Unveiling the silent epidemic: Global prevalence of occult HBV infection in children, adolescents and adults

Introduction

Hepatitis B virus (HBV) is a DNA hepadnavirus causing hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite immunization and antiviral therapy, HBV infection remains a global health concern. In 2019, the World Health Organization reported 296 million individuals with chronic HBV infection and an additional 6 million HBV cases in children under five years old.

Occult HBV infection (OBI) is characterized by HBV DNA presence in individuals who test negative for HBsAg. Mutations in the pre-S/S region can lead to false-negative HBsAg results. OBI can be seropositive (anti-HBc and/or anti-HBs antibodies positive) or seronegative (negative for both antibodies). OBI shares oncogenic properties with HBV and can progress to HCC in adults. Transmission risk is higher in hyper-endemic HBV regions, and children born to OBI or HBV-infected mothers are at risk.

Despite concerns, OBI lacks attention in the global hepatitis elimination agenda. This study aims to determine OBI prevalence worldwide across age groups, including children, adolescents, and adults.

Materials and Methods

A comprehensive search was conducted across multiple databases, including PubMed, Embase, Web of Science, Global Health, and Cochrane, to identify relevant studies investigating the prevalence of OBI in children, adolescents, and adults. The search encompassed articles published in any language between 2010 and 2019. Original articles and conference abstracts of any study design were considered eligible if they provided data on the proportion of individuals who tested negative for HBsAg (hepatitis B surface antigen) but were positive for HBV DNA, indicating the presence of occult HBV infection. The prevalence of OBI was then analyzed both within the general population and within specific groups, such as blood donors, low-risk populations, high-risk populations, and individuals with advanced chronic liver disease. Additionally, the data were stratified based on the HBV endemicity observed in each country.

Statistical analysis

The data was entered into Microsoft Excel 2019 v16.0 for initial processing, and the statistical analysis was performed using R software version 4.3.3 in RStudio (2024). Descriptive analysis was conducted to calculate summary statistics such as median, interquartile range (IQR), frequencies, and proportions of the variables. To compare the prevalence of OBI among children, adolescents, and adults across different countries and continents, Wilcoxon’s rank sum test and Kruskal Wallis test were used. Post hoc analysis was performed using the Dunn’s test. The geospatial map was generated using the leaflet package. All statistical tests were two-sided, and p-values less than 0.05 were considered statistically significant.

Results

Dataset

Geospatial mapping of occult HBV infection studies

To access the study characteristics and findings, you can interact with the map by clicking on the coloured circles. Each circle represents a specific study and provides valuable information when clicked upon. This feature allows users to delve into the details of each study by exploring its unique findings and characteristics. In case you wish to explore data from other countries or revert to the initial map view, you can simply utilize the “reset view” option located below the zoom controls (+ and -). By clicking on this option, the map will return to its original state, enabling you to easily navigate and examine data from different countries.

This user-friendly functionality enhances the user experience by providing a convenient way to access and analyse study-specific information while maintaining the flexibility to explore data from various regions on the map.

Table 1: Characteristic of the studies used in the analysis stratified by population group between 2010 and 2019

Characteristic Overall, N = 4921 Population Group
Adults, N = 437 (89%)1 Children and adolescents, N = 55 (11%)1
Continent


    Africa 71 (14.4) 58 (13.3) 13 (23.6)
    Americas 57 (11.6) 53 (12.1) 4 (7.3)
    Asia 270 (54.9) 242 (55.4) 28 (50.9)
    Europe 89 (18.1) 79 (18.1) 10 (18.2)
    Oceania 5 (1.0) 5 (1.1) 0 (0.0)
Sample size 274 (100, 1,784) 322 (106, 3,417) 99 (44, 253)
    (Missing data) 34 34 0
No of HBsAg negative cases 326 (105, 16,796) 326 (105, 16,796) NA (NA, NA)
    (Missing data) 55 0 55
No of HBsAg positive cases 189 (66, 2,031) 189 (66, 2,031) NA (NA, NA)
    (Missing data) 55 0 55
Total OBI 12 (3, 31) 12 (3, 31) NA (NA, NA)
    (Missing data) 55 0 55
OBI prevalence 3 (0, 15) 3 (0, 15) 5 (0, 12)
1 n (%); Median (IQR)

Table 2: Characteristic of the studies used in the analysis stratified by continent between 2010 and 2019

Characteristic Continent
Africa, N = 71 (14%)1 Americas, N = 57 (12%)1 Asia, N = 270 (55%)1 Europe, N = 89 (18%)1 Oceania, N = 5 (1.0%)1
Population group




