Herpes Simplex Virus Type-2 Infection of Heterosexual Men Attending A Sexual Health Centre

Journal  Medical Journal of Australia, Volume 160, Pages 697-700. 1994.

Ingrid Bassett, Basil Donovan, Neil J Bodsworth, Peter R Field, David W T Ho, Stig Jeansson, Anthony L Cunningham
Sydney Sexual Health Centre, Sydney Hospital, GPO Box 1614, Sydney, NSW 2001

Ingrid Bassett, MB BS, Registrar

Basil Donovan, FACVen, FAFPHM, Director; and Clinical Associate Professor, University of Sydney. Academic Unit in Sexual Health Medicine University of Sydney/University of New South Wales, Sydney Hospital.

Neil J Bodsworth, MM, FACVen, Director of Clinical Research. Virology Department, Centre for Infectious Diseases and Microbiology, Westmead Hospital.

Peter R Field, BScAgr, FASM, Principal Scientific Officer.

David W T Ho, MAppSc, MAIMLS, Senior Scientific Officer.

Anthony L Cunningham, FRACP, FRCPA, Director; and Associate Professor, University of Sydney. Department of Clinical Virology,

Stig Jeansson MD, PhD, Associate Professor. University of Goteborg, Sweden.

No reprints will be available.

Correspondence: Dr Basil Donovan.

Abstract

Objective: To identify risk factors particularly circumcision status, associated with serological evidence of herpes simplex virus type 2 (HSV-2) infection of heterosexual men.

Design: A cross-sectional case-control study employing an anonymous delinked interviewer-administered questionnaire, clinical examination, and a type-specific serological test for HSV-2.

Participants and setting: Three hundred consecutive heterosexual male patients at a public sexually transmissible diseases (STD) clinic in Sydney, Australia.

Main outcome measures: Associations between serological evidence of HSV-2 infection and history of genital herpes or contact with genital herpes, history of other common STDs, and demographic and behavioural factors such as age, education level, number of sexual partners and lack of circumcision.

Results: One hundred and ninety-four patients (64.7%) had antibodies to HSV-2 but only 24% of these gave a history of genital herpes. A history of genital herpes or sexual contact with genital herpes, reported total lifetime number of sexual partners, failure to complete high school and a history of non-gonococcal urethritis or genital warts were associated with serological evidence of HSV-2 infection at the univariate level. Neither increasing age nor lack of circumcision was associated with HSV-2 infection. Following multi-variate analysis only the lifetime number of partners and failure to finish high school were significantly strong predictors of HSV-2 infection.

Conclusion: This is the highest prevalence of HSV-2 infection ever detected in an Australian population and one of the highest recorded globally. As younger men were as commonly infected as older men, and an earlier (1985) study involving the same clinic yielded a lower prevalence, it appears that a high level of ongoing HSV-2 transmission is occurring among Sydney heterosexuals. Increased awareness of this fact could enhance safer sex campaigns.

(Med J Aust 1994; 160: 697-700)

The most common cause of genital ulcers in developed nations is herpes simplex virus type 2 (HSV-2).[1] As well as breaching the epithelium HSV lesions are infiltrated with activated CD4+ lymphocytes,[2] a major target cell for HIV-1. Prospective studies have determined HSV-2 infection to be a risk factor for HIV-1 infection of homosexual men practicing receptive anal intercourse.[3,4] Heterosexual men with penile HSV-2 lesions could also be at higher risk of acquiring HIV-l infection during unprotected vaginal intercourse, as suggested by one cross-sectional study which controlled for sexual preference and other risk factors but not for number of sexual partners.[5] Reliable type-specific serological tests for HSV infection have recently become available which enable the accurate determination of the epidemiology of HSV-2 infection.[6,7] Thus, we sought to determine the risk factors for HSV-2 infection in a population of heterosexual men attending a sexually transmissible diseases (STD) clinic in Sydney. We were particularly interested in investigating any effect that the presence of an intact foreskin might exert on acquiring HSV-2 infection, as a previous Australian study had found a positive association.[8]

Participants and methods

Expecting a lower HSV-2 seroprevalence rate than a study in the same clinic in 1985,[9] we calculated that a sample size of over 270 was required to demonstrate a 50% protective effect from circumcision with 80% power at the 5% significance level. Thus, the study group comprised 300 consecutive heterosexual male patients who saw a particular clinician (I B) and required venopuncture for any other purpose at the Sydney Sexual Health (previously STD) Centre, Sydney Hospital, between December 1990 and May 1991. Men who reported ever having been homosexually active were excluded because HSV-2 infection acquired by receptive anal intercourse could have affected our results.

