E0304206A 1 Supplemental Testing for HIV-1 and HCV Blood Products Advisory Committee Meeting September 18, 2003 Susan L. Stramer, Ph.D. National Testing

E0304206A 1

Supplemental Testing for Supplemental Testing for HIV-1 and HCVHIV-1 and HCV

Blood Products Advisory Committee MeetingBlood Products Advisory Committee Meeting

September 18, 2003September 18, 2003

Susan L. Stramer, Ph.D.Susan L. Stramer, Ph.D.National Testing andNational Testing and

Reference LaboratoriesReference LaboratoriesAmerican Red CrossAmerican Red Cross

Jaye P. BrodskyJaye P. Brodsky

Quality AnalyticsQuality Analytics

E0304206A 2

BackgroundBackground HIV-1 and HCV algorithms utilize immunoassays for HIV-1 and HCV algorithms utilize immunoassays for

confirmationconfirmation– HIV-1 uses Western Blot (WB) containing electrophoresed whole HIV-1 uses Western Blot (WB) containing electrophoresed whole

HIV lysateHIV lysate

– HCV uses Recombinant Immunoblot Assay (RIBA) containing HCV uses Recombinant Immunoblot Assay (RIBA) containing painted recombinant HCV antigenspainted recombinant HCV antigens

Issues with supplemental assaysIssues with supplemental assays– Poor performancePoor performance

• Unreadable or invalidUnreadable or invalid

• False positivity; false negativityFalse positivity; false negativity

• High rates of indeterminate results (neither pos or neg) in High rates of indeterminate results (neither pos or neg) in healthy individualshealthy individuals

E0304206A 3

BackgroundBackground

Issues with supplemental assaysIssues with supplemental assays– High costsHigh costs– Inconsistent availability (HIV)Inconsistent availability (HIV)– Is all the testing necessary, or is redundant Is all the testing necessary, or is redundant

testing being performed?testing being performed?

Can alternatives be validated?Can alternatives be validated?

E0304206A 4

Alternative AlgorithmsAlternative Algorithms HCV Alternative – 1HCV Alternative – 1

– Use of HCV NAT in supplemental algorithms Use of HCV NAT in supplemental algorithms

• Already being performed as a screening test for all donationsAlready being performed as a screening test for all donations

• NAT results integrated into donor counselingNAT results integrated into donor counseling

• Sensitivity high relative to RIBA even though NAT Sensitivity high relative to RIBA even though NAT is performed in pools (16-24)is performed in pools (16-24)

• Specificity high (false-positive donor rates less than 1:40,000)Specificity high (false-positive donor rates less than 1:40,000)

• Already recommended for diagnostic use by CDCAlready recommended for diagnostic use by CDC

– If NAT reactive, RIBA not neededIf NAT reactive, RIBA not needed

HCV Alternative – 2 HCV Alternative – 2 – Use of S/CO to further reduce the need for RIBA in HCV NAT Use of S/CO to further reduce the need for RIBA in HCV NAT

nonreactive individualsnonreactive individuals

E0304206A 5

Alternative AlgorithmsAlternative Algorithms HIV Alternative – 1 HIV Alternative – 1

– Use of NAT and/or S/CO as proposed for HCVUse of NAT and/or S/CO as proposed for HCV

HIV Alternative – 2HIV Alternative – 2

– Use of a second EIA where discordant EIA reactives Use of a second EIA where discordant EIA reactives (EIA-1 Rx and EIA-2 nonRx) are not further tested(EIA-1 Rx and EIA-2 nonRx) are not further tested

– Feasibility for HIV versus HCV Feasibility for HIV versus HCV • Anti-HCV licensed screening assays use same recombinant Anti-HCV licensed screening assays use same recombinant

antigens, same assay format; overlapping populations of antigens, same assay format; overlapping populations of false positivesfalse positives

• Anti-HIV licensed screening assays use different antigens (viral Anti-HIV licensed screening assays use different antigens (viral lysate, recombinants and peptides); populations of lysate, recombinants and peptides); populations of false positives are uniquefalse positives are unique

E0304206A 6

Alternative AlgorithmsAlternative Algorithms

Issues for HIV or HCV alternativesIssues for HIV or HCV alternatives– Potential misclassification of donorsPotential misclassification of donors

• Current algorithms containing RIBA or WB in combination with Current algorithms containing RIBA or WB in combination with NAT (and screening S/CO value) provide specific counseling NAT (and screening S/CO value) provide specific counseling messagesmessages

– Kits will require labeling for intended use (supplemental claims to Kits will require labeling for intended use (supplemental claims to NAT assays or EIAs)NAT assays or EIAs)

• 21 CFR 610.40 Subpart E 21 CFR 610.40 Subpart E

– ““You must further test each donation, including autologous You must further test each donation, including autologous donations, found to be reactive by a screening test …whenever a donations, found to be reactive by a screening test …whenever a supplemental (additional, most specific) test has been approved supplemental (additional, most specific) test has been approved for such use by FDA….”for such use by FDA….”

E0304206A 7

Current: HCV EIA 2.0 (Abbott) Current: HCV EIA 2.0 (Abbott) or 3.0 (Ortho) Repeat Reactiveor 3.0 (Ortho) Repeat Reactive

Perform RIBA 3.0 SIAPerform RIBA 3.0 SIAN = 34,656N = 34,656

IndIndPosPos

ReactiveReactiveIndividuallyIndividually

NegNeg

NonRxNonRxin Pool orin Pool or

IndividuallyIndividually







HCVHCVInfectedInfected

HCV Infected?HCV Infected?Resolved infection (≈20%)Resolved infection (≈20%)

Viral load < NAT cutoffViral load < NAT cutoffFalse Pos RIBAFalse Pos RIBA38%38%

13,19813,198

HCV NotHCV NotInfectedInfected

HCV Infected?HCV Infected?Early seroconversionEarly seroconversion

False Rx NATFalse Rx NAT

HCV Infected?HCV Infected?

