Transcript File - Mayo Clinic Center for Tuberculosis

What’s New in LTBI?
Mayo Clinic Center for Tuberculosis
Webinar
6 Mar 2014
Timothy R. Aksamit, MD
Associate Professor of Medicine
Mayo Clinic
College of Medicine
Consultant
Pulmonary Disease and Critical Care Medicine
Department of Internal Medicine
Mayo Clinic
Rochester, Minnesota
What’s New in LTBI?
DISCLOSURE
Relevant Financial Relationship(s)
None
What’s New in LTBI?
Objectives
•Describe the use of Interferon Gamma Release
Assays (IGRAs) for TB testing in HCW
•Describe the use of shorter drug regimens for the
treatment of Latent TB Infection (LTBI)
•Describe the public health perspective on the
advantages and limitations of using IGRAs and
short LTBI regimens
What’s New in LTBI?
•Background
•Diagnostics – IGRA
•HCW
•Treatment
•RPT-INH 12 weeks
•Summary
What’s New in LTBI?
•Background
•Diagnostics – IGRA
•HCW
•Treatment
•RPT-INH 12 weeks
•Summary
Latent TB Infection (LTBI)
LTBI is the presence of M. tuberculosis
organisms (tubercle bacilli) without symptoms
or radiographic evidence of TB disease.
No GOLD STANDARD
Latent TB Infection (LTBI)
ERJ 33: 956, 2009
Latent TB Infection (LTBI)
LTBI is the presence of M. tuberculosis organisms
(tubercle bacilli) without symptoms or radiographic
evidence of TB disease.
No GOLD STANDARD – Natural history is uncertain
?
“LTBI” = Persistent adaptive M. Tb immune response
Testing for
TB Disease and Infection
TB INFECTION (LTBI)
TB
DISEASE
Pulm and
XP
Terminology
• “Treatment of latent TB infection” replaces the terms
“preventive therapy” and “chemoprophylaxis” to
promote greater understanding of the concept for
both patients and providers.
• Targeted tuberculin testing is used to focus program
activities and provider practices on groups at the
highest risk for TB.
Targeted Tuberculin Testing
• Detects persons with LTBI who would benefit from
treatment
• De-emphasizes testing of groups that are not at
high risk for TB
• Can help reduce the waste of resources and
prevent inappropriate treatment
What’s New in LTBI?
•Background
•Diagnostics – IGRA
•HCW
•Treatment
•RPT-INH 12 weeks
•Summary
Testing for Latent TB Infection
Tuberculin Skin Test (TST)
or
Interferon-γ Release Assay (IGRA):
QuantiFERON®-TB Gold
QuantiFERON®-TB Gold-IT (In-Tube)
T-SPOT®.TB
New Insights in the Diagnosis of
Tuberculosis Infection
IFN-γ Release Assays (IGRAs)
• ESAT-6 and CFP-10 (and TB 7.7(p4))
• no cross reactivity with
• BCG (TST no impact)
• most NTM, except M. kansasii, M.
szulgai, marinum, and riyadhense
• + reactivity with M. bovis, africanum, microti
• Control antigens
• nil (negative) control antigen
• mitogen phytohemagglutinin (positive)
control antigen
New Insights in the Diagnosis of
Tuberculosis Infection
IFN-γ Release Assays (IGRAs)
Can IGRAs testing be used in place of TST?
• Yes
CDC Guidelines QFT-Gold 2005:
QFT-Gold can be used in all circumstances in which
the TST is used including:
• contact investigations
• evaluation of recent immigrants (BCG)
• TB screening HCW, including serial screening
MMWR 54: RR-15, 2005 MMWR 54: RR-17, 2005
New Insights in the Diagnosis of
Tuberculosis Infection
New Insights in the Diagnosis of
Tuberculosis Infection
What’s New in LTBI?
