Validation of A Proposed Testing Strategy using FDA-approved Rapid Tests

1. Validation of A Proposed Testing Strategy using FDA-approved Rapid Tests Eugene Martin, Ph.D. APHA 2008 Annual Meeting San Diego, CA October 25-29, 2008

2. Rapid-rapid VerificationPrograms • Factors to consider: • How is your program organized? • Is it centrally organized or groups of independent labs? • How much confidence do you have in each labs ability to handle multiple assays? • How much experience do your laboratories have in figuring out ‘discordant results’? • What will happen if there is a problem? • How prevalent is HIV where you are testing? As prevalence DECREASES…False Positives results REMAIN constant while true positives decrease. Are you prepared to deal with discordant results?

3. NJ Rapid HIV Testing • One of the largest, most centralized rapid HIV testing programs in the country: • County health departments • Sexually transmitted disease clinics, • Family planning programs, • Federally qualified healthcare centers, • TB clinics, • Prisons, • Hospital-based programs – 13 ERs (8 counties), • Prenatal clinics, and • Outreach through mobile vans.

4. New Jersey ‘sRapid HIV Sites • Rapid HIV Testing in NJ • Testing Began 2003 • 23 primary sites • 32 satellite licenses • Western Blot confirmation at state lab (PHEL) in Trenton • Over 70 CTS sites, including: • Hospitals/EDs • FQHCs • CBOs • Health departments • Mobile vans • Prisons

5. Why a Centralized Program? STEPS • Specialized skills are centralized • Testing and processes are organized • Expenses are optimized • Problems are identified more quickly • Solutions are distributed to all: • http://www.njhiv1.org

6. Problem Preliminary Positive clients fail to return for results (25.2%) NAP succeeds ONLY 20% of the time in locating these clients Solution Confirmatory testing on-site, same day Why Move to Rapid Confirmation?

7. Validationof a Testing Algorithm • “Validation is the process of demonstrating • that an analytical procedure is suitable for • its intended use” – CBER • The use of other rapid tests to confirm a rapid HIV test is not new or novel - WHO recommends this approach for countries in which the prevalence of HIV exceeds 10% for a number of years • What is new and novel is using this approach in sites with 2% or lower prevalence Can a second rapid HIV test confirm preliminary positives as effectively as a Western Blot?

8. NEED TO DO Demonstrate Sensitivity Identify True Positives Not Identify False Positives Demonstrate Reproducibility Demonstrate Robustness - remain unaffected by small, but deliberate, variations in method parameters DATA Sensitivity & Specificity: Manufacturer’s Claims CDC Post Marketing Survey Follow-up Investigations: Existing confirmations Alternative testing What does any rapid test algorithm need to do?

9. Questions for a Rapid Testing Algorithm (RTA): • Are there false negative screening tests? i.e Screening test says NEG, but the client is infected. • Can a positive client result be confirmed by a second rapid test? • Can false positive screening tests be detected by running a second rapid test… or a third? What is the advantage? Disadvantage? • How can inconclusive “second-round” test results (eg, WB vs a second rapid test) be resolved? • What is the impact on the linkage to care?

10. NJ - A Two-Test Algorithm HIV-1/2 Rapid HIV Test (Blood) STAT-Pak Or HIV-1/2 Rapid HIV Test (Oral) Oraquick

11. Unique Characteristics • Area:New Jersey: 7,836 sq. mi> Los Angeles: 469.1 sq mi> San Francisco: 47 sq. miles • Population:Greater LA (2007) ~17.78 million > NJ 8.69 million > San Francisco ~ 4.18 million • Scale:Drive End to End in NJ 3 hrs. (WE 1 ½ hours) • A mixture of urban/suburban and rural communities • North – urban • South – rural • Many different venues perform rapid testing

12. Validation of the NJ algorithm • Three Data Sets: • 2004 • January, 2006 – October, 2007 • 2008

13. 2004 Ability of a Rapid to Confirm a Rapid • ALL confirmatory specimens sent to NJ PHEL during 8 month period: • Re-ran the PHEL specimen using Oraquick again • Re-ran the specimen with other rapid tests • Confirmed negative result by repeat Western blot and Viral Load

14. Rapid confirmation trial • __ ____ _____ _________ • ______ ________ _______ __ _____ ___ ___ ____________ _______ • ______ ___ ________ • ______ ___ ________ • 15,923 OraQuick tests statewide • 363 prelim positive samples to state lab for confirmatory testing • 355 Western Blot positive • 8 Western Blot negative • July 1, 2004 through April 19, 2005

