Background: Thisstudy sought to provide the first population estimates of herpes simplex type2 (HSV-2) seroprevalence inCanada.
Goal: Tomeasure the antenatal seroprevalence of HSV-2 antibodies in reproductive agewomen.
StudyDesign: An anonymous unlinked seroprevalence study usedstored sera collected from pregnant women in British Columbia during 1999.Randomized sampling within age strata selected a total of 1215 subjects, ages15 to 44 years. Serologic testing used the Gull Meridian Test. Overallprevalence was directly standardized to the 1999 Canadian femalepopulation.
Results: Theage-adjusted prevalence for HSV-2 was 17.3% (95% CI, 15.2–19.4).Prevalence ranged from 7.1% (ages, 15–19 years) to 28.1% (ages,40–44 years), with the largest increases after the age of 24years.
Conclusions: TheHSV-2 seroprevalence among pregnant women in British Columbia is similar tothat in the United States and other countries. Seroprevalence continues torise through the later reproductive years. This observation may relate tocontinued transmission, an age cohort effect, orboth.
Fromthe University of British Columbia Centre for Disease Control, Vancouver,British Columbia,Canada
The authorsthank Glaxo Canada for a grant in aid, Dr. Jamie Robinson for discussions ondesign, and Ms. Rashpal Toor for assistance in manuscriptpreparation.
Reprintrequests: David M. Patrick, MD, FRCPC, MHSc, University of British ColumbiaCentre for Disease Control, 655 West 12 Avenue, Room 2104, Vancouver, BC V5Z4R4 Canada. E-mail: email@example.com
Received forpublication December 15, 2000, revised January 31, 2001,and accepted February 6,2001.
GENITALHERPES IS the second most prevalent sexually transmitted viral infectionworldwide, and the most common cause of genital ulceration in the developedworld. 1 Herpes simplex virus type 2(HSV-2) primarily causes genital infections. Although HSV-1 is associated withorolabial disease, up to 50% of new genital ulcers in some developed countriesare caused byHSV-1. 1
Primarygenital HSV infection caused by either HSV-1 or HSV-2 can cause vesiculationand painful ulcers that may recur at intervals. Recurrences take place at ahigher frequency with HSV-2, 2 yetmany cases of genital herpes are subtle. Consequently, up to 75% of peoplewith serologic markers of HSV-2 infection have not had their conditiondiagnosed. 3 Viral shedding from thegenital tract occurs both in those with a diagnosis of genital herpes and inseropositive people with subtle or even nosymptoms. 4
Inaddition to concerns about direct morbidity, genital herpes infections havethree important public health implications. First, undiagnosed casescontribute to the population reservoir and transmission of the virus. Second,perinatal transmission to the neonate may result in disseminated disease,neurologic damage, and high mortality. Third and finally, herpetic ulcersfacilitate the transmission ofHIV. 3,5
Type-specificserologic tests can determine whether an individual has been infected withHSV-1, HSV-2, or both. In several countries, these tests have been used todetermine the prevalence of HSV infections(Table 1). Theprevalence of HSV-1 varies between 50% and 90% across various studypopulations. 6–12
The prevalenceof HSV-2 among adults in the United States increased 30% over a decade, from16.4% in the late 1970s to 21.7% between 1989 and1990. 13 Meanwhile, the prevalence ofHSV-2 has been stable in the German general and Swedish antenatalpopulations, 14 whereas decreases inHSV-1 and HSV-2 prevalences have been documented in ruralJapan. 9
At thiswriting, no accounts of population-based HSV seroprevalence in Canada havebeen published. This study examined the question of age-specific and overallseroprevalence for HSV-1 and HSV-2 in a population of great interest to publichealth: pregnantwomen.
Thestudy was an anonymous unlinked seroprevalence survey that used leftover serumfrom antenatal rubella testing obtained during 1999 in British Columbia. Theprotocol was reviewed and authorized by the institutional review board at theUniversity of British Columbia.
From each age stratum,135 specimens were selected using a computerized randomization strategy.Sampling was deliberately denser (2-year age strata) for subjects ages 15 to24 years, and 5-year age strata were used for subjects ages 25 to 44years.
An aliquot from each specimen was obtained. Onlyage and region of origin were recorded with the aliquot for study purposes.Study specimens were delinked from all unique identifiers. The HSV testingused the glycoprotein G–specific enzyme-linked immunoabsorbent assay(ELISA) system (Gull Meridian) according to the manufacturer’srecommended procedures.