    Adults 58 (81.7) 53 (93.0) 242 (89.6) 79 (88.8) 5 (100.0)
    Children and adolescents 13 (18.3) 4 (7.0) 28 (10.4) 10 (11.2) 0 (0.0)
Sample size 111 (60, 314) 301 (91, 534) 373 (121, 3,058) 278 (63, 89,163) 421,272 (152,961, 10,981,776)
    (Missing data) 1 8 14 11 0
No of HBsAg negative cases 149 (78, 370) 158 (100, 517) 500 (121, 14,755) 733 (89, 293,923) 421,209 (152,838, 10,973,148)
    (Missing data) 13 4 28 10 0
No of HBsAg positive cases 97 (41, 269) 149 (45, 207) 254 (91, 2,031) 326 (67, 293,923) 421,209 (152,838, 10,973,148)
    (Missing data) 13 4 28 10 0
Total OBI 17 (7, 23) 3 (0, 15) 13 (3, 46) 12 (4, 30) 15 (5, 583)
    (Missing data) 13 4 28 10 0
OBI prevalence 17 (6, 28) 3 (0, 11) 3 (0, 12) 0 (0, 7) 0 (0, 0)
1 n (%); Median (IQR)

Distribution of the 15 most frequent countries with studies on occult HBV infection between 2010 and 2019

This study examined the distribution of studies on occult HBV infection across various countries. The analysis aimed to determine the frequency of studies conducted in different geographical regions.

The findings depict the distribution of the 15 most frequent countries with studies on occult HBV infection. Among these countries, China exhibited the highest frequency of occurrences, with 90 studies (18.29%). Iran followed with 42 studies (8.54%), while Spain had the least frequency among the top 15 countries, with only 7 studies (1.42%). The total number of studies for these countries amounted to 366 out of 492, indicating their significant contribution to the body of research on occult HBV infection.

Serological patterns observed in the study population for the criteria to test for occult HBV infection between 2010 and 2019

The serological patterns described in this study were observed in a collection of studies conducted in diverse countries. The data obtained from these studies provide information into the distribution of serological markers within the study populations.

Among the individuals included in the analysis, the majority (352, 71.54%) were found to be negative for HBsAg, This serological pattern was consistently observed across the different countries included in the study. A significant proportion of the cohort (84, 17.07%) demonstrated HBsAg negativity but tested positive for anti-HBc, suggesting a previous HBV infection or a potential “window” phase of acute infection where the surface antigen is not detectable. This serological pattern was consistently identified across the studies conducted in various countries. Other serological patterns encompassing various combinations of HBsAg, anti-HBc, and anti-HBs positivity and negativity were identified but at lower frequencies, each accounting for less than 5% of the study population. These patterns were also observed across the studies conducted in different countries, albeit with lower frequency

Participant study characteristics between 2010 and 2019

During the period from 2010 to 2019, the study cohort comprised various participant groups with distinct characteristics. The largest group within the cohort was blood donors, accounting for 183 studies (37.2%). Following this, individuals without liver disease constituted 67 studies (13.62%). The third most prevalent category consisted of haemodialysis patients, who were the focus of 38 studies (7.72%). Participants with liver impairment were represented in 27 studies (5.49%), while individuals diagnosed with hepatocellular carcinoma (HCC) were the subject of 26 studies (5.28%). It is worth noting that 23 studies (4.67%) centered on patients who tested positive for hepatitis C virus (HCV).

The general population was examined in 21 studies (4.27%), while HIV-positive patients were the focus of 17 observations (3.46%). Studies involving haematology patients accounted for 16 studies (3.25%), and individuals born to mothers positive for hepatitis B surface antigen (HBsAg) were observed in 12 studies (2.44%). Among the participant groups, cirrhotic patients with other etiologies and healthcare workers were each the subject of 8 studies (1.63%). The least frequently studied categories included individuals born to mothers with chronic hepatitis B virus (HBV) infection, with 5 studies (1.02%), pregnant women, with 3 studies (0.61%), and individuals born to mothers positive/non-positive for HBV, with 2 studies (0.41%).

These findings provide valuable insights into the distribution and prevalence of participant characteristics within the study cohort, as observed across multiple countries.

Distribution of population group by continent between 2010 and 2019

The total number of studies across all continents was 492. The graphs indicate a higher number of studies involving adults in Asia followed by Europe and a notable proportion of studies involving children and adolescents in Asia, Africa and Europe. Oceania has studies exclusively involving adults, with no data for children and adolescents.

Distribution of participant study characteristics by continent between 2010 and 2019

The bar chart and accompanying proportions panel provide a comparative overview of the distribution of various patient characteristics across continents, as observed in studies conducted in multiple continents. The proportions panel further elucidates the distribution of these characteristics as a percentage of the total observations for each continent. It is evident that Asia, has a higher proportion of individuals across most medical categories, with particularly high percentages in general population (71.4%), liver impairment (66.7%) and haemodialysis patients (65.8%). Africa, has the highest proportion of HIV positive patients (35.3%) and HCV positive patients (34.8%). Notably, the studies (n = 5) conducted in Oceania, only focused on blood donors.

