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AimCurrent clinical recommendations suggest treating chronic hepatitis B virus (HBV) infection in a minority of cases, but more data are needed to determine the benefits and risks of Tenofovir disoproxil fumarate (TDF) therapy. We aimed to assess the impact of TDF on liver disease, and the risk of nephrotoxicity.MethodWe studied a longitudinal UK chronic HBV (CHB) cohort attending out-patient clinics between 2005 and 2018, analysing data for 206 ethnically diverse adults (60 on TDF, 146 untreated), with median follow-up 3.3±2.8 years.ResultsPatients prescribed TDF were older (39 vs. 35 years, p=0.004) with a male excess (63% vs. 47%, p=0.04) compared to untreated patients. Reflecting treatment eligibility criteria, at baseline, treated patients were more likely to have elevated ALT (pConclusionTDF may have long-term benefits for a wider pool of the CHB population.

Bangladesh is one of the world’s top ten burdened countries for viral hepatitis. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of hepatitis B virus (HBV) infection and to identify cases of occult hepatitis B infection (OBI). HBV exposure (anti-HBc) was documented in 72/201 (36%), and active HBV infection in 16/201 (8%), among whom 3 were defined as OBI (defined as detectable HBV DNA but negative HBsAg). Applying a target-enrichment sequencing pipeline to samples with HBV DNA >3.0log10 IU/ml, we obtained deep whole genome sequences for four cases, identifying genotypes A, C and D. Polymorphisms in the surface gene of the OBI case may account for the negative HBsAg status. We identified mutations associated with nucleos(t)ide analogue resistance, although the clinical significance in this cohort is not known. The high prevalence of HBV in this setting highlights the benefits of offering screening in hospital patients and the importance of HBV DNA testing of transfusion products to reduce the risk of transmission. In order to work towards international Sustainable Development Goal targets for HBV elimination, increased investment is required for diagnosis, treatment and prevention in Bangladesh.

BackgroundTenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into the mechanisms of resistance and potential clinical significance.MethodsWe carried out a systematic literature search in PubMed to identify clinical,in vitroandin silicoevidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.ResultsWe identified a ‘long-list’ of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. Based on quality and quantity of supporting data, we generated a ‘short-list’ of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.ConclusionThere is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets.

IntroductionUnited Nations sustainable development goals aim for the elimination of viral hepatitis as a public health threat by 2030, leading to efforts to upscale the availability and accessibility of hepatitis B virus (HBV) vaccination, diagnosis and treatment globally. However, a variety of societal factors, including beliefs, traditions, and stigma, can be a major obstacle to all of these interventions. We therefore set out to investigate how HBV is understood and described in communities in Uganda, and whether there is evidence of potential stigma.MethodWe carried out a qualitative formative study in two sites in South Western Uganda: a village in Kalungu district (site A) and an area on the outskirts of Masaka town (site B). We undertook a rapid assessment to investigate how adults describe HBV infection and their perceptions about the infection. We collected data by conducting a transect walk, observations, community group discussions, and in-depth interviews, sampling a total of 131 individuals. We used inductive content analysis to extract key themes associated with HBV.ResultsThere is no specific word for HBV infection in local languages, and knowledge about this infection is varied. While some individuals were completely unfamiliar with HBV infection, some had heard of HBV. Radio was a common source of information. There was awareness of HBV as a cause of liver disease, limited knowledge regarding the cause, mode of transmission and treatment. Stigma in HBV may be rare in this community due to limited understanding and experience of HBV.ConclusionThere is an ongoing need to improve awareness and understanding of HBV in this community. Careful dissemination of accurate information is required to promote acceptance of interventions for prevention, diagnosis and treatment.

