Strong Decline in Herpes Simplex Virus Antibodies Over Time among Young Homosexual Men Is Associated with Changing Sexual Behavior
Nicole H. T. M. Dukers1,
Sylvia M. Bruisten1,
J. Anneke R. van den Hoek1,
John B. F. de Wit1,2,
Gerard J. J. van Doornum1 and
Roel A. Coutinho1,3
1 Division of Public Health and Environment, Municipal Health Service Amsterdam, 1000 CE Amsterdam, The Netherlands.
2 Department of Social and Organizational Psychology, University of Utrecht, 3584 CS Utrecht, The Netherlands.
3 Department of Human Retrovirology, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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ABSTRACT
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The objective of this study was to evaluate whether the change in sexual behavior among homosexual men observed after the start of the acquired immunodeficiency syndrome epidemic resulted in a change in herpes simplex virus (HSV) seroprevalence in this group over time. In a cross-sectional study, the prevalence of herpesvirus types 1 (HSV1) and 2 (HSV2) was determined at study entry in 19841985 and 19951997 among 532 young (aged
30 years) homosexual men participating in the Amsterdam Cohort Studies on HIV/AIDS. Risk factors for the presence of HSV antibodies, including human immunodeficiency virus infection, were evaluated, and their influence on HSV prevalence over time was assessed. A strong decrease in HSV1 and HSV2 seroprevalence, from 80.6% to 59.0% and from 51.3% to 19.0%, respectively, was observed between the two time periods. This decrease was not markedly influenced by various demographic and socioeconomic factors. After data were controlled for several markers of sexual activity (such as number of sex partners, human immunodeficiency virus infection, and past episode(s) of gonorrhea), it appeared that the decline in HSV seroprevalence was explained by a concurrent decrease in the presence of these markers. The authors conclude that among young homosexual men in this study, the strong decrease in HSV seroprevalence was associated with a concurrent shift in sexual behavior. Furthermore, these data suggest an increasing sexual component in HSV1 transmission over time. Am J Epidemiol 2000;152:66673.
cross-sectional studies; herpes simplex virus; homosexuality; male; risk factors; sex behavior; sexually transmitted diseases
Abbreviations:
CI, confidence interval; HIV, human immunodeficiency virus; HSV, herpes simplex virus; HSV1, herpesvirus type 1; HSV2, herpesvirus type 2
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INTRODUCTION
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In many countries, including the Netherlands, young homosexual men were especially targeted by acquired immunodeficiency syndrome prevention campaigns in the 1980s and 1990s. This resulted in a strong reduction in human immunodeficiency virus (HIV)-related risk in this group and a marked decrease in the prevalence of several sexually transmitted diseases, such as HIV, gonorrhea, and syphilis (1
). Homosexual men are also known to be at high risk for herpes simplex virus (HSV), which can be transmitted by direct intimate contact with a person who is shedding virus, and not only through ano-genital sex. Herpesvirus type 2 (HSV2) is generally considered a useful marker for sexual behavior in a population (2
, 3
). In addition, genital herpes is the most common cause of genital ulceration in developed countries (4
). Worldwide, there has been renewed interest in HSV, as genital HSV infection may increase the risk of HIV transmission (5



10
).
The observed changes in HSV2 prevalence over time have been dissimilar in several studies. The age-adjusted seroprevalence of HSV2 increased in the general US population between 1976 and 1994 (11
), but it decreased among pregnant Swedish women in 19901993 (12
), after a (slight) increase between 1969 and 1989 (12
, 13
). To our knowledge, temporal trends in the prevalence of herpesvirus type 1 (HSV1) have not been described. To evaluate whether the change in sexual behavior among homosexual men resulted in a change in HSV seroprevalence in this group over time, we conducted a cross-sectional study to compare the prevalence of HSV type-specific antibodies in 19841985 with the prevalence in 19951997 and to evaluate risk factors for the presence of HSV antibodies, using data from the Amsterdam Cohort Studies on HIV/AIDS (Amsterdam, The Netherlands).
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MATERIALS AND METHODS
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Subjects
Our study population comprised a subset of men who are participants in the ongoing Amsterdam Cohort Studies, which study HIV and acquired immunodeficiency syndrome among sexually active HIV-seropositive and -seronegative homosexual men (14
, 15
). From this cohort, we selected young men aged
30 years who had entered the study between October 1984 and April 1985 or approximately 10 years later between 1995 and 1997, and for whom stored serum, taken at enrollment, was available. Recruitment of the participants in both time periods was carried out through "convenience sampling" (brochures were distributed at the Amsterdam clinic for sexually transmitted diseases and at places of entertainment for homosexual men, and advertisements were placed in magazines for homosexual men). Furthermore, in both time periods, every new participant was asked to recruit new participants for the study among his friends and acquaintances. The only difference was that in the second time period, a few participants were especially trained to recruit new participants.
