Clinical Infectious Diseases

MAJOR ARTICLE

The Epidemiology of Herpes Simplex Virus Type 1 in Asia:

Systematic Review, Meta-analyses, and Meta-regressions
Lara Khadr,1,2,a Manale Harfouche,1,a Ryosuke Omori,3 Guido Schwarzer,4 Hiam Chemaitelly,1 and Laith J. Abu-Raddad1,5,6
1
Infectious Disease Epidemiology Group, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha; 2Department of Epidemiology, University of Michigan School of
Public Health, Ann Arbor; 3Division of Bioinformatics, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan; 4Institute of Medical Biometry and Statistics, Faculty of Medicine
and Medical Center, University of Freiburg, Germany; 5Department of Healthcare Policy and Research, Weill Cornell Medicine, Cornell University, New York, New York; and 6College of Health and
Life Sciences, Hamad bin Khalifa University, Doha, Qatar

Background.  Herpes simplex virus type 1 (HSV-1) epidemiology in Asia was characterized by assessing seroprevalence levels
and extent to which HSV-1 is isolated from clinically diagnosed genital ulcer disease (GUD) and genital herpes.
Methods.  HSV-1 reports in Asia were systematically reviewed and synthesized, following PRISMA guidelines. Random-effects
meta-analyses estimated pooled mean seroprevalence and proportion of HSV-1 detection in GUD and genital herpes. Random-
effects meta-regressions identified predictors of seroprevalence and sources of between-study heterogeneity.
Results.  Forty-nine relevant publications were identified. Fifty-four overall seroprevalence measures (182 stratified measures),
and 8 and 24 proportions of HSV-1 detection in GUD and in genital herpes, respectively, were extracted. The pooled mean seroprev-
alence was 50.0% (n = 26; 95% confidence interval [CI], 41.3%–58.7%) for children and 76.5% (n = 151; 73.3%–79.6%) for adults.
By age group, the pooled mean was lowest at 55.5% (n = 37; 95% CI, 47.5%–63.4%) in individuals aged <20 years, followed by 67.9%
(n = 48; 62.4%–73.3%) in those aged 20–39 and 87.5% (n = 44; 83.4%–91.1%) in those aged ≥40 years. In meta-regression, age was
the major predictor of seroprevalence. The mean proportion of HSV-1 detection was 5.6% (n = 8; 95% CI, 0.8%–13.6%) in GUD and
18.8% (n = 24; 12.0%–26.7%) in genital herpes.
Conclusions.  HSV-1 epidemiology is transitioning in Asia. HSV-1 is probably playing a significant role as a sexually transmitted
infection, explaining one-fifth of genital herpes cases. There is a need for expanded seroprevalence monitoring and GUD/genital
herpes etiological surveillance.
Keywords.  seroprevalence; genital ulcer disease; genital herpes; synthesis; region.

Herpes simplex virus (HSV) type 1 (HSV-1) infection is transmitted through oral shedding [5–7], leading to oral man-
widely prevalent [1, 2]. With its persistent shedding [3, 4], ifestations [5, 8], HSV-1 can be transmitted sexually, leading to
HSV-1 is infectious for lifetime, but mostly subclinically genital herpes, given the portal of entry [5, 6, 10].
and asymptomatically [5–7]. When symptomatic, HSV-1 HSV-1 antibody prevalence (seroprevalence) seems to be
can cause mild to severe disease [5, 8]. Although infection very high globally, with the majority of affected persons sero-
is often manifested as orolabial herpes [5, 8], the virus can converting by the time they reach puberty [2, 11, 12]. However,
cause a spectrum of diseases such as herpetic whitlow, gingi- with continuing improvement in hygiene and living conditions,
vostomatitis, meningitis, encephalitis, corneal blindness, and seroprevalence seems to have declined, at least in Western
neonatal herpes [8, 9]. countries [11, 13–20]. About half of youth there reach sexual
HSV-1 clinical manifestations are determined by the virus’s debut before being exposed (nonsexually) to HSV-1 and thus
initial portal of entry [5, 8]. Although it is predominantly are at risk of acquiring the infection genitally [5, 21]. Evidence
indicates a growing role for HSV-1 as a sexually transmitted
infection (STI) and as a leading, if not the leading, cause of ini-
Received 15 January 2018; editorial decision 18 June 2018; accepted 8 July 2018; published
tial episodes of genital herpes in Western countries [5, 21–25].
online July 18, 2018.
a
L. K. and M. H. contributed equally to this work. Although this striking transition in HSV-1 epidemiology
Correspondence: L.  J. Abu-Raddad, Infectious Disease Epidemiology Group, Weill Cornell in the West is well documented [5, 7, 26], the extent to which
Medicine–Qatar, Qatar Foundation–Education City, PO Box 24144, Doha, Qatar (lja2002@qatar-
med.cornell.edu). it is occurring elsewhere is unknown. Understanding HSV-1
Clinical Infectious Diseases®  2019;68(5):757–72 epidemiology in different regions will help characterize the
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases HSV-1 burden, oral and genital, and target the most affected
Society of America.  This is an Open Access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/
populations with interventions. To this end, the World Health
by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Organization and global partners are spearheading efforts to
medium, provided the original work is not altered or transformed in any way, and that the
accelerate the development of HSV vaccines [27, 28]. A  busi-
work is properly cited. For commercial re-use, please contact [email protected]
DOI: 10.1093/cid/ciy562 ness case is being developed that factors public health needs,

