1. Bernard M. Branson, M.D. Associate Director for Laboratory Diagnostics Divisions of HIV/AIDS Prevention National Center for HIV, STD, and TB Prevention Centers for Disease Control and Prevention Clinical Experience with Approved Rapid HIV Tests FDA Blood Products Advisory Committee Meeting March 10, 2006

2. Outline Background: preliminary results and PPV Counseling message: Preliminary positive test Post-marketing surveillance: rapid HIV tests Rapid HIV test experience in urban programs Investigation of false-positive oral fluid tests The findings and conclusions in this presentation are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention

3. 1989 USPHS Recommendation “The Public Health Service recommends that no positive test results be given to clients/patients until a screening test has been repeatedly reactive on the same specimen and a supplemental, more specific test such as the Western blot has been used to validate those results.” - Interpretation and Use of the Western Blot Assay for Serodiagnosis of HIV-1 Infections. MMWR R&R 1989; 38(S-7)

5. SUDS Evaluation: STD Clinic Total Tests HIV Positive Received Results HIV negative HIV positive Returned Required outreach Conventional Protocol n (%) 1,160 29 (2.5) 337 (30) 23 (79) 13 (45) 10 (34) Rapid Protocol n (%) 1,493 32 (2.1) 1,361 (93) 31 (97) 30 (94) 1 (3) % Change 29 -16 210 23 109 -91

6. SUDS Evaluation: STD Clinic Total Tests HIV Positive Received Results HIV negative HIV positive Returned Required outreach Conventional Protocol n (%) 1,160 29 (2.5) 337 (30) 23 (79) 13 (45) 10 (34) Rapid Protocol n (%) 1,493 32 (2.1) 1,361 (93) 31 (97) 30 (94) 1 (3) % Change 29 -16 210 23 109 -91

7. What if rapid HIV tests were used in public testing sites? Source: CDC Client Record Database, 1995 HIV C/T sites STD Clinics Drug Treatment Family Planning Other testing sites Rapid test 1.9% 1.6% 2.9% 0.4% 2.1% HIV+ 82.1% 67.8% 73.6% 76.9% 73.2% 97.0% HIV- 84.3% 48.1% 70.8% 63.0% 64.6% 93.0% Return for Results Site Prevalence

8. Rapid Tests at All Public Sites Learn HIV+ Learn HIV- False + screen 36,082 2,074,454 8,301 27,912 1,385,129 + 8,170 (29%) +689,325 (50%) 8,301 Outcome Rapid Test Algorithm Current Algorithm Difference Total tests: 2,112,270 Prevalence: 1.6% - Update: HIV Counseling and Testing Using Rapid Tests— United States, 1995. MMWR 1998; 47:211-215.

9. 1998: PHS Recommendation Changed “Provide preliminary positive HIV test results before confirmatory results are available in situations where tested persons benefit.”

10. Positive Predictive Value of a Single Test Depends on Specificity & Varies with Prevalence Test Specificity HIV Prevalence Predictive Value, Positive Test 10% 99% 98% 92% 5% 98% 96% 85% 2% 95% 91% 69% 1% 91% 83% 53% 0.5% 83% 71%36% 0.3% 75%60% 25% 0.1% 50% 33% 10% OraQuickSingle EIAReveal 99.9%99.8%99.1% 97% 95% 87% 77% 63% 50% 25% Uni-Gold 99.7% (Calculated based on point-estimates in mfg package insert)

11. Negative Predictive Value of a Single Test Depends on Sensitivity & Varies with Prevalence Test Sensitivity HIV Prevalence Predictive Value, Negative Test 10% 99.96% 100% 99.98% 5% 99.98% 100% 99.99% 2% 99.99% 100% 1% 100% 0.5% 100% 0.3% 100% 0.1%100% OraQuickSingle EIAReveal 99.6%100%99.8% 100% Uni-Gold 100% (Calculated based on point-estimates in mfg package insert)

12. Qualitative Interpretation of Quantitative Probabilistic Expressions Based on positive predictive value: “Very likely” you are infected “Somewhat likely…” “Possible…” “There’s a chance…”

13. CDC’s Recommended Counseling Message “Your preliminary test result is positive, but we won’t know for sure if you are infected with HIV until we get the results from your confirmatory test. In the meantime, you should take precautions to avoid transmitting the virus.” -HIV Counseling with Rapid Tests. http://www.cdc.gov/hiv/pubs/rt-counseling.htm

