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Human Herpesvirus 8 Seroprevalence in an STD Clinic in Paris: A Study of 512 Patients

JANIER, MICHEL MD*; AGBALIKA, FÉLIX MD; DE LA SALMONIÈRE, PAULINE MD; LASSAU, FRANÇOIS MD*; LAGRANGE, PHILIPPE MD; MOREL, PATRICE MD*

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Background Human herpesvirus 8 (HHV-8) is thought to be possibly sexually transmitted in some populations, but few data are available on this mode of transmission.

Goal The goal was to study HHV-8 seroprevalence in patients attending a sexually transmitted disease (STD) clinic and to search for predictive factors of HHV-8 seropositivity.

Study Design Five hundred twelve consecutive patients attending the STD clinic of Hôpital Saint-Louis (Paris) were tested for HHV-8 antibodies (immunofluorescence assay using two cell lines, BCP-1 and ISI n. butyrate [3 mmol/l]). A standardized questionnaire was used to obtain demographic, behavioral, and clinical data. Predictive factors of HHV-8 seropositivity were considered in univariate and multivariate analysis with use of logistic regression models.

Results In testing of the patients for HHV-8 antibodies, 67/512 (13.1%) tested positive: 53/346 (15.3%) of men and 14/166 (8.4%) of women (P = 0.03). The predictive factors of HHV-8 seropositivity for men were the country of origin (Central Africa, odds ratio [OR]: 7.5; North Africa, OR: 5.5), homosexuality (OR: 3.7), and visiting prostitutes (OR: 7.1). For women they were country of origin (Central Africa, OR: 8.3) and presence of HSV-2 antibodies (OR: 6.5, tendency).

Conclusion Our study does not show clear relationships between HHV-8 seropositivity and sexual behavior, apart from homosexuality, but visiting prostitutes (for men) and HSV-2 seropositivity (for women) could be subtle clues supporting the hypothesis of heterosexual transmission.

Human herpesvirus 8 (HHV-8) seroprevalence was studied in 512 consecutive patients in the STD clinic of Hôpital Saint-Louis (Paris); 67 (13.1%) tested positive. The predictive factors were gender, country of origin, homosexuality, visiting prostitutes, and presence of hepatitis C antibodies (in men) and herpes simplex virus type 2 antibodies (in women).

From the *STD Clinic, †Laboratory of Virology, and Department of Biostatistics, Hôpital Saint-Louis, Paris, France

Correspondence: Michel Janier, MD, Centre Clinique et Biologique des M.S.T., Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75475 Paris, Cedex 10, France. E-mail: centre.mst@jupiter.chu-stlouis.fr

Received for publication January 18, 2001,

revised January 15, 2002, and accepted January 31, 2002.

HUMAN HERPESVIRUS 8 (HHV-8), also named Kaposi sarcoma–associated herpesvirus (KSHV), is a gamma 2 herpesvirus (rhadinovirus) consistently linked to all epidemiologic forms of Kaposi sarcoma (KS), HIV–related primary effusion lymphomas, and multicentric Castleman's disease. 1 Unlike other human herpesviruses, HHV-8 infection is not ubiquitous; indeed, HHV-8 seroprevalence differs greatly according to the country and the population studied and the type of assay. HHV-8 seroprevalence reaches 50% in sub-Saharan Africa, where HHV-8 transmission is thought to include mother-to-child transmission. 2 A few seroepidemiologic studies have yielded indirect data on sexual transmission of the virus. 3-5

The aim of our study was to study the HHV-8 seroprevalence in patients attending a sexually transmitted disease (STD) clinic and to search for predictive factors of HHV-8 seropositivity, and, in particular, for sexual risk factors.

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Patients and Methods

Five hundred twelve stored sera from a previous prospective seroepidemiologic study of hepatitis seroprevalence were analyzed. 6 Patients attended the STD clinic of Hôpital Saint-Louis between June 1994 and December 1994 for a new STD episode. Demographic and clinical data and, in particular, sexual behavior were recorded on a standardized questionnaire.

Screening for HHV-8 was performed with use of frozen (−20 °C) stored sera at a 1:50 dilution. Antibodies to HHV-8 were detected with an indirect immunofluorescence assay with use of two cell lines, HHV-8+/Epstein Barr virus (EBV): the BCP-1 cell line for detection of antibodies directed against nuclear antigens (LANA) and the ISI cell line, treated with n. butyrate (3 mmol/l) for 30 hours, for detection of antibodies directed against undefined cytoplasmic lytic antigens. 7

Presence of HHV-8 antibodies was revealed by rabbit antihuman fluorescein isothiocyanate (FTIC) immunoglobulin G at the 1:100 dilution (Sanofi, Institut Pasteur, Paris, France).

