Sexually Transmitted Diseases:
New Estimates of Herpes Simplex Virus Type 2 Seroprevalence in England: ‘High’ But Stable Seroprevalence Over the Last Decade
Morris-Cunnington, Marianne PhD*; Brown, David MSc, MRCPath†; Pimenta, Jeanne PhD‡; Robinson, Noah Jamie PhD‡; Miller, Elizabeth MB, FRCPath*
*Immunisation Division, Communicable Disease Surveillance Centre (CDSC), London, U.K.; the †Enteric, Respiratory and Neurological Laboratory, Central Public Health Laboratory, London, U.K.; and ‡WorldWide Epidemiology, GlaxoSmithKline, Greenford, U.K.
The authors thank Belinda Bickley for performing the HSV-2 testing and Douglas Fleming for valuable comments on previous drafts of the manuscript.
MC and DWG designed the study. MC completed the analysis and the first draft of the manuscript. JMP contributed to the analysis and commented on the manuscript. NJR contributed to the protocol development and commented on the manuscript. EM conceived and set up the serologic network.
This study was funded by GlaxoSmithKline through an unrestricted grant.
JMP and NJR are employed by GlaxoSmithKline; MC is currently employed by GSK, but carried out analyses and the first draft of the report while at CDSC.
This study and the serosurveillance network were approved by the Public Health Service Laboratory Ethics Committee.
Correspondence: Marianne Morris-Cunnington, PhD, GlaxoSmithKline, New Frontiers Park South, Harlow, Essex, CM19 5AW, U.K. E-mail: Marianne.C.Cunnington@gsk.com
Received October 27, 2003,
revised November 20, 2003, and accepted November 26, 2003.
Objectives: There have been few recent population-based herpes simplex virus type 2 (HSV-2) seroprevalence studies in England, but reports from the United States have indicated a 30% rise in HSV-2 seroprevalence between 1976 and 1994. This study aimed to ascertain trends in HSV-2 infection in England between 1991 and 2000.
Study Design: Anonymized serum residues collected through public health laboratories across England from individuals aged 16 to 64 years seeking health care through the National Health Service in 1991 (n = 2259) and 2000 (n = 3646) were tested for anti-HSV-2 IgG using the HerpeSelect 2 enzyme-linked immunosorbent assay IgG (Focus).
Results: In 9 sites across England, the age- and sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval, 8.4–11.0%). Data from 4 sites common to both study years indicated no change in HSV-2 seroprevalence between 1991 and 2000.
Conclusions: After adjustment for age, sex, and geographic location, there was no evidence of a change in seroprevalence between 1991 and 2000.
HERPES SIMPLEX VIRUS type 2 (HSV-2) is almost exclusively sexually transmitted and is the main cause of genital herpes, one of the most common sexually transmitted infections in England and Wales. 1 The public health impact of HSV-2 extends beyond the burden associated with genital ulcer disease. The virus is known to facilitate the transmission of HIV, immunosuppressed individuals are also at a higher risk of severe outbreaks of HSV, and the infection can be passed from mother to child resulting in neonatal herpes infection (the risk is much greater with a primary infection in the third trimester of pregnancy). 2,3
Studies from the United Kingdom have traditionally reported lower HSV-2 seroprevalence estimates than studies from the United States. However, routine surveillance data from genitourinary medicine clinics across the United Kingdom reported a 52% increase in first attacks of genital herpes among females between 1990 and 1999. 4 This could be partly the result of improvements in diagnostics, increased patient awareness, and susceptibility to HSV-1-related genital herpes. However, recent increases in high-risk sexual behavior have also been reported in the United Kingdom, 5 and increases in HSV-2 seroprevalence have been observed in the United States. 6 Sera tested for HSV-2 during 2 consecutive population-based surveys (National Health and Nutrition Examination Surveys [NHANES] II and III) found a 30% increase in the age-adjusted seroprevalence (from 16–21% between 1976 and 1994) in individuals aged 12 years and over. 6 It has been difficult to ascertain whether similar changes have occurred in England because most recent seroprevalence studies have concentrated on specific population groups (eg, GUM clinic attenders and pregnant women 7–9), making it difficult to extrapolate trends to the general population.
