General Session III 01 Ho 04-25...General Session III ‐Christine Ho April 19, 2017 2017 National...

General Session III ‐ Christine Ho April 19, 2017

2017 National TB Conference, Atlanta, Georgia National TB Controllers Association www.tbcontrollers.org 1

Sorting Out the Benefits of TST vs. IGRAs:A Head to Head Comparison Among 11,000 at

High Risk for LTBI

National Tuberculosis Conference

April 19, 2017

Christine S. Ho, M.D., M.P.H.

CDC TBESC Project Officer, SEOIB/DTBE

An estimated 13 million U.S. residents have LTBI

Up to 10 percent will develop TB in their lifetimes

To reach TB elimination, identifying and treating infected persons is critical

3 commercially available tests in the U.S.

Tuberculin Skin Test (TST)

Interferon‐gamma release assays (IGRAs)

• Quantiferon Gold In‐Tube (QFT)

• T.SPOT.TB (TSPOT)

Latent Tuberculosis Infection (LTBI): What We Already Know labile

US-born

*

*

Pre‐elimination target (<10/mill) met by ≈ 2025 if LTBI treatment rate quadrupled in 2008

Approach elimination (<1/mil) after 2030 if LTBI treatment rate quadrupled in 2008 and LTBI prevalence in FB arrivers reduced by 75%

A.N. Hill et al, Epidemiol Infect 2012;140:1862

Road to TB Elimination

TB elimination goal

**



The truth ‐ no gold standard for LTBI diagnosis

The best testing strategy – unknown, testing policies vary across programs

TST alone

IGRA alone (categorical or quantitative results)

TST and IGRA sequentially

Data needed to evaluate how to best use these existing tests to improve clinical decision making in high‐risk populations in the U.S.

LTBI: What We Don’t Know…Yet

Tuberculosis Epidemiologic Studies Consortium(TBESC II)

Focus on LTBI

Conducts research to improve LTBI diagnostic tools, treatments, and approaches to accelerate the decline and achieve the goal of TB elimination

Ten sites in 11 states

Obtain data that influences policy decisions by

Determining which persons with LTBI are at the highest risk for developing TB disease

Determining, of these highest risk groups, who gets screened and treated for LTBI

Determining the best practices to find, screen and treat these highest risk groups

Creating a means to monitor changes in risk, uptake of screening, treatment and adverse events

Long‐term Goals for TBESC‐II

Focus on Prevention



TBESC‐II: Focus on LTBI

Part A: Comparing Predictive Value of LTBI

Tests

Part B: Measuring the TB Prevention

Cascade

Part C: Closing the Gaps in the

Cascade

10 years

2016 20212011

Part D:Ultra‐short LTBI

Regimen Trial

Prospective, multi‐year cohort study

Main objectives

Evaluate agreement between TST and IGRAs

Determine the ability of each test to predict progression to TB disease

Research Questions Which tests or test combinations can best identify LTBI in specific high‐

risk populations in the U.S.?

Can test characteristics (e.g. positive and negative predictive values) be improved by changing testing strategy

Part A Overview

Close contact of a person with pulmonary TB

Foreign‐born from a high incidence country

Foreign‐born from a medium incidence country

who moved to the U.S. within the past 5 years

Spent ≥ 30 days in a high incidence country within the

last 5 years

Belongs to a population with a local LTBI prevalence

≥25% (e.g., homeless)

Part A Eligibility Criteria



Part A Study Enrollment (July 2012 – present)

Studies Number enrolled

Total Part A participants 21,158

TSPOT split sample 546

QFT and TSPOT repeat 947

T‐cell Xtend 315

QFT‐Plus 495

Cost‐effectiveness 1679

Diabetes and LTBI ~500

Flow Diagram of TBESC Participants July 20, 2012 – September 28, 2014

Approached (n=14,682)

Enrolled (n=12,134 [82.6%])

Declined (n=2,548 [17.4%])

Analyzed (n=11,962 [98.6%])

