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Persistent Lack of Detectable HIV-1 Antibody In a Person With HIV Infection -- Utah, 1995

Infection with human immunodeficiency virus (HIV) is diagnosed routinely by the enzyme immunoassay (EIA) for HIV-1 antibody; a nonreactive blood sample is designated as negative without further testing. However, one limitation of this screening algorithm is that a blood sample may be obtained from a patient with recent HIV infection before detectable HIV antibody is present ("window period"). This report describes a patient with confirmed HIV infection in whom EIAs for HIV antibody (HIV-EIAs) were persistently negative beyond the expected "window period." *

Case Investigation

In October 1995, the Utah Department of Health referred to CDC blood samples obtained from a man who had had onset of persistent fatigue and malaise during January 1995. During January-June 1995, he had sought medical care at several clinics. When he was admitted to a hospital in June because of respiratory illness and recent weight loss of 27 lbs, HIV-EIA was negative. In August, he was admitted with lung-biopsy-confirmed Pneumocystis carinii pneumonia (PCP) and a CD4+ count of 129 cells/uL; an HIV-EIA again was negative. The patient reported frequently donating plasma at a plasmapheresis center from August 1990 through April 1994. Review of records at the plasmapheresis center identified 33 donations by the patient. At the time of each donation, testing on an aliquot of the donated plasma was negative by HIV-EIA (Table_1).

The patient was married and reported sexual contact without condom use with his wife during 1989-1993; the couple separated in 1993 and had no further sexual contact. The wife was interviewed and reported sexual contact during 1985-1989 with a bisexual man who had died of acquired immunodeficiency syndrome (AIDS) in 1994. In January 1994, she was diagnosed with PCP and HIV infection (HIV-EIA positive). When the patient became aware of his wife's HIV infection in May 1994, he was tested and was HIV-EIA negative (Table_1). The patient denied male-to-male sexual contact or receipt of a transfusion. He had used multiple nonparenteral illicit drugs, but denied injecting-drug use.

Laboratory Investigation

Two blood samples obtained in October and in December 1995 were analyzed by CDC and the Food and Drug Administration (FDA). Both samples were weakly reactive for antibody (signal/cutoff ratio less than 2.2) when tested by the HIV-EIA kit from manufacturer A, but were negative by kits from manufacturers B and C.

Because antibody detection assays were negative or weakly positive, additional assays were conducted. Assays for HIV-1 p24 antigen using the kit from manufacturer D on both samples were so weakly reactive that neutralization assays were invalid; however, after the samples were subjected to base dissociation to disrupt immune complexes, the p24-antigen results became strongly reactive and neutralizable. Antigen results also were positive using EIA kits from manufacturers E and F without immune complex disruption, including a positive neutralization test (kit E). HIV infection was diagnosed based on the positive p24-antigen test results.

Testing also was conducted to evaluate whether the persistent seronegativity was attributable to infection with an atypical virus or to lack of immune competence. HIV proviral DNA present in the peripheral blood mononuclear cells from the patient and his wife was amplified by a nested polymerase chain reaction (PCR) and sequenced directly. The results indicated that the HIV sequences from the patient and his wife were closely related **, and that these HIV strains were subtype B viruses, the HIV subtype predominant in the United States. Immunologic evaluation of specimens obtained from the patient in August 1995 detected normal levels of serum immunoglobulin G, immunoglobulin M, and immunoglobulin A and a positive immunoglobulin G titer to Epstein-Barr virus and cytomegalovirus.

