Age-Specific Prevalence of Infection with Herpes Simplex Virus Types 2 and 1: A Global Review
- 1International Agency for Research on Cancer, Lyon, France;
- 2GlaxoSmithKline Research and Development, Greenford, United Kingdom
- Reprints or correspondence: Dr. Jennifer S. Smith, International Agency for Research on Cancer (IARC), Unit of Field and Intervention Studies, 150 Cours Albert Thomas, 69372 Lyon, France (smith{at}iarc.fr)
Abstract
Information on age- and sex-specific prevalence of herpes simplex virus (HSV) types 2 and 1 infections is essential to optimize genital herpes control strategies, which increase in importance because accumulating data indicate that HSV-2 infection may increase acquisition and transmission of human immunodeficiency virus. This review summarizes data from peer-reviewed publications of type-specific HSV seroepidemiologic surveys. HSV-2 prevalence is, in general, highest in Africa and the Americas, lower in western and southern Europe than in northern Europe and North America, and lowest in Asia. HSV-2 and -1 prevalence, overall and by age, varies markedly by country, region within country, and population subgroup. Age-specific HSV-2 prevalence is usually higher in women than men and in populations with higher risk sexual behavior. HSV-2 prevalence has increased in the United States but national data from other countries are unavailable. HSV-1 infection is acquired during childhood and adolescence and is markedly more widespread than HSV-2 infection. Further studies are needed in many geographic areas
Herpes simplex virus (HSV) establishes latency in sensory ganglia following initial acquisition, causing an infection that persists for life. HSV-2 infection is the primary cause of genital herpes and is one of the most prevalent sexually transmitted infections (STIs) worldwide [1]. HSV-2 prevalence is negligible among persons who have never been sexually active [2]. Persons with HSV-2 infection do not necessarily develop clinical disease, but most intermittently shed virus from the genital tract [3]. Genital herpes is associated with substantial morbidity and can also cause serious, but relatively rare, sequelae such as meningitis and neonatal herpes [1]. HSV-1 infection is usually transmitted during childhood and adolescence and, if symptomatic, is commonly characterized by oral or facial lesions [4]. Although HSV-1 is most often transmitted via nonsexual contact, recent data from some developed countries indicate that a non-negligible proportion of first-episode genital herpes is caused by HSV-1 [5]
The prevalence of HSV-2 and HSV-1 infections overall and by age varies markedly by country, region within country, and population subgroup. In order to compare the prevalence of herpes infection between geographic areas or countries, age-specific or age-adjusted prevalence among similar populations is necessary. Estimates of HSV-2 and -1 prevalence presented as single summary measures (e.g., mean or median) can be misleading when the age of the population sample is not considered. For example, HSV-2 seroprevalence in young adults with a mean age of 20 years would be expected to be lower than in older persons in the same population
Reliable data on the prevalence of HSV-2 and -1 serum antibodies provide an epidemiologic measure of the population burden of these infections. The presence of HSV-2 antibody almost exclusively indicates past exposure to a genital infection [2] but may underestimate the prevalence of genital herpes infections in areas where genital HSV-1 infection is more common. The strong association between HSV-2 prevalence and sexual behavior in different studies [6, 7] suggests that age-specific HSV-2 prevalence may, in some circumstances, provide a useful marker for sexual behavior. Type-specific seroprevalence data may be useful to identify particular population subgroups that have a notably higher risk of HSV infection [8]. Perhaps of more importance, given the strong associations observed between HSV-2 and human immunodeficiency virus (HIV) seropositivity [9–12], data on HSV-2 antibody status may be useful in predicting those at greater risk of acquiring and transmitting HIV infection and thus may be valuable for guiding HIV prevention efforts [12]. This review summarizes and clarifies current knowledge of the prevalence of HSV-2 and -1 serum antibodies by age for different populations worldwide and highlights areas where further studies are needed
