ARCHITECT® HIV Ag/Ab Combo: Moving HIV ... - The AIDS Institute
ARCHITECT® HIV Ag/Ab Combo: Moving HIV ... - The AIDS Institute
ARCHITECT® HIV Ag/Ab Combo: Moving HIV ... - The AIDS Institute
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ARCHITECT ® <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong>:<br />
<strong>Moving</strong> <strong>HIV</strong> Diagnostics Forward in<br />
the U.S.<br />
Catherine Brennan, Ph.D.<br />
Research Fellow<br />
Infectious Diseases Research<br />
<strong>Ab</strong>bott Diagnostics<br />
1
<strong>Ag</strong>enda<br />
• ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> Assay<br />
• What is the <strong>Combo</strong> assay<br />
• Performance characteristics<br />
• Importance of detecting acute <strong>HIV</strong> infection<br />
• Early data from US laboratories<br />
2
ARCHITECT ® <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong><br />
• Chemiluminescent microparticle immunoassay for in vitro diagnostic use.<br />
• Simultaneous qualitative detection of <strong>HIV</strong> p24 antigen and antibodies to<br />
<strong>HIV</strong>-1 group M and group O and/or <strong>HIV</strong>-2 in human serum and plasma<br />
(EDTA and heparin)<br />
• Intended to be used as an aid in the diagnosis of <strong>HIV</strong>-1/<strong>HIV</strong>-2 infection,<br />
including acute or primary infection<br />
• An ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> reactive result does<br />
not distinguish between the detection of <strong>HIV</strong>-1 p24 antigen, <strong>HIV</strong>-1<br />
antibody, or <strong>HIV</strong>-2 antibody<br />
• May be used to aid in the diagnosis of <strong>HIV</strong>-1/<strong>HIV</strong>-2 infection in pediatric<br />
subjects (i.e. children as young as 2 years of age) and in pregnant woman<br />
• Not intended for use in screening blood or plasma donors. However can<br />
be used as a blood donor screening assay in urgent situations where<br />
traditional licensed blood donor screening assays are unavailable or their<br />
use is impractical<br />
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> Package Insert 34-5589/R1<br />
3
ARCHITECT Instrument<br />
• Fully-automated, random-access<br />
(no Control brackets)<br />
• Stat capability<br />
• <strong>HIV</strong> <strong>Combo</strong> assay:<br />
• 29 minute time to first result<br />
• >150 tests per hour on i2000SR<br />
• >50 tests per hour on i1000SR<br />
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> Package Insert and ARCHITECT Operations Manual<br />
4
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong><br />
• First 4 th generation <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> Combination assay<br />
approved in United States; FDA approval on June<br />
18, 2010<br />
• >100,000 data points to evaluate<br />
• Detection of <strong>HIV</strong> antibodies to <strong>HIV</strong>-1 group M (including diverse<br />
subtypes), <strong>HIV</strong>-1 group O, and <strong>HIV</strong>-2<br />
• Detection of <strong>HIV</strong> p24 antigen (diverse virus isolates,<br />
seroconversion panels, <strong>Ab</strong> negative specimens)<br />
• Specificity and sensitivity in low and high risk populations,<br />
pregnant females, and pediatrics<br />
• Overall specificity: 99.77% (95% CI: 99.62-99.88%)<br />
• <strong>HIV</strong> antibody sensitivity:100% (95% CI: 99.63-<br />
100.00%)<br />
• <strong>HIV</strong> p24 <strong>Ag</strong> analytical sensitivity: 18.39 pg/mL (range<br />
17.80-19.68 pg/mL)<br />
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> Package Insert<br />
5
What is Acute Phase of <strong>HIV</strong> Infection<br />
Appearance of markers of <strong>HIV</strong> infection<br />
AHI<br />
<strong>HIV</strong> RNA<br />
(plasma)<br />
Anti-<strong>HIV</strong> <strong>Ab</strong><br />
<strong>HIV</strong> p24 <strong>Ag</strong><br />
0 10 20 30 40 50 60 70 80 90 100<br />
Day post infection<br />
• <strong>Ab</strong>sence of <strong>HIV</strong> specific antibodies<br />
• Rapid rise in plasma viremia<br />