Excluded from analysis (n=172 [1.4%])• Ineligible, mistakenly enrolled (n=68 [39.5%])• Diagnosed with TB during screening (n=44 [25.6%])• Invalid results for all 3 tests (n=60 [34.9%])

Age and Gender Distribution of TBESC ParticipantsJuly 20, 2012 – September 29, 2014 (N=11,962)

All Participants(N=11,962)

Foreign‐born(n=9,643)

US‐born(n=2,319)

Gender Female 5,661 (47.3) 4,856 (50.4) 805 (34.7)

Male 6,284 (52.5) 4,785 (49.6) 1,499 (64.6)

Other 17 (0.1) 2 (0.0) 15 (0.7)

Age <2 111 (0.9) 106 (1.1) 5 (0.2)

2‐4 405 (3.4) 384 (4.0) 21 (0.9)

5‐9 794 (6.6) 737 (7.6) 57 (2.5)

10‐14 889 (7.4) 826 (8.6) 63 (2.7)

15‐24 2,107 (17.6) 1,925 (20.0) 182 (7.9)

25‐44 4,465 (37.3) 3,758 (39.0) 707 (30.5)

45‐64 2,715 (22.7) 1,502 (15.6) 1,213 (52.3)

≥65 378 (3.2) 324 (3.3) 54 (2.3)

Missing 98 (0.8) 81 (0.8) 17 (0.7)



Race/Ethnicity and Region of Birth of TBESC ParticipantsJuly 20, 2012 – September 29, 2014 (N=11,962)

Race or ethnicity (not mutually exclusive)

n (%)

American Indian/Alaska Native 80 (3.5)

Asian 69 (3.0)

Black/African American 1,326 (57.2)

White/Caucasian 624 (26.9)

Native Hawaiian/Pacific Islander 30 (1.3)

Hispanic/Latino 230 (9.9)

Other 63 (2.7)

Don't know/Refused 21 (0.9)

Region of birth n (%)

Africa 898 (9.3)

Americas 1,396 (14.5)

Eastern Mediterranean

1,593 (16.5)

Europe 92 (1.0)

Southeast Asia 3,253 (33.7)

Western Pacific 1,975 (20.5)

Unknown 436 (4.5)

U.S.‐born (n=2,319) Foreign‐born (n=9,643)

Reason for Enrollment for TBESC participantsJuly 20, 2012 – September 29, 2014 (N=11,962)

Reason for enrollment

All participants(n=11,962)

Foreign‐born(n=9,643)

US‐born(n=2,319)

N (%) N (%) N (%)

Close contact 1,052 (8.8) 660 (6.8) 392 (16.9)

Foreign‐born from high‐risk country* 8,152 (68.1) 8,152 (84.5)

Spent at least 30 days in high risk country in last 5 years 110 (0.9) 27 (0.3) 83 (3.6)

Foreign‐born from medium‐risk country who moved to US within the past 5 years

439 (3.7) 439 (4.6)

HIV‐positive 1,372 (11.5) 73 (0.8) 1,299 (56.0)

Member of a group with LTBI prevalence >25% 834 (7.0) 290 (3.0) 544 (23.5)

Unknown 3 (0.0) 2 (0.0) 1 (0.0)

*includes refugees and B waiver applicants

BCG Status and Medical Conditions of TBESC Participants, July 20, 2012 –September 29, 2014

Self‐reported conditions

All Participants(n=11,962)

n (%)

Foreign‐born(n=9,643)n (%)

U.S.‐born(n=2,319)n (%)

BCG Vaccination 6,332 (52.9) 6,218 (64.5) 114 (4.9)

Medical Condition

HIV+ 1,460 (12.2) 154 (1.6) 1,306 (56.3)

Liver disease 511 (4.3) 82 (0.9) 429 (18.5)

Chronic kidney failure 84 (0.7) 25 (0.3) 59 (2.5)

Diabetes 608 (5.1) 387 (4.0) 221 (9.5)