A total of 238 young men entered the Amsterdam Cohort Studies in 19841985, and from nearly all of them (n = 232), serum was available for testing for HSV antibodies. A total of 453 young men entered the study in 19951997, and serum was available for testing for 300 of those participants. The 153 men for whom no serum was available in the second period did not differ from the other 300 men with respect to age, nationality, education, living situation, or lifetime number of sex partners (using the Kruskall-Wallis test for comparing population distributions and the
2 test for independence).
Laboratory methods
For all participants, the enrollment sample was tested for specific antibodies to HSV1 and HSV2. We applied a strip immunoblot assay (Chiron rapid immunoblot assay HSV type 1/2; Chiron Corporation, Emeryville, California), which utilizes antigens immobilized on nitrocellulose strips as described by Alexander et al. (16
). HSV-gB1 is an HSV1 type-specific peptide, and HSV-gG1 is a recombinant protein specific for HSV1. HSV2-gG2 is a recombinant protein from HSV2, and HSV2-gD2 is cross-reactive for HSV1 and HSV2 antibodies because of 85 percent homology. Control bands for the presence of two levels of human immunoglobulin G are also spotted on the immunostrip. A test was only valid when the human immunoglobulin G control band was present. The assay was carried out and criteria for seropositivity were applied according to the instructions of the manufacturer at the regional public health laboratory in Amsterdam.
Analysis of HIV antibodies was performed with two commercially available enzyme-linked immunosorbent assays (Abbott Laboratories, North Chicago, Illinois, and Organon, Oss, The Netherlands). Results were confirmed by Western blot analyses.
Variables and statistical methods
In this cross-sectional study, we considered various general/sociodemographic and sexual characteristics (table 1), as reported or measured at enrollment. Sexual characteristics included information on several sexual practices, although oro-genital sex could not be evaluated in this study because of differences in questionnaires. Unprotected sex was defined as not always using a condom when engaging in ano-genital receptive sex (versus protected ano-genital sex or no ano-genital sex). Comparable data on unprotected ano-genital insertive sex were unavailable. We considered the sexual characteristics (self-reported sexually transmitted diseases, sexual behavior, lifetime number of sex partners, and the presence of HIV antibodies) to be markers for (unprotected) sexual activity.
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TABLE 1. Differences in sexual and other characteristics measured at baseline among 532 homosexual men aged 30 years in two intake periods (19841985 and 19951997), Amsterdam Cohort Studies on HIV/AIDS
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First, we evaluated whether the level of sexual activity differed between men entering the study in 19841985 and men entering the study in 19951997, comparing variables measured at study entry between the two time periods (using the Kruskall-Wallis test for comparing population distributions and the
2 test for independence). Furthermore, prevalences of HIV and HSV type-specific antibodies were determined and compared between the two periods. Second, we assessed univariate risk factors for the presence of HSV type-specific antibodies, combining data from both time spans. A variable representing time period was included to reflect a change in HSV prevalence over time. Third, to assess independent risk factors for HSV type-specific antibodies, we started by forcing time period into a logistic regression model (since this was the central variable in our study) and further controlled for age, nationality, education, and living situation (since these characteristics differed between the two subgroups). Subsequently, we entered all univariately significant cofactors, except variables on self-reported ano-genital herpes and herpes labialis, in a forward stepwise regression procedure. We left the variables on herpes labialis and ano-genital herpes out because they are caused by infection with HSV. Fourth, in order to evaluate whether a different level of sexual activity resulted in a difference in HSV seroprevalence over time, we evaluated the effect of time period after adding several general/socioeconomic and sexual factors to the model (described below). Fifth, we evaluated the role of the independent predictors for HSV type-specific antibodies in the two time periods, by including an interaction term between risk factor and time period.
Univariate and multivariate odds ratios for risk factors for HSV antibodies were determined using logistic regression. For reasons of model convergence, when calculating odds ratios, we included a separate category for missing values only when the number of missing observations exceeded 2 percent of the total. Interaction was considered to be present when the addition of an interaction term between variables significantly improved the fit of the model. Confounding was determined to be present when inclusion of a variable (or combination of variables) in the multivariate model resulted in a change of more than 15 percent in the odds ratios of factors already present in the model. The likelihood ratio statistic was used to examine whether a term significantly improved the fit of the original model. Statistical significance was defined as a p value of 0.05 or less. Data were analyzed using the Statistical Package for the Social Sciences (17
).
