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Abstract
Objective Sub-Saharan Africa is one of the regions with the highest burdens of HIV and hepatitis B virus (HBV), but data on the impact of antiretroviral therapy (ART) on HBV DNA suppression is limited. In this study, we aimed to determine the prevalence and associated factors of a positive hepatitis B surface antigen (HBsAg) among people living with HIV, and assess the suppression of ART on HBV replication in people living with HIV in Sierra Leone.
Methods A cross-sectional study was designed to recruit people living with HIV aged 18 years or older in ten public hospitals in Sierra Leone between August 2022 and January 2023. Statistical analyses were performed using R software. Logistic regression analysis was used to assess factors independently associated with positive HBsAg and HBV DNA suppression.
Results Of the 3106 people living with HIV recruited in this study, 2311 (74.4%) were women. The median age was 36 years, 166 (5.3%) had serological evidence of HBV vaccination. The overall prevalence of HBsAg positivity was 12.0% (95% CI: 10.9% to 13.2%). Male sex (adjusted OR (aOR) 2.11, 95% CI: 1.67 to 2.68; p<0.001) and being separated (aOR 1.83, 95% CI: 1.06 to 3.16, p=0.031; reference group: being married) were independent predictors of HBsAg seropositivity. Among 331 people living with HIV and HBV receiving ART, 242 (73.1%) achieved HBV DNA suppression (below 20 IU/mL). HBV suppression rate was higher in HIV-virally suppressed patients than those with unsuppressed HIV viral load (p<0.001). In addition, the male sex was more likely to have unsuppressed HBV DNA (aOR 1.17, 95% CI: 1.17 to 3.21; p=0.010).
Conclusions We reported a high prevalence of HBsAg seropositivity and low HBV immunisation coverage in people living with HIV in Sierra Leone. In addition, we observed that ART can efficiently result in a viral suppression rate of HBV infection. Therefore, achieving the global target of eliminating HBV infection by 2030 requires accelerated access to care for people living with HIV and HBV, including HBV testing, antiviral treatment and hepatitis B vaccination.
- HEPATITIS B
- Anti-HIV Agents
- HIV Infections
- Viral Load
Data availability statement
Data are available upon reasonable request. The data for this study is available at Fifth Medical Centre of PLA General Hospital, Beijing, China, and Ministry of Health of Sierra Leone and will be made available upon request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Only two small studies reported the prevalence of hepatitis B virus (HBV) in patients with HIV, and none reported data on HBV virological suppression, making it difficult to understand the impact of antiretroviral therapy on HBV suppression in Sierra Leone.
WHAT THIS STUDY ADDS
We found that the national prevalence of HBV among patients with HIV was 12% and the HBV DNA suppression rate below 20 IU/mL was 73.1%.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our findings call for the integration of HBV-HIV services to achieve elimination by 2030.
Introduction
Viral hepatitis is the seventh leading cause of death worldwide.1 The WHO estimates that 1.1 million people died from chronic viral hepatitis in 2019.1 2 Vaccines against hepatitis B have proven effective in prevention and control, leading to a significant reduction in the prevalence of hepatitis B virus (HBV). More than 296 million of the world population chronically live with HBV, 90% of whom live in low-income and middle-income countries.2 The global prevalence of HBV is 3.5%, but the prevalence in sub-Saharan Africa is higher, estimated at 6.1%.1–3
Owing to these abysmal global and regional statistics, the World Health Assembly proposed the elimination of viral hepatitis as a public health threat by 2030. The goal is to achieve a 90% reduction in new infections and a 65% reduction in death from HBV from the 2015 baseline.4 However, achieving these goals is hampered by several challenges, including limited access to testing services and high rates of HIV/HBV co-infection in many low-income and middle-income countries.5
Co-infection with HBV is common in people living with HIV because of shared transmission routes which may accelerate the clinical course and affect the response to therapy.6 Of the 36 million people living with HIV worldwide, approximately 2.6 million people co-infected with HBV live in sub-Saharan Africa.7
Sierra Leone’s health system response to public health problems such as viral hepatitis has been challenged by a series of viral outbreaks in recent years, including Ebola and SARS-CoV-2. Although there is no published data on the national seroprevalence of HBV to date, small studies in Sierra Leone reported a positive rate of hepatitis B surface antigen (HBsAg) above 8% in different population groups, indicating a high endemicity of HBV in this country.8–14