15. 2004 NJ Data

16. Rapid confirmation trial 2004-5 Rapid Testing Evaluation • All testing in 2004 involved fingerstick rapid Oraquick HIV tests • All 8 Western Blot negative clients: • Negative on follow-up at least 4 weeks later, by both antibody and nucleic acid testing • 4 of 7 tested reacted with non-viral components of OraQuick device • ALL were true Oraquick false positives

17. 2004 TAKE HOME MESSAGES: • A CLIA-waived rapid test matched Western Blot confirmatory results in 100% of the HIV + cases. • Every false positive was identified by a proposed rapid confirmation algorithm between 2004-2006! • Potential consequences using rapid-rapid confirmation: • Eliminate the non-returners • Effective sensitivity would approach 99-100% • Counseling, contact elicitation and referral for treatment could be Done Immediately • In NJ, at least 200 additional HIV + individuals would definitively know their status!!

18. Ability of a Rapid HIV Test to Confirm a Rapid HIV Result January 2006- October 2007 NJ Data Set

19. Jan 2006 – Oct 2007 data BACKGROUND • Oral HIV testing had become the predominant means of rapid HIV testing in New Jersey. • The rate of discordant results had increased with oral testing METHODS • We used retained specimens from follow-up testing of clients that were Rapid Test (+), but Western Blot (-) • Testing done on serum • Confirmed discordants and indeterminates (if they had follow-up). • DID NOT confirm true positives from this data set. • Samples were not from the same time as the screening OraQuick. • Used CLIA-waived tests ONLY: • Repeated OraQuick on blood • Trinity Uni-Gold • Clearview StatPak

20. Follow the data! • NJ Rapid HIV Testing 20056 • Oral Testing Introduced  More False Positive Confirmations Total Rapid HIV Testing Fingerstick Oral Testing

21. Follow-up Information • All follow-ups on negative Western Blot specimens were also NAAT negative (i.e.True OraQuick false positive). • All were "second rapid" negative. • Oral Discordants • OraQuick followed by Blood OraQuick: • 3 tested at CTS site on False Positives: • 2 blood negative; 1 blood positive • 56 tested on follow-up blood specimen • all were blood negative • SUMMARY: 58 specimens were truly negative; 1 specimen was positive • Blood Discordants • 11 tested on follow-up blood specimen • 7 negative • 4 repeat positive

22. Observations • Indeterminate Western Blot: • 12 total: • 4 no follow-up; 3 QNS • 3 NAAT negative were "second rapid" negative • 2 NAAT positive were "second rapid" positive

23. 2008 Data • Randomly sampled serum specimens sent to NJ PHEL some for confirmatory testing; some for standard testing. We didn’t know their identity • Ran: • Oraquick • UniGold • StatPak • Discordant – 2 of the 3 rapids agreed – one did not • UniGold twice • Oraquick three times

24. Potential Issues: Falsely negative 2nd rapid Frequency 1:180 • Falsely positive 2nd rapid • None using Trinity Unigold as the 2nd rapid • Three using StatPak as the 2nd rapid

25. Conclusions: • A second, different rapid HIV test can confirm a preliminary rapid resultas reliably as a Western Blot. • 98% of time the conclusion will be correct • 25% of individuals who would never have received their final result will now!! • New Jersey will implement rapid-rapid verification and immediate linkage to care • Following meetings with Department of Health it was decided to implement rapid-rapid verification statewide

27. Implementation • PLAN: • 3 pilot sites have been identified to begin the ‘roll-out’ • 1 site is up, trained and running. The other 2 - within the month • Policies, Procedures, Counseling Messages and Forms are completed for the entire system • EXPECTATIONS: • It will not eliminate Western blotconfirmation, BUT it will provide the basis for immediate linkage to care! • Less than 1 in 100 will be later removed from care because of a failure to confirm • UNKNOWNS: What will be the real world performance of a rapid test in a confirmatory setting? • Does reducing the delay really improve the linkage to care? • Does post-testing counseling impact positively on prevention messages?

28. Thanks To: RWJMS • Evan Cadoff, MD • Eugene Martin, Ph.D. • Gratian Salaru, MD • Sharon Holswade, MBA • Franchesca Jackson, BS • Nisha Intwala, MT • Claudia Carron, RN • Lisa May • Karen Williams • NJDHSS/DHAS • Sindy Paul, MD, MPH* • Linda Berezny, RN • Maureen Wolski, BS • Aye Maung Maung • NJDHSS/PHEL • Kenneth Earley • Kanjana Garcia • Bruce Wolf, Ph.D. Site coordinators and counselors throughout New Jersey

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