Original Article
Prevalence of Human Immunodeficiency Virus Type 1 p24 Antigen in U.S. Blood Donors — An Assessment of the Efficacy of Testing in Donor Screening
N Engl J Med 1990; 323:1312-1317November 8, 1990
- Abstract
- Abstract
Background.
We performed a multicenter study in 1989 to determine whether screening whole-blood donors for human immunodeficiency virus type 1 (HIV-1) p24 antigen would improve transfusion safety by identifying carriers of the virus who are seronegative for HIV-1 antibody.
Methods.
More than 500,000 donations were tested at 13 U.S. blood centers with test kits from two manufacturers. Units found repeatedly reactive were retested in a central laboratory; if the results were positive, they were confirmed by a neutralization assay. A subgroup of units was also tested for HIV-1 by the polymerase chain reaction. Selected donors confirmed or not confirmed as having p24 antigen were contacted for follow-up interviews to identify risk factors and undergo retesting for HIV-1 markers.
Results.
Positive tests for p24 antigen were confirmed by neutralization in five donors (0.001 percent of all donations tested), all of whom were also positive for HIV-1 antibody and HIV-1 by polymerase chain reaction. Three of the antigen-positive donors had other markers of infectious disease that would have resulted in the exclusion of their blood; two had risk factors for HIV-1 that should have led to self-exclusion. Of 220 blood units with repeatedly reactive p24 antigen whose presence could not be confirmed by neutralization (0.04 percent of the donations studied), none were positive for HIV-1 antibody, HIV-1 by polymerase chain reaction (120 units tested), or virus culture (76 units tested) — attesting to the specificity of confirmatory neutralization.
Conclusions.
The finding that no donation studied was positive for p24 antigen and negative for HIV-1 antibody suggests that screening donors for p24 antigen with tests of the current level of sensitivity would not add substantially to the safety of the U.S. blood supply. (N Engl J Med 1990; 323:1312–7.)
Article Activity
- Article
THE combination of donor education and self-exclusion with serologic testing has proved very effective in reducing the incidence of infection with human immunodeficiency virus type 1 (HIV-1) as a result of transmission by transfusion.1 , 2 There is a residual risk, however, because of the prolonged interval between infection and seroconversion3 and because some donors with recent infections may not report or may not perceive the high risk of the behavior that resulted in their exposure.4 The current risk of HIV transmission from screened blood is not known, but it has been estimated to range from 1 in 38,000 to 1 in 153,000.2 , 5 6 7
A screening procedure to detect the virus itself rather than the immune response to the virus might diminish the risk of transmission by transfusion by narrowing the interval during which infected donors lack serologic evidence of their HIV-1 infection. HIV-1 p24 antigen has been shown to appear in the blood early in HIV-1 infection and may precede the appearance of detectable HIV-1 antibody (anti-HIV-1).8 9 10 To evaluate the potential usefulness of screening donors for p24 antigen, approximately half a million donations were tested to determine the frequency with which the antigen could be detected in the absence of anti-HIV-1 and other markers of infectious disease currently used as a basis for donor exclusion.
Methods
Study Design
The study was performed in 1989 under an Investigational New Drug exemption from the Food and Drug Administration. All the subjects gave informed consent. Thirteen blood centers likely to screen the enrollment target of 500,000 U.S. blood donations during the projected study period, were selected for their geographic distribution and their representation of areas of both high and low prevalence of HIV-1. The testing period in each blood center was generally limited to three months to minimize the number of repeat donations; the linkage of the donor's identity to each sample ensured that no donor positive for p24 antigen would be counted twice in the subsequent analysis.
Initial testing for p24 antigen was performed at the blood centers at the time of donation. Blood units found to be repeatedly reactive for the antigen were shipped to a central laboratory where repeat and confirmatory testing, including neutralization assays for p24 antigen, were performed and where samples were selected and distributed under code for HIV-1 testing by the polymerase chain reaction.
In the second phase of the study, donors with confirmed or unconfirmed reactivity for p24 antigen and appropriate control donors were recalled for the assessment of behaviors likely to have led to HIV-1 exposure and for follow-up testing, including the polymerase chain reaction, viral isolation, and determination of anti-HIV-1 status.