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 757

pathways of vaccine rollout, impact and cost-effectiveness, and data using type-specific diagnostic assays such as Western blot
return on investment [27]. To inform this effort, it is critical to or type-specific (glycoprotein-G-based) enzyme-linked immu-
establish current infection levels and trends. nosorbent assays (ELISAs). The inclusion criteria were also
Our overarching goals were to assess HSV-1 seroprevalence met for any publication that reported a proportion of HSV-1
levels and trends in Asia and the extent to which HSV-1 is detection by standard viral detection and subtyping methods
the cause of genital ulcer disease (GUD) and genital herpes. in GUD or genital herpes—to estimate the “etiological” (or
We specifically aimed to (1) methodologically review and “associative”) fraction for HSV-1 in these clinical conditions.
synthesize available studies on seroprevalence; (2) estimate Included studies had to have a sample size of ≥10, regardless of
seroprevalence in different populations and ages by pooling outcome measure.
existing measures; (3) assess seroprevalence temporal trend, Exclusion criteria included case reports, case series, reviews,
population-level associations with seroprevalence, and sources editorials, letters to editors, commentaries, and qualitative stud-
of between-study heterogeneity; (4) assess the proportion of ies. Measures reporting seroprevalence in <3-month-old infants
HSV-1 viral detection in clinically diagnosed GUD; and (5) were excluded because of maternal antibodies.
assess the proportion of HSV-1 viral detection in clinically For terminology, a “publication” is a document containing a
diagnosed genital herpes. The distinction between the last 2 relevant outcome measure, and a “study” or a “measure” indi-
aims lies in the denominator—the etiology of GUD includes cates all details pertaining to a specific outcome measure—a
several indications other than HSV-1 infection (diagnosis of single publication may contribute multiple measures, and mul-
any GUD) [29], and the etiology of genital herpes includes tiple publications of the same data set are deemed a single study.
only HSV-1 and HSV type 2 (HSV-2) infections (virological
diagnosis of herpes) [30]. Data Extraction and Data Synthesis
Extracted variables included author(s), publication title, year(s)
of data collection, publication year, country of origin, country of
MATERIALS AND METHODS
survey, city, study site, study design, study sampling procedure,
Data Sources and Search Strategy study population and its characteristics (eg, sex and age), sam-
This systematic review was informed by the Cochrane ple size, HSV-1 outcome measures, and diagnostic assay. Data
Collaboration Handbook [31] and followed the Preferred from relevant publications were double extracted by L. K. and
Reporting Items for Systematic Reviews and Meta-analyses M. H., with input from R. O.
(PRISMA) guidelines [32]. The PRISMA checklist is in Extracted overall outcome measures were substituted with
Supplementary Table 1. stratified measures, provided the sample size requirement
Available HSV-1 publications in PubMed (from 1950)  and was fulfilled for each stratum. The stratification hierarchy for
Embase (from 1974)  databases were systematically reviewed seroprevalence included population type, age bracket, and
until 22 April 2018. For inclusiveness, broad search criteria were age group, for epidemiological relevance and analysis. In age-
used, with MeSH/Emtree terms exploded to cover all subhead- bracket stratification, we aimed to assess seroprevalence in
ings and with no language or year restrictions (Supplementary adults (≥15  years of age) versus children (<15  years). In age-
Box 1). Articles in Chinese, English, French, and Japanese were group stratification, we aimed to assess seroprevalence growth
reviewed in their original language. Articles in other languages with age (<20, 20–39, or ≥40 years); these strata were optimal
were translated. Asia region definition was informed by the given reported age-stratified data. Stratification hierarchy for
World Health Organizations definitions for South-East Asia GUD and genital herpes proportions included ethnicity, study
and Western Pacific regions [33]. The list of included countries/ site (eg, hospital or STI clinic), and genital herpes episode (first
territories is in Supplementary Box 2. vs recurrent).
Extracted seroprevalence measures were stratified by popu-
Study Selection and Inclusion/Exclusion Criteria lation type into (1) healthy general populations, consisting of
Search results were imported into Endnote (a reference man- healthy populations such as blood donors, pregnant women,
ager), where duplicate publications were identified and and outpatients with minor health conditions; (2) clinical pop-
excluded. Titles and abstracts of remaining records were ulations, consisting of any population with a major clinical con-
screened for relevance, and full texts of relevant and potentially dition, or a condition related (potentially) to HSV-1 infection;
relevant publications were retrieved for additional screening. and (3) other populations, consisting of the remaining popula-
References of articles and reviews were also checked to identify tions not satisfying the above definitions or populations with an
further publications that could have been missed. undetermined risk of acquiring HSV-1, such as persons with
The inclusion criteria were met for any publication that human immunodeficiency virus infection, sex workers, and
reported HSV-1 seroprevalence measure(s), based on primary men who have sex with men.

758 • CID 2019:68 (1 March) •  Khadr et al

Meta-analyses was further assessed by conducting risk of bias (ROB) assess-
Meta-analyses were conducted to estimate pooled mean HSV-1 ment (as informed by the Cochrane approach [31]) and preci-
seroprevalence by population type and by age bracket or group sion assessment.
and to estimate the pooled mean proportions of HSV-1 detec- Studies were categorized as low versus high ROB using 2
tion in GUD and genital herpes. quality domains assessing the rigor of sampling method (prob-
Pooled means were estimated using DerSimonian-Laird ability based vs otherwise) and response rate (≥80% vs other-
random-effects models [34], provided that ≥3 measures were wise). A study was considered to have high (vs low) precision if
available. This method accounts for sampling variation and het- the sample size was ≥100.
erogeneity in effect size (seroprevalence or GUD/genital herpes
proportion) [34]. The Freeman-Tukey double-arcsine transfor- RESULTS
mation was used for variance stabilization [35].
Search Results and Scope of Evidence
The Cochran Q statistic was calculated to assess existence
Figure  1 describes the study-selection process based on
of heterogeneity in effect size (P <  .10 indicated heteroge-
PRISMA guidelines [32]. A  total of 3517 citations were iden-
neity) [36, 37]. The I2 heterogeneity measure was estimated
tified (988 through PubMed and 2529 through Embase). Of
to assess the percentage of between-study variation in effect
these, 528 were relevant or potentially relevant after removal of
size that is due to actual differences in effect size rather than
duplicates and screening of titles and abstracts. Eventually, 45
chance [37]. Prediction intervals were calculated to describe
publications were eligible for inclusion after full-text screening.
the heterogeneity in meta-analyses [36, 37]. Meta-analyses
Four additional publications were identified through screening
were performed in R software, version 3.4.1 [38] using the
of bibliographies of publications and reviews [45–48].
meta package [39].
A total of 54 overall seroprevalence measures (distinct over-
all measures in different populations) were extracted, and these
Meta-regression Analyses
yielded 182 stratified seroprevalence measures. Eight propor-
Univariable and multivariable random-effects meta-regression
tions of HSV-1 detection in GUD and 24 proportions in genital
analyses were conducted to identify predictors of HSV-1 sero-
herpes were further extracted. Extracted measures originated
prevalence (including temporal trend) and sources of between-
from 13 of 26 Asian countries/territories.
study heterogeneity. The log-transformed proportions were
regressed to estimate risk ratios. Seroprevalence Overview
Relevant independent variables were specified a priori: age Table  1 summarizes the stratified seroprevalence measures.
bracket, age group, assay type (Western blot, ELISA, or other), The earliest measure was published in 1986. Most measures
country’s income, population type, sample size (<100 vs ≥100 were based on cross-sectional study design (n = 152 measures;
subjects), sampling method (probability-based vs non–proba- 83.5%), and convenience sampling (n = 150; 82.4%).
bility-based sampling), sex, year of data collection, and year of Extracted stratified seroprevalence measures varied across
publication. Factors associated with seroprevalence at P ≤ .10 and within populations, with a range of 11.1%–100% and a
in univariable analysis were included in the final multivari- median of 74.1% (Table  2). The range and median for sero-
able analysis. Factors associated with seroprevalence at P ≤ .05 prevalence were 11.1%–78.3% and 46.8%, respectively, in
in the final multivariable analysis were deemed statistically populations of healthy children (n  =  19), 16.7%–75.9% and
significant. 53.1% in clinical populations of children (n  =  7), 14.1%–
For the country’s income variable, countries with available data 100% and 78.5% in healthy adult populations (n  =  103),
were grouped according to the World Bank classification [40]. and 32.1%–95.8% and 67.5% in clinical adult populations
For measures that did not include a year of data collection, (n  =  23). Table  2 also includes the ranges and medians for
missing values were imputed using the median of the values cal- further populations.
culated by subtracting the year of data collection (when avail-
able) from the year of publication. Meta-regression analyses Pooled Seroprevalence Estimates
were conducted with Stata/SE software, version 13 [41], using Table 2 shows the results of the seroprevalence meta-analyses.
the metareg package [42]. Among children, the pooled mean seroprevalence was 48.5%
(n = 19; 95% confidence interval [CI], 37.8%–59.3%) for those
Quality Assessment who were healthy and 54.2% (n  =  7; 40.5%–67.6%) for those
For diagnostic methods, diversity, and potential issues of sen- with clinical conditions. Among adults, the pooled mean was
sitivity or specificity [43, 44], we performed quality assessment 77.4% (n = 103; 95% CI, 73.4%–81.1%) for healthy adults and
with the support of an expert advisor, Rhoda Ashley-Morrow, 67.1% (n = 23; 56.7%–76.8%) for those with clinical conditions.
University of Washington, Seattle. Only publications with suf- Table 2 includes pooled results for further populations. By age
ficiently reliable assays were eligible for inclusion. Study quality group, the pooled mean was lowest, at 55.5% (n = 37; 95% CI,

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Figure 1.  Flow chart of article selection for the systematic review of herpes simplex virus type 1 (HSV-1) in Asia, as adapted from the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA) 2009 guidelines [32].

