Correlates of chronic hepatitis B virus infection in the general adult population of China: Systematic review and meta‐analysis

Chronic infection with hepatitis B virus (HBV) is a significant public health issue in China. Understanding factors associated with chronic HBV is important to enable targeted screening and education and to improve early diagnosis and prevention of disease progression. This systematic review and meta‐analysis aimed to identify and describe correlates of chronic HBV among Chinese adults. Searches were conducted in MEDLINE, EMBASE and grey literature up to 25 June 2020. Eligible papers included observational studies in adults of the general population in China that reported factors associated with chronic HBV, measured by Hepatitis B surface antigen (HBsAg). Meta‐analysis was performed using fixed‐effect models of HBsAg prevalence among factors, and of adjusted odds ratios (ORs) for chronic HBV associated with each factor. Overall 39 articles were included, covering 22 factors, including a range of sociodemographic, behavioural and medical factors. In meta‐analysis of eligible studies, a range of factors were significantly associated with higher HBsAg prevalence, including middle age, male sex, being married, rural residence, lower education, smoking, having a HBsAg positive household contact, family history of HBV, history of surgery or blood transfusion. The adjusted ORs varied, from 1.11 (95% CI 1.05–1.18) for smoking to 5.13 (95% CI 4.99–5.26) for having a HBsAg positive household contact. In Chinese adults, a range of factors are associated with chronic HBV infection, which may help inform targeted screening in the general population.


| INTRODUC TI ON
Hepatitis B virus (HBV) is one of the most common chronic viral infections in the world, affecting 240 million people globally. 1 China has the highest burden of chronic HBV infection in the world, 1 despite progress in controlling HBV, largely through vaccination of newborns being freely accessible since 2005. 2 It is coined a 'silent epidemic', due to its high disease burden and prolonged asymptomatic disease course, compounded by lack of screening, diagnosis and education. 1 Among adults with chronic HBV, up to one in four will progress to cirrhosis or liver cancer, 2,3 and an estimated 10 million people living with HBV in China will die by 2030 from largely avoidable liver cancers. 4 In order to eliminate chronic HBV infection as a public health threat in China, increasing the rate of diagnosis from the current status (19% of cases diagnosed) to the World Health Organization's target of 90% by 2030 is a key priority. 5,6 Although several chronic hepatitis B correlates have been reported in past studies, 7-11 many are constrained by relatively small sample size, [12][13][14][15][16] limited geographic areas 10,12,[17][18][19] or breadth and depth of the risk factors selected. 14,15,17,[20][21][22] Consequently, there is still uncertainty about the relevance, both qualitatively and quantitatively, of a range of factors in relation to chronic HBV infection among adults in China. In China, up to half of HBV transmission occurs at birth from mother to child or horizontally in early childhood 23 ; however, it can also occur via horizontal transmission routes later in life. Given the temporality between chronic HBV infection and 'risk factors' is often unclear, we refer to these as 'factors' or 'correlates' in this review. Appropriate understanding of correlates of HBV chronicity can help inform targeted education and testing, to increase the diagnosis rate and capture infected individuals on the chronic HBV care continuum so they can be monitored and treated. Through conducting a systematic review and meta-analysis of published studies, this paper aims to identify and assess correlates of chronic hepatitis B infection in the general adult population of China. Network (SIGN). 25 All identified references were stored in Endnote and Covidence software. 26

| Inclusion and exclusion criteria
Observational studies on adult participants of the general population in mainland China were included, where at least one factor in relation to chronic HBV as measured by Hepatitis B surface antigen (HBsAg) was reported. Adults were defined as ≥15 years given many studies categorized age groups from ≥15 years, and studies including children were eligible if adult-specific estimates could be extracted.
Studies using the same serosurvey were eligible if they reported data from a different timeframe, location, or additional chronic HBV correlates-otherwise the largest study was included. No language restriction was applied (eTable 3 for detailed criteria).

