Prevalence and burden of HBV co‐infection among people living with HIV: A global systematic review and meta‐analysis

Abstract Globally, in 2017 35 million people were living with HIV (PLHIV) and 257 million had chronic HBV infection (HBsAg positive). The extent of HIV‐HBsAg co‐infection is unknown. We undertook a systematic review to estimate the global burden of HBsAg co‐infection in PLHIV. We searched MEDLINE, Embase and other databases for published studies (2002‐2018) measuring prevalence of HBsAg among PLHIV. The review was registered with PROSPERO (#CRD42019123388). Populations were categorized by HIV‐exposure category. The global burden of co‐infection was estimated by applying regional co‐infection prevalence estimates to UNAIDS estimates of PLHIV. We conducted a meta‐analysis to estimate the odds of HBsAg among PLHIV compared to HIV‐negative individuals. We identified 506 estimates (475 studies) of HIV‐HBsAg co‐infection prevalence from 80/195 (41.0%) countries. Globally, the prevalence of HIV‐HBsAg co‐infection is 7.6% (IQR 5.6%‐12.1%) in PLHIV, or 2.7 million HIV‐HBsAg co‐infections (IQR 2.0‐4.2). The greatest burden (69% of cases; 1.9 million) is in sub‐Saharan Africa. Globally, there was little difference in prevalence of HIV‐HBsAg co‐infection by population group (approximately 6%‐7%), but it was slightly higher among people who inject drugs (11.8% IQR 6.0%‐16.9%). Odds of HBsAg infection were 1.4 times higher among PLHIV compared to HIV‐negative individuals. There is therefore, a high global burden of HIV‐HBsAg co‐infection, especially in sub‐Saharan Africa. Key prevention strategies include infant HBV vaccination, including a timely birth‐dose. Findings also highlight the importance of targeting PLHIV, especially high‐risk groups for testing, catch‐up HBV vaccination and other preventative interventions. The global scale‐up of antiretroviral therapy (ART) for PLHIV using a tenofovir‐based ART regimen provides an opportunity to simultaneously treat those with HBV co‐infection, and in pregnant women to also reduce mother‐to‐child transmission of HBV alongside HIV.


| INTRODUC TI ON
Chronic hepatitis B (CHB) infection, defined as persistence of hepatitis B surface antigen (HBsAg), is a major public health problem resulting in an estimated 900 000 deaths in 2015. [1][2][3][4] Although HBV can be prevented with vaccination, in 2015, there were an estimated 257 million persons chronically infected. 4 Between 20 and 30% of those with chronic infection develop complications, mainly cirrhosis and hepatocellular carcinoma (HCC). 5 CHB accounts for 43% of cases of HCC and 40% of cirrhosis, with much higher proportions in lower middle-income countries, 4 and 5%-10% of liver transplants in high-income countries. 6 Age is a key determinant of the risk of chronic infection: chronicity is common following acute infection in neonates (around 90%) and young children under the age of 5 years (20-60%), but occurs rarely (<5%) when infection is acquired in adulthood. 7,8 Worldwide, most persons with CHB were infected at birth or in early childhood. 9 The highest prevalence of HBsAg (>5%) is in sub-Saharan Africa, East Asia, parts of Balkans, the Pacific Islands and the Amazon Basin. 10 Regional variation exists in the epidemiology of HBV: perinatal or horizontal transmission predominates in sub-Saharan Africa and Asia, whereas in high-income countries transmission is predominantly via injection drug use and high-risk sexual behaviours. 9,11 As PLHIV live longer due to increased access to antiretroviral therapies, liver disease has emerged as a leading cause of death in PLHIV co-infected with HBV or HCV. 12,13 Among people with HBsAg, co-infection with HIV results in higher rates of chronicity and occult HBV (HBV-DNA positivity in the absence of HBsAg), accelerated liver disease progression, higher liver-related mortality and decreased treatment response. 14-17 Co-infection with CHB also increases risk of hepatotoxicity from antiretroviral therapy (ART) three-to five-fold, 18,19 and cross-resistance between HIV and HBV drugs is common. 20,21 Fortunately, tenofovir, a drug commonly included in ART regimens, is also the most effective drug for longterm treatment of HBV, leading to long-term HBV viral suppression, reversal of cirrhosis and fibrosis, and reduction in HBV-related mortality. 22 There is a need to establish the global burden of HBsAg co-infection among PLHIV, to characterize the most affected populations and geographical regions, and to inform national and regional screening programmes and clinical management. However, to date, no review has estimated the global burden of HBV co-infection among PLHIV.
Existing estimates suggest approximately 10% of PLHIV have chronic hepatitis B or 2-4 million people, but were based on small numbers of studies with unclear methodology. 17,23,24 Other reviews have focussed on specific regions 25 or people who inject drugs (PWID). 11,26 We therefore undertook a global systematic review of the prevalence and burden of HBsAg in PLHIV.