47.5%–63.4%), in individuals aged <20 years, followed by 67.9% substantial variation in seroprevalence. Forest plots are shown
(n = 48; 62.4%–73.3%) in those aged 20–39 and 87.5% (n = 44; in Supplementary Figure 1.
83%.4–91.1%) in those aged ≥40 years.
Country-specific meta-analyses were conducted for coun- Predictors of Seroprevalence and Sources of Between-study Heterogeneity
tries with ≥5 measures for healthy children or adults. For China, Table  3 shows the results of the regression analyses. In uni-
the pooled means were 61.3% (n = 12; 95% CI, 53.1%–69.2%) variable analyses, age bracket, age group, assay type, country’s
in children and 93.1% (n  =  23; 90.0%–95.6%) in adults. For income, population type, and sampling method had P values
India and Japan, the pooled means were 66.8% (n = 21; 95% CI, of  <.10 and were included in the final multivariable analyses.
58.6%–74.6%) and 68.1% (n = 34; 61.5%–74.6%), respectively, Age group best explained the seroprevalence variation (adjusted
in healthy adults. R2 = 21.1%).
There was strong evidence for heterogeneity in seropreva- Sample size and sex were not statistically significant. Year of
lence in all meta-analyses (P  <  .003; Table  2). Most variation data collection and year of publication were also not statisti-
was due to true variation in seroprevalence rather than sam- cally significant; strikingly, both risk ratios were 1.0 (95% CI,
pling variation (I2 > 50%). The prediction intervals affirmed 1.0–1.0) supporting a flat seroprevalence over time.

760 • CID 2019:68 (1 March) •  Khadr et al

Table 1.  Studies Reporting Herpes Simplex Virus Type 1 Seroprevalence Among Different Populations in Asia

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %

Healthy Children Populations (n = 19)

Bogaerts et al (2001) [49] 1996–1998 Bangladesh Outpatient clinic CS Conv 1–12-y-old children WB 79 46.0
Chang (1986) [50] 1984–1986 China Hospital CS Conv 7–12-mo-old infants CFT 31 41.9
Chang (1986) [50] 1984–1987 China Hospital CS Conv 13–24-mo-old CFT 31 51.6
children
Chang (1986) [50] 1984–1988 China Hospital CS Conv 24–35-mo-old CFT 30 43.3
children
Chang (1986) [50] 1984–1989 China Hospital CS Conv 3–4-y-old children CFT 31 67.7
Chang (1986) [50] 1984–1990 China Hospital CS Conv 5–6-y-old children CFT 31 48.4
Chang (1986) [50] 1984–1991 China Hospital CS Conv 7–8-y-old children CFT 31 71.0
Chang (1986) [50] 1984–1992 China Hospital CS Conv 9–14-y-old children CFT 31 74.2
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 1-y-old children ELISA 90 11.1
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 2-y-old children ELISA 127 14.2
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 3-y-old children ELISA 92 31.5
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 4-y-old children ELISA 84 23.8
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 5–9-y-old children ELISA 111 46.8
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 10–14-y-old children ELISA 92 46.7
Li et al (1990) [52] 1988–1989 China Community CS Conv 1–10-y-old Koreans PHA 16 38.0
Lin et al (2011) [53] 2006 China Community CS RS 5–9-y-old girls ELISA 40 64.9
Lin et al (2011) [53] 2006 China Community CS RS 10–14-y-old girls ELISA 45 78.3
Lin et al (2011) [53] 2006 China Community CS RS 5–9-y-old boys ELISA 75 59.8
Lin et al (2011) [53] 2006 China Community CS RS 10–14-y-old boys ELISA 64 78.0
Healthy Adult Populations (n = 103)
Armelia et al (2012) [54] 2010–2011 Indonesia Hospital CSa Conv Kidney donors Anti-HSV-1 23 72.7
IgG
Ashley et al (2004) [55] 2000–2001 Thailand Community CS Conv ≥15-y-old women in WB 98 92.9
Lampang
Ashley et al (2004) [55] 2000–2001 Thailand Community CS Conv ≥15-y-old women in WB 90 61.1
Songkla
Ashley et al (2004) [55] 2000–2001 Vietnam Community CS Conv ≥15-y-old women in WB 99 100.0
Hanoi
Ashley et al (2004) [55] 2000–2001 Vietnam Community CS Conv ≥15-y-old women in WB 100 98.0
Ho Chi Minh
Bogaerts et al (2001) [49] 1996–1998 Bangladesh Outpatient clinic CS Conv Healthy women ELISA 183 97.0
Bu et al (2015) [45] 2012–2013 China Hospital CC Conv Healthy individuals ELISA 135 78.5
Chang (1986) [50] 1984–1986 China Hospital CS Conv >14-y-old adults CFT 30 93.3
Cowan et al (2003) [56] 1998–2000 India Community CS Conv 15–20-y-old adults ELISA 239b 85.7
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 15–19-y-old adults ELISA 115 53.0
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 20–29-y-old adults ELISA 123 69.9
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 30–39-y-old adults ELISA 129 84.5
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 40–49-y-old adults ELISA 100 94.0
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 50–59-y-old adults ELISA 91 98.9
Chen et al (2013) [51] 2007 Taiwan Community CS Conv 60–69-y-old adult ELISA 122 100
Chen et al (2013) [51] 2007 Taiwan Community CS Conv >70-y-old adults ELISA 96 100
Cowan et al (2003) [56] 1998–2000 India Community CS Conv 20–30-y-old adults ELISA 239b 79.9
Cowan et al (2003) [56] 1998–2000 India Community CS Conv 30–35-y-old adults ELISA 239b 80.0
Cowan et al (2003) [56] 1998–2000 India Community CS Conv 25–40-y-old adults ELISA 239b 84.8
Cowan et al (2003) [56] 1998–2000 India Community CS Conv 40–45-y-old adults ELISA 239b 86.2
Cowan et al (2003) [56] 1998–2000 India Community CS Conv >45-y-old adults ELISA 239b 92.5
Doi et al (2009) [57] 2002 Japan Community CSa RS 18–29-y-old women ELISA 83 45.8
Doi et al (2009) [57] 2002 Japan Community CSa RS 30–39-y-old women ELISA 184 50.5
Doi et al (2009) [57] 2002 Japan Community CSa RS 40–49-y-old women ELISA 198 66.7
Doi et al (2009) [57] 2002 Japan Community CSa RS 50–59-y-old women ELISA 200 79.0
Doi et al (2009) [57] 2002 Japan Community CSa RS 18–29-y-old men ELISA 45 44.4
Doi et al (2009) [57] 2002 Japan Community CSa RS 30–39-y-old men ELISA 129 44.2
Doi et al (2009) [57] 2002 Japan Community CSa RS 40–49-y-old men ELISA 198 49.0