| Selection procedure, data extraction and quality assessment
Two reviewers (EH, WR) screened all articles and performed full text eligibility assessment. At least two authors (EH, WR, AS) independently extracted qualitative (study methodology details; characteristics of study population; correlates reported, measurement of HBV; statistical methods), and quantitative data (number of participants; categorization of correlates; HBsAg prevalence; effect estimate; variables included in multivariable model). Quality assessment (EH, AS) was conducted using a modified Newcastle Ottawa Scale 27 (NOS) (eTable 4) for assessing quality of nonrandomized studies, which assesses quality under three domains: selection, comparability, and outcomes. Articles were scored as 'good', 'fair' or 'poor' based on scores in each domain. Two Chinese language reviewers completed this process of study selection (YY, SN) and quality assessment (YY, JZ) for Chinese language articles.

| Data synthesis and meta-analysis
Qualitative data synthesis of chronic HBV correlates included tabulating the number of studies reporting each correlate, where they smoking to 5.13 (95% CI 4.99-5.26) for having a HBsAg positive household contact.
In Chinese adults, a range of factors are associated with chronic HBV infection, which may help inform targeted screening in the general population.

K E Y W O R D S
China, chronic hepatitis B infection, hepatitis B surface antigen, prevalence, risk factors were reported by ≥3 studies. Two separate meta-analyses were conducted to be as inclusive as possible, as several studies reported either HBsAg prevalence or odds ratios (ORs). First, a meta-analysis of adult specific HBsAg prevalence estimates among comparable variables was performed to generate overall pooled HBsAg prevalence. Second, a meta-analysis was conducted of ORs relating variables to chronic HBV, where there was adjustment for age or sex at a minimum. Since most of the studies reported ORs, we treated the risk ratios reported in two studies 8,28 as ORs given the relatively low prevalence of HBsAg. 29 Meta-analysis was not performed if (1) the requisite number of studies (≥3 studies) was not met, and/or (2) categories of a factor were not comparable among studies.
Fixed effect meta-analysis using the inverse-variance weighted method was conducted. Heterogeneity between study subgroups was assessed using Cochrane's Q test of heterogeneity and the I 2 statistic. In meta-analysis of studies reporting HBsAg prevalence, the parameter estimate was pooled HBsAg prevalence with 95% confidence interval (CI), while for meta-analysis of studies reporting ORs, the parameter estimate was pooled OR (pOR) and 95% CI. In the presence of moderate heterogeneity (I 2 ≥ 50%), random effects meta-analysis was also conducted. Publication bias was assessed by visual inspection of funnel plots and Egger's test if at least 10 studies reported a risk factor. 30  north-eastern; south; western; nationwide) and study quality (poor; fair; good) was performed. Sensitivity analyses excluding 'poor' quality studies were conducted. The significance threshold was p < .05 and meta-analysis were conducted using R version 4.1.0 using the 'meta' package.

| Selection and study characteristics
A total of 6944 articles were identified in the initial search. Following removal of duplicates along with title and abstract screening, fulltext assessment of 264 articles was completed (eTable 5), resulting in 39 articles ( Figure 1) being included in the systematic review. Of these 39 articles (see Table 1 Where possible mean and SD reported, otherwise age-range provided. b In overall population aged 1-70 years.

TA B L E 1 (Continued)
TA B L E 2 Modified Newcastle-Ottawa quality assessment of included studies. a

Individual criterion
Overall domain

| Quality assessment
Overall, 13, 22, and 4 of the 39 included studies were assessed as 'good', 'fair', and 'poor' quality, respectively ( Table 2). The most frequent limitation was in the 'selection' domain in the 'nonrespondents' criteria, whereby one-third of studies did not report information about non-respondents or provide a response rate. The most common method of recruitment was stratified multi-cluster sampling (71.8%, n = 28) and most studies (74.4%, n = 29) used interviewer administered questionnaires to assess baseline factors, while six used self-administered questionnaires, 9,17,[33][34][35][36] two used hospital records 8,37 and two did not report the method used. 18

| Chronic HBV correlates
Overall

| Sociodemographic factors
3  Colours for overall rating are green (good), yellow (fair) and red (poor).