The aims of the study were explained to all subjects and signed informed consent was obtained. There were no refusals. The study was approved by the Eastern Sydney Area Health Service Research Ethics Committee.

A data collection form with an anonymous identifier code was completed by the clinician, and an extra 5 ml of blood were collected for the study. The data collected included:

Current clinical diagnoses were added to each subject's history of STDs on the data collection form.

The serological analyses for HSV were performed at the Virology Department Centre for Infectious Diseases and Microbiology, Institute for Clinical Pathology and Medical Research, Westmead Hospital, on an anonymousand blinded basis.

As described elsewhere,[6] sera were screened for total HSV antibody by a complement fixing antibody (HSV-CFA) test. Positive specimens on HSV-CFA testing were then subject to an indirect IgG enzyme immune assay (EIA) specific to the 92 kDa HSV-2 glycoprotein G (gG-2).[6] All 15 randomly selected sera that were positive for HSV-2 by EIA testing were confirmed by western blot[7] as having antibody to the specific gG-2 glycoprotein. Those samples that were positive for total HSV antibody by CFA but negative to HSV-2 by EIA were assayed by western blot for antibody to the HSV-1-specific 130 kDa gG-1 glycoprotein.[7]

The X2 test was used for categorical variables and Student's t test for continuous variables. Variables of significance in univariate analysis were entered into multivariate models. All t values were two tailed and significance was set at the 5% level.

Results

The patients were representative of the general clinical load of exclusively heterosexual men at the Centre (over 95% of the men are white, with most of the rest of Asian origin). Their reasons for attendance or diagnosis at the time of consultation are outlined in the Box. Only 14 participants (4.7%) attended because of a current problem with genital herpes. HIV-1 infection is rare among heterosexual men attending the Centre[10] and none of the subjects had HIV-1 infection. Two hundred and twenty-one men (73.7%) had positive results of total HSV-CFA testing. One hundred and ninety-four (64.7%) had HSV-2 antibodies on eia testing, although only 46 (23.7%) of these recorded a history of genital herpes. Put in another way, of the 254 men never diagnosed with genital herpes, 148 (58.3%) were HSV-2 seropositive. All 15 randomly selected sera that were positive for HSV-2 gG-3 by eia were also positive for gG-2 by western blot, confirming the specificity of the eia test as previously reported.[6,7] All of the 27 men who had positive results of total HSV-CFA testing, but negative results for HSV-2 by eia testing, had sera that reacted with the specific gG-1 (130 kDa) glycoprotein of HSV-l and not the HSV-2-specific gG-2 (92 kDa) glycoprotein on western blot assay.

Univariate analysis

All of the 46 men who gave a history of genital herpes had serological evidence of HSV-2 infection, again confirming the sensitivity of the eia test. On univariate analysis a past history of nongonococcal urethritis (NGU), genital warts, genital herpes, and known sexual contact with a woman with genital herpes, were associated with the presence of HSV-2 antibodies (Table 1).

Lower level of education (failure to complete high school) was also associated with HSV-2 infection (Table 1). Age, lack of circumcision, or history of undiagnosed genital ulcer(s) or itches was not associated with HSV-2 antibodies (Table 1). Men with HSV-2 antibodies reported almost twice as many lifetime partners as men without such antibodies (?= 0.014 [Table 1]). The positive correlation was also proportionate to lifetime number of sexual partners - 48% of the 35 men with one to five partners rising to 100% of 17 men with 41-50 partners had HSV-2 antibodies (Figure). There was a slightly, but not significantly, lower prevalence of HSV-2 antibodies among men reporting more than 50 lifetime partners compared with those with 41-50 partners (Figure). The men with one to five partners were not more likely to have a history of genital herpes or contact with genital herpes than the group as a whole (data not shown). Other STDs such as gonorrhoea, syphilis and hepatitis B were reported too infrequently to determine any association with a positive HSV-2 test.

Multivariate analysis

Mantel-Haenszel estimates of odds ratio were calculated (categories as in the Figure) after allowing for the effect of lifetime number of sexual partners (Table 2). After this transformation, the positive association of HSV-2 seropositivity with failure to finish high school remained significant, while the positive association with a history of contact with genital herpes became only marginally significant (P=0.067). The associations of HSV-2 antibodies with a history of NGU and a history of genital warts lost significance (Table 2).

