“You want me to take how many months of medication?”:

Advising your patient on risks vs. benefits of LTBI treatment

David Horne, MD, MPHDivision of Pulmonary and Critical Care

Harborview Medical CenterUniversity of Washington

Outline

• LTBI: Definition, Guideline History

• Risks: Progression to Active TB

• Risks: Treatment

• Cost vs. Benefit

• Discussing with your patient

• Caveat – examples use TST & isoniazid

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 infectionSpectrum

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

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

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

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”

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

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

Updated Risk Estimates for Active TB

Risk of TB: Comparing Estimates

RR Estimates, ATS Guidelines

10-25

2-4 30

2-5

Risk Active TB: Age

Horsburgh, NEJM 2004 350

Risk of Active TB

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)

U.S. TB Cases: Different Trends by Birth

TB Case Rates Remain Elevated in Foreign Born for Years after Immigration

Cain JAMA 2008

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

Changes in Reactivation Risk Among Immigrants

Walter AJRCCM 2014

Durable Reactivation Risk Differs by Region of Origin

Cain AJRCCM 2007

PHSKC Annual Report on TB, 2010

Seattle-King County Experience

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

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

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)

Cost-Benefit – the Societal Perspective

Assessing your patient’s risk…

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

TB – Risk Estimates tstin3d.com

• 22 y/o Filipino woman, immigrated 3 years ago: TST 15mm, CXR normal5.8% lifetime risk

• 42 y/o Filipino woman, immigrated 3 years ago: TST 15mm, CXR normal3.8% 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

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

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

Risk Estimates - tstin3d.com

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

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

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

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

Questions/Comments?