Methods
Material Reviewed
Source material was selected from more than 2500 citations generated from MEDLINE, references cited in the selected papers, and from the Search ISI Research software program (Reference Manager). Key search words included HSV-2, HSV-1, herpes, prevalence, and epidemiology. The literature search was restricted to peer-reviewed articles that provided a clear description of type-specific serologic methodology for detection of HSV-2 and/or HSV-1 antibodies. Studies citing the use of nonspecific serologic assays only (i.e., neutralizing antibody tests, IFAs or micro-IFAs, or indirect hemagglutination tests) were excluded. Articles were included for review only if data on age were available. Sample sizes were required to be ⩾20 per age group; when necessary, age groups were combined. Conference abstracts and other unpublished manuscripts were excluded since the detailed information required was rarely available
Data Extraction and Analysis
For each study, we extracted the following information: date of sample collection or, if not known, manuscript submission date; serologic test methodology; population studied (e.g., national, antenatal, or commercial sex worker [CSW]); sex; mean or median age of sample, with range where available; sample size; and prevalence of HSV-2 and/or HSV-1 serum antibodies. When published results were presented only graphically, estimates of prevalence were obtained directly from the graphs. In some cases, age-specific sample sizes were not available
Presentation of Results
Non–high-risk and higher risk populationsResults are presented separately for non–high-risk populations (table 1) and for higher risk groups (table 2). Non–high-risk populations were defined as those with no specific high-risk sexual behavior or characteristics. Populations at higher risk were defined as those having a greater risk of acquiring genital HSV infection, such as HIV-seropositive persons, CSWs, and people with other STIs. Results are stratified by the following geographic areas: Africa, Central and South America, North America (i.e., the United States [USA] and Canada), Asia (including Australia), and Europe and the Middle East. Within each geographic area, studies are ordered by country and then by region or state within the country
Time trendsTable 3 shows trends for prevalence of HSV-2 and -1 infections over time for both non–high-risk and higher risk populations
HSV prevalence in relation to ageThe association of HSV-2 prevalence with age is illustrated graphically for the following geographic areas: Africa, Central and South America, North America, Asia (including Australia), Europe (including the Middle East, excluding the United Kingdom [UK]), and the UK (figures sgmlp ignore [ln],[tn]>1–sgmlp ignore [ln],[tn]>6). UK data are presented separately from the rest of Europe because of the extensive information available. The figures use the same scale and present age-specific HSV-2 prevalence in each geographic area for non–high-risk and higher risk populations. sgmlp ignore [ln],[tn]>Figure 7 shows HSV-1 prevalence by age
Figure 1
HSV-2 prevalence by age in Africa among non–high-risk and higher risk populations (A, B respectively) by country and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
Results
Comparisons of the prevalence of HSV-2 and -1 infections by geographic area or country are hampered by differences among populations surveyed and the use of different serologic assays. However, some general trends are apparent
Age-Specific HSV-2 Prevalence in Non–High-Risk Populations
HSV-2 prevalence was in general highest in areas of Africa and in parts of the Americas. HSV-2 prevalence in western and southern Europe was usually lower than in northern Europe and North America. HSV-2 prevalence in Asia tended to be lower than in all other geographic areas
AfricaMost data on HSV-2 prevalence in Africa originate from countries south of the Sahara (table 1), including Benin [13], Cameroon [13, 14], Central African Republic [9], Eritrea [15], The Gambia [16, 17], Kenya [13], South Africa [10], Tanzania [18], Uganda [19–21], Zambia [13], and Zimbabwe [11, 22, 23]. Most studies have been limited to women and men aged 15–49 years. HSV-2 seroprevalence in sub-Saharan Africa is among the highest in the world, sometimes reaching ⩾80% in women and men aged ⩾35 years
