The Canadian Journal of Human SexualityVolume 6 - Number 2 1997 Genital Herpes: The Epidemiology and Control of a Common Sexually Transmitted DiseaseMarc Steben Stephen L. Sacks Abstract:Genital herpes is a treatable but, at present, incurable sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2), usually acquired through genital-genital contact, but also by herpes simplex virus type 1 (HSV-1), usually through oral-genital contact. Although genital herpes is not a reportable STD in Canada, international data and clinical reports suggest that it is common. Factors associated with HSV-2 seroprevalence include age, lifetime number of sexual partners, and being a female in a sexual relationship with an infected male. Risk of transmission is associated with lack of condom use, and with frequency of asymptomatic viral shedding and symptomatic recurrences. This paper reviews current medical and epidemiological concepts related to genital herpes and proposes strategies for the control of genital herpes in Canada. These strategies include serosurveillance studies, public education, cost/benefit analysis of suppressive therapy, development of less expensive and easier to perform screening tests, and planning for the eventual deployment of a vaccine. Key words:
Correspondence concerning this paper should be addressed to Dr. Marc Steben, Direction de la santé publique de Montréal-Centre, Unité maladies infectieuses, MPC-MTS/sida, 161 boul. René-Lévesque Ouest, 3e étage, Montreal, Quebec, H3H 1P8 IntroductionSeroprevalence studies on selected populations in the United States, the United Kingdom, South America, and Africa indicate that infection with one or both forms of the herpes simplex virus (HSV) is extremely common (Table 1). The herpes simplex I virus (HSV-1) tends to infect the oro-labial area and is the source of the common cold sore. The closely-related herpes simplex II virus (HSV-2) is the main cause of genital herpes infection, a lifelong viral infection that is usually acquired through direct physical contact. HSV-1, which can be transmitted from lips to genitals during oral-genital sex, can also cause genital herpes. Although globally HSV infection has become the most frequent cause of genital ulceration (Kroon, 1994), many aspects of HSV infection are still poorly understood. Our experience suggests, for example, that: (1) because they have had prior, and perhaps unrecognized, exposure to HSV-1 infection on the lips or oro-labial area, most people who acquire genital herpes do not have strongly identifiable symptoms of genital infection with HSV-2; (2) most people who have acquired genital herpes will first visit a physician or clinic in a stage of recurrence and not in an acute attack; and (3) most persons are infected through penile-vaginal sexual intercourse, oral-genital sex, or anal sex with a person who is shedding the virus without visibly obvious lesions and/or without even knowing that s/he is infected by a herpes virus. Overall, at least 75% of people infected with HSV-2 are asymptomatic (Breinig, Kingsley, Armstrong, Freeman, & Ho, 1990; Boucher et al., 1990; Kulhanjian et al., 1992). When present, however, symptoms of genital herpes may be clinically significant. Although the majority of first episodes are non-primary, true primary infection can lead to clinically severe manifestations and short term sequelae. The symptoms of primary infection may be characterized by noticeable, painful vesiculo-ulcerative disease of the genitals, buttocks, thighs and urethra, or by usually unnoticed inflammation on the cervix or vagina. Initial infection is followed by dormant, asymptomatic periods with recurrences of both symptoms and silent infectivity occurring with unpredictable frequency. Recurrences can be triggered by a variety of factors, although most recurrences will have identifiable triggers. In the absence of a cure, infected individuals can employ strategies to reduce reactivation frequency (e.g., chronic suppressive antiviral medication) or to minimize the intensity or duration of symptoms when recurrence does occur (e.g., episodic oral antiviral medication). Nevertheless, the effects of primary and recurrent infection, and the need to be vigilant in preventing transmission to others, can be a source of considerable emotional stress and psychological discomfort (Sacks, 1997). In addition, pregnant women who are experiencing first episodes of genital herpes need to be aware of the risks of transmission and of the