17.2%17.2%

5,9675,967

0.15%0.15%

5050

34.5%34.5%

11,96311,963HCV InfectedHCV InfectedEarly seroconversionEarly seroconversion

0.5%0.5%

159159

9.6%9.6%

3,3193,319

HCV NATHCV NAT HCV NATHCV NAT HCV NATHCV NAT

E0304206A 8

Option 1: HCV EIA 2.0 (Abbott) Option 1: HCV EIA 2.0 (Abbott) or 3.0 (Ortho) Repeat Reactiveor 3.0 (Ortho) Repeat Reactive

Review HCV NAT ResultsReview HCV NAT ResultsN = 34,656N = 34,656

Pool or Individual UnitPool or Individual UnitNonRxNonRx

(16 dtns (16 dtns HIV-1/HCV TMA, HIV-1/HCV TMA,24 dtns 24 dtns HCV PCR) HCV PCR)

Individual UnitIndividual UnitNAT RxNAT Rx

(dHCV TMA or (dHCV TMA or HCV PCR)HCV PCR)

No Further TestingNo Further TestingHCV InfectedHCV Infected

38.7%38.7%

13,40713,407

98.4% PPV98.4% PPV

13,198 RIBA Pos13,198 RIBA Pos

61.3%61.3%

21,24921,249

Perform RIBAPerform RIBA

IndIndPosPos NegNeg

28.1%28.1%

5,9675,967

15.6%15.6%

3,3193,319

56.3%56.3%

11,96311,963

79.9% Sensitivity79.9% Sensitivity

E0304206A 9

Option 2: HCV EIA 2.0 (Abbott) Option 2: HCV EIA 2.0 (Abbott) or 3.0 (Ortho) Repeat Reactiveor 3.0 (Ortho) Repeat Reactive

Review HCV NAT ResultsReview HCV NAT ResultsN = 34,656N = 34,656


(16 dtns (16 dtns HIV-1/HCV TMA, HIV-1/HCV TMA,24 dtns 24 dtns HCV PCR) HCV PCR)


(dHCV TMA or (dHCV TMA or HCV PCR)HCV PCR)


38.7%38.7%

13,40713,407

98.4% PPV98.4% PPV


61.3%61.3% 21,24921,249

82.9%82.9%SensitivitySensitivity

Perform RIBAPerform RIBA

IndIndPosPos NegNeg

31%31%

5,0555,055

3.5%3.5%

566566

65.5%65.5%

10,69210,692

Review S/CO Values of EIAReview S/CO Values of EIA

S/CO ≥ 3.8S/CO ≥ 3.8

23.2%23.2% 4,9364,936

No Further TestingNo Further TestingHCV Infected?HCV Infected?

55.8% PPV55.8% PPV


S/CO < 3.8S/CO < 3.8

76.8%76.8% 16,31316,313


13,17713,177

S/CO ≥ 3.8S/CO ≥ 3.8

E0304206A 10

RIBA Result

Correlation of NAT Screening withCorrelation of NAT Screening withSupplemental HCV Serological ResultsSupplemental HCV Serological Results

(36,536 RR donations of which 34,656 (94.9%) had EIA and RIBA data)(36,536 RR donations of which 34,656 (94.9%) had EIA and RIBA data)

NATResult

Rx

NonRx

Total

Pos Ind Neg

13,182(13,198***)

(80%)

3,319

16,502(16,517***)

(48%)

174*(159***)

5,967

6,141(6,126***)

50**

11,963

12,013

(1.7%)

Total

13,407

21,249

34,656

9/8/99 to 6/30/039/8/99 to 6/30/03

** 140/174 (80%) dHCV and PCR Rx (<100-48,000,000 copies/mL)140/174 (80%) dHCV and PCR Rx (<100-48,000,000 copies/mL)**** 16/50 (32%) dHCV and PCR Rx (<100-24,000,000 copies/mL)16/50 (32%) dHCV and PCR Rx (<100-24,000,000 copies/mL)

****** 15 RIBA Ind due to 15 RIBA Ind due to 1 + hSOD (1:2310 in RR samples)1 + hSOD (1:2310 in RR samples)

E0304206A 11

Identification of HCV RIBA-Positive, Identification of HCV RIBA-Positive, NAT-Nonreactive SamplesNAT-Nonreactive Samples

9/8/99 – 12/31/029/8/99 – 12/31/02

2,2552,255HCV RIBA Pos, NAT Neg NeatHCV RIBA Pos, NAT Neg Neat

812812Screened Neat,Screened Neat,Neat Neg (36%)Neat Neg (36%)

730730

2929Screened Pools,Screened Pools,

Pool Rx, Neat Neg (1%)Pool Rx, Neat Neg (1%)

2525

1,4141,414Screened Pools,Screened Pools,Pool Neg (63%)Pool Neg (63%)

1,3971,397

* A minimum of one of two reps positive* A minimum of one of two reps positive

Pos*Pos*1515

(2.1%)(2.1%)

NegNeg715715

PosPos11

(3.7%)(3.7%)

NegNeg2424

Pos*Pos*2929

(2.1%)(2.1%)

NegNeg1,3681,368

Neat Retest:NGI x1, orGen-Probe x2

E0304206A 12

Viral Loads of HCV RIBA-Positive Samples Viral Loads of HCV RIBA-Positive Samples Screened NAT Nonreactive in Pools or Individually Screened NAT Nonreactive in Pools or Individually

and that Retested NAT Reactiveand that Retested NAT Reactive

Copies/mL at NGICopies/mL at NGI

Screened in Pools Screened in Pools (N=29) 20+ Quant/24 sent(N=29) 20+ Quant/24 sent

100 100 (11)(11)11**

380 (2)380 (2)

460460

910910

1,500* 1,500*

7,700*7,700*

9,400*9,400*

34,000*34,000* 5,200,000*5,200,000*

Screened Individually Screened Individually (N=15) 10+ Quant/12 sent(N=15) 10+ Quant/12 sent

100 (5)100 (5)11**

200 200

430*430*

2,0002,000

7,400*7,400*

12,000*12,000*

* Of 30+ Quant, 10 (30%) tested PCR positive when diluted 1:16; * Of 30+ Quant, 10 (30%) tested PCR positive when diluted 1:16; frequency 8 of 2255 (1:282) total with viral loads >1000 copies/mL frequency 8 of 2255 (1:282) total with viral loads >1000 copies/mL representing >16 million donations screenedrepresenting >16 million donations screened

E0304206A 13

Relationship between HCV 3.0 EIA and RIBARelationship between HCV 3.0 EIA and RIBAAll Samples 9/8/99 to 6/30/03All Samples 9/8/99 to 6/30/03