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 761

Table 1.  Continued

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %
Doi et al (2009) [57] 2002 Japan Community CSa RS 50–59-y-old men ELISA 198 71.7
Hashido et al (1998) [58] NA Japan Community CS Conv <30-y-old men blood EIA 12 33.0
donors
Hashido et al (1998) [58] NA Japan Community CS Conv 30–50-y-old men EIA 17 70.0
blood donors
Hashido et al (1998) [58] NA Japan Community CS Conv >50-y-old men blood EIA 12 92.0
donors
Hashido et al (1998) [58] NA Japan Community CS Conv 20–39-y-old healthy EIA 20 65.0
women
Hashido et al (1998) [58] NA Japan Community CS Conv 40–99-y-old healthy EIA 28 89.0
women
Hashido et al (1998) [58] NA Japan Community CS Conv >50-y-old healthy EIA 27 92.5
women
Hashido et al (1998) [58] NA Japan Community CS Conv Pregnant women EIA 58 47.0
from Tokyo
Hashido et al (1998) [58] NA Japan Community CS Conv Pregnant women EIA 100 61.0
from Kagoshima
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old men in ELISA 31 64.5
1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old men in ELISA 25 76.0
1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old men in ELISA 15 86.7
1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old men in ELISA 24 37.5
1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old men in ELISA 30 76.7
1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old men in ELISA 33 90.9
1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old men in ELISA 30 33.3
1993
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old men in ELISA 30 56.7
1993
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old men in ELISA 45 75.6
1993
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old women ELISA 32 59.4
in 1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old women ELISA 33 84.8
in 1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old women ELISA 23 100.0
in 1973
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old women ELISA 35 51.4
in 1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old women ELISA 36 77.8
in 1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old women ELISA 34 97.1
in 1983
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 20–29-y-old women ELISA 63 31.7
in 1993
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 30–39-y-old women ELISA 54 69.1
in 1993
Hashido et al (1999) [59] 1973–1993 Japan Community CS Conv 40–49-y-old women ELISA 41 80.5
in 1993
Kaur et al (1999) [60] NA India Outpatient clinic CS Conv 16–20-y-old preg- EIA 24 50.0
nant women
Kaur et al (1999) [60] NA India Outpatient clinic CS Conv 21–25-y-old preg- EIA 36 44.4
nant women
Kaur et al (1999) [60] NA India Outpatient clinic CS Conv 26–30-y-old preg- EIA 34 55.8
nant women
Kaur et al (1999) [60] NA India Outpatient clinic CS Conv 31–35-y-old preg- EIA 14 14.1
nant women

762 • CID 2019:68 (1 March) •  Khadr et al

Table 1.  Continued

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %
Kaur et al (1999) [60] NA India Outpatient clinic CS Conv >36-y-old pregnant EIA 12 83.3
women
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 16–20-y-old women ELISA 12 50.0
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 21–25-y-old women ELISA 17 47.1
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 26–30-y-old women ELISA 18 50.0
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 31–40-y-old women ELISA 13 46.1
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 16–20-y-old men ELISA 13 46.1
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 21–25-y-old men ELISA 20 25.0
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 26–30-y-old men ELISA 14 71.4
Kaur et al (2005) [61] NA India Outpatient clinic CS Conv 31–40-y-old men ELISA 13 46.1
Li et al (1990) [52] 1988–1989 China Community CS Conv >21-y-old Hans PHA 78 99.0
Chinese
Li et al (1990) [52] 1988–1989 China Community CS Conv >21-y-old Koreans PHA 34 97.0
Lin et al (2011) [53] 2006 China Community CS RS 15–19-y-old women ELISA 78 87.5
Lin et al (2011) [53] 2006 China Community CS RS 20–24-y-old women ELISA 101 86.1
Lin et al (2011) [53] 2006 China Community CS RS 25–29-y-old women ELISA 135 93.3
Lin et al (2011) [53] 2006 China Community CS RS 30–34-y-old women ELISA 152 96.7
Lin et al (2011) [53] 2006 China Community CS RS 35–39-y-old women ELISA 154 95.5
Lin et al (2011) [53] 2006 China Community CS RS 40–44-y-old women ELISA 129 98.4
Lin et al (2011) [53] 2006 China Community CS RS 45–49-y-old women ELISA 97 98.0
Lin et al (2011) [53] 2006 China Community CS RS 50–54-y-old women ELISA 101 98.1
Lin et al (2011) [53] 2006 China Community CS RS 55–60-y-old women ELISA 44 97.8
Lin et al (2011) [53] 2006 China Community CS RS 15–19-y-old men ELISA 89 76.5
Lin et al (2011) [53] 2006 China Community CS RS 20–24-y-old men ELISA 93 81.9
Lin et al (2011) [53] 2006 China Community CS RS 25–29-y-old men ELISA 112 86.5
Lin et al (2011) [53] 2006 China Community CS RS 30–34-y-old men ELISA 137 90.4
Lin et al (2011) [53] 2006 China Community CS RS 35–39-y-old men ELISA 144 93.7
Lin et al (2011) [53] 2006 China Community CS RS 40–44-y-old men ELISA 118 97.4
Lin et al (2011) [53] 2006 China Community CS RS 45–49-y-old men ELISA 89 96.7
Lin et al (2011) [53] 2006 China Community CS RS 50–54-y-old men ELISA 82 98.7
Lin et al (2011) [53] 2006 China Community CS RS 55–60-y-old men ELISA 62 98.4
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv <24-y-old Indian ELISA 40 40.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv 25–29-y-old Indian ELISA 49 34.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv 30–34-y-old Indian ELISA 50 60.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv 35–39-y-old Indian ELISA 50 36.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv 40–44-y-old Indian ELISA 50 48.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv 45–49-y-old Indian ELISA 50 58.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 India Community CS Conv >50-y-old Indian ELISA 35 62.0
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 763

Table 1.  Continued

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %
Nasrallah GK, Dargham SR, 2013–2016 Philippines Community CS Conv <34-y-old Filipino ELISA 52 84.6
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 Philippines Community CS Conv 35–44-y-old Filipino ELISA 40 82.5
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Nasrallah GK, Dargham SR, 2013–2016 Philippines Community CS Conv >45-y-old Filipino ELISA 28 85.7
Harfouche M, and Abu- men
Raddad LJ (2018, unpub-
lished data)
Patnaik et al (2007) [62] 1985–2007 Thailand Hospital CC Conv Healthy women WB 78 51.3
Schmid et al (1999) [63] 1991–1993 Thailand Hospital CS Conv >21-y-old army men WB 1158 77.9
Shivaswamy et al (2005) 2001–2003 India Outpatient clinic CC Conv Healthy individuals ELISA 135 91.8
[64]
Yue (1990) [65] 1987–1989 China Outpatient clinic CS Conv Pregnant women ELISA 295 82.0
Zegans et al (1999) [66] 1997 India Hospital CC Conv Controls for a study ELISA 44 64.0
of Mooren ulcer
Healthy Mixed-Age Populations (n = 4)
Li et al (1990) [52] 1988–1989 China Community CS Conv 11–20-y-old Hans PHA 17 94.1
Chinese
Li et al (1990) [52] 1988–1989 China Community CS Conv 11–20-y-old Koreans PHA 13 85.0
Shen et al (2015) [67] 2007 Taiwan Community CS RS Healthy women ELISA 830 64.5
Shen et al (2015) [67] 2007 Taiwan Community CS RS Healthy men ELISA 581 52.0
Clinical Children Populations (n = 7)
Cowan et al (2003) [56] 1998–2000 India Hospital CS Conv 1–5-y-old children ELISA 90b 40.2
Cowan et al (2003) [56] 1998–2000 India Hospital CS Conv 5–10-y-old children ELISA 90b 68.4
Cowan et al (2003) [56] 1998–2000 India Hospital CS Conv 10–15-y-old children ELISA 90b 75.9
Cowan et al (2003) [56] 1998–2000 Sri Lanka Hospital CS Conv 1–5-y-old children ELISA 144b 40.5
Cowan et al (2003) [56] 1998–2000 Sri Lanka Hospital CS Conv 5–10-y-old children ELISA 144b 53.1
Cowan et al (2003) [56] 1998–2000 Sri Lanka Hospital CS Conv 10–15-y-old children ELISA 144b 74.0
Shymala et al (2008) [68] 2005–2006 India Outpatient clinic CS Conv Infants with congen- ELISA 18 16.7
ital cataract
Clinical Adult Populations (n = 23)
Armelia et al (2012) [54] 2010–2011 Indonesia Hospital CSa Conv Pre–kidney trans- Anti-HSV-1 23 68.2
plant patients IgG
Bu et al (2015) [45] 2012–2013 China Hospital CC Conv Patients with ELISA 128 85.2
Alzheimer
disease
Hashido et al (1998) [58] NA Japan Community CS Conv <39-y-old patients EIA 10 60.0
with STD
Hashido et al (1998) [58] NA Japan Community CS Conv >40-y-old patients EIA 16 81.2
with STD
Hashido et al (1998) [58] NA Japan Community CS Conv Pregnant Tokyo EIA 32 56.0
women with
HTLV-1
Hashido et al (1998) [58] NA Japan Community CS Conv Pregnant Kagoshima EIA 100 83.0
women with
HTLV-1
Kaur et al (2006) [69] NA India Outpatient clinic CS Conv Women attending ELISA 52 82.7
an STD clinic
Kaur et al (2006) [69] NA India Outpatient clinic CS Conv Women attending ELISA 76 73.7
an STD clinic
Patwardhan and Bhalla NA India Hospital CS Conv Patients with first ELISA 21 42.8
(2016) [70] genital herpes
Patwardhan and Bhalla NA India Hospital CS Conv Patients with re- ELISA 23 65.2
(2016) [70] current genital
herpes
Shivaswamy et al (2005) 2001–2003 India Outpatient clinic CC Conv <40-y-old patients in ELISA 111 90.1
[64] an STI clinic