The results were analyzed usingSPSS 9.0 (SPSS Inc., Chicago, IL). For each age stratum, prevalence andassociated 95% CI were calculated. A directly standardized prevalence wascalculated using the 1999 Statistics Canada population of Canadian women 15 to44 years of age. The age-specific rates observed in this study were applied toa weighting formula based on the Canadian female population ages 15 to 44years. The regional prevalences for HSV-1 and HSV-2 also werecalculated.
Forthis study, 1215 specimens from the same number of women were used. Theoverall age-adjusted seroprevalence was 58.9% for HSV-1 and 17.3% for HSV-2.The age-specific prevalence rates appear in Figure 1. Forsubjects 15 to 44 years of age, the age-specific seroprevalence rate for HSV-1did not change significantly (χ 2 =0.15). However, the prevalence rate for HSV-2 increased from 7% for15-year-old subjects to 28% for 44-year-old subjects(χ 2 < 0.001). Notably, the prevalence didnot increase dramatically between the ages of 15 and 24 years, but didincrease notably throughout later reproductive years.
Theregional distribution is displayed in Figure 2. No largedifferences were found between major metropolitan areas and less urbanizedregions. The highest regional rates were seen in urban and suburbanpopulations adjacent to Vancouver, British Columbia: 19.9% for the lowermainland (excluding Vancouver) and 18.4% for Vancouver Island.
Theage-standardized prevalence of HSV-2 among pregnant women from a Canadianprovince was found to be 17%, slightly lower than the 25.6% prevalence forwomen in the US Third National Health and Nutrition Examination Survey and the29.3% from Seattle. 3,13 Asexpected, a large number of undiagnosed HSV-2 infections exist that may serveas a reservoir for subsequent transmission to partners and possiblyneonates.
The lifetime sexual partners and many of thelifetime sexually transmitted diseases accrue for many people during theirinitial 10 years of sexual activity. It is interesting to note that in thisstudy, relatively little increase in age-specific prevalence was seen insubjects between the ages of 15 and 24 years. Much more obvious incrementswere observed in those older than 25 years. Several explanations are possible.An age cohort effect is plausible. Swedish seroprevalence studies havedocumented high age-specific HSV-2 seroprevalence in subjects who were youngerthan 25 years during the 1970s, although that age group exhibited the lowestprevalence rates during the 1990s. 14 Swedish women older than 34 years had the highest HSV-2 prevalence in the1990s. Therefore, women with sexual experience during the sexual revolutionand before intensive condom promotion may have had greater cumulativeexposure.
Because this study sampled only pregnantfemales, its subjects would be sexually active and not making consistent useof barrier contraception. Pregnant girls, ages 15 to 19 years, likely wouldcarry a higher burden of HSV-2 infection than their nonpregnant peers. Thiseffect would blunt the ability to detect apparent increases in subjectsbetween the ages of 15 to 24 years. This may explain why the seroprevalence inthe 15- to 19-year-old group in this study was higher than the comparable agegroup in the population-based NHANES III study from the UnitedStates. 13 Also, this pattern couldreflect continued transmission in the later reproductiveyears.
Chlamydia and HPV have very high rates oftransmission after even a few encounters. Furthermore, HSV may be transmittedafter only one or a few encounters. However, because the virus is shed onlyintermittently from genital skin, it may take more encounters on the averagebefore transmission. In at least one prospective study of couples discordantfor HSV-2 infection, transmission occurred at an annual rate of only 10%, withup to 70% of the infections transmitted in the asymptomaticphase. 15 Data on HSV-2 incidencealso are available from at least three prospective trials in the UnitedStates. The incident rate in sexually active couples was determined to be 4.6to 5.1 per 100person-years. 16,17
Diversityin age-specific prevalence trends is documented around the world. Studies inboth Finland and Spain show no significant difference in HSV-2 prevalence withage. 18,19 The NHANES IIIshows a significant jump in HSV-2 prevalence from subjects younger than 30years (17.2%) to those who are older (27.8%). The prevalence of HSV-2 thenremains fairly constant between subjects 30 years of age and those older than70 years. Similar trends are seen in NHANESII. 13 Age-related increases inprevalence are seen in population-based studies in Japan andSweden. 10,14
Thecurrent cross-sectional prevalence study did not measure the incidence ofHSV-2 either directly or indirectly. The incidence of HSV-2 among pregnantwomen drives much of the risk for neonatal infection. A steady increment ofnearly 1% in prevalence per year suggests a similar rate of incidence if thereis no major age cohort effect, and would hint that a measurable proportion ofpregnancies are exposed to new primary HSV infections. The rate of HSV-2acquisition in pregnancy for HSV-1–seropositive individuals has beenmeasured at 1.7%. 20 British Columbiarecords between one and three cases of neonatal herpes in 45,000 live birthsannually.
