Biological False-Positive Syphilis Test Results for Women Infected with Human Immunodeficiency Virus

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1 1040 Biological False-Positive Syphilis Test Results for Women Infected with Human Immunodeficiency Virus Michael H. Augenbraun, Jack A. DeHovitz, Joseph Feldman, Lorraine Clarke, Sheldon Landesman, and Howard M. Minkoff From the Departments ofmedicine. Preventive Medicine and Community Health. Pathology. and Obstetrics-Gynecology. State University ofnew York Health Science Center at Brooklyn, Brooklyn. New York Regardless of the nontreponemal test used for the screeningand diagnosis of syphilis, biological false-positive results (BFPs) are documented in 1%-2% of all cases. An association between BFPs and human immunodeficiency virus (HIV) infection in men has been suggested. We conducted a cohort study to determine whether a similar association between HIV seropositivity and BFPs exists for women. Among 156 HIV-seropositive women, 9 (5.8%) had a BFP for syphilis. Among 633 HIV-seronegative women, only 1 (0.2%) had a BFP. When the 25 HIV-seropositive patients and 55 HIV-seronegative patients with reactive rapid plasma reagin tests and microhemagglutination assays for antibodies to Treponema pallidum were excluded from the calculations, 6.9% and 0.2% of HIV-seropositive and HIV-seronegativewomen, respectively, had BFPs (P < ; odds ratio, 39.45; 95% confidence interval, ). An association was found between injection drug use and BFPs for the population of HIV-infected women but did not entirely account for the differences between this group and the HIV-seronegative group. While remaining the cornerstones of syphilis screening and diagnosis, the nontreponernal serological tests (NTSTs)-including the VORL (Venereal Disease Research Laboratory) test, the RPR (rapid plasma reagin) test, and the TRUST (toluidine red unheated serum test)-are at best imperfect. One of the most vexing problems associated with NTSTs is the phenomenon ofbiological false-positive results (BFPs). NTSTs provide a nontreponemal substrate ofcardiolipin-cholesterol-lecithin as the antigen to which the patient's antibody must adhere [I]. In certain pathogenic and nonpathogenic physiological processes other than syphilis, antibodies with similar affinities may be produced. Such processes include aging, pregnancy, autoimmune disease, injection drug use, vaccination, and a variety ofbacterial and viral infections [2]. Infection with human immunodeficiency virus (HIV) and syphilis are significantly interrelated [3]. As sexually transmitted diseases (STDs), each is a marker for the other. In addition, syphilitic lesions probably facilitate the transmission of HIV [4]. while the immunosuppression associated with HIV infection may alter the natural history of syphilis and its response to therapy [5-7]. Received 18 January 1994: revised 8 April These data were presented in part at the 9th International Conference on AIDS held on 9-11 June 1993 in Berlin. Financial support: National Institutes of Health (AI3 I834-03). National Institute of Allergy and Infectious Diseases (NOI-AI ) and the Centers for Disease Control and Prevention/Contraceptive Research and Development Program (CSA ). Reprints or correspondence: Dr. Michael H. Augenbraun, Box 56 SUNY HSCB, 450 Clarkson Avenue. Brooklyn. New York Clinical Infectious Diseases 1994;19: by The University of Chicago. All rights reserved /94/ $02.00 Altered production of antibody is a well-recognized phenomenon in HIV infection and may be seen early or late in the course of infection [8, 9]. Its impact on the serological diagnosis ofsyphilis has been suggested by reports ofunusual serological findings in patients dually infected with Treponema pallidum and HIV [10, II]. Investigators in Baltimore reported that BFPs were more frequent among HlV-seropositive patients seen at an STD clinic than in their HIV -seronegative counterparts [12]. Although the population studied included both men and women, the association between HIV seropositivity and BFPs was documented only for men. While women in this study had an overall higher rate of BFPs, none were concomitantly HIV-seropositive. To determine whether BFPs are associated with HIV serological status in women, we evaluated the prevalence of BFPs in a population of HIV -infected women and in a group of HIVseronegative women from the same urban area. Methods Between September 1991 and May 1993, 156 HIV-infected women were enrolled in the Women's AIDS Cohort Study, a prospective investigation of the natural history of HIV infection in women. The study was conducted at a large inner-city medical center in Brooklyn, where enrollees were recruited from ambulatory care facilities serving HIV-infected women. Women who had a history ofan AIDS-defining illness (according to the 1987 case definitions of the Centers for Disease Control and Prevention [13]) were not eligible to participate. Six hundred thirty-three HIV-seronegative women from the same inner-city community who were enrolled in the Heterosexual AIDS Transmission Study served as controls. This study is a prospective examination of the behavioral and biological risk factors that determine HIV

