“you want me to take how many months of medication?”: advising your patient on risks vs....
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“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…
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?
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