1. QuantiFERON-TB Gold ® : Practical Applications L. Masae Kawamura M.D. Director, San Francisco TB Control Section, Department of Public Health Francis J. Curry National TB Center

2. Diagnosis of tuberculosis infection TB Skin Test (TST) QuantiFERON Blood Test (QFT) “.. the greatest needs in the United States are new diagnostic tools for the more accurate identification of individuals who are truly infected and who are also at risk of developing tuberculosis” US Institute of Medicine Report,“Ending Neglect”; 2000

3. Problems with TST… Poor inter-reader reliability 9 mm (negative) vs. 10mm (positive)? False-positives/specificity  NTM infection  Prior BCG Poor positive-predictive value in low prevalence populations (like US) Cost/time of patient visits  Unread tests Sensitivity?  Reaction wanes over time  Lack of gold standard

4. Program Implications of a More Specific Blood-Based TB Test ↓Societal costs and  public safety: Elimination of unnecessary CXRs, evaluation and treatment  Program efficiency: More results means targeting efforts on “positives” instead of on retesting individuals who fail to show up for TST readings (homeless, jails, employee testing)  Public confidence : Reliable and specific results New surveillance capabilities: laboratory-based targeted testing

5. SF QFT Guidelines/Philosophy QFT: Acceptable alternative to TST in all patients In contacts, use in same fashion as TST —Follow-up test needed at 8-12 weeks TB Suspects: Use QFT in conjunction with TST to maximize diagnostic yield in suspects and highest risk patients (especially immunocompromised patients and contacts under age 5) Don’t “confirm” TST unless it will change patient management

6. Programmatic use of QFT-G in San Francisco Targeted testing —Homeless and IDUs (high rates of TB, HIV and ongoing transmission) Rationale: poor TST return rates -New immigrants and refugees (high infection prevalence) Rationale: BCG-induced, false positive TSTs Contact investigation Prioritizing TB suspects for outreach Surveillance: Homeless shelters, Newcomers

7. Current implementation Limited use: 15 sites — public health clinics and community clinics targeting newcomers, homeless and IDUs (methadone clinics) Non-health department requests: must be approved by “gate keeper” Planned expansion: 2006-2007 Access to all HD providers when automation is available Unresolved: private provider demand for QFT

8. QFT-TB n=4574 QFT-G n=6124

9. TB testing by Quantiferon-TB Gold by clinic type San Francisco, Mar. 2005 – Feb. 2006 Result Homeless n=3594 (%) TB Clinic n=693 (%) Methadone n=546 (%) Immigrant n= 626 (%) HIV n=154 (%) Positive221 (6)182 (26)21 (4)72 (12)4 (3) Negative3168 (88)463 (66)494 (90)490 (78)142 (92) Indetermin.118 (3)32 (5)26 (5)58 (9)5 (3) Not Tested87 (2)16 (2)5 (1)6 (1)3 (2) *2 clinic types not listed: refugee clinic (n=147) & community clinics (n=399)

10. QFT-G Test Results by Age Category March 2005 – February 2006 (3) (1) (6) (7) (12) (31)

11. TB Infection Prevalence by Test and Clinic Type HomelessTB ClinicMethadoneImmigrant TST (2001-2003) 26%>50%10%37% QFT-1 (11/04- 2/05) 17 % n=1848 48 % n=292 18 % n=346 37 % n=344 QFT-Gold (3/05-2/06) Decline in positive rate from TST 6 % n=3594 77% 26 % N=693 48% 4 % n=546 60% 12 % n=626 66%

12. Preliminary HIV results from SF AIDS Clinic 3/1/06 and 5/31/06 Why they were anxious to switch: TST return rate <50% # samples submitted: 44 Results:93% Results w/o indeterminates:86% Indeterminate: 3 (7%) Not Tested: 3 (7%) Positive: 1 (2%) Negative: 37 (84%)

13. Wisconsin Shelter TST Results January 2004 – March 2005 268 TSTs were given –152 people returned (56%) –14 were positive (9%) Data provided by the Wisconsin Division of Public Health

14. QFT shift: Wisconsin Shelter testing April – December 2005 306 QFT-TB Gold (95% initial results) –31 positives (10%) 5 people previously documented negative TST 4 people known TST positives 12 people previously in other shelters within one year –259 negative (85%) 17 people previously documented positive TST –17 indeterminate (5%) 7 people retested — 1 positive Multiple medical and immunity problems Data provided by the Wisconsin Division of Public Health

