Effectively screening for Latent TB HIV/STD/TB/Hepatitis Symposium North Dakota April 2012

Sample & Assay Technologies- 1 -For Internal Use Only

Effectively screening for Latent TB

HIV/STD/TB/Hepatitis SymposiumNorth Dakota

April 2012

.

Mary ShragalArea Director Sales,

Northern Region USACellestis, Inc. a Qiagen Company

QuantiFERON®-TB Gold In-Tube


A little history

•

In the 1980’s the need for a better test for TBinfection in cattle was addressed in Australia

• The tuberculin skin test in cattle had very similarproblems to the TST in humans and thus a new

test was neededI

But also was a very messy test to perform


History of QuantiFERON®

1980’sDeveloped by Australian researchers at CSIRO for detecting TB in

Australian cattle herds

Early 1990’sCSL (Australia) acquired exclusive license to patents; and undertook

commercialization of a cattle diagnostic test and development of a human diagnostic for TB

2000Cellestis, founded by two of the inventors of the QuantiFERON®

technology, was chosen to commercialize the human TB diagnostic, known as QuantiFERON® -TB


Developed in Cattle – An Excellent Model for Human TB

4


Skin Testing Cows Australia 1990’s

Injecting tuberculin from M.bovis into the caudal fold

(base of tail) of a cow.


Tuberculosis (TB) Review

Bacterial infection caused by Mycobacterium tuberculosis complex organismsM. tuberculosis, M. bovis, M. africanum

Infection may be eitherActive (with all symptoms and highly contagious)Latent (without any symptoms, not contagious)

Latent TB infection (LTBI)Needs treatmentProgression to active disease

Treatment involves 6-9 months antibiotic therapy; new therapy once per week for 12 weeks.


LTBI Active TB

• LTBI means infection, no active disease, no symptoms, not contagious

• If undetected and untreated

10% will progress to disease

50% do so within 2 years

Higher for immuno-compromised individuals


Active tuberculosis: Signs and symptoms


Sample & Assay Technologies World Facts on TB

• At least one person becomes infected every second

• Each year, more than 9 million people develop TB disease

• The WHO estimates that TB takes a life every 17 sec

• Almost 2 million TB-related deaths occur each year

• TB is the leading killer of people who are HIV-infected

• Global mobility, immigration, and inadequate control strategies make it a worldwide problem


Global travel makes it worse

Journal of the American Medical Association


Transmission of TB

Family, friends, workmates etc.

exposed

Active TB:Infectious

Not infected

Infected, but no symptoms“Latent TB infection”

If not identified & treated ~10%

develop TB disease during their lifetime

If identified & treated they don't develop TB disease


Conventional TB Diagnostics, desperately in need of an upgrade

Purified Protein Derivative (PPD) is injected intradermally

48 – 72 hours later the size of the resultant reaction is measured


Tuberculin Skin Test (TST) Limitations:

TST responses are often not read within time window Poor compliance Cost implications (follow up and re-testing) Employee health implications

False positives due to BCG & NTM

Inaccuracy of measuring induration; Subjective interpretation 1 in 3 TST’s failed to be properly diagnosed (Kendig et.al. 1998)

2-step testing required for new hires Up to 4 consultations (usually 10 days)


TB and the 21st Century

QuantiFERON®-TB Gold ‘‘In-tube’


And counting…

1,100,000tests/year in the US

• Testing rate >3,000,000 per year and growing

• US rate >1,100,000 per year– Majority are serial screening of HCW’s– In Europe, mainly contacts, immunesuppressed,

TB suspects– In Asia, contacts, TB suspects, HCWs

• Worldwide > 1000 labs running QFT– In the US >300 routinely using QFT


for…HCW Screening

by…Public Health Departments

for…Clinical & Immune Suppressed Patients

for…• Contact Investigations• Homeless• Refugees• Recent Immigrants• TB/Chest Clinics

by…• Major University Hospitals &

Medical Centers• VA Hospitals• Military Facilities• Foreign Students at University

Hospitals • HIV & Other Infectious Disease Clinics• TNF inhibitors (Rheumatologists)

Principle use of QFT in the United States…


Immunological Basis for QuantiFERON® Testing

In normal circumstances, there is no Interferon Gamma (IFN- ) within the blood.

In the presence of the TB specific antigens, T cells of infected persons are stimulated to produce IFN-

In the QFT test whole blood is exposed to 3 TB specific

antigens T cells of infected persons are activated and

secrete IFN- Measurement of IFN- using an ELISA assay

is the basis for the QFT test

T-cells activate and secrete IFN-γ.