A multiple logistic regression model confirmed that the associations of HSV-2 antibodies with NGU and genital warts were not significant. In models that included the log of lifetime number of partners, completion of high school (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.16-0.92; P=0.031) and history of contact with genital herpes (OR, 2.86; 95% CI, 1.04-7.86; P= 0.042) remained significant after allowing for each other.

Discussion

The simple index of lifetime number of sexual partners used in this study provided clear evidence of the sexual transmissibility of HSV-2 infection. Although starting from a high base (48% of men with five or fewer partners were seropositive), the correlation between number of sexual partners and HSV-2 infection was strong. Previous studies using other indices, e.g. years of sexual experience[11] and a number of partners in the previous month,[11,12] also produced significant trends. However, lifetime number of sexual partners is a crude index. Most women with HSV-2 infection are asymptomatic.[13] As HSV-2 is shed from the female genital tract intermittently, repeated sexual exposure to a single asymptomatic partner with HSV-2 infection over several months or years could pose a greater cumulative risk of acquiring HSV-2 than isolated encounters with many women.[14] This could explain why HSV-2 infection was common in this study among men with fewer partners. Men with fewer partners may also have been less likely to use condoms. Similarly, it is possible that men with very high numbers of partners may have been more likely to practice safer sex, thus yielding the slightly lower prevalence of HSV-2 antibodies than men with intermediate numbers of partners. As most of these men began sexual activity before the safer sex campaigns, and markers of HSV-2 infection are cumulative over time, data on the use of safer sexwere not collected in this study.

Univariate associations between HSV-2 infection and NGU or HSV-2 infection and genital warts may be attributable to these diseases having the common risk factor of number of sexual partners. This finding affirms that future studies of the role of genital herpes as a risk factor for HIV-1 infection - or for any other STD - should also control for numbers of sexual partners.

The reduced correlation between HSV-2 infection and history of sexual contact with genital herpes when the number of lifetime sexual partners was taken into account may be due to awareness of infection: possibly, with more partners there is a greater chance of one of the female partners suffering symptoms and reporting it to the man. The high prevalence of HSV-2 infection (64.7%) detected in the study group is remarkable and has rarely been exceeded even in STD clinic studies.[1] Although the study group was probably more sexually active than the general population and, by attending an STD clinic, was exhibiting concern about STDs, most men with HSV-2 infection reported no diagnosis or history of symptoms suggestive of genital herpes. While serological screening and closer clinical scrutiny would probably increase the diagnostic yield, as with women in STD clinics,[14] unrecognized genital herpes is clearly extremely common and possibly increasing among multi-partnered heterosexual men in Sydney.

A previous survey of male and female patients from the same clinic in 1985 revealed a seroprevalence of HSV-2 infection of 45% (unpublished data) compared with an average of 40.6% in three STD clinics surveyed in a later study using a slightly less sensitive assay.[9] The previous survey also included female prostitutes and homosexually active men - groups that would be expected to have higher prevalence rates of HSV-2 infection than heterosexual men.[1] We were particularly concerned that 53% of men under the age of 25 years had evidence of HSV-2 infection despite most of their sexually active lives coinciding with an era of public education about HIV-l infection. While female prostitutes in Sydney may have been able to reduce the incidence of a core group-associated STD such as gonorrhoea by using condoms,[15] when sex is not related to prostitution there appears to be less acceptance of condoms.[16] Although data on condom use were not collected in this study, our findings suggest that safer sex was not the usual practice of these young men. Alternatively, the in-vitro efficacy of condoms[17] translated poorly into in-vivo protection against HSV-2 infection. Studies are needed of the in-vivo efficacy of condoms as protection from genital herpes.

The significance of the association between HSV-2 infection and lower level of education is uncertain but has been noted previously.[11] One possibility is that this reflects factors influencing partner selection. Another is that lower education levels indicate poor compliance with strategies for safer sex. We have no data to evaluate either hypothesis.

Although not an objective of this study, given the apparent greater efficiency of male-to-female transmission of genital HSV[18] and higher prevalences of markers of HSV-2 infection in female populations in the United States,[19] our results suggest even higher rates of HSV2 infection in the female partners of these men. Further studies including women with multiple partners as well as population-based seroprevalence studies are indicated.

In contrast with previous studies,[8,20] we found no evidence of the presence of an intact foreskin being a risk factor for HSV-2 infection.