Immunosuppressive therapy 202 (1.7) 86 (0.9) 116 (5.0)



Descriptive analysis of single and combination test results

Use Kappa statistics to examine test agreement at different combinations of IGRA test cut‐points

Compare ratio of LTBI prevalence by TST and by QFT with published literature

Use latent class analysis (LCA) to estimate the “true” prevalence of LTBI in our study population, as well as the sensitivities and specificities of each test

8 spots are greater considered positive for TSPOT (U.S. cut‐off)

Analytic Approach

Single Test LTBI Prevalence for Foreign‐born Persons Who Were Not Close Contacts

July 2012‐September 2014 (n=11,962)

0

10

20

30

40

50

60

<2 2‐4 5‐9 10‐14 15‐24 25‐44 45‐64 65+

Percent positive

Age group (years)

TST

QFT

T‐SPOT (Int)

T‐SPOT (US)*

Test Result CombinationsJuly 2012‐September 2014 (n=11,962)

Test result TST QFT TSPOT All Participantsn (%)

Foreign‐bornn (%)

U.S.‐bornn (%)

All 3 tests positive + + + 1612 (15) 1519 (17.5) 93 (4.5)

All 3 tests negative ‐ ‐ ‐ 6021 (56.1) 4290 (49.5) 1731 (83.9)

1 test positive+ ‐ ‐ 1980 (18.4) 1883 (21.7) 97 (4.7)

‐ + ‐ 279 (2.6) 200 (2.3) 79 (3.8)

‐ ‐ + 70 (0.7) 62 (0.7) 8 (0.4)

2 tests positive

+ + ‐ 471 (4.4) 442 (5.1) 29 (1.4)

‐ + + 156 (1.5) 134 (1.5) 22 (1.1)

+ ‐ + 151 (1.4) 146 (1.7) 5 (0.2)



Test Combinations for Foreign‐born Persons Who Were Not Close Contacts, by Age Group

0

10

20

30

40

50

60

70

80

<2 2‐4 5‐9 10‐14 15‐24 25‐44 45‐64 65+

Percent

Age group (years)

Single IGRA+

TST+ only

2 tests +

3 tests +

n=97

n=360n=680

n=745

n=1,595

n=3,096

n=1,158

n=244

Kappa Measure of Test Agreement for Foreign‐born Persons

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2‐4 5‐9 10‐14 15‐24 25‐44 45‐64 65+

Kappa

Age group (years)

TST vs. QFT TST vs. TSPOT QFT vs. TSPOT

Substantial agreement

Moderate agreement

Fair agreement

Slightagreement

Kappa Measure of Test Agreement for U.S.‐born Persons

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2‐4 5‐9 10‐14 15‐24 25‐44 45‐64 65+

Kappa

Age group (years)

