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Seroprevalence of Herpes Simplex Virus-2 in Suburban Primary Care Offices in the United States

LEONE, PETER MD*; FLEMING, DOUGLAS T. MD; GILSENAN, ALICIA W. PhD, MS, BS, PHARM; LI, LEI PhD; JUSTUS, SCOTT MT (ASCP)§

Sexually Transmitted Diseases: May 2004 - Volume 31 - Issue 5 - p 311-316
doi: 10.1097/01.OLQ.0000123651.84697.D6
Article

Objective: The objective of this study was to estimate herpes simplex virus-2 (HSV-2) seroprevalence from a weighted sample of adults attending relatively affluent, suburban primary care physician (PCP) offices.

Goal: Many PCPs in relatively affluent areas do not believe national estimates of HSV-2 seroprevalence are representative of their patient populations. This study aimed to measure HSV-2 seroprevalence in these patient populations.

Study Design: We conducted a cross-sectional study with approximately 5400 individuals aged 18 to 59 years. Individuals were recruited at 36 PCP offices in 6 U.S. cities and tested for HSV-2 using Focus enzyme-linked immunosorbent assay. A computer-assisted questionnaire was used to assess risk behaviors associated with genital herpes.

Results: Among 5452 individuals who provided an analyzable blood sample, the overall weighted HSV-2 seroprevalence was 25.5% (95% confidence interval, 20.2–30.8%). Only 11.9% of HSV-2-seropositive patients reported a history of genital herpes.

Conclusions: Results illustrate the need for greater suburban PCP and patient awareness of the high HSV-2 seroprevalence in this setting.

A cross-sectional study of primary care patients in the United States found the overall HSV-2 seroprevalence to be 25.5%, 88.1% of whom had no previous history of genital herpes.

From the *University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Mathematica Policy Research, Inc., Princeton, New Jersey; RTI Health Solutions, Research Triangle Park, North Carolina; and §GlaxoSmithKline, Research Triangle Park, North Carolina

The authors thank the local site investigators, as well as the project teams from RTI Health Solutions, ASHA, Quest Diagnostics, and GlaxoSmithKline. This study was sponsored by GlaxoSmithKline.

Correspondence: Alicia W. Gilsenan, PhD, MS, BS Pharm, RTI Health Solutions, 3040 Cornwallis Road, Research Triangle Park, NC 27709. E-mail: agilsenan@rti.org

Received for publication November 15, 2003, and accepted January 5, 2004.

Genital Herpes Is One of the most common sexually transmitted diseases worldwide. 1 A general population survey of seroprevalence of herpes simplex virus-2 (HSV-2) in the United States from 1988 to 1994 in people 12 years and older measured a prevalence of 21.9% overall, corresponding to 45 million Americans. Seroprevalence rose 30% since a similar survey was conducted in the late 1970s. 2 It has been projected that an additional 1,000,000 people will become infected with HSV each year. 3 As many as 70% to 90% of these people could be unaware of their infection or be asymptomatic. 4

Genital herpes can cause devastating disease among neonates and immunosuppressed people and facilitates transmission of human immunodeficiency virus (HIV). Neonatal herpes is a rare but serious consequence of genital herpes and could cause encephalitis and disseminated disease, which can be fatal. The risk of transmission to the infant is 30% to 50% with primary or initial genital HSV-2 infection during late pregnancy. 5 In addition, genital ulceration caused by HSV-2 increases susceptibility to and transmissibility of HIV. 6–10

HSV-2 seropositivity is indicative of genital herpes disease. In a study of 53 seropositive individuals without a history of genital herpes, 81% recognized clinical disease after education on the subtle signs and symptoms of genital herpes. 11 After the initial diagnosis of genital herpes, over 90% of individuals with HSV-2 infection will have recurrent episodes of genital herpes and will shed virus across mucosal surfaces even in the absence of visible lesions or symptoms. Subclinical shedding can occur on 5% to 20% of days, whether individuals are diagnosed clinically or serologically. All infected individuals could, therefore, be intermittently infectious. 11,12

Anecdotal reports suggest that primary care physicians (PCPs) in the United States, especially those from relatively affluent suburbs, believe that genital herpes is uncommon in the patient populations they serve. This belief could contribute to poor recognition of genital herpes disease. With this concern in mind, we undertook this study to measure HSV-2 seroprevalence of 5452 patients from 36 PCP offices located in relatively affluent suburban areas in 6 U.S. cities and to identify predictors of HSV-2 infection in these populations.