| Search strategy and selection criteria
The systematic review was conducted alongside a companion review examining prevalence and burden of HIV-HCV antibody co-infection (consistent with current or past infection) which contains detailed description of the search and synthesis methods. 27 The review was registered with the PROSPERO prospective register of systematic reviews (CRD42019123388).
In brief, we searched eight databases for material that reported and 'prevalen* OR inciden* OR seroprevalen* OR screening OR surveillance OR population* OR survey* OR epidem* OR data collection OR population sample* OR community survey* OR cohort OR cross-sectional OR longitud* OR follow-up'. Searches were tailored to the search functionality of each database. The reference lists of articles identified as reviews were screened for additional relevant sources.
We included papers with country-level estimates of HBsAg co-infection among an HIV population sample greater than 50, recruited based on their HIV-positive status or other behavioural characteristics, such as injecting drug use. We excluded editorials or reviews containing no primary data, samples recruited based on their HBsAg status or HIV-HBsAg-positive status; studies based on self-reported HIV or HBsAg status, hospital-based studies, or in healthcare workers, organ or tissue donors, or from populations with other co-morbidities such as persons with TB or mental illness, or undergoing interventions that put them at greater risk of co-infection, including those receiving haemodialysis, those with haemophilia, cancer, cardiovascular disease, other co-infections, kidney, liver or neurological diseases.

| Screening and data extraction
Six reviewers (CF, CM, BM, AT, JS and JO) screened each record with a seventh reviewer (LP) consulted when there was no consensus.
Data extracted included the following: study methods; field-work dates; population; recruitment site; sample size; diagnostic assays

| Quality assessment
To address concerns of variable quality of studies in previous reviews, we assessed and rated the quality of included studies based on study design and assay quality (Supporting information S1). Studies with larger sample sizes, recruited from multiple sites, recording age and sex or HIV risk factors were scored higher (A); studies with >200 cases from >1 site, with some HIV risk factors recorded but not designed to measure prevalence was scored lower (B); and studies with <200 case from a single site with no risk factors recorded were scored lowest (C). HBsAg assay methods were rated from 0 where no assay type was specified, to up to 3 where a second confirmatory HBsAg assay was done, with or without a neutralisation step. Best estimates were selected for each population group per country based on the highest assay and study design score. Where multiple estimates were available, we applied decision rules to select the best estimate (Supporting information S1).

Burden of Disease region
Countries were initially grouped according to the 21 Global Burden of Disease regions, and these were then combined into ten regions to be consistent with previous published reviews on HIV, HBsAg and HCV burden. 11,27,29

| Definition of Population groups
We extracted data on risk behaviours associated with HIV and HBV transmission and populations were categorized according to their main HIV-exposure categories. A general population sample was considered to be low-risk and included samples of blood donors (unpaid), ante-natal clinic attendees or general population and household surveys not recruited based on HIV-positive status. Samples of PLHIV reporting heterosexual transmission as the main risk factor and HIV-positive pregnant women were grouped together. We categorized study populations as PWID when >75% of the sample had current or past experience of injecting, and as men who have sex with men (MSM) when >50% reported main HIV exposure to be sex with men. The PWID and MSM population categories included studies of both known PLHIV as well as populations recruited based on their risk behaviour but where HIV testing was also done. Two other population groups included the following: high-risk populations (PLHIV reporting any injecting drug use or sex between men (but ≤75% of the sample for PWID and ≤50% for MSM), sex workers; prison inmates, non-injecting drug users, STI clinic attendees or a mixed population engaging in sexual and/ or injecting risk behaviours but with ≤75% of the sample injecting); and children and young people (aged between two months and 17 years).

| Data synthesis
We report HIV-HBsAg co-infection prevalence among six popu-

| Role of the funding source
The WHO commissioned this review for the purpose of informing the update of the WHO guidelines on testing for viral hepatitis. 22,23 The funder contributed to the data collection, analysis, interpretation and writing of the review. All authors had full access to the study data and share final responsibility for the findings submitted for publication. The full dataset and statistical source code used to generate estimates and select best estimates is available from the corresponding author on request.

