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

4. 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

5. 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

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
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

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
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

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

10. 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

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

12. Risk Active TB: Age
Horsburgh, NEJM

13. 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

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
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?

16. 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

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)
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

18. 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

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

20. 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

21. 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

22. Treatment Risks
Of INH adverse effects, drug-induced liver injury (DILI) most feared
Significant transaminase elevation: %
RFs: age, EtOH, ethnicity
USPHS study from 1970’s still quoted: years 0.3%, = 1.2%, 50 – 64 = 2.3%, >65 years = 4.6%
Seattle study: 0.28% of >65 years
:17 severe adverse events associated with INH
5 died, 5 liver txp…estimated 291, ,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

23. 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)

24. 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 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)

25. Assessing your patient’s risk…

26. Individual Risk Stratification:
Online TST/IGRA Interpreter
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…

27. 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

28. 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.

29. 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.

30. 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.

31. 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

32. 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

33. 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: % per year
More recent data: % per year
Think about future benefit (age) and…
Dominant risk factors:
HIV, other immunosuppression
Fibrosis
Recent acquisition
Diabetes and other key medical conditions

34. 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: % per year
More recent data: % per year
Think about future benefit (age) and…
Dominant risk factors:
HIV, other immunosuppression
Fibrosis
Recent acquisition
Diabetes and other key medical conditions

35. Questions/Comments?