Contribution of Latent TB Diagnosis and Treatment to TB Control with Supporting Evidence Multiple facets and perspectives

Juzar Ali MB.,BS (MD); FRCP(C); FCCP

Interim LSU Public Hospital (ILH) & CLINICS System Interim CEO / Medical Director ; UMOB, 2025 Gravier St., 7th Floor NEW ORLEANS , LA 70112 Off: (504) 903 4900, 4907, 4917,; Fax : 504 903 4952 Email: JALI@lsuhsc.edu Cell : 504 444 3975 **Russell C. Klein,LSU-Alumni Professor of Clinical Medicine) ; **Faculty: Section of Pulmonary & Critical Care Medicine, LSUHSC 1901 Perdido , Suite 3205, MEB, New Orleans, LA 70112 LSUHSC Academic Office: 504 568 4634 Fax 504 568 4295 ** Adjunct Professor, School of Nursing , LSUHSC ** Medical Director : Region 1 OPH ; Metro- Wetmore TB Clinics ** Adjunct Professor , Dept of Tropical Medicine, Tulane University School of Public Health and TM & Faculty: Tulane University Dept of Preventive Medicine & Community Medicine** Guest Faculty: Ege University & Hospital , Chest Unit , IZMIR Turkeywebsites www.tbeducation.org www.tbinfo.lsuhsc.edu

PERSONAL INSTITUTIONAL

ACKNOWLEDGEMENTSWETMORE TB CLINIC TEAM ; TB CONTROL OFFICE LEADERSHIPMs Maureen Vincent , LSU TB Clinic Coordinator; Drs. Dean Ellithorpe & Louis Trachtman Mr Charles DeGraw et team

TWO DISCLOSURES

TB Elimination or Control ?

•Early rapid Dx, Rx …but this is only 50% ( WHO data) ; Implement standard transmission prevention guidelines •Only severe cases under radar •Those untreated infect 20 persons /per year •Transmission before Dx: a huge issue •Transmission by Smear negative cases

INDEX CASE

CONTROL OF TB

Regular Transmission FactorsInfectivity of Index casePrimary PreventionSecondary preventionEngineering and administrative Controls

Identify TB case ( awareness/sputum? E NO ??)Rx asap ** Avoid quinolones , non expert consultations/other specialtiesRx right and earlyTarget High Risk ContactsAvoid Wasting Resources

HCWImmune comp hostsHigh risk groupsClose contacts Identify LTBI and access

need for “chemoprophylaxis”

Another approach

• Detect LTBI patients • Rx LTBI patients ( reduce subsequent disease

by 25-92% ( 6months Rx at least : 69% ) • Reduce reservoir

• ………………….But…..

Problems with this approach

• Length of Rx• ADRs specially in medically vulnerable pops• Compliance even in non INH , Rif alone Rx,

although better with the once weekly 12 weeks DOPT regimen of RP & INH?

• Completion of Rx appx 50 %

• …..and that leads us to think …….

Thought process

• “Philosophy”• Approach• Logistics• Cost of testing• Goals• Priority

LTBI incidence

4.2 % of the civilian , non instutionalized US population aged more than 1 year had LTBI , representing a 60 % decline from 1972

MMWR June 2010

Tests for LTBI Background data of TST and IGRA pros and cons known

• Sensitivity of IGRA not compromised in immunocomp hosts , diabetics etc

• TST and then IGRA ( proposed by Mahan et al Int J Tuberc Lung dis 20011 ; 15: 628-634

• Newer proteins ( interferon inducible protein IP-10 superior biomarker IN Rh art patients receiving Anti TNF alpha Rx? Chen et al IJTub LD 2011 ;15: 192-199

• TST and IGRAs : predictors of disease : General• Does quantifying help in either case ?• Specific Quantification in TB spot test : Culture filtrate

protein 10 spot count, but not early secretary antigenic target 6 spot count, was significantly associated with subsequent TB development. ( Hongkong study in silicotic pts )

• Issue of discordance & Borderline data• Effect of Smoking Negative effect of smoking on the performance of the QuantiFERON TB gold in

• tube test BMC Infectious Diseases 2012, 12:379 doi:10.1186/1471-2334-12-379

• IMPORTANCE OF DEFINITION OF CONVERTORS SPECIALLY IN HCWs Challenges of IGRAs conversion in serial testing of HCW Fong et al Chest 2012 ;142 (1): 55-62

Questions I ask ? Curiosity

• IGRA responses are higher in active disease than in LTBI– However, there is a very large overlap in the results so it will not be possible to use IGRAs to differentiate

between active disease and latent infection

Active Vs latent

Janssens et al ERJ (2007)

