1. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination October 2012 John Jereb, Sundari Mase, FSEB, DTBE, CDC Special thanks to Christine Ho and Andrey Borisov The findings and conclusions in this presentation are those of the presenter and do not necessarily represent the views of CDC.

2. Disclosures No financial conflicts of interest Experimental treatment regimens Off-label usage of FDA-approved medications

3. Treatment of latent M. tuberculosis infection is a key component of TB prevention and elimination. 9 months of isoniazid (INH) is highly efficacious, but effectiveness is diminished by low completion rates (30–60%). A shorter regimen is needed. – High completion rates, effectiveness, and tolerability Public Health Motivation

4. Outline Origins of current INH-RPT guidelines Summary of current guidelines Project for post-marketing surveillance Study 33: self-supervised INH-RPT Plans for additional guidelines

5. Treatment Trial, Brazil Schechter M. AJRCCM 2006 Household contacts to AFB+ – 399 TST+ adults (age ≥ 18 yr) 2 mo. daily RIF-PZA self-sup. – 20/193 grade 3 or 4 hepatitis – 1 TB case 3 mo. DOT weekly INH-RTP – 2/206 grade 3 or 4 hepatitis – 3 TB cases

6. Treatment Trial, RSA Martinson NA. NEJM 2011 1148 HIV-infected, TST+; no HIV Tx – 6 mo. INH daily self-supervised – Indefinite INH daily self-supervised – 3 mo. INH-RIF twice weekly DOT – 3 mo. INH-RPT weekly DOT Endpoint: TB-free survival Followed up to 6 yr

7. RSA Trial, Results 6 INHIndef. INH3 INH-RIF3 INH-RPT TB per 100 P-Y3.62.72.93.1 AE per 100 P-Y15.418.410.68.7 58 TB cases overall No TB difference by regimen Death rate 5.7/100 P-Y

8. Treatment Trial, Brazil, Canada, Spain, and the United States Sterling TR. NEJM 2011 Largest trial (almost 8000 participants) Longest enrollment period Children age ≥2 yr Spectrum of “high-risk” predictors Both effectiveness and efficacy

9. Difference in TB rates between the 2 study arms, and non-inferiority “delta” Modified Intention to Treat Population; A33 analysis

10. Difference in TB rates between the 2 study arms, and non-inferiority “delta” Per Protocol Population; A33 analysis

11. Reported Adverse Events Among persons receiving > 1 dose During treatment or within 60 days of the last dose Regardless of attribution to study drug Toxicity9H N=3,759 3HP N=4,040 P-value Grade 1-2364 (9.7%)325 (8.0%)0.01 Grade 3194 (5.2%)181 (4.5%)0.16 Grade 439 (1.0%)34 (0.8%)0.37

12. Reported Adverse Events Among persons receiving > 1 dose During treatment or within 60 days of the last dose Accounting for attribution to study drug Toxicity9H N=3,759 3HP N=4,040 P-value Related to drug206 (5.5)328 (8.1)<0.0001 Rash only17 (0.5)35 (0.9)0.02 Possible HS15 (0.4)158 (3.9)<0.0001 Other71 (2.0)122 (3.0)0.001 Not related399 (10.3)220 (5.5)<0.0001 HS: hypersensitivity reaction

13. Hepatotoxicity Among persons receiving > 1 dose During treatment or within 60 days of the last dose Toxicity9H N=3,759 3HP N=4,040 P-value All hepatotoxicity 113 (3.0)24 (0.6)<0.0001 Related to drug103 (2.7)18 (0.5)<0.0001 Not related 13 (0.4)6 (0.2)0.08

14. MMWR 2011; 60: 1650–1653

15. CDC Guidelines for Weekly INH-RPT DOT, 12 Doses Equal alternative for 9 mo INH – Otherwise healthy persons with LTBI and factors predicting progression – Age ≥12 yr Consideration for other patients if feasibility favors INH-RPT DOT MMWR 2011; 60: 1650–1653

16. INH and RPT Dosages

17. CDC Guidelines for Weekly INH-RPT DOT, 12 Doses, Children 2–11 Years Old Small numbers in treatment trials No pediatric formulation of RPT INH-RPT recommended if both – Notable risk of TB – Unlikely to complete 9 mo INH MMWR 2011; 60: 1650–1653

18. Not Recommended for Children <2 yr old Patients taking anti-retrovirals for HIV Women who are pregnant Patients with INH- or RIF-resistant LTBI

19. Precautions Exclude TB disease carefully if – “Class IV” (old, healed pulmonary TB) – HIV infection (i.e., not being treated) Drug-drug interactions with rifamycins DOT

20. Completion of Therapy No evidence basis for definition criteria No consensus definition of completion No CDC guidance for interruptions PreventTB (Study 26) definition – 11 or 12 doses – Doses separated by >72 hr – Within 16 weeks

21. Adverse Effects and Monitoring Few problems in the treatment trials Monitoring recommendations – Vigilance for hypersensivity Thrombocytopenia Hypotension – Hepatotoxicity Baseline ALT for few conditions – HIV infection – Post-partum period – Liver disease; alcohol usage