Striking increases in HSV-2 seropositivity were observed with age (figure 1A), particularly among younger women (15–24 years) [10, 18–20]. HSV-2 prevalence consistently increased with age in all geographic areas; however, HSV-2 seropositivity decreased in women >40 years in Uganda [13, 19] and Zambia [13], in men >35 or 40 years in Ethiopia [138] (data not shown) and Benin [13], and in adults >35 years in Uganda [20]
Central and South AmericaOf several studies in Central and South America (table 1), only one study in Costa Rica in the mid-1980s was based on a national representative sample [25]. HSV-2 prevalence in the women surveyed increased from 33% in those 25–29 years old to 45% in those ⩾40 (sgmlp ignore [ln],[tn]>figure 2A)
Figure 2
HSV-2 prevalence by age in Central and South America among non–high-risk and higher risk populations (A, B respectively) by country and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
In a population-based study in Mexico City, HSV-2 prevalence also increased with age, reaching 45% among women >60 years (figure 2A). The highest HSV-2 prevalence in Central or South America (60%) was reported for Cali, Colombia, in a random sample of women (mean age, 48 years) [27]. A comparable prevalence (54%) was observed in a considerably younger group of antenatal patients in Haiti (mean age, 25 years) [30]
Age-specific HSV-2 prevalence data from Central and South America are predominantly for females and show HSV-2 seropositivity generally increasing with age and reaching a maximum of about 50% (figure 2A). Among older women, HSV-2 prevalence appears to increase or plateau with age in most countries. Data from a large multinational cervical cancer study in Colombia, Costa Rica, Mexico, and Panama show that among a combined group of female control participants prevalence of HSV-2 infection is high in women <30 years old (30%) and steadily increases with age to 52% in those aged 50–59 years [24]. In Peru, HSV-2 prevalence increased dramatically among women in their 30s; in men it remained notably lower than in their female counterparts [33]
In Campinas City, Brazil, HSV-2 seroprevalence was higher (23%) in a small group of antenatal patients than in female and male college students of similar age (6.9%) [25]. In one study from São Paulo, HSV-2 prevalence was >41% in women of childbearing age (mean, 27 years) [26]. In another small São Paulo study, HSV-2 positivity did not appear to increase with age in women ⩾40 years [7]. HSV-2 prevalence was 50% among women aged 40–49 years, 33% among women 50–59, and 42% among women >60
North AmericaThe third National Health and Nutrition Examination Survey (NHANES III) estimated HSV-2 seroprevalence in a representative national sample of the noninstitutionalized US population aged ⩾12 years [35]. Overall HSV-2 prevalence in females and males was 26% and 18%, respectively (table 1) and consistently increased with age from the mid-teens to about age 35 (sgmlp ignore [ln],[tn]>figure 3A). Prevalence among black Americans was more than double that of whites and about twice that of Mexican Americans. In black Americans, HSV-2 prevalence increased even more sharply with age, reaching >50% in those 30–39 years and >70% in those ⩾60. In studies conducted in different states, HSV-2 prevalence varied by area, population, age, and sex (table 1). Results from these studies were broadly consistent with those of NHANES III
Figure 3
HSV-2 prevalence by age in the USA (by national or state) and Canada among non–high-risk and higher risk populations (A, B respectively). Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
In terms of regional differences within the USA, HSV-2 prevalence was particularly high (35%) in young women aged 18–29 years from low-income neighborhoods of San Francisco [40]. Another San Francisco study found a dramatic increase in HSV-2 seropositivity in a combined random sample of unmarried men and women 25–29 (24%) and 30–34 years of age (49%) [41]. In Seattle, age-specific HSV-2 prevalence among male family medicine clinic attendees aged 18–45 years was notably lower than among females of similar ages (15% vs. 27%) or for combined groups of men and women in other US studies [58]. In a Canadian study, HSV-2 prevalence clearly increased with age among female antenatal patients, rising from 7% in women aged 15–19 years to 28% in those 40–44 [34]
