VITROS® HIV-1/2 Assay

VITROS® HIV-1/2 Assay

Development of an Anti-HIV 1+2 Assay for use on a Random Access System B Boyer, S Edwards, JM Glover: Ortho-Clinical Diagnostics, Rochester NY This assay is currently pending FDA approval. This is not a solicitation for sale but a scientific exchange of information for study. 1 Development of an Anti-HIV 1+2 Assay for use on a Random Access System Description of the test/protocol Clinical Performance Result Algorithm Intellicheck Summary/Conclusion 2 The Vitros Anti-HIV 1+2 Assay* Test for the in vitro qualitative detection of antibodies to Human Immunodeficiency Virus types 1 and/or 2 (antiHIV 1 and antiHIV 2) in human serum and plasma (heparin, EDTA or citrate) using the VITROS ECi/ECiQ Immunodiagnostic System. * Pending FDA approval 3 Architecture HIV 1 Env 13 - gp 120 and gp 41 region. HIV-1 Env 10 - gp41 region which extends beyond the Cterminus of Env 13. HIV-1 p24 - full length core protein of HIV-1. 4 HIV-2 Env AL - contains a region from gp 36 of HIV-2.

Protocol 80 l sample 20 l assay reagent Incubate 29 minutes 20 seconds at 37C Wash 100 l conjugate reagent Incubate 8 minutes at 37C Wash 200 l signal reagent Read Assay Type Immunometric assay Assay Time and Temperature Incubation time: 37 minutes Time to first result: 48 minutes Temperature: 37 C 5 Calibration and QC A single calibrator is run in duplicate once every 28 days 3 QC controls are available. Negative, HIV 1, HIV 2 Recommendation is that these controls are run in singleton: once every 24 hours of testing after calibration after certain service events 6 Performance: US Clinical Trials High Risk Populations Population Positive Percent Agreement Negative Percent

Agreement High Risk (U.S.) 100% (54/54) 99.81% (2117/2121) High Risk (Ivory Coast) 100% (26/26) 98.92% (457/462) HIV Positive (U.S.) 100% (1121/1121) HIV Positive (International) 99.48% (193/194) HIV-2 Positive (Ivory Coast) 100% (208/208) Pregnant (High RiskU.S.) 100% (5/5) 99.59% (243/244)

7 Performance: US Clinical Trials (continued) Low Risk Populations Population Pregnant (Low RiskU.S.) Positive Percent Agreement Negative Percent Agreement 100% (1/1) 100% (296/296) Labor and Delivery (Low RiskU.S.) Insurance Applicants (Low RiskU.S.) 97.96% (48/49) 100% (5/5) Pediatric (Low RiskU.S.) Pediatric HIV Positive (U.S.) Total (High and low risk populations) 99.80% (992/994) 100% (99/99) 100%

(40/40) 99.94% (1653/1654) 99.70% (4252/4265)8 3274 500 450 926 Performance: US Clinical Trials (continued) HIV Ab Positive Number of samples 400 HIV Ab Negative 350 Borderline Range 300 250 200 150 100 50 0 0 2 0. 4 0.

6 0. 8 0. 1 3 5 7 9 Result (Sample/Cut-off) 20 40 60 80 9 0 0 1 Performance: Seroconversion 20 Seroconversion panels tested with a licensed assay and the Vitros Assay*. 14 panels converted at the same sample. 6 panels showed differential conversion between assays. Days to Evidence of HIV Infection Panel ID Licensed Assay Vitros Assay* Difference days to HIV

reactivity: Licensed assay minus Vitros Assay* - + - + PRB927 0 28 28 33 -5 PRB929 21 25 18 21 4 PRB934 0 7 0 0

7 PRB940 7 11 0 7 4 PRB952 14 17 10 14 3 10 * Pending FDA approval HIV 1 Genotype Detection Mean Result Genotype (s/c) n Result Range (s/c) A 64.2 3