The objective of this study was to provide an up-to-date estimate of HSV-2 seroprevalence from the general population in England and to assess trends in seroprevalence over time. We report a population-based multisite survey with sera collected from over 3500 individuals across England in 2000. These results were compared with sera collected from England and stored in 1991 to ascertain whether any changes in HSV-2 seroprevalence had occurred.
Materials and Methods
Sera from an age-stratified sample of 3646 adults (aged 16–64 years, 43.3% male) were collected in 2000 for routine diagnostic purposes from 9 laboratories within the Public Health Laboratory Service serologic network in England. 10 The laboratories served the immediate urban and surrounding areas of Bristol (n = 389), Cambridge (331), Dorchester (849), Exeter (199), Leeds (520), Liverpool (328), Manchester (852), Portsmouth (137), and Preston (41). Sera were tested August 2002 for HSV-2 using the HerpeSelect 2 enzyme-linked immunosorbent assay (ELISA) IgG (Focus) assay. The sera were anonymized residues from routine diagnostic testing and retained information on the individuals’ age, sex, and laboratory of testing only. Sera were diluted using the ratio 1:101 and were considered positive or negative according to the test kit cutoff value. Samples with an equivocal result (0.6% of total) were retested using an in-house monoclonal antibody blocking assay. 11 A further 2259 samples (aged 16–64 years, 42.6% male) were available from 1991 from 4 laboratory sites common to the 2000 collection (Exeter [n = 519], Leeds [n = 504], Manchester [n = 381], and Preston [n = 855]). The serologic network and study were approved by the PHLS ethics committee.
Seroprevalence estimates were age- and sex-standardized to the English population in 2000. Age, sex, and geographic effects in 2000 were investigated using a logistic regression model in STATA 6.0 (Stata Corp.) with HSV-2 seropositivity as the dependent variable and age group, and sex and laboratory as the explanatory variables. All variables significant at the 10% statistical level in single variable analyses were entered into a multivariable model in which significance at the 5% level was ascertained using likelihood ratio tests. Changes over time were explored with a similar regression model but using only data from the 4 sites common to both sampling periods.
The study was powered to detect an increase in HSV-2 seroprevalence from 4% in 1991 to 6% in 2000 (baseline from Vyse et al. 12) with 80% power at the 5% statistical level.
HSV-2 Seroprevalence in 2000 (based on 9 sites)
The overall age- and sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval [CI], 8.4–11.0%) (crude seroprevalence of 8.5%; 95% CI, 7.6–9.4%). The crude age-specific seroprevalence increased with age from 4.6% in 16 to 19 year olds to over 10% in 45 to 64 year olds. Figure 1 illustrates age-specific patterns in HSV-2 seroprevalence by gender. In females, the overall age- and sex-standardized seroprevalence was 12.3% (95% CI, 10.2–14.3%) compared with 7.1% (95% CI, 5.4–8.8%) in males; a similar pattern of a higher seroprevalence in females was observed in all age groups. Figure 2 illustrates the considerable variation in the overall seroprevalence by laboratory (ranging between 4.2% in Cambridge and 13.1% in Leeds). Age group, sex, and laboratory all proved significantly associated with HSV-2 seropositivity in the multivariable logistic regression model. There was a 2% relative increase in seroprevalence with each year of age (odds ratio [OR], 1.02; 95% CI, 1.01–1.03) and a 2-fold increase in the odds of seropositivity among females compared with males (OR, 2.0; 95% CI, 1.5–2.5). Laboratory site also proved significant in the multivariable model (likelihood ratio test for variable: chi-squared = 17.6, P = 0.02).
Changes in HSV-2 Seroprevalence (1991–2000)
Comparing data from the 4 common sites gave an overall age- and sex-standardized seroprevalence of 11.6% (95% CI, 9.9–13.4%) in 1991 and 11.6% (95% CI, 9.2–14.1%) in 2000 (Fig. 3). The logistic regression model adjusting for age, sex, and laboratory site confirmed no marked change in HSV-2 seroprevalence over time (1991 baseline: OR, 1.1; 95% CI, 0.9–1.4). Increasing age and female gender remained independent predictors of HSV-2 seropositivity (Table 1).
