1. “You want me to take how many months of medication?”: Advising your patient on risks vs. benefits of LTBI treatment David Horne, MD, MPH Division of Pulmonary and Critical Care Harborview Medical Center University of Washington

2. Outline LTBI: Definition, Guideline History Risks: Progression to Active TB Risks: Treatment Cost vs. Benefit Discussing with your patient Caveat – examples use TST & isoniazid

3. What is Latent TB Infection? Evidence of prior exposure to Mtb, based on interrogation of T cells, without clinical, radiographic or microbiologic evidence of active disease –“latency” should not imply dormancy of Mtb without metabolic activity TB historically 2-state condition: active TB or latent infection Spectrum 

4. TB: Outcomes after Exposure Dogma  Lifetime risk of reactivation TB: 5-10% Patient – May be substantial over- or under- estimate of risk Small NEJM 2001

5. LTBI Screening & Treatment Balance 70% of TB cases in U.S. due to reactivation LTBI treatment is effective Only 10% of individuals with positive LTBI test will progress to active TB Adverse effects related to treatments Poor completion rates

6. LTBI Screening Recommendations – A History Isoniazid - introduced in 1952 for treatment of active TB –In 1955, use expanded to include treatment of LTBI –Campaign for widespread prophylaxis instituted (genl popln screening) Early 1970s, liver injury & deaths due to isoniazid hepatotoxicity –1974, ATS recommended restricting prophylaxis to < 35 years of age unless increased risk for activation –Ensuing years, further decrease in INH use among young individuals 2000 Guidelines -“Targeted Tuberculin Testing” –INH-related morbidity lower than believed –Focus on testing/treatment of individuals at high risk of progression to active TB

7. LTBI recommendations “Targeted tuberculin testing for LTBI identifies persons at high risk for developing TB who would benefit by treatment of LTBI, if detected.” –2000 ATS Guidelines, “Targeted Tuberculin Testing and Treatment of LTBI”

8. Targeted Testing ( 2000 Guidelines ) Recent Infection with M. tuberculosis Close contacts Recent immigrants from areas with high TB rates (< 5 years) Known converters Children younger than 5 years Homeless, IVDU, institutional setting exposures Increased Risk for Progression HIV infection CXR suggestive of old TB (fibrotic) Medical conditions: diabetes, silicosis, dialysis, cancer, underweight Medically immunosuppressed

9. Targeted Testing – Broad Identification 22 y/o Filipino woman, immigrated 3 years ago: TST 15mm, CXR normal Same person, but 42 years of age & immigrated 3 years prior Same person, but 72 years of age & immigrated 3 years prior

10. Updated Risk Estimates for Active TB

11. Risk of TB: Comparing Estimates RR Estimates, ATS Guidelines 10-25 2-4 30 2-5

12. Risk Active TB: Age Horsburgh, NEJM 2004 350

13. Risk of Active TB

14. Risk of Active TB: Immigration Targeted Testing includes recent (< 5 years) immigrants from areas with high TB rates –New arrivals from high-incidence countries hypothesized to arrive with high-risk “early latency” because of ongoing exposure –High TB rates immediately after arrival assumed to indicate that reactivation risk declines with time in US U.S. TB cases –63% among foreign born (2012)

15. U.S. TB Cases: Different Trends by Birth

16. TB Case Rates Remain Elevated in Foreign Born for Years after Immigration Cain JAMA 2008

17. Changes in Reactivation Risk Among Immigrants To address marked difference between 1 st year and subsequent years following immigration, Walter et al looked at immigration from Philippines Separated out those who had abnormal immigration CXR and developed TB in 1 st year (presumed active & inactive TB) Among those with normal CXRs: There was no decline in TB reactivation over 9-year period (32/100,000) Walter AJRCCM 2014

18. Durable Reactivation Risk Differs by Region of Origin Cain AJRCCM 2007

19. PHSKC Annual Report on TB, 2010 Seattle-King County Experience

20. Risk of Active TB - Summary Major Risk Factors include: –Age –HIV –CXR: upper lobe fibronodular disease Moderate Risk: –Recent Conversion Among immigrants risk varies by region of origin and may persist

21. Treatment Risks Of INH adverse effects, drug-induced liver injury (DILI) most feared Significant transaminase elevation: 0.1-0.6% –RFs: age, EtOH, ethnicity –USPHS study from 1970’s still quoted: 20 - 34 years 0.3%, 35-49 = 1.2%, 50 – 64 = 2.3%, >65 years = 4.6% –Seattle study: 0.28% of >65 years 2004-08:17 severe adverse events associated with INH –5 died, 5 liver txp…estimated 291,000-433,000 treated annually Other LTBI regimens likely safer than INH

22. Cost-Benefit – the Societal Perspective Older studies have supported screening and treatment of LTBI as cost-effective for all risk groups (e.g. Rose Arch Int Med 2000) Recent study using revised estimates of LTBI progression, completion rates of LTBI identified cost effectiveness for certain risk groups (Linas AJRCCM 2011)

23. Cost-Benefit – the Societal Perspective

24. Assessing your patient’s risk…

25. Individual Risk Stratification: Online TST/IGRA Interpreter www.tstin3d.comwww.tstin3d.com

26. TB – Risk Estimates tstin3d.com 22 y/o Filipino woman, immigrated 3 years ago: TST 15mm, CXR normal  5.8% lifetime risk 42 y/o Filipino woman, immigrated 3 years ago: TST 15mm, CXR normal  3.8% lifetime risk 42 y/o Filipino woman, immigrated 3 years ago : TST 15mm, DM (Hgb A1c 7.9)  10.6% lifetime risk 42 y/o Filipino woman, immigrated 3 years ago : TST 15mm, CXR shows stable RUL fibronodular changes  47.6% lifetime risk 73 y/o Filipino woman, immigrated 3 years ago : TST 15mm, CXR normal  0.7% lifetime risk

27. Risk Estimates - tstin3d.com May overestimate individual risk of TB progression –Assumes baseline annual risk of TB = 0.1% in healthy persons –If patient is recent close contact, then risk of TB is 5% for the first 2 years and 0.1% thereafter –Horsburgh differences Same baseline risk, lower risks following new conversion by age group Lower risks for progression in co-existing conditions May overestimate INH DILI risk

28. Shared Decision Making – Risk Stratification & Advising Your Patient At what level of risk for TB progression should you recommend LTBI Treatment? –No guideline recommendations Some experts use cut-offs of 3% risk or 5% risk Based on USPHS study estimated risk of age-related INH toxicity (50 – 64 = 2.3%, >65 years = 4.6 percent) Remember: Seattle study, 0.28% of >65 years

29. Shared Decision Making Firm cut-off will not be appropriate for all situations –Individual “costs” involve more than DILI Discuss with patient using available tools Patients need to be motivated to actually complete treatment –Completion rates < 50% in many series

30. In Summary… Risk for progression to active TB varies by patient factors Age of patient important in calculating life-time risk Duration of risk following immigration likely longer than previously stated; region of origin may impact risk

31. In Summary… Better tools are available for risk assessment and may aid clinicians and patients in considering LTBI treatment To treat or not to treat? Have a discussion Alternative Regimens are increasingly popular – improved completion rates LTBI guidelines overdue for update

32. Questions/Comments?