QFT Species Specificity vs. TST

Tuberculosis Complex

ESAT-6

CFP-10 TB-7.7 TST Environmenta

l StrainsESAT-

6CFP-

10TB-7.7 TST

M. tuberculosis + + + + M. abcessus - - - +M. africanum + + + + M. avium - - - +M. bovis + + + + M. branderi - - - +

M. celatum - - - +

BCG Substrain

ESAT-6

CFP-10 TB-7.7 TST M. chelonae - - - +

Gothenberg - - - + M. fortuitum - - - +Moreau - - - + M. gordonii - - - +Tice - - - + M. intracellulare - - - +Tokyo - - - + M. kansasii + + - +Danish - - - + M. malmoense - - - +Glaxo - - - + M. marinum + + - +Montréal - - - + M. oenavense - - - +Pasteur - - - + M. scrofulaceum - - - +

M. smegmatis - - - +M. szulgai + + - +M. terra - - - +M. vaccae - - - +M. xenopi - - - +


QuantiFERON®-TB Gold

Procedures & Guidance

• Blood Collection• Laboratory ELISA• Data Analysis


In the field:• 3 tubes: TB specific

antigen, Nil & Mitogen

• Blood collected directly into tubes (1mL each)

In the lab:• ELISA for detection of

IFN-gamma


Blood Collection

Set of three collection tubes: Nil, TB-Antigen, Mitogen• Draw 1 mL of blood into each of the 3 tubes• Black side marking on the tube indicates the 1mL fill line


Shaking of Tubes

• Tubes are mixed by shaking for 5 seconds (~10x)• After shaking, the entire inner surface of each tube

should be coated with blood• Proper shaking will lead to some frothing of the blood


After Blood Collection and Shaking

Tubes can be held at Room Temperature for up to 16 hours

Following incubation, tubes have up to 3 days for transfer to

lab for QFT ELISA

Within 16 hours of collection/shaking, tubes must be incubated at 37ºC for 16-24

hours

Option 1:

Option 2:


Data Analysis and Results

Results are reported as: Positive Negative Indeterminate

Indeterminate Low mitogen High Nil


Clinical performance of QuantiFERON ®-TB Gold

A sensitive test would accurately identify people with infection, whether latent or active (maximize true positive results)

A specific test would accurately identify people who are uninfected (maximize true negative results)


Real World Experiences

NYC Dept. of Health

San Francisco Dept. of Health

University of Illinois Chicago

Cleveland Clinic





2nd Global symposium on IGRA’s (Dubrovnik, Croatia, June 2009)



Performance of IGRAs and the TST:An up-to-date TB Test Meta-Analysis

RDiel, R Loddenkemper and A NienhausEvidence based comparison of commercial interferon-gamma release assays for detecting active tuberculosis – a meta-analysis. Chest, 2009, Published on Dec 18, 2009 in electronic format;


Key findings from meta-analysis:IGRA and TST specificity

*QFT significantly more specific than both the TST and T-Spot (p<0.0001)

p<0.0001


Key findings: IGRA and TST Specificity

QFT In-Tube

T-Spot.TB TST0

100

200

300

400

500

8

137

410

Fal

se-P

ositi

ves/

1000

test

s

p<0.0001

How does this translate into false-positives per 1,000 tested people without TB?


IGRA Indeterminate rates from Diel et al, Chest, 2009

QFT Number of subjects

Number Indeterminate

% indeterminate

Immune competent 16,449 227 1.38%

Immune suppressed 5,473 242 4.42%

T-Spot.TB

Immune competent 9,584 304 3.17%

Immune suppressed 2,581 158 6.12%

For both IGRAs there are significantly more indeterminate results in those immune suppressed


Negative and positive predictive value of a whole-blood IGRA for developing active TB - an updateDiel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A

Am J Respir Crit Care Med 2010. [Epub Aug 27, 2010]

M31635074C

An analysis of 954 tuberculosis contacts comparing QuantiFERON® TB Gold (QFT®) and tuberculin skin test (TST)

Cellestis Synopsis


Predictive Value of QFT(Diel et al AJRCCM Aug 2010)

954 close contacts

142 QFT-positive/TST-positive

Chemoprophylaxis RIF and/or INH

No active TB

51 QFT-positive(49 TST-positive)

Mean follow-up >3.5 yrTST cut-off >5mm

Not treated

17 developed active TB

343 TST negative

5 QFT-positiveTST-negative

Not treated


413 TST positive

Not treated Not treated

No active TB No active TB

198 QFT-positive 756 QFT-negative

Contact Investigation – Summary




No active TB


Not treated

343 TST negative


Not treated


413 TST positive


No active TB No active TB

198 QFT-positive 756 QFT-negativeQFT-negative contacts


Contact Investigation – Results



343 TST negative

413 TST positive


756 QFT-negativeQFT-negative contacts

• 55% of QFT-negative were TST-positive

• No progression to active TB at 3.5 years

• In this study, QFT demonstrates 100% NPV*

* Negative Predictive Value (NPV)


No active TBNo Active TB No Active TB





No active TB


Not treated



Not treated


413 TST positive

Not treated

No active TB

198 QFT-positive 756 QFT-negativeQFT-positive contacts






No active TB


Not treated



Not treated


198 QFT-positive


QFT-positive contacts

• All 19 untreated contacts who progressed to active TB were QFT-positive.

