drug Resistance: Isolates Analyzed

25. Does the GLC achieve it’s objective of preventing acquired drug resistance?Comparison of DST results in first vs. last paired isolates*

26. Considerations for Acquired Drug Resistance Analysis • There are many country specific factors other than whether sites applied for GLC or not that need to be considered for association with acquired drug resistance • Genotyping results are necessary to confirm that BL and Final isolates are the same strain • For matching genotypes, repeat DSTs are required for confirmation • We do occasionally see a loss of resistance between BL and final isolates. Again, genotyping and repeat DSTs are essential

27. Acquired Resistance to ≥1 Second-line Injectable Drug x Treatment Outcome

28. Acquired Resistance to Fluoroquinolones x Treatment Outcome

29. Acquired Extensive Drug Resistance (XDR) x Treatment Outcome

30. Summary • Treatment data complex, results preliminary • Several risk factors have very strong associations with outcome • Country, GLC, previous treatment, severity of disease, baseline drug resistance, DOT, persistence of positive cultures • Acquired drug resistance has a severe impact on outcomes

31. Next Steps • Completion of data checking and cleaning • Extend analyses to identify salient risk factors controlling for differences between samples from different countries • Compare genotypes of baseline and final isolates • Test isolates between first and last to determine timing and specific mutations leading to acquired drug resistance

32. CDC, Atlanta, Georgia, USA Ken Castro Eugene McCray Charles Wells Tracy Dalton* Ekaterina Kurbatova* Julia Ershova* Allison Taylor* Bryan Kim* Gail Starks* AndreyBorisov* Michael Chen* Lauren Cowan Lois Diem* Denise Hartline* Jamila Franklin* Dorothy Kaminski* Heather Alexander Beverly Metchock Tom Shinnick David Sikes Kathrine Tan* Andy Vernon Emory University, Atlanta, Georgia, USA Charlotte Kvasnovsky* Melanie Wolfgang* Tropical Disease Foundation, Manila, Philippines Janice Campos Caoili* Grace Egos MaricelleGler RuffyGuilatco Nellie Mangubat Imelda Quelapio Thelma Tupasi Acknowledgements Tartu University, No. Estonia Regional Hospital & National TB Registry,,Tallinn, Estonia Kai Kliiman Piret Viiklepp Manfred Danilovitz Tiina Kummik Klavdia Levina State Centre of TB and Lung Disease, Riga, Latvia Girts Skenders Ingrida Sture Liga Kuksa Gunta Dravniece Vaira Leimane Medical Research Council, Pretoria, S. Africa Martie van der Walt Jeannette Brand Joey Lancaster Ronel Odendaal Karin Weyer Office of Disease Prevention and Control 7th Muang District, Ubon Ratchatani, Thailand: Rattanawadee Akksilp Somsak Akksilp Wanlaya Sitti Wanpen Wattanaamornkiet Korean Institute of TB, Seoul, and National Masan TB Hospital, Masan, South Korea Hee Jin Kim Hee Jung Lee Chang-ki Kim Woojin Lew Ray Cho Sungkyu Park Nackmoon Sung Russian Federation: Central TB Research Institute, Moscow; Orel Oblast TB Dispensary; Vladimir Oblast TB Dispensary; Northern State Medical University and Arkhangelsk Reg. TB Dispensary; Vladislav Erokhin & CTRI Team, Moscow Andrey Maryandyshev, Nina Nizovtseva, Director Perkhin, and team from Arkhangelsk Boris Kazenniy and team from Orel Grigory Volchenkov and team from Vladimir Ministry of Health / National TB Strategy, National Institute of Health, Socios en Salud Sucursal, Lima City & Lima East Health Districts, LIma, Peru Oswaldo Jave Jaime Bayona Luis Asencios Carmen Contreras Cesar Bonilla Martin Yagui Gloria Yale National Institute of Allergy & Infectious Disease, Bethesda, Maryland, USA Clifton Barry III Laura Via USAID Washington & Moscow Christy Hansen Amy Bloom Cheri Vincent Nikita Afanasiev WHO Geneva, Copenhagen, Moscow, Lima Mario Raviglione Paul Nunn Melina Abrahan Richard Zaleskis Wieslaw Jakubowiak Mario Valcarcel * Global Coordinating Team

33. Smoking x Treatment Outcome

34. Alcohol Abuse x Treatment Outcome

35. Previous Treatment History x Treatment Outcome

36. Radiographic Extent of Disease x Treatment Outcome

37. Cavitary Lung Disease x Treatment Outcome

38. Number of positive cultures

39. Baseline Resistance to All 4 First-line Drugs x Treatment Outcome

40. Emergence of Resistance to Fluoroquinolones: Preliminary Data

41. Emergence of Resistance to SL-INJ: Preliminary Data

42. Emergence of XDR TB: Preliminary DataMDR (no FQ or SL-INJ resistance) XDR

43. Emergence of XDR TB: Preliminary Datapre-XDR XDR *Pre-XDR refers to BL MDR isolates that also have resistance to either a FQ or ≥1 SL-INJ

44. Study sample for analysis of acquired resistance vs. treatment outcomes Core Clinical Database n=1654 Baseline DST results n=1426 patients No follow up isolate n=486 Follow up isolate no growth/contam. n=46 Only baseline culture positive n=566 Baseline and final isolate pairs with DST results n=894 Baseline and ≥1 follow up cultures positive n=1088 Analysis of acquired resistancen=860 confirmed MDR