Latent TB Infection on
World TB Day 2014
Elizabeth A. Talbot MD
Associate Professor, Deputy State Epi
Infectious Disease & International Health
Geisel School of Medicine at Dartmouth
Outline
• 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
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2013 Global Epi Snapshot
• 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**
*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 MDRTB 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 resistance
To FQ and injectable agent
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To control TB (and solve many of our testing dilemmas):
PRIORITIZE LTBI TESTING FOR THOSE
WITH RISK FACTORS
FOR DEVELOPMENT OF TB
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6
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
resource
CDC 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
bypass
Horsburgh & Rubin, NEJM 2011; 364 (154): 1441-8
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For best (and credible) patient care:
UNDERSTAND KEY FEATURES OF LTBI
TESTING METHODS AND
INTERPRETATION
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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
Neither is Preferred
• IGRAs
• Recent contact to case
– 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
– IGRA should be repeated
high
at 8-10 weeks (like TST)
st
– Data on timing of IGRA • When 1 test is pos, but
more evidence is
conversion not available
needed to encourage
– IGRA may be more
compliance
sensitive than TST
• When IGRA is
• Periodic screening (e.g.,
indeterminate,
HCW)
borderline or invalid
• If suspect 1st test is
wrong
*PPD may “boost” IGRA response. If you
do TST then IGRA, do it within 7d of TST
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The goal is treating LTBI to control TB:
UPDATES REGARDING LTBI TREATMENT
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16
LTBI Treatment Regimens
Drugs
INH
Months of
Duration
9*
INH
6
RIF***
4
Interval
Minimum
Doses
Daily
270
2x wkly**
76
Daily
180
2x wkly**
52
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 halflife 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 monotherapy
More 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
GEISELMED.DARTMOUTH.EDU
Current LTBI Treatment Regimens
Drugs
INH
Months of
Duration
9*
Interval
Minimum
Doses
Daily
270
2x wkly**
76
Daily
180
2x wkly**
52
INH
6
RIF***
4
Daily
120
INH-RPT
3
Weekly**
12
*Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted
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Programmatic Use of INH+RPT
• 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”
GEISELMED.DARTMOUTH.EDU
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
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THANK YOU!!
And thanks to my trusted colleagues at NH
DHHS for their encouragement and expertise