Impaired humoral and cellular response to primary COVID-19 vaccination in patients less than 2 years after allogeneic bone marrow transplant.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.

Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is a leading cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is uncertain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore, we performed a systematic literature review and meta-analysis to seek evidence for significant associations. MEDLINE, EMBASE and Web of Science databases were searched from 1 January 2000 to 24 June 2020 for studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection, written in English. We extracted data for meta-analysis and generated pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. We identified 40 observational studies reporting on associations of diabetes mellitus (DM), hypertension, dyslipidaemia and obesity with HCC risk. Only DM had a sufficient number of studies for meta-analysis. DM was associated with >25% increase in hazards of HCC (fixed-effects hazards ratio [HR] 1.26, 95% confidence interval (CI) 1.20-1.32, random-effects HR 1.36, 95% CI 1.23-1.49). This association was attenuated towards the null in a sensitivity analysis restricted to studies adjusted for metformin use. In conclusion, in adults with chronic HBV infection, DM is a significant risk factor for HCC, but further investigation of the influence of antidiabetic drug use and glycaemic control on this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.

Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated: a retrospective longitudinal UK cohort study.

BACKGROUND: Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. METHODS: We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. RESULTS: We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. CONCLUSIONS: Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.

A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) resistance in people treated with entecavir or tenofovir.

BACKGROUND: As nucleos/tide analogue (NA) therapy (e.g. entecavir and tenofovir) for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. A systematic review to quantify resistance to these agents has not previously been undertaken. METHODS: We performed a systematic review and random-effects meta-analysis to estimate the risk of HBV resistance to entecavir and tenofovir. We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting treatment ≥48 weeks, with assessment of HBV resistance based on viral sequence data. Data were analysed according to prior exposure history to NA, and choice of NA agent. Analyses were performed in R. FINDINGS: 62 studies involving a total of 12,358 participants were included. For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), resistance increased over time to 0.9 % at ≥5 years (95 %CI 0.1-2.3 %), and resistance was increased in NA-experienced individuals (18 studies; 1112 individuals), to 20.1 % (95 %CI 1.6-50.1 %) at ≥5 years. For tenofovir, pooled resistance risk was 0.0 % at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis. INTERPRETATION: We have generated the first pooled estimates of HBV entecavir and tenofovir resistance over time. HBV resistance to entecavir in treatment-experienced groups in particular may represent a clinical and public health challenge. To date, tenofovir appears to have an excellent resistance profile, but due to data gaps, we caution that existing studies under-estimate the true real-world risk of resistance. Robust prospective data collection is crucial to reduce health inequities and reduce blind-spots in surveillance as treatment is rolled out more widely.

A systematic review of Hepatitis B virus (HBV) prevalence and genotypes in Kenya: Data to inform clinical care and health policy.

The aim of this systematic review and meta-analysis is to evaluate available prevalence and viral sequencing data representing chronic hepatitis B (CHB) infection in Kenya. More than 20% of the global disease burden from CHB is in Africa, however there is minimal high quality seroprevalence data from individual countries and little viral sequencing data available to represent the continent. We undertook a systematic review of the prevalence and genetic data available for hepatitis B virus (HBV) in Kenya using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 checklist. We identified 23 studies reporting HBV prevalence and 8 studies that included HBV genetic data published in English between January 2000 and December 2021. We assessed study quality using the Joanna Briggs Institute critical appraisal checklist. Due to study heterogeneity, we divided the studies to represent low, moderate, high and very high-risk for HBV infection, identifying 8, 7, 5 and 3 studies in these groups, respectively. We calculated pooled HBV prevalence within each group and evaluated available sequencing data. Pooled HBV prevalence was 3.4% (95% CI 2.7-4.2%), 6.1% (95% CI 5.1-7.4%), 6.2% (95% CI 4.64-8.2) and 29.2% (95% CI 12.2-55.1), respectively. Study quality was overall low; only three studies detailed sample size calculation and 17/23 studies were cross sectional. Eight studies included genetic information on HBV, with two undertaking whole genome sequencing. Genotype A accounted for 92% of infections. Other genotypes included genotype D (6%), D/E recombinants (1%) or mixed populations (1%). Drug resistance mutations were reported by two studies. There is an urgent need for more high quality seroprevalence and genetic data to represent HBV in Kenya to underpin improved HBV screening, treatment and prevention in order to support progress towards elimination targets.

Disparities in care and outcomes for primary liver cancer in England during 2008-2018: a cohort study of 8.52 million primary care population using the QResearch database.

