Latent TB Infection on World TB Day 2014

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

2. Outline • 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

3. 2013 Global Epi Snapshot • 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** *MDR=resistance to H+R **XDR=MDR with resistance to FQ and injectable

4. 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. 2013 US Epi Snapshot *MDR=resistance to H+R **XDR=MDR with resistance To FQ and injectable agent

7. To control TB (and solve many of our testing dilemmas): Prioritize LTBI Testing for Those with Risk Factorsfor Development of TB

8. 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. 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. 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. High Risk for Progression from LTBI to Active TB • Plus, persons with certain other medicalconditions: • Silicosis • Carcinoma of head or neck • Gastrectomy or jejunoilial bypass Horsburgh& Rubin, NEJM 2011; 364 (154): 1441-8

12. For best (and credible) patient care: Understand key features of LTBI Testing methods and interpretation

13. Tuberculin Skin Test Do’s and Don’t’s *BCG: TB vaccine derived from M. bovis, most commonly given vaccine worldwide! • 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 . . .

14. 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. 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. Do Which When? • 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) 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 1sttest is neg, but risk for progression is high • When 1sttest is pos, but more evidence is needed to encourage compliance • When IGRA is indeterminate, borderline or invalid • If suspect 1st test is wrong • *PPD may “boost” IGRA response. If you • do TST then IGRA, do it within 7d of TST

17. The goal is treating LTBI to control TB: Updates regarding LTBI Treatment

18. LTBI Treatment Regimens • *Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

19. Rifapentine (Priftin) • Rifamycinderivative 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. 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. RPT+INH clearly non-inferior to INH monotherapy More pronounced in intention to treat analysis

22. 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. 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. Current LTBI Treatment Regimens • *Preferred; **Intermittent treatment only with DOT; ***Rifabutin can be substituted

26. Programmatic Use of INH+RPT • 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”

27. 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