Reported by: L Reimer, MD, Veterans Affairs Medical Center and Univ of Utah; C Brokopp, DrPH, S Mottice, PhD, R Den, C Nichols, MPA, State Epidemiologist, Utah Dept of Health. Salt Lake City Resident Post and Office of Blood Research and Review, Food and Drug Administration. Div of HIV/AIDS Prevention, National Center for Prevention Svcs; Div of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: This report documents persistently negative HIV test results from an HIV-infected man. HIV-infected blood may test EIA negative for HIV antibody for at least three reasons. First, infectious blood may be tested during the "window period." Second, infections with divergent HIV strains (e.g., group O viruses) may not be detected by EIAs designed to detect antibody to HIV-1 and HIV-2 (1). However, a recently completed retrospective study in the United States did not document any serum samples with peptide reactivity consistent with HIV-1 group O infection (2). In the case described in this report, genetic analysis indicated that the husband and wife were infected with similar subtype B strains, typical of HIV-1 strains found in the United States. Third, although HIV-infected patients who are initially HIV seropositive have been reported to become seronegative (serorevert) (3), this phenomenon is rare when current HIV-EIAs are used (4).

The persistently seronegative status of the patient described in this report was not associated with one of the previously recognized reasons. Based on the similarity of the genetic sequences between the patient and his wife and results of the epidemiologic investigation, the most likely mode of HIV transmission to the case-patient was by heterosexual contact with his HIV-infected wife; the persistent seronegativity probably resulted from an atypical host response and not from infection with an atypical viral strain. A small number of such patients have been reported previously (5,6); in these cases, disease progression has been rapid, and diagnostic specimens were collected and analyzed only after the patient became ill.

Plasma obtained by plasmapheresis (source plasma) is either heat-treated or treated by a solvent/detergent process to inactivate HIV. Because the products derived from pools containing these donations were treated, no recall of plasma derivatives was initiated. CDC has not received reports of instances of HIV transmission by plasma products processed according to recommended procedures to inactivate HIV. In comparison, whole-blood donations are not treated, and failure to detect HIV antibody in an infected person is a safety concern for whole-blood donations. The blood supply in the United States is screened through predonation donor deferral based on history of exposure risks and postdonation laboratory testing (7). Of the 12 million units of blood donated in the United States annually, an estimated 32-49 blood components are potentially infectious for HIV and available for distribution by blood banks for infusion into patients -- primarily because of "window period" donations (8). Since screening of donated blood began in 1985, a total of 35 cases of AIDS have been associated with receipt of "window period" donations; the sensitivity of the screening test has improved during this period.

FDA recently issued guidelines to blood and plasma establishments (e.g., plasmapheresis centers) and recommends that all blood and plasma donations be screened for HIV-1 p24 antigen beginning within 3 months of the licensing of a test kit for screening use (9). Although this recommendation was promulgated primarily to decrease the number of "window period" HIV-seronegative blood donations, p24-antigen testing may have an additional benefit of identifying blood from the rare HIV-infected donor with persistently undetectable HIV antibody. Kits to detect HIV-1 p24 antigen have not yet been licensed for screening purposes by FDA, but one or more such tests are expected to be licensed soon. The Public Health Service has issued guidelines for testing and counseling blood and plasma donors with HIV-1 p24 antigen (10).

Although the conditions characterizing the case described in this report are rare, such cases must be diagnosed correctly. Physicians who treat patients with AIDS-defining conditions -- but for whom EIAs fail to detect HIV antibody -- should seek specialized laboratory assistance from their state or local health departments. Laboratory procedures such as antigen testing, antigen testing after immune complex disruption, DNA-PCR, and reverse-transcriptase PCR can assist in defining the HIV-infection status of such persons.

References

  1. Schable C, Zekeng L, Pau CP, et al. Sensitivity of United States HIV antibody tests for detection of HIV-1 group O infections. Lancet 1994;344:1333-4.

  2. Pau CP, Hu DJ, Spurill C, et al. Surveillance for HIV-1 group O infections in the United States. Transfusion 1996 (in press).

  3. Farzadegan H, Polis MA, Wolinsky SM, et al. Loss of human immunodeficiency virus type 1 (HIV-1) antibodies with evidence of viral infection in asymptomatic homosexual men: a report from the Multicenter AIDS Cohort Study. Ann Intern Med 1988;108:785-90.

