What’s New in LTBI? 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 Rochester, Minnesota

Relevant Financial Relationship(s)
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

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

ERJ 33: 956, 2009

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 :

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, MMWR 54: RR-17, 2005

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

What’s New in LTBI? IGRAs –Serial testing phenotypes

What’s New in LTBI? IGRAs – HCW Screening
Am J Respir Crit Care Med 189: 77, 2014

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

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

(“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

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

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

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 (3.2%) only two of 71 TST positive Reversions: 37 of 41of 71 (90%) /AnnalsATS OC 21Jan14

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: persist positive 2.59) Conversion TST: 1 of 241 (0.4%) Conversion QFT: 13 of 245 (5.3%) PLOS ONE 8: e54748, 2013

Minnesota Department of Health
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.

Relevant Financial Relationships Off-Label/Investigational Uses
Disclosure Relevant Financial Relationships None Off-Label/Investigational Uses

TB Burden, Worldwide, 2010 Source: WHO: Global Tuberculosis Control Report, 2010

Estimated 5-10 million people with LTBI in the U.S. (4-5% of population) Most U.S. cases result from reactivation of LTBI. This is the most infectious form of TB Persons with LTBI are the reservoir of future TB Active TB LTBI Reactivation reasons often poorly understood. Tx is therefore a personal and public health issue. 90% of infected adults never become ill. So, control strategies focused on recent transmission will have limited success 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 47

Targeted TB Testing (2) Prevent the development of TB disease
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 48

Tuberculosis Incidence Rates per 100,000 Population, United States and Minnesota, 1998-2012
This slide depicts the incidence rate for TB in Minnesota and the United States from 1998 to After increasing throughout much of the 1990s, the incidence rate for TB disease in Minnesota peaked in 2007 (4.6 TB cases per 100,000 Minnesota residents). The rate declined in the following years and, in 2010, reached the lowest recorded rate (2.5/100,000) since at least the 1960s. During the last two years, Minnesota has seen a slight rise in TB incidence. The rate of TB in Minnesota has consistently been lower than the national rate, with the exception of one year (2007) when there were 4.6 cases/100,000 Minnesotans and 4.4/100,000 nationally. The rates of TB in Minnesota and nationally have not met the Healthy People 2010 and 2020 objectives of 1.0 TB case per 100,000.

Percentage of Foreign-Born Tuberculosis Cases, United States and Minnesota, 2003-2012
Percentage of Cases The most distinguishing characteristic of the epidemiology of TB disease in Minnesota is the very high percentage of cases that occur among persons born outside the United States. During the past decade, the percentage of foreign-born persons among TB cases reported in Minnesota averaged 81%, ranging from 73% in 2008 to 87% in The average foreign-born percentage during this time period nationally was 58%. In 2012, 84% of TB cases in Minnesota were born outside the U.S., compared to 63% of TB cases reported nationally. Year of Diagnosis

Tuberculosis Cases by Risk Category*, Minnesota, 2008-2012
NOTE: THIS SLIDE PRESENTS SIMILAR DATA TO THE PRIOR SLIDE, BUT IN GRAPHICAL FORMAT. Tuberculosis disproportionately affects certain high-risk subgroups of the population. This slide presents several common risk factors for TB disease and the number and percentage of TB cases reported from 2008 through 2012 that reported any of these risk factors. These risk categories are not mutually exclusive; an individual patient may have more than one. The most distinguishing characteristic of the epidemiology of TB disease in Minnesota is the very large proportion of cases that occur among foreign-born persons. Eighty percent of TB cases reported during the past 5 years were born outside the United States. In contrast, 61% of cases reported nationwide during this 5-year period were foreign-born. The very high percentage of TB cases in Minnesota that occur among foreign-born persons is influenced by the demographics of new refugees and immigrants, many of whom come from regions of the world where TB is prevalent. Notably, however, the number of foreign-born TB cases reported declined 12% from 2008 to This reflects decreasing numbers of new refugees and immigrants arriving in Minnesota, and changes in overseas health screening protocols. Other high-risk population subgroups represented much smaller proportions of the TB cases reported during this period, each representing no more than 15% of the total cases reported statewide. Persons with certain medical conditions that increase the risk for progression from latent TB infection to active TB were the largest of these other high-risk population subgroups, representing 14% of TB cases. Having a history of substance abuse was the second most common of these other risk factors, with 6% of TB cases having a history of substance abuse during the 12 months prior to their TB diagnosis. Four percent of TB cases were co-infected with HIV, which was a lower prevalence than that among TB cases reported nationwide during this period. Three percent of TB cases reported in Minnesota from 2008 through 2012 were homeless, 2% were correctional facility inmates, and 1% were residents of long-term care facilities. The percentage of cases who were homeless or had a history of substance abuse was higher in 2008 than in subsequent years due to two outbreaks that occurred in those populations. •* 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.

Tuberculosis Cases With Other Medical Conditions, by Type of Condition, Minnesota, 2008-2012
No. ( %) Medical conditions* Diabetes Other Immunosuppressive Therapy End Stage Renal Disease Prolonged Corticosteroid Therapy Weight loss/Undernutrition Hematologic/Reticuloendothelial Disease ( 8) ( 5) ( 2) 2 (<1) 6 ( 1) 1 (<1) Certain medical conditions increase the risk that latent TB infection will progress to active TB disease. Of the 806 TB cases reported in Minnesota during , 8% were reported as having diabetes and 5% were on prolonged corticosteroid or other immunosuppressive therapy at the time of the TB diagnosis. End stage renal disease was present in 2% of TB cases. Hematologic/reticuloendothelial disease and weight loss/undernutrition unrelated to TB each were present in 1% of TB cases or less. This illustrates that screening for tuberculosis (and treatment for latent TB infection, if indicated) should be routinely considered for individuals with these medical conditions. *Patients could have > 1 medical condition.

Interferon-Gamma Release Assays (IGRAs)
53

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 follow-up 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

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) self-administered 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

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

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

23 expert consultants, reviewed TBTC 26 as well as other INH-RPT 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

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

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

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: kg 300 mg kg 450 mg kg 600 mg 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: , 2005 CID 45: , 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

“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? 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 84

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 ( ) for inclusion in CDC’s adverse events surveillance system, -AND- - FDA MedWatch at

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

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