• TST missed progression;

• 11% missed @ >5mm

• 47% missed @ >10mm



QFT +ve TST +ve >5mm TST +ve >10mm0

200

400

600

147

555

207

Num

ber o

f Con

tact

s

• QFT identified 100% (19/19) of contacts who progressed to active TB

• TST @ >5mm cut-off missed 11% (2/19)

• TST @ 10mm cut-off missed 47% (9/19)

• By using QFT, at least 60 fewer contacts required treatment

Number of Contacts Needing Treatment to Prevent Progression to Active TB


QFT demonstrated 100% NPV in this study No contacts who tested QFT-negative

developed TB

Lower program costs by only treating those who really need it

Recommendations & Guidelines suggest QFT can be used as a replacement for the TST

US: Centers for Disease Control & Prevention

Japan: Kekkaku 2010

Be Confident Using QFT



Sahni et al 2009. Infect. Control Hosp. Epidemiol.

2,048 QFT results on HCWs90 were QFT positiveINH acceptance compared to when using the TSTAcceptance increased from 11% to 52%

Reduces the “I am positive because of BCG” effect


CDC Guidelines - 2010

• IGRAs may be used in place of (and not in addition to) TST in all situations in which CDC recommends TST

• Which IGRA or TST to be used should be based on the context for testing, test availability, and overall cost effectiveness of testing.

• Neither IGRAs, nor TST should be used for testing persons who have a low risk of TB infection

• IGRA is preferred – for testing persons from groups

that historically have poor rates of return for TST reading.

– for testing persons who have received BCG

• TST is preferred – for testing children younger than

5 years old

‘QFT-G can be used in all circumstances in which the TST is currently used’

…now able to detect TB with greater specificity than previously possible’


TBoss Program Overview


Role of Public Health

Public Health in charge. CDC involved only in case of outbreaks

Reference – Maryam Haddad, CDC


Role of Cellestis

• Have Program Coordinator on site who works closely with DOH• Work through checklist to mobilize resources needed• Ensure

– QFT kits are available on site– Blood draw logistics in place including trained phlebotomists, blood

collection kit (butterflies etc…)– Identify preferred laboratory for QFT testing– Coordinate collection, tube handling and shipment to testing

laboratory– Be a liaison with lab and DOH to ensure data integration


Reimbursement for Diagnostic Use

CPT Code: 86480 Tuberculosis test, cell mediated immunity measurement of gamma

interferon antigen response listed under all state Medicare laboratory fee schedule

Medicare: $92.00 for most statesMedicaid: up to $86.59

some states not yet covered

Private Payers: Aetna: QFT a medically necessary preventive service for LTBI screening

in recent immigrants, injection-drug users, residents and employees of prisons and jails, HCW and military

United Healthcare: enrollees who are at increased risk for tuberculosis in all benefit plans

Blue Cross/Blue Shield: approved in some states


True’ cost of a TST program

Lambert et.al. Infect. Control Hosp. Epidemiol. (2003)Annual cost of implementing and maintaining a TST program (4 hospital sites and 2 health departments):

Hospital: cost per HCW = $41 to $362Health Dept: cost per HCW = $176 to $264

TST supply costs accounted for less than 1.5% of the total cost of the TST program for all sites

QuantiFERON®-TB GOLD is cost effective!


Cost-effectiveness of Interferon Gamma Release Assays vs Tuberculin Skin Tests in Health Care Workers

Marie A. de Perio, MD; Joel Tsevat, MD, MPH; Gary A. Roselle, MD; Stephen M. Kralovic, MD, MPH; Mark H. Eckman, MD, MS

Result:the QFT-GIT is the most effective and least costly strategy.

Conclusion: Use of the QFT-G and QFT-GIT leads to superior clinical outcomes and lower costs than the TST and should be considered in

screening non–BCG vaccinated and BCG-vaccinated new HCWs for LTBI.

Arch Intern Med. 2009;169(2):179-187


Significant improvement in diagnosis of TB infection• Eliminate BCG and NTM false positives• QFT-Gold positive result is highly predictive of TB infection• More sensitive for active TB• Eliminates subjectivity

Improves testing compliance• Contact investigations, Homeless, Jail inmates, HCW’s

Minimizes inappropriate treatment and toxicity

QuantiFERON®-TB GOLD = Better Healthcare!


QUESTIONS?

Documents

Effectively screening for Latent TB HIV/STD/TB/Hepatitis Symposium North Dakota April 2012