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

Abstract 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

Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Challenges and solutions to system-wide use of precision oncology as the standard of care paradigm

The personalised oncology paradigm remains challenging to deliver despite technological advances in genomics-based identification of actionable variants combined with the increasing focus of drug development on these specific targets. To ensure we continue to build concerted momentum to improve outcomes across all cancer types, financial, technological and operational barriers need to be addressed. For example, complete integration and certification of the ‘molecular tumour board’ into ‘standard of care’ ensures a unified clinical decision pathway that both counteracts fragmentation and is the cornerstone of evidence-based delivery inside and outside of a research setting. Generally, integrated delivery has been restricted to specific (common) cancer types either within major cancer centres or small regional networks. Here, we focus on solutions in real-world integration of genomics, pathology, surgery, oncological treatments, data from clinical source systems and analysis of whole-body imaging as digital data that can facilitate cost-effectiveness analysis, clinical trial recruitment, and outcome assessment. This urgent imperative for cancer also extends across the early diagnosis and adjuvant treatment interventions, individualised cancer vaccines, immune cell therapies, personalised synthetic lethal therapeutics and cancer screening and prevention. Oncology care systems worldwide require proactive step-changes in solutions that include inter-operative digital working that can solve patient centred challenges to ensure inclusive, quality, sustainable, fair and cost-effective adoption and efficient delivery. Here we highlight workforce, technical, clinical, regulatory and economic challenges that prevent the implementation of precision oncology at scale, and offer a systematic roadmap of integrated solutions for standard of care based on minimal essential digital tools. These include unified decision support tools, quality control, data flows within an ethical and legal data framework, training and certification, monitoring and feedback. Bridging the technical, operational, regulatory and economic gaps demands the joint actions from public and industry stakeholders across national and global boundaries

Association between SGLT2 inhibitor treatment and diabetic ketoacidosis and mortality in people with type 2 diabetes admitted to hospital with COVID-19

   Objective  To determine the association between prescription of SGLT2 inhibitors and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes hospitalized with COVID-19.  Research Design and Methods  This was a retrospective cohort study based on secondary analysis of data from a large nationwide audit from a network of 40 centres in United Kingdom with data collection up to December 2020 that was originally designed to describe risk factors associated with adverse outcomes among people with diabetes who were admitted to hospital with COVID-19.. The primary outcome for this analysis was DKA on or during hospital admission. The secondary outcome was mortality. Crude, age-sex adjusted and multivariable logistic regression models, were used to generate odds ratios and 95% confidence intervals for people prescribed SGLT2 inhibitor compared to those not prescribed SGLT2 inhibitor.   Results  The original national audit included 3067 people with type 2 diabetes who were admitted to hospital with COVID-19, of whom 230 (7.5%) were prescribed SGLT2 inhibitors prior to hospital admission. Mean (SD) age of the overall cohort was 72 years, 62.3% were men and 34.9% were prescribed insulin. Overall, 2.8% of the total population had DKA and 35.6% people died. The adjusted odds of DKA were not significantly different between those prescribed SGLT2 inhibitors and those not (OR 0.56, 0.16-1.97). The adjusted odds of mortality associated with SGLT2 inhibitors were similar in the total study population (OR 1.13, 0.78-1.63 ), in the sub-group prescribed insulin (OR 1.02, 0.59-1.77), and in the sub-group that developed DKA (OR 0.21, 0.01-8.76).  Conclusions We demonstrate a low risk of DKA and high mortality rate in people with type 2 diabetes admitted to hospital with COVID-19 and limited power but no evidence of increased risk of DKA or in-hospital mortality associated with prescription of SGLT2 inhibitors. </p

A nationwide study of adults admitted to hospital with diabetic ketoacidosis or hyperosmolar hyperglycaemic state and COVID‐19

AimsTo investigate characteristics of people hospitalized with coronavirus-disease-2019 (COVID-19) and diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS), and to identify risk factors for mortality and intensive care admission.Materials and methodsRetrospective cohort study with anonymized data from the Association of British Clinical Diabetologists nationwide audit of hospital admissions with COVID-19 and diabetes, from start of pandemic to November 2021. The primary outcome was inpatient mortality. DKA and HHS were adjudicated against national criteria. Age-adjusted odds ratios were calculated using logistic regression.ResultsIn total, 85 confirmed DKA cases, and 20 HHS, occurred among 4073 people (211 type 1 diabetes, 3748 type 2 diabetes, 114 unknown type) hospitalized with COVID-19. Mean (SD) age was 60 (18.2) years in DKA and 74 (11.8) years in HHS (p < .001). A higher proportion of patients with HHS than with DKA were of non-White ethnicity (71.4% vs 39.0% p = .038). Mortality in DKA was 36.8% (n = 57) and 3.8% (n = 26) in type 2 and type 1 diabetes respectively. Among people with type 2 diabetes and DKA, mortality was lower in insulin users compared with non-users [21.4% vs. 52.2%; age-adjusted odds ratio 0.13 (95% CI 0.03-0.60)]. Crude mortality was lower in DKA than HHS (25.9% vs. 65.0%, p = .001) and in statin users versus non-users (36.4% vs. 100%; p = .035) but these were not statistically significant after age adjustment.ConclusionsHospitalization with COVID-19 and adjudicated DKA is four times more common than HHS but both associate with substantial mortality. There is a strong association of previous insulin therapy with survival in type 2 diabetes-associated DKA