Asia (including Australia)Studies have been conducted in Hong Kong [66], Japan [67, 68], Thailand [71, 72], Australia [61–63], and New Zealand [69, 70] (table 1). There is a relative paucity of data on HSV-2 prevalence in non–high-risk populations in Asia. HSV-2 prevalence tended to be lower than in other areas of the world, with the possible exceptions of Thailand [71, 72] and Australia [61–63]. In two Japanese studies, age-specific HSV-2 prevalence was low (<7% in all age groups) [67, 68] (sgmlp ignore [ln],[tn]>figure 4A). These estimates are lower than in women of similar ages in the Philippines (9%) [7] and in antenatal Australian patients (15%) [63]. Although still relatively low, other Japanese studies found higher HSV-2 prevalence (e.g., 15% among older female clinic attendees from Osaka [mean age, 49 years] and 17% among pregnant women from Kagoshima [mean age, 29 years]) [68]. In Sydney, HSV-2 prevalence among a large sample of antenatal clinic attendees (mean age, 28 years) was 11% [61], similar to that observed several years earlier [63]
Figure 4
HSV-2 prevalence by age in Asia/Australia among non–high-risk and higher risk populations (A, B respectively) by location and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
Europe and the Middle EastData from non–high-risk populations are available for many European countries: Denmark [73], Finland [74–76], Germany [77–80], Greenland [73], Italy [82–84], Norway [86, 87], Spain [27, 88–90], Sweden [91–94], Switzerland [95], and the UK [6, 98–101] (table 1). For the Middle East, information is only available for Israel [81], Jordan [85], Syria [96], and Turkey [97] (table 1)
The highest prevalence of HSV-2 infection was found among Greenland women: 57% among those aged 20–24 years and rising to 74% in those 25–39 [73] (sgmlp ignore [ln],[tn]>figure 5A). Other studies in Europe found HSV-2 prevalence in adults of 4%–40%. In one German study [77], HSV-2 infection was lower among male and female blood donors and hospital patients but was >20% among men and women ⩾60 years. Another German study (in Frankfurt) found similar HSV-2 prevalence among healthy women ⩾30 years (22%–27%) [79]
Figure 5
HSV-2 prevalence by age in Europe (excluding the UK) and the Middle East among non–high-risk and higher risk populations (A, B respectively) by location and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
In Spain, HSV-2 prevalence appeared low (2%–6%) in a large sample of males and females 14–17 years old [90], in men and women 15–45 years old in eight different geographic areas [88], and in Madrid females [89]. In one study, HSV-2 seroprevalence increased from 1.7% in females aged 15–24 years to 6.0% in those aged 35–45 years [89] (figure 5A). In another Spanish study, HSV-2 infection was not associated with age [88]. In older women from Barcelona (mean ages, 36 and 53 years), prevalence was 11% and 12%, respectively [27]
In Scandinavia, HSV-2 prevalence was relatively higher than in other areas of Europe, about 15%–35% among women aged 25–35 years [73, 86, 87, 92, 93]. However, in a small study of schoolgirls aged 15–17 years, HSV-2 prevalence was low (1%) [89]. Three studies in Finland estimated HSV-2 prevalences of 16%, 26%, and 31% among women with mean ages of 30, 39, and ∼44 years, respectively [74–76], although the studies differed by population, location, and date
Data on age-specific HSV-2 prevalence were available for three Italian studies [82–84] (table 1). HSV-2 prevalence was low (0.1%) in a national sample of young male draftees aged 18–25 years [82, 83], in patients (median age, 26 years) attending a hepatitis B immunization center (1.1%) [82, 83], and in health professionals of either sex (mean age, 30 years; 4.8%)