IntroductionLiver disease is a major cause of morbidity and mortality in sub-Saharan Africa. However, its prevalence, distribution and aetiology have not been well characterised. We examined liver function tests (LFTs) and calculated liver fibrosis scores in a rural population in Uganda.MethodologyA cross-sectional survey of LFTs was undertaken in 2011 in a rural population cohort in South-Western Uganda. We classified abnormal LFTs based on reference ranges set in America and in Africa. We derived fibrosis scores (AST to Platelet Ratio Index, fibrosis-4, GGT to platelet ratio, red cell distribution width to platelet ratio, and S-index) to evaluate the potential prevalence of liver disease. We collected information about alcohol intake, and infection with HIV, HBV and HCV, to determine the contribution made by these factors to liver inflammation or fibrosis.ResultsData were available for 8,099 participants (median age 30 years; 56% female). The prevalence of HBV, HCV and HIV infection were 3%, 0.2% and 8%, respectively. The prevalence of abnormal LFTs was higher based on the American reference range compared to the African reference range (e.g. for AST 13% vs 3%, respectively). The prevalence of AST/ALT ratio >2 was 11%, suggestive of alcoholic hepatitis. The highest prevalence of fibrosis was suggested by the GPR score, with 24% of the population falling above the threshold for fibrosis. By multivariate analysis, elevated LFTs and fibrosis scores were most consistently associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption. Based on population attributable risk, the highest proportion of elevated fibrosis scores was associated with alcohol use (e.g. 64% of elevated S-index scores).ConclusionFurther work is required to determine normal reference ranges for LFTs in this setting, to evaluate the specificity and sensitivity of fibrosis scores, and to determine aetiology of liver disease.KEY FINDINGSWhat is already known?Liver disease is not well characterised in many parts of sSA despite the high prevalence of chronic viral infections (HIV, HBV and HCV), and potential exposure to hepatotoxins including alcohol, aflatoxins and traditional herbal medicine.Non-invasive blood tests for markers of fibrosis are relatively simple and offer a safe route to assess for liver fibrosis, however, their diagnostic accuracy is not well established in sSA.Appropriate reference ranges for LFTs are crucial for optimising the sensitivity and specificity of the detection of underlying liver disease.What are the new findings?There is a disparity in the prevalence of abnormal LFTs in our study cohort when comparing two references ranges (American vs. local reference ranges).Based on GPR score, there is a high prevalence of liver fibrosis (almost 1 in 4 of this population) and elevated GPR score is associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption.Alcohol consumption accounted for 64% of abnormal S-index scores, 32% of elevated FIB-4 scores, and 19% of GPR abnormalities.What do the new findings imply?Appropriate reference ranges for LFTs are necessary to contribute to an understanding of the burden and aetiology of liver disease.Alcohol, HIV and HBV are risk factors for deranged LFTs and liver fibrosis, with alcohol making the most significant and striking contribution.Further investigation is needed to determine other factors that contribute to liver disease in this setting.

International goals for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In many African populations, HBV prevalence remains high (≥8%) despite the roll-out of infant HBV immunisation from the mid-1990’s onwards. Enhanced efforts are now urgently required to improve an understanding of population epidemiology, in order to determine which interventions are most likely to be effective in advancing populations towards elimination goals. In populations with a high prevalence of infection, catch-up HBV vaccination of adults has sometimes been deployed as a preventive strategy. An alternative approach of ‘test and treat’ could be applied as a tool to interrupt transmission. We used a systematic approach to investigate the relationship between prevalence of HBV infection (HBsAg) and exposure (anti-HBc) in Africa, and then applied a mathematical model to investigate the impact of catch-up vaccination and a ‘test and treat’ strategy in Uganda, representing a high prevalence setting. We demonstrate a strong relationship between the prevalence of HBsAg and anti-HBc (p

HBsAg and HBeAg have gained traction as biomarkers of control and clearance during monitoring of chronic hepatitis B virus infection (CHB). An improved understanding of the correlates of clearance of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR-HIC), adopting an unbiased approach to generating a robust longitudinal dataset for adults testing HBsAg-positive from a large UK teaching hospital over a six year period (2011-2016 inclusive). From 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. HBsAg clearance rate was similar in individuals on NA therapy (n=4, median clearance time 150 weeks) vs those not on NA therapy (n=9, median clearance time 157 weeks). Those who cleared HBsAg were significantly older, and less likely to be on NA therapy compared to non-clearers (p=0.003 and p=0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (p=0.025). HBeAg clearance occurred both on NA therapy (n=24, median time 49 weeks) and off NA therapy (n=19, median time 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematised approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and underpin improvements in clinical care provision.IMPORTANCEAdvances in the diagnosis, monitoring and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical datasets that can help to inform advances in patient care, and provide clues that inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been under-represented in the literature. Tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualised clinical care and may provide important clues into the immune events that underpin disease control.

In light of sustainable development goals for 2030, an important priority for Africa is to have affordable, accessible and sustainable hepatitis B virus (HBV) prevention of mother to child transmission (PMTCT) programmes, delivering screening and treatment for antenatal women and implementing timely administration of HBV vaccine for their babies. We developed a decision-analytic model simulating 10,000 singleton pregnancies to assess the cost-effectiveness of three possible strategies for deployment of tenofovir in pregnancy, in combination with routine infant vaccination: S1: no screening nor antiviral therapy; S2: screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. Our outcome was cost per infant HBV infection avoided and the analysis followed a healthcare perspective. S1 predicts 45 infants would be HBV-infected at six months of age, compared to 21 and 28 infants in S2 and S3, respectively. Relative to S1, S2 had an incremental cost of $3,940 per infection avoided. S3 led to more infections and higher costs. Given the long-term health burden for individuals and economic burden for society associated with chronic HBV infection, screening pregnant women and providing tenofovir for all who test HBsAg+ may be a cost-effective strategy for South Africa.