Functions of the Blood Centers
The blood centers used one of three investigational assays for p24 antigen provided by two manufacturers (Abbott Laboratories, North Chicago, and Coulter Immunology, Hialeah, Fla.). One of the assays was licensed by the FDA during the study. Testing for p24 antigen at the blood centers was done in conjunction with standard testing for infectious diseases; the results of tests for other viral markers were not known before the selection of samples for p24-antigen testing. Because of the limited availability of test kits and personnel, not every donation from each center was tested. The samples tested generally represented those first available, up to the maximal daily testing capacity of the laboratory. Donors of blood for autologous and directed transfusions and for apheresis represented less than 4 percent of the total population tested.
Samples found to be initially reactive for p24 antigen were retested in duplicate. A sample was considered repeatedly reactive if it was reactive on at least one of the two repeat tests. All blood products from a repeatedly reactive donation were quarantined and shipped immediately to the central laboratory.
Functions of the Central Laboratory
At Blood Systems Central Laboratory, the study's reference laboratory, all repeatedly reactive blood units and randomly selected units negative for p24 antigen were processed to separate and freeze the plasma and isolate lymphocytes for cryopreservation in 10 percent dimethyl sulfoxide. Representative pairs of lymphocyte and plasma samples were shipped frozen to the FDA for detection of the HIV-1 gene sequence by polymerase chain reaction.
All blood units received from the blood centers were tested in duplicate for p24 antigen by each of the two manufacturers' assays. Those found repeatedly reactive on either assay were tested further for p24-antigen specificity with the neutralization test established for that assay.
Follow-up Epidemiologic and Laboratory Investigations
All donors with positive (neutralized) antigen assays were notified of their test results at the local blood center, asked to participate in the follow-up study, and asked to sign a separate consent form for retesting and a personal interview. A sample of donors whose p24-antigen assays were repeatedly reactive but not neutralized and a sample of control donors negative for both p24 antigen and anti-HIV-1 were randomly selected for follow-up at eight blood centers that were participating concurrently in a study of HIV-1—seropositive blood donors conducted by the Centers for Disease Control (CDC).11
The study subjects and controls were interviewed by trained CDC study interviewers who used a standardized questionnaire to identify risks for HIV-1 infection; demographic data about the donors and a history of their blood donations were abstracted from the records of the blood banks. In addition, a follow-up blood specimen was collected at least one month after the original donation for repeat p24 antigen and anti-HIV-1 testing, and in some study subjects for the detection of HIV-1 by polymerase chain reaction and lymphocyte cocultivation.
p24-Antigen Screening and Neutralization
The HIV-1 p24-antigen testing used the following enzyme immunoassays (EIAs): HIV AG-1 EIA (Abbott Laboratories; total incubation time, 24 hours), HIV-1 Antigen Monoclonal EIA (Abbott; incubation time, 6 hours), and Coulter HIV Ag Assay (Coulter Immunology; incubation time, 3 hours).
Blood samples were considered negative unless they were repeatedly reactive. Those that were found repeatedly reactive were tested by the respective manufacturer's confirmatory neutralization assay. Confirmatory neutralization tests were repeated in duplicate if the percentage of neutralization was 20 percent or more. In each neutralization assay, a sample was considered positive if the neutralization (the reduction in the optical-density absorbance signal) was 50 percent or more, as compared with controls.*
Proficiency Testing
Proficiency samples containing 332 and 111 pg of HIV-1 p24 antigen per milliliter were assayed 237 and 238 times, respectively, in the 13 laboratories and were always found to be reactive. A sample containing 36 pg per milliliter was assayed 213 times and found to be positive in 85 percent of the tests; a sample containing 12 pg per milliliter was assayed 167 times and found to be reactive less than 5 percent of the time. There was only one false positive result among the 497 negative control assays. The level of proficiency was equivalent in all the blood centers and the central reference laboratory, and the results were similar for the three different assays.