In the UK, HSV-2 prevalence was consistently lower than in other areas of northern Europe (table 1) [6, 98–101]. The highest prevalence was in London females [6, 101]. Among London antenatal patients, HSV-2 prevalence increased from 3% in those 18–25 years old to 25% among those 41–45 and subsequently decreased to <10% among women >60 years old [6] (figure 6A). In another study among London antenatal patients, HSV-2 prevalence was similar, increasing from 4.4% among women <20 years to 19% in those ⩾35 [101]. In a national UK sample, HSV-2 prevalence was 4.7% among women aged 20–44 years who were controls in a cervical cancer study [99]. In this study and in the remaining UK studies, HSV-2 prevalence was <9% for women and men in all age groups (figure 6A). There was a suggestion that HSV-2 prevalence might decrease in the oldest age bands as observed in male and female London blood donors >40 years old [6], immunocompetent men >60 in England and Wales [98], and in a random selection of women >40 years old [99]
Figure 6
HSV-2 prevalence by age in the UK among non–high-risk and higher risk populations (A, B respectively) by location and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines)
In the Middle East, no women and only 1 man of a combined total of 654 surveyed in Syria were HSV-2 seropositive [96]. HSV-2 prevalence was also notably low among women (5%) and men (4%) aged 18–95 years in Israel [81]. A study of Jordan university students (aged 18–24 years) reported very high HSV-2 prevalence in women (41%) and men (53%); this may require confirmation [85] (table 1). A study of pregnant women in Turkey found high levels of HSV-2. Even in the youngest age group (20–25 years), HSV-2 prevalence was 38% (figure 5A) [97]
Figure 7
HSV-1 prevalence by age among non–high-risk populations in Africa, North America, and Asia (A) and Europe and the Middle East (B). C Prevalence among higher risk populations. Data are shown by country and study. Where HSV data are defined in the tables for individuals above or below a certain age, the data points on the graphs are plotted at the age specified. F, females (dashed lines); M, males (solid lines); F+M, females and males (dotted lines)
Table 1
HSV-2 and HSV-1 prevalence estimates from non–high-risk populations by continent, country, and study year
Age-Specific HSV-2 Prevalence among Higher Risk Groups
In populations with evidence of higher risk sexual behavior and in STI clinic attendees, the prevalence of HSV-2 infection was consistently higher than in non–high-risk populations. HIV-seropositive populations also showed consistently higher HSV-2 prevalence than their HIV-seronegative peers
HSV-2 seroprevalence was 59% and 82% among CSWs (mean ages, 25 and 26 years) in Lagos, Nigeria [104, 105], and in Kinshasa, Democratic Republic of Congo [102], respectively. HSV-2 seropositivity was consistently high among young CSWs elsewhere: Thailand (76%; mean age, 24 years) [126], Osaka, Japan (80%; mean age, 35 years) [68], and Mexico City (64% [ages 23–27 years] and 65% [ages 24–30]) [108, 109] (table 2)
Table 2
HSV-2 and HSV-1 prevalence estimates from higher risk populations by continent, country, and study year
Across geographic areas, STI clinic attendees consistently had higher prevalences of HSV-2 infection than did non–high-risk groups (e.g., London blood donors) [6] and age-matched populations of antenatal clinic attendees (Brazil [25], Haiti [30], and Australia [63]). In London, 25% of women STI clinic attendees (mean age, 25) were HSV-2 positive in comparison with 12% of women blood donors (mean age, 30) [6]. HSV-2 prevalence was also higher among homosexual than in heterosexual STI clinic attendees of similar ages in Rome [129], Amsterdam [131], and London [6]. In the latter study, homosexual men attending a London STI clinic (mean age, 29 years) had a higher HSV-2 prevalence (27%) than heterosexual men of similar ages attending an STI clinic (17%) [6]. In Nagoya, Japan, HSV-2 prevalence was higher in men having sex with men than in male blood donors (24% vs. 2.4%) [68], respectively. People with HIV infection showed consistently higher HSV-2 prevalence than HIV-negative persons in studies from Australia [121], Central African Republic [9], Zimbabwe [11], Haiti [30], USA (Seattle) [5], and Germany [77, 79]
HSV-2 seroprevalence by sexFew surveys have been carried out in men relative to studies in women (table 1). For the USA, NHANES III found that age-specific HSV-2 seropositivity was consistently higher among females than males (overall 26% vs. 18%) [35]. HSV-2 prevalence was also higher for women than men of similar age in Benin [13], Cameroon [13], The Gambia [17], Kenya [13], Tanzania [18], Uganda [19], South Africa [10], and Zambia [13]. In younger women (aged 15–19 years), HSV-2 prevalence was about three-fold or more higher than in men of similar age in Tanzania [18] and Uganda [19] and in one study in Seattle [59]. HSV-2 prevalence was 60% and 45% greater among women than in men of similar age in New Zealand [70] and Switzerland [95], respectively. In contrast, in some Asian and European countries, age-specific HSV-2 antibody prevalence among women and men was similar, particularly where HSV-2 prevalence was relatively low, for example, Hong Kong [66], Japan [67], Germany [77], and Spain [88]