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RESULTS
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The study group comprised 532 young homosexual men, of whom 232 entered the Amsterdam Cohort Studies in 19841985 (period 1) and 300 entered in 19951997 (period 2). Study characteristics and group differences between the two periods are depicted in table 1. Differences could be observed with regard to several general/socioeconomic factors, such as age and educational level. Furthermore, it was obvious that sexual behavior as measured or reported at study entry differed drastically between the two time periods: There were decreases in the practice of (unprotected) ano-genital sex, lifetime number of sex partners, and the prevalence of gonorrhea, syphilis, and ano-genital herpes. However, the prevalence of herpes labialis remained stable, as did the practice of oro-anal sex.
Concurrent with a profound drop in HIV prevalence over time, the prevalence of HSV type-specific antibodies decreased strongly: HSV1 prevalence decreased by 26.8 percent and HSV2 prevalence decreased even more, by 63.0 percent. As a consequence, the proportion of men having no antibodies to either HSV1 or HSV2 increased from 10.3 percent (24/232) to 38.3 percent (115/300).
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Predictors for HSV1 and HSV2 infection in periods 1 and 2
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Univariate analyses. To evaluate which factors were associated with HSV1 and HSV2 infection, we combined the groups of participants in the two time periods into one study group, using a variable on time period to reflect the decrease in HSV prevalence over time. In univariate analyses (table 2), the odds ratio for having HSV antibodies increased with age and was higher among men with a lower level of education (statistically significantly in the case of HSV1). The presence of HIV infection was associated with both HSV1 and HSV2 antibodies; the extremely strong relation between HIV and HSV2 was striking. Furthermore, aside from HIV, several markers for (unprotected) sexual activity were profoundly related to both HSV1 and HSV2. Whereas self-reported ano-genital herpes was associated with both types of HSV, herpes labialis was associated only with HSV1.
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TABLE 2. Prevalence of and risk factors for herpesvirus types 1 (HSV1) and 2 (HSV2) infection at study entry among 532 homosexual men aged 30 years in two intake periods (19841985 and 19951997), Amsterdam Cohort Studies on HIV/AIDS
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Multivariate analyses. The independent predictors for the presence of HSV type-specific antibodies obtained after multivariate modeling (see "Materials and Methods") are presented in table 3. Independent predictors for HSV1 infection included a higher number of sex partners, previous episode(s) of gonorrhea, and concurrent HSV2 infection. Independent predictors for HSV2 infection were HIV infection, a higher number of sex partners, previous episode(s) of gonorrhea, and concurrent HSV1 infection.
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TABLE 3. Multivariate model of risk factors independently associated with herpesvirus type 1 (HSV1) or type 2 (HSV2) infection at study entry among 532 homosexual men aged 30 years in two intake periods (19841985 and 19951997), Amsterdam Cohort Studies on HIV/AIDS
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To evaluate whether predictors for HSV differed between the two periods, we included an interaction term between time period and each of the independent risk factors. For both HSV1 and HSV2, there appeared to be a statistically significant interaction between the alternate type of HSV and time period. Concurrent HSV1 infection was closely associated with HSV2 infection and vice versa, but only in period 2 (table 3).
Although interaction terms between other risk factors and time period did not reach statistical significance, it was remarkable that the association between HSV1 infection and number of sex partners was dramatically stronger in period 2 than in period 1 (interaction between "time period" and ">200 sex partners": p = 0.1141). Compared with a low number of sex partners (121 partners), the odds ratios for having 22200 and more than 200 sex partners were 0.84 (95 percent confidence interval (CI): 0.24, 2.90) and 1.35 (95 percent CI: 0.40, 4.93), respectively, in period 1 and 2.63 (95 percent CI: 1.49, 4.64) and 6.82 (95 percent CI: 1.43, 32.52), respectively, in period 2. This large difference in the strength of the association between the two time periods was not observed when HSV2 was examined as a dependent variable. Furthermore, we examined potential confounding by other variables that were not included in the multivariate models (table 2). However, after the addition of these factors to the models, the odds ratios presented in table 3 did not change substantially and appeared to be stable.
