Sexually Transmitted Diseases:
Type-Specific Seroprevalence of Herpes Simplex Virus Type 2 and Associated Risk Factors in Middle-Aged Women From 6 Countries: The IARC Multicentric Study
PATNAIK, PADMAJA PhD*†; HERRERO, ROLANDO MD, PhD‡; MORROW, R ASHLEY PhD§; MUÑOZ, NUBIA MD|¶; BOSCH, F XAVIER MD#; BAYO, SINÉ MD**; EL GUEDDARI, BRAHIM MD††; CACERES, EDUARDO MD‡‡; CHICHAREON, SAIBUA B. MD§§; CASTELLSAGUÉ, XAVIER MD, MPH, PhD#; MEIJER, CHRIS J. L. M. MD||; SNIJDERS, PETER J. F. PhD||; SMITH, JENNIFER S. MPH, PhD*
From the *Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; †Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, North Carolina; ‡Proyecto Epidemiológico Guanacaste, Fundacion, INCIENSA, Costa Rica; §Laboratory Medicine, University of Washington, Seattle, Washington; |International Agency for Research on Cancer (IARC), Lyon, France; ¶Institut Catala d’Oncologia (ICO), 24, Quai Fulchiron, Lyon, France; #IDIBELL, Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain; **Institut National de Recherche en Santé Publique, Bamako, Mali; ††Institut National d’Oncologie, Sidi Mohamed Ben Abdellah, BP 6213 Ri Agdal Rabat, Morocco; ‡‡Maes-Heller Cancer Research Centre, Lima, Peru; §§Department of Obstetrics-Gynecology, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkla, Thailand; ||Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
The authors thank Dr. Silvia Franceschi, International Agency for Research on Cancer (IARC), Lyon, France, and Dr. Cristina Bosetti, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy, for their assistance in conducting this study; Dr. Jamie Robinson for his support through the Worldwide Development Post-Doctoral Fellowship; and Dr. Julius Atashili for his assistance.
The study was supported by the European Community CI 1-0371-F(CD); The Fondo de Investigaciones Sanitarias (FIS), Spain 86/753, 87/1513, 88/2049, 90/0901, 95/0955, 01/1237, 01/1236, PI051308 and BAE 01/5013; The International Agency for Research on Cancer, Lyon, France FI/92/3-2 PAR; Preventiefonds, The Netherlands 28-1502·1; Programa Interministerial de Investigación y Desarrollo, Spain SAF 96/0323, The Conselho Nacional de Desenvolvimiento Cientifico e Tecnologico, Brazil (CNPq) JEN-204453/88·7 and the Department of Reproductive Health and Research at the World Health Organization, Grant No. 98·101; and the National Institutes of Health, USA Grant AI30731.
The Worldwide Development Post-Doctoral Fellowship sponsored by the University of North Carolina at Chapel Hill and GlaxoSmithKline supported Dr. Padmaja Patnaik in analyzing the data and preparing the manuscript. Dr. Jennifer Smith was supported through the Centers for AIDS Research, National Institute of Allergy and Infectious Diseases (grant 5 P30 AI050410-07).
Current affiliation for Padmaja Patnaik is Family Health International, Durham, North Carolina.
Correspondence: Dr. Jennifer Smith, Department of Epidemiology, CB# 7435, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435. E-mail: JenniferS@unc.edu.
Received for publication March 13, 2007, and accepted May 17, 2007.
Goal: To determine type-specific seroprevalence of herpes simplex viruses (HSV-1 and HSV-2) and HSV-2 risk factors.
Study Design: Six-hundred fifty eight middle-aged control women (hospital-based in 4 of 6 countries) from a multicenter cervical cancer case–control study participated from 1985 to 1997. Type-specific serum IgG antibodies against HSV-1 and HSV-2 were detected with Western Blot.
Results: HSV-1 seroprevalence was 89% to 100% everywhere except Thailand (51%). HSV-2 seroprevalence ranged from 9% (Spain) to 57% (Colombia), and was independently associated with having ≥2 lifetime sexual partners overall [Odds ratio (OR), 2.1; 95% confidence interval (CI) 2.5–3.1], and in Morocco (OR, 2.7; 95% CI, 1.2–6.1) and Thailand (OR, 4.4; 95% CI, 1.3–15.4), and with being unmarried in Colombia, Peru, Spain, but not significantly in Mali. Women whose male partner’s sexual debut was ≤17 years had a higher HSV-2 risk (OR, 4.3 95% CI, 1.3–13.7).