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Materials and Methods

Study Population and Study Design

The study took place at 36 randomly selected PCP offices in relatively affluent suburban areas surrounding 6 U.S. cities (Atlanta, Baltimore, Boston, Chicago, Dallas, and Denver) between September and December 2002. The 6 cities were selected based on population, income (state-level), and geographic location. Suburban areas were identified using a geographic information system (GIS) and 2002 U.S. census track data (provided by Claritas, Inc.) within suburban metropolitan areas (MA) of the 6 cities. Suburban area selection was based on frequency of home ownership above the median and population density below the 90th percentile, household income above the median, and housing values above the median for that particular MA.

Approximately 100 PCP offices located within suburban areas in each city were randomly selected as a base sample for recruitment from a database of over 2200 PCP offices within suburban areas surrounding the 6 cities (taken from the NDCHealth Practitioner database). The PCP sample was selected using probability proportional-to-size random sampling with volume of total prescriptions written for any medication (from NDCHealth data) used as a surrogate for the practice size.

It was anticipated that some PCP offices would either not want to participate or be ineligible to participate, or that some PCP offices listed in the database would not have accurate contact information. To account for these nonavailable PCP offices, a large base sample was initially selected from each city. The base sample from a city was randomly divided into small waves of 12 PCP offices for initial contact. Waves were released sequentially for contact and recruitment into the study.

PCP offices were contacted, screened for eligibility, and invited to participate. Offices were excluded if they 1) did not have at least 1 full-time PCP on staff; 2) saw <75 adult PCP patients between 18 to 59 years old per week; 3) were a publicly funded clinic (eg, health department, specialty clinic); or 4) had logistic barriers that would prevent them from completing the study per protocol. Offices were invited until 6 offices in each city agreed to participate. Offices were compensated equally for use of their office space during the data collection period.

The participation rate of PCP offices was relatively low in many of the 6 selected cities. Between 21 and 76 eligible PCP offices were contacted in each city to recruit the 6 participating offices.

At each office, a field interviewer recruited approximately 150 individuals aged 18 to 59. Equal distributions of males and females were sought across 4 age categories. Eligible patients had to be able to read and comprehend English. Patients who were known to be pregnant were not eligible.

During a normal PCP office visit, office staff presented cards to individuals aged 18 to 59 years on check-in to inform them that the physician’s office was participating in a research study (with no mention of HSV-2 or herpes). The card directed patients to the field interviewer (FI) to learn more about the study. Office staff also recorded the number of eligible patients by age and gender for 2 consecutive weeks in each office for the purpose of sample weighting. Patients who approached FIs were screened for eligibility and asked to provide consent. After providing consent, patients were asked to complete a 15-minute, computer-assisted self-interview and to provide a blood sample. Patients were provided $50 compensation for their participation.

A total of 5732 patients approached FIs and were screened. Of these, 107 (1.9%) were determined to be ineligible, and 111 (1.9%) refused to participate after learning about the details of the study. Twenty-five blood samples were not analyzable, and 19 patients did not complete the interview, leaving 5452 patients who provided blood and 5433 patients who provided a blood sample and completed the questionnaire.

To protect the privacy of patients who were not interested in participating in the study, and to comply with the Health Insurance Portability and Accountability Act of 1996 (HIPAA), individual information was not available to describe the population who approached the FIs compared with those who did not.

This study was approved by RTI International’s Institutional Review Board. RTI International has a multiple-project federal-wide assurance (the assigned OHRP number is 00003331 with an expiration date of September 16, 2005).

At the completion of the study, summary information on the HSV-2 serology results from the participating PCP was provided to each PCP. Subject-specific results were not reported to the principal investigator or the PCP office staff. Participants were given a toll-free number and password to obtain their HSV-2 serology results, as well as information concerning genital herpes and the significance of test results from a trained counselor. All participants were offered educational material regarding genital herpes. Patients were referred back to their PCP for medical management.