764 • CID 2019:68 (1 March) •  Khadr et al

Table 1.  Continued

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %
Shivaswamy et al (2005) 2001–2003 India Outpatient clinic CC Conv ≥40-y-old patients in ELISA 24 95.8
[64] an STI clinic
Sun et al (2005) [48] NA China Hospital CS Conv Diabetic inpatients ELISA 206 46.1
Sun et al (2005) [48] NA China Hospital CS Conv Nondiabetic ELISA 1360 36.3
inpatients
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv <29-y-old men ELISA 72 47.2
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv 30–39-y-old men ELISA 50 52.0
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv 40–49-y-old men ELISA 41 58.8
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv >50-y-old men ELISA 37 78.4
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv <20-y-old female ELISA 28 32.1
patients
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv 20–29-y-old women ELISA 98 49.0
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv 30–39-y-old women ELISA 40 67.5
Theng et al (2006) [71] 2003–2004 Singapore Outpatient clinic CS Conv >40-y-old women ELISA 32 78.2
Zegans et al (1999) [66] 1999 India Hospital CS Conv Patients with ELISA 21 86.0
Mooren ulcers
Clinical Mixed-Age Population (n = 1)
Lee and Lee (2015) [72] NA South Korea Community CSa Conv >11-y-old patients Multiplex 2317 73.8
immu-
noassay
Other Populations (n = 25)
Chu et al (2006) [73] NA Thailand Hospital CS Conv HIV-infected men ELISA 66 53.0
Chu et al (2006) [73] NA Thailand Hospital CS Conv HIV-infected women ELISA 70 73.0
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv 15–20-y-old healthy/ ELISA 622b 74.3
clinical patients
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv 20–30-y-old healthy/ ELISA 622b 79.2
clinical patients
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv 30–35-y-old health/ ELISA 622b 74.6
clinical patients
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv 25–40-y-old healthy/ ELISA 622b 74.5
clinical patients
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv 40–45-y-old healthy/ ELISA 622b 77.1
clinical patients
Cowan et al (2003) [56] 1998–2000 Sri Lanka Outpatient clinic CS Conv >45-y-old healthy/ ELISA 622b 82.0
clinical patients
Hashido et al (1998) [58] NA Japan Community CS Conv Female sex workers EIA 70 75.7
Hashido et al (1998) [58] NA Japan Community CS Conv <39-y-old MSM EIA 15 53.3
Hashido et al (1998) [58] NA Japan Community CS Conv >40-y-old MSM EIA 19 97.4
Lin et al (2011) [53] NA China Community CS Conv 18–29-y-old HIV- ELISA 191 94.3
infected patients
Lin et al (2011) [53] NA China Community CS Conv 30–39-y-old HIV- ELISA 503 92.6
infected patients
Lin et al (2011) [53] NA China Community CS Conv 40–49-y-old HIV- ELISA 290 89.7
infected patients
Lin et al (2011) [53] NA China Community CS Conv 50–59-y-old HIV- ELISA 96 85.4
infected patients
Lin et al (2011) [53] NA China Community CS Conv 60–94-y-old HIV- ELISA 30 93.3
infected patients
Limpakarnjanara et al 1994 Thailand Community CS Conv >16-y-old female WB 500 91.0
(1999) [74] sex workers
Neal et al (2011) [75] NA China Community CS Conv Sex workers WB 273 91.9
Qutub and Akhter (2003) NA Bangladesh Community CSa Conv Female sex workers WB 463 92.7
[76]
Theng et al (2006) [77] 2003–2004 Singapore Outpatient clinic CS Conv 20–29-y-old sex ELISA 146 80.1
workers
Theng et al (2006) [77] 2003–2004 Singapore Outpatient clinic CS Conv 30–39-y-old sex ELISA 56 67.9
workers
Theng et al (2006) [77] 2003–2004 Singapore Outpatient clinic CS Conv 40–49-y-old sex ELISA 60 68.3
workers

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 765

Table 1.  Continued

HSV-1 HSV-1
Year(s) of Data Study Sampling Serological Sample Seroprevalence,
Authors (Year) Collection Country Study Site Design Method Population Assay Size, No. %
Theng et al (2006) [77] 2003–2004 Singapore Outpatient clinic CS Conv >50-y-old sex ELISA 38 89.5
workers
Van Griensven et al (2013) 2006–2010 Thailand Community CS Conv >18-y-old MSM ELISA 1740 56.5
[78]
Yap et al (2017) [79] NA Malaysia Hospital CS Conv HIV-infected ELISA 232 70.7
patients

Abbreviations: CC,  case-control; CFT,  complement fixation test; Conv,  convenience; CS,  cross-sectional; EIA,  enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; HIV,
human immunodeficiency virus; HSV-1, herpes simplex virus type 1; HTLV-1, human T-lymphotropic virus 1; MSM, men who have sex with men; NA, not available; PHA, passive hemagglu-
tination assay; RS, random sampling; STD, sexually transmitted disease; STI, sexually transmitted infection; WB, Western blot.
a
The actual study design was cohort, but the extracted seroprevalence measure was for the baseline measurement.
b
The study included overall sample size but no sample sizes for individual strata. Each stratum sample size was assumed to be equal to the overall sample size divided by the number of
strata in the study.