TST vs. QFT TST vs. TSPOT QFT vs. TSPOT

Substantial agreement

Moderate agreement

Fair agreement

Slightagreement



TST & IGRA Agreement in the Literature:Ratio of LTBI Prevalence by TST/IGRA1

Year Country Population TST/IGRA Prevalence Ratio

2007 Italy Undocumented persons 0.3

2011 Iran Children 0.5

2011 U.S. Refugees 0.6

2008 Turkey Child household contacts 0.7

2010 Gambia Child household contacts QFT 0.8, TSPOT 0.8

1999 New Zealand Immigrants 0.8

2010 Italy Undocumented persons 0.8

2009 U.S. Refugee Somali women 1.0

2017 India Household contacts 1.0

2011 S. Africa High school cohort 1.0 (5),1.2 (10),1.3 (15)*

2015 U.S. National survey 1.3

2010 Hong Kong Silicosis patients 1.3

* mm cutoff points for TST1 LTBI prevalence by TST/ LTBI prevalence by IGRA

TST & IGRA Agreement in the Literature:Ratio of LTBI Prevalence by TST/IGRA1

Year Country Population Ratio of LTBI prevalence by TST/IGRA1

2009 Italy Recent immigrants 1.3

2010 Senegal Contacts 1.4 (~6 spots), 1.2 (~8 spots)

2010 Norway Recent immigrants 1.7 (6), 0.5 (15)*

2011 Germany Child contacts 1.8 (5), 1.8 (10)*

2014 S. Korea Children 2.1 (10) 0.7 (15)*

2008 Germany Foreign‐born contacts 3.6 (5), 1.2 (10)*

2014 Turkey Children ∞

2013 Vietnam U.S. visa applicants > 15 years old 2.1(5),1.4 (10),0.7(15) normal CXR

1.2(5), 0.9 (10),0.49(15) abnormal CXR

2008 Australia Child contacts or immigrants 2.3(5), 2.0(10), 1.9(15) QFT

3(5), 2.5(10), 2.4(15) TSPOT

* mm cutoff points for TST1 LTBI prevalence by TST/ LTBI prevalence by IGRA

Ratio of LTBI Prevalence by TST/IGRA in TBESC Cohort

Age TST/QFT1 TST/TSPOT1

<2 ∞ ∞

2‐4 5 11

5‐9 2 3

10‐14 2 3

15‐24 2 2

25‐44 2 2

45‐64 1 2

65+ 1 1

Total 2 2

Group TST/QFT1 TST/TSPOT1

U.S.‐Born 0.9 1.5

Foreign‐born 1.6 2

Foreign‐born <5 8 16

Foreign‐born>5 2 2

U.S.‐born>65 1.5 2

Foreign‐born>65 0.9 1.1

1 LTBI prevalence by TST/ LTBI prevalence by IGRA



Requires at least 3 separate measurements of the phenomenon of interest ( TST, QFT, TSPOT to measure latent TB)

Uses patterns of correlations among tests to derive a latent (not observable) gold standard

With 3 tests can separate into 2 groups—here assumed to be with and without LTBI

Provides estimates of LTBI prevalence, sensitivity, and specificity of each test for LTBI

Also systematically examined whether test performance was the same across 3 groups:

Foreign‐born vs. US‐born

HIV+ vs. HIV‐

Children <5 vs. people aged 5 and older

Latent Class Analysis (LCA)

Performance Characteristics of LTBI Tests by LCA for

Foreign‐born persons with Age ≥5 years (n=8,018)Preliminary Results

Sensitivity

(95% CrI*)

Specificity

(95% CrI*)

Positive

Predictive Value

(95% CrI*)

Negative

Predictive Value

(95% CrI*)

LTBI Prevalence: 37.9 (32.6‐42.9)

TST 74.8% (67.2‐82.4) 69.6% (67.7‐71.4) 60.0% (56.4‐62.7) 81.8% (73.8‐89.3)

QFT 71.6% (63.3‐79.9) 98.9% (97.8‐99.9) 97.6% (94.0‐99.6) 85.0% (78.5‐91.1)

TSPOT 70.3% (61.4‐79.1) 99.4% (98.6‐100) 98.6% (95.8‐99.8) 84.5% (77.8‐91.0)

*CrI=credible interval

What This Means for the Clinician: High‐risk for LTBI Population

LTBI No LTBI

TST+ 285 186 471

TST‐ 95 434 529

380 620 1000

• Sensitivity of 75%• Specificity of 70%Of 1000 people—• 39% (186/471) of TST+ don’t have LTBI• Positive predictive value (PPV) is 61%• 25% (95/380) with LTBI are missed

Hypothetical cohort of 1000 foreign‐born patients ≥5 yrs (38% LTBI prevalence)

LTBI No LTBI

IGRA+ 266 12 278

IGRA‐ 114 608 722

380 620 1000

• Sensitivity of 70%• Specificity of 98%Of 1000 people—• 4% (12/278) with IGRA+ don’t have LTBI• PPV is 96%• 30% (114/380) with LTBI are missed

• 174 extra people diagnosed by TST that don’t have LTBI• 19 people with LTBI would be missed by IGRA