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Responses to the Questionnaire

Patients enrolled in the study were asked to complete a 15-minute questionnaire using audio computer-assisted self-interview (ACASI) technology. 13 Of the 5452 who provided a blood sample, 5433 completed the questionnaire. The questionnaire included demographic questions as well as a series of questions designed to elicit sexual attitudes, behavior, and symptom history relating to genital herpes. The ACASI technology provided a confidential method for the patients to provide sensitive information. ACASI technology has been shown to improve the accuracy of reporting for sensitive information. 13

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Serologic Testing

Trained healthcare professionals collected 2-mL blood samples that were shipped to and analyzed by Quest Laboratories (Van Nuys, CA).

Serum samples were tested for antibodies to HSV-2 using the FOCUS HerpeSelect 2 enzyme-linked immunosorbent assay (ELISA) IgG kit, which is licensed by the U.S. Food and Drug Administration (FDA). Confirmatory testing was not performed on positive or equivocal samples. The hypothetical positive predictive value in a sexually active population with 25% prevalence rate is 91.4%, and the negative predictive value is 99.0%. 14 At the prevalence rates noted in our study, we calculate that the estimated maximum absolute error in estimating the sample prevalence is 1% to 2%.

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Statistical Analysis

Patient samples were first weighted to represent the targeted study population (residents who visited PCP offices in the selected relatively affluent suburban areas). Given that there were 2 stages of sample selection in this study (first selecting the PCP offices and then selecting patient samples in selected offices), a set of PCP office sample weights and a set of patient sample weights were calculated, respectively. These weights were simply the reciprocal of their selection probability. The PCP office weights were then adjusted to exclude the ineligible physician offices on the sampling frame within each city. The patient weights were adjusted for nonresponses according to age group and sex. The final weights used for analysis were the product of these 2 sets of adjusted weights.

SUDAAN, statistical software for sample survey data analysis, was used for estimating the seroprevalence and logistic regression analysis. 15 The SUDAAN procedures take into account the clustering effect of patients within each PCP office and unequal weighting effect across PCP offices, yielding approximately consistent estimates of standard errors. The 95% confidence intervals for the seroprevalence rate estimates were presented. Standard errors were calculated using the Taylor series linearization method. 16

Logistic regression analysis was conducted to identify predictors of HSV-2 infection. A backward elimination variable selection procedure was followed. All selected demographic and behavioral variables were initially included in the model, and variables whose t test statistics had a P value greater than 0.10 were removed from the model. At each elimination step, the combined effect of the removed variables was examined to ensure that their combined effect was not significant.

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Results

Study Population

The respondents were largely white (75%), married (57%), and employed full- or part-time (80%). Approximately 74% had education beyond high school, and 45% reported a household income of $60,000 or more for the year 2001. Most respondents had private health insurance (82%), and only 8% reported having no health insurance.

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Demographic Variables

The overall weighted estimate of the seroprevalence rate among patients aged 18 to 59 years who attended primary care offices in affluent suburban areas within these 6 cities was 25.5% (95% confidence interval [CI], 20.2–30.8%) (Table 1). The seroprevalence was higher among women (28.3%; 95% CI, 22.0–34.6%) than among men (22.0%; 95% CI, 17.3–26.7%) with a female: male prevalence ratio of 1.3 (95% CI, 0.89–1.67). The overall HSV-2 seroprevalence was higher among those aged 30 to 59 (range, 25–31%) compared with those aged 18 to 29 (13%). Within each age group, HSV-2 seroprevalence was higher among females compared with males (Fig. 1), but the difference was not statistically significant.

TABLE 1

TABLE 1

Fig. 1

Fig. 1

The seroprevalence was 20.6% among whites, 52.4% among blacks, 21.9% among Hispanics, 11.2% among Asians, 11.5% among Native Americans, and 27.0% among mixed race (Table 2), yielding a black:white prevalence ratio of 2.5 (95% CI, 2.24–2.84). HSV-2 seroprevalence was lowest among full-time students (9.2%) and ranged from 23% to 32% among those who were employed, unemployed, or worked as housewives or homemakers. HSV-2 status was significantly lower among those with a postgraduate education (17.5%) compared with those with high school or less education (29.4–34.2%). Across the 6 cities, the HSV-2 seroprevalence ranged from 19.8% to 36.8%.

TABLE 2

TABLE 2

There was no statistically significant difference in HSV-2 seroprevalence by household income or marital status.

