Signe Bollerup

Introduction: The Danish Database for Chronic Hepatitis B and C (DANHEP) was established in 2002 to support research into the clinical, epidemiological, virological, and immunological aspects of chronic viral hepatitis in Denmark. The objective of this paper is to describe methods of data acquisition, content, completeness and accuracy of data in DANHEP. Methods: Since 2002 all individuals with chronic viral hepatitis B or C at least 16 years of age, who has presented to a hospital department specialized in infectious diseases or gastroenterology in Denmark, have been enrolled in DANHEP. Information on co-infections, viral DNA/RNA detection, serology, liver parameters, liver fibrosis, treatment initiation, -cessation and -efficacy is manually transferred from electronic patient files and recorded in DANHEP annually. In 2004, a biobank storing annual blood samples was established. Results: By December 2023 DANHEP stored data on 15,886 individuals with chronic hepatitis B or C and the biobank held approximately 38,180 samples. We verified a random sample of key variables by comparing with electronic patient files and found an error proportion of less than 5%. Conclusion: DANHEP is well suited for studying the epidemiology, virology and immunology of chronic viral hepatitis. We encourage future collaborations to address the many remaining questions in the field of viral hepatitis.

The impact of hepatitis B virus (HBV) diversity and evolution on disease progression is not well-understood. This study aims to compare intra-individual viral evolution in two groups of chronic hepatitis B (CHB) patients, using antiviral treatment initiation as a measure of lack of immunological control. From the Danish Database for Hepatitis B and C (DANHEP), 25 CHB patients were included; 14 with antiviral treatment initiation (TI group), and 11 without (NTI group). For each patient, three serial plasma samples taken before potential treatment initiation were selected. HBV DNA was amplified by PCR and analyzed by next-generation sequencing. HBV DNA and alanine transaminase were elevated in the TI group throughout the study period. Significantly higher substitution rates in the NTI group versus the TI group were found both within the viral population and at consensus level. Putative predicted CD8⁺ T cell epitopes contained significantly more substitutions in the NTI group. Genome-wide association analysis revealed several amino acid residues in the HBV genome associated with treatment initiation. This study shows that HBV has a higher rate of substitutions in CHB patients not requiring treatment. This could be linked to host immune pressure leading to disease control.

To evaluate liver complications in patients with chronic hepatitis B, both with and without cardiometabolic comorbidities, and to compare the incidence of cardiometabolic comorbidities in these patients with that of the general population. This nationwide registry-based cohort study included data from 2002-2020. In the primary analysis, we used multivariate Poisson regression to estimate the incidence rate and incidence rate ratio of liver complications in patients with chronic hepatitis B, stratified by the presence of cardiometabolic comorbidities. In the secondary analysis, we compared the incidence rate of developing cardiometabolic comorbidities in patients with chronic hepatitis B to those of the general population. Both analyses were adjusted for sex, age, and country of origin, while the primary analysis was additionally adjusted for time since cardiometabolic comorbidity diagnosis and calendar year. The primary analysis included 4731 patients with chronic hepatitis B, of whom 532 (11%) had at least one cardiometabolic comorbidity. The unadjusted overall incidence rate of liver complications in patients with cardiometabolic comorbidities was 1.0 per 100 person-years (95% confidence intervals: 0.84-1.30) compared to 0.4 per 100 person-years (95% confidence intervals: 0.30-0.42) in those without. The incidence rate ratio for liver complications was highest in the first year following the diagnosis of cardiometabolic comorbidity. The incidence rate ratio for developing cardiometabolic comorbidities in the chronic hepatitis B cohort compared to the general population, was 1.10 (95% confidence intervals: 1.02-1.19). Sensitivity analyses revealed a higher incidence rate ratio for type 2 diabetes and hypertension but a lower incidence rate ratio for hypercholesterolemia. Patients with chronic hepatitis B and cardiometabolic comorbidities exhibit a higher incidence of liver complications, particularly in the first year following comorbidity diagnosis compared to those without comorbidities. Furthermore, patients with chronic hepatitis B have a higher incidence of cardiometabolic comorbidities than the general population.

Purpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population. Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first. Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0– 15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0– 12.3) and 0.2% (95% CI 0.1– 0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5– 1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5– 1.8), and 8.7 (95% CI 1.0– 16.4) in persons scoring < 10, 10– 17 and > 17, respectively (c-statistic 0.91 (95% CI 0.84– 0.98)). Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.

