Table 1

Detailed methodology for this study

MethodologyDetailed description
Data source and search strategy
  • Search conducted on 16 September 2019 in PubMed and Embase

  • Search strategies included exploded MeSH/Emtree terms and broad terms with no language or time restriction

  • The definition of Europe included 53 countries stratified by European subregion/country:

    • Eastern Europe: Belarus, Bulgaria, Czech Republic, Hungary, Poland, Republic of Moldova, Romania, Russian Federation, Slovakia and Ukraine.

    • Northern Europe: Denmark, Estonia, Finland, Iceland, Ireland, Latvia, Lithuania, Norway, Sweden and UK

    • Southern Europe: Albania, Andorra, Bosnia and Herzegovina, Croatia, Greece, Italy, Malta, Montenegro, Portugal, Republic of Macedonia, San Marino, Serbia, Slovenia and Spain

    • Western Europe: Austria, Belgium, France, Germany, Luxembourg, Monaco, The Netherlands and Switzerland

    • Intersection of Europe and Asia: Armenia, Azerbaijan, Cyprus, Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan

    • Israel

    • Turkey

Study selection and inclusion and exclusion criteria
  • Search results were imported into the reference manager Endnote (Thomson Reuters, USA)

  • Screening was performed in four stages:

    • Duplicate publications were identified and excluded

    • Titles and abstracts were screened for relevant and potentially relevant publications

    • Full texts of relevant and potentially relevant publications were retrieved and screened for relevance

    • Bibliographies of relevant publications and reviews were checked for additional potentially relevant publications

  • Inclusion criteria were any publication, with a minimum sample size of 10, reporting primary data on any of the following outcome measures:

    • HSV-1 seroprevalence as detected by a type specific diagnostic assay

    • Proportion of HSV-1 in GUD, as detected by standard viral detection and subtyping methods

    • Proportion of HSV-1 in genital herpes (as opposed to HSV-2), as detected by standard viral detection and subtyping methods

  • Exclusion criteria were:

    • Case reports, case series, reviews, editorials, commentaries and qualitative studies

    • Measures reporting seroprevalence in infants aged <6 months as their antibodies are maternal in origin

Data extraction and data synthesis
  • Extracted variables included: author(s), publication title, year(s) of data collection, publication year, country of origin, country of survey, city, study site, study design, study sampling procedure, study population and its characteristics (eg, sex and age), sample size, HSV-1 outcome measures and diagnostic assay

  • For studies including overall sample size, but no individual strata sample sizes, the sample size of each stratum was assumed equal to overall sample size divided by the number of strata in the study

  • Stratification hierarchy for seroprevalence in descending order of preference were population type, age bracket and age group:

    1. Population type classified as:

      • Healthy general populations: healthy populations such as blood donors, pregnant women and outpatients with minor health conditions

      • Clinical populations: any population with a major clinical condition, or a condition related (potentially) to HSV-1 infection

      • Other populations: other populations not satisfying above definitions, or populations with an undetermined risk of acquiring HSV-1, such as HIV positive patients, sex workers, men who have sex with men and prisoners

    2. Age category classified as:

      • Children: age ≤15 years

      • Adults: age >15 years

    3. Age group classified as (groups optimised to best fit reported data):

      • <20 years

      • 20–30 years

      • 30–40 years

      • 40–50 years

      • >50 years

  • Stratification hierarchy for GUD and genital herpes included genital herpes episode status and study site:

    1. Genital herpes episode status classified as:

      • First episode genital herpes

      • Recurrent genital herpes

    2. Study site stratification classified as:

      • Hospital

      • Sexually transmitted disease clinic

Quality assessmentThe Cochrane’s approach for risk of bias assessment included:
  • Study’s precision classification into low vs high based on the sample size (<100 vs ≥100)

  • Study’s appraisal into low vs high risk of bias was determined using two quality domains:

    • Sampling method: probability based vs non-probability based

    • Response rate: ≥80% vs <80% or unclear

Meta-analyses
  • Meta-analyses were conducted using the DerSimonian–Laird random effects models with inverse variance weighting. The variance of each outcome measure was stabilised using the Freeman–Tukey double arcsine transformation

  • Pooled means HSV-1 seroprevalence were estimated by age bracket, age group, European subregion/country, population type, genital herpes episode status, sex and year of publication range.

  • Pooled proportions of HSV-1 detection in genital herpes cases were estimated by age group, European subregion/country, sex and year of publication range.

  • Overall pooled proportion of HSV-1 detection in GUD cases was estimated

  • Heterogeneity assessment was based on three complementary metrics:

    • Cochran’s Q statistic to assess existence of heterogeneity in effect size (p value <0.1 indicated heterogeneity)

    • I2 heterogeneity measure to assess the percentage of between study variation in effect size that is due to actual differences in effect size rather than chance

    • Prediction interval to describe the distribution of true outcome measures around the pooled mean

Meta-regressions
  • Univariable and multivariable random effects meta-regression analyses using log transformed proportions were carried out to identify predictors of HSV-1 seroprevalence and HSV-1 proportion in genital herpes

  • Factors in the univariable model with a p value <0.1 were included in the multivariable analysis

  • Factors in the multivariable model with a p value ≤0.05 were deemed to be significant predictors

  • Variables included in the meta-regression models for HSV-1 seroprevalence were:

    • Age bracket

    • Age group

    • Sex

    • Population type

    • European subregion/country

    • Country’s income: upper middle income countries and high income countries according to the World Bank classification, for countries with available data

    • Assay type (western blot, ELISA and others)

    • Sample size

    • Sampling method

    • Response rate

    • Year of publication

    • Year of publication range (<2000; 2000–2010; >2010)

  • Variables included in the meta-regression models for proportion of HSV-1 detection in genital herpes were:

    • Age group

    • Sex

    • Genital herpes episode status

    • European subregion/country

    • Sample size

    • Year of publication

    • Year of publication range

  • ELISA, enzyme linked immunosorbent type specific assay; GUD, genital ulcer disease; HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2.