19th Annual APIC Conference “The heart of Infection Control”
Challenges in diagnosing TB infection: screening & treatment
February 27, 2015
Albuquerque, NM
Marcos Burgos, MD
Medical Director TB Program, NM DOH
Objectives
• Describe the pathogenesis of TB infection and
disease
• Describe who is at risk for Latent TB disease (LTBI)
and who should we test for LTBI
• Understand the LTBI screening cascade of Care
and its relevance to TB control
• Describe new diagnostic and treatment tools for
LTBI
Why do we care if someone has LTBI?
Latent TB Infection
• If we identify a LTBI case,• We can treat it and prevent an active case
• We can prevent secondary cases
• Treating LTBI is an effective approach to reduce the incidence of TB?
Reported TB Cases United States, 1982–2012*
*Updated as of June 10, 2013.
0
5,000
10,000
15,000
20,000
25,000
30,000
No
. of
Cas
es
Year
Latent TB Infection
• LTBI treatment is a major public health strategy to reduce the
incidence of tuberculosis disease
• There are around 11 million cases of LTBI in the United States
• Approximately 5–10% of persons latently infected with M.
tuberculosis will develop active tuberculosis
• TB infected HIV individuals and those with recent conversions
have high rates of progression to active TB
• LTBI treatment is warranted in those with HIV and recently
infected
Case # 1
• 45 year old white male with uncontrolled DM, US born, homeless
• Patient with multiple visits to ER for ETOH withdraw,
• History of IVDU
• Exposed to an active TB case in a homeless shelter 2 months before
• Denies fever, chills, cough, weight loss
• TST = 6 mm
Case # 1 cont.
Questions
1. What are the patient risk factors for TB infection or disease?
2. What is the appropriate management for this patient?
Who should be tested for LTBI?
• HIV positive individuals
• Contacts of persons with active disease
• Recent immigrants < 5 years from high prevalence countries
• Injection Drug Users
• Residents and employees of high congregate settings
• Immunocompromised patients
Tuberculosis Screening Flowchart
Evaluate for active TB
At-risk person
TST +or IGRA +; symptom review
Negative Positive
Chest x-ray
Normal Abnormal
Treatmentnot indicated
Potential candidate for Rx
of latent TB
Tuberculin Skin TestingMantoux Method
48 to 72 hours5 TU of PPD
Interpretation depends on
person’s risk factors
Tuberculin Skin TestCriteria for a Positive Reaction
≥5 mm ≥10 mm ≥15 mm
HIV infection Recent immigrants No risk
Contact to Injection drug users
active TB case Children
Abnormal CXR High-risk medical
Immunosuppression conditions
Residents and employeesof jails/nursing homes,hospitals
Case # 1 cont.
• Normal CXR, normal labs
• Patient started on INH for LTBI, he was lost to follow up after the second month of treatment
The clinical reality of TB screening cascade among, HIV positive, New York City
Completed LTBI– 41%
AIDS 1998;12:2017-23
The clinical reality of TB screening cascade among
contacts of AFB smear + cases
Completed LTBI treatment 53%
Int J Tuberc Lung Dis. 2014: 18(4)
68,219
56,253
11,236 8,082 5,475
4890
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
ContactsExposed to
TB
Screenedfor TB
Diagnosedwith LTBI
StartedTreatment
for LTBI
CompletedTreatment
for LTBI
Contactswith TBCases
US TB Contact Investigations: AFB+, 2010 ARPE
=1
49%72%
Slide provided by Dr. Randall Reeves
The clinical reality of TB screening cascade in the community
• Missing data:
– Who are the individuals at risk in the community?
– Who is getting LTBI testing?
– Of those that are tested, who is positive (LTBI not a reportable condition)
– How many of those positive for LTBI are referred for evaluation
– How many are referred for treatment?
– How many complete treatment?
– Of those not treated, how many developed active TB?
Case # 1 cont.
• A year later patient admitted with pneumonia
• He was treated for CAP and discharge to homeless shelter
• 3 months later homeless clinic send patient to the TB clinic for evaluation because of persistent cough
Case # 1 cont .
• CXR demonstrated right upper lobe cavity
• HbA1C 11, HIV neg
• Sputum's smear positive 2 +, NAAT test positive for MTB complex
• Patient started on 4 drugs
• Drug susceptibility report susceptible to all 4 drugs
Case # 1, cont.
• What can we do to make sure the patient completes treatment?
• Individualized treatment to incorporate measures that facilitate his adherence to treatment with a patient-centered approach
– DOT
– social service support
– treatment incentives and enablers,
– housing assistance
– referral for treatment of substance abuse,
– management of comorbidities with PCP
Who should be treated for LTBI?
• A decision to test is a decision to treat!
