Mortality and cause of death in persons with chronic hepatitis B virus infection versus healthy persons from the general population in Denmark.

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).

Implementation of treatment recommendations for chronic hepatitis B in patients attending specialized hospital care in Denmark - a region wide study.

Objective: To evaluate implementation of national guideline recommendations on treatment initiation for chronic hepatitis B (CHB) in Denmark.Methods: Using DANHEP, a nationwide cohort of chronic hepatitis B and C patients attending specialized hospital care in Denmark, we performed a descriptive cohort study from January 2002 through December 2017. We identified patients with CHB in 3 of 5 Danish regions, with at least two hospital/outpatient clinic visits during the study period.Results: We identified 990 CHB patients who remained untreated throughout the study period, and 265 who initiated treatment. At their last visit 952/990 (96%, 95% CI 95-97) untreated patients did not meet current national criteria for treatment initiation while 198/265 (75%, 95% CI 69-80) who initiated treatment met the national criteria. Overall, 198/236 (84%, 95% CI 79-88) who met national treatment criteria, initiated treatment.Conclusion: The majority of CHB patients received care in line with national guideline recommendations for treatment initiation. We found that only few patients eligible for treatment remained untreated. However, a fourth of patients who received treatment were not eligible according to national guidelines.

The Consensus Hepatitis C Cascade of Care: Standardized Reporting to Monitor Progress Toward Elimination.

Cascade-of-care (CoC) monitoring is an important component of the response to the global hepatitis C virus (HCV) epidemic. CoC metrics can be used to communicate, in simple terms, the extent to which national and subnational governments are advancing on key targets, and CoC findings can inform strategic decision-making regarding how to maximize the progression of individuals with HCV to diagnosis, treatment, and cure. The value of reporting would be enhanced if a standardized approach were used for generating CoCs. We have described the Consensus HCV CoC that we developed to address this need and have presented findings from Denmark, Norway, and Sweden, where it was piloted. We encourage the uptake of the Consensus HCV CoC as a global instrument for facilitating clear and consistent reporting via the World Health Organization (WHO) viral hepatitis monitoring platform and for ensuring accurate monitoring of progress toward WHO's 2030 hepatitis C elimination targets.

Significant Reduction in the Incidence of Genital Warts in Young Men 5 Years into the Danish Human Papillomavirus Vaccination Program for Girls and Women.

BACKGROUND: Denmark introduced the quadrivalent human papillomavirus vaccine into the vaccination program for 12- to 15-year-old girls in 2008 to 2009. In 2012, the program was supplemented with a catch-up program for women aged up to 27 years. We evaluated the effectiveness of the Danish vaccination program on the nationwide incidence of genital warts (GWs), after the second catch-up by including information on both hospital treatments and on self-administered treatment with podophyllotoxin. Genital wart incidence was investigated in both sexes; however, the main focus was on potential herd protection of men. METHODS: Incident cases of GWs were identified from the Danish National Patient Register and through redemptions of prescription for podophyllotoxin in the Danish National Prescription Registry in 2006 to 2013. Age-specific incidence rates (IRs) were assessed, and estimated annual percentage change (EAPC) was calculated by Poisson regression. RESULTS: Genital wart incidence was either stable or increased in both sexes in 2006 to 2008. After introduction of the vaccination program, GW incidence decreased significantly in women aged 12 to 35 years and men aged 12 to 29 years, with rapid decrease among 16- to 17-year-olds (IRwomen, from 1071 to 58 per 100,000 person-years [EAPC, -55.1%; 95% confidence interval, -58.7 to-51.2]; IRmen, from 365 to 77 per 100,000 person-years [EAPC, -36.6%; 95% confidence interval, -40.5 to -32.5] in 2008-2013). CONCLUSIONS: We found a significantly decreasing incidence of GWs in women up to 35 years of age after the start of the human papillomavirus vaccination program. A similar pattern was observed for men aged 12 to 29 years, indicating substantial herd protection.

Clinical trial: An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B.

