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ARCHITECT® HIV Ag/Ab Combo:

Moving HIV Diagnostics Forward in

the U.S.

Catherine Brennan, Ph.D.

Research Fellow

Infectious Diseases Research

Abbott Diagnostics

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Agenda

ARCHITECT HIV Ag/Ab Combo Assay

What is the Combo assay

Performance characteristics

Importance of detecting acute HIV infection

Early data from US laboratories

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ARCHITECT® HIV Ag/Ab Combo

Chemiluminescent microparticle immunoassay for in vitro diagnostic use.

Simultaneous qualitative detection of HIV p24 antigen and antibodies to HIV-1 group M and group O and/or HIV-2 in human serum and plasma (EDTA and heparin)

Intended to be used as an aid in the diagnosis of HIV-1/HIV-2 infection, including acute or primary infection

An ARCHITECT HIV Ag/Ab Combo reactive result does not distinguish between the detection of HIV-1 p24 antigen, HIV-1 antibody, or HIV-2 antibody

May be used to aid in the diagnosis of HIV-1/HIV-2 infection in pediatric subjects (i.e. children as young as 2 years of age) and in pregnant woman

Not intended for use in screening blood or plasma donors. However can be used as a blood donor screening assay in urgent situations where traditional licensed blood donor screening assays are unavailable or their use is impractical

ARCHITECT HIV Ag/Ab Package Insert 34-5589/R1

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ARCHITECT Instrument

Fully-automated, random-access

(no Control brackets)

Stat capability

HIV Combo assay:

29 minute time to first result

>150 tests per hour on i2000SR

>50 tests per hour on i1000SR

ARCHITECT HIV Ag/Ab Package Insert and ARCHITECT Operations Manual

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ARCHITECT HIV Ag/Ab Combo

First 4th generation HIV Ag/Ab Combination assay

approved in United States; FDA approval on June

18, 2010

>100,000 data points to evaluate • Detection of HIV antibodies to HIV-1 group M (including diverse

subtypes), HIV-1 group O, and HIV-2

Detection of HIV p24 antigen (diverse virus isolates,

seroconversion panels, Ab negative specimens)

Specificity and sensitivity in low and high risk populations,

pregnant females, and pediatrics

Overall specificity: 99.77% (95% CI: 99.62-99.88%)

HIV antibody sensitivity:100% (95% CI: 99.63-

100.00%)

HIV p24 Ag analytical sensitivity: 18.39 pg/mL (range

17.80-19.68 pg/mL)

ARCHITECT HIV Ag/Ab Combo Package Insert

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What is Acute Phase of HIV Infection?

Fiebig et al AIDS, 17:1871-1879 (2003)

Absence of HIV specific antibodies

Rapid rise in plasma viremia

Acute viral syndrome: fever, rash, diarrhea, fatigue, headache –

opportunity for HIV testing

Detect AHI by NAT or p24 antigen

0 10 20 30 40 50 60 70 80 90 100

HIV RNA

(plasma)

HIV p24 Ag

Day post infection

Anti-HIV Ab

Appearance of markers of HIV infection

AHI

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Why is Detection of AHI Important?

AHI makes a significant contribution to the ongoing epidemic

May account for 15-50% of new infections

During the acute phase, substantially increased risk of transmission

Estimated 28-fold increase compared to chronic phase

Period of high viremia

Virus appears to be more infectious

Individual unaware of infection status

Often test negative

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HIV Combo Acute HIV Infection Studies

Dr J. Stekler, University of Washington, Seattle

Dr. M. Pandori, San Francisco Department of Public Health

Dr. S. Eshleman, Johns Hopkins University, Baltimore

Dr. P. Patel, CDC, Atlanta

K. Delaney, CDC, Atlanta

Dr. M. Owen, CDC, Atlanta

Dr. L. Wesolowski, CDC, Atlanta

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Acute HIV Infection Studies

Basic testing strategy:

Specimens screened with an HIV antibody test

All negative specimens tested by HIV NAT

Define acute HIV infection:

Specimens detected utilizing HIV NAT

Stored specimens blinded and sent to Abbott for Combo testing

Included HIV antibody positive, Western blot confirmed specimens and

HIV negative specimens

Used ARCHITECT HIV Ag/Ab Combo (CE marked version; 4J27)

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Seattle Study Stekler JD, et al, Clin Infectious Diseases 2009; 49:444-453