possibility of Caesarean delivery. Despite evidence that recurrences of genital herpes are less problematic, current medical practice still suggests Caesarean delivery if lesions are active. An added health concern is that genital lesions arising from herpes infection can provide a site for infection with other STDs, particularly human immunodeficiency virus (HIV) and possibly hepatitis C virus. Despite the high psychosexual and physical consequences of infection, there is almost no information on the epidemiology of genital herpes infection in Canada. Since genital herpes is not a reportable STD in Canada, we do not have the large reservoir of national data to guide our prevention efforts that is available for the other common STDs. This paper will therefore rely heavily on international data to provide an overview of the epidemiology of HSV infection in different populations. This information, coupled with the Canadian data that are available, will be used to suggest goals for prevention in Canada and to identify interventions needed to achieve these goals. Epidemiology of Genital Herpes GloballyTesting for the seroprevalence of antibodies to HSV-2 is one way to estimate the prevalence of genital herpes in a population. A 1994 report of the International Herpes Management Forum (IHMF) summarized findings from nine countries in the 1980s which showed high and increasing seroprevalence of antibodies to HSV-2. The report indicated, as well, that HSV infection had overtaken bacterial STD infection as the most common cause of genital ulceration worldwide (Kroon, 1994). The general populations sampled included blood donors, partners of pregnant women in obstetrical clinics, and men in a fertility clinic; other studies reported specifically on seroprevalence of HSV-2 antibodies in pregnant women (Nahmias, Lee & Beckman-Nahmias, 1990; Johnson et al., 1993). Studies cited in the IHMF report (Kroon, 1994) show higher HSV-2 seroprevalence in the USA (13-40%) than in Europe (7-16%), and higher in Africa (30-40%) than in the USA (e.g., Nahmias et al., 1990; Johnson et al., 1993). Comparisons should be made with caution, however, because of differences in demography, selection criteria, and other characteristics of the sample populations. It should also be noted that these percentages, and those listed below, probably underestimate the extent of genital herpes infection since the HSV-2 antibody assay would not have detected genital herpes caused by HSV-1. Such cases of HSV-1 acquisition are thought to be transmitted mainly through oral-genital sex, and to represent an increasingly frequent route for genital herpes infection. HSV-1 now accounts for approximately 40% of first genital episodes in Canadian patients (Loveless, Harris, & Sacks, 1995). Even given these reservations, the findings among pregnant women also suggest wide variation in HSV-2 seroprevalence in different populations (e.g., 50% seroprevalence in one study of African-American women vs. 7% in Japan) (Nahmias, Lee, & Beckman-Nahmias, 1990). There are also reports of a higher prevalence of HSV-2 in African-American than Caucasian women (Johnson et al., 1993), and of a trend toward increasing prevalence of infection in a number of populations. For example, HSV-2 seroprevalence in "general population" samples in the U.S. increased from 16.4% in the late 1970s, to 21.7% in the late 1980s, to 31% in 1992 (Nahmias et al., 1990; Johnson et al., 1993). Kroon's (1994) summary of reports on HSV-2 seroprevalence among sex workers and attendees at STD clinics reflects the expected higher level of infection in these groups than in general population samples. For example, 25% of female attendees at an STD clinic in the U.K. were HSV-2 seropositive vs. 10% for women at a blood donor clinic; comparable figures for heterosexual men and male blood donors in the two setting's were 17% and 3% respectively (Cowan, Johnson, Ashley, Corey, & Mindel, 1993). In a U.K. STD clinic, men who have sex with men were more likely to be seropositive for HSV-2 (27%) than their heterosexual counterparts (17%) (Cowan et al., 1993). Nahmias et al. (1990) reported 12.8% seroprevalence among men attending an STD clinic in Spain vs. 83% at an STD clinic in Peru. Similar variations within and between other populations are reported in Table 1. Annual rates of acquisition of new HSV-2 infections (i.e., seroconversion rates) varied among the populations identified in Table 1 with values of 1.7%-2% for pregnant women in the