2 CID 1994; 19 (December) BFPs for Syphilis in HIV-Infected Women 1041 Table 1. Demographic characteristics of HIV-infected and HIV-uninfected women enrolled in a study of the association of HIV infection and biological false-positive results in tests for syphilis. Value for indicated group Characteristic: HIV-positive HIV-negative unit ofmeasure (n = 156) (n = 633) p Mean age: y Ethnic group: % African-American Hispanic 24 7 Place ofbirth: % United States Another country History ofinjection drug use: % 26 NA* Lifetime sexual partners: no. Median 6 5 Mean Pregnancies: Mean no Education: no. (%) ofenrollees No high school diploma 47 (44.9) 231 (37.3) High school diploma 44(34.6) 276 (44.5) Technical or vocational school diploma 16 (12.6) 74 (11.9) College orjunior college attendance 10(7.9) 38 (6.3) NOTE. Numbers in parentheses represent percentage of individuals with indicated educational experience outoftotal number ofindividuals for whom information on education was available. *Not applicable. acquisition in a cohort of HIV-seronegative inner-city women; it excludes women with a history of injection drug use. Serum from all participants was screened for antibody to HIV in an enzyme immunoassay (DuPont, Wilmington, DE). Specimens positive in two such assays were confirmed as positive by western blot (DuPont). Study personnel administered a standard questionnaire to all enrollees. Information pertaining to basic demographic characteristics, socioeconomic status, history of alcohol or drug use, and sexual practices was obtained. A standard medical history was recorded and a physical examination performed. Serological status for syphilis was evaluated in a standard RPR test (Macro-Vue; Becton-Dickinson, Cockeysville, MD). Reactivity in this test was confirmed in the microhemagglutination assay for antibodies to T. pallidum (MHA TP, Sera-Tek; Miles, Elkhart, IN). Finally, specimens reactive in the RPR test but not in the MHA-TP were evaluated with the fluorescent-treponemal antibody absorption (FTA Abs) test (Zeus Scientific, Branchburg, NJ). Any specimen reactive in the RPR test, nonreactive in the MHA-TP, and nonreactive in the FTA-Abs test was judged to represent a BFP in the RPR test. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined by exact maximum likelihood methods with StatXact (Cytel Software, Cambridge, MA). Results > The HIV-seropositive population studied is compared with controls in terms of demographic factors in table I. HIV-seropositive women were, on average, 2.4 years older and were more likely to report a history ofinjection drug use, to have a Hispanic ancestry, and to have been born in the United States (P <.0 I). The groups were similar in terms of lifetime mean number ofsexual partners, pregnancy history, and education. BFPs for syphilis were documented for 9 (5.8%) ofthe 156 HI V-seropositive women but for only I (0.2%) of the 633 HIV-seronegative women (P <.00 I; OR, 38.46; 95% CI, ). The likelihood ofan RPR result's being a BFP was 20 times greater for HIV-seropositive than HIV-seronegative women (table 2; P < ). When women with true serological syphilis were excluded from both groups, 6.9% of HIV-seropositive women and 0.2% of HIV-seronegative women had BFPs. Information on drug-use history was available for 144 HIV-seropositive women. Among HIV-seropositive women, there was an association between BFPs and a history ofintravenous or subcutaneous drug use: after adjustment for the lifetime number of sexual partners, age, and ethnic background, users were 5.0 times more likely than nonusers to have a BFP (P =.02; OR, 5.0; 95% CI, ). After adjustment for age, ethnic background, and place of birth,

3 1042 Augenbraun et al. CID 1994; 19 (December) Table 2. Biological false-positive results (BFPs) in the RPR test for syphilis in HIV-seropositive and HIV-seronegative women. No. of patients with HIV serological Serological Reactive status (n) syphilis* BFpt RPR test Positive ( 156) 25 9 (26.4) 34 Negative (633) 55 I (1.8) 56 NOTE. P <.00 I; OR, 19.2; 95% CI, * Serological syphilis is defined as a reactive RPR test and either a reactive MHA-TP or a nonreactive MHA-TP with a reactive ITA-Abs test. t A BFP is defined as a reactive RPR test with a nonreactive MHA-TP and a nonreactive ITA-Abs test. Numbers in parentheses are percentages. the likelihood that a reactive RPR would yield a BFP was 13.2 times greater for HI V-seropositive women with no history of injection drug use (95% CI, ) and 35.5 times greater for HIV -seropositive women with such a history (95% CI, ) than for HIV-seronegative women. When the results for all patients (irrespective of the RPR test) were considered. the likelihood of a BFP for women with no history ofinjection drug use was 25 times greater for the HI V-seropositive group than for HIV-seronegative controls (table 3). There was no association between BFPs and CD4 cell counts. The rate of BFPs varied from 0 among women with CD4 counts of <200/mm 3 to 5.7% among women with 4 counts of /mm 3 and 9.5% among women with counts of>500/mm 3. Demographic characteristics of HIV -seropositive women with and without a BFP are compared in table 4. The mean ages ofthese two groups ofwomen were 37.2 years and 32.8 years. respectively (P <.12). The groups did not differ in terms ofethnic background or place ofbirth. No women with BFPs were pregnant. The lifetime median number ofsexual partners was similar for the two groups. as was the mean number of pregnancies. Other variables related to pregnancy. such as premature births. abortions. miscarriages. and stillbirths. were not significantly different for the two groups. Table 3. Biological false-positive results (BFPs) in the RPR test for syphilis