However, these earlier studies relied on the presence of clinical lesions for the diagnosis of genital herpes and reported no quantitative data on sexual behaviour.

Increased efforts to control the spread of HSV-2 infection in the community or to control the frequency of recurrences of genital herpes lesions may be justified because of the direct morbidity of HSV2 infection for adults[11] and neonates. If genital herpes is proven to be a cofactor for HIV-l transmission in the heterosexual context, a spin-off could be a contribution to HIV-1 control.

A screening program for HSV-2 infection would be resource intensive and likely to have only a limited impact at a population level, but it might raise the community awareness of STDs other than HIV-l infection, and thus reinforce the need for safer sex. It should be a salutary lesson that, as a consequence of the singular attention given to it, a recent survey of British teenagers found that most of them thought that HIV-1 infection was the most common STD.[21] Fewer than half of a large sample of Australian Year 10-12 students listed genital herpes as an STD.[22] This study records one of the highest prevalences of HSV-2 infection in the world, and the highest ever detected in an Australian population. A high level of ongoing HSV-2 transmission is apparent among Sydney heterosexuals.

Increased awareness of this situation is necessary to enhance safer sex campaigns.

Acknowledgments

Supported by a Commonwealth AIDS Research Grant. Our thanks to Professor G Berry University of Sydney, for statistical advice sod Professor A Mindel for comments on an early draft of the manuscript.

Reasons for attendance at an STD clinic by 300 heterosexual men tested for HSV-2antibodies.

No STD (screening only) 168 (56 0%)
Non-gonococcal urethritis       57 (19.0%)
Genital warts                   26 (8.7%)
Gonorrhoea                      1(0.3%)
Genital herpes (clinical diagnosis)
Initial episode                 4 (1.3%)
Recurrence                      10 (3.3%)
Syphilis                                0
Chancroid                       0
Other genital ulcer             3 (1.0%)
Other (non-infectious) condition        31(10.3%)
Total                           300 (100%)

Table 1: Correlation of HSV-2 antibody status with selected variables of 300 heterosexual men on univariate analysis

Selected        HSV-2 antibody  HSV-2 antibody  Odds ratio
variable        positive (n= 194)       negative (n= 106)
(95% CI)
p
-Mean age in years (range)      31-89 (19-69)   30.54 (1860)
-
0.157 NS
Mean lifetime number of
sexual partners (95% CI)*       53.2 (40.1-66.3)        28.7
(17.8-39.6)
-       0.014

Finished high school    82.5%   93.4%   0.33 (0.13-0.82) 0.014

Circumcised     59 3%   66.0%   0.75 (0.44-1.26)        NS

Past history of
Genital herpes  23.7%   0       -       < 0.000001

Contact with genital herpes     13.4%   4.7%    3.13 (1.10-9 60.) 00.3

 Undiagnosed genital  -ulcer(s) or itches    8.8%    8 5%    1 0.6
(043-2 67)
 NS

Non-gonococcal urethritis       51 0%   34      1 94(1.16-3.27)  0.0.1

 Genital warts  20.6%   10      2.24 (1 05-4 89) 0.036

Gonorrhoea      10.8%   5.7%    2.02 (0.74-5.80)         NS
*95% CI = 95% confidence intervals-Cornfield method

NS = not significant.
                0       1-5     6-10    11-20   21-30 31-40   41-50
51-100  >100

Lifetime number of partners

Number  35      63      77      33      17      17      35
23
tested
HSV-2
positive                17      34      40      24      14
17      30
18
95% CI          31.36   40.94-66.61     40.26-63.48
54.48-86.70
56.57-96.20     80.49-100.00    69.74-95.19     56.30-92.54
Mean            48.57   53.97   51.95   72.73   82.35
10000   85.71
78.26
HSV-2 antibodies among 300 heterosexual men according to life time
number of sexual partners (vertical bars indicate 95% confidence
intervals).

Table 2: Multivariate analysis of risk factors for HSV-2 antibody after allowing for reported number of lifetime partners

                Odds
Risk factor:     ratio*  95% Cl  P

Finished high
 school 0.39    0..1t=0..93     0.034

History of:

Contact with
 genital herpes 2.69    0.93-7.74       0. 0.67

NGU     1.31    0.76-2.26       033

Genital warts   1.69    0.81-3.53       016

*Mantel-Haenszel estimates (categories as in the Figure).
CI = confidence interval; NGU = non-gonococcal urethritis.

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(Received 3 Nov 1993, accepted 22 Feb 1994)

Citation:

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