U.S., 2% for U.S. university students, and 4% for homosexual men in San Francisco in the mid-1980s (Kroon, 1994; Johnson et al., 1993; Johnson et al., 1989). Not surprisingly, this seroconversion rate varies with age, as does seroprevalence. For example, in the Swedish study by Christenson et al. (1992), 15-19 year olds had a seroconversion rate of 0.5% per year compared to 2.3% for 25-29 year olds. The potential for lifetime acquisition of HSV-2 infection is highlighted by the finding that 81% of African-American women and 61% of African-American men between the ages of 60 and 74 were HSV-2 seropositive (Johnson et al., 1993). The authors attributed these high levels, and the increasing seroprevalence in white Americans, to the trend toward later marriage, and hence to a longer period in which to be sexually active with different partners. Epidemiology of Genital HSV in CanadaSince HSV infection is not a reportable STD in Canada, we have limited knowledge of the epidemiology of genital herpes and of the seroprevalence of HSV-2. In a currently unpublished study, Sacks and colleagues used Western blot analysis to determine HSV-2 seroprevalence in a randomized sample of 409 women in labour in a Vancouver hospital between May 1985 and February 1987 (Sacks & Garland, personal communication). Interview data made it possible to draw an association between lifetime number of sexual partners and HSV-2 seropositivity which showed, for example, that women who reported 6-10 partners were over 7 times more likely to be seropositive for HSV-2 (33.3%) than those who reported 1 partner (4.6%), and that 55% of women with more than 10 partners (about 10% of the sample) were seropositive (Table 2). Overall, 20% of women in this "average risk" sample of low to middle class women in Vancouver were seropositive for HSV-2. Given that a sizeable proportion of young adults in Canada have had 3-5, or more, partners by the time they are 20 years old (for review see Maticka-Tyndale, 1997), and that the number of partners increases with age, we hypothesize that the prevalence of HSV-2 infection in Canada at least parallels that in the mid-range countries identified in Table 1. For example, a Swedish study of 14-15 year old young women found that 0.4% were HSV-2 seropositive; 15 years later, the number was 22% for the same sample (Christenson et al., 1993). In the mid-1980s, HSV-2 seroprevalence in pregnant Swedish women was 27.9% vs. 25.3-34.9% in pregnant Caucasian women in the U.S (see Kroon, 1994). Although these percentages suggest a possible range for the current overall HSV-2 seroprevalence in Canada, the discussion below on risk factors for genital herpes and HSV-2 infection (see Table 3) makes it clear that some sub-groups within the population carry an elevated burden of risk. Neonatal HSVNeonatal HSV infection is not reportable at the federal level in Canada, and we therefore have little epidemiological information on which to base prevention strategies. The Sixth Annual Report of the British Paediatric Surveillance Unit gave a rate of 1 case of neonatal herpes per 60,000 births ( 1.7 per 100,000 births) in England in 1991. Kroon (1994) places Canada and Scandinavia closer to this level than to the much higher rates of 1 in 2,000 to 1 in 5,000 (20-50 per 100,000 births) cited by Whitley (1990) for the U.S. The weaknesses inherent in passive surveillance make it likely, at least in Canada, that the reported figures under-represent actual occurrence. The surveillance situation in Canada would be improved by mandatory reporting of all positive cultures of herpes in infants under 3 months of age and of any autopsy results compatible with neonatal herpes. Although knowledge of a woman's infection with genital herpes should signal a risk of neonatal transmission (and hence of the possible desirability of Caesarean delivery), findings from a large study in the U.S. showed that only 28% of women known to have transmitted herpes to their newborns had a history of genital herpes, and that newborns at greatest risk were those born to women experiencing genital herpes for the first time (true primary or non-primary first episode) near the time of delivery (Brown et al., 1991). Similarly, an 18-month U.S. hospital surveillance study conducted by the Centers for Disease Control in 1984 on 184 cases of neonatal HSV infection found that 22% of the women had a history of genital herpes infection, 9% had genital lesions at delivery, 33% had Caesarean delivery, and