Time trends in HSV-2 prevalenceIn the USA, a 30% increase in overall HSV-2 prevalence was observed between the late 1970s (16.0%) and early 1990s (20.8%) [35] (table 3). In Hong Kong, HSV-2 prevalence rose from 7% to 18% from 1977 to 1995 [66]. Increases in HSV-2 prevalence were also apparent in Sweden from studies conducted between 1969 and 1989 in pregnant women (17%–33%) [93] and between 1970–1990 in male STI clinic attendees (13%–24%) [135]. HSV-2 prevalence remained relatively constant among antenatal patients in Malmö, Sweden [92], and decreased in a random population sample from central Japan [67]. In Amsterdam, HSV-2 prevalence was markedly lower in men having sex with men during 1995–1997 (19%) compared with 1984–1988 (51%) [130] and appeared to decrease in STI clinic attendees from 1993–1994 to 1998 [133]
Table 3
Trends in HSV-2 and HSV-1 prevalence with time
Age-Specific HSV-1 Prevalence
Prevalence of HSV-1 infection was high in most geographic areas worldwide and was more prevalent than HSV-2 infection in all non–high-risk populations surveyed. Exceptions were groups of HIV-positive persons and CSWs, where HSV-2 prevalence was >65% [68, 120] (table 2). No data on HSV-1 prevalence were available for Central or South America
Among children, HSV-1 prevalence was particularly high in Eritrea: 97% of those >5 years old were HSV-1 seropositive (table 1, figure 7A) [15]. Among New Mexico Navajo children, HSV-1 prevalence was 59% in those aged 1–5 years and 79% in those 6–15 years old [46] (table 1, figure 7A). Similar results were found among children and young adults in Syria (55% among 1–5 year olds, 80% among 11–20 year olds) [81]. In Germany, HSV-1 prevalence was lower among children aged 1–5 years (31%), increasing to 44%–49% among those 6–16 years old [77] (figure 7B). Among hospital attendees in Israel, HSV-1 prevalence was 38% among children aged 2–4 years and 54% among those 15–17 years old [81]. In England and Wales, HSV-1 prevalence was 46%–49% among newborns, probably reflecting, at least in part, maternal antibody status, and 17%–27% among children aged 1–14 years [98] (figure 7B)
Among adolescents and adults ⩾15 years, HSV-1 prevalence was high (>91%) in the Central African Republic [9], Eritrea [15], and Uganda [20] (table 1). Lower HSV-1 prevalence was found in young American women (∼18–24 years old) in San Francisco (58%) [41], South Carolina (37%) [52], New Mexico (71%) [45], Pennsylvania (52%) [51], and Texas (34%) [53] (figure 7A); in population-based samples of young US men and women aged 12–19 years (44%) [36]; and among Canadian women aged 15–19 years (52%) [34]. In a study in Japan, about one-third of study participants aged 20–29 years were HSV-1 positive [67]. In Europe and the Middle East, HSV-1 prevalence was 72% among women <20 years old in Helsinki [74] and 85%, 60%, 72%, and 84%, respectively, among women 18–25 years old in Italy [83], 17–19 years in Germany [77], 15–24 years in Spain [89], and 11–20 years in Syria [96]. Prevalence of HSV-1 infection was about 50% in adolescents (mean age, 15 years) in a Madrid study (46%) [90] and in hospital attendees in Israel (54% for those aged 15–17 years) [81]
In most studies, HSV-1 prevalence increased consistently with age across the age spectrum or plateaued after age 30. Data from the US population-based NHANES III study showed a consistent increase of HSV-1 prevalence with age, increasing from 44% in young adults (12–19 years) to 90% among those >70 years old [36]. In contrast, HSV-1 seropositivity decreased in older women (⩾40 years) in selected sites, particularly Uganda [20], New Mexico [45], and Turkey [97]
Among specific population groups with higher risk sexual behavior in South Africa, HSV-1 seropositivity was ubiquitously high (>97%) across all age groups [106]. Among young female CSWs aged 16–22 years in Mexico City, HSV-1 prevalence was >93% [108] (figure 7C)
