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Appendix 1
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HIV Antibody Testing -- Appendix 1: Performance Characteristics of Fourth-Generation Assays
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Appendix 1: Performance Characteristics of Fourth-Generation Assays
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References
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Back to Chapter: HIV Antibody Assays
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Appendix 1: Performance Characteristics of Fourth-Generation Assays
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A brief summary of the performance of fourth-generation assays, as reported in the literature(1-19), follows. A comparison of four of the commercial fourth-generation assays versus four third-generation antibody ELISAs using seroconversion panels reported that all four of the fourth-generation assays detected infection in fewer days than all the third-generation antibody ELISAs, thus supporting that these assays show promise in reducing the window period and detecting early infection. The VIDAS HIV DUO (bioMerieux), an earlier version of the VIDAS HIV DUO Ultra, demonstrated the highest sensitivity by detecting infection in the shortest number of days. Additional promising performances by fourth-generation ELISAs have been reported. These assays have demonstrated sensitivities ranging from 99.5 - 100%. Several studies with large sample sizes have reported sensitivities of 98 - 99.87% by the Vironostika HIV Uni-Form II Ag/AB, the Enzymun_-Test HIV Combi, AxSYM_ HIV Ag/AB, and the Enzygnost HIV Integral. Using seroconversion panels, several evaluations have calculated a reduction in the diagnostic window by a minimum of four days and some have even reported a reduction of up to nine days using the fourth-generation assays. The specificities have ranged from 98 - 100%, excluding one study that reported a specificity of only 88.2%. This latter study tested the performance of the HIV DUO with a sample size of only 250 potentially cross-reactive samples such as specimens from pregnant women, patients with autoimmune disorders or rheumatoid factor, patients reactive for IgM antibodies to cytomegalovirus, herpes simplex virus, rubella virus, or toxoplasmosis, and patients infected with hepatitis C or Epstein-Barr virus. Three of the four studies have reported sensitivities of 100% when testing samples from individuals with early and established infections. The only study reporting a sensitivity of 91.4% used 17 seroconversion panels, and thus assessed analytical sensitivity, not epidemiologic sensitivity (ability to detect established infection). In addition to the study noted above that reported a specificity of 88.2%, another study using the HIV DUO demonstrated a specificity ranging from 98.2 - 100% when small cohorts of potentially cross-reactive samples were tested. The fourth study reported a specificity of 99.5% in a very large, multi-center evaluation using samples from 29,657 patients. In addition to detecting all 453 HIV-infected individuals, the HIV DUO had the ability to detect early infection in 17 samples containing p24 antigen that were non-reactive by the reference third-generation assays and by Western blot, further supporting the benefits of adding the antigen testing component to a screening test. Interestingly, only 11 of the 17 samples had detectable levels of RNA, and all 17 resolved as acute infections upon follow-up testing. Our laboratory was the first to evaluate a new version, the VIDAS HIV DUO Ultra, with 2,847 samples and to utilize the largest variety of sample populations including hospitalized patients, outpatients, blood donors, HIV-2 samples, HIV-1 Group O samples, HIV-1 Group M clades, patients from three geographical locations, and seroconversion panels.(20) The VIDAS HIV DUO Ultra demonstrated 100% sensitivity and at least a 99.5% specificity overall, with a 99.7 % specificity in low-risk individuals. The analytical sensitivity, as assessed by seroconversion panels and p24 antigen in samples, was equivalent to, or better than, the reference assays used to characterize these panels. This assay, and others, not only detect antibody and antigen simultaneously, but also can discriminate by indicating which of the two analytes is positive.

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References

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1.   Weber B, Fall EH, Berger A, Doerr HW. Reduction of diagnostic window by new fourth-generation human immunodeficiency virus screening assays. J Clin Microbiol. 1998 Aug;36(8):2235-9.
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2.   van Binsbergen J, Keur W, Siebelink A, van de Graaf M, Jacobs A, de Rijk D, Nijholt L, Toonen J, Gurtler LG. Strongly enhanced sensitivity of a direct anti-HIV-1/-2 assay in seroconversion by incorporation of HIV p24 ag detection: a new generation vironostika HIV Uni-Form II. J Virol Methods. 1998 Dec;76(1-2):59-71.
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3.   van Binsbergen J, Siebelink A, Jacobs A, Keur W, Bruynis F, van de Graaf M, van der Heijden J, Kambel D, Toonen J. Improved performance of seroconversion with a 4th generation HIV antigen/antibody assay. J Virol Methods. 1999 Sep;82(1):77-84.