about 8% of the neonatal cases occurred in women who had Caesarean delivery initiated prior to membrane rupture (Stone, Brooks, Guinan, & Alexander, 1989). Most neonatal infection occurs when the woman is not recognized as having genital herpes (Brown et al., 1991). Furthermore, women with a known history of genital herpes may not be symptomatic at the time of delivery and may or may not be shedding virus if they are asymptomatic. Timing and methodology of prepartum testing are also important in identifying risk of transmission. For example, in a Canadian study, Sacks and Lee (1992) compared prepartum and intrapartum HSV cultures in 198 pregnant women referred to the University of British Columbia Herpes Clinic because they were considered to be at high risk for genital herpes. They found that a positive culture for HSV on one prepartum visit predicted a positive culture on the second visit 58.5% of the time if the second visit occurred within 2 days, but only 19.3% of the time if the second visit was more than 2 days later. In other words, with this methodology, prepartum testing could not predict if a woman would be shedding virus at the time of delivery if the test were done longer than 2 days before. Serological data obtained from these "high risk" pregnant women, and from the previously described sample of "average risk" Vancouver women in labour, were also featured in a study that demonstrated the superiority of the Western blot antibody assay over the microneutralization method for type-specific antibody detection in both groups (Garland, Lee, Ashley, Corey, & Sacks, 1995). The foregoing observations highlight the complexities involved in preventing neonatal herpes infection, and the importance of surveillance, detection and appropriate management of infection in this regard. Risk Factors for Genital Herpes and HSV-2 SeropositivityTable 3 documents some of the common factors which have been established or may be associated with HSV-2 seropositivity and genital herpes. Having a higher number of sexual partners, being a woman in a partnership with an infected man and having frequent symptomatic recurrences after primary infection are included. Furthermore, as shown, several studies suggest that prior exposure to HSV-1 may reduce risk (Table 3). However, the preventative nature of HSV-1 is not proven. Prior HSV-1 may also increase the likelihood of silent genital acquisition of HSV-2. Regular condom use also has some protective effect, although condom protection is incomplete and under-utilized. Further studies regarding safer sex and HSV are definitely required. Goals for Prevention of Genital Herpes in Canada
Achievement of these goals will require interventions (summarized in Table 4) in the areas of surveillance, research, control strategies, and preparation for the eventual use of a vaccine. In considering these interventions, we should reflect on the factors that have had an impact on Canada's modest public health response to genital herpes to date. The reasons cited by Corey and Wald (1995) for under-reporting of genital herpes may also explain the low profile of genital herpes in public health planning. For example, genital herpes has a variety of clinical manifestations, inexpensive and easily-performed screening tests are not available, its epidemiology is complex, and reporting requirements and procedures vary among the provinces. In addition, traditional STD control measures are either unavailable or disappointing. For example: vaccination is a long way from large-scale availability; contact tracing is not very useful because of the high proportion of asymptomatic individuals and the difficulty of explaining or motivating caution in such circumstances; genital herpes infection is lifelong with no cure available comparable to those for bacterial STDs (hence treatment of asymptomatic contacts is not possible); and, for these and other reasons, screening of asymptomatic individuals is not cost/effective. Our recommendations for action (Table 4) suggest a beginning response to three issues:
Table 1- Serologic Prevalence of HSV in Different Populations*
Table 2 - Relationship Between Lifetime Number of Sexual Partners and HSV-2 Serostatus of 409 Canadian Women.*
Table 3 - Risk Factors Associated with HSV-2 Seroprevalence and Transmission of Genital Herpes Infection in Different Populations
Table 4 - Needs and Strategies for Control of Genital Herpes in Canada
References
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