Performance Characteristics of LTBI Tests by LCA for

Foreign‐born Children <5 years (n=463)

Preliminary Results

Sensitivity

(95% CrI*)

Specificity

(95% CrI*)

Positive

Predictive Value

(95% CrI*)

Negative

Predictive Value

(95% CrI*)

LTBI Prevalence: 4.2 (1.9‐6.7)

TST 68.8% (58.2‐79.1) 74.0% (69.7‐78.0) 10.2% (5.0‐16.9) 98.3% (96.7‐99.3)

QFT 70.4% (54.4‐86.1) 98.9% (97.7‐99.9) 73.8% (43.3‐95.5) 98.7% (97.3‐99.6)

TSPOT 58.9% (42.5‐75.7) 99.0% (98.1‐99.9) 71.9% (45.4‐93.2) 98.2% (96.5‐99.4)

*CrI=credible interval

Performance Characteristics of LTBI Tests by LCA forChildren <5 years (n=463)

TST TSTQFT QFTT‐SPOT T‐SPOT

What This Means for the Clinician: BCG‐vaccinated Children for LTBI Population

LTBI No LTBI

TST+ 28 186 214

TST‐ 12 774 786

40 960 1000

• Sensitivity of 70%• Specificity of 74%Of 1000 people—• 87% (186/214) of TST+ don’t have LTBI• Positive predictive value (PPV) is 13%• 30% (12/40) with LTBI are missed

Hypothetical cohort of 1000 foreign‐born children <5 yrs (4% LTBI prevalence)

LTBI No LTBI

IGRA+ 28 10 38

IGRA‐ 12 950 962

40 960 1000

• Sensitivity of 70%• Specificity of 99%Of 1000 people—• 26% (10/38) with IGRA+ don’t have LTBI• PPV is 74%• 30% (12/40) with LTBI are missed

• 176 extra people diagnosed by TST that don’t have LTBI• 12 people with LTBI would be missed by both TST and IGRA



Comparison of LTBI Prevalence Estimates

Source Group LTBI Prevalence

TBESC by LCA Foreign‐born, HIV(‐), >5 years old 37‐38%

NHANES Foreign‐born persons by TST 21%

NHANES Foreign‐born persons by IGRA 16%

TBESC by LCA Foreign‐born, HIV(‐), <5 years old 4‐5%

TBESC by LCA U.S.‐born, HIV(+), >5 years old 3‐5%

NHANES U.S.‐born persons by TST 1.5%

NHANES U.S.‐born persons by IGRA 3%

• LTBI prevalence among foreign‐born is several fold higher using any analytic method• LTBI prevalence among foreign‐born children <5 is low; similar to NHANES U.S.‐born estimates• U.S.‐born persons uninfected by HIV were only enrolled in TBESC if high‐risk (contacts, etc.) so not comparable

to general U.S.‐born population• LTBI prevalence among U.S.‐born HIV‐infected persons similar to NHANES U.S.‐born estimates

Caveats for Using Latent Class Analysis (LCA)

LCA assumes conditional independence of the three tests

Some conditional dependence exists ‐ LTBI tests all depend on response to shared antigens

Use statistical techniques to correct for this dependence

Bayesian analysis, random effects model, mixed effects model

See if different models converge on similar results

Analyzing continuous and categorical results

Rectifying differences between models

Next steps

Adding clinical factors into the model (abnormal CXR, source case characteristics)

Summary

TBESC has largest cohort data on LTBI testing which compares all 3 tests

Discordance between TST and IGRA greatest for children <5 but present for all age groups

Ratio of LTBI prevalence by TST/IGRA from TBESC cohort fits within range of published studies

LCA provides a method to estimate prevalence and test characteristics in the absence of a reference standard for LTBI

LTBI prevalence estimates by LCA for U.S.‐born and foreign‐born similar to NHANES

LTBI prevalence estimates for foreign‐born children <5 by LCA similar to prevalence for low‐incidence settings