• Test should be placed only on those that will
benefit from treatment
LTBI Regimens
• Isoniazid (INH) for 9 months
• Rifapentine (P) plus Isoniazid (H) for 3 months weekly dosing (3HP)
• Rifampin (Rif) for 4 months
• Rifampin (R) plus Isonaizid (H) for 3 months
3HP vs. 9 month INH
Outcome 9H
N=3,745
3HP
N=3,986
P-value
Treatment
completion
2,585 (69.0%) 3,362 (82.0%) < 0.0001
Permanent drug d/c-
any reason
1,160 (31.0%) 624 (18.0%) < 0.0001
Permanent drug d/c-
due to an adverse
event
135 (3.6%) 188 (4.7%) 0.004
Death 39 (1.0%) 31 (0.8%) 0.22
N Engl J Med 2011; 365:2155-2166
PreventTB,
Study26
(MITT)
% Post-marketing
Project
%
Hepatotoxicity* 18/4040 0.4 10/2134 0.5
Hospitalizations 56/3986 1.4 17/2134 0.8
Death 4/3986 0.1 0/2134 0
CompletionRate 82.1 1745/2061 84.7
Preliminary Comparison Between TBTC Prevent TB Studyand Post-marketing Project for Treatment Discontinuation
Rates by Reason, 17 Sites
Presented 18th Annual Conference of the Union-NAR, Boston, MA. March 1,2014
LTBI treatment 3HP Vs. 9 months INH
• Patients treated for LTBI with 9 months of INH are significantly
less likely to complete treatment
• 3HP studies demonstrate high completions rates, even in difficult
populations
• Initial field experience with 3HP is similar to treatment trial
experiences
• 12-dose INH-RPT is being adopted in the U.S.
3HP a new tool to increase LTBI treatment completion rates?
• It is thought that the completion rates of 3HP versus 9 months
of INH are significantly better because 3HP is given for only 3
months
• Another important component is the use of DOT, the most
important component of a patient-centered approach for the
treatment of TB
• Could we get the same results on 3HP without DOT?
• Results of iAdhere in the next 6 months (Study 33 - directly
observed vs. self administered 3HP)
• administered therapy
T-Spot.TB
Nil Control
Positive Control
Infection
Infection
Oxford Immunotec
Whole Blood IFN- AssayQuantiFERON-TB Gold, in-tube (QFT)
Tuberculosis Complex
ESAT-6 CFP-10 TB-7.7 TSTEnvironmental
StrainsESAT-6 CFP-10 TB-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 - - - +
IGRAS vs. TST
34
• Requires single patient visit to conduct test
• Results can be available in 24 hours
• Does not cause booster phenomenon
• Less likely to have incorrect reading of results as compared to TST
• BCG vaccination does not affect results
IGRA Advantages
CDC Recommendations:
• IGRAs may be used in place of TST in all
situations in which CDC recommends TST
• 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
Who Should Be Tested with IGRAS?
• Foreign-born from areas with a high incidence of
active TB
• Visitors to areas with a high prevalence of active
TB
• Residents and employees of congregate settings
whose clients are at increased risk for active
tuberculosis
• Healthcare workers who serve clients at increased
risk for active TB
• Populations defined locally with increased risk of
MTB infection
Case 2
• 24 year old female, UNM student, QTF-GIT reactive refer to DOH for LTBI treatment
• What questions do we need to ask?
• How do we work her up?
• What do you do?
Case 2 (cont.)
• Volunteering in a hospital no patient contact
• Born in the U.S., no known exposures to TB, no symptoms
• No medical problems, no medications
• CXR was normal
Case 2 (cont.)
• Treat for LTBI
• Treat for active TB
• Repeat TST
• Repeat QTF-GIT
Case 2 (cont.)
• QTF-GIT repeat not reactive
TB antigen minus nil = 0.05
What do you do?
“When IGRAS do not behave”
• CDC guidelines in 2005 recommended use of
• CDC guidelines recommended use of IGRAs for HCW screening with:
• Simplistic neg to pos was defined as conversion • No published data on serial testing• No independent, peer-reviewed literature on IGRA reproducibility
A single IGRA or TST has limited predictive value
Pai. Nat Rev Microbiol 2010
Conversion rates with IGRAS in low TB incidence settings
2000 HCWs in 4 US hospitals CDC TO18 study**
TST = 0.9%
QTF = 6.1%
T-SPOT = 8.3% conversion rates
Arkansas study of > 2000 HCWs
(Joshi M. Chest 2012)
TST = 0.1%
QTF = 3.2% conversion rates
Canadian study in HCWsZwerling et al. Plos ONE 2013
TST = 0%QTF = 5.3%c conversion
rates
Stanford study of >9000 HCWs
Slater et al. AJRCCM 2013
TST = 0.4%
QTF = 4.4% conversion rates
**Most conversions appear to be false positives because the majority upon retesting demonstrated reversion
Challenges in interpretation criteria with QTF-GIT
• Serial testing challenges have put the spotlight on reproducibility
• Within subject variability, false positive results, different results with different blood volumes
• Different studies demonstrate different interpretation criteria and re-testing strategies
Sources contributing to variability in the results ofQuantiFERON-TB Gold In-Tube assay
LTBI testing with IGRAS
• IGRAS appear to show a lower specificity than TST in populations at low risk for TB infection
• To interpret serial IGRA testing results we need to understand the reproducibility of the test and define cut-offs for conversions– Labs must standardized testing protocols
– Simple negative to positive cut-off for conversion is not enough
– We need a borderline zone or retesting strategy to handle conversions
Summary
• We have new diagnostic test and new treatment approaches
• We need shorter treatment regimens and a gold standard for diagnosing LTBI disease
IGRAS meta-analysis of predictive value
20 cohort studies
• Neither IGRA nor the TST have high accuracy for the prediction of active tuberculosis
• In the foreign born use of IGRAS reduces the number of people considered for preventive treatment
Rangaka MX, Lancet Infect Dis 2012; 12:45-55