Conclusions: HSV-2 seroprevalence in middle-aged women varied over 4-fold and was associated with riskier sexual behaviors in women and their male partners.
Herpes simplex virus type-2 (HSV-2) and -1 (HSV-1) are among the most common infections in the world and may persist in a latent form to reactivate throughout life.1 HSV-2 is typically transmitted sexually, asymptomatic, and infects anogenital sites causing clinical and subclinical localized sores, while HSV-1 is generally transmitted via nongenital contact, is clinically associated with orolabial infection, but is also capable of infecting anogenital sites.2 Genital HSV-2 infections have greater clinical importance than HSV-1 infections because of more frequent clinical recurrences1 and viral shedding.3
A number of epidemiologic studies of HSV-2 seroprevalence4–6 have been limited by the use of nonspecific serologic assays, which cannot clearly differentiate antibodies produced against HSV-2 versus HSV-1.7 In recent years, several HSV-2 surveys have used type-specific serology,8 but comparison of HSV-2 seroprevalence across countries has been difficult due to differences in testing methodology, sampling, and other factors. Use of current gold standard Western blot assays,9 combined with a standardized protocol and laboratory methods, would allow for valid global comparisons of HSV-2 seroprevalence and associated risk factors in women.
Previously-identified risk factors for genital HSV-2 infection in women include older age,8 early age of sexual debut,10 higher number of lifetime sexual partners,6and presence of other sexually transmitted infections (STI).11 With few exceptions,10,12 studies examining male characteristics as risk factors of HSV-2 infection in women have relied on data elicited from women regarding their male partners’ behaviors rather than direct interview of the men.13
Type-specific Western blot was used for HSV-2 serologic testing in case–control studies of invasive cervical cancer conducted by International Agency for Research on Cancer (IARC) to examine the role of HSV-2 infection as a cofactor of human papillomavirus infection in the etiology of invasive cervical cancer worldwide.14 The present analysis aims to compare HSV-2 seroprevalence and risk factors in control women from 6 countries: Colombia, Peru, Mali, Morocco, Thailand, and Spain.
Materials and Methods
Population and Design
The study population constituted women who were controls in 6 case–control studies of invasive cervical cancer coordinated by IARC from 1985–1997 in Colombia,15 Peru,16 Mali,17 Morocco,18 Thailand,19 and Spain15 as previously described. In brief, a central standard protocol and questionnaire were used for recruitment and data collection at each site. Controls were population-based in Spain and Colombia and hospital-based at other sites. Hospital controls were excluded if they had any condition that shared risk factors with cervical cancer, including neoplasia of the breast, reproductive or respiratory organs, anus, oral cavity, esophagus, bladder, or liver, or other conditions such as cardiovascular or cerebrovascular diseases, chronic bronchitis, or emphysema. Participants were selected by frequency-matching to case patients by 5-year age-groups and presence of type-specific HSV-2 Western blot serology data.
Study participants were interviewed by trained personnel on demographics, smoking habits, and sexual and reproductive history. Regular sexual partners included any men with whom the participant had had a sexual relationship for at least 6 months, regardless of marital status or cohabitation. Men who were sexual partners for less than 6 months were considered casual partners. All participants were asked to provide 10 mL of blood for detection of infections, including type-specific serum antibodies to HSV-2 and HSV-1. Blood samples were processed by centrifugation for 10 minutes at 2000 rpm at the site of collection. The separated serum was then aliquotted, frozen at −20°C, and shipped to Lyon, France for storage before serological testing in Seattle, WA.
HSV-2 Antibody Detection
Serologic testing for the presence of type-specific antibodies to HSV-2 was conducted using Western blot, the reference gold standard,9,20–22 at the University of Washington Virology Laboratory (Seattle, WA). All laboratory personnel were masked to the case or control status of blood samples tested.14
All women who agreed to participate in the original study provided written informed consent to have their sera tested for infectious agents, including HSV-1 and HSV-2. Study protocols were approved by the Institutional Review Boards in each site in Colombia, Mali, Morocco, Peru, Spain, and Thailand and the IARC in accordance with the revised Helsinki Declaration of 1983.