  4. Roy MJ, Damato JJ, Burke DS. Absence of true seroreversion of HIV-1 antibody in seroreactive individuals. JAMA 1993;269:2786-9.

  5. Martin-Rico P, Pedersen C, Skinhoj P, Nielsen C, Lindhardt B. Rapid development of AIDS in an HIV-1-antibody-negative homosexual man. AIDS 1995;9:95-6.

  6. Soriano V, Dronda F, Gonzalex-Lopez A, Chaves F, Bravo R, Gutierrez M. HIV-1 causing AIDS and death in a seronegative individual. Vox Sang 1994;67:410-1.

  7. Food and Drug Administration. Revised recommendations for the prevention of human immunodeficiency virus transmission blood and blood products {Memorandum to all registered blood and plasma establishments}. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Biologics Evaluation and Research, 1992.

  8. Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995;333:1721-5.

  9. Food and Drug Administration. Recommendations for donor screening with a licensed test for HIV-1 antigen {Memorandum to all registered blood and plasma establishments}. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Biologics Evaluation and Research, 1995.

  10. CDC. U.S. Public Health Service guidelines for testing and counseling blood and plasma donors for human immunodeficiency virus type 1 antigen. MMWR 1996;45(no. RR-2).

Single copies of this report will be available until March 8, 1997, from the CDC National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003; telephone (800) 458-5231 or (301) 217-0023. ** DNA sequence analysis determined that sequences from the patient and his wife differed by 7.4% over 345 nucleotides of the C2V3 region of the env gene, and 3.1% over 393 nucleotides of the p17 region of gag. Phylogenetic tree constructions demonstrated the close relation between the HIV sequences from the patient and his wife, with a bootstrap support of 98% and 100%, respectively, for each gene region.


Table_1
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Table 1. Laboratory results for a patient with HIV infection -- Utah, 1995
=========================================================================================================================

                                                                     HIV-1 Antigen
                   HIV-1 EIA *                                   signal/cutoff ratio @    Antigen test       Test
Date(s)          (Manufacturer)   Western blot   PCR +  RT-PCR &     (Manufacturer)          comments       location
-------------------------------------------------------------------------------------------------------------------------
June 1990-      33 Samples,                                                                                  Plasma
  April 1994    all negative (A)        ND **      ND      ND               ND                               Center

May 1994        Negative (B)            ND         ND      ND               ND                               UDH ++

June 1995       Negative (A)            ND         ND      ND               ND                               UVAMC &&

September 1995  Negative (A)            ND         ND      ND               ND                               UVAMC

September 1995  Negative (C)         Negative      ND      ND               ND                               UDH

October 1995    Negative (B)         Weak gag     IND @@  Positive        3.75 (D)       Not neutralizable   CDC
                                      bands                               7.48 (D)       Following immune    CDC
                                                                                          complex disruption
                                                                          3.47 (E)       Neutralization ND   FDA ***
                                                                         10.52 (F)       Neutralization ND   FDA
                Positive (A)                                                                                 FDA
                Negative (C)                                                                                 FDA
                Negative (B)                                                                                 FDA

December 1995   Negative (B)         Weak gag    Positive   ND            1.96 (D)       Not neutralizable   CDC
                                       bands                              9.84 (D)       Following immune    CDC
                                                                                          complex disruption
                                                                          2.77 (F)       Neutralization ND   FDA
                                                                          3.03 (E)       Positive
                                                                                          neutralization     FDA
                Positive (A)                                                                                 FDA
                Negative (C)                                                                                 FDA
                Negative (B)                                                                                 FDA
-------------------------------------------------------------------------------------------------------------------------
*  Enzyme immunoassay for HIV-1 antibodies.
+  Polymerase chain reaction.
&  Reverse-transcriptase PCR.
@  Ratio of sample optical density (OD) to minimum OD required for a positive test.
** Not done.
++ Utah Department of Health.
&& Utah Veterans Affairs Medical Center.
=========================================================================================================================

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