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12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 1
Diagnosis of HIV-1 Infection in Phase I & II HIV Vaccine Trials
RW Coombs1, J Dragavon1, B Metch2, CJ Cooper2 and the NIAID HIV Vaccine Trials Network (HVTN)
1University of Washington & 2Fred Hutchinson Cancer Research Center, Seattle, Washington
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 2
Objective To evaluate the UNAIDS & WHO HIV Testing
Strategy III for diagnosis of HIV infection in low-risk, low-seroprevalence phase I/II HIV vaccine trials conducted in the United States
Hypothesis: The UNAIDS/WHO HIV testing strategy III would be unreliable for diagnosis HIV infection post-vaccination in this study population
Significance: This information will be useful for developing HIV diagnostic criteria for both domestic & international HIV vaccine trials
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 3
Background UNAIDS/WHO recommends that resource
limited countries consider HIV testing strategies, which use a combination of ELISAs and/or simple/rapid assays rather than ELISA/Western blot for HIV antibody detection WHO/HIV Assays: Operational Characteristics,
Report 14/Simple/Rapid tests (2004); page 3
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 4
Background cont’d UNAIDS & WHO
recommend three testing strategies, which depend on the testing objective and the prevalence of HIV in the population
WHO/HIV Assays: Operational Characteristics, Report 14/Simple/Rapid tests (2004); page 3
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 5
Background cont’d Strategy III
Based on three tests that use different antigen preparations and/or different test principles
Serum reactivity on all three tests is considered HIV antibody positive
Serum that remains discordant in the second assay, or is reactive in the first & second but non-reactive in the third test, is considered indeterminate Redraw
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 6
Methods Study design
HVTN initiated 15 phase-I and one phase-II vaccine trials in the United States since January 2004 at the following 13 study sites in 12 cities:
US HIV Vaccine Trial Network (HVTN) Sites
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 7
Methods cont’d A routine diagnostic algorithm that distinguished
between vaccine-induced seropositivity and true HIV infection was used for participants who completed these clinical trials after March 2006
Testing was performed by the HVTN HIV diagnostic laboratory in Seattle, Washington
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 8
Methods cont’d Algorithm
Three enzyme-immunoassay (EIA) test kits were used Abbott HIVAB HIV-1/HIV-2 (rDNA) EIA (3rd generation) bioMerieux Vironostika HIV-1 Microelisa System (1st generation) Bio-Rad Genetic Systems HIV1/2 Plus O EIA (3rd generation)
A specimen that was reactive in all three EIA tests (Strategy III criterion for asymptomatic HIV infection with a prevalence of ≤10%) or was repeatedly reactive in one or two of the three EIA tests was confirmed by the Bio-Rad Genetic Systems HIV-1 Western Blot (WB)
HIV-1 RNA testing was used to confirm all indeterminate or positive WB results
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 10
Figure 1
EIA test results (N=733)
Non-reactive Reactive0
50100150200250300350400450
(57.4%)
(42.6%)
312
421
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 11
Figure 2Western blot results (N=312)
0
100
200
108
157*
47*
(34.6%)
(50.3%)
(15.1%)
* All specimens were HIV-1 RNA undetectable(<30 RNA copies/mL of plasma)
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 12
Figure 3Number of reactive EIA kits and Western blot result (INDETERMINATE or
POSITIVE; Total = 204 Participants)
0
10
20
30
40
50
60 59 59
39
1
32
14
12/6/07 v.3 CDC 2007 HIV Diagnostic Conference 13
Table 1: Participants with a reactive Western blot (N=204)
Reactive EIA test kit
WB result Number Percent
Bio-Rad Indeterminate 62 30.4
False-positive 14 6.8
Abbott Indeterminate 152 74.5
False-positive 47 23.0
bioMerieux Indeterminate 80 39.2
False-positive 46 22.5
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Summary of HIV-1 infection status The UNAIDS/WHO Testing Strategy III assigned
53/733 (7.2%) of these uninfected vaccine participants as HIV-1 infected using EIA criteria
Fourteen (26%) of these 53 participants had a positive (confirmed) Western blot using CDC criteria and would have been assigned as HIV-1 infected
An additional 33 participants were infected using CDC criteria, for a total of 47/733 (6.4%)
Importantly, all 86 (11.7%) participants (EIA + or WB + or both) were HIV-1 uninfected using HIV RNA criteria
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Conclusions In the United States, current HIV-1 diagnostic
algorithms based solely on serologic criteria for infection are inadequate for diagnosing HIV-1 infection in HIV vaccine trial participants because of vaccine-induced false-positive confirmatory Western blot results
Similar concerns may be associated with EIA-based algorithms specified by UNAIDS/WHO for resource-limited countries with a seroprevalence of ≤10%
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Conclusions cont’d As such, future diagnostic algorithms should
incorporate HIV nucleic acid testing Finally, to reduce potential harm for vaccine trial
participants, HIV testing outside of the study protocol should be approached with caution until health care providers are educated about HIV vaccines and the need for diagnostic algorithms that incorporate HIV nucleic acid testing (see poster by CJ Cooper et al: Implications for HIV testing outside of the study during preventative HIV vaccine trials in the United States)