These findings, suggest a varied distribution of patient characteristics across continents, with Asia showing a higher frequency in several categories.

Prevalence of OBI by continent between 2010 and 2019

The prevalence of occult HBV infection (OBI) was examined across continents using data derived from studies conducted in various countries. The Kruskal-Wallis test revealed a significant difference in OBI prevalence among the continents (χ² = 50.18, p < 0.001, η² = 0.10, CI95% [0.07, 1.00], n = 492). Pairwise comparisons showed significant differences between several pairs of continents, with the highest median OBI prevalence observed in Africa (16.80%) and the lowest in Oceania (0.00%). The Americas and Asia also displayed relatively higher medians (3.30% and 2.60%, respectively) compared to Europe and Oceania, both with medians of 0.00%. The adjusted p-values indicate significant differences between the distributions of OBI prevalence across the compared continents.

These findings, suggest a varied pattern of OBI prevalence across continents, with Africa showing a notably higher median prevalence.

Comparison of OBI prevalence among adults and children/adolescents in various continents between 2010 and 2019

For adults (number of studies = 437), the median prevalence of OBI exhibits significant variation across continents, with the highest median reported in Africa (16.10%) and the lowest in Europe and Asia (both 0.00%). The Kruskal-Wallis test indicates a significant difference in OBI prevalence distributions across continents, with a small effect size (0.09). Pairwise comparisons conducted with adjusted p-values reveal significant differences between certain continents.

Similarly, for children and adolescents (number of studies = 55), the median OBI prevalence demonstrates considerable variation, with the highest median observed in Africa (23.10%) followed by the Americas (6.65%) and the lowest in Europe (0.00%). The Kruskal-Wallis test confirms significant differences in OBI prevalence distributions across continents, with a small effect size (0.28). Pairwise comparisons, supported by adjusted p-values, indicate significant differences between specific continents.

These findings, suggest a heterogeneous distribution of OBI prevalence across continents for both adults and children/adolescents. The observed significant disparities in pairwise comparisons further emphasize the varying OBI prevalence among these population groups across continents.

Prevalence of OBI across various African countries between 2010 and 2019

The prevalence of OBI was examined across 15 African countries, based on data derived from studies conducted in the region. The dot plot visually represents the range of OBI prevalence observed in these countries, with a median prevalence of 14.14%. Statistical analysis using the Wilcoxon rank biserial correlation indicates a statistically significant association (p < 0.001), suggesting a non-random distribution of OBI prevalence across the countries. The data points in the scatter plot are dispersed on either side of the median line, indicating the variability in OBI prevalence within the continent.

Comparison of OBI prevalence among adults and children/adolescents in various African countries between 2010 and 2019

The prevalence of OBI was compared among adults and children/adolescents across sampled African countries, based on data derived from studies conducted in Africa.

For adults (number of studies = 13), the median OBI prevalence is reported as 15.00%, with a statistically significant Wilcoxon test result (p < 0.001), suggesting a non-random distribution of OBI prevalence rates among the sampled African countries. The rank biserial correlation of 1.00 is reported, indicating a perfect correlation. However, it is important to interpret this value with caution due to the small sample size and the nature of the test.

In contrast, for children and adolescents (number of studies = 5), the median OBI prevalence is lower at 11.80%, and the Wilcoxon test result is not statistically significant (p = 0.10), indicating no strong evidence against the null hypothesis of a random distribution of OBI prevalence rates among the sampled African countries. The rank biserial correlation is also reported as 1.00; however, similar to the adult category, caution should be exercised in interpreting this value due to the small sample size.

These findings, highlight the heterogeneity in OBI prevalence among the different African countries examined. The statistically significant result in the adult category suggests a more distinct pattern of OBI prevalence across these African countries, whereas the prevalence among children and adolescents does not exhibit a strong pattern. It is important to note that the small sample size and other limitations may impact the generalizability of these findings.

Prevalence of OBI across various American countries between 2010 and 2019

The dot plot demonstrates a distribution of OBI prevalence among the American countries studied. The Wilcoxon rank-sum test yields a value of 28.00 with a p-value of 0.02, suggesting a statistically significant difference in the Willcox scores between the countries. This suggests that there are variations in OBI prevalence among the American countries included in the study.

The rank-biserial correlation coefficient of -1.00 indicates a perfect negative association, which may reflect an inverse relationship when considering the ranks of the data points. The median Willcox score is 5.25, as shown by the dashed blue line. The confidence interval for the rank-biserial correlation is tightly fixed at [1.00, 1.00], reinforcing the strong negative association. The analysis includes a total of seven observations, corresponding to the seven countries represented in the plot.