15. QFT and Contact Investigation Expect maximum benefit: Populations with poor return rates (homeless and hotel dwellers) F.B. with high background prevalence of LTBI and BCG vaccination Example: SF low-cost hotel drug-resistance investigation Prior QFT results easy to track down in database 9/31 converters found! (6 QFT conversions and 1 case found) 4 negative TSTs → positive QFT 2 negative QFTs → positive QFT 3 negative TSTs → positive TST Example: XDR investigation involving F.B. contacts (88% FB, ½ with prior +TST) 1 out of 25 contacts with positive QFT (Is QFT weeding out remote infection?)…..stay tuned!

16. Don’t use QFT-G to “rule out” TB! TB Suspects: 37/242 had culture-confirmed tuberculosis (3/2/05-12/31/05) QFT-G sensitivity: 64% (TST sensitivity = 88%) Very poor performance in extrapulmonary TB (14% sensitivity 1/7 cases) Conclusion: low sensitivity and poor correlation to published studies Note: No cases were missed due to a negative QFT result

17. TST is not perfect either … 282 B notifications reported 3/1/05 to 4/3/06 217 with either QFT-G or TST QFT-G – 84/164 positive = 51.8% positive rate 73 B1 - 40 positive = 55.8% 91 B2 - 45 positive = 49.5% TST - 38/53 positive = 71.6% positive rate 32 B1 - 21 positive = 65.6% 21 B2 - 17 positive = 81.0% 11 cases identified with either QFT or TST QFT- /TST + : 2 cases potentially missed by QFT QFT+ /TST - : 2 cases potentially missed by TST

18. Estimated Costs in High Usage Setting Commercial Kit QFT-G In-tube QFT-G In-tube T-SPOT Assay typeELISA ELISPOT Lab Automation partial FullPartial TOTAL ($)29.2226.7425.0957.79 Costs include facility space, equipment, consumables and staff time TST cost estimated (Medicare) $12-14 per patient tested

19. Remaining issues… Interpretation of discordant TST and QFT results Management of indeterminate results QFT-G thresholds set for higher specificity… has it sacrificed too much sensitivity? Serial testing: no long-term data on conversions, reversions, management of changing results and evidence-based thresholds for conversion Unknown dynamics of T-cell responses during and after treatment for LTBI and active treatment

20. Is the TST still useful? Of course! When there is no phlebotomy expertise or patient is a “difficult stick “ E.g., very young children and some IDUs When TB screening opportunities are limited (e.g., contact investigation, jail screening) Until 12-hour laboratory submission time eliminated or access to blood-based testing becomes widespread and 24/7, PPD may be more practical When maximizing sensitivity in suspects, immunocompromised, and young children

21. Conclusions QFT-G is highly specific!!! It will result in a significantly lower number of positive results compared to QFT-TB and TST While this is disconcerting, there is no evidence to date that cases are being missed Long-term studies are needed to study discordants, QFT-G negative contacts and high-risk children Blood-based TB testing is a superior surveillance tool with more believable results Training lab personnel is much easier than the training countless providers of a whole city QFT-G is most useful in nonadherent and BCG- vaccinated populations NEVER USE A QFT TO RULE OUT DISEASE… it’s a tool, not a panacea!

22. QFT-Gold: Clinical Applications The distraught mother…. Feisty 4 year-old Chinese adoptee with history of 2 BCGs and 12mm TST result. QFT-1: conditionally positive QFT-Gold: negative The BCG-vaccinated baby… MDR newborn contact to smear+ mother. BCG given X2. TST at 4 months negative Results at 6 months QFT-1: conditionally positive QFT-Gold: negative

23. QFT-Gold: Clinical Applications The nonbeliever: “I’m TST positive because of BCG!” French-born HIV researcher with documented BCG X3 returns from a 10-day trip in Africa (worked in HIV clinic). Refuses LTBI treatment. -PPD 20mm -QFT-Gold positive Other potential uses: Solving disputes -Waxing and waning TST results in serial testing -Funny-looking TST results -“Well, it might be swollen and it sure is red!” -Referred patient: “I think they read my skin test wrong.”

24. Acknowledgments: Puneet Dewan, M.D., SF TB Control staff, SFDPH laboratory (Sally Liska, Ernest Wong), SF community clinics Tanya Oemig RM(NRM) TB Program Director Wisconsin Division of Public Health