N = 34,656N = 34,656

S/CO

HCV SIA (3.0) Results

2.433

1.637

1.274

3.079

1.876

>5.000

NegN = 12,013

34.7%

IndN = 6,126

17.7%

PosN = 16,517

47.6%

1.024 - >5.000 95% Range1.032 - >5.000 3.077 - >5.000

1.354

4.9434.583

0.00

1.00

2.00

3.00

4.00

5.00

E0304206A 14

Relationship between HCV 3.0 EIA and RIBARelationship between HCV 3.0 EIA and RIBANAT Reactive Samples 9/8/99 to 6/30/03NAT Reactive Samples 9/8/99 to 6/30/03

N = 13,407N = 13,407

S/CO


4.393

1.800

1.354

>5.0004.763

4.221

>5.0004.9714.627

NegN = 500.4%

IndN = 159

1.2%

PosN = 13,198

98.4%

1.026 - >5.000 95% Range1.212 - >5.000 4.145 - >5.0000.00

1.00

2.00

3.00

4.00

5.00

E0304206A 15

Relationship between HCV 3.0 EIA and RIBARelationship between HCV 3.0 EIA and RIBANAT Nonreactive Samples 9/8/99 to 6/30/03NAT Nonreactive Samples 9/8/99 to 6/30/03

N = 21,249N = 21,249

S/CO


2.428

1.636

1.274

2.955

1.840

>5.000

NegN = 11,963

56.3%

IndN = 5,967

28.1%

PosN = 3,319

15.6%

1.024 - >5.000 95% Range0.00

1.00

2.00

3.00

4.00

5.00

1.031 - >5.000 1.388 - >5.000

1.348

4.7954.311

E0304206A 16

ARC HCV Testing 9/8/99 Through 6/30/03ARC HCV Testing 9/8/99 Through 6/30/03NAT Reactive Specimens Only (N = 13,407)NAT Reactive Specimens Only (N = 13,407)

S/CORIBANEG

RIBAIND

RIBAPOS Total

%RIBAPOS

1.0 to 1.999 27 17 8 52 15.4%

2.0 to 2.999 8 6 5 19 26.3%

3.0 to 3.799 1 4 8 13 61.5%

3.8 to 4.999 8 70 6,954 7,032 98.9%

> 5.0 6 62 6,223 6,291 98.9%

Note: 13,323 of 13,407 (99.4%) NAT POS specimens had an S/CO ≥ 3.8;Note: 13,323 of 13,407 (99.4%) NAT POS specimens had an S/CO ≥ 3.8;13,177/13,323 (98.9%) specimens with S/CO ≥ 3.8 confirmed POS;13,177/13,323 (98.9%) specimens with S/CO ≥ 3.8 confirmed POS; 95% CI = 98.7 - 99.1 by binomial distribution95% CI = 98.7 - 99.1 by binomial distribution

Chi-square tests for independence were significant (p<0.0001)Chi-square tests for independence were significant (p<0.0001)

E0304206A 17

S/CORIBANEG

RIBAIND

RIBAPOS Total

%RIBAPOS

1.0 to 1.999 7,731 3301 198 11,230 1.8%

2.0 to 2.999 2,191 1,209 181 3,581 5.1%

3.0 to 3.799 770 545 187 1,502 12.5%

3.8 to 4.999 953 678 1,522 3,153 48.3%

> 5.0 318 234 1,231 1,783 69.0%

Note: 4,936 of 21,249 (23.2%) NAT NEG specimens had an S/CO ≥ 3.8;Note: 4,936 of 21,249 (23.2%) NAT NEG specimens had an S/CO ≥ 3.8;2,753/4,936 (55.8%) specimens with S/CO ≥ 3.8 confirmed POS;2,753/4,936 (55.8%) specimens with S/CO ≥ 3.8 confirmed POS;95% CI = 54.4 – 57.2 by binomial distribution95% CI = 54.4 – 57.2 by binomial distribution


ARC HCV Testing 9/8/99 Through 6/30/03ARC HCV Testing 9/8/99 Through 6/30/03NAT Nonreactive Specimens Only (N = 21,249)NAT Nonreactive Specimens Only (N = 21,249)

E0304206A 18

PPV and Sensitivity of PPV and Sensitivity of EIA and NAT vs RIBAEIA and NAT vs RIBA

RIBARIBA

POSPOS NEG or INDNEG or IND TOTALTOTAL

EIA RR, NAT Rx 13,198 209 13,407

EIA RR, NAT NR 3,319 17,930 21,249

TOTAL 16,517 18,139 34,656

PPV = 13,198/13,407 = 98.4%PPV = 13,198/13,407 = 98.4%Sens = 13,198/16,517 = 79.9%Sens = 13,198/16,517 = 79.9%

E0304206A 19

PPV and Sensitivity of PPV and Sensitivity of High S/CO (≥ 3.8) vs RIBAHigh S/CO (≥ 3.8) vs RIBA

RIBARIBA


EIA RR, S/CO ≥ 3.8 15,930 2,329 18,259

EIA RR, S/CO < 3.8 587 15,810 16,397

TOTAL 16,517 18,139 34,656

PPV = 15,930/18,259 = 87.2% PPV = 15,930/18,259 = 87.2% Sens = 15,930/16,517 = 96.4%Sens = 15,930/16,517 = 96.4%Note:Note: Increasing the S/CO limit to ≥ 5.0 increases the PPV to 92.3% Increasing the S/CO limit to ≥ 5.0 increases the PPV to 92.3%

and decreases the sensitivity to 45.1% and decreases the sensitivity to 45.1%

E0304206A 20

PPV and Sensitivity of High S/CO PPV and Sensitivity of High S/CO (≥ 3.8) vs RIBA Where NAT is Reactive(≥ 3.8) vs RIBA Where NAT is Reactive

RIBARIBA


EIA RR, S/CO ≥ 3.8 13,177 146 13,323

EIA RR, S/CO < 3.8 21 63 84

TOTAL 13,198 209 13,407

PPV = 13,177/13,323 = 98.9% PPV = 13,177/13,323 = 98.9% Sens = 13,177/13,198 = 99.8%Sens = 13,177/13,198 = 99.8%

E0304206A 21

PPV and Sensitivity of High S/CO PPV and Sensitivity of High S/CO (≥ 3.8) vs RIBA Where NAT is Nonreactive(≥ 3.8) vs RIBA Where NAT is Nonreactive

RIBARIBA


EIA RR, S/CO ≥ 3.8 2,753 2,183 4,936

EIA RR, S/CO < 3.8 566 15,747 16,313

TOTAL 3,319 17,930 21,249

PPV = 2,753/4,936 = 55.8%PPV = 2,753/4,936 = 55.8%Sens = 2,753/3,319 = 82.9% Sens = 2,753/3,319 = 82.9%