55.3 to 82.6 B 80.7 3 74.1 to 86.7 C 72.3 2 55.2 to 89.4 D 64.4 4 59.2 to 73.0 E 75.6 2 72.7 to 78.4 F 79.6 1 79.6 G

66.7 4 56.4 to 85.3 O 15.3 14 2.73 to 36.6 100% Sensitivity with all genotypes tested including O 11 Performance: Precision Clinical Site Site 1 Site 2 Site 3 Mean VITROS Anti-HIV 12 Assay Results (s/c) 0.07 6.06 4.12 1.32 0.08 6.66 4.39 1.39 0.07 6.22 4.42 1.34

Negative HIV-1 HIV-2 HIV-1 Negative HIV-1 HIV-2 HIV-1 Negative HIV-1 HIV-2 HIV-1 Repeatability* S.D. C.V.(%) 0.007 9.9 0.071 1.2 0.046 1.1 0.023 1.8 0.006 7.6 0.169 2.5 0.060 1.4 0.045 3.2 0.003 4.4 0.085 1.4 0.033 0.7 0.028 2.1 Between Day** S.D. C.V.(%) 0.005

6.9 0.172 2.8 0.163 3.9 0.046 3.5 0.003 4.3 0.163 2.5 0.100 2.3 0.035 2.5 0.004 5.6 0.131 2.1 0.158 3.6 0.034 2.5 Total*** S.D. C.V.(%) 0.008 12.1 0.186 3.1 0.169 4.1 0.052 4.0 0.007 8.7 0.235 3.5 0.117 2.7 0.057 4.1 0.005 7.1

0.156 2.5 0.162 3.7 0.044 3.3 No. of Obs. No. of Days 40 40 40 40 40 40 40 40 40 40 40 40 20 20 20 20 20 20 20 20 20 20 20 20 * Repeatability: Variability of the assay performance from replicate to replicate. ** Between Day: Variability of the assay performance from day to day. *** Total: Variability of the assay combining the effects of repeatability and between day. Within occasion CV = 1.9%

Day to day CV = 2.9% Total CV = 3.5% 12 Result Algorithm An initial singleton result of <0.90 s/c indicates a nonreactive Sample that is Negative for Anti-HIV 1+2 An initial result of >/= 0.90 and < 1.00 s/c (Retest?) indicates a sample that requires duplicate repeat testing for Anti-HIV 1+2 Retest in Duplicate If 2 of 3 results < 1.00 S/C, the Sample is Negative for Anti- HIV 1+2 No further testing required. Negative An initial singleton result of >/= 1.00 s/c indicates a sample that is Reactive for Anti-HIV 1+2 If 2 of 3 results >/= 1.00 S/C, the Sample is Reactive for Anti- HIV 1+2 No repeat testing required: Perform Supplemental Testing as Appropriate 13 Mistake proofing diagnostic systems

Integrated Process Control Series of technologies that perform, monitor, verify and document diagnostic checks throughout sample and assay processing and reporting results Sample and Result Integrity Verification Traceability with real-time operator notifications and documentation for exceptions 14 Intellicheck Example: Sample Integrity Verification Patented Pressure Level-Sensing Technology Bubble, Clot, Viscosity, Short Sample, Thin Layer Fluid detection Positive pressure detects Negative pressure aspirates Pressure profile detects anomalies Normal Aspiration Abnormal Aspirate bubble detected 15 Summary Parameter Clinical Performance Performance Positive Percent Agreement 99.94% (1653/1654) Negative Percent Agreement 99.70% (4252/4265) Excellent separation of positive and negative populations

Precision Total precision of 3.5% in PMA studies Genotypes All genotypes detected Seroconversion Early detection of seroconversions Sample type Validated for serum and plasma with normal, high risk and pediatric populations. Resolution Algorithm Singleton testing for both negative and positive samples. Repeat testing only for borderline samples. Calibration and controls Calibration only required once every 28 days Controls run once every 24 hours of testing System Control of a random access system with the security of Intellicheck 16

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