1. Elizabeth A. Talbot MD Associate Professor, Deputy State Epi Infectious Disease & International Health Geisel School of Medicine at Dartmouth Latent TB Infection on World TB Day 2014

2. GEISELMED.DARTMOUTH.E DU 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 Outline

3. GEISELMED.DARTMOUTH.E DU 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** 2013 Global Epi Snapshot *MDR=resistance to H+R **XDR=MDR with resistance to FQ and injectable

4. GEISELMED.DARTMOUTH.E DU One-third of TB cases missed 50% of ~1.1 million new cases of HIV-related TB missed 75% with MDR- TB missed “Missed” = gap between estimated number who became ill with TB and the number notified to national TB programs

5. GEISELMED.DARTMOUTH.E DU 2013 US Epi Snapshot *MDR=resistance to H+R **XDR=MDR with resistance To FQ and injectable agent

6. GEISELMED.DARTMOUTH.E DU

7. PRIORITIZE LTBI TESTING FOR THOSE WITH RISK FACTORS FOR DEVELOPMENT OF TB To control TB (and solve many of our testing dilemmas): 6

8. GEISELMED.DARTMOUTH.E DU 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

9. GEISELMED.DARTMOUTH.E DU 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

10. GEISELMED.DARTMOUTH.E DU 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

11. GEISELMED.DARTMOUTH.E DU 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

12. GEISELMED.DARTMOUTH.E DU UNDERSTAND KEY FEATURES OF LTBI TESTING METHODS AND INTERPRETATION For best (and credible) patient care:

13. GEISELMED.DARTMOUTH.E DU 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!

14. GEISELMED.DARTMOUTH.E DU 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

15. GEISELMED.DARTMOUTH.E DU 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

16. GEISELMED.DARTMOUTH.E DU Do Which When? One is Preferred IGRAs – 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 1 st test is neg, but risk for progression is high When 1 st test is pos, but more evidence is needed to encourage compliance When IGRA is indeterminate, borderline or invalid If suspect 1 st test is wrong Neither is Preferred Recent contact to case – IGRA should be repeated at 8-10 weeks (like TST) – Data on timing of IGRA conversion not available – IGRA may be more sensitive than TST Periodic screening (e.g., HCW) *PPD may “boost” IGRA response. If you do TST then IGRA, do it within 7d of TST

17. GEISELMED.DARTMOUTH.E DU UPDATES REGARDING LTBI TREATMENT The goal is treating LTBI to control TB: 16

18. GEISELMED.DARTMOUTH.E DU LTBI Treatment Regimens Drugs Months of Duration Interval Minimum Doses INH9* Daily270 2x wkly**76 INH6 Daily180 2x wkly**52 RIF***4Daily120 *Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

19. GEISELMED.DARTMOUTH.E DU Rifapentine (Priftin) Rifamycin derivative developed in 1950s, marketed 1998 Similar spectrum as rifampin, but with longer half- life 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

20. GEISELMED.DARTMOUTH.E DU 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

21. GEISELMED.DARTMOUTH.E DU RPT+INH clearly non-inferior to INH monotherapy More pronounced in intention to treat analysis

22. GEISELMED.DARTMOUTH.E DU 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

23. GEISELMED.DARTMOUTH.E DU 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

24. GEISELMED.DARTMOUTH.E DU Current LTBI Treatment Regimens Drugs Months of Duration Interval Minimum Doses INH9* Daily270 2x wkly**76 INH6 Daily180 2x wkly**52 RIF***4Daily120 INH-RPT3Weekly**12 *Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

25. GEISELMED.DARTMOUTH.E DU

26. 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” Programmatic Use of INH+RPT

27. GEISELMED.DARTMOUTH.E DU 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

28. THANK YOU!! And thanks to my trusted colleagues at NH DHHS for their encouragement and expertise