Table 2.  Pooled Mean Estimates for Herpes Simplex Virus Type 1 Seroprevalence Among Different Populations in Asia

HSV-1 Seroprevalence Heterogeneity Measuresa

Pooled
Outcome Mean HSV-1 Prediction
Measures, Total Samples, Total Seroprevalence, Interval,
2
Population Type No. No. Range Median Mean (95% CI) Q (P Value) I (95% CI), % %

Healthy general populations

 Children 19 1131 11.1–78.3 46.8 48.5 (37.8–59.3) 228.6 (<.001) 92.1 (89.1–94.3) 7.1–91.2
 Adults 103 9514 14.1–100 78.5 77.4 (73.4–81.1) 1841.6 (<.001) 94.5 (93.7–95.1) 34.9–100
  Mixed ages 4 1441 52.0–94.1 74.8 68.9 (56.3–80.3) 36.5 (<.001) 91.8 (82.2–96.2) 16.6–100
All healthy 126 12 086 11.1–100 73.4 73.1 (68.9–77.1) 2955.4 (<.001) 95.8 (95.3–96.2) 25.3–100
general
populations
Clinical populations
 Children 7 720 16.7–75.9 53.1 54.2 (40.5–67.6) 78.4 (<.001) 92.3 (86.8–95.6) 11.0–93.9
 Adults 23 2601 32.1–95.8 67.5 67.1 (56.7–76.8) 456.4 (<.001) 95.2 (93.8–96.3) 17.3–100
  Mixed ages 1b 2317 - - 73.8 (71.9–75.6) -b -b -b
  All clinical 31 5638 16.7–95.8 67.5 64.3 (56.3–71.9) 809.2 (<.001) 96.3 (95.5–97.0) 21.1–97.0
populations
Other populations
 HIV-infected 8 1476 53.0–94.3 87.6 83.3 (74.0–91.0) 119.4 (<.001) 94.1 (90.6–96.3) 45.7–100
patients
 MSM 3 1774 53.3–97.4 56.5 69.7 (42.9–91.7) 15.5 (<.001) 87.1 (63.2–95.5) 0.0–100
  Sex workers 8 1606 67.9–92.7 84.9 84.1 (77.6–89.7) 63.2 (<.001) 88.9 (80.5–93.7) 59.3–98.6
 Healthy/ 6 3732 74.3–82.0 75.9 77.0 (74.4–79.5) 18.0 (.003) 72.3 (36.0–88.0) 68.1–84.8
clinical adult
populations
Age groups
  <20 y 37 3101 11.1–94.1 51.6 55.5 (47.5–63.4) 654.8 (<.001) 94.5 (93.3–95.5) 11.7–94.6
  20–39 y 48 5601 14.1–96.7 67.7 67.9 (62.4–73.3) 784.3 (<.001) 94.0 (92.8–95.0) 23.0–96.0
  ≥40 y 44 4966 48.0–100 89.3 87.5 (83.4–91.1) 633.6 (<.001) 93.2 (91.7–94.4) 55.2–100
  All children 26 1851 11.1–78.3 47.6 50.0 (41.3–58.7) 343.6 (<.001) 92.7 (90.5–94.4) 10.2–89.8
  All adults 151 20 705 14.1–100 77.8 76.5 (73.3–79.6) 3951.1 (<.001) 96.2 (95.8–96.5) 34.2–100
  All mixed-age 5 3758 52.0–94.1 73.8 70.6 (59.4–80.8) 112.8 (<.001) 96.5 (94.0–97.9) 29.6–98.3
groups
All studies/ 182 26 314 11.1–100 74.1 72.9 (69.8–75.9) 5038.0 (.001) 96.4 (96.1–96.7) 30.3–99.4
strata

Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus type 1; MSM, men who have sex with men.
a
The Cochran Q statistic is a measure assessing the existence of heterogeneity in effect size; I2, a measure that assesses the magnitude of between-study variation due to actual differences
in effect size across studies rather than chance; and prediction interval, a measure that estimates the distribution (95% interval) of true effect sizes around the estimated mean.
b
No meta-analysis was done owing to the small number of studies (n < 3).

766 • CID 2019:68 (1 March) •  Khadr et al

Table 3.  Univariable and Multivariable Meta-regression Analyses of Herpes Simplex Virus Type 1 Seroprevalence Among Different Populations in Asia

Univariable Analysis Multivariable Analysis

Model 1a Model 2b
Outcome Variance
Measures, Samples, RR Explained, ARR ARR
Variable Total No. Total No. (95% CI) P Value Adjusted R2, % (95%CI) P Value (95% CI) P Value

Age bracket
 Children 26 1851 1.0 … 1.0 … … …
 Adults 151 20 705 1.5 (1.3–1.7) <.001 1.5 (1.3–1.7) <.001 … …
  Mixed ages 5 3758 1.4 (1.1–1.9) .01 18.6 1.5 (1.1–2.0) .006 … …
Age group
  <20 y 37 3101 1.0 … … … 1.0 …
  20–39 y 48 5601 1.2 (1.0–1.4) .008 … … 1.3 (1.0–1.5) <.001
  ≥40 y 44 4966 1.5 (1.3–1.8) <.001 … … 1.6 (1.4–1.9) <.001
 Mixed 53 12 646 1.3 (1.1–1.5) <.001 21.1 … … 1.3 (1.1–1.5) <.001
Assay type
  Western blot 9 2859 1.0 … 1.0 … 1.0 …
 ELISA 137 20 032 0.8 (.6–1.0) .09 0.9 (.8–1.1) .63 0.9 (.7–1.0) .28
 Others 36 3423 0.8 (.6–1.0) .13 0.5 1.0 (.8–1.2) .98 1.0 (.8–1.2) .72
Country’s income
 LMIC 58 8047 1.0 … 1.0 … 1.0 …
 UMIC 55 10 084 1.2 (1.0–1.3) .02 1.1 (1.0–1.3) .01 1.1 (1.0–1.3) .03
 HIC 69 8183 0.9 (.8–1.1) .39 7.1 0.9 (.8–1.2) .13 0.9 (.8–.9) .01
Population type
 Healthy 126 12 086 1.0 … 1.0 … 1.0 …
general
populations
 Clinical 31 5638 0.9 (.8–1.0) .17 1.0 (.8–1.1) .74 1.0 (.9–1.1) .87
populations
 Other 25 8590 1.1 (1.0–1.3) .07 0.2 1.1 (.9–1.2) .53 1.0 (.9–1.2) .52
populations
Sample sizec
 <100 22 905 1.0 … … … … …
 ≥100 160 25 409 0.9 (.8–1.1) .65 0.0 … … … …
Sampling method
 Probability 33 7104 1.0 … 1.0 … 1.0 …
based
 Non–proba- 149 19 210 0.9 (.8–1.0) .04 1.4 1.0 (.9–1.2) .67 1.0 (.8–1.1) .93
bility based
Sex
 Female 56 5665 1.0 … … … … …
 Male 55 6422 0.9 (.8–1.1) .29 … … … …
 Mixed 71 14 227 0.9 (.8–1.1) .46 1.4 … … … …
Year of data 182 26 314 1.0 (1.0–1.0) .84 0.0 … … … …
collection
Year of 182 26 314 1.0 (1.0–1.0) .58 0.0 … … … …
publication

Abbreviations: ARR, adjusted risk ratio; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; HIC, high-income country; LMIC, lower-middle-income country; RR, risk ratio;
UMIC, upper-middle-income country. 
a
The variance explained by the final multivariable model 1 (adjusted R2) was 26.0%
b
The variance explained by the final multivariable model 2 (adjusted R2) was 33.9%
c
Sample size denotes the sample size for each study population found in the original publication.

Two final multivariable analyses were conducted, instead of one, lower-middle-income countries. No association with assay type,
because of collinearity between age bracket and age group. The population type, and sampling method was found.
model including age bracket, assay type, country’s income, popula- The model including age group instead of age bracket
tion type, and sampling method explained 26.0% of seroprevalence explained 33.9% of seroprevalence variation and yielded similar
variation. Seroprevalence in adults was 1.5-fold (95% CI, 1.3–1.7- results. Seroprevalence in individuals aged 20–39 years was 1.3-
fold) higher than in children. Seroprevalence in upper-middle-in- fold (95% CI, 1.0–1.5-fold) higher than in individuals <20, and
come countries was 1.1-fold (95% CI, 1.0–1.3-fold) higher than in for those aged ≥40 years, it was 1.6-fold (1.4–1.9-fold) higher.