IGRAs
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Sources of variability
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Sources of variability
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Sources of variability
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Sources of variability
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Sources of variability
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs –Serial testing phenotypes
Clin Micro Rev 27: 3, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
•
•
•
•
Prospective longitudinal study 2563 HCWs
Four centers: Denver, Baltimore, Houston, NYC
12% foreign-born high TB burden countries, 9% BCG reported
TST, QFT-GIT, and T-SPOT.TB baseline and every 6 months for
18 months
• Sub-studies for repeatability, reproducibility, and boosting
• Baseline:
• Positive – overall (previously screened)
• TST: 5.2% (1.8%)
• QFT-GIT: 4.9% (3.8%)
• T.SPOT-TB: 6.0% (5.0%)
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
• Reversions (baseline positive tests):
• TST: 29 of 54 (54%) retested negative
• QFT-GIT: 67 0f 118 (57%)
• T.SPOT: 92 of 144 (64%)
• Conversions:
• TST: 21 of 2293 (0.9%)
• QFT-GIT: 138 of 2263 (6.1%)
• T.SPOT: 177 of 2137 (8.3%)
• No association with TB exposure
• No patient converted all three tests
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
• (“transient”) Conversions:
• TST: 11 of 12 retested (92%) negative
• QFT-GIT: 81 of 106 (76%)
• T.SPOT: 91 of 118 (77%)
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
• Boosted:
• 9.1% QFT-GIT
• 11% T.SPOT
• More boosting (qualitatively and quantitatively) in those
baseline positive TST
• Repeatability (w/i 2 weeks):
• QFT-GIT: neg to pos: 10 of 134 (7.5%)
• T.SPOT: neg to pos: 9 of 111 (8.1%)
• Reproducibility (same time 2 tubes):
• QFT-GIT: discordant: 10 of 172 (5.8%)
• T.SPOT: discordant: 10 of 153 (6.5%)
Am J Respir Crit Care Med 189: 77, 2014
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 188: 1005, 2013
What’s New in LTBI?
IGRAs – HCW Screening
• Retrospective
• 9153 HCWs with 2 or more QFT June 2008 and July 2010
• Stanford Medical Center, Palo Alto, CA
• Conversion: 4.4% (361)
• Reversions: 169 of 261 repeated tests <60 days (65%)
• Reversions: 38 of 60 repeated tests >60 days (63%)
• Reversions and conversions most 0.35 – 1.0 IU/ml
• 74% reversions, 62% conversions, 28% persistent +ve
• 12 of 16 (75%) ‘persistently’ positive REVERTED
Am J Respir Crit Care Med 188: 1005, 2013
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 188: 1005, 2013
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 188: 1005, 2013
What’s New in LTBI?
IGRAs – HCW Screening
Am J Respir Crit Care Med 188: 1005, 2013
What’s New in LTBI?
IGRAs – HCW Screening
• Retrospective
• 2303 HCWs – QFT-GIT Nov 2008 and Jan 2011, >2 IGRAs >1yr
apart
• Central Arkansas Veterans Healthcare System
•
•
•
•
Baseline positive tests: 69 (3.1%)
Reversions (baseline): 31 of 69 (45%)
Conversion: 71 of 2232 (3.2%) only two of 71 TST positive
Reversions: 37 of 41of 71 (90%)
10.1513/AnnalsATS.201310-378OC 21Jan14
What’s New in LTBI?
IGRAs – HCW Screening
• Prospective
• 258 HCWs – TST and QFT-GIT at baseline(2-step TST) and 1
year later
• 38% BCG-vaccinated 71% Canadian born
• McGill University Health Centre Montreal, Canada
• Baseline positive TST tests: 17 of 258 (6.5%)
• Baseline positive QFT-GIT tests: 13 of 258 (5.0%)
• Reversions QFT: 8 of 13 (62%)
• (baseline median QFT : reversion: 1.0 persist positive 2.59)
• Conversion TST: 1 of 241 (0.4%)
• Conversion QFT: 13 of 245 (5.3%)
PLOS ONE 8: e54748, 2013
Interferon-Gamma Release Assays
and the 12-week INH/RPT Regimen
for Latent TB Infection:
Public Health Implications
Deborah Sodt, RN, PHN, MPH
TB Program Manager
Minnesota Department of Health
March 6, 2014
Objective
• Describe public health perspectives on the
advantages and limitations of IGRA testing
and shorter LTBI treatment regimens.
Disclosure
Relevant Financial Relationships
None
Off-Label/Investigational Uses
None
TB Burden, Worldwide, 2010
•Source: WHO: Global Tuberculosis
Latent TB Infection (LTBI)
• Estimated 5-10 million
people with LTBI in the U.S.