in HIV-seropositive and HIV-seronegative women without a history ofinjection drug use. HIV serological status Positive Negative With BFP* 4 (3.9) I (0.2) No. ofwomen in indicated group Without BFP NOTE. P =.002; OR, 25.3; 95% CI, * Numbers in parentheses are percentages Total Three HIV-seropositive patients with a BFP reported a history of syphilis and its treatment occurring>5 years before enrollment. The single BFP in the HIV -seronegative control group was documented in the case ofa 34-year-old Hispanic woman born in the United States. This woman had had 200 sexual partners and reported frequent use ofcrack cocaine. During this study. follow-up syphilis serological test results became available for six HIV -seropositive women with BFPs. Sera from three ofthese six women had lost their reactivity in the RPR test by 6, 12. and 18 months offollow-up. respectively. Discussion BFPs in serological tests for syphilis have long been recognized. In the general population the prevalence of BFPs is Table 4. Demographic characteristics of Hlv-seropositive women with and without biological false-positive results (BFPs) in the RPR test for syphilis. Value for indicated group* With Without Characteristic BFP BFP Ethnic group Hispanic 4 (44) 34 (23) African-American 5 (56) 97 (66) Other 16 (II) Age <30y I (II) 58 (39) >30y 8 (89) 89 (61) Place ofbirth United States 7 (78) III (76) Another country 2 (22) 36 (24) Lifetime sexual partners Median 5 6 Mean P * Data on ethnic group. age, and place ofbirth are given as number (percentage) ofenrollees; data on lifetime sexual partnersare given as numberof partners.

4 CID 1994:19(December) BFPs for Syphilis in HIV-Infected Women 1043 estimated to be -- 1%-2% [14]. In this large cohort of HIVseropositive women, we found a prevalence of BFPs significantly higher than that among a control group ofhiv-seronegative women. Moreover, a high frequency ofbfps among injection drug users had been noted before the onset ofthe HIV epidemic [15]. Concomitant injection drug use among HIV-seropositive women in our study was associated with an elevated risk ofbfps; however, ofindividuals with no history ofinjection drug use, those who were HIV-seropositive were 25 times more likely to have a BFP than those who were HIV-seronegative. Rompalo and colleagues reported a BFP prevalence of 3.8% among 159 HIV-seropositive men and women seen at an inner-city STD clinic in Baltimore [12]. This rate was considerably higher than that for the HIV-seronegativc population seen at the same facility. All of these HIV-associated BFPs were obtained with sera from men. Although overall BFP rates were higher among women, none of the female patients with BFPs were HIV-seropositive. (The specific number ofhiv-seropositive women examined was not reported.) In addition, among these HIV-seronegative women, BFPs were associated with a history of injection drug use. Other studies have failed to find an association between HIV serological status and BFPs for syphilis in populations with a low incidence of injection drug use [16, 17]. The explanation for our finding is not clear. Reports of unexpected serological findings in tests for syphilis among patients coinfected with HIV have raised questions about altered immunoglobulin synthesis in this population. Polyclonal gammopathy resulting from B-cell dysfunction in HIV-infected individuals has been reported [8]. This phenomenon might account for nonspecific immunoglobulins that could react with the RPR card test. Hicks et al. [18] reported the case ofan HIV-infected patient who had secondary syphilis documented by histology and had neither a positive NTST nor a positive treponemal serological test (TST). In another study, western blot analysis of serum from an HIV-infected man with secondary syphilis showed a markedly diminished response ofantibodies to various treponemal antigens [19]. The loss of the TST response, long regarded as lifelong after infection, has been reported infrequently among both HI V-seropositive patients and those presumed to be HIVseronegative [11, 20-22]. Yet in none of these studies was this response lost in patients with persistently reactive NTSTs. To date, the loss ofthe TST response as the explanation for a BFP has not been clearly documented. If, over time, HI V-seropositive individuals can lose the TST response yet maintain a reactive NTST, this pattern might explain the history of syphilis in three of our patients with BFPs. This situation might also lead to BFPs in the cases of individuals with a history ofclinically unrecognized syphilis. The apparent intrapatient variability ofthe BFP over time in three cases in our study is curious and may suggest that precipitating factors other than HIV infection or injection drug use (e.g., intercurrent illness) playa role in this phenomenon. None ofour patients reported injection drug use during the study. In our cohort of HIV-seropositive women, BFPs represented nearly 25% ofall reactive RPR tests. This study demonstrates that BFPs may be fairly common among women with HIV infection, particularly-although not exclusively -in cases with concomitant injection drug use. The high rate of false-positive results documented in this group reemphasizes the need for confirmatory TSTs for HIV-seropositive women who have a reactive NTST, especially those with a history of injection drug use. Acknowledgment The authors thank William M. 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