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 767

HSV-1 Detection in GUD and Genital Herpes quality. Of all studies, 70.4% were of high precision, 7.4% had
Table 4 summarizes the studies reporting proportion of HSV-1 low ROB in the sampling method domain, and 38.9% had low
detection in GUD (n = 8) and genital herpes (n = 24). Table 5 ROB in the response rate domain. Only 7.4% of studies had
shows the results of meta-analyses, with strong evidence for het- high ROB in both quality domains.
erogeneity. Forest plots are shown in Supplementary Figure 2.
The proportion of HSV-1 detection in GUD ranged between
0.0% and 28.4%, with a median of 2.5%. The pooled mean pro- DISCUSSION
portion was 5.6% (n = 8; 95% CI, 0.8%–13.6%). The proportion We presented a comprehensive systematic review and syn-
of HSV-1 detection in genital herpes ranged between 0.0% and thesis of HSV-1 epidemiology in Asia. Fifty percent of
62.0%, with a median of 16.3%. The pooled mean proportion children and 75% of adults were infected. Seroprevalence
was 18.8% (n  =  24; 95% CI, 12.0%–26.7%). HSV-1 was more increased with age, with most infections acquired in child-
frequently detected in first-episode genital herpes than in hood. No evidence was found for a temporal trend; sero-
recurrent genital herpes (Table 4). prevalence appeared stable for 3 decades. Nonetheless,
seroprevalence was 60% higher in those aged ≥40 than in
Quality Assessment those aged <20  years, possibly reflecting a higher exposure
Outcomes of the quality assessment are shown in Supplementary risk in earlier times, and an earlier transition toward lower
Table  2. Overall, seroprevalence studies were of reasonable seroprevalence.

Table 4.  Studies From Asia Reporting Proportion of Herpes Simplex Virus Type 1 (HSV-1) Viral Detection in Clinically Diagnosed Genital Ulcer Disease, or
Proportion of HSV-1 Viral Detection in Clinically Diagnosed Genital Herpes

Proportion
Year(s) of Data Sampling HSV-1 Sample Size, of HSV-1
Authors (Year) Collection Country Study Site Study Design Method Biological Assay Population No. Detection, %

HSV-1 Detection in Clinically Diagnosed GUD (n = 8)

Chu et al (2006) NA Thailand Hospital CS Conv PCR Patients with gen- 26 0.0
[73] ital ulcers
Chua and 1993 Singapore Outpatient CS Conv CF Male patients 121 8.3
Cheong clinic with primary
(1995) [80] genital ulcers
Chua and 1993 Singapore Outpatient CS Conv CF Female patients 54 27.8
Cheong clinic with primary
(1995) [80] genital ulcers
Chua and 1993 Singapore Outpatient CS Conv CF Male patients 181 1.6
Cheong clinic with recurrent
(1995) [80] genital ulcer
Chua and 1993 Singapore Outpatient CS Conv CF Female patients 24 0.0
Cheong clinic with recurrent
(1995) [80] genital ulcers
Hooi et al 1990–1999 Malaysia Hospital CS Conv IF Patients attending 102 28.4
(2002) [81] a university
hospital
Hooi et al 1990–1999 Malaysia Outpatient CS Conv IF Patients attending 204 3.4
(2002) [81] clinic an STD clinic
Thirumoorthy 1984 Singapore Outpatient CS Conv IF Male patients 80 0.0
et al (1986) clinic with penile
[82] ulcers
HSV-1 Detection in Clinically Diagnosed Genital Herpes (n = 24)
Cheong et al 1986–1987 Singapore Hospital CS Conv IF First genital 62 33.9
(1990) [83] herpes episode
Chiam et al 1982–2008 Malaysia Hospital CS Conv DFA Malaysian patients 49 61.2
(2010) [84]
Chiam et al 1982–2008 Malaysia Hospital CS Conv DFA Indian patients 36 50.0
(2010) [84]
Chiam et al 1982–2008 Malaysia Hospital CS Conv DFA Chinese patients 30 6.7
(2010) [84]
Chio et al (2015) 2014 Singapore Outpatient CS Conv PCR Patients with gen- 193 13.9
[46] clinic ital herpes
Chua and 1993 Singapore Outpatient CS Conv CF Male patients 98 10.2
Cheong clinic with primary
(1995) [80] genital herpes

768 • CID 2019:68 (1 March) •  Khadr et al

Table 4.  Continued

Proportion
Year(s) of Data Sampling HSV-1 Sample Size, of HSV-1
Authors (Year) Collection Country Study Site Study Design Method Biological Assay Population No. Detection, %
Chua and 1993 Singapore Outpatient CS Conv CF Female patients 52 28.9
Cheong clinic with primary
(1995) [80] genital herpes
Chua and 1993 Singapore Outpatient CS Conv CF Male patients 116 2.5
Cheong clinic with recurrent
(1995) [80] genital herpes
Chua and 1993 Singapore Outpatient CS Conv CF Female patients 19 0.0
Cheong clinic with recurrent
(1995) [80] genital herpes
Doraisingham 1984–1986 Singapore Hospital CS Conv IF Genital lesions 215 21.4
et al (1987) positive for
[85] HSV
Doraisingham 1984–1986 Singapore Hospital CS Conv IF Genital HSV 49 32.7
et al (1987) isolates
[85]
Hooi et al 1990–1999 Malaysia Hospital CS Conv IF Patients attending 55 52.7
(2002) [81] a university
hospital
Hooi et al 1990–1999 Malaysia Outpatient CS Conv IF Patients attending 165 4.2
(2002) [81] clinic an STD clinic
Ishiguro et al 1975–1978 Japan Outpatient CS Conv Nab Patients with gen- 13 53.8
(1982) [86] clinic ital herpes
Jacob et al 1983–1986 India Outpatient CS Conv IF Patient with pri- 10 10.0
(1989) [87] clinic mary genital
herpes
Jacob et al 1983–1986 India Outpatient CS Conv IF Patient with re- 42 0.0
(1989) [87] clinic current genital
herpes
Kao et al (1991) 1981–1990 Taiwan Hospital CS Conv IF Genital HSV iso- 53 0.0
[88] lates in men
Kao et al (1991) 1981–1990 Taiwan Hospital CS Conv IF Genital HSV iso- 96a 9.4
[88] lates in women
Kawana et al NA Japan Outpatient CS Conv Nab Patients with pri- 50 62.0
(1982) [47] clinic mary genital
herpes
Kawana et al NA Japan Outpatient CS Conv Nab Patients with re- 49 10.2
(1982) [47] clinic current genital
herpes
Puthavathana 1994–1996 Thailand Hospital CS Conv IF Women with gen- 75 18.7
et al (1998) ital herpes
[89]
Sen et al (2008) 1996–2006 Singapore Outpatient CS Conv PCR Patients with gen- 13 53.8
[90] clinic ital herpes
Theng and 2001 Singapore Outpatient CS Conv IF First genital 114 19.3
Chan (2004) clinic herpes episode
[91]
Theng and 2001 Singapore Outpatient CS Conv IF Recurrent genital 127 4.7
Chan (2004) clinic herpes episode
[91]

Abbreviations: CF, complement fixation; Conv, convenience; CS, cross-sectional; DFA, direct fluorescent assay; GUD, genital ulcer disease; HSV-1, herpes simplex virus type 1; IF, immuno-
fluorescence; NA, not available; Nab, neutralization antibody test; PCR, polymerase chain reaction; STD, sexually transmitted disease. 
a
This population included a mix of patients with clinically diagnosed genital herpes and patients suspected of a viral infection from whom cervical swab samples were collected (n = 47).