Factors affecting the decrease in HSV antibodies over time
To examine whether the decrease in HSV antibodies between the two periods could be explained by general and socioeconomic group differences (age, nationality, education, and living situation), we adjusted the odds ratio for time period (which reflects the decline over time) for these factors simultaneously. After controlling for these variables, it appeared that the estimated risks for time period (crude odds ratios are presented in table 2) changed only slightly and were still statistically significant (adjusted odds ratio for time period: for HSV1, adjusted odds ratio = 0.40 (95 percent CI: 0.26, 0.61); for HSV2, adjusted odds ratio = 0.24 (95 percent CI: 0.16, 0.37)). However, this time effect strongly increased to unity and became nonsignificant after we corrected simultaneously for number of sex partners and past episode(s) of gonorrhea (and HIV antibodies in the case of HSV2). After controlling for these markers of sexual activity, the odds ratio for time period for HSV1 increased to 1.08 (95 percent CI: 0.77, 2.30) and that for HSV2 increased to 0.73 (95 percent CI: 0.42, 1.29), indicating that the time effect was explained by these sexual activity markers.
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DISCUSSION
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In the present study, we demonstrated a strong decline in both HSV1 and HSV2 antibodies when comparing a group of young homosexual men assessed just after the start of the acquired immunodeficiency syndrome epidemic with a group of young homosexual men 10 years later. This decline cannot be explained by various general and socioeconomic group differences. It most likely results from the drastic change in sexual activity among homosexual men during this period. The strong decline in HSV2 prevalence in this group may seem at first sight to contradict the increase in HSV2 prevalence found in the population-based National Health and Nutrition Examination Surveys (11
). However, these trend differences might be explained by differences in study groups. Whereas in the National Health and Nutrition Examination Surveys trends are examined in the general US population, our study specifically focused on a high risk group with documented and profound changes in sexual behavior over time (behavior which is correlated with HSV infection) (1
). Furthermore, next to population differences, patterns of HSV infection are likely to vary around the world. For example, a study among pregnant Swedish women revealed a decreasing prevalence in women younger than age 20 years, suggesting a higher incidence of HSV2 in the 1970s than in the 1990s (4
, 12
).
Several limitations of this study should be taken into account. First, from the observation that the sexual behavior of young men entering the cohort differed drastically between the two time periods, we inferred that sexual behavior among young men in our study had changed over the interval between 19841985 and 19951997. However, only information obtained at study entry was used, and no repeated measurements that would have allowed evaluation of changes in sexual activity were performed. Therefore, no inferences can be made regarding within-person behavior over time. On the other hand, it is unlikely that an important part of the observed differences between time periods was caused by differences in selection mechanisms, since recruitment of the participants in both time periods occurred in virtually the same way. Second, because the Amsterdam Cohort Studies have been performed among self-selected groups, behavioral data and the prevalence of sexually transmitted disease cannot be generalized to the homosexual population at large. In a study by Veugelers et al. (18
), data from the cohort study were compared with data from a cross-sectional survey among 71 randomly selected homosexual men aged 1855 years. It appeared that the respondents in the cross-sectional survey were less sexually active than participants in the cohort study. They reported fewer sex partners and less receptive ano-genital intercourse, and fewer men had a history of syphilis. Although the sample size was small and the sample comprised men of a wider age range, the study by Veugelers et al. (18
) suggested that among the general young homosexual population in Amsterdam, sexual activity levels and therefore HSV prevalence rates might be somewhat lower than those found in the present study. Third, whether risk factors for HSV in the general homosexual population differ from risk factors found in our cohort is unknown. However, we have no reason to assume that the sexual predictors are different in an important way.
Quite a number of different serologic assays for HSV testing have been used in previous studies (2
, 11
13
, 19




25
). The rapid immunoblot assay applied in the present study (not commercially available) was shown to have a high concordance of 93.3 percent with the Gull enzyme-linked immunosorbent assay, which is presently available in the United States and has been approved by the US Food and Drug Administration (26
, 27
). Furthermore, a comparison by van Doornum et al. (28
) showed that the rapid immunoblot assay is highly comparable to Western blot, which is generally considered the gold standard, with sensitivity and specificity rates exceeding 93 percent in both tests. Thus, different serologic tests, such as the Gull test and the rapid immunoblot assay, are quite comparable and useful in epidemiologic studies.
In previous studies on risk factors for HSV infection, a strong relation was consistently found between infection and older age, sexual activity, and (sometimes) lower socioeconomic status (2
, 11
13
, 19




25
). In our study group, the univariate elevated risks for older age and lower level of education (in the case of HSV1) disappeared when data were controlled for lifetime number of sex partners. As a consequence, we conclude that sexual behavior was by far the most important correlate for both HSV1 and HSV2 infection in this group of homosexual men. We were not able to identify specific sexual practices involved in HSV1 and HSV2 transmission. It is possible that our study design was not sensitive enough to detect these associations; information on specific sexual behaviors (reported over the past 6 months) might not reflect the exact period of exposure to HSV. On the other hand, a specific mode of sexual transmission may be difficult to find, as different sexual practices can be involved in HSV transmission.