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Behavioral Variables

HSV-2 seroprevalence was not statistically different between those who first had sex at age 15 or younger and those who first had sex at age 16 or later, but seroprevalence increased markedly with increased lifetime number of sexual partners (Table 2). Interestingly, there was a 7% prevalence in those who reported not having been sexually active. HSV-2 seroprevalence was the same for both males and females with 1 lifetime sex partner. However, at higher numbers of lifetime sex partners, females had a higher seroprevalence than males in the same category after adjusting for age (Fig. 2). For example, among people who reported 2 to 4 lifetime sex partners, the age-adjusted seroprevalence was 14.5% for males and 23.1% for females.

Fig. 2

Fig. 2

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History of Genital Herpes

Only 4.3% of study participants reported ever having been told they had genital herpes. Persons with a history of genital herpes had an HSV-2 seroprevalence of 68.7%, whereas all other persons had a seroprevalence of 23.8% (Table 2). Of all individuals who were HSV-2-seropositive, only 11.9% reported a history of genital herpes.

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Multivariate Analyses

In a multivariate model that examined the demographic and behavioral variables associated with HSV-2 status, differences associated with geographic location, employment status, income, marital status, and age at first intercourse were found not to be statistically significant (P >0.10) and were, therefore, dropped from the model. In the final model, the multivariate independent predictors of HSV-2 infection were female gender, black race, older age, less than postgraduate education, greater lifetime number of partners, and not having private insurance (Table 3). The strongest predictors (with odds ratios greater than 3.0) were race, age, and lifetime number of sexual partners.

TABLE 3

TABLE 3

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Discussion

HSV-2 seroprevalence was high for primary care patients in these relatively affluent suburban areas, emphasizing the need for a high index of suspicion for genital herpes even among patients considered by many to be at low risk. The overall estimate of HSV-2 seroprevalence was 25.5% based on a sample of 5452 patients. The study found that 88.1% of HSV-2-seropositive patients were unaware that they had genital herpes. Independent predictors of HSV-2 infection were gender, age, race, and number of lifetime partners. All these results are generally similar to those reported in the nationally representative NHANES III study, from 1988 to 1994, which measured a seroprevalence of 21.9%. 2

The high prevalence of HSV-2 infection among the primary care patients, and the infrequent recognition of genital herpes, in this study emphasizes the importance of increased awareness of genital herpes among both physicians and patients. For the patient, symptoms of genital herpes could be nonspecific such as pruritus, discharge, dysuria, or other symptoms. On physical examination, the large majority of HSV outbreaks appear in an “atypical” form, with nonspecific ulceration, erosions, fissures, excoriations, erythematous patches, or other nonspecific lesions. 4,17 For these reasons, many HSV outbreaks are mistaken for other conditions such as urinary tract infection, vaginal yeast infection, folliculitis, or trauma. In such cases, the only way to avoid misdiagnosis and incorrect treatment is to maintain a high suspicion for genital herpes. 18 Viral culture is an appropriate first step in the evaluation of patients presenting with genital lesions. Serologic testing, however, could be useful to support a clinical diagnosis because of the high rate of false-negative viral cultures, especially in recurrent genital herpes. 19,20

In primary care, the diagnosis of genital herpes is important both for the patient and for the patient’s sex partners. First, the patient can be counseled to reduce transmission to sex partners or to neonates. Second, appropriate use of antiviral medications can reduce the severity of established outbreaks or prevent future outbreaks when used daily at “suppressive” doses. Third, a recent randomized trial showed that an antiviral medication, valacyclovir, used daily and in combination with safer sex practices, reduced transmission of HSV-2 from infected individuals to their uninfected partners. 21

Our study had several limitations. First, a relatively large number of primary care offices were approached in each city before the desired sample of offices was reached. Investigators were not aware of any systematic factors that distinguished participating offices from nonparticipating ones, but there was little information on office characteristics to do a formal participation analysis. Second, although the commercial test for type-specific antibody to HSV has good test characteristics relative to the gold standard Western blot, it could have slightly overestimated seroprevalences by 1% to 2% (absolute) overall at the measured HSV-2 seroprevalence.

In summary, the seroprevalence of HSV-2 infection was high in the suburban primary care practices in this study. A high index of suspicion for genital herpes in primary care could improve diagnosis of genital herpes, with benefits both for the patient and for the patient’s sex partners.

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