Frequency distributions in each geographic setting were used to determine country-specific prevalence of HSV-2 and HSV-1 serum antibodies. For each country, risk factors for HSV-2 were initially identified through bivariate analyses using χ2 tests. In addition, for each country, age-adjusted odds ratios (OR) and 95% confidence intervals (CI) were determined as approximations of relative risks using unconditional, multiple logistic regression. Multivariate analyses were then conducted to determine adjusted OR (AOR) and 95% CI for HSV-2-seropositivity, controlling for age, marital status, total number of sexual partners in lifetime, and history of oral contraceptive use. In addition, multivariate analyses pooled across the 6 countries were adjusted for country. Observations with missing values were excluded from analyses. All analyses were conducted using Stata.
In Colombia, Spain, and Thailand, responses elicited from the current regular male partner of female participants were available.15,19 These data were used to examine selected male sexual characteristics as risk factors for HSV-2 in their female partner.
Women in our study were somewhat younger in the African countries (median age 40 years in Morocco and 45 years in Mali) and 6 to 12 years older in Thailand and Spain (Table 1). In all sites, except in Colombia and Peru, the majority of women were married. Median number of lifetime sexual partners, including regular and casual partners, was 2 in Mali and Peru, and 1 in all other countries. Reported history of hormonal (primarily oral) contraceptive use was low across all countries with the exception of Morocco (57.2%) (Table 1).
HSV-2 seropositivity was highest in Colombia (57%) and Mali (43%) and was lowest in Spain (9%) (Table 2). HSV-2 seroprevalence was similar in magnitude among women in Peru (36%) and Thailand (37%) and was 26% in Morocco. Overall, HSV-2 seroprevalence pooled across the 6 countries was 33%. In contrast, overall HSV-1 seropositivity was 90% and nearly 90% or higher in all study sites, ranging from 89% in Colombia to 100% in Spain, with the exception of Songkla, Thailand (51%).
Risk Factors for HSV-2 Seropositivity
In the analysis pooling data across all countries, a greater number of reported lifetime sexual partners emerged as a strong and significant risk factor for HSV-2-seroprevalence (AOR, 2.1; 95% CI, 1.5–3.1). The association was stronger in Thailand (AOR, 4.4; 95% CI, 1.3–15.4) and Morocco (AOR, 2.7; 95% CI, 1.2–6.1) (Table 3). Compared to women with 1 lifetime sex partner, those with more than 1 lifetime partner had a higher risk of HSV-2 in Peru (AOR, 1.6; 95% CI, 0.8–3.1) and Spain (AOR, 3.2; 95% CI, 0.2–52.6), although these associations were not statistically significant.
Similarly, not being married was a significant risk factor for HSV-2-seropositivity in the combined analysis (AOR, 2.7; 95% CI, 1.8–3.9). Positive associations were detected in Peru, Colombia, and Spain, but not in Thailand and Morocco (Table 3). In Mali, unmarried women were nearly twice as likely to be HSV-2 seropositive, compared to their married counterparts, although the associations was not statistically significant (AOR, 1.9; 95% CI, 0.7–4.8).
In pooled analyses, women who were at least 40 years old were 50% more likely to be HSV-2 seropositive compared to younger women (AOR,1.5; 95% CI, 1.0–2.2). Older age was associated with higher HSV-2 seroprevalence in Mali and Morocco where women who were 40 years or older were nearly twice as likely to be HSV-2 seropositive (Table 3). This association was not statistically significant in any individual country.
No significant association was found between history of using hormonal (primarily oral) contraceptives and HSV-2 seroprevalence in pooled estimates or in any country except Spain where the association was strong, but imprecise (AOR, 11.8; 95% CI, 1.1–129.9) (Table 3).
Overall, women whose sexual debut occurred before age 17 years (age- and country-adjusted OR, 1.9; 95% CI, 1.4–2.7) and women who had never used a condom (age- and country-adjusted OR, 1.8; 95% CI, 1.0–3.1) were more likely to be HSV-2 seropositive than their counterparts, but these associations did not remain after adjustment for additional factors in all analyses (data not shown). Similarly, type-specific Chlamydia trachomatis serum antibodies were associated with HSV-2 seropositivity in age- and country-adjusted analyses, but not after adjusting for behavioral factors in the multivariate model (data not shown). Human papillomavirus DNA was not associated with HSV-2 seropositivity in country-specific and adjusted pooled analyses (data not shown). History of smoking and douching were not associated with HSV-2 positivity in any analyses.
