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TB Prevention, innovating an old idea to reach a new target:

TB Elimination

Davide Manissero, MD

Senior Director, Medical and Scientific Affairs

QuantiFERON, EMEA & APAC

DISCLOSURE

I am currently a QIAGEN employee.

The information and opinions provided hereby are b ased

solely on my personal experience and judgment and d o not

represent QIAGEN’s opinion.

TB PREVENTION BIAS

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LTBI Screening Tools

Targeted Testing – Migrant Case Study

TB Prevention – global policy breakthrough

Targeted Testing – HCW Case Study

Thanks to two innovators:

………. but the world has changed.

Robert KochRobert KochRobert KochRobert Koch

Karel StybloKarel StybloKarel StybloKarel Styblo

“….for the control of the disease, the sources from which the infectious

material flows must be closed as far as is humanly possible……

the most essential one, is thesputum of consumptives .”

70% case detection

85% treatment success

Georges CanettiGeorges CanettiGeorges CanettiGeorges Canetti

Tuberculosis Control Strategies

ReactivationCases

Large reservoir of LTBI – 2 billion people

Larger reservoir of uninfected persons

Newcases

New infections

+New TB cases annually

TARGETED TESTING

Importance of LTBI detection and treatment

Active TB case finding and treatment

Mass LTBI detection & treatment

Active and latent TB detection& treatment

Expected success if active TB is diagnosed and treated compared with also finding and treating LTBI.

For major impact on TB disease rates we must address latent TB infection

Adapted from Abu-Raddad et al. Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. PNAS. 2009; 106; 13980-5.

Synergy of interventions !Action on both transmission and reactivation pathways

2 new policies and a guideline

Primary target countries for the WHO LTBI guidelines

113 high or upper middle income countries with an estimated TB incidence rate of less than 100 per 100,000 population

Identification of at-risk Populations

for LTBI Testing and Treatment

In high income/upper middle-income countries,

systematic testing and treatment should be performed in:Risk ratio

• People living with HIV 50-170

• Adult and child contacts 15

• Patient initiating anti-TNF treatment 2-9

• Patients receiving dialysis 10-25

• Patients preparing for transplantation 20-74

• Patients with silicosis 30

WHO. Guidelines on Management of Latent TB Infection, 2014Lobue P, Menzies D. Respirology 2010;15:603-622

Recommendations on at-risk populationsRisk population groups Strength of recommendation

• People living with HIV

• Adult and child PTB contacts

• Patients initiating anti-TNF treatment

• Patients receiving dialysis

• Patients preparing for transplantation

• Patients with silicosis.

Strong: systematic testing and

treatment should be performed

(Low to very low quality of

evidence)

• Prisoners

• Health workers

• Immigrants from high burden countries

• Homeless persons

• Illicit drug user

Conditional: Systematic testing

and treatment should be

considered (Low to very low

quality of evidence)

• Patients with diabetes

• People with harmful alcohol use

• Tobacco smokers

• Under-weight people

Conditional: systematic testing

and treatment is not

recommended unless they belong

in the upper two groups (Very low

quality of evidence)

Either TST or IGRA can be used to test for latent TB infection.

IGRA should not replace TST in low and middle income

countries1.

(Strong recommendation, very low quality of evidence)

Recommendation on ruling in latent TB infection

1 Use of tuberculosis interferon-gamma release assays (IGRAS) in low- and middle-income countries. Policy

statement. Geneva: World Health Organization; 2011.

Targeted Testing - TB Screening Algorithm

Evaluate for active

TB

At-risk person

TST/IGRA + symptom review

Negative Positive

Chest x-ray

Normal Abnormal

Treatmentnot indicated

Potential candidate for

Tx of latent TB

The following treatment options are recommended for the

treatment of latent TB infection:

• 6 months isoniazid (6H)

• 9 months isoniazid (9H)

• 3 months weekly rifapentine plus isoniazid (3HP)

• 3 to 4 months isoniazid plus rifampicin (3-4HR)*

• 3 to 4 months rifampicin alone (3-4R)**

(Strong recommendation, moderate to high quality of evidence) * Voted by 53% of panel and ** voted by 60% of panel as equivalent optionsfor 6H

Treatment options

17

LTBI Screening Tools

Targeted Testing – Migrant Case Study

TB Prevention – global policy breakthrough

Targeted Testing – HCW Case Study

Tuberculin Skin Testing

48 to 72 hours5 TU of PPD

• Uses PPD : a crude antigenic mixture

• Limitations of TST :

– fairly high proportion of false positives and false negatives– technical problems in administration and interpretation– difficulty in separating true infection from the effects of BCG and non-tuberculous

mycobacteria (NTM)– repeated TST boosts the immune response– requires a 3-dimensional interpretation

Immunological Basis of IGRA and TST

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QuantiFERON-PLUS exploring CD8 response

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Depend on detection of cell mediated immune response to proteins encoded in the “Region of Difference 1” section of the MTB genome

RD1 is absent from BCG and most NTM and present in all MTB strains

IGRA SPECIFICITY ADVANTAGE

Antigens in QFT predominantly evoke CD4 + T cell response highly specific to M tuberculosis complex

Sensitivity/Specificity of IGRAs

Active TB and Low-risk Persons

Test TB Studies (N) Pooled

Sensitivity

TST 12 0.65 (0.61-0.68)

QFT-IT 8 0.80 (0.75-0.84)