22. National Surveillance for Severe Adverse Effects Since 2004, at DTBE “Severe” = death, or hospital admission LTBI treatment – Any regimen – At least one dose Forms available by contacting LTBIdrugevents@cdc.gov On-site CDC investigations, on request

23. Adverse Effects in Study 26: Work in Progress Hypersensitivity syndrome – Panel of immunologists – Working definition – One scientific abstract, submitted Methadone interactions – Mainly, withdrawal – Preliminary findings in early 2013

24. Adverse Effects in Study 26: Work in Progress Adverse effects trends analysis – Total AEs decreased over time – Most decrease: HS reactions – Findings in 2013 Hepatitis sub-study – Matched case-control design – Focus on viral hepatitis infections – Findings in 2013

25. Adverse Effects in Study 26: Work in Progress HIV extended enrollment Pediatric extended enrollment Focus on INH-RPT safety – 60 day monitoring is complete – Data collection is complete 33-month monitoring is ongoing

26. Post-implementation INH/Rifapentine Project Takin’ It To the Streets… (And Keeping it Safe) Sundari Mase, M.D., M.P.H. FSEB/DTBE/CDC

27. “Those who do not remember the past are condemned to repeat it…..” – Santayana LTBI Treatment and a History of Adverse Events

28. Learning from History This CDC-funded project will use the experience of the field to conduct post- implementation surveillance to inform national TB program activities Actively monitor for adverse effects of the new 12 weekly dose INH-RPT regimen through TB programs Collect information on programmatic issues Treatment trials are not good predictors of program experience

29. Objectives Assess the use of INH-RPT in non-research settings for adverse effects –Collect ‘denominator data’ prospectively –Note if certain populations, risk factors or settings are more often associated with adverse effects Assess adherence and treatment completion Assess impact of INH-RPT on programs –Staffing –Costs Match patients with TB registry at 2 years

30. Program requirements Use of INH-RPT regardless of project participation Able to track and evaluate patients for adverse events Able to notify CDC contact of adverse events within 1 day Able to collect basic demographic information, number of people started and completed on regimen, and symptom review checklist from each weekly dosing visit

31. INH-RPT Project Sites Arkansas Arizona – Pima Bureau of Prisons California Georgia Hawaii Illinois – Kane Kansas Mississippi Minnesota New Mexico Nevada New York North Dakota Ohio – Columbus Oregon South Carolina Seattle WA Tennessee Virginia Wisconsin

32. Ideally would want the same information collected across sites and populations to promote comparability Essential data- core set of variables needed for assessment –Number of patients started and completed on regimen –Weekly screening for symptoms and adverse effects –Demographics in aggregate form –Notification of adverse events Full complement – ideal set of variables for assessment –Individual demographics –Epidemiological risk factors (homeless, correctional) –Medical risk factors (diabetes, HIV, smoking) –Medications –Timing of doses Information To Be Collected

33. Program Evaluation Effectiveness –Adherence –Medication procurement Feasibility –DOT –Staffing –Cost

34. Adverse Events Key person for each project site and CDC contact person for adverse effects All adverse events reviewed at DTBE Conference calls (monthly) and transmission of information (quarterly) at set frequency –Ensure needed modifications are made –Share patterns of adverse events across sites TB registry match at 2 years (or later) Coalesce and report information

35. Adverse Events Approximately 650 patients started on INH- RPT Seven hospitalizations reported to CDC Six out of seven have been investigated by CDC; the seventh investigation this week Not all hospitalizations will be attributable to INH-RPT

36. Take Home Messages INH/Rifapentine has only been studied in treatment trials and the surveillance project tracks what is happening in the real world CDC recommendation is to only give INH-RPT by DOT Any SAE should be reported to Public Health Important to track SAEs systematically, in real time

37. Thank You! Field Services and Evaluation Branch –Terry Chorba –John Jereb –Sundari Mase –Mark Lobato –Neha Shah –Field Medical Officer Team –Evaluation Team –Program Consultants and Public Health Advisors Clinical Research Branch –Andy Vernon –Elsa Villarino –Andre Borisoff –Stefan Goldberg Surveillance, Epidemiology and Outbreak Branch –Tom Navin –Krista Powell

38. TBTC Study 33: iAdhere Comparison of DOT, SAT INH-RPT, and Short Messaging Service (SMS) Open label Randomized by household group Primary endpoint: Tx completion MEMS caps monitoring for SAT 1000 patients, age >18 yr

39. TBTC Study 33: iAdhere Opened for enrollment September 18 2 of 13 sites Phased in, site by site

40. FDA Review for LTBI Indication Meeting with Sanofi Aventis, September 4 Study 26 data from CDC No foreseeable timetable

41. Guidelines: What’s Coming New Targeted Testing Guidelines ATS, IDSA, CDC collaboration AAP participation Evidenced-based structure Forecast: summer 2013