E0304206A 22

HCV Alternate Algorithm SummaryHCV Alternate Algorithm Summary

Use of NAT as the first step of the supplemental test Use of NAT as the first step of the supplemental test algorithm will reduce the amount of RIBA performed algorithm will reduce the amount of RIBA performed by approximately 40%by approximately 40%

HCV NAT-reactive samples (even using pooled NAT HCV NAT-reactive samples (even using pooled NAT for screening):for screening):– Sensitivity of 79.9% (detection of RIBA confirmed positives)Sensitivity of 79.9% (detection of RIBA confirmed positives)

• Those not detected by NAT will be tested by RIBA (as true Those not detected by NAT will be tested by RIBA (as true today)today)

– 98.4% are RIBA pos (PPV)98.4% are RIBA pos (PPV)• Small percent of NAT-reactive samples likely representing Small percent of NAT-reactive samples likely representing

early seroconversion are RIBA ind or negearly seroconversion are RIBA ind or neg

E0304206A 23

HCV Alternate Algorithm SummaryHCV Alternate Algorithm Summary Use of S/CO of Use of S/CO of >> 3.8 can be applied following separation of RR 3.8 can be applied following separation of RR

population into NAT Rx and nonRxpopulation into NAT Rx and nonRx– Since NAT results are available for all donations, and is a Since NAT results are available for all donations, and is a

specific test for HCV, S/CO introduced for NAT nonRx to specific test for HCV, S/CO introduced for NAT nonRx to further reduce the dependence on RIBAfurther reduce the dependence on RIBA

S/CO S/CO >> 3.8 does have high sensitivity and PPV relative to RIBA 3.8 does have high sensitivity and PPV relative to RIBA in populations where NAT is not performedin populations where NAT is not performed– Sensitivity of 96.4%Sensitivity of 96.4%– PPV of 87.2%PPV of 87.2%

However, use of a high S/CO for NAT nonRxs would only However, use of a high S/CO for NAT nonRxs would only eliminate 23% of RIBAs performed with poor performanceeliminate 23% of RIBAs performed with poor performance– Sensitivity of 82.9%Sensitivity of 82.9%– PPV of 55.8%PPV of 55.8%

E0304206A 24

Cambridge BiotechCambridge BiotechHuman Immunodeficiency Virus Type 1 (HIV -1)Human Immunodeficiency Virus Type 1 (HIV -1)

Western Blot KitWestern Blot Kit

March 16, 2000 BPACMarch 16, 2000 BPAC Any bands present but pattern does not meet criteria Any bands present but pattern does not meet criteria

for POSITIVE = INDETERMINATEfor POSITIVE = INDETERMINATE Non-viral bands have been observed with certain Non-viral bands have been observed with certain

specimens. These bands are not usually accompanied specimens. These bands are not usually accompanied by any of the major viral bands of diagnostic by any of the major viral bands of diagnostic significance (p24, gp41/120/160). The non-viral bands significance (p24, gp41/120/160). The non-viral bands appear to be cell related with the most common in the appear to be cell related with the most common in the molecular weight range of 70K, 51-55K (possible molecular weight range of 70K, 51-55K (possible HLA-DR) and 43K (possible HLA-ABC).HLA-DR) and 43K (possible HLA-ABC).

E0304206A 25

HIV-1 Blood Donor Screening/SupplementalHIV-1 Blood Donor Screening/SupplementalTest Results (ARC); March 16, 2000 BPACTest Results (ARC); March 16, 2000 BPAC

12.4 Million Donations Screened12.4 Million Donations Screened

PositivePositive791 (7.1%)791 (7.1%)

NegativeNegative5,128 (46.3%)5,128 (46.3%)

IndeterminateIndeterminate5,161 (46.6%)5,161 (46.6%)

1998-19991998-1999

11,080 Repeat Reactive (0.09%)11,080 Repeat Reactive (0.09%)HIV-1 WB (Cambridge Biotech)HIV-1 WB (Cambridge Biotech)

E0304206A 26

HIV-1 Blood Donor Screening/SupplementalHIV-1 Blood Donor Screening/SupplementalTest Results (ARC) (Cont.); March 16, 2000 BPACTest Results (ARC) (Cont.); March 16, 2000 BPAC

5,161 Indeterminate (46.6%)5,161 Indeterminate (46.6%)

MultipleMultipleViralViralBandsBands

(p24, gp41,(p24, gp41,gp120/160,gp120/160,

but +/- intensity)but +/- intensity)

46 (1%)

OneOneViralViralBandBand

2,752 (53.3%)

MultipleMultipleViralViralBandsBands

589 (11.4%)

BackgroundBackgroundOnlyOnly

(obscures(obscuresreading)reading)

1,050 (20.3%)

Non-Non-ViralViralBandsBands

724 (14%)

16 (35%)16 (35%)“ENV” only“ENV” only

1,925 (70%)1,925 (70%)p24 “GAG” onlyp24 “GAG” only

464 (79%) 464 (79%) “GAG” “GAG” reactivity with reactivity with or without or without other bandingother banding

569 (79%)569 (79%)“p70”“p70”

65.7% Viral Banding65.7% Viral Banding

1998-19991998-1999

E0304206A 27

Calypte Biotech HIV-1 Western BlotCalypte Biotech HIV-1 Western Blot

gp160gp160gp120gp120

p66p66p55/51p55/51

gp41gp41

p31p31

p24p24

p17p17

E0304206A 28

Calypte HIV-1 Western BlotCalypte HIV-1 Western Blot

gp160gp160gp120gp120

p66p66p55/51p55/51

gp41gp41

p31p31

p24p24

p17p17

E0304206A 29

HIV-1 RNA Concentrations During SC Based on NGI’s HIV-1 RNA Concentrations During SC Based on NGI’s PCR of 28 Plasma Donor Panels (N=221)PCR of 28 Plasma Donor Panels (N=221)

Categories

PCR–/Ag–/Ab–(n=19)

PCR+/Ag–/Ab–(n=22)

PCR+/Ag+/Ab–(n=22)

PCR+/Ag+/–/IgM+/IgG–WB–/IND

(n=19)

PCR+/Ag+/–/IgM+/IgG–WB POS(n=12)

6Median Days

6

100

1,000

10,000

100,000

1,000,000

PCR+/Ag+/–/Ab+

(n=20)