Screening for hepatitis A (HAV), B (HBV), C (HCV), and E virus (HEV), cytomegalovirus (CMV), human T-cell lymphotrophic virus I (HTLV-I), and HIV-1 was performed with ELISA (Abbott Diagnostics). Screening for herpes simplex virus (HSV)-1 and HSV-2 glycoproteins was performed by an EIA-specific method (Smithkline Beecham Biologicals) as previously described. 6Treponema pallidum hemagglutination assay (TPHA) was performed with use of the Eurobio TPHA (Eurobio, Les Ulis, France).

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Statistical Study

Comparisons between groups were performed with the Wilcoxon test for continuous variables and Fisher exact test for categorical variables; 95% CIs of percentages were calculated with the exact method. Predictive factors of HHV-8 seropositivity were considered in univariate and multivariate analysis with use of logistic regression models.

Two-sided tests were computed and P values of 0.05 or less were considered statistically significant. SAS software (SAS Institute, Cary, NC) was used.

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Results

The main demographic and clinical characteristics of the cohort (346 men and 166 women) are shown in Table 1. The HHV-8 seroprevalence and other serologic markers are shown in Table 2.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

HHV-8 seroprevalence was high (total: 67/512 [13.1%; 95% CI: 10.3–16.3]), more so in men (53/346 [15.3%; 95% CI: 11.7–19.6]) than in women (14/166 [8.4%; 95% CI: 4.7–13.7];P = 0.03), and differed between people originating from Europe/North America (13/218 [6.0%; 95% CI: 3.2–10.0]) and Central Africa (30/126 [23.8%; 95% CI: 6.7–32.2;P < 0.0001) and between people originating from Europe/North America and North Africa (19/104 [18.3%; 95% CI: 11.4–27.1;P < 0.001).

The predictive factors of HHV-8 seropositivity are summarized in Tables 3–5. As HHV-8 seroprevalence differed significantly between men and women, the results are presented separately (Tables 3 and 5). Furthermore, as HHV-8 seroprevalence differed between white males and other males, a separate analysis of white males was also performed (Table 4).

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

In the global cohort the only predictive factor of HHV-8 seropositivity in the multivariate analysis that was not confirmed in the analysis by gender was a history of gonorrhea (odds ratio [OR], 1.37 [95% CI: 1.01–1.86]).

In men, predictive factors in the multivariate analysis were country of origin, with an increasing risk of HHV-8 seropositivity from North to South (Europe/North America OR: 1; North Africa OR: 5.5; Central Africa OR: 7.5), visiting prostitutes (OR: 2.5), homosexuality (OR: 3.7), and presence of anti-HCV antibodies (OR: 7.1) (Table 3). In white males, only homosexuality (OR: 9.6) and presence of anti-HCV antibodies (OR: 13.0) were independent predictors of HHV-8 seropositivity (Table 4). HAV seropositivity and presence of any HBV marker were significantly associated with HHV-8 seropositivity in the univariate analysis (respectively, P = 0.05 and P = 0.01) but not in the multivariate analysis. No association was found between HHV-8 seropositivity and the use of condoms, marital status, current STD, age at first sexual intercourse, number of sexual partners in the past 6 months, history of STDs, and other serological markers (CMV, HEV, HIV-1, HSV-1, HSV-2, and TPHA).

In women, predictive factors for HHV-8 seropositivity in the multivariate analysis were the country of origin, with an increasing risk of HHV-8 seropositivity in patients from Europe/North America (OR: 1) and North Africa (OR: 1.8) to Central Africa (OR: 8.3) and the presence of anti-HSV-2 antibodies (OR: 6.5) (P = 0.08, tendency). Presence of any HBV marker was significantly associated with HHV-8 seropositivity in the univariate analysis (P = 0.05) but not in the multivariate analysis. No association was found between HHV-8 seropositivity and all the other clinical, behavioral, and serological data.

