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