The current study has several limitations.First, it sampled only women. Male rates tend to be somewhat lower in otherpopulation-based studies. Second, antenatal sampling did not allow sampling ofthe entire female population. However, women ages 15 to 44 years are preciselythose most at risk for new sexually transmitted infection, and those for whomthe issue of transmitting infection vertically to the neonate is the mostrelevant. This study took place in one Canadian province. However, thestatistics on a highly prevalent and widely disseminated sexually transmittedinfection are not likely to differ dramatically in distribution betweenprovinces. Within British Columbia, there was no significant difference inage-adjusted rates between different regions.
Comparisonof these findings among many studies is limited by a lack of agestandardization in published data. Different study population structures couldaccount for many of the apparent differences between countries and regions.Also, many studies have used the gold standard type-specific HSV serologictesting method: Western Blot. Type-specific ELISAs using the glycoprotein Gmoiety have become available more recently. Their performance characteristicsrange from 89.9% to 99.7% for sensitivity and 97.1% to 99.3% for specificity,as compared with Western Blot. 21 Lowbut measurable rates of seroreversion have been documented in somestudies. 18,22 Such aphenomenon may be biologically or technologically based. Despite theselimitations, type-specific assays based on the glycoprotein G moiety havesufficient accuracy to paint an epidemiologic picture of HSV-2 seroprevalencein the population, and may do so at considerably less expense than studiesusing Western Blot. Because various nations are using similar kits for theirstudies, comparisons among studies remainfeasible.
Herpes simplex type 2 infection is prevalentamong pregnant Canadian women. Its frequently subtle nature and occulttransmission patterns pose a problem for public health. Condom use reduces butdoes not eliminate HSV-2 transmission. Greater awareness by the public andbetter diagnostic acuity by clinicians armed with type-specific serology maybe helpful. Elimination of genital HSV infections may have to await theavailability of a vaccine efficacious for primaryprevention.
1. Mindel A. Genital herpes: how much of a public health problem? Lancet 1998; 351 (suppl III): 16–18.
2. Lafferty WE, Coombs RW, Bennedetti J, et al. Recurrences after oral and genital herpes simplex virusinfection: influence of site of infection and viral type. N Engl J Med 1987; 316: 1444–1449.
3. Wald A, Koutsky L, Ashley R, Corey L. Genital herpes in a primary care clinic: demographic and sexual correlates of herpes simplex type 2infections. Sex Transm Dis 1997; 24: 149–155.
4. Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection inasymptomatic seropositive persons. N Engl J Med 2000; 342: 844–850.
5. Halioua B, Malkin JE. Epidemiology of genital herpes: recent advances. Eur J Dermatol 1999; 9: 177–184.
6. Austin H, Macaluso M, Nahmias A, et al. Correlates of herpes simplex virus seroprevalence among womenattending a sexually transmitted disease clinic. Sex Transm Dis 1999; 26: 329–334.
7. Conde-Glez CJ, Juarez-Figueroa L, Uribe-Salas F, et al. Analysis of herpes simplex virus 1 and 2 infection in women withhigh-risk sexual behaviour in Mexico. Int J Epidemiol 1999; 28: 571–576.
8. Ghebrekidan H, Ruden U, Cox S, Wahren B, Grandien M. Prevalence of herpes simplex virus types 1 and 2, cytomegalovirus,and varicella-zoster virus infections in Eritrea. J Clin Virol 1999; 12: 53–64.
9. Hashido M, Kawana T, Matsunaga Y, Inouye S. Changes in prevalence of herpes simplex virus types 1 and 2antibodies from 1973 to 1993 in the rural districts of Japan. Microbiol Immunol 1999; 43: 177–180.
10. Hashido M, Lee FK, Nahmias AJ, et al. An epidemiologic study of herpes simplex virus types 1 and 2infection in Japan based on type-specific serologic assays. Epidemiol Infect 1998; 120: 179–186.
11. Lo JYC, Lim WWL, Ho DWT, Field PR, Cunningham AL. Difference in seroprevalence of herpes simplex virus type 2infection among antenatal women in Hong Kong and southern China. Sex Transm Infect 1999; 75: 123.