The national HIV prevalence in Sierra Leone is 1.7%, but HIV service delivery faces many challenges, such as the lack of routine HBV screening of people living with HIV.15 Therefore, data reporting the prevalence of HBV among people living with HIV in Sierra Leone are limited to two small single-centre studies.9 10 Nonetheless, fixed-dose combination antiviral drugs containing tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) recommended in HIV treatment guidelines in Sierra Leone are effective against both HBV and HIV. Consequently, the HIV treatment programme has been providing treatment to people living with HIV using these drugs to maintain both HIV and HBV viral suppression in those co-infected.16 However, unlike HIV, Sierra Leone lacks data on HBV virological suppression in individuals co-infected with HBV and HIV, which hinders the understanding of the impact of antiretroviral therapy (ART) on HBV virological suppression.17
Given the many challenges in HIV service delivery, such as the high rates of late diagnosis and treatment interruption among people living with HIV in Sierra Leone, understanding the prevalence of HIV and HBV co-infection and the impact of ART on HBV viral suppression in this population has important policy implications.18 19 In this study, we aimed to (1) determine the prevalence and associated factors of a positive HBsAg in people living with HIV, and (2) assess the impact of ART on HBV DNA suppression in people living with HIV in Sierra Leone.
Methods
This study was conducted in accordance with the relevant guidelines and regulations and the Declaration of Helsinki. Each participant provided written informed consent. For illiterate participants, the study, and the consent form content were explained to them verbally and they gave their consent using fingerprints.
Study design, study population and study setting
Sierra Leone is divided into five regions, and almost 22% of Sierra Leone’s population resides in the Western Area where the country’s capital Freetown is located (online supplemental figure 1). We selected facilities with more than 800 people living with HIV receiving ART at a time when the study was being planned. The hospitals, the people living with HIV populations and levels of care are shown in online supplemental table 1. Two health facilities in the East (Well Body Clinic and Koidu Hospital) and two hospitals in Western Sierra Leone (Wellness Clinic and United Methodist Church Urban Centre) with more than 800 people living with HIV were excluded due to the distance or delay in obtaining consent to conduct the study. The study employed a cross-sectional design to collect primary data on adult patients aged 18 years or older in 10 public hospitals in Sierra Leone (online supplemental figure 1). Six tertiary/regional hospitals (Connaught Hospital, Princess Christian Maternity Hospital, 34 Military Hospital and Bo, Kenema and Makeni Government Hospitals), two secondary hospitals (Rokupa and Lumley Government Hospitals) and two primary health facilities (Jenner Wright Clinic and Waterloo Community Health Centre) were included.
Supplemental material
Supplemental material
Participants selection and sample processing
We consecutively recruited all people living with HIV presenting to the 10 health facilities between August 2022 and January 2023, with the majority recruited in Western Sierra Leone (online supplemental table 1). We recruited participants aged above 18 years and above who were able and willing to provide their informed consent. The demographic and HIV-related information of these individuals were collected by completing a questionnaire.
Following informed written consent, blood samples were collected in EDTA-containing vacutainer tubes from each participant and processed at the Infectious Disease Prevention and Control Center of the 34 Military Hospital. Plasma samples were separated from 10 mL of collected venous blood by centrifugation at 2000 revolutions per minute for 10 min and transferred to cryogenic vials. All samples were stored at −80°C until analysis.
HBV serological detection and determination of HBV DNA
We used the Wondfo One Step HBV Whole Blood/Serum/Plasma Test Kit (Wondfo, Guangzhou, China), a rapid immunochromatographic assay, to determine the serological markers of HBV such as HBsAg and hepatitis B surface antibody (HBsAb). The sensitivity and specificity of HBsAg were 96.2% and 99.3%, respectively. For HBsAb, the sensitivity and specificity were 93.0% and 99.0%, respectively.