It is not surprising that various sexually transmitted diseases were associated with HSV infection, since sexually transmitted diseases share epidemiologic features and will thus show a mutual association. Whether transmission of a sexually transmitted disease occurs depends on several factors, such as the number of sexual encounters, prevalence in the population, and certain sexual behaviors that can facilitate transmission (29
). Gonorrhea, syphilis, and HIV most likely are markers for a high number of sex partners, but they could also reflect a certain mode of transmission (e.g., ano-genital sex) or type of sex partner (e.g., high risk partners).
Recently, much attention has been given to the association between HSV2 and HIV, because genital ulcerations may enhance both HIV susceptibility and infectiousness (5



10
) and prevention of HSV2 infection could indirectly have an impact on HIV epidemiology. In addition, HSV2 is being considered as a useful surrogate marker for the presence of sexually transmitted diseases, including HIV, and more generally as a marker for sexual activity in a population (2
, 3
). Our findings underline these considerations, since a strong independent relation between HSV2 (not HSV1) and HIV was observed. Additional analyses (data not shown) revealed that the presence of HSV2 was the strongest predictor for the presence of HIV, independent of other predictors for HIV such as syphilis and gonorrhea. Furthermore, the strength of the association between HIV and HSV2 did not change over time. HSV infections are also among the most common clinical presentations and manifestations of HIV infection (30
). In concordance with other studies of homosexual men (6
, 7
, 9
), a large number of HIV-infected men possessed antibodies to HSV: Over 80 percent and 70 percent of the HIV-infected men had antibodies to HSV1 and HSV2, respectively (table 2).
In the present study, we demonstrated that risk factors for the presence of HSV antibodies were similar in 19841985 and 19951997, with the exception of the correlation with the other HSV type. The strong association found between the two HSV types in the second time period could reflect an increasing similarity in risk factors (not specifically captured in our analyses) for HSV1 and HSV2 over time. Such factors might be biologic, demographic, or socioeconomic characteristics related to both types of HSV. However, we consider it more likely that the increasing relation between HSV1 and HSV2 infections points to an increasing similarity in transmission mode. An observation hinting that sexual transmission of HSV1 is gaining more importance over time is found in the much stronger (though not statistically significant) risk of HSV1 infection with a higher number of sex partners in 19951997 as compared with 19841985. Such a large difference in time was not found for the other evaluated risk factors and was not observed when HSV2 was used as a dependent variable. Furthermore, several investigators have reported that an important and ever increasing proportion of genital herpes is caused by HSV1 rather than HSV2 (27
, 31
33
). It seems likely that, at least among the homosexual men in our study, HSV1 is now less often acquired during childhood than it was 10 years ago and is becoming more and more a sexually transmitted disease.
In conclusion, in comparing young homosexual men in 19841985 and 19951997, we observed a profound decrease in HSV1 and HSV2 seroprevalence. This decline most likely was due to a change in sexual behavior in this group in the direction of safer sexual practices and fewer sex partners. Furthermore, our data are suggestive of an increasing sexual component in HSV1 transmission over time.
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ACKNOWLEDGMENTS
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This study was supported by a grant from the AIDS Fund (grant 1300). It was performed as part of the Amsterdam Cohort Studies on HIV/AIDS, a collaboration between the Amsterdam Municipal Health Service, the Academic Medical Center, the Central Laboratory of the Netherlands Blood Transfusion Service (Amsterdam, The Netherlands), and the Department of Social and Organizational Psychology, University of Utrecht (Utrecht, The Netherlands).
The authors thank the Chiron Corporation for supplying the rapid immunoblot assay; the laboratory of Dr. Jaap Goudsmit for performing HIV tests; Nel Albrecht, Marja Dekker, and Dr. Jaap Maas for interviewing and taking blood samples; Mark Buimer for providing laboratory support; and Dr. Miranda Langendam for critically reading the manuscript.
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NOTES
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Correspondence to N. H. T. M. Dukers, Municipal Health Service Amsterdam, Nieuwe Achtergracht 100, 1000 CE Amsterdam, The Netherlands (e-mail: ndukers{at}gggd.amsterdam.nl).
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Received for publication September 1, 1999.
Accepted for publication December 22, 1999.