0 7 3 4

HIV

-1 R

NA

Cop

ies/

mL

E001372A 29

E0304206A 30

Comparison of HIV-1 p24 Ag PositiveComparison of HIV-1 p24 Ag PositiveWindow-Case U.S. Blood DonorsWindow-Case U.S. Blood Donors

11 IndexIndex 6 x 106 x 1055** 14.0*14.0* 9595 0.10.11212 3 x 103 x 1044 1.21.2 9595 2.32.3 POS – minus p31POS – minus p312222 1 x 101 x 1055 0.30.3 5.65.6 POS – all bandsPOS – all bands

22 IndexIndex 2 x 102 x 1066** 28.5*28.5* 9494 0.80.82020 1 x 101 x 1055 0.70.7 1.61.6 POS – minus p31POS – minus p314343 1 x 101 x 1044 0.10.1 5.35.3 POS – all bandsPOS – all bands

33 IndexIndex 1 x 101 x 1055 8.18.1 9595 0.10.11313 5 x 105 x 1055** 26.5*26.5* 9090 8.88.8 POS – minus p31 POS – minus p31

44 IndexIndex 1 x 101 x 1055 2.42.4 9595 0.00.01313 1 x 101 x 1066** 17.5*17.5* 8989 2.72.7 IND – p66IND – p667575 5 x 105 x 1044 0.10.1 17.417.4 POS – all bandsPOS – all bands

55 IndexIndex 3 x 103 x 1055 18.6*18.6* 9999 0.30.31010 4 x 104 x 1055** 0.20.2 4.34.3 POS – minus p31POS – minus p311717 1 x 101 x 1055 0.90.9 12.512.5 POS – minus p31POS – minus p312424 3 x 103 x 1044 0.70.7 8.58.5 POS – minus p31POS – minus p313131 2 x 102 x 1044 0.10.1 13.113.1 POS – minus p31POS – minus p31

SCSC

Sample Sample CollectionCollection

(days)(days) WBWBRNA RNA

Copies/mLCopies/mLp24 Ag p24 Ag S/COS/CO

PercentPercentNeut.Neut.

HIV-1/HIV-1/HIV-2 Ab HIV-2 Ab

S/COS/CO

E0304206A 31

Current: HIV-1/HIV-2 EIACurrent: HIV-1/HIV-2 EIA(Abbott rDNA or GSC pEIA)(Abbott rDNA or GSC pEIA)

Perform WBPerform WBN = 17,090N = 17,090

IndIndPosPos


NegNeg









HIVHIVInfectedInfected

HIV Infected?HIV Infected?Viral load < NAT cutoffViral load < NAT cutoff

False Pos WBFalse Pos WB4.4%4.4%

759759

HIV NotHIV NotInfectedInfected

HIV Infected?HIV Infected?Early seroconversionEarly seroconversion

False Rx NATFalse Rx NAT

HIV NotHIV NotInfected?Infected?

51%51%

8,6548,654

0.2%0.2%

37 (0)37 (0)

44%44%

7,5257,525HIV InfectedHIV InfectedEarly seroconversionEarly seroconversion

0.3%0.3%

56 (6)56 (6)

0.3%0.3%

5959

HIV NATHIV NAT HIV NATHIV NAT HIV NATHIV NAT

E0304206A 32

Option 1: HIV-1/HIV-2 EIAOption 1: HIV-1/HIV-2 EIA(Abbott rDNA or GSC pEIA)(Abbott rDNA or GSC pEIA)

Review HIV-1 NAT ResultsReview HIV-1 NAT ResultsN = 17,090N = 17,090


(16 dtns (16 dtns HIV-1/HCV TMA, HIV-1/HCV TMA,24 dtns 24 dtns HIV PCR) HIV PCR)


(dHIV TMA or (dHIV TMA or HIV PCR)HIV PCR)

No Further TestingNo Further TestingHIV InfectedHIV Infected

5%5%

852 (765)852 (765)

89.1% PPV89.1% PPV(99.2%)(99.2%)

759 WB Pos759 WB Pos

95%95%

16,23816,238

Perform WBPerform WB

IndIndPosPos NegNeg

53.3%53.3%

8,6548,654

0.4%0.4%

5959

46.3%46.3%

7,5257,525


E0304206A 33

Option 2: HIV-1/HIV-2 EIAOption 2: HIV-1/HIV-2 EIA(Abbott rDNA or GSC pEIA)(Abbott rDNA or GSC pEIA)

Review HIV-1 NAT ResultsReview HIV-1 NAT ResultsN = 17,090N = 17,090


(16 dtns (16 dtns HIV-1/HCV TMA, HIV-1/HCV TMA,24 dtns 24 dtns HIV PCR) HIV PCR)


(dHIV TMA or (dHIV TMA or HIV PCR)HIV PCR)


5%5%

852 (765)852 (765)

89.1% PPV89.1% PPV(99.2%)(99.2%)

759 WB Pos759 WB Pos

95%95% 16,23816,238

33.9%33.9%SensitivitySensitivity

Perform WBPerform WB

IndIndPosPos NegNeg

53.3%53.3%

8,5108,510

0.2%0.2%

3939

46.5%46.5%

7,4287,428

Review S/CO Values of EIAReview S/CO Values of EIA

S/CO ≥ 15S/CO ≥ 15

1.6%1.6% 261261

No Further TestingNo Further TestingHIV Infected?HIV Infected?

7.7% PPV7.7% PPV

20 WB Pos20 WB Pos

S/CO < 15S/CO < 15

98.4%98.4% 15,97715,977


694694

S/COS/CO > > 15 15

E0304206A 34

Western Blot Result

Correlation of NAT withCorrelation of NAT withSupplemental HIV Serological DataSupplemental HIV Serological Data

(17,791 RR donations of which 17,090 (96.1%) had EIA and WB data)(17,791 RR donations of which 17,090 (96.1%) had EIA and WB data)

NATResult

Rx

NonRx

Total

Pos Ind Neg

759(89.1%)

59(0.4%)

818(4.8%)

56*

8,654

8,710

37**

7,525

7,562

(10.9%)

Total

852

16,238

17,090

9/8/99 to 6/30/039/8/99 to 6/30/03

** 6/56 (11%) dHIV and PCR Rx (9,500-800,000 copies/mL)6/56 (11%) dHIV and PCR Rx (9,500-800,000 copies/mL)**** 0/37 (0%) dHIV and PCR Rx0/37 (0%) dHIV and PCR Rx