MSM population – high risk, frequent testing

Specimens collected at Public Health-Seattle and King County

2003-2008 specimens screened N=14,005

HIV antibody positive N=328 (2.3%)

HIV Ab-/RNA+ (acute) N=36 (0.3%)

NAT algorithm increased yield of HIV infection by 11%

Median time from collection to report of NAT+ result: 16-19 days

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Seattle Combo Results

16 of 36 acute HIV

specimens available for

ARCHITECT HIV Combo

testing

HIV Combo detected 15 of

16 (94%)

HIV RNA for Combo

negative: 4,946 copies/mL

Median HIV RNA for Combo

positive: 4.5 million

copies/mL

Specimen

ID

HIV-1 EIA

s/co

ARCHITECT

Combo s/co

HIV RNA

copies/mL*

47 0.18 0.2 4,946

9 0.4 2.17 133,120

10 nd 2.68 284,605

12 nd 5.09 483,329

11 0.3 9.85 1,133,033

45 0.24 10.36 637,151

16 0.08 21.32 1,714,915

42 0.02 36.31 5,678,616

41 0.59 36.43 4,510,685

43 0.12 42.75 5,678,616

44 0.25 45.87 4,510,685

48 0.14 54.55 8,795,135

46 0.19 80.68 22,092,380

14 0.6 101.6 26,560,883

13 0.5 108.9 6,519,924

15 0.4 463.4 >90,000,000 *RealTime HIV-1 assay performed using

residual specimen volume

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Seattle Conclusions

Extrapolation of Combo results to entire study population:

Testing Strategy % HIV Infections Detected

EIA/NAT algorithm 100

HIV Combo 99.4

1st/2nd Gen EIA 90

OraQuick Rapid 80

The sensitivity of ARCHITECT HIV Combo greatly reduces or

eliminates the need for NAT even in a high risk, high prevalence

population.

Combo assay could shorten time to report results. For HIV prevention

and partner notification, CDC target for time to report an HIV positive

result is <72 hours.

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ARCHITECT HIV Combo Detects Acute HIV Infections

*Site used individual NAT instead of pooled NAT

Site # AHI Combo

tested

# AHI Combo

detected

Seattle (Stekler, CID 2009; 49:444-453) 16 15 (94%)

San Francisco (Pandori, JCM 2009; 47:2639-2642) 64 57 (89%)

EXPLORE (Eshleman, JAIDS 2009; 52:121-124) 21 13 (62%)*

CDC AHI Study (Patel, Arch Int Med 2010; 170:66-74) 38 34 (89%)

CDC Rapid Study (Delaney, CROI 2009, poster 997) 17 13 (76%)*

Total 156 132 (85%)

Combo assay detected 85% of acute HIV infections

AHI not detected by HIV Combo: 724 - 21,548 RNA copies/mL

AHI detected by HIV Combo: 30,734 - >10,000,000 copies/mL

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ARCHITECT HIV Combo Seroconversion Sensitivity

Seroconversion Panel HIV 9079 (Vendor data: ZeptoMetrix Corp)

Based on 31 panels, Combo reduced window period a median of 7 days

relative to 3rd generation Ab assay; range 0-20 days1

Roche Cobas ARCHITECT BioRad

Days RNA copies/mL Combo BioRad 1/2/O Unigold Multispot Oraquick HIV-1 WB

0 not detected 0.12 0.648 - - -

2 not detected 0.07 0.133 - - -

9 not detected 0.15 2.116 - - -

18 not detected 0.10 0.580 - - -

20 not detected 0.10 0.177 - - -

28 not detected 0.11 0.222 - - -

33 not detected 0.08 0.102 - - -

35 >400 0.15 0.352 - - -

40 271,000 3.58 0.287 - - - -

42 >750,000 23.85 0.119 - - - -

47 >750,000 43.06 1.065 - - - -

49 >750,000 68.68 2.679 - - - ind

55 211,000 34.81 9.689 - + - ind

57 46,300 3.78 9.949 - + - ind

62 11,000 4.13 10.239 - + - +

64 11,500 8.38 10.239 - + - +

69 21,700 12.83 10.239 - + - +

71 20,400 13.51 10.239 - + - +

76 18,800 19.63 10.239 + + + +

78 26,500 20.99 10.239 + + + +

83 18,700 24.17 10.239 + + + +

85 29,600 24.23 10.239 + + + +

90 23,800 25.15 10.239 + + + +

92 21,100 27.52 10.239 + + + +

97 15,400 29.39 10.239 + + + +

1ARCHITECT HIV Ag/Ab Combo Package Insert

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Reduction in Seroconversion Window Period

