Elizabeth A. Talbot MDAssociate Professor, Deputy State EpiInfectious Disease & International HealthGeisel School of Medicine at Dartmouth

Latent TB Infection onWorld TB Day 2014

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• World TB Day 2014– Relevant global and US

epidemiology• Top issues re: latent TB

infection (LTBI)– Testing: Interferon gamma

release assays (IGRAs) and tuberculin skin test (TST)

– Treatment options– Operational tidbits

Outline

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• Number of new TB cases decreased to ~9M

– India+China 40%, Africa 24%– 13% co-infected with HIV

• 1.4 million people died from TB• Multi-drug resistant (MDR*) TB

– 3.7% among new cases– 20% among previously treated– 9% of MDR is XDRTB**

2013 Global Epi Snapshot

*MDR=resistance to H+R**XDR=MDR with resistance to FQ and injectable

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• One-third of TB cases missed

• 50% of ~1.1 million new cases of HIV-related TB missed

• 75% with MDR-TB missed

“Missed” = gap between

estimated number who

became ill with TB and the

number notified to national TB

programs

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2013 US Epi Snapshot

*MDR=resistance to H+R**XDR=MDR with resistanceTo FQ and injectable agent

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PRIORITIZE LTBI TESTING FOR THOSE WITH RISK FACTORSFOR DEVELOPMENT OF TB

To control TB (and solve many of our testing dilemmas):

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Most US TB is Reactivated LTBI• >80% of US TB is result of reactivated LTBI• Data from representative survey of US pop

showed 4.2% of persons screened 1999-2000 had LTBI

• Two risk categories for reactivation TB – LTBI prevalence is increased: e.g., foreign-born

persons– Rate of reactivation during LTBI is increased: e.g., HIV – Both risks are present: e.g., recent contact with case

• Nearly all these cases can be prevented by treatment of LTBI

Horsburgh & Rubin, NEJM 2011; 364 (154): 1441-8

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Targeted Testing

• Identify, evaluate, and treat persons at high risk for – LTBI or – Progression LTBI to TB

• If you test for LTBI, have strategy to evaluate and treat those found to be infected– Local health

department is a resourceCDC Core Curriculum

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High Risk for TB Exposure• Close contacts to TB

– HCWs who serve people at high risk for TB

• Persons who were born in or visit TB endemic areas– >40/100,000 population

• Persons who work or reside in high-risk congregate settings– Prisons, LTCFs, shelters

• Local populations at high risk for infection or disease– Drug users

Horsburgh & Rubin, NEJM 2011; 364 (154): 1441-8

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High Risk for Progression from LTBI to Active TB

Plus, persons with certain other medical conditions:• Silicosis• Carcinoma of head or

neck• Gastrectomy or jejunoilial

bypassHorsburgh & Rubin, NEJM 2011; 364 (154): 1441-8

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UNDERSTAND KEY FEATURES OF LTBI TESTING METHODS AND INTERPRETATION

For best (and credible) patient care:

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Tuberculin Skin Test Do’s and Don’t’s

• Do TST– Prior to immunosuppression– 8–10 weeks after prior negative

TST for contact investigation• Health department does contact

investigations• Don’t test

– If previous positive result• Especially severe reaction

– <6 weeks after live virus vaccine• Can be done at same time as

vaccine• What if patient has history of

BCG* vaccination?– IGRA is preferred because no cross

reaction– But . . .

*BCG: TB vaccine derived from M. bovis, most commonly given vaccine worldwide!

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Effect of BCG on TST reaction

• BCG given in infancy (age <2)– 23 studies with 78,846

vaccinees• 6.3% positive TST• 1% positive TST after

>10y• BCG given to older (age

>2)– 11 studies with 4,026

vaccinees• 40% positive TST due to

BCG• 20% positive TST after

>10y

Farhat, Menzies. Int J Tuberc Lung Dis 2006;10:1192-204

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False Positive LTBI Testing Results

• Many persons who have positive screening result are at low risk for reactivation, and even the best screening test would identify many more false positive results than true positive results

• Quantitative test results can help– TST induration– IGRA values

• Patient considerations– Costs/risks/benefits of treating or not treating?