14. Background Oraquick Rapid HIV-1 Antibody Test Approved for use with whole blood November 2002 CLIA-waived February 2003 Approved for use with oral fluid March 2004 Approved for HIV-2 detection and name changed to “OraQuick Advance” June 2004 CDC initiated post-marketing surveillance in 2003

15. Postmarketing Surveillance: Aug 2004-June 2005 Seropositivity Median % (range) Observed Specificity Median % (range) Whole blood (n=135,724) Oral fluid (n=26,066) 0.83 (0.08 - 2.60) 1.00 (0 - 4.02) 99.98 (99.73 - 100) 99.89 (99.44 -100) Median seropositivity and specificity for 17 project areas

16. Postmarketing Surveillance: Aug 2004-June 2005 Specificity and Positive Predictive Value Total Tests True Positive False Positive SpecificityPPV Chicago Whole blood Oral fluid 3,687 2,018 55 (1.5%) 15 (0.7%) 1212 99.97% 99.90% 98% 88% Indiana Whole blood Oral fluid 4,868 593 37 (0.8%) 1 (0.2%) 1111 99.98% 99.83% 97% 50% New York City Whole blood Oral fluid 13,673 8,248 199 (1.4%) 92 (1.1%) 7 11 99.95% 99.87% 97% 89%

17. Rapid Test Implementation: Chicago 1/1/05 – 12/31/05 14 Community-Based Partners Clinics, community centers, outreach, mobile units 4861 tests 78 (1.6%) confirmed positive 7 Chicago Dept of Public Health Clinics Clinics, special testing events, outreach, jail 3244 tests 52 (1.6%) confirmed positive

18. Rapid Test Implementation: Chicago Receipt of HIV-positive test results 64% in 2004 with conventional testing 94% in 2005 with rapid testing False-positives: 7 (0.056%) of 12,395 rapid tests in 2004-2005 Rapid testing now offered at all CDPH HIV/STD sites

19. Rapid Test Implementation: San Francisco January – September 2005 January – September 2005 Test # of Tests% of Tests Confirmed Positives Positivity Rate Rapid Oral574135%1372.4% Rapid Finger stick179611%452.5% Conventional903254%3113.4% ■ As of the third quarter in 2005, 46% of HIV tests were conducted using oral/fingerstick rapid tests. *Note that positivity rate is higher for conventional testing, but known positives are sometimes retested to screen for access into care.

20. Rapid Test Implementation: Los Angeles 1/1/05 – 2/9/06 # of Tests InvalidPrelim Positive Confirmed Positive False Positive Incon- clusive Pending Rapid9,9229137 * 131 (1.3%)3 (.03%)21 Conventional11,274182 (1.6%)1251 Total21,196 *Preliminary data. Data on confirmatory testing were not recorded for an additional 51 preliminary positive rapid tests that are being investigated

21. Rapid Test Implementation: Houston 1/1/05 – 11/04/05 %PTC %New (+) New (+) PTC Total Tests19,729 73.44%328 (1.7%)178 (54%) Conventional9,98450.61%48.70%262 (2.6%)112 (43%) Rapid9,74549.39%98.78%66 (0.7%)66 (100%) Note: - Conventional testing is performed in Houston Dept of Health clinics - Rapid testing is performed in community-based organizations

22. Investigation of False-Positive Oral Fluid Rapid Tests Press reports of false-positives: SF Clinics Getting High False-Positive Rate on Oral HIV Test - San Francisco Chronicle 12/10/05 False Positives from HIV Test - NY Times 12/11/05 Facility Halts Use of Oral HIV Test – LA Times 12/16/05 More Sites Drop Oral HIV Test - LA Times 12/20/05

23. Sources of Data 4 prospective studies with parallel testing of whole blood & oral fluid OraQuick, EIA, & Western blot, 2000 - 05 Outlier analysis, 41 sites in 3 states Sept –Nov 05 Recent testing data, NY City STD clinics, Dec 05 – Jan 06

24. Combined Results: 4 Prospective Studies Reference Negative False Positive Specificity OraQuick Whole blood 12,0101299.9% OraQuick Oral Fluid 12,0105499.6% Serum EIA12,0103599.7%