• Acute viral syndrome: fever, rash, diarrhea, fatigue, headache –<br />
opportunity for <strong>HIV</strong> testing<br />
• Detect AHI by NAT or p24 antigen<br />
Fiebig et al <strong>AIDS</strong>, 17:1871-1879 (2003)<br />
6
Why is Detection of AHI Important<br />
AHI makes a significant contribution to the ongoing epidemic<br />
• May account for 15-50% of new infections<br />
During the acute phase, substantially increased risk of transmission<br />
• Estimated 28-fold increase compared to chronic phase<br />
• Period of high viremia<br />
• Virus appears to be more infectious<br />
Individual unaware of infection status<br />
• Often test negative<br />
7
<strong>HIV</strong> <strong>Combo</strong> Acute <strong>HIV</strong> Infection Studies<br />
Dr J. Stekler, University of Washington, Seattle<br />
Dr. M. Pandori, San Francisco Department of Public Health<br />
Dr. S. Eshleman, Johns Hopkins University, Baltimore<br />
Dr. P. Patel, CDC, Atlanta<br />
K. Delaney, CDC, Atlanta<br />
Dr. M. Owen, CDC, Atlanta<br />
Dr. L. Wesolowski, CDC, Atlanta<br />
8
Acute <strong>HIV</strong> Infection Studies<br />
Basic testing strategy:<br />
• Specimens screened with an <strong>HIV</strong> antibody test<br />
• All negative specimens tested by <strong>HIV</strong> NAT<br />
Define acute <strong>HIV</strong> infection:<br />
• Specimens detected utilizing <strong>HIV</strong> NAT<br />
Stored specimens blinded and sent to <strong>Ab</strong>bott for <strong>Combo</strong> testing<br />
• Included <strong>HIV</strong> antibody positive, Western blot confirmed specimens and<br />
<strong>HIV</strong> negative specimens<br />
• Used ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> (CE marked version; 4J27)<br />
9
Seattle Study<br />
Stekler JD, et al, Clin Infectious Diseases 2009; 49:444-453<br />
MSM population – high risk, frequent testing<br />
Specimens collected at Public Health-Seattle and King County<br />
2003-2008 specimens screened N=14,005<br />
• <strong>HIV</strong> antibody positive N=328 (2.3%)<br />
• <strong>HIV</strong> <strong>Ab</strong>-/RNA+ (acute) N=36 (0.3%)<br />
NAT algorithm increased yield of <strong>HIV</strong> infection by 11%<br />
Median time from collection to report of NAT+ result: 16-19 days<br />
10
Seattle <strong>Combo</strong> Results<br />
16 of 36 acute <strong>HIV</strong><br />
specimens available for<br />
ARCHITECT <strong>HIV</strong> <strong>Combo</strong><br />
testing<br />
<strong>HIV</strong> <strong>Combo</strong> detected 15 of<br />
16 (94%)<br />
<strong>HIV</strong> RNA for <strong>Combo</strong><br />
negative: 4,946 copies/mL<br />
Median <strong>HIV</strong> RNA for <strong>Combo</strong><br />
positive: 4.5 million<br />
copies/mL<br />
*RealTime <strong>HIV</strong>-1 assay performed using<br />
residual specimen volume<br />
Specimen<br />
ID<br />
<strong>HIV</strong>-1 EIA<br />
s/co<br />
ARCHITECT<br />
<strong>Combo</strong> s/co<br />
<strong>HIV</strong> RNA<br />
copies/mL*<br />
47 0.18 0.2 4,946<br />
9 0.4 2.17 133,120<br />
10 nd 2.68 284,605<br />
12 nd 5.09 483,329<br />
11 0.3 9.85 1,133,033<br />
45 0.24 10.36 637,151<br />
16 0.08 21.32 1,714,915<br />
42 0.02 36.31 5,678,616<br />
41 0.59 36.43 4,510,685<br />
43 0.12 42.75 5,678,616<br />
44 0.25 45.87 4,510,685<br />
48 0.14 54.55 8,795,135<br />
46 0.19 80.68 22,092,380<br />
14 0.6 101.6 26,560,883<br />
13 0.5 108.9 6,519,924<br />
15 0.4 463.4 >90,000,000<br />
11
Seattle Conclusions<br />
Extrapolation of <strong>Combo</strong> results to entire study population:<br />
Testing Strategy<br />
EIA/NAT algorithm 100<br />
<strong>HIV</strong> <strong>Combo</strong> 99.4<br />
1 st /2 nd Gen EIA 90<br />
OraQuick Rapid 80<br />
% <strong>HIV</strong> Infections Detected<br />
• <strong>The</strong> sensitivity of ARCHITECT <strong>HIV</strong> <strong>Combo</strong> greatly reduces or<br />
eliminates the need for NAT even in a high risk, high prevalence<br />
population.<br />
• <strong>Combo</strong> assay could shorten time to report results. For <strong>HIV</strong> prevention<br />
