Performance of rapid HIV tests used singly and in combination:
Moving toward a point of care diagnosis.
Kevin Delaney, MPHHIV Diagnostics: New Developments and
ChallengesMarch 1, 2005
Background• Rapid test combinations
– Many countries throughout the world use multi-test algorithms for HIV confirmatory testing
• 4 FDA-approved tests– 2 CLIA-waived– more likely on the way
• US experience to date– “Traditional” outreach testing → Rapid testing – Provide immediate results
• Negative• “Preliminary Positive”
Background
• All FDA approved rapid HIV test package inserts now state:
“This test is suitable for use in multi-test algorithms designed for statistical validation of rapid HIV test results. When multiple rapid HIV tests are available, this test should be used in appropriate multi-test algorithms.”
Objectives• Describe the performance of individual rapid tests
– Sensitivity, specificity and predictive value
• Evaluate the performance of combinations of rapid tests used in sequence– Particular focus on tests designed for use at point of
care
• Foster discussion of a point of care diagnostic algorithm
• Location – Two clinics in Los Angeles, CA
• Participants– Persons of unknown serostatus seeking HIV
testing– Persons known to be HIV positive
Methods
• Testing – Multiple specimens from participants were tested
with several rapid tests including:• Multispot (Serum and plasma)*• Oraquick (Oral fluid, whole blood and plasma)• Reveal (Serum and plasma)• STAT-PAK (Whole blood and plasma)• Unigold (Whole blood and plasma)*
Methods
• Testing – Serum also tested with EIA and Western blot:
• Vironostika HIV-1 Microelisa system • Genetic Systems HIV-1 Western Blot • Samples of both serum and plasma retained for
future testing (e.g. RNA NAT, DNA NAT, other EIAs)
Methods
• Analysis– Single rapid test results compared to EIA/WB
• Sensitivity, specificity and predictive value
– Rapid test algorithms simulated using results of rapid tests as if they were performed sequentially
• Specificity and predictive value positive
Methods
Initial Rapid Test Screen
2nd Rapid test Screen
Third Rapid Test “Tie-Breaker”
Confirmed Positive
Confirmed Negative
Negative
Positive Positive
Negative
Negative
Positive
Sequential Antibody Screening Algorithm
Sample Size≈ 4800 total participants
(including known positives)
≈ 4400 total participants Not on antiretroviral therapy
≈ 2400 total participants tested
≈ 800 EIA/WB+ ≈ 4000 EIA Negative
≈ 400positives on treatment
Results – SensitivityTest Specimen
typeRT + False
negSensitivity (95% CI)
Oraquick Oral fluid 400 2 99.5 (98.2-99.9)Whole blood 401 0 100 (99.3-100)
Unigold Whole blood 139 1 99.3 (96.1-100)Plasma 245 1 99.6 (97.8-100)
Stat-pak Whole blood 257 3 98.9 (96.7-99.8)Plasma 366 2 99.5 (98.1-99.9)
Reveal Serum 397 2 99.5 (98.2-99.9)
Results – SensitivityTest Specimen
typeRT + False
negSensitivity (95% CI)
Oraquick Oral fluid 400 2 99.5 (98.2-99.9)Whole blood 401 0 100 (99.3-100)
Unigold Whole blood 139 1 99.3 (96.1-100)Plasma 245 1 99.6 (97.8-100)
Stat-pak Whole blood 257 3 98.9 (96.7-99.8)Plasma 366 2 99.5 (98.1-99.9)
Reveal Serum 397 2 99.5 (98.2-99.9)
Results – Specificity, single rapid test
Test Specimen type
RT neg
False +
Specificity (95% CI)
Oraquick Oral fluid 4156 1 100 (99.9-100)
Whole blood 4171 1 100 (99.8-100)
Unigold Whole blood 2282 0 100 (99.9-100)Plasma 2288 0 100 (99.9-100)
Stat-pak Whole blood 3442 0 100 (99.9-100)Plasma 3435 2 99.9 (99.8-100)
Reveal Serum 4155 3 99.9 (99.6-100)Multispot Plasma 487 0 100 (99.4-100)
Results – Specificity, POC rapid tests
Test Specimen type
RT neg
False +
Specificity (95% CI)
Oraquick Oral fluid 4156 1 100 (99.9-100)
Whole blood 4171 1 100 (99.8-100)
Unigold Whole blood 2282 0 100 (99.9-100)
Stat-pak Whole blood 3442 0 100 (99.9-100)
Results – Specificity, POC rapid tests
Test Specimen type
RT neg
False +
Specificity (95% CI)