T-SPOT.TB spot numbers in subjects with active disease compared to LTBI (TST+ve and TST-ve)

Chee et al Eur J Clin Microbiol Infect Dis (2008)

T-SPOT.TB spot numbers in subjects with active disease compared to LTBI

No cross-reactivity to BCG and most NTMs

Issue of Borderline results

• Both IGRAs are biological assay so results will have some variation around the cut-off

• Using a cut-off reduces fluctuations in results that are near the cut-off

• Benefit of cut-off is highlighted by CDC in 2010 guidelines: • “Use of a borderline category might address test variation

and uncertainty for results near a dichotomous cut point.”• Re-testing borderline results 2 weeks later should give definitive

result• Bordeline zones used by IGRAs:

• T-SPOT.TB has a borderline of 5, 6 and 6 spots throughout the world

• QFT only has borderline zone in Japan (0.1 - 0.35 IU/IFN gamma)

“These findings support the extensive literature showing that measurement of TB-specific T-cells using the ex vivo ELISPOT technique (upon which the T-SPOT.TB test is based) is more accurate than the TST, as it has closer correlation to exposure history and is unaffected by prior BCG vaccination.” p. 1246

Zellweger et al., Int J Tuberc Lung Dis (2005)

Explaining discordant results; Contact tracing

Zellweger et al., Int J Tuberc Lung Dis (2005)

Explaining discordant results; Contact tracing

Setting: contact tracing in an institution for alcoholics in Lausanne, Switzerland

Index case: • 47-year old female, born in Brazil• Smear-positive pulmonary TB, infectious for 1 month• She had stopped TB treatment 3 years before so possibility of MDR-TB

Background• Preventive treatment associated with liver toxicity (most contacts >35 years

old, residents all had history of alcoholic liver disease)• Ideally preventive treatment limited to contacts with a proven tuberculosis infection

Study: Duration & intensity of contact with the index case was assessed and subjects divided into high and low exposure groups

Zellweger et al., Int J Tuberc Lung Dis (2005)

All close contactsAll close contactsAll BCG vaccinatedAll BCG vaccinated

Explaining discordant results; Contact tracing

Vassilopoulus et al., J Rheumatology (2008)

“(BCG) vaccination was associated with TST+/Elispot– discordant results (p = 0.01), whereas steroid use was linked to TST–/Elispot+ discordant results (p = 0.04).” p 1

• 70 subjects attending a rheumatology clinic in Athens

• All candidates for anti-TNF therapy

• 43/70 on immunosuppressive drugs

• 15/70 had co-morbid conditions (e.g. chronic liver disease, diabetes, COPD)

• Results of TST and the T-SPOT.TB test compared, multivariate analysis used to analyse discordant results

Explaining discordant results; TNF screening

Indeterminate results

• Indeterminate results occur when nil or positive controls fail.

• Caused by:• Errors during processing (usually resolved when re-

tested)• Maybe patient specific (not usually possible to

resolve)

• Indeterminate results should be repeated 2 weeks later

• ~ two thirds will then give a reportable result

• The performance of IGRAs in children is still being studied; little data are available, particularly for preschool-aged children or children with suspected TB

• A test with greater specificity for children at intermediate risk (ie, risk factors exist but no identifiable source case) for LTBI would decrease the need for unnecessary intervention1

• Whereas an immunocompetent older child or adult with untreated LTBI has about a 5% to 10% lifetime risk of developing TB, an infant’s risk is as high as 40% to 50%; most disease cases occur within 12 months of infection1

• In general, children < 4 years old are unable to contain the spread of TB from LTBI to active TB2

• In young children, a major limitation of the TST is that false-negative results cannot be detected; while IGRAs show promise of greater accuracy, they may also be impaired by cellular immunity, resulting in indeterminate results2

Children and TB

Testing High-Risk Populations for TB

High Risk for Progression or Reactivation

TB Screening for HIV Patients1

Using QFT and T-SPOT.TB

• 275 patients had results for all 3 tests• Patients with QFT-Gold positive results had

higher CD4 cell counts• T-SPOT.TB results were independent of CD4 cell

counts

1. Stephan C, Wolf T, Goetsch U, et al. AIDS. 2008;22:2471-2479.

TST (n = 275)

QFT (n = 275)

T-SPOT.TB(n = 275)

Positive 33 52 66

Negative 243 222 201

Indeterminate NA 1 8

If TST had its problems with administration variability , inter- observer variation etcIGRAs are problematic too in some ways as they are dynamic assays with we see frequent conversions and reversions

So ? Do we need to do TST or IGRA testing at all prior to therapy ?