Sixty-day consequences of COVID-19 in patients discharged from hospital: an electronic health records study

Data on patients discharged following COVID-19 hospitalization is scarce. We conducted an electronic health records study of community-acquired COVID-19 patients discharged between 15 March and 14 July 2020 from hospitals in Oxfordshire, UK. Of 403 discharged patients, 114 (28%) were readmitted or died within 60 days (incidence rate 18/100 person-months). Rates of readmission or death were twice as high among those ≥ 65 years as those &lt; 65 years [standardized rate ratio: 2.21 (95% CI: 1.45–3.56)] and among women than men [2.25 (1.05–4.18)]. These findings suggest important sex differences in 60-day outcomes following COVID-19 hospitalization that have not previously been well described

Patient Biochemistry and Treatment Need in Chronic Hepatitis B Virus Infection Across Three Continents: Retrospective Cross-Sectional Cohort Studies

INTRODUCTION: Chronic hepatitis B virus (HBV) infection is associated with significant global morbidity and mortality. Low treatment rates are observed in patients living with HBV; the reasons for this are unclear. This study sought to describe patients' demographic, clinical and biochemical characteristics across three continents and their associated treatment need. METHODS: This retrospective cross-sectional post hoc analysis of real-world data used four large electronic databases from the United States, United Kingdom and China (specifically Hong Kong and Fuzhou). Patients were identified by first evidence of chronic HBV infection in a given year (their index date) and characterized. An algorithm was designed and applied, wherein patients were categorized as treated, untreated but indicated for treatment and untreated and not indicated for treatment based on treatment status and demographic, clinical, biochemical and virological characteristics (age; evidence of fibrosis/cirrhosis; alanine aminotransferase [ALT] levels, HCV/HIV coinfection and HBV virology markers). RESULTS: In total, 12,614 US patients, 503 UK patients, 34,135 patients from Hong Kong and 21,614 from Fuzhou were included. Adults (99.4%) and males (59.0%) predominated. Overall, 34.5% of patients were treated at index (range 15.9-49.6%), with nucleos(t)ide analogue monotherapy most commonly prescribed. The proportion of untreated-but-indicated patients ranged from 12.9% in Hong Kong to 18.2% in the UK; almost two-thirds of these patients (range 61.3-66.7%) had evidence of fibrosis/cirrhosis. A quarter (25.3%) of untreated-but-indicated patients were aged ≥ 65 years. CONCLUSION: This large real-world dataset demonstrates that chronic hepatitis B infection remains a global health concern; despite the availability of effective suppressive therapy, a considerable proportion of predominantly adult patients apparently indicated for treatment are currently untreated, including many patients with fibrosis/cirrhosis. Causes of disparity in treatment status warrant further investigation

National Institute for Health Research Health Informatics Collaborative:development of a pipeline to collate electronic clinical data for viral hepatitis research

Objective The National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres. The aim of the NIHR HIC is to improve the quality and availability of routinely collected data for collaborative, cross-centre research. This is demonstrated through research collaborations in selected therapeutic areas, one of which is viral hepatitis. Design The collaboration in viral hepatitis identified a rich set of datapoints, including information on clinical assessment, antiviral treatment, laboratory test results and health outcomes. Clinical data from different centres were standardised and combined to produce a research-ready dataset; this was used to generate insights regarding disease prevalence and treatment response. Results A comprehensive database has been developed for potential viral hepatitis research interests, with a corresponding data dictionary for researchers across the centres. An initial cohort of 960 patients with chronic hepatitis B infections and 1404 patients with chronic hepatitis C infections has been collected. Conclusion For the first time, large prospective cohorts are being formed within National Health Service (NHS) secondary care services that will allow research questions to be rapidly addressed using real-world data. Interactions with industry partners will help to shape future research and will inform patient-stratified clinical practice. An emphasis on NHS-wide systems interoperability, and the increased utilisation of structured data solutions for electronic patient records, is improving access to data for research, service improvement and the reduction of clinical data gaps