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4.  Donie F, Upmeier B, Hoess E and Faatz E: HIV screening with the Elecsys automated analyzer: combined testing for anti-HIV and HIV Ag within 18 minutes. 12th World AIDS Conference, Geneva. July 1998 (abstract 163/41102).
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5.   Martinez-Martinez P, Martin del Barrio E, De Benito J, Landinez R. New lineal immunoenzymatic assay for simultaneous detection of p24 antigen and HIV antibodies. Eur J Clin Microbiol Infect Dis. 1999 Aug;18(8):591-4.
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6.  Courouce AM and the Retrovirus Work Group at the S.F.T.S.: Combined screening tests for anti-HIV antibodies and p24 antigen. La Gazette de la Transfusion 1999, 155:4-18.
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7.  Faatz E, Donie F, Melhior W, Upmeier B, Seidel C: A new generation of HIV-diagnostic assay: results of the evaluation of the Enzymun-Tests HIV Combi. 12th World AIDS Conference, Geneva. July 1998 (abstract 41113).
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8.   Yerly S, Simon F, Perrin L. [Early diagnosis of primary HIV infections: using a combined screening test (p24 antigen and anti-HIV antibodies)].Schweiz Med Wochenschr. 1999 Feb 27;129(8):319-22. German.
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9.   Hayashi T, Watanabe S, Kondo M, Saito T, Imai M. [Evaluation of a new screening assay kit for the combined detection of HIV p24 antigen and antibody--comparison of the performance of the new kit and HIV antibody assay kits]. Kansenshogaku Zasshi. 1999 Jul;73(7):681-8. Japanese.
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10.  Tros C, Laan E: Evaluation of Organon Teknika's new Vironostika HIV Uni-Form II Ag/Ab assay. J Amer Assoc Blood Banks 1999, 39(10S):73S.
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11.  Schelstraete B, Bijnens BB and Wuyts G: Evaluation of Organon Teknika Vironostika HIV Uni-Form II Ag/Ab on the Ortho Summit Processor. J Amer Assoc Blood Banks 1999, 39(10S):74S.
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12.  Moncharmont P, Monneron P, Tsounias N: Evaluation of combined tests to human immunodeficiency viruses type 1 and 2 antibodies screening. J Amer Assoc Blood Banks 1999, 39(10S):73S.
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13.  Shah DO, Chang CD, Cheng K, Finley AK, Stewart JL: A prototype fully automated chemiluminescent screening assay for the combined detection of HIV antigens and antibodies. J Amer Assoc Blood Banks 1999, 39(10S):72S.
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14.  Brust S and Knapp S: A new combined HIV antigen/antibody screening assay reduces significantly the window period between HIV infection and seroconversion. XIII International AIDS Conference, Durban. July 2000 (abstract MoPeA2111).
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15.  West D, Hall-Steele G, Collins D, Daghfal D, Mullner M: Development of an HIV immunoassay combining antigen and antibody detection on an automated analyzer. XIII International AIDS Conference, Durban. July 2000 (abstract TuPeA2991).
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16.  Schalken J, van Binsbergen J, Jacobs A, Reddy R, Deltmann C, Siebelink A et al.: Vironostika HIV Uni-Form II Ag/Ab with almost HIV p24 Ag assay performance. XIII International AIDS Conference. Durban, July 2000 (abstract TuPeA2996).
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17.  Biron MP, Basse J, Jego J, Gadelle S: Reduction of the HIV diagnostic window with Genscreen Plus HIV Ag-Ab, a new combined p24 antigen and anti-HIV -1/2 antibody screening assay. XIII International AIDS Conference, Durban. July 2000 (abstract TuPeA3000).
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18.  Schmitt U, Andres H, Faatz E: HIV-screening with the COBAS CORE automated analyser: combined testing for anti-HIV and HIV Ag in one determination. XIII International AIDS Conference, Durban. July 2000 (abstract MoOrA112).
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19.   Ly TD, Edlinger C, Vabret A. Contribution of combined detection assays of p24 antigen and anti-human immunodeficiency virus (HIV) antibodies in diagnosis of primary HIV infection by routine testing. J Clin Microbiol. 2000 Jun;38(6):2459-61.
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20.   Saville RD, Constantine NT, Cleghorn FR, Jack N, Bartholomew C, Edwards J, Gomez P, Blattner WA. Fourth-generation enzyme-linked immunosorbent assay for the simultaneous detection of human immunodeficiency virus antigen and antibody. J Clin Microbiol. 2001 Jul;39(7):2518-24.
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