Background: Liver cancer has one of the fastest rising incidence and mortality rates among all cancers in the UK, but it receives little attention. This study aims to understand the disparities in epidemiology and clinical pathways of primary liver cancer and identify the gaps for early detection and diagnosis of liver cancer in England. Methods: This study used a dynamic English primary care cohort of 8.52 million individuals aged ≥25 years in the QResearch database during 2008-2018, followed up to June 2021. The crude and age-standardised incidence rates, and the observed survival duration were calculated by sex and three liver cancer subtypes, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and other specified/unspecified primary liver cancer. Regression models were used to investigate factors associated with an incident diagnosis of liver cancer, emergency presentation, late stage at diagnosis, receiving treatments, and survival duration after diagnosis by subtype. Findings: 7331 patients were diagnosed with primary liver cancer during follow-up. The age-standardised incidence rates increased over the study period, particularly for HCC in men (increased by 60%). Age, sex, socioeconomic deprivation, ethnicity, and geographical regions were all significantly associated with liver cancer incidence in the English primary care population. People aged ≥80 years were more likely to be diagnosed through emergency presentation and in late stages, less likely to receive treatments and had poorer survival than those aged <60 years. Men had a higher risk of being diagnosed with liver cancer than women, with a hazard ratio (HR) of 3.9 (95% confidence interval 3.6-4.2) for HCC, 1.2 (1.1-1.3) for CCA, and 1.7 (1.5-2.0) for other specified/unspecified liver cancer. Compared with white British, Asians and Black Africans were more likely to be diagnosed with HCC. Patients with higher socioeconomic deprivation were more likely to be diagnosed through the emergency route. Survival rates were poor overall. Patients diagnosed with HCC had better survival rates (14.5% at 10-year survival, 13.1%-16.0%) compared to CCA (4.4%, 3.4%-5.6%) and other specified/unspecified liver cancer (12.5%, 10.1%-15.2%). For 62.7% of patients with missing/unknown stage in liver cancer, their survival outcomes were between those diagnosed in Stages III and IV. Interpretation: This study provides an overview of the current epidemiology and the disparities in clinical pathways of primary liver cancer in England between 2008 and 2018. A complex public health approach is needed to tackle the rapid increase in incidence and the poor survival of liver cancer. Further studies are urgently needed to address the gaps in early detection and diagnosis of liver cancer in England. Funding: The Early Detection of Hepatocellular Liver Cancer (DeLIVER) project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725).

Where do those data go? Reuse of screening results from clinical trials to estimate population prevalence of HBV infection in adults in Kilifi, Kenya.

Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6-4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4-6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity.

Estimating the epidemiology of chronic Hepatitis B Virus (HBV) infection in the UK: what do we know and what are we missing?

Background: HBV is the leading global cause of cirrhosis and primary liver cancer. However, the UK HBV population has not been well characterised, and estimates of UK HBV prevalence and/or incidence vary widely between sources. We aimed to i) extract and summarise existing national HBV prevalence estimates, ii) add a new estimate based on primary care data, and; iii) critique data sources from which estimates were derived. Methods: We undertook a narrative review, searching for national estimates of CHB case numbers in the UK (incorporating incidence, prevalence and/or test positivity data) across a range of overlapping sources, including governmental body reports, publications from independent bodies (including medical charities and non-governmental organisations) and articles in peer-reviewed scientific journals.  An alternative proxy for population prevalence was obtained via the UK antenatal screening programme which achieves over 95% coverage of pregnant women. We also searched for diagnoses of HBV in the QResearch primary care database based on laboratory tests and standardised coding. Results: We identified six CHB case number estimates, of which three reported information concerning population subgroups, including number of infected individuals across age, sex and ethnicity categories. Estimates among sources reporting prevalence varied from 0.27% to 0.73%, congruent with an estimated antenatal CHB prevalence of <0.5%. Our estimate, based on QResearch data, suggests a population prevalence of ~0.05%, reflecting a substantial underestimation based on primary care records. Discussion: Estimates varied by sources of error, bias and missingness, data linkage, and "blind spots" in HBV diagnoses testing/registration. The UK HBV burden is likely to be concentrated in vulnerable populations who may not be well represented in existing datasets including those experiencing socioeconomic deprivation and/or homelessness, ethnic minorities and people born in high-prevalence countries. This could lead to under- or over-estimation of population prevalence estimation. Multi-agency collaboration is required to fill evidence gaps.

Development and validation of personalised risk prediction models for early detection and diagnosis of primary liver cancer among the English primary care population using the QResearch® database: research protocol and statistical analysis plan.