(4-5% of population)
•Active
TB
• Most U.S. cases result from
•LTBI
reactivation of LTBI. This is
the most infectious form of
TB
• Persons with LTBI are the
reservoir of future TB
Adapted from Ann Settgast,
M.D. March 2010
Targeted TB Testing (1)
• Targeted testing is a TB control strategy used to
identify and treat persons:
• At high risk for infection with M.
tuberculosis
• At high risk for developing TB
disease once infected with
M. tuberculosis
Module 3 – Targeted Testing and the Diagnosis of
Latent Tuberculosis Infection and Tuberculosis Disease
Targeted TB Testing (2)
• Identifying persons with LTBI is an important goal of
TB elimination because LTBI treatment can:
• Prevent the development of TB
disease
• Stop the spread of TB
Module 3 – Targeted Testing and the Diagnosis of
Latent Tuberculosis Infection and Tuberculosis Disease
•Year of Diagnosis
•Percentage of Cases
•* Risk categories are not mutually exclusive.
• †Alcohol abuse and/or illicit drug use.
•** Conditions or therapies that increase risk for progression from latent TB infection to active TB disease.
Medical conditions*
Diabetes
Other Immunosuppressive Therapy
End Stage Renal Disease
Prolonged Corticosteroid Therapy
•Weight loss/Undernutrition
Hematologic/Reticuloendothelial Disease
*Patients could have > 1 medical condition.
Cases
(N=806)
No. ( %)
65
41
13
2
6
1
( 8)
( 5)
( 2)
(<1)
( 1)
(<1)
Interferon-Gamma
Release Assays
(IGRAs)
Disadvantages of IGRAs
• Potential for false positive or negative
results
• Requires trained phlebotomists and careful
specimen handling
• Not universally available
• Cost/perceived cost
Advantages of IGRAs (1)
• One visit; results available within 24 hours
• High level of specificity makes it a good
test for persons who have received BCG
• Convenience makes it a good test for
groups that historically have low rates of
return for TST reading (homeless persons,
drug-users, [HCWs?])
Advantages of IGRAs (2)
• Less likely to have incorrect reading of
results as compared to TST
• Does not boost responses measured by
subsequent tests
• Potential for cost savings by decreasing
the number of persons receiving followup medical evaluation and LTBI
treatment
Key Points: IGRA Testing (1)
• As with TST, IGRAs generally should
not be used for testing persons at low
risk of infection and low risk of disease
due to M. tuberculosis.
• Birth in an area of the world where TB is
common is by far the primary risk factor
for TB in Minnesota
• IGRA is recommended for individuals
who have had BCG vaccine
Key Points: IGRA Testing (2)
• Caution should be used when interpreting
results in certain populations because of
limited data on IGRAs
• Each facility should evaluate the
feasibility of IGRAs in deciding whether to
use them
• IGRAs are preferred in certain groups
and TSTs are preferred in others, but use
of either test is acceptable medical and
public health practice
What’s New in LTBI?
•Background
•Diagnostics – IGRA
•HCW
•Treatment
•RPT-INH 12 weeks
•Summary
Initiating Treatment
Before initiating treatment for LTBI
• Rule out TB disease (i.e., wait for culture result if
specimen obtained) – PULMONARY or
EXTRAPULMONARY
• Determine prior history of treatment for LTBI or TB
disease
• Assess risks and benefits of treatment
• Determine current and previous drug therapy
LTBI Treatment Regimens
LTBI Regimens
• ISONIAZID (INH) *
• 9 months
• Combination: RIFAPENTINE (RPT) plus ISONIAZID *
• 3 months, weekly dosing
• RIFAMPIN (RIF)
• 4 months
• Others: 6INH, intermittent INH, 3IR
*preferred
Isoniazid Regimens
• 9-month regimen of DAILY isoniazid (INH) selfadministered is the historical preferred regimen
• Alternative: 3-month, WEEKLY RPT and INH, DOT
• Age >12, LTBI and risk for developing TB
disease:
• Recent exposure, new conversion, or x-ray
healed TB
Latent TB Infection (LTBI)
Treatment – 3RPT/INH
NEJM 365: 2155, 2011
Latent TB Infection (LTBI)
Treatment – 3RPT/INH
• PREVENT TB Study – TBTC Study 26
• N= 8,053, 10 years; US, Brazil, and Spain 33wk f/u
• Randomized 9INH versus 3Rifapentine plus INH(weekly)
NEJM 365: 2155, 2011
Latent TB Infection (LTBI)
Treatment – 3RPT/INH
• PREVENT TB Study – TBTC Study 26
• N= 8,053, 10 years; US, Brazil, and Spain 33wk f/u
• Randomized 9INH versus 3Rifapentine plus INH(weekly)
NEJM 365: 2155, 2011
Latent TB Infection (LTBI)
Treatment – 3RPT/INH
•
•
•
•
•
•
•
PREVENT TB Study – TBTC Study 26
N= 8,053, 10 years; US, Brazil, and Spain 33wk f/u
Randomized 9INH versus 3Rifapentine plus INH (weekly)
3Rifapentine plus INH safe and effective
TB dis: 7 cases 3RPT/INH (0.19%) vs 15 cases 9INH (0.43%)
Completion: 82% 3RPT/INH versus 69% 9INH (p<0.001)
AE: 4.9% vs 3.7% (p=0.009), hepatotoxicity: 0.4% vs 2.7%
(p<0.001)
• Applicable to:
• Countries with low-to-medium TB incidence
• Treatment given via DOT (directly observed therapy)
NEJM 365: 2155, 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
MMWR 60: 1650, 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
• 23 expert consultants, reviewed TBTC 26 as well as other INHRPT trials
• RECOMMENDED via DOT!
• Age >12, LTBI and risk for developing TB disease
• Recent exposure, new conversion, or x-ray healed TB
• DOT resources available
• NOT RECOMMENDED:
• Age < 2 years
• HIV / AIDS taking antiretroviral treatment
• Presumed infected with INH or RIF-resistant M.
tuberculosis and
• Pregnant women or women expecting to become
pregnant within the 12 week regimen
MMWR 60: 1650, 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
• FAVORED ALTERNATIVE (to 9INH):
• Practical advantage – correctional settings, recent
immigrants, homeless shelters
• Social circumstances that makes adherence
questionable
• Dosing 3RPT/INH - DOT
• Completion 11 or 12 doses within 16 weeks
• Doses separated by > 72 hours to be counted
MMWR 60: 1650, 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
• 3RPT/INH for age 2 – 11 years old:
• If completion of 9INH unlikely
• (and) likelihood of TB high
• 9INH monotherapy PREFERRED age 2-11
MMWR 60: 1650, 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
Latent TB Infection (LTBI) Treatment
3RPT-INH - CDC 2011
• Dosing 3 RPT/INH arm
• Rifapentine:
• Persons weighing > 50.0 kg received rifapentine 900 mg once-weekly
• Persons weighing < 50.0 kg were dosed once-weekly according to the
following scale:
•
•
•
•
•
•
10.0-14.0 kg 300 mg
14.1-25.0 kg 450 mg
25.1-32.0 kg 600 mg
32.1-50.0 kg 750 mg
Isoniazid:
Persons 2-11 years old received isoniazid 25 mg/kg (rounded up to the
nearest 50 or 100 mg; 900mg max) once-weekly
• Persons > 12 years old received isoniazid 15 mg/kg (rounded up to nearest
50 or 100 mg; 900mg max) once-weekly
MMWR 60: 1650, 2011
Short Course Therapy with RIF plus
INH 3 Months versus Standard INH
• Not CDC approved for LTBI (as of 2000 with updates)
• Meta-analysis LTBI treatment
• Pooled 1926 patients (5 studies) Hong Kong, Spain, and Uganda
• Equivalent to standard therapy with INH (IR3 vs I6-12) :
• Efficacy (4.2% vs. 4.1%)
• Severe side effects (4.9% vs. 4.8%)
• Mortality (9.5% vs. 10.4%)
• Also equally effective in pediatric population, better completion
(Greece)
CID 40: 670-676, 2005
CID 45: 715-722, 2007
Latent TB Infection (LTBI) Treatment
Monitoring RPT-INH - CDC 2011
• Monitoring 3RPT/INH arm
• DOT:
• Symptom checklist: fever, yellow eyes, dizziness,
paresthesias, rash, aches or > 1 day of nausea,
vomiting, weakness, abdominal pain, dark urine, easy
bruisability, bleeding, or loss of appetite
• REFER if positive
• Monthly:
• Clinical assessment
• Assess adverse effects