| General population samples
The mid-point prevalence of HBsAg co-infection among 45 general population samples testing positive for HIV was 7.4% (IQR 1.4%-15.7%) with country-level prevalence estimates shown in Figure 2A.

| Heterosexual and pregnant women
The mid-point prevalence of HBsAg co-infection among 90 studies in PLHIV heterosexual or pregnant women was 6.1% (IQR 3.4%-11.0%) with country-level prevalence estimates shown in Figure 2B.  Table 1 for country-specific estimates).

| People who inject drugs
The mid-point prevalence among PWID based on 36 studies was 11.8% (IQR 6.0%-16.9%) with country-level prevalence estimates shown in Figure 2C.

| Men who have sex with men
The mid-point prevalence among MSM was 6.1% (IQR 5.0%-9.2%) based on 70 studies with country-level prevalence estimates shown in Figure 2D. Prevalence was highest in South and South-East Asia (10.6%), West and Central Africa (9.2%, one study), followed by East

| Other high-risk groups
In addition to the main HIV-exposure categories, there were 243 estimates from samples of PLHIV engaging in mixed sexual and/or injecting risk behaviours (Table S3) with country-level prevalence estimates shown in Figure 2E. The point prevalence was 6.4% (IQR 4.3%-9.6%) and was similar across the regions, except for East Asia (15.6%), and West and Central Africa (10.6%).

| Children and young people
There were 22 estimates of HIV-HBsAg co-infection among children and young people from 13 countries ( HIV-exposure categories were not consistently reported.

| Odds of HBsAg positivity among PLHIV compared to HIV-negative persons
Overall 95% CI 0.71-10.25), but not with other population groups. This is summarized in Figure 3 and Table S4. and Latin America (6%). All other regions account for <5% each (Table 2).

| D ISCUSS I ON
This is the first systematic review to provide global, regional and HBsAg prevalence was broadly similar across different HIVpositive population groups, with a prevalence of 6%-7% reported among general population samples, heterosexually exposed or pregnant women, children, MSM and high-risk populations. Only among PWID was prevalence higher at 11.8%. PWID accounted for only 3% of the global co-infected population, but a much higher proportion in Eastern Europe (45% of cases). We were limited in our ability to make regional comparisons across sub-populations  Median prevalence and IQRs are calculated across the best estimates for all population groups (except PWID estimates) and countries in each region (for regional estimates) or globally (for 'Total' estimates).
c Proportion of HIV cases among PWID. d No regional estimate available, so global median used as a proxy.
e Only one country estimate available, therefore no IQR presented.
f Median prevalence and IQRs are calculated across the best PWID estimates for each country in each region (for regional estimates) or globally (for 'Total' estimates) co-infection. Despite this, estimates were available for only 41% of countries, half being in sub-Saharan Africa. Five regional prevalence estimates for different sub-populations were based on data from a single country, possibly unrepresentative of the true regional profile.
Few countries had data for all sub-populations making regional comparisons difficult. We excluded studies that only presented regional-level data, not disaggregated by country, to enable us to observe how prevalence varied by country and risk group within a region and to take account of the differing epidemiology of HIV at a country level.
However, this resulted in the exclusion of large cohorts that aggregate across country and region. One major cohort that reports data across Europe, Israel and Argentina found a comparable prevalence of HIV-HBsAg co-infection (7.1%-8.7%) with similar high prevalence observed in Argentina among PLHIV (exposure group not specified) to the range of prevalence we found among MSM. 61,62 The quality of studies was also variable. with 60% of persons on ART receiving a tenofovir-based regimen. 67 Our findings clearly show the need to scale-up tenofovir-based ART to address HIV-HBsAg co-infection, particularly focusing on sub-Saharan Africa.

ACK N OWLED G EM ENTS
The authors wish to thank Jane Falconer (Information Services Librarian at the LSHTM) for her assistance with the search strategy and Yvan Hutin for inputs on the manuscript.

CO N FLI C T S O F I NTE R E S T
No conflicts of interest to declare.

AUTH O R CO NTR I B UTO R S
PE conceived the study proposal. LP, PV and PE developed the overall methods for use in the report. LP developed the methodology and oversaw the search and data extraction for the report.

D I SCL A I M ER
The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated, including UNAIDS and the WHO.