1. IGRAs in Practice: The San Francisco Health Department Experience Jennifer Grinsdale, MPH Program Manager/Epidemiologist Acting Director Tuberculosis Control Section San Francisco Department of Public Health

2. Setting for QFT Implementation: San Francisco 49 square miles Population ~805,000 35% foreign born 27,000 living with AIDS >6,000 homeless (1,500 in shelter) 18,000+ injection drug users (22% HIV+) ~55,000 jail bookings each year

3. Setting for QFT Implementation: TB Morbidity, 1980-2011 QFT Implemented in 2003

4. Setting for QFT Implementation: Case Finding Methods Passive  Hospital and MD referral of suspects Active  Immigration screening  Contact Investigation  Targeted testing 2005-2009: 30% of cases found through active TB screening2005-2009: 30% of cases found through active TB screening Targeted testing yields 3x more cases than CI and immigration screening combined (2009: 27 of 37 cases from TT)Targeted testing yields 3x more cases than CI and immigration screening combined (2009: 27 of 37 cases from TT)

5. Setting for QFT Implementation: Targeted Testing Model Community-Based 12 Primary Care Health Centers 10 DPH-Affiliated Partners 7 Fee-for Service Clinics 6 Youth Clinics Most screen for TB using TST (and now QFT) and refer to TB clinic for evaluation and LTBI treatment

6. 2001-2003: Implementation Why switch to QFT? Better test Reduce the number of false positives No quality control of >10,000 TSTs/yr at community sites Low confidence in the TST by providers caring foreign-born because of BCG vaccination A less subjective test is better and safer for the public Operational advantages Results for every patient – eliminate wasted effort Reduce unnecessary CXR and MD evaluation of false positives Improved documentation, surveillance & communication ‘Use it or lose it’ time FDA approved in 2001 but no one was using it It was time to try something new

7. Program Implications: Our Hopes… New surveillance capabilities: Citywide laboratory-based surveillance for LTBI through the public health lab More efficient: Eliminate unnecessary CXRs, evaluation and treatment More results means targeting efforts on “positives” instead of on retesting individuals who fail to show up for TST readings (homeless, jails, employee testing) Behave as “expected”: Increase patient and provider confidence with more reliable and specific resultsIncrease patient and provider confidence with more reliable and specific results

8. Program Implications: Our Fears… Feasibility and Acceptability: Blood-based testing might not be feasible or acceptable to the lab, patients and providers Moving cost of screening from the program to the labSensitivity: No gold standard for LTBI Missed diagnosis of active disease Risk of Progression in QFT positives: Would we identify the “right” patients for LTBI treatment?

9. We took the leap…

10.  Is QFT feasible and acceptable?  Can QFT be used as a LTBI surveillance tool?  Is QFT programmatically more efficient than TST?  Does QFT behave as expected (more specific than TST)?  Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

11. QFT-1st Generation: 2003-2005 During the first 18 months QFT was implemented at 6 clinics (including TB clinic) QFT results were available to the TB program for 92% of persons tested Indeterminate results were uncommon (2%) Phlebotomy refusal/failure was uncommon A valid result was obtained for 99% of homeless clients (88% with TST prior to QFT implementation) IGRA implementation cost the health care system in San Francisco approximately $33.89 per patient tested – 83% of that by the lab Dewan et al. BMC Infectious Diseases 2006, 6:47

12. Is QFT feasible and acceptable?  Can QFT be used as a LTBI surveillance tool?  Is QFT programmatically more efficient than TST?  Does QFT behave as expected (more specific than TST)?  Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

13. QFT-TB n=4,574 QFT-G n=23,529 QFT Tests Performed By Month, November 2003 – December 2011 QFT-GIT n=34,806 20042005200620072008200920102011

14. QFT Results by Clinic Type March 2005 – December 2011 HomelessTB ClinicMethadone Immigrant/ Refugee HIVCommunityAll Positive Gold In-tube 734 (7) 629 (7) 942 (22) 2293 (23) 51 (3) 128 (5) 392 (14) 882 (23) 24 (3) 20 (5) 349 (10) 1340 (14) 2603 (11) 5292 (15) Negative Gold In-tube 8646 (89) 8033 (92) 3177 (73) 7186 (74) 1514 (93) 2129 (92) 2235 (80) 2920 (76) 800 (93) 359 (93) 3531 (84) 8249 (85) 19903 (85) 28876 (83) Indeterm. Gold In-tube 352 (4) 114 (1) 217 (5) 249 (3) 62 (4) 67 (3) 157 (6) 39 (1) 39 (5) 6 (2) 196 (5) 163 (2) 1023 (4) 638 (2) Total Tests Gold In-tube 9732 8776 4336 9728 1627 2324 2784 3841 863 385 4187 9752 23529 34806

15. Is QFT feasible and acceptable? Can QFT be used as a LTBI surveillance tool?  Is QFT programmatically more efficient than TST?  Does QFT behave as expected (more specific than TST)?  Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

16. TB Infection Prevalence By Test Version and Clinic Type HomelessTB ClinicMethadoneImmigrant TST (2001-2003) 26%>50%10%37% QFT-1 (11/03-2/05) 17%48%18%37% QFT-gold (3/05-2/09) 7%22%3%14% QFT-gold IT (1/08-12/11) 7%23%5%23% Decline in positive rate from TST 73%>54%50%38%

