“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

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 infection Spectrum  Latent as in “undeveloped” not as in “dormant”

TB: Outcomes after Exposure Dogma  Lifetime risk of reactivation TB: 5-10% Patient – May be substantial over- or under-estimate of risk This usual estimate based on data collected before LTBI tx was routinely recommended. is thought that infection results when as few as one to five bacteria are deposited in a terminal alveolus. Primary tuberculosis, a self-limited, mild pneumonic illness that generally goes undiagnosed, may develop in a subgroup of infected persons. During this illness, bacillemia and seeding of other organs may occur, setting the stage for subsequent reactivation in extrapulmonary sites. A precarious balance is subsequently struck between the host and the pathogen. In about 5 percent of persons, the infection progresses from a latent form to active disease within two years after infection, and an additional 5 percent have active disease at some later point in their lives. Among persons who are seronegative for the human immunodeficiency virus (HIV), approximately 30 percent of heavily exposed persons will become infected. In 5 percent of persons with latent infection, active disease will develop within two years, and in an additional 5 percent, progression to active disease will occur later. The rate of progression to active disease is dramatically increased among persons who are coinfected with HIV Small NEJM 2001

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

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 Early 1970’s thru 2000, immigrants > 35 years not recommended for treatment The reasons for the controversy may be the history of repeated cycles of enthusiastic recommendations of new regimens, followed by imprudent application of therapy, followed by disastrous adverse events

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 Greatest risk period for developing active TB is shortly after LTBI develops (e.g., hospitals, shelters, corrections, nursing homes) Medically immunosuppressed: solid organ transplants, steroids, TNF-alpha blockers

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 Under targeted testing, all these patient presentations would be tested and (since TST positive) treated. Is that appropriate?

Updated Risk Estimates for Active TB Risk among persons with non-conversion positive TST appx .11%/year Risk declines for 9 years following conversion then decreases 10% every decade

Risk of TB: Comparing Estimates RR Estimates, ATS Guidelines 10-25 2-4 30 2-5 Silicosis 30 Diabetes mellitus 2.0-4.1 (42-44) Chronic renal failure/hemodialysis 10.0-25.3 (39-41) Castrectomy 2-5 (4547) lejunoileal bypass 27-63 (48, 49) Solid organ transplantation Renal 37 (50) Cardiac 20-74 (51, 52)

Risk Active TB: Age Horsburgh, NEJM 2004 350

Risk of Active TB Individual risk based on relative risk of condition and age. So you would want to establish a PPD cut-off that reflects risk of progression and likelihood that it is not a false positive

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 As you can see the number of cases of TB among the foreign born has not decreased in the same manner as U.S. born. This has raised the question whether a change in strategy is required?

TB Case Rates Remain Elevated in Foreign Born for Years after Immigration Despite risk being highest in year following immigration, rates remain significantly elevated many years post 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) New arrivals from high-incidence countries were hypothesized to arrive with high-risk “early latency” because of ongoing exposure and reinfection with new TB strains until U.S. arrival (8, 9). Because TB risk is highest immediately after infection, high TB rates immediately after arrival were assumed to indicate that reactivation risk declines with time in the United States. U.S. guidelines therefore target LTBI testing and treatment toward foreign-born persons in the United States within 5 years of their arrival  Walter AJRCCM 2014

Changes in Reactivation Risk Among Immigrants New arrivals from high-incidence countries were hypothesized to arrive with high-risk “early latency” because of ongoing exposure and reinfection with new TB strains until U.S. arrival (8, 9). Because TB risk is highest immediately after infection, high TB rates immediately after arrival were assumed to indicate that reactivation risk declines with time in the United States. U.S. guidelines therefore target LTBI testing and treatment toward foreign-born persons in the United States within 5 years of their arrival  Walter AJRCCM 2014

Durable Reactivation Risk Differs by Region of Origin Cain AJRCCM 2007

Seattle-King County Experience Risks vary by region of origin; risk remains elevated for many groups beyond the five years following immigration PHSKC Annual Report on TB, 2010

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 In several large series, transaminase elevation .1-.6% (ATS Guidelines) RF’s: older age, EtOH consumption, Asian ethnicity couble rate compared to whites, 14x that of blacks. Differences in age-related estimates due to differing defintions hepatotoxicity, patient selection, ability to exclude other causes of hepatotoxicity

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 For Close contact children ICER is $5200/QALY, close contact adults $8900 & HIV-infected $12,800. Immigrants the cost remains < $100k up to age 44…ICER for a 25-44 yo immigrant in US > 5 years is $57400. IVDU cost is $104,000 and the cost continues to climb for further groups (e.g. prisoner $147k, silicosis $385k)

Assessing your patient’s risk…

Individual Risk Stratification: Online TST/IGRA Interpreter www.tstin3d.com Risk estimates based on older data (not Horsburgh’s re-estimates) Risk of INH DILI based on USPHS study (not Nolan et al) Estimates of predictive value and risk of disease for a positive test (TST or IGRA) from this algorithm cannot be made for children aged 5 or younger Instructions for using the online tool If the patient is born in the U.S., then an option for state and race/ethnicity appears. Race/ethnicity option only applies to US-born patients. If the patient is born in Canada, then an option for native/aboriginal/Indian status appears. If the patient is born in India, then an option for state/territory appears. If the patient is born in China, then an option for Province/SAR/AR/Municipality appears. If the patient is born in Argentina, then an option for Provinces/District appears. If the patient is born in Brazil, then an option for state appears. If the patient is born in Australia, then an option for state/territory appears. If the patient immigrated to a low TB incidence country (such as Canada, US, UK, Western Europe, Australia), then age at immigration is used in the calculations. If the patient was BCG-vaccinated before 2 years of age and had a TST of size…