12. Rosenthal SL, Stanberry LR, Biro FM, et al. Seroprevalence of herpes simplex virus types 1 and 2 andcytomegalovirus in adolescents. Clin Infect Dis 1997; 24: 135–139.
13. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to1994. N Engl J Med 1997; 337: 1105–1111.
14. Persson K, Mansson A, Jonsson E, Nordenfelt E. Decline of herpes simplex virus type 2 and chlamydia trachomatisinfections from 1970 to 1993 indicated by a similar change in antibodypattern. Scand J Infect Dis 1995; 27: 195–199.
15. Ashley R, Wald A. Genital herpes: review of the epidemic and potential use of type-specificserology. Clin Microbiol Rev 1999; 12: 1–8.
16. Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV2 infection: two randomized controlled trials. Chiron HSV Vaccine Group. JAMA 1999; 282: 379–380.
17. Langenberg AG, Corey L, Ashley RL, Leong WP, Straus SE. A prospective study of new infections with herpes simplex virustype 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med 1999; 341: 1432–1438.
18. Arvaja M, Lehtinen M, Koskela P, Lappalainen M, Paavonen J, Vesikari T. Serologic evaluation of herpes simplex virus type 1 and type 2infections in pregnancy. Sex Transm Infect 1999; 75: 68–71.
19. Garcia-Corbeira P, Dal-Re R, Aguilar L, Granizo JJ, Garcia-de-Lomas J. Is sexual transmission an important pattern for herpes simplex type2 virus seroconversion in the Spanish general population? J Med Virol 1999; 59: 194–197.
20. Brown ZA, Selke S, Zeh J, et al. The acquisition of herpes simplex virus duringpregnancy. N Engl J Med 1997; 337: 509–515.
21. Groen J, van Dijk G, Niesters HGM, van der Meijden WI, Osterhaus ADME. Comparison of two enzyme-linked immunosorbent assays and one rapidimmunoblot assay for detection of herpes simplex virus type 2 specificantibodies in serum. J Clin Microbiol 1998; 30: 845–847.
22. Schmid DS, Brown DR, Nisenbaum R, et al. Limits in reliability of glycoprotein G-based type-specificserologic assays for herpes simplex virus types 1 and 2. J Clin Microbiol 1999; 37: 376–379.
23. Laubereau B, Zwahlen M, Neuenschwander B, Heininger U, Schaad UB, Desgrandchamps D. Herpes simplex virus types 1 and 2 in Switzerland [inGerman]. Schweiz Med Wochenschr 2000; 130: 143–150.
24. Enders G, Risse B, Zauke M, Bolley I, Knotek F. Seroprevalence study of herpes simplex virus type 2 among pregnantwomen in Germany using a type-specific enzyme immunoassay. Eur J Clin Microbiol Infect Dis 1998; 18: 870–872.
25. Eberhart-Philips J, Dickson NP, Paul C, et al. Herpes simplex type 2 infection in a cohort aged 21years. Sex Transm Inf 1998; 74: 216–218.
26. Janier M, Lassau F, Bloch J, et al. Seroprevalence of herpes simplex virus type 2 antibodies in an STDclinic in Paris. Int J STD AIDS 1999; 10: 522–526.
27. Vande Laar MJW, Termorshulzen F, Slomka MJ, et al. Prevalence and correlates of herpes simplex virus type 2infection: evaluation of behavioral risk factors. Int J Epidemiol 1998; 27: 127–134.
28. McFarland W, Gwanzura L, Bassett MT, et al. Prevalence and incidence of herpes simplex virus type 2 infectionamong male Zimbabwean factory workers. J Infect Dis 1999; 180: 1459–1465.
29. Dobbins JG, Mastro TD, Nopkesorn T, et al. Herpes in the time of AIDS: a comparison of the epidemiology of HIV-1 and HSV-2 in youngmen in northern Thailand. Sex Transm Dis 1999; 26: 67–74.
30. Lewis LM, Bernstein DI, Rosenthal SL, Stanberry LR. Seroprevalence of herpes simplex virus type 2 in African-Americancollege women. J Natl Med Assoc 1999; 91: 210–212.
31. DaRosa-Santos OL, Goncalves Da Silva A, Pereira AC Jr. Herpes simplex virus type 2 in Brazil: seroepidemiologic survey. Int J Dermatol 1996; 35: 794–796.