HBV DNA was determined using a one-step HBV PCR kit (Sansure Biotech, Hunan, China). About 5 µL nucleic lysis buffer and 5 µL plasma specimen were mixed and incubated at room temperature for 10 min to allow rapid lysis and release of HBV DNA. Then, 40 µL of the reaction mixture was added. Each reaction mixture contained 38 µL of HBV PCR mixture, 2 µL of enzyme mixture and 0.2 µL of positive internal control. HBV amplification and detection were performed with the CFX96 real-time PCR detection system (Bio-Rad Laboratories, Hercules, California, USA). HBV DNA was detected in the FAM/Green channel and internal control was detected in the VIC/Yellow channel. The Lower Limit of Quantitation and Lower Limit of Detection for the Definition of undetectable HBV DNA is 20 and 5 IU/mL, respectively.
Data analysis
Statistical analyses were performed using R (R Core Team, Vienna, Austria). Baseline characteristics were summarised using frequencies and medians. We used Pearson’s χ2 and Fisher’s exact test to assess statistical significance. Binomial logistic regression was used to construct a model to identify risk factors for hepatitis B infection among demographic parameters. A p value≤0.05 was considered statistically significant. For univariate analysis, categorical variables were analysed separately with the function glm. Multivariate testing for comparing the significance of each variable was performed using the function glm. To avoid over-fitting and collinearity, we first estimated Pearson correlation coefficients (PCC) between every two variables with the function corr.test from the package psych and adjusted R squared (adjusted R2) using the function regsubsets from the package leaps. The variables ‘ART status’ were excluded due to the PCC>0.5, and ‘HIV-1 viral load’ was excluded based on adjusted R2 results. Subsequently, characteristics that are not clinically or biologically relevant were also excluded, such as ‘Duration of ART’ and ‘ART regimen’. Besides, ‘Geography information’ which is likely to HBsAg status was included to construct the model. Eventually, we used ‘Age’, ‘Gender’, ‘Marital status’, ‘Hospital level’ and ‘Hospital location’ for further logistic regression analysis to calculate OR with 95% CIs. The same method was also used to identify risk factors for unsuppressed HBV DNA. We provided p values with Wald and likelihood-ratio test for each category with the function Wald test and analysis of variance, respectively.
Results
Demographic characteristics of study participants
Of the 3106 people living with HIV recruited in this study, 2311 (74.4%) were women. The median age and duration of ART were 36 years (IQR: 29–45 years) and 38 months (IQR: 9–80 months), respectively. Most used the fixed-dose combination of TDF, 3TC and dolutegravir (1856, 59.8%), while a majority were virally suppressed (defined as HIV viral load below 200 copies/mL) (2442, 78.6%) (table 1).
Basic demographic characteristics of people living with HIV in this study
Prevalence and risk factors of HBV infection among people living with HIV
The overall prevalence of HBsAg was 12.0% (95% CI: 10.9% to 13.2%) (table 2 and figure 1). The median age of people living with HIV co-infected with HBV was 37 years (IQR: 29–46 years) compared with 36 years (IQR: 29–45) in those without HBV co-infection. The seroprevalence of HBsAg was higher in men (18.1%, 95% CI: 15.6% to 20.9%) than women (9.9%, 95% CI: 8.7% to 11.2%) (p<0.001), but not statistically different for age, marital status, hospital level of care, hospital location and ART treatment and duration. In univariate analysis, the risk of a positive HBsAg was higher in age 40–50 years (OR 1.40, 95% CI: 1.05 to 1.86; p=0.023; reference group: age <30), male sex (OR 2.04, 95% CI: 1.63 to 2.56; p<0.001) and separated people (OR 1.71, 95% CI: 1.00 to 2.92, p=0.05). In multivariable analysis, male sex (adjusted OR (aOR) 2.11, 95% CI: 1.67 to 2.68; p<0.001) and being separated (aOR 1.83, 95% CI: 1.06 to 3.16, p=0.031; reference group: being married) were independent predictors of HBsAg seropositivity (table 2). Among 3106 people living with HIV who were screened for HBV serological markers (table 1), 166 (5.3%, 95% CI: 4.6% to 6.2%) were HBsAb positive and were regarded immunised by HBV vaccination.