BACKGROUND AND RESEARCH AIM: The incidence and mortality of liver cancer have been increasing in the UK in recent years. However, liver cancer is still under-studied. The Early Detection of Hepatocellular Liver Cancer (DeLIVER-QResearch) project aims to address the research gap and generate new knowledge to improve early detection and diagnosis of primary liver cancer from general practice and at the population level. There are three research objectives: (1) to understand the current epidemiology of primary liver cancer in England, (2) to identify and quantify the symptoms and comorbidities associated with liver cancer, and (3) to develop and validate prediction models for early detection of liver cancer suitable for implementation in clinical settings. METHODS: This population-based study uses the QResearch® database (version 46) and includes adult patients aged 25-84 years old and without a diagnosis of liver cancer at the cohort entry (study period: 1 January 2008-30 June 2021). The team conducted a literature review (with additional clinical input) to inform the inclusion of variables for data extraction from the QResearch database. A wide range of statistical techniques will be used for the three research objectives, including descriptive statistics, multiple imputation for missing data, conditional logistic regression to investigate the association between the clinical features (symptoms and comorbidities) and the outcome, fractional polynomial terms to explore the non-linear relationship between continuous variables and the outcome, and Cox/competing risk regression for the prediction model. We have a specific focus on the 1-year, 5-year, and 10-year absolute risks of developing liver cancer, as risks at different time points have different clinical implications. The internal-external cross-validation approach will be used, and the discrimination and calibration of the prediction model will be evaluated. DISCUSSION: The DeLIVER-QResearch project uses large-scale representative population-based data to address the most relevant research questions for early detection and diagnosis of primary liver cancer in England. This project has great potential to inform the national cancer strategic plan and yield substantial public and societal benefits.

Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK.

Background: To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load). Methods: We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts. Results: We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient. Conclusions: These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic. Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

Risk of Reactivation of Hepatitis B Virus (HBV) and Tuberculosis (TB) and Complications of Hepatitis C Virus (HCV) Following Tocilizumab Therapy: A Systematic Review to Inform Risk Assessment in the COVID-19 Era.

Objectives: Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of severe COVID-19 caused by infection with SARS-CoV-2. However, unintended consequences of TCZ therapy include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), and worsening of hepatitis C virus (HCV). We set out to assimilate existing data for these complications, in order to help inform evidence-based risk assessments for the use of TCZ, and thus to reduce the risk of serious but preventable complications. Methods: We searched the global WHO database of Individual Case Safety Reports (ICSRs) and adverse drug reactions (ADRs) ("VigiBase") and undertook a systematic literature review, in accordance with PRISMA guidelines. We generated mean cumulative incidence estimates for infection complications. Results: Mean cumulative incidence of HBV and TB were 3.3 and 4.3%, respectively, in patients receiving TCZ. Insufficient data were available to generate estimates for HCV. These estimates derive from heterogeneous studies pre-dating SARS-CoV-2, with differing epidemiology and varied approaches to screening and prophylaxis, so formal meta-analysis was not possible. Conclusions: We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm to guide clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.

Longitudinal Analysis of the Utility of Liver Biochemistry as Prognostic Markers in Hospitalized Patients With Corona Virus Disease 2019.

The association of liver biochemistry with clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently unclear, and the utility of longitudinally measured liver biochemistry as prognostic markers for mortality is unknown. We aimed to determine whether abnormal liver biochemistry, assessed at baseline and at repeat measures over time, was associated with death in hospitalized patients with COVID-19 compared to those without COVID-19, in a United Kingdom population. We extracted routinely collected clinical data from a large teaching hospital in the United Kingdom, matching 585 hospitalized patients who were SARS-CoV-2 real-time reverse transcription-polymerase chain reaction (RT-PCR) positive to 1,165 hospitalized patients who were RT-PCR negative for age, sex, ethnicity, and preexisting comorbidities. A total of 26.8% (157/585) of patients with COVID-19 died compared to 11.9% (139/1,165) in the group without COVID-19 (P < 0.001). At presentation, a significantly higher proportion of the group with COVID-19 had elevated alanine aminotransferase (20.7% vs. 14.6%, P = 0.004) and hypoalbuminemia (58.7% vs. 35.0%, P < 0.001) compared to the group without COVID-19. Within the group with COVID-19, those with hypoalbuminemia at presentation had 1.83-fold increased hazards of death compared to those with normal albumin (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.25-2.67), while the hazard of death was ~4-fold higher in those aged ≥75 years (adjusted HR, 3.96; 95% CI, 2.59-6.04) and ~3-fold higher in those with preexisting liver disease (adjusted HR, 3.37; 95% CI, 1.58-7.16). In the group with COVID-19, alkaline phosphatase (ALP) increased (R = 0.192, P < 0.0001) and albumin declined (R = -0.123, P = 0.0004) over time in patients who died. Conclusion: In this United Kingdom population, liver biochemistry is commonly deranged in patients with COVID-19. Baseline hypoalbuminemia and rising ALP over time could be prognostic markers for death, but investigation of larger cohorts is required to develop a better understanding of the relationship between liver biochemistry and disease outcome.