25. Individual Study Results Reference Negative False Positive Specificity (95% CI) Los Angeles5,327 Whole blood499.9% (99.8-100.0) Oral fluid2199.6% (99.4-99.8 ) EIA2399.6% (99.4-99.7 ) MIRIAD2,278 Whole blood299.9% (99.8-100.0) Oral fluid599.6% (99.4-99.8 ) EIA799.6% (99.4-99.7 )

26. Individual Study Results Reference Negative False Positive Specificity (95% CI) Phoenix2,000 Whole blood399.9% (99.6-100.0) Oral fluid599.8% (99.4-99.9) EIA0100% (99.9-100.0) Minnesota2,405 Whole blood299.9% (99.6-100.0) Oral fluid2399.0% (98.6-99.4) EIA599.8% (99.5-99.9)

27. Minnesota Cluster, Oral Fluid False Positives - 2004 March 2002 – March 2004: –7 false positives, 2017 tests (Specificity 99.7%) April 2004 – August 2004: –16 false positives, 407 tests (Specificity 96.1%) Follow-up study, Feb-May 2005, 9 sites in 3 states: –0 false positives, 2,314 tests (Specificity 100%) –Case-control study could not proceed

28. Outlier Analysis, 41 Sites in 3 Jurisdictions: False-positive Oral Fluid tests, Sept-Nov 2005 New York CityNew JerseySan Francisco

29. New York City: Sept – Nov 2005 NYC - 3 sites with excess FPNYC -7 sites without excess FP # tests# false posSpecificity# tests# false posSpecificity Sept1662499.8%2316299.9% Oct17621099.4%2279199.9% Nov15813298.0%2164399.9%

30. San Francisco: Sept – Nov 2005 SF - 1 site with excess FPSF -11 sites without excess FP # tests# false posSpecificity# tests# false posSpecificity Sept232896.5%472199.8% Oct262996.5%587399.5% Nov160696.3%551599.1%

31. New York City STD Clinics Month# False Positive# of TestsSpecificity August5378699.87 September6397899.85 October11404399.73 November35375499.07 12/6-21/05 Fingerstick testing only 12/22/05 – 1/17/06 31480799.35

32. Counseling Message: Both rapid tests we ran today were preliminary positive. It is likely that you have HIV. To make absolutely sure, we are going to draw blood and send it to our lab so they can run confirmatory testing. The results of those tests will be ready in 1 week. In the meantime, you should assume that you are infected with HIV, and take all necessary precautions to protect your partners. OraQuick Advance Reactive with oral fluid Conduct OraQuick Advance Fingerstick Fingerstick Negative Fingerstick Reactive Counseling Message: Although the oral rapid test we ran today was preliminary positive, the fingerstick test was negative. Because the fingerstick test is a more accurate test, it’s likely that you don’t have HIV. In order to know for sure, we need to draw blood and send it to our lab for confirmation. The results of those tests will be ready in 1 week. In the meantime, you should assume that you may be infected with HIV, and take all necessary precautions to protect your partners. Lab runs EIA, IFA/WB Interim Algorithm, NYC & San Francisco: Finger-stick after Reactive Oral Fluid Test

33. Positive Oral Fluid Tests with Reflex to Finger-stick, New York City STD Clinics Oral FluidFinger-StickWestern blot 69 reactive32 reactive31 positive 1 pending 6 refused6 positive 31 negative29 negative 2 indeterminate December 22, 2005 – January 27, 2006

34. Conclusions Rapid HIV tests demonstrate high specificity, but as with all screening tests, false-positive tests will occur and should be expected. Confirmatory testing after a reactive test must always be performed. More persons learn their HIV status when they receive timely results from rapid tests than with conventional HIV testing. OraQuick specificity is slightly lower with oral fluid than with whole blood, but well above FDA’s minimum threshold (98%) with both specimen types. Excess false-positive oral fluid tests occurred at a limited number of sites and appear to be related to unidentified site- or host-specific factors.

35. Acknowledgements Susan Banks (NYC) Bob Bolan (LA) Evan Cadoff (NJ) Jim Dilley (SF) Stephen Dziuban Shelley Facente (SF) Gloria Ferko (OTI) Ann Gardner (AZ) Keith Kardos (OTI) Peter Kerndt (LA) Kathleen Krchnavek (WI) Patrick Keenan (MN) Krishna Jafa (CDC) Sindy Paul (NJ) Steve Rubin (NYC) Ellen Rudy (LA) Tracey Sides (MN) Patrick Sullivan (CDC) Apurva Uniyal (LA) Laura Wesolowski (CDC)