Discussion
Some trends may be drawn from this systematic review of type-specific HSV prevalence in different geographic areas and subpopulations. First, HSV-2 prevalence is highly variable and depends on many factors, including country and region of residence, population subgroup, sex, and age. Second, HSV-2 prevalence is, in general, higher among higher risk sexual behavior groups. Third, HSV-2 prevalence is generally higher in women than men. Fourth, HSV-2 prevalence is strongly associated with age, increasing from negligible levels in children younger than 12 years to as high as 80% among higher risk populations. Fifth, in a given population and age group, HSV-1 prevalence is almost always greater than HSV-2 prevalence
Striking variations in HSV-2 prevalence were noted in different geographic regions. HSV-2 prevalence is highest in areas of Africa and parts of the Americas. In western and southern Europe, HSV-2 prevalence is usually lower than in northern Europe and North America. In Asia, HSV-2 prevalence appears lower than in other geographic areas. Direct comparisons in overall prevalence from independent studies should be made with caution given substantial differences in the populations surveyed, age distributions, and HSV serologic test methods. Comparisons of age-specific HSV-2 prevalence among similar populations in different regions may be useful and further data acquired by using the same serologic methods would be desirable
HSV-2 prevalence was consistently higher in higher risk populations compared with those considered at a lower risk. In some countries such as the USA, HSV-2 prevalence was strongly dependent on race; black Americans had a much higher prevalence of infection than whites and Mexican Americans of all ages [35]. These results suggest that within populations, the risk of acquiring HSV-2 infection is highly variable
Most studies reviewed were undertaken in women. However, in those involving both men and women, higher HSV-2 prevalence was almost always found in women. This finding appears to be consistent across several geographic sites [13, 18, 19, 29, 33, 35, 58, 70, 95] and suggests a higher risk of HSV-2 acquisition in women than men
The shape of the graphs of HSV-2 and -1 prevalence by age differ, reflecting patterns expected for an STI (HSV-2) compared with a mainly non-STI (HSV-1). Although data on HSV-2 prevalence in those <15 years old are limited, where available, HSV-2 prevalence in this age group is usually very low [15, 46, 77, 88, 90, 94]. Among young adults, HSV-2 prevalence consistently increases with age in different countries, populations, and within sexes, with increases depending in particular on geographic area, population group, and sex. The most striking increases in HSV-2 prevalence were among younger women from high-prevalence areas such as many parts of sub-Saharan Africa. After an increase during the sexually active years, HSV-2 prevalence often tends to plateau after about age 40, albeit with substantial variation across countries and populations. In contrast, HSV-1 prevalence in non–high-risk populations tends to increase in a roughly linear fashion with increasing age, with most acquisition occurring in childhood and adolescence. HSV-1 prevalence commonly reaches ⩾40% by age 15 years, before increasing to 60%–90% in older adults
In the few countries in which HSV-2 seroprevalence surveys have been conducted at different times, notably the USA [35], Sweden [93], and Hong Kong [66], there is strong evidence that HSV-2 prevalence has increased over the last few decades in these populations. In other populations, HSV-2 prevalence has either remained stable, shown no clear trends [92, 137], or decreased [67]. In general, data on time trends in HSV-2 prevalence from around the world are limited
There are some limitations to the meaning of prevalence data on HSV-2 and HSV-1 serum antibodies [2]. HSV-2 seroprevalence data alone underestimate the prevalence of genital HSV infection due to the omission of genital infections caused solely by HSV-1. Furthermore, serologic evidence of infection does not reflect the extent of symptomatic genital HSV-2 disease because most genital HSV-2 infections are unrecognized, undiagnosed, or truly asymptomatic, particularly in persons with prior HSV-1 infection [1, 139]. However, given the chronic nature of HSV infections, these seroepidemiologic findings provide a picture of the endemicity of HSV-2 and -1 infections in different populations worldwide