T-Spot.TB 15 0.81 (0.78-0.84) Sester M, et al. 2011

Test Low-risk Studies

(N)

Pooled Specificity

QFT-IT 5 0.99 (0.98-1.00)

T-Spot.TB 3 0.86 (0.81-0.90)

TST Non BCG

BCG

97%

Very low and

inconsistent

Diel R et al. 2011

Pai M et al. 2008t

Comparative Performance of QFT and TST

LTBIprevalence

Test PPV%

NPV %

Accuracy%

1% QFT 58.3% 99.8% 99.2%

TST 3.2% 99.6% 77.9%

5% QFT 87.9% 99.1% 98.6%

TST 14.6% 98.1% 77.7%

25% QFT 97.9% 94.6% 95.3%

TST 52.0% 89.1% 76.4%

50% QFT 99.3% 85.4% 91.2%

TST 76.5% 73.2% 74.8%

FOR INTERNAL USE ONLY QFT Product Training TST QM31635263A Approved 06/2013 23

How does QFT and TST compare in accuracy?

QFT Se. 83%, Sp. 99.4%. TST Se. 71.5%, Sp. 78%

PPV – Positive predictive valueNPV – Negative predictive value

QFT is more accurate than TST at various LTBI prevalence rates

Specificity:QFT (1) – 99.1%

TST (2)– 86%

Sensitivity:QFT (1) – 89%TST (1) – 76%

Over-diagnosed TB infection missed

Operational impact of IGRA accuracy

FOR INTERNAL USE ONLY QFT Product Training Tech Performance QM31635227A Approved 05/2013 24

QFT vs TST in a setting with 10% TB infection prevalence

1,000 population

900TB uninfected

100TB infected

892 QFT-ve

8 QFT+ve (false)

774 TST-ve

126 TST+ve (false)

89 QFT+ve

11 QFT-ve (false)

76 TST+ve

24 TST-ve (false)

QFT8

TST126

QFT11

TST24

Abbreviations:+ve = positive-ve = negative 1. QuantiFERON-TB Gold Package Insert (05990301J July 2012).

2. Centers for Disease Control and Prevention. (2010) MMWR 59:RR05.

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LTBI Screening Tools

Targeted Testing – Migrant Case Study

TB Prevention – global policy breakthrough

Conclusions

One third of the world population is infected with TB

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Concept of high risk groups

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Screen and treatConditionally

screen and treat

Conditionallyscreen and treat

Low prevalence,Low progression risk

LTBI prevalencehigh low

Pro

gres

sion

risk hi

ghlo

w

Don’t forget ATTRIBUTABLE FRACTION to determine PUB LIC HEALTH importance

28CONFIDENTIAL

Risk management Elimination/Control

Diabetes

Occupational risk

Elderly

Congregate

setting

Contacts

Children

Migrants

Community prev.

S RP

Therapeutical

TNF-alpha inh

Oncology

Solid Organ Trans.

Inh. Corticosteroids

ESRD

Outcome (other than TB)

PREVENTION PREVENTION

TB Outcome

Public Health Marketing

Population and individual benefits

From individual to population benefit

UK Epidemiology

0

10

20

30

40

50

1982 1987 1992 1997 2002 2007Year

Tuberculosis rates, England & Wales,1982-2007

London

Sources: Statutory notifications of infectious diseases (NOIDs) 1982-1998, Enhanced Tuberculosis Surveillance 1999-2007, Office for National Statistics mid-year population estimates, Enhanced Surveillance of Mycobacterial Infections

66% of UK TB cases in migrant/non UK born

70% of UK TB cases in high risk groups

Non-UK born tuberculosis cases by time since entry to the UK

Migrant Heath Report (2011 slide set)Data source: Health Protection Agency

Reactivation Epidemic

Epidemic tail

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Point of entry

A B C

A conceptual model

Post-entryPre- entry

Forecasting tuberculosis in migrants :

Sake de Vlas

Bram Meima

Gerard Borsboom

Davide Manissero (ECDC)

Department of Public Health, Erasmus MC, Rotterdam

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Model predictions ‘Africa’

-13% -32%* ideal = 100% sensitive and specific

How should we maximize effectiveness of targeted screening on the basis of incidence ?

KNOW YOUR EPIDEMIC, KNOW YOUR NUMBERS

Using TB incidence in the UK and migration data the study estimated:Number needed to be tested and treated to prevent one case of TB disease

Assumptions: IPT efficacy (50-80%) IGRA Sensitivity (81-87%)

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LTBI Screening Tools

Targeted Testing – Migrant Case Study

TB Prevention – global policy breakthrough

Conclusions

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Comparison of treatment of hypertension vs treatmen t of LTBI

Hypertension Latent TB infection

Asymptomatic condition Asymptomatic condition

Very serious complications:� Death � Major disability

Very serious complications:� Death � Major disability� AND transmission

Treatment is for years� Expensive medications� Potential serious side effects� Requires close monitoring and follow-up

Treatment is max 9 months� Cheap medications� Potential serious side effects� Requires close monitoring and follow-up

BUT – No debate about Treating WHY the debate about treating for LTBI?

LTBI treatment helps to reduce TB risk

1 Menzies et al Indian J Med Res 2011

HIV RETHINKING PREVENTIONTB NOT THINKING AT ALL?

The formula of TB Elimination

TB Control= diagnosis + treatment of infectious cases

TB Elimination= TB Control + TB prevention== TB Control + (LTBI diagnosis + LTBI treatment)

Courtesy Prof. GB Migliori