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 INH toxicity estimates are from USPHS study in 1970s

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 ARD =  PPV x [baseline annual risk of TB] x [RR for specific risk factors]. Baseline annual risk of TB = 0.1% in healthy persons with normal CXR and no other risk factors. This was taken from a large cohort of healthy TST-positive US military recruits followed up for 4 years (Comstock et al). If the patient is a recent close contact, then the baseline risk of TB is 5% for the first two years and the baseline annual risk of TB is 0.1% for the years after. Close contact is defined as someone living in the same household, or a non-household member who regularly (more than 4 hours per week) has contact with the index case; and is being seen at the time of recent close contact, i.e. as part of a contact investigation, but not if the person has had close contact in the remote past. If the patient was recently infected, then the relative risk increases by 15 folds for the first two years, but not for the years after. RR = Relative risk for specific factors - ranges from 2 to 50. See Table 2 from Chapter 4 (page 65) from 2007 Canadian TB Standards (6th edition) for values for RR. Cumulative Risk of Disease The cumulative risk of disease (CRD) is the product of the annual ARD and the number of years before the patient reaches the age of 80. Why the difference? Older methods assume that after the initial decade following infection, lifetime risk remains constant. The lifetime risks associated with co-morbidities are lower per Horsburgh…This difference results from the failure of previous analyses to distinguish among the risk of exposure, the risk of infection, and the risk of reactivation. Horsburgh makes an important assumption that it is assumed that the relative risk of infection equals the relative risk of disease in immunosuppressive conditions associated with TB.

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 ARD =  PPV x [baseline annual risk of TB] x [RR for specific risk factors]. Baseline annual risk of TB = 0.1% in healthy persons with normal CXR and no other risk factors. This was taken from a large cohort of healthy TST-positive US military recruits followed up for 4 years (Comstock et al). If the patient is a recent close contact, then the baseline risk of TB is 5% for the first two years and the baseline annual risk of TB is 0.1% for the years after. Close contact is defined as someone living in the same household, or a non-household member who regularly (more than 4 hours per week) has contact with the index case; and is being seen at the time of recent close contact, i.e. as part of a contact investigation, but not if the person has had close contact in the remote past. If the patient was recently infected, then the relative risk increases by 15 folds for the first two years, but not for the years after. RR = Relative risk for specific factors - ranges from 2 to 50. See Table 2 from Chapter 4 (page 65) from 2007 Canadian TB Standards (6th edition) for values for RR. Cumulative Risk of Disease The cumulative risk of disease (CRD) is the product of the annual ARD and the number of years before the patient reaches the age of 80. Why the difference? Older methods assume that after the initial decade following infection, lifetime risk remains constant. The lifetime risks associated with co-morbidities are lower per Horsburgh…This difference results from the failure of previous analyses to distinguish among the risk of exposure, the risk of infection, and the risk of reactivation. Horsburgh makes an important assumption that it is assumed that the relative risk of infection equals the relative risk of disease in immunosuppressive conditions associated with TB.

Risk Estimates - tstin3d.com ARD =  PPV x [baseline annual risk of TB] x [RR for specific risk factors]. Baseline annual risk of TB = 0.1% in healthy persons with normal CXR and no other risk factors. This was taken from a large cohort of healthy TST-positive US military recruits followed up for 4 years (Comstock et al). If the patient is a recent close contact, then the baseline risk of TB is 5% for the first two years and the baseline annual risk of TB is 0.1% for the years after. Close contact is defined as someone living in the same household, or a non-household member who regularly (more than 4 hours per week) has contact with the index case; and is being seen at the time of recent close contact, i.e. as part of a contact investigation, but not if the person has had close contact in the remote past. If the patient was recently infected, then the relative risk increases by 15 folds for the first two years, but not for the years after. RR = Relative risk for specific factors - ranges from 2 to 50. See Table 2 from Chapter 4 (page 65) from 2007 Canadian TB Standards (6th edition) for values for RR. Cumulative Risk of Disease The cumulative risk of disease (CRD) is the product of the annual ARD and the number of years before the patient reaches the age of 80. Why the difference? Older methods assume that after the initial decade following infection, lifetime risk remains constant. The lifetime risks associated with co-morbidities are lower per Horsburgh…This difference results from the failure of previous analyses to distinguish among the risk of exposure, the risk of infection, and the risk of reactivation. Horsburgh makes an important assumption that it is assumed that the relative risk of infection equals the relative risk of disease in immunosuppressive conditions associated with TB.

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 TST+, HIV-negative, no fibrosis, not recently infected: Historical incidence: 0.10-0.16% per year More recent data: 0.04-0.056% per year Think about future benefit (age) and… Dominant risk factors: HIV, other immunosuppression Fibrosis Recent acquisition Diabetes and other key medical conditions http://www.tstin3d.com/en/calc.html

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 TST+, HIV-negative, no fibrosis, not recently infected: Historical incidence: 0.10-0.16% per year More recent data: 0.04-0.056% per year Think about future benefit (age) and… Dominant risk factors: HIV, other immunosuppression Fibrosis Recent acquisition Diabetes and other key medical conditions http://www.tstin3d.com/en/calc.html

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