Oraquick Oral fluid 4156 1 100 (99.9-100)
Whole blood 4171 1 100 (99.8-100)
Unigold Whole blood 2282 0 100 (99.9-100)
Stat-pak Whole blood 3442 0 100 (99.9-100)
98.399.2 10099.291.6
96.296.1 100
76.6
88.288.1100
0
20
40
60
80
100
Oraquick Oral fluid Oraquick Whole Blood Unigold/Stat-pak WholeBlood
Stat-pak Plasma(Sp=99.94)
5.0% 1.0% 0.3%
PV+
Results – Predictive value positive, single rapid test
Prevalence
Results – Sequential testing, 1st testTests Algorithm Results Comparison to
EIA/WB
1st test - +
OQ-b 2234 135
OQ-b 2234 136
OQ-o 2235 135
OQ-o 2235 135
UG 2235 135
UG 2235 135
UG 2235 135
SP 2238 133
SP 2238 131
SP 2238 132
Results – Two tests used sequentiallyTests Algorithm Results Comparison to
EIA/WB
1st test2nd test
-nd
++
+-
OQ-b UG 2234 133 2
OQ-b SP 2234 132 4
OQ-o UG 2235 133 2
OQ-o SP 2235 131 4
UG OQ-b 2235 135 0
UG OQ-o 2235 134 1
UG SP 2235 132 3
SP OQ-b 2238 132 1
SP OQ-o 2238 131 0
SP UG 2238 132 0
Tests Algorithm Results Comparison to EIA/WB
1st test2nd test
3rd test
-nd nd
++nd
+-+
+--
OQ-b UG SP 2234 133 1 1
OQ-b SP UG 2234 132 3 1
OQ-o UG SP 2235 133 1 1
OQ-o SP UG 2235 131 3 1
UG OQ-b 2235 135 0 0
UG OQ-o SP 2235 134 1 0
UG SP OQ-b 2235 132 3 0
OQ-o 2235 132 3 0
SP OQ-b 2238 132 0 0
SP OQ-o UG 2238 131 1 0
SP UG 2238 132 0 0
Results – Adding the 3rd test
Results – Adding the 3rd testTests Algorithm Results Comparison to
EIA / WB
1st test2nd test
3rd test
-nd nd
++nd
+-+
+--
False Pos
False Neg
OQ-b UG SP 2234 133 1 1 0 0
OQ-b SP UG 2234 132 3 1 0 0
OQ-o UG SP 2235 133 1 1 0 1
OQ-o SP UG 2235 131 3 1 0 1
UG OQ-b 2235 135 0 0 0 0
UG OQ-o SP 2235 134 1 0 0 0
UG SP OQ-b 2235 132 3 0 0 0
OQ-o 2235 132 3 0 0 0
SP OQ-b 2238 132 0 0 0 0
SP OQ-o UG 2238 131 1 0 0 3
SP UG 2238 132 0 0 0 3
10098.399.2 10099.2 10091.6
96.296.1100 100
76.688.288.1
100
0
20
40
60
80
100
Oraquick Oral fluid Oraquick WholeBlood
Unigold/StatpackWhole Blood
Statpack Plasma Multitest Algorithm
5.0% 1.0% 0.3%
PV+
Results – Predictive value positive, single rapid test v. multitest algorithm
Prevalence
• Imperfect “Gold Standard” (EIA/Western blot)– Clinical follow-up is the “true gold” standard– Plan perform additional testing on residual specimens to
address sensitivity of gold standard• Lack of complete testing data for all specimens• Testing was performed by trained technicians
– Not counselors, nurses or others who might do testing in outreach settings
Limitations
• Sensitivity of all rapid tests was >98%– Comparable to current EIAs– Negative predictive value suggests < 2 false
negatives/10,000 negatives tested @ 1% prevalence– Important to consider “realized sensitivity”
• Specificity of a single rapid test >99%– At low prevalence, the proportion of positive tests that
are false positive increases.– Adding a second different rapid test increased specificity
to 100% for specimens reactive on both tests– 0-4 specimens required a third “tie-breaker” rapid test
Summary
• Data suggest ANY combination of rapid tests gives results comparable to EIA/Western blot algorithm– Use of combinations of waived tests would allow for
POC testing and immediate return of confirmed results for both negatives and positives
– Cost of rapid tests ≈ ½ cost of a Western blot; suggesting opportunity for significant cost savings
– Other factors warrant consideration (e.g. CLIA status, ease of use, biohazards with different specimen types, shelf life, differentiation of HIV-2)
Discussion
• Need clinical follow-up of persons with discordant results – the true gold standard
• Evaluate on larger numbers
• Compare the sensitivity of rapid tests to NAT, 3rd and 4th generation EIAs
• Validate use of a POC diagnostic algorithm in a variety of field and clinical settings
Next Steps
• For discussion– More pros and any cons– Implementation barriers
• What do we need to do to catch up to Zimbabwe and Botswana?
Outstanding Questions
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