Prevalence of hepatitis B infection among people living with HIV. Forest plot showing the prevalence of HBV infection stratified by demographic characteristics. The blue dotted line indicates the overall prevalence of HBV among people living with HIV. The red dot represents the prevalence of HBV in each group and the horizontal lines indicate the CI. ART, antiretroviral therapy; HBV, hepatitis B virus; TLD, tenofovir, lamivudine and dolutegravir; TLE, tenofovir, lamivudine and efavirenz.
Prevalence and risk factor analysis of hepatitis B infection by demographic parameters
Impact of ART on HBV replication
We used multivariable analysis to investigate the factors associated with HBV DNA suppression rate (online supplemental table 2). We found male sex (aOR 1.72, 95% CI: 1.01 to 2.91; p=0.044) and those with HIV-1 viral load of more than 1000 copies/mL (aOR: 3.29, 95% CI: 1.68 to 6.46; p<0.001) are more likely to have unsuppressed HBV DNA.
We further explored the impact of ART on HBV replication in patients receiving ART containing at least one drug with anti-HBV activity. In patients with detectable HBV DNA, the median HBV DNA was 306.6 (IQR: 72.2–15 217.4) IU/mL. Among 331 HIV/HBV co-infected patients receiving ART, 242 (73.1%) achieved HBV DNA suppression below 20 IU/mL and HBV DNA suppression rate was 75.6% (183/242) in those treated for more than 12 months. Among 286 individuals receiving TDF-containing regimen, the HBV DNA suppression rate was 73.4% (210/286) and HBV DNA suppression rate was 75.4% (156/207) for those treated for more than 12 months. We then evaluated the duration of ART on HBV DNA suppression and found that patients on ART for 12–24 months had the highest HBV DNA suppression rate (77.78%, 28/36), following with patients on ART for more than 24 months (75.24%, 155/206) (figure 2A). For patients who received ART for more than 6 months with HIV viral load below 200 copies/mL, the rate of patients with undetectable HBV DNA was 78.40% (185/236). In contrast, the rate decreased to 52.17% (24/46) in those receiving ART with an unsuppressed HIV viral load (p<0.001) (figure 2B). We also evaluated the HBV DNA suppression rate in HIV/HBV co-infected patients receiving treatment containing TDF and 3TC (online supplemental figure S2). Similarly, we found that 78.13% (25/32) patients on ART for 12–24 months and 78.43% (160/204) patients with suppressed HIV viral load achieved suppressed HBV replication.
HBV DNA suppression rate in ART-experienced HIV/HBV co-infected patients. HBV DNA suppression rate was evaluated in HIV-HBV co-infected patients receiving more than 6 months of ART based on (A) different duration of ART and (B) HIV viral load. ART, antiretroviral therapy; HBV, hepatitis B virus.
Discussion
We observed an overall HBV prevalence of 12.0%, which was in agreement with the 13.0% reported in a systematic review of studies from different populations in Sierra Leone.20 Moreover, sub-Saharan African countries such as Ethiopia, Nigeria, Ghana and Kenya reported lower prevalence rates of HBV in people living with HIV than that reported in our study.21–24 These differences in the prevalence of HBV could reflect on the variation in public health interventions across Africa and emphasise the need for Sierra Leone to take immediate steps to integrate HBV services such as routine HBV screening and vaccination of susceptible people living with HIV to the HIV response in the country. It has been reported elsewhere that the integration of hepatitis B care into routine HIV services is feasible and widely acceptable by service providers and recipients of care if the health system is properly planned to avoid inherent challenges.25
We identified age 40–50 and male sex as risk factors for HBV infection among people living with HIV, similar to a report from Ethiopia.26 Hence, we recommend offering specific support, including routine HBV screening and HBV vaccination, to people living with HIV who have been identified as being at higher risk for HBV infection in the country.
Only 5.3% of the people living with HIV have serological evidence of past HBV vaccination. This could be explained by the fact that individuals that participated in our study were born before 2007, when the government introduced the HBV vaccine into the routine immunisation programme. Therefore, we were unable to assess the impact of routine HBV vaccination on preventing maternal HBV transmission to children of HIV/HBV co-infected mothers, which could be done in future studies. In addition, the low hepatitis B vaccination coverage reflects the lack of a hepatitis B prevention programme for people living with HIV in Sierra Leone.