Comparison of OBI prevalence among adults and children/adolescents in various American countries between 2010 and 2019

Comparing the prevalence of occult HBV infection (OBI) between adults and children/adolescents in different American countries, two dot plots were analyzed.

For adults (number of studies = 5), the median OBI prevalence was 5.50%, with countries including Mexico, USA, Canada, Brazil, and Argentina. Though prevalence varied (below 10% to around 30%), statistical analysis didn’t show a significant difference (p = 0.06). The rank-biserial correlation coefficient was 1.00, indicating a perfect correlation between country ranks and prevalence values. However, the limited number of studies (n = 5) may affect the robustness of these findings.

In the children/adolescents (number of studies = 4), the median OBI prevalence was 6.65%, with countries like Brazil, Colombia, Canada, and Cuba. Prevalence varied similarly (below 10% to around 30%), and statistical analysis also didn’t show a significant difference (p = 0.10). The rank-biserial correlation coefficient was 1.00. However, the number of studies was limited (n = 4), potentially affecting generalizability.

The findings, suggest comparable OBI prevalence among sampled American countries in both adults and children/adolescents, with no significant differences observed. However, the limited number of studies and small sample sizes may impact the reliability and generalizability of these findings. Further research with larger studies is needed to enhance understanding of OBI prevalence in American countries.

Prevalence of OBI across various Asian countries between 2010 and 2019

A dot plot was used to visualize the distribution of OBI prevalence, with each country represented as a data point. The median OBI prevalence was found to be 6.45%. The findings, highlight the significant variation in OBI prevalence among the countries studied. The strong negative correlation and statistically significant results underscore the importance of further investigation into the factors influencing OBI prevalence.

Comparison of OBI prevalence among adults and children and adolescents in various Asian countries between 2010 and 2019

The dot plots illustrate the prevalence of OBI across various countries, segregated into two categories: adults and children/adolescents. The number of studies for adults is 25, while for children and adolescents, is 7, indicating a smaller sample size for the latter group. For adults, the median OBI prevalence is 8.29%, with values ranging approximately from below 10% to 50%. Yemen exhibits the highest prevalence among the countries displayed, while Jordan shows the lowest. The Wilcoxon signed-rank test indicates a statistically significant difference in OBI prevalence among the countries (V = 276.00, p < 0.001).

In the children and adolescents, the median OBI prevalence is 5.60%, with a narrower range than adults, extending from near 0% to about 20%. India shows the highest prevalence, whereas Japan has the lowest among the listed countries. The Wilcoxon signed-rank test for this category suggests a non-significant difference in OBI prevalence (V = 15.00, p = 0.06).

The findings, suggest significant variation in OBI prevalence among adults across the Asian countries examined. However, the variation among children and adolescents is less pronounced and not statistically significant.

Prevalence of OBI across various European countries between 2010 and 2019

A dot plot was used to visualize the distribution of OBI prevalence, with each country represented as a data point. The median OBI prevalence was found to be 0.69% with Ukraine and Bulgaria showing the the highest OBI prevalence at 35% and 28%, respectively. The findings, suggest a significant variation in OBI prevalence across European countries.

Comparison of OBI prevalence among adults and children and adolescents in various European countries between 2010 and 2019

The analysis compared the prevalence of OBI among adults and children/adolescents in various European countries. For adults, the OBI prevalence ranged from 0% to over 30%, with a median prevalence of 0.79%. A Wilcoxon signed-rank test indicated a statistically significant difference in OBI prevalence among countries (V = 66.00, p < 0.001). The number of studies was 18, with a rank biserial correlation coefficient of 1.00.

In children and adolescents, the OBI prevalence ranged from 0% to around 6%, with a median prevalence of 0.00%. The Wilcoxon signed-rank test showed no statistically significant difference in OBI prevalence among countries (V = 6.00, p = 0.18). The number of studies for this group was 10, with a rank biserial correlation coefficient of 1.00.

The findings, suggest significant variation in OBI prevalence among adults across European countries, while the variation among children and adolescents is less pronounced and not statistically significant.

Concluding remarks

Occult HBV infection is a significant global health concern. This analysis of 492 studies revealed varying prevalence rates across different populations of the world. However, due to limited studies targeting the general population and regional data over-representation, accurately estimating global prevalence remains challenging. Nonetheless, OBI is common, particularly in high-endemicity countries and high-risk groups, and carries clinical and economic implications due to its potential for transmission and increased hepatocellular carcinoma risk. The prevalence is higher in children born to HBsAg-positive mothers and HIV-infected individuals. Current global guidance on viral hepatitis testing and elimination lacks sufficient consideration of OBI. Improved access to diagnosis, population-based serosurveys, and prospective studies are needed. The inclusion of occult HBV infection in HBV elimination efforts is crucial. However, the high cost and limited availability of testing pose challenges, especially in resource-limited, highly endemic regions.

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