• HIV population data mainly • Definite benefit if given to TST positive cases

even in high incidence and other countries

Multiple references available

Country

Total screen

ed with

TST (N)

TST positive

(N)

Medically evaluated

(N)

Started INH (N) Completed INH

(N)Of all

positive TST (%)

Of all screened (%)

Canada52 19,001 4,292 814 452 11 2

USA53 4,840 2,039 1,528 853 716 35 15

Canada54 720 162 142 56 52 13 7

Canada55 33,146 7,668 2,600 1589 21 5

Canada16

* 3,300 1,598 647 347 251 31 18

USA56 66,767 12,901 9,018 5746 37 9

Canada45 7,669 782 525 293 140 13 2

Uganda57 *9,862 5227* 579 520 322 6 3

Table IIITrue impact of large scale screening programmes

TRUE IMPACT OF LARGE SCALE SCREENING PROGRAMS Multiple references : Base reference IJMR 2011 ; 133(3) 257-266

1. TST vs T

-SPOT ?

Beginning in April 2010, the Wetmore TB Clinic IN NEW ORLEANS began using the T-SPOT blood assay in place of the Tuberculin Skin Test. All patients referred to Wetmore with a positive TST/hx. of positive TST are now administered the T-SPOT in order to “confirm” TB Infection. If the results of the

test are positive, the patient is SCREENED FOR ACTIVE TB AND AFTER THAT EXCLUSION , diagnosed as infected and

Latent TB treatment is offered. DISCORDANT AND BORDERLINE RESULTS ARE REVIEWED ON A CASE BY CASE

BASIS In patient we created a protocol of use for selected group of

patients

What we did ?

2, Assessing Risk Risk factors algorithm

• www.tstin3d.com

Recent developments in treatment of latent tuberculosis infection.htm

IJMR 2011 March ;133(3)257-266Menzies et al

The Online TST/IGRA InterpreterVersion 3.0

TST /QST Interpreterwww.TSTin3d.com

TST/IGRA status, Country of birth, Ethnicity CXR , BCG history, contact history

30 yr old , Turkish man , smoker BCG vaccinated, granulomas on CXR Close contact ; casual contact ; no contact

• PPV 94.43%• Risk of developing active TB

disease in 2 years 21.35%• Annual Risk after 2 years

0.42%• Cumulative risk up to age

80 is 41.64%• Probability of DILI 0.3%

• PPV 98

• Annual Risk after 2 years 0.69%

• Cumulative risk up to age 80 is 34 %

• Probability of DILI 0.3%

• PPV 94%

• Annual risk 0.42% • Cumulative risk 21.15 % • DILI 0.3 %

Risk factors for MTB infection

• Close contacts • Foreign born in USA• Frequent visitors to high prevalence areas • Residents and employees of congregate settings such

as nursing homes and shelters • HCWs • In areas which are medically underserved ; low

income populations, substance abuse• Infants and children

Risk of infection to disease progression

• HIV• Infants• On immunosuppressive therapy• Recent infection• Old fibrotic lesions on CXR with undocumented or

incomplete Rx hx• Specific medical conditions : DM /malignancy etc

Hazard ratios increase 3 to 17 ( refs available )• Low weight, low income population, Vit D def.

( increased risk and higher level of resistance

Population attributable factor 7.5% to 26% in all groupsJ Infec Dis 2011 May 203:

1240Study in miceSmoking suppresses TNF alpha and I-12

High Risk for Progression/Reactivation: HIV

19 newly diagnosed HIV patients with active TB

T-SPOT.TB test positive results were independent of CD4 T-cell counts

“In conclusion, in HIV-infection, immune responses in the TST and QFT-G-IT are both strongly related to the degree of immunodeficiency, while the T-

SPOT.TB seems to function independently of the level of CD4+ T-cell depletion.”1

1. Leidl L, Mayanja-Kizza H, Sotgiu G, et al. ERJ Express. 2009;.

Sensitivity

T-SPOT.TB Test 89% (17/19)

In-Tube 68% (13/19)

High Risk for Progression/Reactivation: HIV

•Performance of T-SPOT.TB test for diagnosis of active/probable TB in HIV-1 patients1

1. Clark SA, Martin SL, Pozniak A, et al. Clin Exp Immunol. 2007;150:238-244.

Patient Group No. Sensitivity Specificity

All HIV w/ active/probable TB 30 90.3% 100%

CD4 T-cell count < 300 cells/µL 22 95.4% 100%

CD4 T-cell count < 200 cells/µL 14 92.9% 100%

CD4 T-cell count < 100 cells/µL 8 87.5% 100%

A “positive” TST / IGRA : suggested plan

QUANTIFYASSESS BORDERLINEINDETERMINATEDISCORDANT RESULTS

RULE OUTACTIVE DISEASE

RULE OUTEXTRA-PULM DISEASE

SIZE OF TST: is it helpful?IN CHILDREN;Degree of IGRA ??