Women’s regular male partners were interviewed in a subset of women in Colombia, Spain and Thailand (N = 128; 56% of women from these countries). In multivariate analyses of male characteristics as risk factors for HSV-2 seropositivity in women, men with sexual debut at 17 years or earlier were significantly more likely to have female partners with HSV-2 (OR, 4.3; 95% CI, 1.3–13.7) (Table 2). Having a male partner who was unmarried (OR, 14.6; 95% CI, 2.8–75.0), had a history of sex with a prostitute (OR, 5.5; 95% CI, 1.7–18.1), or had a history of anal intercourse (OR, 4.3; 95% CI, 1.3–13.7) were risk factors for HSV-2 in women, though these associations were not significant after controlling for other factors (Table 4).
This is the first study, to our knowledge, to measure type-specific seroprevalence of HSV-2 and HSV-1 in women from 6 countries across 3 continents using the gold-standard Western blot assay as well as centralized study protocols and laboratory testing to reliably compare HSV-2 and -1 prevalence across countries. HSV-2 seroprevalence was variable across countries (9% in Spain to 57% in Colombia), whereas HSV-1 seroprevalence was consistently high (>89%) in all countries except Thailand (51%). Having multiple sexual partners over a lifetime was a significant risk factor for HSV-2 infection overall and specifically in Morocco and Thailand, whereas being unmarried was an important factor in Peru, Colombia, Spain. Older age (≥40 years) was associated with HSV-2 seropositivity in Mali and Morocco though associations were not statistically significant. Sexual behavior of the male partners was also associated with HSV-2 seropositivity in women, particularly men’s early age at sexual debut (17 years or earlier).
Few data are currently available on the effect of men’s self-reported sexual behavior on HSV-2 risk in their female partners. Consistent with previous studies,10,23 we found a higher risk of HSV-2 in women having a male sexual partner with riskier sexual behavior. In a study in Brazil, women whose male partners had higher numbers of lifetime sexual partners and a history of anal sex were at a higher risk for HSV-2 infection.10 Although male circumcision was shown to reduce the risk of C. trachomatis infection in female sexual partners,24 a similar protective effect of male circumcision on HSV-2 seropositivity in women was not found in our analyses. Although the lack of association with male circumcision in our study may have resulted from our small sample of men (most of whom were uncircumcised), a recent systematic review of the protective effect of male circumcision on STI in men supports our findings by demonstrating that although male circumcision is associated with lower levels of ulcerative STI such as syphilis and chancroid, the relationship for male circumcision is weaker and less consistent for HSV-2 infection in men.25 Women with male sexual partners who reported an earlier age of sexual debut (≤17 years) had a higher HSV-2 risk. Earlier sexual debut in men may be a proxy for a higher number of sexual partners over a lifetime; men reporting an age of intercourse less than or equal to 17 years of age had a higher mean number of partners (4.7) than those reporting sexual debut over 17 years of age (2.6). It is plausible that men’s report of age of sexual debut may be a more valid measure than reports of lifetime sexual partners. A large variation in HSV-2 seroprevalence was found in participating women in the 6 different countries, despite relatively small differences in women’s reported prevalence of lifetime sexual partners. In areas where women had higher HSV-2 seroprevalence (e.g., Colombia), the proportion of male partners who reported high numbers of lifetime sexual partners (6 or more) was higher (93%) than in countries with lower HSV-2 seroprevalence (e.g., Thailand and Spain), where the proportion of male partners reporting 6 or more lifetime partners was notably lower (48% and 35%, respectively).
Other male characteristics (e.g., history of sex with a prostitute; history of anal intercourse; being divorced, separated, widowed, or single) were not statistically significant risk factors for HSV-2 risk in their female partners in the multivariate models, possibly due to the relatively small sample size in analyses among male partners in our study. Larger studies of these associations may reveal stronger relationships between male characteristics on the risk of HSV-2 infection in their female partners. Additional data on previous male sexual partners, rather than the current partner only, would be informative.