We explored the impact of ART with anti-HBV activity on the HBV DNA suppression rate. There are limited studies in sub-Saharan Africa evaluating the effect of ART on HBV DNA viral suppression rates, particularly in people living with HIV. In Senegal, a study of children with HBV reported an HBV DNA suppression rate of 71.4% at 3.5 years after starting ART.27 Correspondingly, Day et al in Kenya reported an HBV DNA suppression rate of 82% after a median follow-up of 3.4 years.28
HBV infection poses a threat to long- term liver health among people living with HIV in West Africa, a study conducted in Ghana by Villa et al reported that people living with HIV co-infected with HBV had a higher prevalence of ≥F2 fibrosis measured by FibroScan.29 In addition, liver fibrosis measured by transient elastography was independently associated with HBV DNA load in lamivudine-treated people living with HIV, and tenofovir treatment can improve HBV control and reduce liver stiffness in subjects with high HBV DNA load.30
In our study, the rate of HBV DNA suppression was higher in people living with HIV with suppressed HIV viral load than those with unsuppressed HIV viral load. We are concerned about this finding because of the high rate of unsuppressed HIV RNA levels and late HIV diagnosis in our setting.17–19 As liver-related mortality and potential for aggravated HIV-associated immune deficiency in people living with HIV co-infected with HBV could worsen with these challenges, we emphasise that the introduction of routine HBV screening to HIV services and the provision of effective HIV treatment with TDF and 3TC in a combined regimen can save lives.6
Our study has limitations. First, we were unable to differentiate between acute and chronic HBV infection because the kit used in this study did not detect HBcAb (Hepatitis B core antibody) IgM. Second, we did not assess liver function and liver fibrosis in people living with HIV to determine the extent of liver disease in this patient population. Third, owing to logistical challenges, we recruited participants primarily from four of the five geographical regions of Sierra Leone, the majority of which are from Western Sierra Leone, making this study not truly representative of the hepatitis B situation in Sierra Leone. Additionally, this was a cross-sectional study assessing the effect of ART on HBV replication, but baseline HBV DNA levels were not assessed. Future studies should recruit patients with active HBV replication to longitudinally assess the effect of ART on HBV replication in Sierra Leone. In addition, HBV/HIV resistance testing is not available in our setting. Finally, the lack of immunisation records and HBcAb status makes it difficult to differentiate prior vaccination from naturally acquired infection. Nonetheless, this study provides the first large-scale data on HBV prevalence and the first evidence of the impact of ART on HBV replication in Sierra Leonean people living with HIV.
In summary, we reported a high prevalence of HBsAg seropositivity and low HBV immunisation coverage in people living with HIV in Sierra Leone. In addition, we observed that ART can efficiently result in a viral suppression rate of HBV infection. Therefore, achieving the global target by eliminating HBV infection by 2030 requires accelerated access to care for people living with HIV with chronic HBV infection, including HBV testing, antiviral treatment and HBV vaccination.
Abstract translation
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.Data availability statement
Data are available upon reasonable request. The data for this study is available at Fifth Medical Centre of PLA General Hospital, Beijing, China, and Ministry of Health of Sierra Leone and will be made available upon request.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Sierra Leone Ethics and Scientific Review Committee (SLESRC) of the Ministry of Health and Sanitation of Sierra Leone. Until January 2023, the Sierra Leone Ethics and Scientific Review Committee of the Ministry of Health and Sanitation did not issue out ethics approval numbers. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We gratefully acknowledge all the participants enrolled in this study and healthcare workers in the different hospitals where the patients were recruited.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Handling editor Apostolos Beloukas
X @mohamednyambe@gmail.com
J-WS, SL and S-YC contributed equally.
Contributors J-WS, GYa and F-SW conceived and designed the study. J-WS, GYa and SL performed the experiment. MBJ, SS, MKN, VDN and MB collected the blood samples and clinical information. S-YC analysed the data and performed the statistical analysis. J-WS, GYa, SL, F-SW and GYe wrote the manuscript. All authors read and approved the final manuscript. GYa is responsible for the overall content as guarantor.
Funding This work was supported by grants from the Beijing Natural Science Foundation (grant number 7222171), the National Natural Science Foundation of China (grant number 82101837, 82371766).
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Competing interests None declared.
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Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.