David Horne, MD, MPH Division of Pulmonary and Critical Care Harborview Medical Center

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 1st 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 1st 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. Seattle-King County Experience PHSKC Annual Report on TB, 2010

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.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?