Anti-HIV-1 Testing
At the central laboratory, anti-HIV-1 was measured with a commercially available HIV-1 enzyme-linked immunosorbent assay kit (Du Pont, Wilmington, Del.). Blood samples that were repeatedly reactive for anti-HIV-1 were tested by Western immunoblotting with the FDA-licensed Biotech/Du Pont HIV Western Blot Kit (Du Pont), and the results were interpreted according to the package insert.
Gene Amplification by Polymerase Chain Reaction
Nucleic acid extracts from serum or peripheral-blood lymphocytes were amplified by the polymerase chain reaction as described elsewhere,12 , 13 with use of primer pairs from the gag (SK38/39) and env (SK68/69) regions of HIV-1 and a commercially available reagent kit (Perkin—Elmer Cetus, Emeryville, Calif). A positive result on the polymerase chain reaction was defined as a visible band with both gag and env probes at the molecular weights expected for the properly amplified sequences. In the case of samples with a negative polymerase chain reaction for HIV-1, the quality of the sample was verified by the presence of an amplified gene product with primers to the HLA-DQ alpha locus.14
Viral Isolation
Cell specimens collected from the donor at the time of follow-up were cocultivated with peripheral-blood lymphocytes for the isolation of HIV-1 as described elsewhere.15 Lymphocyte cultures were considered positive if elevated levels of reverse transcriptase were detected in the culture fluid.
Statistical Analysis
The subgroups were compared with respect to the presence of risk factors with use of the standard, unadjusted chi-square statistic whenever the expected values in each cell exceeded 5; otherwise, the two-sided Fisher's exact test was used.
Results
Characteristics of the Study Population
Between January 1 and June 30, 1989, samples from 515,494 donated units of blood were tested for p24 antigen. The number of donations tested at each center ranged from 16,905 to 61,661 (Table 1Table 1
Prevalence of Transfusion-Transmitted Viral Markers in Donor Populations Studied for p24 Antigen.*).Data on the sex of the donors were available from 12 centers (representing 88 percent of the donors); 47 to 60 percent of the donors at these centers were male (median, 56 percent). Data on age were available from eight centers (representing 54 percent of the donors); the median age ranged from 30 to 38 years. At the five centers that provided data on race and ethnicity, 87 percent of the donors were white, 5 percent black, 5 percent Hispanic, and 3 percent from other groups.
Serologic Markers of Transfusion-Transmitted Viruses
Aggregate data on the seroprevalence of anti-HIV1 were available for all donations, and at most centers for the donations tested specifically for p24 antigen. Of all donations tested, the proportion of units positive for HIV-1 on immunoblotting was 0.021 percent (range, 0 to 0.065 percent) (Table 1). Among donors tested for p24 antigen, the proportion was estimated to be 0.018 percent (Table 1). The centers with the highest prevalence of anti-HIV-1 during this period did not consistently have the highest seroprevalence of the other viral markers.
Screening Assays for p24 Antigen
Of 515,494 donor samples tested for p24 antigen at the blood centers, 0.43 percent were initially reactive (range, 0.06 to 0.56). Of these samples, only 18 percent were repeatedly reactive, for an overall rate of repeated reactivity in the blood-center laboratories of 0.08 percent (range, 0.02 to 0.17). Among the repeatedly reactive samples identified in the blood centers and retested at the central laboratory, 58 percent (representing 0.05 percent of the total population) were verified as repeatedly reactive; 50 percent of the samples that were not reactive in the central laboratory had optical-density readings at the blood centers that were less than 25 percent above the cutoff value of the assay.