E0304206A 35

Characteristics of HIV-1 WB Characteristics of HIV-1 WB Pos/TMA Nonreactive SamplesPos/TMA Nonreactive Samples

All samples p24 Ag negativeAll samples p24 Ag negative

Sample Pool Neat HIV-1/HIV-2 S/CO WB HIV PCR1 NR 1.43 41, 120, 160 Neg2 NR 1.03 41, 160 Neg3 NR 1.62 41, 160 Neg4 NR 1.11 41, 55, 160 Neg5 NR 2.50 24, 41, 51, 61, 160 Neg6 NR 20.18 all bands Neg7 NR 1.22 24, 41, 160 Neg8 NR 1.11 17, 41, 120, 160 Neg9 NR 1.84 41, 160 Neg10 NR 1.40 24, 41, 160 Neg11 NR 1.70 17, 24, 41, 51, 160 Neg12 NR 20.00 all bands Pos (200 copies/mL)13 NR 17.84 all bands Neg

9/8/99 – 8/31/009/8/99 – 8/31/00

E0304206A 36



Sample Pool Neat HIV-1/HIV-2 S/CO WB HIV PCR

14 NR 8.73 17, 24, 160 Neg

15 NR 10.56 24, 55, 120, 160 Neg

16 NR 19.30 all bands Neg

17 NR 19.47 all bands Pos (200 copies/mL)

18 NR 1.04 41, 66, 120, 160 Neg

19 NR 4.72 41, 160 Neg

20 NR 1.50 24, 41, 160 Neg

21 NR 1.53 24, 41, 160 Neg

22 NR 1.60 24, 160 Neg



9/1/00 – 12/29/019/1/00 – 12/29/01

E0304206A 37



Sample Pool Neat HIV-1/HIV-2 S/CO WB HIV PCR

25 NR 1.00 24, 120, 160 Neg

26 NR 1.19 41, 120, 160 Neg


28 NR 1.37 41, 160 Neg

29 NR 1.40 24, 41, 120, 160 Neg

30 NR 1.43 24, 160 Neg

31 NR 15.20 17, 24, 120, 160 Neg



34 NR 1.34 41, 160 Neg

9/1/00 – 12/29/019/1/00 – 12/29/01

E0304206A 38

N = 17,090N = 17,090

Relationship between HIV-1/HIV-2 EIA andRelationship between HIV-1/HIV-2 EIA andWestern Blot-All Samples 9/8/99 to 6/30/03Western Blot-All Samples 9/8/99 to 6/30/03

EIAS/CO

Western Blot Results

2.6001.6021.225

2.6721.598

19.178

NegN = 7,562

44.2%

IndN = 8,710

51.0%

PosN = 818

4.8%

1.018 – 11.370 95% Range1.018 – 12.329 1.513 – 20.9521.231

18.030

16.008

0.00

5.00

10.00

15.00

20.00

25.00

E0304206A 39

Relationship between HIV-1/HIV-2 EIA and Western BlotRelationship between HIV-1/HIV-2 EIA and Western BlotNAT Nonreactive Samples 9/8/99 to 6/30/03NAT Nonreactive Samples 9/8/99 to 6/30/03

N = 16,238N = 16,238(95% of total)(95% of total)


2.6021.6021.225

2.6721.599

16.268

NegN = 7,525

46.3%

IndN = 8,654

53.5%

PosN = 590.4%

1.018 – 11.368 95% Range0.00

5.00

10.00

15.00

20.00

25.00

1.018 – 12.258 1.013 – 20.0921.230

2.3901.400

EIAS/CO

E0304206A 40

Relationship between HIV-1/HIV-2 EIA and Western BlotRelationship between HIV-1/HIV-2 EIA and Western BlotNAT Reactive Samples 9/8/99 to 6/30/03NAT Reactive Samples 9/8/99 to 6/30/03


2.5451.5781.314

2.5601.581

19.298

NegN = 374.3%

IndN = 566.6%

PosN = 75989.1%

1.076 – 12.398 95% Range1.012 – 18.385 8.130 – 20.9521.299

18.182

16.296

N = 852N = 852(5% of total)(5% of total)

0.00

5.00

10.00

15.00

20.00

25.00

EIAS/CO

E0304206A 41

S/COWB

NEGWBIND

WBPOS Total

%WBPOS

1.0 to 4.999 35 48 5 88 5.7%

5.0 to 9.999 1 2 23 26 88.5%

10.0 to 14.999 1 3 37 41 90.2%

15.0 to 19.999 0 3 591 594 99.5%

> 20.0 0 0 103 103 100.0%

Note: 697 of 852 (81.8%) NAT POS specimens had an S/CO ≥ 15.0;Note: 697 of 852 (81.8%) NAT POS specimens had an S/CO ≥ 15.0;694/697 (99.6%) specimens with S/CO ≥ 15.0 confirmed POS;694/697 (99.6%) specimens with S/CO ≥ 15.0 confirmed POS;95% CI = 98.8 - 99.9 by binomial distribution95% CI = 98.8 - 99.9 by binomial distribution


ARC HIV Testing 9/8/99 Through 6/30/03ARC HIV Testing 9/8/99 Through 6/30/03NAT Reactive Specimens Only (N = 852)NAT Reactive Specimens Only (N = 852)

E0304206A 42

S/COWB

NEGWBIND

WBPOS Total

%WBPOS

1.0 to 4.999 6,769 7,749 35 14,553 0.2%

5.0 to 9.999 515 609 3 1,127 0.3%

10.0 to 14.999 144 152 1 297 0.3%

15.0 to 19.999 86 133 18 237 7.6%

> 20.0 11 11 2 24 8.3%

Note: 261 of 16,238 (1.6%) NAT NEG specimens had an S/CO ≥ 15.0;Note: 261 of 16,238 (1.6%) NAT NEG specimens had an S/CO ≥ 15.0;20/261 (7.7%) specimens with s/co ≥ 15.0 confirmed POS;20/261 (7.7%) specimens with s/co ≥ 15.0 confirmed POS;95% CI = 4.7 – 11.6 by binomial distribution95% CI = 4.7 – 11.6 by binomial distribution


ARC HIV Testing 9/8/99 Through 6/30/03ARC HIV Testing 9/8/99 Through 6/30/03NAT Nonreactive Specimens Only (N = 16,238)NAT Nonreactive Specimens Only (N = 16,238)