and partner notification, CDC target for time to report an <strong>HIV</strong> positive<br />
result is
ARCHITECT <strong>HIV</strong> <strong>Combo</strong> Detects Acute <strong>HIV</strong> Infections<br />
Site<br />
# AHI <strong>Combo</strong><br />
tested<br />
# AHI <strong>Combo</strong><br />
detected<br />
Seattle (Stekler, CID 2009; 49:444-453) 16 15 (94%)<br />
San Francisco (Pandori, JCM 2009; 47:2639-2642) 64 57 (89%)<br />
EXPLORE (Eshleman, J<strong>AIDS</strong> 2009; 52:121-124) 21 13 (62%)*<br />
CDC AHI Study (Patel, Arch Int Med 2010; 170:66-74) 38 34 (89%)<br />
CDC Rapid Study (Delaney, CROI 2009, poster 997) 17 13 (76%)*<br />
Total 156 132 (85%)<br />
*Site used individual NAT instead of pooled NAT<br />
• <strong>Combo</strong> assay detected 85% of acute <strong>HIV</strong> infections<br />
• AHI not detected by <strong>HIV</strong> <strong>Combo</strong>: 724 - 21,548 RNA copies/mL<br />
• AHI detected by <strong>HIV</strong> <strong>Combo</strong>: 30,734 - >10,000,000 copies/mL<br />
13
ARCHITECT <strong>HIV</strong> <strong>Combo</strong> Seroconversion Sensitivity<br />
• Based on 31 panels, <strong>Combo</strong> reduced window period a median of 7 days<br />
relative to 3 rd generation <strong>Ab</strong> assay; range 0-20 days 1<br />
Seroconversion Panel <strong>HIV</strong> 9079 (Vendor data: ZeptoMetrix Corp)<br />
Roche Cobas ARCHITECT BioRad<br />
Days RNA copies/mL <strong>Combo</strong> BioRad 1/2/O Unigold Multispot Oraquick <strong>HIV</strong>-1 WB<br />
0 not detected 0.12 0.648 - - -<br />
2 not detected 0.07 0.133 - - -<br />
9 not detected 0.15 2.116 - - -<br />
18 not detected 0.10 0.580 - - -<br />
20 not detected 0.10 0.177 - - -<br />
28 not detected 0.11 0.222 - - -<br />
33 not detected 0.08 0.102 - - -<br />
35 >400 0.15 0.352 - - -<br />
40 271,000 3.58 0.287 - - - -<br />
42 >750,000 23.85 0.119 - - - -<br />
47 >750,000 43.06 1.065 - - - -<br />
49 >750,000 68.68 2.679 - - - ind<br />
55 211,000 34.81 9.689 - + - ind<br />
57 46,300 3.78 9.949 - + - ind<br />
62 11,000 4.13 10.239 - + - +<br />
64 11,500 8.38 10.239 - + - +<br />
69 21,700 12.83 10.239 - + - +<br />
71 20,400 13.51 10.239 - + - +<br />
76 18,800 19.63 10.239 + + + +<br />
78 26,500 20.99 10.239 + + + +<br />
83 18,700 24.17 10.239 + + + +<br />
85 29,600 24.23 10.239 + + + +<br />
90 23,800 25.15 10.239 + + + +<br />
92 21,100 27.52 10.239 + + + +<br />
97 15,400 29.39 10.239 + + + +<br />
1<br />
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> Package Insert<br />
14
Reduction in Seroconversion Window Period<br />
3 rd Gen <strong>HIV</strong> <strong>Ab</strong><br />
1 st Gen <strong>HIV</strong> <strong>Ab</strong><br />
4 th Gen <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong><br />
<strong>HIV</strong> RNA<br />
(plasma)<br />
Anti-<strong>HIV</strong> <strong>Ab</strong><br />
<strong>HIV</strong> p24 <strong>Ag</strong><br />
0 10 20 30 40 50 60 70 80 90 100<br />
Day post infection<br />
17<br />
22<br />
35<br />
1 st Gen <strong>Ab</strong><br />
3 rd Gen <strong>Ab</strong><br />
4 th Gen <strong>Ag</strong>/<strong>Ab</strong><br />
Fiebig et al, <strong>AIDS</strong> 2003; 17:1871-1879 Owen et al, J Clin Micro 2008; 46:1588-1595<br />
Kleinman et al, Transfusion 2009; 49:2454-2489 Patel et al, Arch Int Med 2010; 170:66-74<br />
15
Erie County Medical Center Buffalo, NY:<br />
Increased <strong>HIV</strong> Testing and Identification of AHI<br />
• Implementation of NYS law resulted in 5-fold increase in <strong>HIV</strong><br />
tests performed<br />
• Tested 3601 patients w/ ARCHITECT <strong>HIV</strong> <strong>Combo</strong> assay:<br />
• 31 confirmed <strong>HIV</strong> infections (0.9%)<br />
• 6 newly diagnosed chronic <strong>HIV</strong> infections<br />
• 1 diagnosed acute <strong>HIV</strong> infection<br />
• Specificity: 99.92%<br />
• AHI case:<br />
• 37 year old with acute viral syndrome came to emergency room<br />
• Reactive for <strong>HIV</strong>: ARCHITECT <strong>HIV</strong> <strong>Combo</strong>, <strong>HIV</strong>-1 RNA<br />