Confirmatory Testing
Neutralization of p24 Antigen
As indicated in Figure 1Figure 1
p24 Antigen and Anti-HIV-1 Status of the Study Donors, with Results of the Analysis for HIV-1 Specificity., of the 515,494 donations initially screened for p24 antigen, 515,248 were negative and 225 were repeatedly reactive on EIA in both the blood-center and the central laboratories. twenty-one samples that were repeatedly reactive in the blood centers were unavailable for follow-up and were excluded from further analysis. Of the 225 repeatedly reactive samples, 220 were negative for anti-HIV-1 and failed to neutralize in the neutralization assay for p24 antigen. The other five repeatedly reactive samples were both positive for anti-HIV-1 (on EIA and Western blotting) and neutralized in the confirmatory assay for p24 antigen; the degree of neutralization was 100 percent in four samples and 77 percent in the fifth sample. The five samples that were neutralized represented 2.2 percent of the repeatedly reactive units and 0.001 percent of the total population. None of the five neutralized samples were positive for p24 antigen by both manufacturers' assays.Polymerase Chain Reaction
As shown in Figure 1, the five samples repeatedly reactive for p24 antigen that also neutralized were all positive by the polymerase chain reaction. In contrast, none of the 120 donors who had repeatedly reactive samples that failed to neutralize had positive results on the polymerase chain reaction (55 percent of such samples were tested by the polymerase chain reaction). The polymerase chain reaction was also negative for 32 donors whose samples were repeatedly reactive in the blood-center laboratories but nonreactive in the central laboratory (19 percent of such samples were tested). In additional testing, the polymerase chain reaction was negative in 50 samples from donors whose blood was nonreactive on EIA screening for both p24 antigen and anti-HIV-1, and it was positive in 9 controls positive for anti-HIV-1 but negative for p24 antigen.
Follow-up Investigations
The eight centers that participated in the follow-up study collected 286,289 of the 515,494 study donations (55 percent). These centers reported a somewhat higher rate of positivity for anti-HIV-1 than the other participating centers (0.022 vs. 0.014 percent), and they identified all five donors who had repeatedly reactive assays for p24 antigen that were confirmed by neutralization.
The characteristics of the five donors with confirmed p24 antigen are shown in Table 2Table 2
Epidemiologic and Laboratory Data on Five Male Blood Donors Confirmed as Positive for p24 Antigen.*. All five were men, and four were under the age of 30; three had other markers of infectious disease that would have resulted in their exclusion as donors. One donor confirmed as positive for p24 antigen was lost to follow-up and could not be evaluated further. Among the four donors available for follow-up, two were first-time donors, one of whom was making a directed donation, and three had identified risk factors for HIV-1 infection; two were homosexual men, and one had received blood in 1981 from a donor who was subsequently implicated in a case of the acquired immunodeficiency syndrome (AIDS) that was transmitted by transfusion. The proportion of persons with HIV-1 risk factors among the donors with confirmed p24 antigen (three of four) was significantly higher (P<0.001 by Fisher's exact test) than among the seronegative controls, of whom 2 of 67 (3 percent) reported known risk factors for HIV-1 exposure.Follow-up laboratory evaluation in the four donors with p24 antigen confirmed by neutralization showed that three remained positive for p24 antigen after a mean sampling interval of 81 days (range, 71 to 90); one was negative for p24 antigen on retesting 56 days after the initial donation. The loss of detectable p24 antigen in this donor was accompanied by an evolution of the Western blot banding pattern in a manner consistent with recent HIV-1 infection. Each of these four donors confirmed as positive for p24 antigen had been positive for anti-HIV-1 and positive by the polymerase chain reaction on initial evaluation, and each remained positive on follow-up. HIV-1 was isolated in lymphocyte culture from one of the four.
In addition to the donors with p24 antigen that neutralized, 110 donors from these eight blood centers were contacted because their serum was repeatedly reactive but failed to neutralize. Of the 110, 79 (72 percent) could be located and agreed to participate in the study; they did not differ from the remaining 31 with respect to median age (40 vs. 41 years, respectively) or sex (60 vs. 47 percent male) but were significantly more likely to have donated previously (94 vs. 66 percent, P<0.001).
Follow-up laboratory testing was performed in 78 of the 79 donors whose original tests for p24 antigen were reactive but failed to neutralize; only 51 (65 percent) remained repeatedly reactive for p24 antigen. In none of these 51 donors did p24 antigen neutralize, nor was anti-HIV-1 detected in the follow-up samples obtained a median of 99 days (range, 21 to 254) after the initial donation reactive for p24 antigen. In addition, none of the 76 tested were positive by the polymerase chain reaction or on viral culture.