• Help patient weigh, be honest about uncertainties, advise

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Do Which When?One is

Preferred• IGRAs

– History of BCG vaccination

– For those with low rates of return for TST reading

• Homeless, IVDA

• TST– Children <5

• When other unavailable

Both is Justifiable*

• When 1st test is neg, but risk for progression is high

• When 1st test is pos, but more evidence is needed to encourage compliance

• When IGRA is indeterminate, borderline or invalid

• If suspect 1st test is wrong

Neither is Preferred

• Recent contact to case– IGRA should be

repeated at 8-10 weeks (like TST)

– Data on timing of IGRA conversion not available

– IGRA may be more sensitive than TST

• Periodic screening (e.g., HCW)

*PPD may “boost” IGRA response. If you do TST then IGRA, do it within 7d of TST

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UPDATES REGARDING LTBI TREATMENT

The goal is treating LTBI to control TB:

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LTBI Treatment Regimens

Drugs Months of Duration Interval

Minimum

Doses

INH 9*Daily 270

2x wkly** 76

INH 6Daily 180

2x wkly** 52RIF*** 4 Daily 120

*Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

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Rifapentine (Priftin)

• Rifamycin derivative developed in 1950s, marketed 1998• Similar spectrum as rifampin, but with

longer half-life for weekly dosing• For active TB treatment

– Higher relapse rates• Difficulty complying with asynchronous regimen

– Drug-drug interactions HIV protease inhibitors

– New clinical trials underway for TB

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PREVENT TB: INH & Rifapentine for 12wks

• INH for 9m vs. INH + RPT weekly for 12wks with DOT

• Study population: 8,000 patients– TST+ close contacts 70%– Converters 25%– TST+ HIV or HIV with close contact 2%– TST+ with fibrotic changes 2%

• Efficacy was similar – 0.19 v 0.43% developed TB disease

• Completion rate higher – 82 v 69%

• Cost higher $160 v $6, but may be cost-effective

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RPT+INH clearly non-inferior to INH monotherapyMore pronounced in intention to treat analysis

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Recommendations

• Equal alternative to 9m INH in ≥12y plus high risk for TB disease

– Close contact– Converter– Fibrotic changes on CXR– HIV not on ART, otherwise healthy

• Consider other patients on an individual basis

• Children 2-11y can be considered, especially if unlikely to complete 9m plus high risk to progress to TB disease

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INH-RPT NOT Recommended

• Children < 2 years old• HIV on ART• Pregnancy, or likely to become

pregnant during treatment• Presumed INH or RIF resistance• Prior adverse reaction with INH or

rifamycin

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Current LTBI Treatment Regimens

Drugs Months of Duration Interval

Minimum

Doses

INH 9*Daily 270

2x wkly** 76

INH 6Daily 180

2x wkly** 52RIF*** 4 Daily 120

INH-RPT 3 Weekly** 12

*Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

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• 65/90 contacts chose INH+RPT• DOT at school, calls/texts/visits• Treatment completion similar

– 94%-100% for 3 regimens• 4 did not complete HP; 1 each

– HA+nausea– Rash+dizziness– F+aches– Unknown

• “CDC collaborating with health departments and institutions for more data nationally”

Programmatic Use of INH+RPT

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Summary

• TB remains a global threat• In US, treatment of LTBI is key TB control strategy• Diagnosis of LTBI should

– Target risk populations– Incorporate updated approaches using TST and

IGRAs• Treatment options for LTBI now include 12

dose rifapentine-INH regimen• State and local health departments offer up to

date epidemiology and medical consultation

THANK YOU!!And thanks to my trusted colleagues at NH DHHS for their encouragement and expertise