BACKGROUND: Stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB) may trigger a beneficial immune response leading to HBsAg loss, but clinical trials on re-start strategies are lacking. AIM: To assess whether it is beneficial to undergo a prolonged flare after NA cessation. METHODS: One-hundred-and-twenty-seven patients with HBeAg negative, non-cirrhotic CHB with at least 24 months of viral suppression on NA therapy were included. All study participants stopped antiviral therapy and were randomised to either low-threshold (ALT > 80 U/L and HBV DNA > 2000 IU/mL) or high-threshold (ALT > 100 U/L for >4 months, or ALT > 400 U/L for >2 months) for the re-start of therapy. The primary endpoint was HBsAg loss within 36 months of stopping antiviral treatment. The primary analysis was based on intention-to-treat allocation with last observation carried forward. RESULTS: There was a numerical but not statistically significant difference in HBsAg loss between the low-threshold (3 of 64; 4.7%) and the high-threshold (8 of 63; 12.7%) group (risk difference: 8.0%, 95% CI: -2.3 to 19.6, p = 0.123). None of the patients with end-of-treatment HBsAg > 1000 IU/mL achieved HBsAg loss; among those with end-of-treatment HBsAg < 1000 IU/mL, 8 of 15 (53.3%) achieved HBsAg loss in the high-threshold group compared to 3 of 26 (11.5%) in the low-threshold group. CONCLUSIONS: We could not confirm our hypothesis that a higher threshold for restart of therapy after NA withdrawal improves the likelihood of HBsAg loss within 36 months in patients with HBeAg negative CHB. Further studies including only patients with HBsAg level <1000 IU/mL and/or larger sample size and longer follow-up duration are recommended.

Increasing prevalence of chronic hepatitis B virus infection and low linkage to care in Denmark on 31 December 2016 - an update based on nationwide registers.

OBJECTIVES: We aimed to update the estimated prevalence of both diagnosed and undiagnosed chronic hepatitis B virus infection in Denmark. Moreover, we aimed to determine the number of people with chronic hepatitis B virus infection in specialised care and to assess the completeness of reporting to the national register of communicable diseases. METHODS: Using four registers with national coverage, we identified all individuals registered with chronic hepatitis B virus infection, aged 16 years or older, and alive in Denmark on 31 December 2016. The diagnosed population was then estimated using capture-recapture analysis. The undiagnosed population was estimated using data from the Danish pregnancy screening program. RESULTS: We estimated that 14,548 individuals were living with chronic hepatitis B virus infection corresponding to 0.3% of the Danish population. Of them, 13,530 (93%) were diagnosed and 7942 (55%) were registered in one or more of the source registers. Only 4297 (32%) diagnosed individuals had attended specialised care and only 3289 cases (24%) were reported to the Danish communicable disease register. CONCLUSION: The prevalence of chronic hepatitis B virus infection increased from 2007 to 2017. The majority that had been diagnosed did not receive care as recommended by national guidelines and were not reported to the communicable diseases register responsible for hepatitis B virus surveillance. Future efforts should focus on linking individuals diagnosed with chronic hepatitis B virus infection to specialised care and improving reporting to the hepatitis B virus surveillance system.

Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial.

OBJECTIVES: The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if pre-emptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14. METHODS: Between 9 June 2021 and 27 January 2022, this randomized, double-blinded, placebo-controlled, single-centre clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomly assigned 1:1 to either amantadine 100 mg or placebo twice daily for 5 days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (a) age ≥40 years, age ≥18 years and (b) at least one comorbidity, or (c) body mass index ≥30. The study protocol was published at www. CLINICALTRIALS: gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22). RESULTS: With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm, respectively. No participants in either group were admitted to hospital or died. The OR of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (CI 1.0-3.3, [p 0.051]). On day 7, one participant was hospitalized in each group; throughout the study, this increased to five and three participants for amantadine versus placebo treatment (p 0.72). Similarly, on day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p 0.84). CONCLUSION: We found no effect of amantadine on disease progression of SARS-CoV-2 infection.

Durability and breadth of neutralisation following multiple antigen exposures to SARS-CoV-2 infection and/or COVID-19 vaccination.