Eight of the 79 donors (10 percent) in the group with p24 antigen whose serum samples failed to neutralize had risk factors for HIV-1 infection. Three had received a blood transfusion before 1985, two were homosexual men, one had used intravenous drugs, and two were women who had had sexual contact with men at increased risk for HIV-1 infection. Although this represented a higher proportion of donors with risk factors for HIV-1 than that observed in the control population negative for p24 antigen (2 of 67, 3 percent), the difference was not statistically significant (P = 0.11 by Fisher's exact two-tailed test).
Discussion
Although only a small number of HIV-1 infections have been attributed to transfusion with blood tested for anti-HIV-1,2 persistent public concern about the residual risk has prompted efforts to identify screening tests for donors that would indicate seropositivity earlier in the course of HIV-1 infection. One suggestion for further risk reduction has been that blood donors be tested for p24 antigen. This recommendation was based in part on the observation that in prospectively followed persons at high risk for HIV-1 infection,9 , 10 in plasmapheresis donors,17 and in experimentally infected chimpanzees,18 the presence of p24 antigen occasionally preceded the appearance of anti-HIV-1. In addition, p24 antigen has been detected in the absence of anti-HIV-1 during the mononucleosis-like syndrome that sometimes heralds the onset of HIV-1 infection.19
Despite these observations, the effect of screening for p24 antigen is anticipated to be small, for several reasons. First, the prevalence of HIV-1 infection in the donor population has declined.7 Second, the period during which antigen could be detected (generally less than two weeks) is short as compared with the average interval between donations (32 weeks).20 In addition, efforts to improve the effectiveness of donor self-exclusion have been intensified and now include direct questioning about high-risk behavior. Finally, even in very high risk settings, such as clinics for sexually transmitted diseases, the detection of p24 antigen in the absence of anti-HIV-1 or other markers of infectious disease that result in the exclusion of the donor is unusual.21
The results of this study provide a strong argument against the need to introduce currently available tests for p24 antigen into programs for the routine screening of blood donors. Although 0.05 percent of the donated units had repeatedly reactive results on p24-antigen testing that could be reproduced in the reference laboratory, only five donors (0.001 percent) had a repeatedly reactive sample that was also positive in the neutralization assay used to determine the specificity of the reaction. Each of these five donors was also positive for anti-HIV-1 and demonstrated HIV-1 gene sequences by the polymerase chain reaction. Hence, no blood unit among the 515,494 tested had a confirmed test for p24 antigen in the absence of anti-HIV-1. Furthermore, of the estimated 93 donors seropositive for anti-HIV-1 on Western blotting in the study population (0.018 percent of 515,494) (Table 1), only 5 were confirmed as positive for p24 antigen, demonstrating the low sensitivity of this assay in screening for HIV-1—infected donors.
Several additional observations are noteworthy. First, one donor positive for p24 antigen appeared to be in an early stage of HIV-1 infection, as indicated by an evolving Western blot pattern on the follow-up sample; even in this case, anti-HIV-1 testing was sufficient to detect the infection. Second, three of the five donors positive for p24 antigen would have been excluded by surrogate assays (such as those for hepatitis B core antibody and alanine aminotransferase) currently used in the routine screening of blood donors. Third, two of the five donors had a risk factor for HIV-1 infection (homosexual contact) that should have resulted in self-exclusion. Methods of improving the process of self-exclusion are currently being developed and may be as efficient as additional testing. One of the donors subsequently found to have engaged in high-risk behavior was making a directed donation. There are no data demonstrating that blood from donors selected by the patient is safer than blood from random volunteer donors22; conversely, as shown in this study, it has been reported that directed donors may not report behavior that places them at risk for HIV-1 infection.23
The follow-up study served not only to provide additional information on donors positive for p24 antigen but also to affirm the validity of the neutralization assay in distinguishing true positive from false positive screening results. Although the presence of HIV-1 infection was confirmed by the detection of anti-HIV-1 and HIV-1 gene sequences in all the neutralized samples, none of the donors whose samples failed to neutralize were found to be positive for anti-HIV-1, positive by the polymerase chain reaction, or positive for HIV-1 on culture initially or during follow-up. Hence, it is unlikely that the repeatedly reactive, nonneutralized samples represented infections with HIV-1.