TA B L E 2 (Continued)
p < .01) ( Table 3). Meta-analysis of ORs were not performed due to insufficient number of studies reporting this.

| Ethnicity
In eight studies reporting ethnicity, 7

| Income
Of three studies reporting income, two 35,48 found higher income was inversely correlated with chronic HBV, while one found no difference by income level. 46 One study 48 compared participants reporting income of <50,000, 50-100,000, ≥100,000 RMB/year with HBsAg prevalence of 4.1%, 3.2% and 2.8% respectively, while another study 25 found those in the lower income group (<2000 RMB/ month) had a 23% (95% CI 8%-42%) higher relative risk of chronic HBV than the higher income group (≥2000 RMB/month). In another study 46 there was no significant difference in HBsAg prevalence between participants earning <800 and ≥800 RMB/year. Metaanalysis was not performed due to insufficient number of studies reporting either HBsAg prevalence or ORs.

| Alcohol
Alcohol intake was reported in five studies, 8

TA B L E 3 (Continued)
F I G U R E 3 (A-I) Meta-analysis of odds ratios for baseline correlates and chronic HBV.

| Smoking
Smoking was reported in four studies 8,39,46,52 where all reported higher HBsAg prevalence in smokers compared to non-smokers.

| Tattooing
Three of four 18,28,35,43 studies reporting tattooing found no significant association between tattooing and chronic HBV, where history of tattooing varied between 6.3% 28 to 33.2% 18 of participants.

| Piercing
Of three studies 28,35,43 that investigated piercing, all found there was no significant association with chronic HBV. Piercing was relatively common, reported in 24.9% 28 and 77.3% 35 of participants. One 43 study reported piercing compared to no piercing was associated with a non-significant decrease in chronic HBV while two 28,35 found a nonsignificant increase. Meta-analysis was not performed due to insufficient number of studies reporting either HBsAg prevalence or ORs.

| Sharing syringes
Of five studies reporting sharing syringes, 18,28,41,43,48 the frequency of sharing syringes was reported in two studies at 1.2% 18 and 17.7% 28 of the total study population. All five studies found greater chronic HBV risk among those reporting shared syringe-use, remaining significant after multivariable adjustment in two studies. 43,48 These latter studies reported a higher odds of chronic HBV of 28% (95% CI 3%-57%) 48 and 44% (95% CI 12%-86%) 43 in participants reporting sharing syringes compared to those not. One study reported a nonsignificant association with chronic HBV after multivariable adjustment, 41 while a further study 28 with an unreported adjustment level reported an OR of 2.07 (95% CI 1.26-3.41). Meta-analysis was not performed due to insufficient number of studies reporting either HBsAg prevalence or ORs.

| Household HBsAg positive contact
Seven studies 18,21,42,48,49,54 reported a positive correlation between chronic HBV and having a household HBsAg positive contact.

| Dental therapy
Of five studies 18,28,35,43,49 reporting dental therapy in relation to chronic HBV, none found an association with chronic HBV. Dental therapy was relatively common, reported in 20.3% 49  in those those with and without a history of dental therapy, respectively (Test for subgroup differences: χ 2 = 6.6, df = 1, p = .01) (

| Publication bias, heterogeneity and sensitivity analyses
Funnel plots (eFigure 1) for did not demonstrate obvious asymmetry, other than for household contact. This may reflect geographic vari-  including sexual practices and injecting drug use (IDU). Although we found sharing syringes to be correlated with chronic HBV, IDU was not explicitly explored, and factors related to sexual practices were not included in this review due to lack of studies reporting this. The

Thank you to Nuffield Department Population Health librarian Nia
Roberts who assisted with development of the search strategy.

CO N FLI C T O F I NTE R E S T S TATE M E NT
None of the authors have any conflicts of interest in relation to this report.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data used is publicly available from respective studies.