12/6/07 v.3CDC 2007 HIV Diagnostic Conference1 Diagnosis of HIV-1 Infection in Phase I & II HIV Vaccine Trials RW Coombs 1, J Dragavon 1, B Metch 2, CJ

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


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


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


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


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


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


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


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



Figure 1

EIA test results (N=733)

Non-reactive Reactive0

50100150200250300350400450

(57.4%)

(42.6%)

312

421


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)


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


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


bioMerieux Indeterminate 80 39.2



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


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%


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)


Acknowledgements NIAID/DAIDS funding for the HVTN HVTN HIV Diagnostic Laboratory staff University of Washington CFAR

Documents

12/6/07 v.3CDC 2007 HIV Diagnostic Conference1 Diagnosis of HIV-1 Infection in Phase I & II HIV Vaccine Trials RW Coombs 1, J Dragavon 1, B Metch 2, CJ