A high prevalence (≥89%) in Western-blot confirmed HSV-1-seropositivity was observed at 5 of the 6 study sites. In general, published data on type-specific HSV-1 seroprevalence in middle-aged women from developing countries are scarce.8 The exceptional finding in our study was that HSV-1 seroprevalence of only 51% among women in Thailand. The unexpectedly low HSV-1 seroprevalence in Hat-Yai, southern Thailand is consistent with another study that found a Focus ELISA HSV-1 seroprevalence of 65% among women aged at least 15 years in Songkla.26 The low HSV-1 seroprevalence in a less-developed country setting is contrary to expectations of a higher adult HSV-1 as found in other countries.27
HSV-2 seroprevalence estimates found in this study are consistent with those reported in the global literature. Our estimates in Colombia were similar to type-specific ELISA seroprevalence previously measured in random samples of middle-aged Colombian women (50%–60%).6 A seroprevalence of 43% in Malian women in our study was in agreement with other studies of type-specific HSV-2 seroprevalence in sub-Saharan African countries that have among the highest levels of HSV-2 infection in the world.8,28 Our HSV-2 seroprevalence of 36% in Peruvian women is consistent with a Western blot-based seroprevalence of 38% in a previous study of middle-aged Peruvian women in Lima.29 High seroprevalence of HSV-2 in specific geographical areas may be explained by other epidemiologic factors such as dynamics of sexual mixing patterns, lower mean age of sexual debut, barriers to condom use, and a relatively high prevalence of other sexually transmitted infections. Specifically, in Mali and Morocco, factors such as early age of marriage to older men, polygamy, and sexual partnerships with female sex workers24,25 may be contributing to the HSV-2 seroprevalence. However, our estimate of 37% HSV-2 seroprevalence in Thailand is higher than in other Asian countries reported in a global review of HSV-2 prevalence,8 such as the Philippines10 and China.30 Our low HSV-2 seroprevalence estimate of 9% in Spain is consistent with the 6% type-specific HSV-2 seroprevalence reported in a past study of Spanish middle-aged women6and is not easily explained by demographic, behavioral, biologic or cultural factors although it has been suggested that men in Spain may be relatively monogamous.31
Multiple lifetime sexual partners emerged as a strong independent risk factor for HSV-2 infection in our study population overall, notably in Thailand and Morocco. Previous studies have similarly shown that a greater number of lifetime sexual partners was associated with a higher risk of Western blot-confirmed HSV-2 seropositivity in middle-aged women in Mexico,32 Brazil,10 and the Philippines.10 Further, associations of type-specific HSV-2 seropositivity with multiple lifetime sexual partners in women aged 15 to 49 years have been found in Kenya,28 Zambia,28 Cameroon,28 Benin,28 and Tanzania.11
Being unmarried was the most important demographic risk factor for HSV-2 seropositivity in 4 of the 6 countries surveyed and in pooled analyses. Previous reports in Kenya and Zambia indicate that women who were widowed, divorced, or separated were at greater risk of being HSV-2 seropositive.28 Women who are single, divorced, separated, widowed, or cohabiting with their current partner may be more likely to have multiple sexual partners when compared to married women. Unlike past studies,8,10,28,33 older age (at least 40 years) was associated with HSV-2 only weakly and inconsistently in our study, possibly due to the relatively narrow age range of middle-aged women that constituted our study population.
The lack of association of hormonal contraceptive use with HSV-2-seropositivity across all sites in this study was consistent with previous findings in Colombia,6 Spain,6 and Brazil.10 Lack of an association between contraceptive use and HSV-2 seropositivity in some countries like Mali and Spain may have been partially attributable to small numbers of women who reported ever having used contraceptives. These data are in contrast to the association of oral contraceptive use and HSV-2 risk reported in the Philippines10 where HSV-2 seropositivity was low (10%).
Limitations of our study included small sample sizes in some stratified analyses, which led to imprecise estimates. Hospital-based controls from countries other than Colombia and Spain16–19 may have had underlying illnesses associated with HSV-2, which may have overestimated seroprevalence at the population level. However, the likelihood of a selection bias due to hospital controls was considered minimal because controls had a broad range of diagnoses and were enrolled at large tertiary public hospitals with far-reaching catchment areas and extensive reference populations.
The multicenter design of this study allowed for augmentation of sample size by pooling data across 6 countries. Additional strengths of our study include the use of a standardized protocol across 6 diverse countries located in 3 continents. Further, our study used a high-quality central laboratory for systematic testing of specimens using the gold standard University of Washington Western Blot assay. Our study is also among the few studies on HSV-2 seroprevalence in women, which assess the effect of partners’ sexual behaviors as reported directly from current male partners of female participants.
This multicenter study highlights the high levels of HSV-2 seroprevalence and related behavioral risk factors in middle-aged women in Latin American, African, and Southeast Asian countries.
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