Specificity of diagnostic test drives the rates of false‐positive results, IGRAs more specific

Follow‐up for progression to TB is the true litmus test for test performance



TBESC Acknowledgements

CDC/TBESC

Tom Navin

Dolly Katz

Thara Venkatappa

Pei‐Jean Feng

Jim Wu

Rose Punnoose

Matt Whipple

Michael Chen

Andy Vernon

Part A manuscript WG

Jason Stout

Richard Garfein

Renuka Khurana

Randall Reves

Michael Lauzardo

Lisa Pascopella

Smita Ghosh

TBESC Principal Investigators

TBESC Project Coordinators

TBESC Advisory Committee

Study participants

Part A study and sub‐studies

Comparison of TST, QFT‐GIT, TSPOT.TB

2 year follow‐up for active TB

Split TSPOT.TB samples

Repeat QFT‐IT and TSPOT.TB within 76 hours

T‐cell Xtend sub‐study

Compare 4th generation QFT‐Plus with 3 other tests

Cost‐effectiveness of LTBI diagosis and treatment strategies

Main Study

IGRA Reproducibility Sub‐studies

QFT‐Plus

Cost‐effectiveness Study

Test result combinations for adults>65, Foreign‐born and US‐born populations

Test combinationAll Participants Foreign‐Born US‐Born

n(%) n(%) n(%)

Triple Positive (+++) 66 (19.8) 62 (21.9) 4 (7.8)

Triple Negative (‐‐‐) 168 (50.3) 126 (44.5) 42 (82.4)

Isolated TST+ (+‐‐) 29 (8.7) 24 (8.5) 5 (9.8)

Isolated QFT+ (‐+‐) 19 (5.7) 19 (6.7) 0 (0.0)

Isolated TSPOT+ (‐‐+) 8 (2.4) 8 (2.8) 0 (0.0)

TST+ and QFT+ (++‐) 17 (5.1) 17 (6.0) 0 (0.0)

QFT+ and TSPOT+ (‐++) 20 (6.0) 20 (7.1) 0 (0.0)

TST+ and TSPOT+ (+‐+) 7 (2.1) 7 (2.5) 0 (0.0)

Total334 283 51



What This Means for the Clinician: Low Prevalence Population

LTBI No LTBI

TST+ 18 359 377

TST‐ 12 9611 9623

30 9970 1000

• Sensitivity of 61%• Specificity of 96%

Of 1000 people—• 95% (359/377) with positive

TST don’t have LTBI• 12 /30 with LTBI are missed

Hypothetical cohort of 1000 US‐born HIV+ patients (3% LTBI prevalence)

Predictive Value of Test Combinations for foreign‐born children<5

Test Combination (TST/QFT/TSPOT) Positive Predictive Value

‐‐‐ 0.5% (0‐1.8%)

‐‐+ 26.9% (0‐66.7)

‐+‐ 38.0% (0‐100)

‐++ N/A

+‐‐ 1.3% (0‐3.5)

+‐+ 56.0% (0‐100)

++‐ 67.3% (16.7‐100)

+++ 99.2% (88.9‐100)

Effect of Small Difference in Specificityin Low‐Prevalence Population

LTBI NoLTBI

IGRA1 + 28 39 67

IGRA1‐ 2 931 933

30 970 1000

• Sensitivity of 91.8%• Specificity of 96%Of 1000 people—• 58% (39/67) with IGRA1+

don’t have LTBI• Positive predictive value (PPV)

is 42%• 2/200 with LTBI are missed

Hypothetical cohort of 1000 FB‐born children <5 (3% LTBI prevalence)

LTBI NoLTBI

IGRA2+ 28 10 38

IGRA2‐ 2 960 962

30 970 1000

• Sensitivity of 91.8%• Specificity of 99%Of 1000 people—• 26% (10/38) with IGRA+

don’t have LTBI• PPV is 74%• 2/200 with LTBI are missed

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