This large, population-based survey from 9 sites across England found an age- and sex-standardized HSV-2 seroprevalence in 2000 of 9.7% (95% CI, 8.4–11.0%). The substantial increases in seroprevalence between the 16 to 19 and 20 to 24 year olds in 2000 (2-fold in both males and females) suggest the potential for substantial transmission among young adults giving a focus for future prevention efforts.
We did not observe the dramatic increase in seroprevalence as has been reported in the United States over recent decades. This could reflect the differing time periods investigated as NHANES II and III spanned the mid-1970s to the mid-1990s. More recent data from NHANES 1999 to 2000 also reported no increase in HSV-2 seroprevalence relative to NHANES III (21.3% in 1988–1994 and 17.3% in 1999–2000 in those aged 14–49 years). 13 Greater stability of HSV-2 seroprevalence over time could also have been seen in other countries; data from Swedish antenatal clinics noted a pattern of substantial increases from the 1960s to the mid-1980s followed by little change in consecutive HSV-2 seroprevalence estimates (1983–1989). 14
It remains difficult to reconcile the stable HSV-2 seroprevalence with the increase in first attacks of genital herpes reported from U.K. GUM clinics observed during the 1990s. The latter is consistent with the increases in high-risk sexual behavior (number of lifetime heterosexual partners and partners in last 5 years, number of concurrent partnerships, inconsistent condom use over the past 4 weeks) reported through consecutive national surveys (National survey of Sexual Attitudes and Lifestyles [NATSAL]) covering the same time period (1990–2000). 5 These behavioral changes were more pronounced in women in whom increases in genital herpes episodes were concentrated. However, differences could be explained by increased patient awareness and improved diagnoses in clinical settings. Increases in the proportion of genital herpes resulting from HSV-1 infection have also been documented, 12 and this is supported by increases in oral–genital contact as reported by NATSAL. 5
A further possibility is that an increase in the use of antivirals for suppressive therapy has led to reductions in viral shedding and consequent transmission. Despite there being evidence of increased prescribing of antivirals indicated for genital herpes infections during the 1990s, 15 this is unlikely to explain the observed HSV-2 stability. The majority of infections are undiagnosed, and only a small percentage of infected patients who attend specialist clinics with symptoms of genital herpes are then treated with suppressive antiviral therapy. 7,16
The test used in the study (Focus ELISA) has a reported sensitivity of 98% and specificity of 97% among sexually active adults. 17 With this in mind, the absolute HSV-2 seroprevalence figures presented here should be interpreted with care, because false-positives will occur. Taking the population prevalence perspective, some false-positives can be acceptable as long as they are balanced out by false-negatives. However, at lower seroprevalences (<10%), false-positives are likely to be predominant, leading to overestimates. As a result of the test performance, the likely error in estimation of the population prevalence in this study is between 2% and 3%.
The survey estimates are also substantially higher than those from a previous study using sera collected in 1994 to 1995 from 4 sites within the same serosurveillance network (n = 3347, aged 16–69 years). The latter study reported a seroprevalence of 4.0%, although data were not age- and sex-standardized. 12 The difference could be a chance finding at the lower end of the seroprevalence scale, the influence of different testing methods because an in-house ELISA was used in the 1994 study, or more likely, the capture of different populations because only the Manchester and Preston laboratories were common contributors to both studies.
Despite recruitment efforts, London laboratories have rarely participated in the serologic network and samples were therefore not available from the capital. However, previous reports have tended to indicate a higher disease burden in London, making it an area of interest. Unfortunately, the inclusion of London sera from other collections (eg, unlinked anonymous HIV surveillance program) was not possible as a result of ethical considerations. Although our study indicates a substantial burden of HSV-2, it could still underestimate the national HSV-2 seroprevalence in England.
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