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Discussion

Our study demonstrates a high HHV-8 seroprevalence (13.1%) in patients attending an inner-Paris STD clinic and yielded consistent data on the epidemiology of HHV-8 infection in France. HHV-8 is more prevalent in males and in patients originating from North Africa and Central Africa, with a north-to-south gradient. Sexual risk factors were homosexuality and visiting prostitutes (for males) and HSV-2 seropositivity (for females).

HHV-8 is not ubiquitous in the population. In the general population and blood donors, the seroprevalence varies greatly according to the country: 0.2% in Japan, 8 2% in France, 9 3% in Great Britain, 10 0% to 12% in the USA, 11–13 10% in Haïti, 14 4% to 35% in Italy (with a heterogenous repartition between the north and the south, as HHV-8 seroprevalence is much higher in Sicily, Sardinia, Apulia, and Calabria than in Northern Italy), 15–17 18% in Saudi Arabia, 18 and 45% in Egypt. 19 The extent of the spread of HHV-8 infection in northern West Africa (Maghreb) is not known. In sub-Saharan Africa, seroprevalence is very high: from 20% to 30% among children to 30% to 40% among teenagers and 50% to 60% among adults, suggesting mother-to-child transmission. 2,10,11,20–23

Sexual transmission of HHV-8 has been alleged earlier, given the higher HHV-8 prevalence in patients attending STD clinics 3,10,24 and in homosexuals, 4,10,25–28 particularly HIV-seropositive homosexuals. 11,13,25,26,29,30 Direct evidence of sexual transmission is lacking, and few epidemiologic studies have pointed to sexual risk factors in multivariate analyses. In homosexuals, HHV-8 seropositivity has been linked to a high number of sexual partners, 4,26,31 to various types of STDs (syphilis, 3,4,31 genital herpes, 3,4,30 urethritis, 4 hepatitis B, 31 and some fecal-oral STDs 4,30,31), and to risky sexual behavior like anilingus, 31 fellatio, 26 receptive anal intercourse, 5,32 and even deep kissing 28 and to the use of amphetamines 5 and poppers. 28

Very few data from studies of heterosexuals are available: one study by Smith did not show any sexual risk factor for HHV-8 seropositivity in an STD clinic of London 3; one by Bestetti did not find any predictive factors for HHV-8 seropositivity other than age and prostitution in women from Cameroon 21; one by Sitas of patients with cancer in South Africa showed that only the number of sexual partners and African origin were predictive of HHV-8 seropositivity 33; and one by Rezza showed that only STDs were predictive of HHV-8 infection. 23 In countries with a high HHV-8 seroprevalence such as sub-Saharan Africa, southern Italy, and probably North Africa, nonsexual transmission of HHV-8 is well documented, including mother-to-child transmission and transmission by close nonsexual contacts at home. 2,16,23 The transmission could be similar to that of Epstein-Barr virus, cytomegalovirus, HHV-6, and HBV.

In countries with low HHV-8 seroprevalence such as Europe and the United States, sexual transmission of HHV-8 is highly probable but is much better documented in homosexuals than in heterosexuals. AIDS-associated Kaposi sarcoma is more frequent in HIV-seropositive homosexuals who engage in high-risk sexual behavior, and HHV-8 seropositivity is more strongly associated with homosexuality than with HIV status. The precise anatomical means of transmission of HHV-8 among homosexuals is not known. Very few large epidemiologic studies have been conducted, and these studies have yielded discrepant results; some have analyzed the number of sexual partners, others the various STDs and, very rarely, the nature of sexual contact. No coherent data have been established. The means of sexual transmission of HHV-8 could differ from that of HIV transmission, given the fact that HHV-8, although present in all body fluids, is more frequently recovered from saliva and the oral cavity than from semen, urine, or cervical samples. 28 A high HHV-8 viral load such as in Kaposi sarcoma is probably determinant of the sexual transmission of the virus. 28

Our study does not show clear relationships between HHV-8 seropositivity and sexual behavior, apart from homosexuality (OR: 3.7). Nevertheless, the findings that visiting prostitutes (for men) and HSV-2 seropositivity (for women, approaching the level of significance) are predictive of HHV-8 seropositivity are interesting and could be subtle clues supporting the hypothesis of sexual transmission. The relationship to HCV seropositivity is not understood. Clearly, the major predictive factor remains geographic origin.

Many questions remain unanswered, such as the exact mode of sexual transmission, the role of cofactors (such as HIV infection and male gender) in linking HHV-8 and Kaposi sarcoma, and the sensitivity and specificity of serological tests in low-prevalence countries.

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