Transcript A Clinical Study of Antigen-Antibody Rapid Testing for Acute HIV Infection Christopher D.

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A Clinical Study of Antigen-Antibody Rapid Testing for Acute HIV Infection
Christopher D. Pilcher1, Brian Louie2, Sheila Keating3, Mark Pandori2, Falk Fish4, Tomer Keren4, Sally Liska2, Michael P. Busch3, Frederick M. Hecht1, Jeffrey Klausner1,2 and Grant Colfax1,2
We sought to measure the potential impact of these new screening
tests on the performance of real-world, public health and research
testing programs in San Francisco.
Methods - Specimens
Testing programs were included that used both HIV antibody and HIV RNA
amplification tests in their diagnostic algorithm:
45%
40%
35%
+
Ab Status
Confirmation
-
Programs with the highest
yield of acute HIV
infections were those
targeting patients with
high risk exposures
Pooled RNA
HIV RNA
RealtimePCR
WB
30%
%
Screening HIV
Ab Test
+
25%
20%
15%
10%
10%
7%
6%
5%
0%
nPEP
Partner Services
High Risk MSM
STD Clinic
Testing Population
-San Francisco
+
-
HIV Ab (+)
HIV Ab (-) RNA (+)
HIV Ab (-) RNA (-)
Established HIV
Acute HIV
HIV Negative
Rapid Test Panel
Central Lab Test Panel
OraquickAdvance
3rd Gen EIA ( Gen Systems HIV ½ Plus O)
ClearviewStat - Pak
4th Gen IA (Abbott ARCHITECT HIV Ag/Ab Combo)
Unigold Recombigen
Western Blot ( Biorad Genetic Systems)
MultispotHIV 1/2
Determine HIV1/2 Ag/Ab Combo
Antibody (Ab)-plus-RNA testing reference standard: The complete
algorithm, including Ab and RNA tests, was used to define HIV infection.
The combined reference standard was used to determine
Sensitivity, Specificity and Positive/Negative Predictive Values for each
screening assay. Western blot was used to categorize samples as
STD Clinic Population (n=14573)— attendees to the muncipal STD clinic,
representing acute (WB negative/indeterminate) or established (WB
not meeting above criteria
positive) HIV infection.
Non-occupational Post Exposure Prophylaxis (nPEP) Population
Head to head comparative
(n=989)— patients evaluated for, or receiving, nPEP
performance evaluation: Acute
Determine HIV-1/2 Ag/Ab
specimens (RNA+, WB- or
Combo: Rapid Test Readout
Partner Services (PS) Testing Population (n=173)— sexual or
indeterminate) were submitted to
needlesharing partners to newly diagnosed HIV+
Rapid Test and Central Lab panel
tests. Sensitivity and Negative
Acute HIV Diagnostic Testing Population (n=1114; 1998-2008)— patients Predictive Values (NPV) were
screened for having acute HIV by the UCSF Options study based on acute
calculated for each panel test,
retroviral symptoms and/or high risk exposure.
assuming 100% detection of WB
positive specimens.
High Risk MSM, Targeted Testing Population (n=6661)— MSM at public
testing sites meeting high risk criteria (sex with HIV+, unprotected anal
intercourse, or STD)
Acute HIV infections, as a proportion of all HIV cases detected
by each testing program.The % of all HIV infected cases
identified that were Western blot
-negative or indeterminate is shown.
40%
A key factor influencing HIV test performance, particularly in higherrisk testing sites, is the ability to detect acute HIV cases. These cases
are often negative on tests designed to detect only anti-HIV IgG
“4th generation” immunoassays (e.g., the ARCHITECT HIV Ag/Ab
Combo) can detect both HIV p24 antigen and anti-HIV antibodies for
earlier detection. A new rapid test (the Determine HIV-1/2 Ag/Ab
Combo) is also designed to detect HIV p24 antigen and anti-HIV
antibodies.
Results
Methods - Testing
Sensitivity was compared head-to-head in the high risk MSM testing population,
The sensitivity estimates associated with each rapid test (light blue) and central lab
immunoassay (dark blue) are shown.
Se
Background
50%
100%
98%
96%
94%
92%
90%
88%
86%
84%
82%
80%
78%
96%
93%
94%
92%
92%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1st Gen EIA
Stat-Pak Rapid
Genetic Systems HIV
-1/2
Plus 0
Determine HIV
-1/2 Ag/Ab
Combo Rapid
ARCHITECT HIV Ag/
Ab
Combo
Summary
In practice in San Francisco testing programs, HIV screening tests differed
significantly in their ability to detect HIV infections. Assays that detected
acute HIV substantially increased case identification.
98%
93%
The majority of RNA + patients
found in high risk testing
populations (high risk MSM,
non-targeted STD clinic VCT,
partner services and nPEP)
were detectable by the 4th
generation EIA or by the new
rapid Ag/Ab combo assay, but
not by 1st generation or even
3rd generation EIAs.
% Acute Infections Positive on Each Test
from 1UCSF HIV/AIDS Division; 2SF Department of Public Health; 3Blood Systems Research Institute; 4Inverness Medical Innovations
91%
86%
Despite differences in clinical sensitivity, negative predictive values for each test to
were >99.5%.
Specificity was estimated to be 100.00% for all immunoassays.
Oraquick Advance specificity was lower on oral fluid (Sp 99.86) vs. blood (99.96).
The Determine HIV Ag/Ab Combo correctly identified 80 of 81 HIV negative
Options specimens, with 1 false positive result (Sp 98.9).
•The Determine® HIV-1/2 Ag/Ab Combo, a novel point of care assay,
increased detection of HIV infection compared to all existing antibody-only
rapid tests. Separate signals for HIV-1 p24 antigen and HIV antibodies make
immediate, point of care identification of acute cases possible. Speed and
simplicity make the test appropriate for both developed and developing
world settings.
•The ARCHITECT ® HIV Ag/Ab Combo, a 4th generation immunoassay,
showed even greater sensitivity for acute HIV infections. This assay could
eliminate the need for pooled HIV RNA for central laboratory screening of
acute HIV infections.
•Confirmatory algorithms must be modified (e.g., to incorporate HIV RNA),
as these screening tests are more sensitive than established Western blot or
immuno-fluorescence assays, and have imperfect specificity.
The Oraquick oral fluid test device (with an estimated sensitivity of 86%)
may not be appropriate for testing of high risk individuals in San Francisco.
Acknowledgements
The work was supported by R01- MH068686; we are grateful to Shelley Facente for analysis and to John Hackett, Jr. for providing 4th generation IA
data, previously submitted for publication (Pandori MW, Hackett Jr., Louie B, et al., as “Assessment of the Ability of a Fourth Generation
Immunoassay for HIV Antibody and p24 Antigen to Detect both Acute and Recent HIV Infection in a High-Risk Setting.”)