BACKGROUND: Given the importance of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the prevention of severe coronavirus disease 2019 (COVID-19), detailed long-term analyses of neutralising antibody responses are required to inform immunisation strategies. METHODS: In this study, longitudinal neutralising antibody titres to an ancestral SARS-CoV-2 isolate and cross-neutralisation to delta and omicron isolates were analysed in individuals previously infected with SARS-CoV-2, vaccinated against COVID-19, or a complex mix thereof with up to two years of follow-up. FINDINGS: Both infection-induced and vaccine-induced neutralising responses against SARS-CoV-2 appeared to follow similar decay patterns. Following vaccination in previously infected individuals, neutralising antibody responses were more durable than prior to vaccination. Further, this study shows that vaccination after infection, as well as booster vaccination, increases the cross-neutralising potential to both delta and omicron SARS-CoV-2 variants. INTERPRETATION: Taken together, these results suggest that neither type of antigen exposure is superior for neutralising antibody durability. However, these results support vaccination to increase the durability and cross-neutralisation potential of neutralising responses, thereby enhancing protection against severe COVID-19. FUNDING: This work was supported by grants from The Capital Region of Denmark's Research Foundation, the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Candys Foundation, and the Danish Agency for Science and Higher Education.

Psychological Distress among Hospitalized COVID-19 Patients in Denmark during the First 12 Months of the Pandemic.

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.

[The antiviral targeting potential of viroporins].

Viroporins are ion channels found in many viruses, where they contribute to virus life cycle and thereby pathogenesis. Viroporin targeting is a known, yet largely unexplored, therapeutic strategy so far only used in Influenza A with the drugs amantadine and rimantadine. In this review, we seek to utilize the inhibition by amantadine of the viroporin Protein E in SARS-CoV-2 in an attempt to treat COVID-19 in its early stages. We are executing a double-blinded placebo-controlled trial based on promising in vivo and in vitro work as a stepping-stone for establishing a therapeutic antiviral regime: blocking of viroporins.

Analysis of Neutralization Titers against SARS-CoV-2 in Health-Care Workers Vaccinated with Prime-Boost mRNA-mRNA or Vector-mRNA COVID-19 Vaccines.

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.

Incidence of Hepatocellular Carcinoma and Decompensated Liver Cirrhosis and Prognostic Accuracy of the PAGE-B HCC Risk Score in a Low Endemic Hepatitis B Virus Infected 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.

Ischemic Heart Disease in Chronic Hepatitis B: A Danish Nationwide Cohort Study.

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.

Hepatitis B virus elimination status and strategies in circumpolar countries, 2020.

Hepatitis B virus (HBV) infection remains a global health threat. The World Health Organization (WHO) established a goal to eliminate HBV infection as a public health threat by 2030, and defined targets for key interventions to achieve that goal. We evaluated HBV burden and relevant national recommendations for progress towards WHO targets in circumpolar countries. Viral hepatitis experts of circumpolar countries were surveyed regarding their country's burden of HBV, achievement of WHO targets and national public health authority recommendations for HBV prevention and control. Eight of nine circumpolar countries responded. All countries continue to see new HBV infections. Data about HBV prevalence and progress in reaching WHO 2030 elimination targets are lacking. No country was able to report data for all seven WHO target measures. All countries have recommendations targeting the prevention of mother-to-child transmission. Only the USA and Greenland recommend universal birth dose vaccination. Four countries have recommendations to screen persons at high risk for HBV. Existing recommendations largely address prevention; however, recommendations for universal birth dose vaccination have not been widely introduced. Opportunities remain for the development of trackable targets and national elimination planning to screen and treat for HBV to reduce incidence and mortality.

In vitro Characterization of Fitness and Convalescent Antibody Neutralization of SARS-CoV-2 Cluster 5 Variant Emerging in Mink at Danish Farms.