• Physical exam (icterus, liver tenderness, or rash)
• Blood work
• (liver disease, post-partum, EtOH use, HIV)
MMWR 60: 1650, 2011
Latent TB Infection (LTBI) Treatment
Monitoring RPT-INH - CDC 2013
Latent TB Infection (LTBI) Treatment
Monitoring RPT-INH - CDC 2013
Latent TB Infection (LTBI) Treatment
Monitoring RPT-INH - CDC 2013
Latent TB Infection (LTBI) Treatment
Monitoring RPT-INH - CDC 2013
• “possible hypersensitivity”: INH-RPT 3.8% vs. SAT 9H 0.5%
• Fever, chills, HA, fatigue, red eyes, urticaria , pruritus,
petechiae
• Implementation and safety of the DOT INH-RPT regimen
•
•
•
•
•
•
TBTC Study 33: “iAdhere study” – SAT INH-RPT
Ongoing LTBI surveillance for severe AE (hosp or death)
Post-marketing sentinel site evaluation DOT INH-RPT
In-depth evaluation of “possible hypersensitivity” TBTC 26
State health department evaluation of DOT INH-RPT
Collaboration with Sanofi
What’s New in LTBI?
•Background
•Diagnostics – IGRA
•HCW
•Treatment
•RPT-INH 12 weeks
•Summary
What’s New in LTBI?
Summary
• IGRA testing for TB infection represents a new tool for the
evaluation of TB infection with increased specificity relative to
TST, especially in BCG-vaccinated individuals
• IGRA testing used for annual screening (in HCW) has intrinsic
variability and limits its general applicability
• Shorter course therapy (RPT-INH) is an effective LTBI regimen
and has advantages over standard 9INH daily but may also
have unique side effects and needs to be administered by DOT
with close monitoring
INH/RPT
Regimen
1/4 of high-priority LTBI patients in
Minnesota do not complete therapy
• In 2010, 90% of newly infected contacts in
Minnesota started LTBI treatment
- 73% completed treatment
• In 2010, 87% of TB Class B immigrants and
refugees diagnosed with LTBI in Minnesota
started LTBI treatment
- 75% completed treatment
Barriers to LTBI Treatment
• Inconvenient clinic hours/location
• Cultural awareness of staff
• Misinformation (e.g., BCG)
• Mistrust of public health or medical system
• Stigma of TB
• Length of treatment
• Concern about potential side effects
• etc.
INH-RPT: Advantages
• Fewer doses/Shorter treatment time
• May increase patient willingness to be
treated for LTBI
• Higher completion of therapy rates
INH-RPT: Disadvantages
• Not appropriate for all patients
• Higher cost (Rifapentine)
• Large # of pills (up to 10)
• DOT required
- Local public health agencies may vary in
their ability to provide DOT
Pre-treatment education
• Commit to 12 weeks of weekly DOT
- No moves; no travel
• Agree to take up to 9-10 tablets each time
• Avoid pregnancy
• Schedule monthly physical examinations
with provider
• If these cannot reasonably be assured, one
of the other LTBI treatment regimens
should be used
Reporting severe adverse events
• With previous LTBI regimens (e.g., INH,
rifampin-pyrazinamide), fatal liver injuries
came to attention only after the regimens
were widely adopted.
• Adverse events leading to hospitalization or
death associated with the use of any LTBI
regimen should be reported to
- MDH (651-201-5414) for inclusion in
CDC’s adverse events surveillance system,
-AND- FDA MedWatch at
http://www.fda.gov/medwatch
Key Points: 12-week regimen
• As the incidence of TB disease in the United
States and Minnesota, focus on detecting and
treating LTBI will play an increased role
• TB is decreasing but increasingly occurs in
population subgroups where it can be hard to
detect and treat.
• Low completion of LTBI therapy rates
• The second most common risk factor is the
presence of other medical conditions that
increase the risk of active TB
References
• CDC, Division of TB Elimination
http://www.cdc.gov/tb/
• MDH TB Prevention and Control
Program
www.health.state.mn.us/tb
651-201-5414
Questions?