17. QFT and Contact Investigation March 2005 – December 2007 TSTQFT-G Contacts tested650641 Fully evaluated *361 (56%)410 (64%) Cases found5 (1%)8 (2%) Infection prevalence* 141 (39%)120 (29%) Initiation of LTBI * treatment 100/139 (72%)105/118 (89%) Completion of treatment among those who started 73/100 (73%)83/105 (79%) Completion of treatment among those infected * 73/139 (53%)83/118 (70%) J. Grinsdale, et al. IJTLD, 2011. *P<0.05

18. Role of QFT in Diagnosing Active TB Adding quantitative QFT-G results significantly improved clinical prediction model performance in reclassifying suspects as low, intermediate, and high risk of active disease Odds of active tuberculosis increased by 7% for each doubling of interferon-γ level Quantitative results did not significantly improve appropriate risk reclassification beyond that provided by SF clinician assessment of risk Not better than subjective clinical assessment but better than using objective risk criteria alone J. Metcalf et al, AJRCCM 2010

19. Is QFT feasible and acceptable? Can QFT be used as a LTBI surveillance tool? Is QFT programmatically more efficient than TST?  Does QFT behave as expected (more specific than TST)?  Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

20. QFT Results by Age Group and Test Version

21. Pediatric TST/QFT Discordance by Age and BCG or Foreign-born Status

22. CI Infection Rates by Exposure QFT-G*TSTQFT-G*TST Index Smear + 88/384 (23%) 113/439 (26%) 70/233 (30%) 92/164 (56%) Index Smear-/ Culture + 37/257 (14%) 47/211 (22%) 25/125 (20%) 42/88 (48%) QFT-G*TST*QFT-G*TST Household 82/267 (31%) 95/253 (38%) 76/207 (37%) 84/149 (56%) Non-household 43/374 (12%) 65/397 (16%) 19/150 (13%) 50/103 (49%) All Contacts Foreign-Born Contacts J. Grinsdale, et al. IJTLD, 2011. *P<0.05

23. Is QFT feasible and acceptable? Can QFT be used as a LTBI surveillance tool? Is QFT programmatically more efficient than TST? Does QFT behave as expected (more specific than TST)?  Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

24. Culture Confirmed TB: TST and QFT Sensitivity Test type Sensitivity(n=321)Concordance TST+83.6% (112/134)- QFT-G+73.3% (137/187)- QFT-G+ or TST+ 91.1% ( 92/101)69% Test type Sensitivity(n=383)ConcordanceTST+ 82.2% (134/163) - QFT-IT+ 76.4% (168/220) - QFT-IT+ or TST+ 91% (134/145) 68.3%

25. Is QFT feasible and acceptable? Can QFT be used as a LTBI surveillance tool? Is QFT programmatically more efficient than TST? Does QFT behave as expected (more specific than TST)? X Is QFT more sensitive in diagnosing active TB?  Does QFT correctly identify patients who will progress to disease? QFT Checklist

26. Pediatric QFT Screening Outcomes (Preliminary) 1,087 children followed for a median of 3.6 years (>4000 person-years of follow-up) No one developed active TB 979 untreated QFT-negative or indeterminate children 47 children <2 yrs 214 children ages 2-4 55 children <5 with TST+/QFT- results

27. Adult QFT Screening Outcomes (Preliminary) “Quick and Dirty” analysis suggests: QFT-positives Active TB develops “quickly” when LTBI is untreated, usually within 2 years Most were new arrivers or contacts QFT-negatives Active TB develops ”later” (>2-10 years) Most were contacts to multiple cases in large outbreaks where ongoing opportunities for infection couldn’t be ruled out - screened early in the investigation but not again after new cases were diagnosed

28. Is QFT feasible and acceptable? Can QFT be used as a LTBI surveillance tool? Is QFT programmatically more efficient than TST? Does QFT behave as expected (more specific than TST)? X Is QFT more sensitive in diagnosing active TB? Does QFT correctly identify patients who will progress to disease? QFT Checklist

29. QFT: The Test of Choice for San Francisco PERFORMANCE Single step to get results Higher specificity and reliability of results SURVEILLANCE Superior to TST Strengthen our partnership with the PHL CONTACT INVESTIGATION IGRA preferred by investigators Better evaluation and treatment outcomes Results correlate to intensity of exposure

30. TARGETED TESTING Screening BCG vaccinated populations Significantly decreased the number of referrals to the TB Clinic and LTBI treatment Made mandatory shelter clearance screening possible PEDIATRIC No cases missed Negative predictive value excellent at >24 months follow up Phlebotomy is more difficult but parents continue to want QFT results because of its higher specificity and avoidance of unnecessary treatment QFT: The Test of Choice for San Francisco

31. The Keys to Our Success… Targeted the patient and provider population who would most benefit from the test (e.g., Community clinics, refugees, shelter clients) Developed political will through education Partnerships with laboratory and providers Resource assessment and development Communication, communication, communication

32. Regarding QFT-G….. This has been the single biggest advance in delivering healthcare to people who are homeless in my 20 years of doing healthcare Barry Zevin San Francisco homeless healthcare provider May 5, 2008 Regarding QFT-G….. This has been the single biggest advance in delivering healthcare to people who are homeless in my 20 years of doing healthcare. Barry Zevin San Francisco homeless healthcare provider May 5, 2008

33. CDC Recommends New Blood Test for TB – Associated Press, 2005 "This is one of the first TB advancements made since the discovery of antibiotics. … This is a huge deal," said Jennifer Grinsdale, an epidemiologist with the San Francisco Department of Public Health. In San Francisco, QFT is a HUGE DEAL!