As many as 50% of youth reach sexual debut with no pro- as in Western countries [5, 7, 26], possibly mediated by Asia’s
tective antibodies against HSV-1, and thus potentially at risk of rapid socioeconomic modernization.
sexual acquisition. Remarkably, based on virological diagnosis The seroprevalence of HSV-1 varied somewhat by country
studies, there was a substantial role for HSV-1 in genital herpes income but was highest in upper-middle-income countries
and GUD: 19% of genital herpes cases were due to HSV-1 (as (including China). The weaker socioeconomic association
opposed to HSV-2), and 6% of GUD cases. These findings sug- may relate to recent modernization, say for China, and to
gest an apparently ongoing HSV-1 epidemiological transition, unexplained low seroprevalence in populations on the Indian

HSV-1 Epidemiology in Asia  •  CID 2019:68 (1 March) • 769

Table 5.  Pooled Proportions in Asia of Herpes Simplex Virus Type 1 Viral Detection in Clinically Diagnosed Genital Ulcer Disease or Genital Herpes

Proportion of HSV-1
Detection, % Heterogeneity Measurea
Pooled Proportion
Measures, Samples, of HSV-1 Prediction
Total Total Detection Mean Interval,
Population Type No. No. Range Median (95% CI), % Q (P Value) I2 (95% CI), % %

Patients with 8 792 0.0–28.4 2.5 5.6 (.8–13.6) 91.1 (<.001) 92.3 (87.2–95.4) 0.0–43.7
clinically
diagnosed
GUD
Patients with 24 1781 0.0–62.0 16.3 18.8 (12.0–26.7) 330.4 (<.001) 93.0 (90.8–94.7) 0.0–62.9
clinically
diagnosed
genital
herpes

Abbreviations: CI, confidence interval; GUD, genital ulcer disease; HSV-1, herpes simplex virus type 1.
a
The Cochran Q statistic is a measure assessing the existence of heterogeneity in effect size; I2, a measure that assesses the magnitude of between-study variation due to actual differences
in effect size across studies rather than chance; and prediction interval, a measure that estimates the distribution (95% interval) of true effect sizes around the estimated mean.

subcontinent [92]; seroprevalence in adults was 93% in China neutralization antibody test, and nucleic acid amplification
but only 67% in India. test), but these may differ in HSV-1 detection [96]. HSV-1
Strikingly, there were no differences in seroprevalence by sex, detection in GUD and genital herpes varied across studies,
population type, assay type, sampling method, or sample size. possibly reflecting variation in the underlying epidemiology.
Age was the only major predictor of seroprevalence. This speaks For example, a Malaysian study found >50% HSV-1 detection
for how HSV-1 is a general-population infection that permeates rates in genital herpes in a university hospital, but <5% in a sex-
all strata of society. This also demonstrates the ease of sampling ually transmitted disease clinic [81], probably reflecting differ-
a representative sample to measure seroprevalence, provided ences in the populations attending these facilities (general vs
that the sample age distribution is representative of the under- sexual high-risk population).
lying population age distribution. In conclusion, HSV-1 seroprevalence remains high in Asia,
Although seroprevalence was much higher in older than in with 50% of children and 75% of adults testing seropositive.
younger cohorts, there was no evidence for a recent temporal However, there seems to be an epidemiological transition,
decline in seroprevalence. This finding may be explained by with lower seroprevalence in younger cohorts. Close to 50%
an earlier transition toward lower seroprevalence, or (specula- of youth reach sexual debut uninfected and potentially at risk
tively) by a demographic effect. HSV-1 seroincidence could be of sexual acquisition. HSV-1 is possibly playing an influential
declining, but with rapidly declining fertility and increasing life role as an STI, explaining a fraction of GUD and genital her-
expectancy rates, the overall seroprevalence could remain sta- pes diagnoses. These findings demonstrate the importance of
ble, masking the decline in seroincidence. Findings from com- seroprevalence monitoring and GUD/genital herpes etiolog-
munity-based Japanese study (performed over 2 decades) seem ical surveillance, as well as expansion of HSV-1 epidemiol-
to support such a conjecture; seroprevalence in persons aged ogy research in different age groups and countries; for half of
20–49 years declined by nearly 10% every decade [59]. countries, no data were available. These findings also highlight
Our study has limitations. Data availability varied by country the need to accelerate HSV-1 vaccine development to control
and no data were identified for 13 mostly lower-income coun- transmission and prevent associated clinical and psychosocial
tries and territories (Bhutan, Brunei, Cambodia, Hong Kong, disease burden.
Laos, Macau, Mongolia, Myanmar, Nepal, Papua New Guinea,
North Korea, Tibet, and Timor-Leste). Seroprevalence showed Supplementary Data
high heterogeneity, but examined predictors explained only Supplementary materials are available at Clinical Infectious Diseases online.
34% of the variation. Different diagnostic assays were used Consisting of data provided by the authors to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the authors,
across studies, but assays may vary by sensitivity and specificity so questions or comments should be addressed to the corresponding author.
(eg, ELISA vs Western blot) [43, 44], as well as in the differential
effect of HSV-2 antibodies—particularly for the classic “relative Notes
reactivity” methods [93–95]. However, no evidence was found Author contributions.  L.  K.  and M.  H.  conducted the systematic
search, screening, data extraction, and data analysis. R.  O.  contributed
for differences in seroprevalence by assay type (Table 3).
to data extraction. G.  S.  contributed to the statistical analysis. H.  C.  pro-
Similarly, various diagnostic assays were used for viral vided support in study design and data extraction. L. J. A.-R. conceived
detection (immunofluorescence, direct fluorescent assay, the study and supervised study conduct and analyses. L. K., M. H., and L.

770 • CID 2019:68 (1 March) •  Khadr et al

J. A.-R. wrote the first draft of the manuscript. All authors have read and 20. Vyse AJ, Gay NJ, Slomka MJ, et  al. The burden of infection with HSV-1 and
approved the final manuscript. HSV-2 in England and Wales: implications for the changing epidemiology of gen-
Acknowledgments.  We gratefully acknowledge Rhoda Ashley Morrow ital herpes. Sex Transm Infect 2000; 76:183–7.
21. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus
from the University of Washington, for her support in assessing the quality
type 1 as a cause of genital herpes infection in college students. Sex Transm Dis
of study diagnostic methods and for critically reviewing the manuscript. We
2003; 30:797–800.
are also grateful to Adona Canlas for administrative support and to Fang Yu 22. Löwhagen GB, Tunbäck P, Andersson K, Bergström T, Johannisson G. First epi-
for providing Chinese translations. sodes of genital herpes in a Swedish STD population: a study of epidemiology
Disclaimer.  The findings reported herein are solely the responsibility and transmission by the use of herpes simplex virus (HSV) typing and specific
of the authors. serology. Sex Transm Infect 2000; 76:179–82.
Financial support.  This work was supported by the Qatar National 23. Nilsen A, Myrmel H. Changing trends in genital herpes simplex virus infection in
Research Fund (member of the Qatar Foundation; grant NPRP 9-040-3- Bergen, Norway. Acta Obstet Gynecol Scand 2000; 79:693–6.
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structure support from the Biostatistics, Epidemiology, and Biomathematics
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trends in herpes simplex virus type 1 and 2 infection in British Columbia and the
Potential conflicts of interest.  All authors: No reported conflicts of changing etiology of genital herpes. Can J Public Health 2011; 102:225–9.
interest. All authors have submitted the ICMJE Form for Disclosure of 26. Whitley RJ. Changing epidemiology of herpes simplex virus infections. Clin
Potential Conflicts of Interest. Conflicts that the editors consider relevant to Infect Dis 2013; 56:352–3.
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