Confidence in the findings from this review partly depends on the criteria used for including or excluding individual studies. Study data were included only if they complied with predetermined criteria. Studies ranged from national population-based surveys (i.e., in the USA [35] and Costa Rica [29]) to those conducted in specific populations of a particular age in a specific region of a country. NHANES III [35], for example, provided national estimates of HSV-2 prevalence in US noninstitutionalized men and women. The majority of the other studies are unlikely to have been statistically representative of the national population. Thus, inferences from estimates and comparisons across countries should be made with caution
Accurate type-specific HSV ELISAs are becoming more widely available, thereby facilitating seroepidemiologic studies, which should improve the understanding of the evolving pattern of HSV infections. It is unlikely that important published studies have been inadvertently excluded from this extensive review. However, some data presented at recent international conferences and not yet fully published were excluded. These studies were conducted in Argentina [140], Belgium [141], Bulgaria [141], Canada [142], Costa Rica [140], Czech Republic [141], Estonia [143], France [144], India [143], Korea [140], Mali [145], Mexico [141], Morocco [143, 145], The Netherlands [141], Slovenia [141], Spain [140], Sri Lanka [143], Thailand [140], and Vietnam [140]
Conclusions
Seroprevalence estimates of HSV infections allow a better understanding of the burden of infection and how this is evolving with time. Age-specific HSV-2 prevalence data should be considered when designing trials to evaluate potential microbicides and prophylactic and therapeutic HSV vaccines [146–148] in order to identify subgroups that may benefit most from such interventions. HSV-2 prevalence data can also ascertain the extent of HSV-2 infection in an area so that HIV/STI control efforts can be tailored and, in time, prevalence data may be used for evaluation purposes [149]
Further data are needed on age-specific prevalence of HSV-2 and -1 infections in population-based samples as many countries have little or no existing data. Where available, data are frequently limited to a specific local area and/or population. Prospective surveys to determine the prevalence of HSV-2 infection in the USA [150], for example, provide important insights on the relatively rapid spread of infection over the past 25 years. These findings are engendering renewed efforts toward STI control initiatives. Multicenter studies that use similar protocols and the same HSV serologic methods would permit more meaningful comparisons across sites and countries. Further research on the natural history of HSV infections would provide a better understanding of the apparent declining HSV-2 prevalence among older participants following peak levels in some populations. Possible interpretations of this observation are that older cohorts are less widely infected with HSV-2 or that HSV-2 antibody levels may decline in older ages
Observational data suggest that HSV-2 infection may enhance the acquisition and/or transmission of HIV infection [9–12, 150, 151]. At least one intervention trial was initiated to assess the impact of the suppression of HSV-2 shedding and symptoms on HIV shedding in persons dually infected with HSV-2 and HIV [152]. Other intervention trials of the effect of herpes antivirals on HIV acquisition and transmission are being planned. If associations between HSV-2 and HIV infections are causal, then understanding and minimizing the burden of HSV-2 infection will become even more pressing
Acknowledgments
We thank Rhoda Ashley, University of Washington, Seattle, for guidance in literature selection according to type-specific HSV serologic test methodology; Lorraine Folder for valuable assistance with the literature search and the drafting of tables and figures; and Jane Crooks for valuable comments and critique of a previous version of this review
- © 2002 by the Infectious Diseases Society of America
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