The finding of no donations that were negative for anti-HIV-1 and positive for p24 antigen among the half million tested corroborates similar negative results in a study of more than 295,360 German blood donors performed in 1987 and 198824 and in a study of 4367 young male donors in San Francisco in 1984 and 1985.25 Because of the high prevalence of anti-HIV-1 in donors at the time of the San Francisco study, it was estimated that a sample of 4367 donors in 1984 and 1985 would be the equivalent of a sample of 475,000 donors today.25 Hence, in three large field studies, no donor has been found to be both positive for p24 antigen and negative for anti-HIV-1. Furthermore, a model designed to assess the potential benefit of testing for p24 antigen estimated that the introduction of such a test would result in the detection of no more than one additional blood unit infected with HIV-1 in each 4,860,000 units tested.20 These data do not imply that there will never be a unit infected with HIV-1 that is detectable only by the p24-antigen test, but they emphasize the extreme rarity of such an event.
These data from volunteer donors of whole blood who donate infrequently cannot necessarily be extrapolated to plasma donors who receive payment and donate frequently. Therefore, the data do not contradict a previous report of the detection of p24 antigen in the absence of anti-HIV-1 in such a population.17 However, universally applied procedures of viral inactivation have virtually eliminated the transmission of HIV-1 by the transfusion of plasma derivatives — implying that additional testing for p24 antigen is unnecessary in plasmapheresis donors.
The 95 percent confidence limit for zero observations was 7.4 per million in the present study and would be still lower if the worldwide experience were considered. This suggests that p24-antigen assays of the current level of sensitivity will not add appreciably to the rate of detection of carriers of HIV-1 infection. Thus, this study does not support the implementation of routine testing for p24 antigen in blood donations at the present time. This conclusion may need to be revised if tests of markedly increased sensitivity are developed.
Supported by a contract (223–89–1000) with the Food and Drug Administration and by the American Association of Blood Banks and the AABB Foundation.
Presented in part at the annual meeting of the American Association of Blood Banks, October 23–26, 1989, in New Orleans.
*The members of the HIV-Antigen Study Group were as follows: American Red Cross — Northeast Region: Mark Popovsky and Hilda McDonald; Penn—Jersey Region: Jay Herman, William Sherwood, and Jan Forey; Chesapeake Region: Kate Rothko, Paul Ness, and Sandy Ellisor; Atlanta Region: Gerald Shulman and Alfred Grindon; Los Angeles—Orange County Region: Steven Kleinman; South Florida Region: Bruce Lenes and Peter Tomasulo; Oklahoma Blood Institute — Ron Gilcher, Linda Chandler, and Linda Belcher; Gulf Coast Regional Blood Center — Pablo Fortes and David Fortenberry; Blood Center of Southeast Wisconsin — Jay Menitove; Blood Systems, Inc. — Ernest Simon; Irwin Memorial Blood Bank — Mike Busch and Herbert Perkins; Sacramento Blood Center — Robert Randell and Paul Holland; Southwest Florida Blood Bank — German Leparc and Paul Schmidt; and Centers for Disease Control — Mark Rayfield, Lynda Doll, and Lyle Peterson.
Source Information
From the National Institutes of Health (H.J.A., M.J.V., R.A.K., H.G.K.) and Warren G. Magnuson Clinical Center, the Food and Drug Administration (J.S.E., I.K.H.), both in Bethesda, Md.; the Blood Systems Central Laboratory, Scottsdale, Ariz. (S.G. Swenson); the Centers for Disease Control, Atlanta (J.W.W.); the Milwaukee Blood Center, Milwaukee (J.E.M.); the American Red Cross, Washington, D.C. (S.G. Sandler); the Puget Sound Blood Center, Seattle (M.H.S.); and the American Association of Blood Banks, Arlington, Va. (A.I.C.).
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See NAPS document no. 04810 for three pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada add postage of $4.50 ($1.50 for microfiche postage).
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