Dx; LTBIShould we offer Rx? Based on many factors

DOCUMENT SYMPTOMSH/P

ROSLN EXAM

GO BACKto STEPS B&CIF IN DOUBT

RISK OF ADR*

CHECK HIV CXRCT Scan if needed

CORRELATEwith Chestimaging

PRE-LAB CHECK

STRATIFYRISK, CHECKSOURCE CASEWHY???

SPUTUMINDUCE if needed

PRE-TEST PROBABILITY?

IF SURE GO TOSTEP E

TREAT FOR LTBI.ASSESSRISK BENEFIT RATIO

CONCLUDE AFTER FULL EVALUATION:IF POSITIVESTEPS B-E

PRE-TEST PROBABILITY?TREAT FOR ACTIVETB ?

TREAT FOR TB ? MONITORSIDE EFFECTS* AND Rx

A : DATA B: EVALUATE C: SCAN D : RECAP E: TREAT

JALI

steps

*ATS 2006 DILI consensus statement

• Individuals with LTBI had a 79% lower risk of progressive TB after re infection than uninfected individuals

• Andrews et al CID Jan 19th 2012

So then : Why Rx LTBI?

Issues with Low to Middle Income Resource Challenged Countries and communities

• Who to give• Quality of data and evaluation• How : logistics• Cost • Total program buy- in

WHO Policy statement 2011

Perspectives on Rx for LTBI

• Different priorities • General Reluctance; What is the goal?• Imprudent applications of Rx• Up and down enthusiasm of regimens• ADRs and press thereof• Poor performance of programs • Contradictory risk benefit studies • If we should treat Asymptomatic Hypertension why

should we not treat asymptomatic LTBI ?

RegimenEfficacy

(relative to placebo)#

Completion of therapy Serious adverse events

Type Rate

INH: 6 months 69%12 50%6,8,54 Hepatitis 1 -5%23,68

INH: 9-12 months 90 – 93%12,17 <50%31,33,34,69 Hepatitis 1 -5%23,31,34,68

RIF&PZA: 2 months

Equal to 6 -12INH27,63 6% > 6-12INH*27 Hepatitis 3 -5%27,68,70

INH&RIF: 3-4 months

Equal to 6INH30,36

6% > 6-12INH**36 Hepatitis† 1 – 5%36,37

RIF: 3-4 months 65% ##30 22% > 9INH***31–34,71 Rash Hepatitis 1- 2%31,34

<1%31,32,34

Table ISummary of LTBI regimens in common use

Why should we treat LTBI? 1

Study Year Age group (yr) Preferred (INH or Not)

Margin of benefit* (days)

Low risk reactors

Rose et al44 1986 10-80 INH 1- 16

Tsevat45 1988 20-80 No INH 4-17

Colice46 1990 30 INH 3-19

Jordan et al47 1991 20-35 INH 3-19

50 No INH 2-33

Salpeter et al48 1997 35-70 INH 3-5

High risk reactors (HIV infected)

Jordan et al49 1991 20-60 INH 285

Rose50 1998 Adults INH 254

Table IIRisk benefit studies of INH for tuberculin reactors

Why should we treat LTBI ? 2

Factors related to public health impact by LTBI Screening & Rx

• Non participation in initial screening• Failure of follow up at various levels• Non compliance of Rx doctors• Pt refusal and non completion• Bottom line ; it is not the test , treatment but

the program that needs to be evaluated and reviewed

How to achieve control vis a vis LTBI ?

Targeted testing and prioritization

Almost Universally accepted approach ( National programs/ Societies Guidelines*) *Multiple references

The “ Onion whorl” approach ; better to have The “Mango core” approach

Further

• Use of TST / IGRAs as applicable • Augment Measures to stress completion of Rx a. Shorter course b. DOPT ? Resources c. Registry and tracking d. Public/ Private/ Community liaison e. Academic and “non academic” par f. Communication and HIEs g. Incentives and User friendly approach

We all have got to do what we got to do and get it done

Some issues are sometimes as “simple” or “complex” as these….

Thank you

J

teşekkür ederim/ sağ olun for your kind attention

JA

TEŞEKKÜRLER

Honored to be a “self declared” honorary citizen of Turke and Ege University