E0304206A 43

Western BlotWestern Blot


EIA RR, NAT Rx 759 93 (6) 852 (765)

EIA RR, NAT NR 59 16,179 16,238

TOTAL 818 16,272 17,090

PPV = 759/852 = 89.1% (759/765 = 99.2%) PPV = 759/852 = 89.1% (759/765 = 99.2%) Sens = 759/818 = 92.8% Sens = 759/818 = 92.8%

PPV and Sensitivity of HIV-1/HIV-2 EIA and NAT vs PPV and Sensitivity of HIV-1/HIV-2 EIA and NAT vs Western BlotWestern Blot

E0304206A 44



EIA RR, S/CO ≥ 15.0 714 244 958

EIA RR, S/CO < 15.0 104 16,028 16,132

TOTAL 818 16,272 17,090

PPV = 714/958 = 74.5%PPV = 714/958 = 74.5%Sens = 714/818 = 87.3% Sens = 714/818 = 87.3%

PPV and Sensitivity of High S/CO PPV and Sensitivity of High S/CO (≥ 15.0) vs Western Blot(≥ 15.0) vs Western Blot

E0304206A 45



EIA RR, S/CO ≥ 15.0 694 3 697

EIA RR, S/CO < 15.0 65 90 155

TOTAL 759 93 (6) 852 (765)

PPV = 694/697 = 99.6% PPV = 694/697 = 99.6% Sens = 694/759 = 91.4% Sens = 694/759 = 91.4%

PPV and Sensitivity of High S/CO PPV and Sensitivity of High S/CO (≥ 15.0) vs WB Where NAT is Reactive(≥ 15.0) vs WB Where NAT is Reactive

E0304206A 46



EIA RR, S/CO ≥ 15.0 20 241 261

EIA RR, S/CO < 15.0 39 15,938 15,977

TOTAL 59 16,179 16,238

PPV = 20/261 = 7.7% PPV = 20/261 = 7.7% Sens = 20/59 = 33.9% Sens = 20/59 = 33.9%

PPV and Sensitivity of High S/CO PPV and Sensitivity of High S/CO (≥ 15.0) vs WB Where NAT is Nonreactive(≥ 15.0) vs WB Where NAT is Nonreactive

E0304206A 47

HIV Alternate Algorithm SummaryHIV Alternate Algorithm Summary

Use of NAT as the first step of the supplemental test Use of NAT as the first step of the supplemental test algorithm will reduce the amount of HIV WB performed algorithm will reduce the amount of HIV WB performed by only 5%by only 5%

HIV NAT-reactive samples (even using pooled NAT for HIV NAT-reactive samples (even using pooled NAT for screening):screening):– Sensitivity of 92.8% (detection of WB confirmed positives)Sensitivity of 92.8% (detection of WB confirmed positives)

• Those not detected will be tested by WB; only 0.4% of Those not detected will be tested by WB; only 0.4% of positives remain and majority are false positive on WB positives remain and majority are false positive on WB (as indicated by repeat NAT nonRx, low EIA S/CO and (as indicated by repeat NAT nonRx, low EIA S/CO and weak WB banding patterns)weak WB banding patterns)

E0304206A 48

HIV Alternate Algorithm SummaryHIV Alternate Algorithm Summary

Use of S/CO Use of S/CO >> 15 following separation of RR 15 following separation of RR population into NAT Rx and nonRx is not practicalpopulation into NAT Rx and nonRx is not practical– Vast majority of HIV RR samples are not from individuals Vast majority of HIV RR samples are not from individuals

with HIV infection and consequently are NAT nonRx and with HIV infection and consequently are NAT nonRx and have low S/CO valueshave low S/CO values

– Of those with an S/CO Of those with an S/CO >> 15, the PPV is 7.7% (20/261) 15, the PPV is 7.7% (20/261)– Of those with an S/CO < 15, it is likely that all WB pos Of those with an S/CO < 15, it is likely that all WB pos

are false posare false pos

Other optionsOther options– Dual EIA Algorithm Dual EIA Algorithm

E0304206A 49

Dual EIA AlgorithmDual EIA Algorithm

Feasibility based on the concept:Feasibility based on the concept:– If two assays with comparable sensitivity are composed of If two assays with comparable sensitivity are composed of

differing rare reagents and have a different format, the false differing rare reagents and have a different format, the false positive populations should have limited cross over; the more positive populations should have limited cross over; the more unique the tests, the greater the separation of false positive unique the tests, the greater the separation of false positive populationspopulations

Used successfully for HTLV and HBsAg to eliminate Used successfully for HTLV and HBsAg to eliminate >60% of repeat reactives requiring further testing by >60% of repeat reactives requiring further testing by expensive, complicated, error prone and expensive, complicated, error prone and unavailable/unlicensed tests (e.g., HTLV)unavailable/unlicensed tests (e.g., HTLV)

E0304206A 50

0

100

200

300

400

500

600

700

800

900

MA

Y-0

0

JUN

-00

JUL

-00

AU

G-0

0

SE

P-0

0

OC

T-0

0

NO

V-0

0

DE

C-0

0

JAN

-01

FE

B-0

1

MA

R-0

1

AP

R-0

1

MA

Y-0

1

JUN

-01

JUL

-01

AU

G-0

1

SE

P-0

1

OC

T-0

1

NO

V-0

1

DE

C-0

1

JAN

-02

FE

B-0

2

MA

R-0

2

AP

R-0

2

MA

Y-0

2

JUN

-02

JUL

-02

AU

G-0

2

SE

P-0

2

OC

T-0

2

NO

V-0

2

DE

C-0

2

JAN

-03

FE

B-0

3

MA

R-0

3

AP

R-0

3

MA

Y-0

3

JUN

-03

JUL

-03

Total OTC RR PosNegIndAbbott Neg (WB not done)

ARC HTLV Supplemental Results

** State of California Testing Initiated

Month (2000-2002)

Nu

mb

er

E0304206A 51

HIV Dual EIA Algorithm QualificationHIV Dual EIA Algorithm Qualification

Qualified in both directions based on the two FDA Qualified in both directions based on the two FDA licensed HIV-1/HIV-2 EIAs:licensed HIV-1/HIV-2 EIAs:– Abbott (EIA-1) Abbott (EIA-1) Genetic Systems (EIA-2) (ARC) Genetic Systems (EIA-2) (ARC)– Genetic Systems (EIA-1) Genetic Systems (EIA-1) Abbott (EIA-2) (BSL) Abbott (EIA-2) (BSL)