• Nonreactive for <strong>HIV</strong>: 3 rd generation EIA, rapid test, western blot<br />
Myers JB, et al., 27 th Clinical Virology Symposium, May 2011, Daytona Beach FL<br />
16
ARCHITECT <strong>HIV</strong> <strong>Combo</strong>: <strong>The</strong> U.S. Experience<br />
• Avera McKennan Hospital, Sioux Falls, SD<br />
• 3533 ARCHITECT <strong>HIV</strong> <strong>Combo</strong> tests run in 7 months<br />
• 16 confirmed <strong>HIV</strong> infections; prevalence 0.45%<br />
• 4 newly diagnosed <strong>HIV</strong> infections<br />
• 3 acute <strong>HIV</strong> infections<br />
• 48 minute average turn around time for <strong>HIV</strong> <strong>Combo</strong> result (from<br />
time of draw)<br />
• Specificity: 99.86%<br />
• Dallas-Fort Worth, TX<br />
• Tested 220 specimens from patients being screened for <strong>HIV</strong><br />
• Compare ARCHITECT <strong>Combo</strong> to comparator tests<br />
• <strong>Combo</strong> detected 4 AHI not detected by comparator plus 1 recent<br />
infection with indeterminant Western blot<br />
Dr L Serrano, <strong>Ab</strong>bott Workshop, AACC 2011.<br />
Wians FH, et al., Labmedicine (2011) 42:523-535.<br />
17
ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong>: Conclusions<br />
• <strong>HIV</strong> <strong>Combo</strong> detects <strong>HIV</strong> infections during the acute, recent, and<br />
established phases of infection.<br />
• Substantial improvement over <strong>HIV</strong> <strong>Ab</strong> immunoassays<br />
• Sensitive <strong>Ag</strong> and <strong>Ab</strong> detection across <strong>HIV</strong> subtypes/groups<br />
• High specificity (reduced cost associated with false-positives)<br />
• Fully automated, random access, high through-put<br />
• Time to first result: 29 minutes<br />
• Early implementation of ARCHITECT <strong>HIV</strong> <strong>Combo</strong> assay has<br />
demonstrated benefits of the assay both high and low prevalence<br />
settings<br />
18
Publications on ARCHITECT <strong>HIV</strong> <strong>Combo</strong><br />
1. Ly TD, et al, J Virol Meth 2007, 143:86-94. Could the new <strong>HIV</strong> combined p24 antigen and antibody<br />
assays replace p24 antigen specific assays<br />
2. Pandori MW, et al, J Clin Micro 2009, 47:2639-2642. Assessment of the ability of a fourth-generation<br />
immunoassay for human immunodeficiency virus (<strong>HIV</strong>) antibody and p24 antigen to detect both acute<br />
and recent <strong>HIV</strong> infections in a high risk setting.<br />
3. Stekler JD, et al Clin Infect Dis 2009, 49:444-453. <strong>HIV</strong> testing in a high incidence population: is<br />
antibody testing alone good enough<br />
4. Eshleman SH, et al, J Acquir Immune Defic Syndr 2009, 52:121-124. Detection of individuals with<br />
acute <strong>HIV</strong>-1 infections using the ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> assay.<br />
5. Patel P, et al, Arch Intern Med 2010, 170:66-74. Detecting acute human immunodeficiency virus<br />
infection using 3 different screening immunoassays and nucleic acid amplification testing for human<br />
immunodeficiency virus RNA, 2006-2008.<br />
6. Bischof JJ, et al <strong>AIDS</strong> 2011, 25:1927-1929. Prospective study of the ARCHITECT <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong><br />
4 th generation assay to detect <strong>HIV</strong> infection in STI clinics.<br />
7. Wians FH, et al, Labmedicine 2011, 42:523-535. Evaluation of four qualitative third-generation <strong>HIV</strong><br />
antibody assays and the fourth-generation <strong>Ab</strong>bott <strong>HIV</strong> <strong>Ag</strong>/<strong>Ab</strong> <strong>Combo</strong> test.<br />
8. Masciotra S, et al, J Clin Virol 2011, dio:10.1016/j.jcv.2011.09.011. Evaluation of alternative <strong>HIV</strong><br />
diagnostic algorithm using specimens from seroconversion panels and persons with established <strong>HIV</strong><br />
infections.<br />
B. Branson, CDC: APHL Webcast, Nov 15, 2011: <strong>HIV</strong> Diagnostics: New Tests and New Algorithms<br />
19