In addition to humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. Among these, mink are particularly susceptible. Indeed, 10 countries in Europe and North America reported SARS-CoV-2 infection among mink on fur farms. In Denmark, SARS-CoV-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions with unknown consequences for virulence and antigenicity. Here we describe a mink-associated SARS-CoV-2 variant (Cluster 5) characterized by 11 amino acid substitutions and four amino acid deletions relative to Wuhan-Hu-1. Temporal virus titration, together with genomic and subgenomic viral RNA quantitation, demonstrated a modest in vitro fitness attenuation of the Cluster 5 virus in the Vero-E6 cell line. Potential alterations in antigenicity conferred by amino acid changes in the spike protein that include three substitutions (Y453F, I692V, and M1229I) and a loss of two amino acid residues 69 and 70 (ΔH69/V70), were evaluated in a virus microneutralization assay. Compared to a reference strain, the Cluster 5 variant showed reduced neutralization in a proportion of convalescent human COVID-19 samples. The findings underscore the need for active surveillance SARS-CoV-2 infection and virus evolution in susceptible animal hosts.

Neutralisation titres against SARS-CoV-2 are sustained 6 months after onset of symptoms in individuals with mild COVID-19.

BACKGROUND: Given the importance of neutralising antibodies in protection against SARS-CoV-2 infection, it is critical to assess neutralisation persistence long-term following recovery. This study investigated neutralisation titres against SARS-CoV-2 up to 6 months post-symptom onset in individuals with mild COVID-19. METHODS: Plasma neutralisation titres in convalescent COVID-19 individuals were determined at baseline and 6 months post-symptom onset using a cell culture infectious SARS-CoV-2 assay. Total SARS-CoV-2 spike-specific IgG and IgA binding was measured using a lectin capture ELISA and compared between timepoints and correlated to neutralising titres. FINDINGS: All 48 convalescent COVID-19 individuals were found to have detectable SARS-CoV-2 50% inhibitory dilution neutralisation titres (ID50) at baseline and 6 months post-symptom onset with mean ID50 of 1/943 and 1/411, respectively. SARS-CoV-2 neutralisation titres peaked within 1-2 months post-symptom onset. However, 50% of individuals showed comparable ID50 at baseline and 6 months post-symptom onset. Both SARS-CoV-2 spike-specific IgG and IgA levels correlated well with neutralising titres. IgG binding was found to be sustained up to 6 months post-symptom onset, whereas IgA levels declined. INTERPRETATION: This study demonstrates durability of SARS-CoV-2 spike-specific IgG and neutralisation responses following recovery from mild COVID-19. Thus, all subjects included in this study might potentially have protective levels of neutralising antibodies 6 months post-symptom onset. This study also demonstrates a relationship between spike-specific IgA and neutralisation decline, with implications for long-term protection against SARS-CoV-2 infection. FUNDING: Novo Nordisk Foundation, Independent Research Fund Denmark and Danish Agency for Science and Higher Education.

Socioeconomic predictors of human papillomavirus vaccination in Danish men - A nationwide study.

BACKGROUND: The quadrivalent human papillomavirus vaccine was licensed in Denmark in 2006. Unlike women, men are not offered human papillomavirus vaccination free of charge but can have it at their own expense. We investigated human papillomavirus vaccine uptake by men in Denmark and the socioeconomic factors that may predict human papillomavirus vaccination. METHODS: Using the Civil Registration System, we identified all boys and men aged 9-26 years in 2006-2013 and their mothers. By linkage to Statistics Denmark and the National Prescription Registry, we obtained information on socioeconomic variables and human papillomavirus vaccination during the study period. Using Cox regression, we examined the associations between socioeconomic variables and human papillomavirus vaccination. RESULTS: Between 2006 and 2013, 6253 (0.8%) males aged 9-26 years were vaccinated against human papillomavirus. The strongest predictor identified was ethnicity. Males who were immigrants (hazard ratio, 0.12; 95% confidence interval, 0.08-0.180) or sons of immigrant parents (hazard ratio, 0.13; 95% confidence interval, 0.10-0.17) were less likely to be vaccinated than Danish males. Additionally, sons of mothers who were unemployed, unmarried, had a low income, and basic education initiated human papillomavirus vaccination less frequently. Finally, sons of mothers who were physicians or nurses were more likely to be vaccinated than sons of other highly educated mothers. CONCLUSION: We found low uptake, with social disparities in human papillomavirus vaccination of boys and young men in Denmark.