All HIV EIA repeat reactive samples from 1/1/00-3/31/02 All HIV EIA repeat reactive samples from 1/1/00-3/31/02 having adequate volume for additional testing were having adequate volume for additional testing were evaluatedevaluated

Western Blot and NAT (TMA pools of 16) test-of-record Western Blot and NAT (TMA pools of 16) test-of-record data were used for analysisdata were used for analysis

All 2All 2ndnd EIA testing was performed centrally at BSL EIA testing was performed centrally at BSL

E0304206A 52

HIV Dual EIA AlgorithmHIV Dual EIA AlgorithmGenetic Systems pEIA (EIA-1) at BSLGenetic Systems pEIA (EIA-1) at BSL

N = 1,657 RR Samples (1/1/00 – 3/31/02)N = 1,657 RR Samples (1/1/00 – 3/31/02)

IndInd544 (32.8%)544 (32.8%)

PosPos80 (4.8%)80 (4.8%)

RRRR8080

NegNeg1,033 (62.4%)1,033 (62.4%)

NRNR00

RRRR3131

NRNR513513

RRRR4949

NRNR984984

Tested by Western Blot (Bio-Rad)Tested by Western Blot (Bio-Rad)

AbbottAbbott EIA-2EIA-2 AbbottAbbott EIA-2EIA-2 AbbottAbbott EIA-2EIA-2

++7979

––11

++00

––3131

++00

––513513

++00

––4949

++00

––984984

NATNATNATNATNATNAT

(all WB bands;(all WB bands;high S/COhigh S/COboth EIAs)both EIAs)

E0304206A 53

HIV Dual EIA AlgorithmHIV Dual EIA AlgorithmAbbott rDNA EIA (EIA-1) at ARCAbbott rDNA EIA (EIA-1) at ARC

N = 6,227 RR Samples (1/1/00 – 3/31/02)N = 6,227 RR Samples (1/1/00 – 3/31/02)

IndInd2,890 (46.4%)2,890 (46.4%)

PosPos266 (4.3%)266 (4.3%)

RRRR250250

NegNeg3,071 (49.3%)3,071 (49.3%)

NRNR1616

RRRR1616

NRNR2,8742,874

RRRR1313

NRNR3,0583,058

Tested by Western Blot (Calypte)Tested by Western Blot (Calypte)

GSCGSC EIA-2EIA-2 GSCGSC EIA-2EIA-2 GSCGSC EIA-2EIA-2

++237237

––1313

++11

––1515

++00

––2,8742,874

++00

––1313

++00

––3,0583,058

NATNATNATNATNATNAT++00

––1616

(+/- 24, 160)(+/- 24, 160)

E0304206A 54

N = 13, Abbott RR, WB Pos, GSC RR, NAT NRN = 13, Abbott RR, WB Pos, GSC RR, NAT NR

WB Banding Pattern Abbott S/CO GSC S/CO

1 24, 31, 41, 51, 66, 120, 160 17.43 5.80

2 17, 24, 120, 160 15.52 2.91

3 all bands 15.93 9.30

4 all bands 17.19 8.62

5 all bands 19.30 8.87

6 17, 24, 61, 160 2.40 7.06

7 24, 31, 41, 51, 66, 120, 160 20.95 4.39

8 24, 41, 120, 160 1.40 1.33

9 all bands 19.30 8.07

10 41, 66, 120, 160 1.04 9.38

11 all bands 17.60 8.59

12 all bands 17.84 8.93

13 all bands 18.80 11.12

E0304206A 55

N = 16, Abbott RR, WB Pos, GSC NR, NAT NRN = 16, Abbott RR, WB Pos, GSC NR, NAT NR

WB Banding Pattern Abbott S/CO GSC S/CO1 17, 41, 160 1.53 0.172 17, 41, 160 1.50 0.203 41, 160 1.34 0.304 41, 120, 160 4.90 0.255 41, 160 4.72 0.316 24, 120 1.52 0.297 41, 120, 160 4.92 0.258 24, 41, 160 1.00 0.389 41, 120, 160 1.19 0.2910 24, 160 1.43 0.2211 24, 160 1.60 0.3212 17, 24, 41, 120, 160 2.36 0.3313 17, 41, 120, 160 1.11 0.1714 24, 55, 120, 160 10.56 0.57*15 17, 24, 160 8.73 0.62*16 41, 160 1.37 0.28

* Both samples PCR and repeat TMA (undilute) NR; one of two reported participation in an HIV vaccine trial* Both samples PCR and repeat TMA (undilute) NR; one of two reported participation in an HIV vaccine trial

E0304206A 56

GSC – GSC – BSLBSL N = 1,657N = 1,657 No. Abbott RRNo. Abbott RR No. NAT RxNo. NAT Rx

No. WB: Pos = 80 (5%) 80 (100%) 79

(Bio-Rad) Ind = 544 (33%) 31 (6%) 0

Neg = 1,033 (62%) 49 (5%) 0

HIV Dual EIA SummaryHIV Dual EIA Summary

Abbott – Abbott – ARCARC N = 6,227N = 6,227 No. GSC RRNo. GSC RR No. NAT RxNo. NAT Rx

No. WB: Pos = 266 (4%) 250 (94%) 237

(Calypte) Ind = 2,890 (46%) 16 (0.6%) 1

Neg = 3,071 (49%) 13 (0.4%) 0

E0304206A 57

HIV Dual EIA Algorithm FindingsHIV Dual EIA Algorithm Findings

Using NAT as the “gold standard”Using NAT as the “gold standard”

Sensitivity = 100% (317/317)Sensitivity = 100% (317/317)– 95% CI 98.84-100%95% CI 98.84-100%

Specificity = 98.4% (7,447/7,567)Specificity = 98.4% (7,447/7,567)– 95% CI 98.11-98.68%95% CI 98.11-98.68%

No. WBs eliminated = 98.4% (7,764/7,884)No. WBs eliminated = 98.4% (7,764/7,884)

No. indeterminate interpretations eliminated = 98.6% No. indeterminate interpretations eliminated = 98.6% (3,387/3,434)(3,387/3,434)

Documents

E0304206A 1 Supplemental Testing for HIV-1 and HCV Blood Products Advisory Committee Meeting September 18, 2003 Susan L. Stramer, Ph.D. National Testing