This study aimed to investigate psychological distress among patients hospitalized with a COVID-19 diagnosis in Denmark during the first 12 months of the pandemic and to assess changes in psychological distress in the three months following discharge. A single-center prospective observational survey study among patients hospitalized with a COVID-19 diagnosis between May 2020 and May 2021 was conducted. Participants completed a survey at three time points: at admission, and 1 and 3 months after discharge. Psychological distress was assessed by validated scales measuring symptoms related to depression, anxiety, stress, insomnia, post-traumatic stress disorder (PTSD), and health-related quality of life (HRQoL). In total, 95 patients were included. At admission, the proportion of patients with symptoms of depression was 43%, symptoms of anxiety 32%, moderate/high level of stress 39%, insomnia 52%, and probable/positive PTSD 19%. The burden of symptoms related to depression and anxiety decreased significantly over time, while there was no significant change over time in stress, insomnia, or PTSD. Suboptimal levels of physical and mental HRQoL were detected at admission but improved over time. Patients hospitalized due to COVID-19 during the first year of the pandemic experienced considerable levels of psychological distress at admission, with some improvements within 3 months after discharge.

Objective: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population. Study Design and Setting: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model. Results: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91– 1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76– 1.21). Conclusion: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population.

The study aimed to determine adjusted all-cause mortality and cause of death in persons with chronic hepatitis B virus (HBV) infection compared with age- and sex-matched persons from the general population. We used nationwide registers to identify persons aged >= 18 years with chronic HBV infection in 2002-2017 in Denmark and included 10 age- and sex-matched controls for each. Follow-up was from 6 months after diagnosis until death, emigration, or 31 December 2017. Mortality rate ratios (MRRs) adjusted for age, sex, employment, origin and comorbidity were calculated using Poisson regression. Unadjusted cause-specific mortality rate ratios with 95% confidence intervals were calculated assuming a Poisson distribution. A total of 6988 persons with chronic HBV infection and 69,847 controls were included. During a median follow-up of 7.7 years (range 0.0-15.5), 315 (5%) persons with-and 1525 (2%) without-chronic HBV infection died. The adjusted all-cause MRR was 1.5 (95% CI 1.2-2.0). Persons with chronic HBV infection had increased mortality due to liver disease including hepatocellular carcinoma (MRR 12.3 [8.6-17.7]), external causes (MRR 3.3 [2.5-4.7]), endocrine disease (MRR 3.2 [1.8-5.4]), genitourinary disease (MRR 3.2 [1.2-7.6]) and neoplasms (except hepatocellular carcinoma; MRR 1.6 [1.2-2.0]). In conclusion, this study showed an increased all-cause mortality in persons with chronic HBV infection in comparison with age- and sex-matched persons without chronic HBV infection which remained after adjustment for several confounding factors. Excess mortality was mainly associated with liver disease, but also external factors, endocrine disease, genitourinary disease and neoplasms (excluding hepatocellular carcinoma).

With increasing numbers of vaccine-breakthrough infections worldwide, assessing the immunogenicity of vaccinated health-care workers that are frequently exposed to SARS-CoV-2-infected individuals is important. In this study, neutralization titers against SARS-CoV-2 were assessed one month after completed prime-boost vaccine regimens in health-care workers vaccinated with either mRNA–mRNA (Comirnaty^®, BioNTech-Pfzier, Mainz, Germany/New York, NY, USA, n = 98) or vector-based (Vaxzevria^®, Oxford-AstraZeneca, Cambridge, UK) followed by mRNA-based (Comirnaty^® or Spikevax^®, Moderna, Cambridge, MA, USA) vaccines (n = 16). Vaccine-induced neutralization titers were compared to time-matched, unvaccinated individuals that were infected with SARS-CoV-2 and presented with mild symptoms (n = 38). Significantly higher neutralizing titers were found in both the mRNA–mRNA (ID₅₀: 2525, IQR: 1667–4313) and vector–mRNA (ID₅₀: 4978, IQR: 3364–7508) prime-boost vaccine regimens when compared to SARS-CoV-2 infection (ID₅₀: 401, IQR: 271–792) (p < 0.0001). However, infection with SARS-CoV-2 induced higher titers when compared to a single dose of Vaxzevria^® (p = 0.0072). Between mRNA–mRNA and vector–mRNA prime-boost regimens, the vector–mRNA vaccine regimen induced higher neutralization titers (p = 0.0054). Demographically, both age and time between vaccination doses were associated with vaccine-induced neutralization titers (p = 0.02 and p = 0.03, respectively). This warrants further investigation into the optimal time to administer booster vaccination for optimized induction of neutralizing responses. Although anecdotal (n = 3), those with exposure to SARS-CoV-2, either before or after vaccination, demonstrated superior neutralizing titers, which is suggestive of further boosting through viral exposure.