Fiebig et al, AIDS 2003; 17:1871-1879 Owen et al, J Clin Micro 2008; 46:1588-1595

Kleinman et al, Transfusion 2009; 49:2454-2489 Patel et al, Arch Int Med 2010; 170:66-74

1st Gen HIV Ab

3rd Gen HIV Ab

0 10 20 30 40 50 60 70 80 90 100

HIV RNA

(plasma)

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22

HIV p24 Ag

4th Gen HIV Ag/Ab

Day post infection

Anti-HIV Ab

35 1st Gen Ab

3rd Gen Ab

4th Gen Ag/Ab

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Erie County Medical Center Buffalo, NY:

Increased HIV Testing and Identification of AHI

Implementation of NYS law resulted in 5-fold increase in HIV tests performed

Tested 3601 patients w/ ARCHITECT HIV Combo assay:

31 confirmed HIV infections (0.9%)

6 newly diagnosed chronic HIV infections

1 diagnosed acute HIV infection

Specificity: 99.92%

AHI case:

37 year old with acute viral syndrome came to emergency room

Reactive for HIV: ARCHITECT HIV Combo, HIV-1 RNA

Nonreactive for HIV: 3rd generation EIA, rapid test, western blot

Myers JB, et al., 27th Clinical Virology Symposium, May 2011, Daytona Beach FL

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ARCHITECT HIV Combo: The U.S. Experience

Avera McKennan Hospital, Sioux Falls, SD

3533 ARCHITECT HIV Combo tests run in 7 months

16 confirmed HIV infections; prevalence 0.45%

4 newly diagnosed HIV infections

3 acute HIV infections

48 minute average turn around time for HIV Combo result (from time of draw)

Specificity: 99.86%

Dallas-Fort Worth, TX

Tested 220 specimens from patients being screened for HIV

Compare ARCHITECT Combo to comparator tests

Combo detected 4 AHI not detected by comparator plus 1 recent infection with indeterminant Western blot

Dr L Serrano, Abbott Workshop, AACC 2011.

Wians FH, et al., Labmedicine (2011) 42:523-535.

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ARCHITECT HIV Ag/Ab Combo: Conclusions

HIV Combo detects HIV infections during the acute, recent, and

established phases of infection.

Substantial improvement over HIV Ab immunoassays

Sensitive Ag and Ab detection across HIV subtypes/groups

High specificity (reduced cost associated with false-positives)

Fully automated, random access, high through-put

Time to first result: 29 minutes

Early implementation of ARCHITECT HIV Combo assay has

demonstrated benefits of the assay both high and low prevalence

settings

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Publications on ARCHITECT HIV Combo

1. Ly TD, et al, J Virol Meth 2007, 143:86-94. Could the new HIV combined p24 antigen and antibody assays replace p24 antigen specific assays?

2. Pandori MW, et al, J Clin Micro 2009, 47:2639-2642. Assessment of the ability of a fourth-generation immunoassay for human immunodeficiency virus (HIV) antibody and p24 antigen to detect both acute and recent HIV infections in a high risk setting.

3. Stekler JD, et al Clin Infect Dis 2009, 49:444-453. HIV testing in a high incidence population: is antibody testing alone good enough?

4. Eshleman SH, et al, J Acquir Immune Defic Syndr 2009, 52:121-124. Detection of individuals with acute HIV-1 infections using the ARCHITECT HIV Ag/Ab Combo assay.

5. Patel P, et al, Arch Intern Med 2010, 170:66-74. Detecting acute human immunodeficiency virus infection using 3 different screening immunoassays and nucleic acid amplification testing for human immunodeficiency virus RNA, 2006-2008.

6. Bischof JJ, et al AIDS 2011, 25:1927-1929. Prospective study of the ARCHITECT HIV Ag/Ab Combo 4th generation assay to detect HIV infection in STI clinics.

7. Wians FH, et al, Labmedicine 2011, 42:523-535. Evaluation of four qualitative third-generation HIV antibody assays and the fourth-generation Abbott HIV Ag/Ab Combo test.

8. Masciotra S, et al, J Clin Virol 2011, dio:10.1016/j.jcv.2011.09.011. Evaluation of alternative HIV diagnostic algorithm using specimens from seroconversion panels and persons with established HIV infections.

B. Branson, CDC: APHL Webcast, Nov 15, 2011: HIV Diagnostics: New Tests and New Algorithms