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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). [ABSTRACT FROM AUTHOR]

Enhancing treatment uptake for hepatitis C to achieve the elimination goals set by the World Health Organization could be achieved by reducing the treatment duration. The aim of this study was to compare the sustained virological response at week 12 (SVR12) after four weeks of glecaprevir/pibrentasvir (GLE/PIB) + ribavirin compared to eight weeks of GLE/PIB and to estimate predictors for SVR12 with four weeks of treatment through a multicenter open label randomized controlled trial. Patients were randomized 2:1 (4 weeks:8 weeks) and stratified by genotype 3 and were treatment naïve of all genotypes and without significant liver fibrosis. A total of 27 patients were analyzed for predictors for SVR12, including 15 from the first pilot phase of the study. In the 'modified intention to treat' group, 100% (7/7) achieved cure after eight weeks and for patients treated for four weeks the SVR12 was 58.3% (7/12). However, patients with a baseline viral load <2 mill IU/mL had 93% SVR12. The study closed prematurely due to the low number of included patients due to the COVID-19 pandemic. Our results suggest that viral load should be taken into account when considering trials of short course treatment. [ABSTRACT FROM AUTHOR]

Background & Aims: Shortening the treatment duration for chronic hepatitis C may increase feasibility and reduce the cost of cure. The aims of this study were to compare 4 weeks of glecaprevir/pibrentasvir (GLE/PIB) treatment with and without ribavirin for patients with chronic hepatitis C and favourable baseline characteristics and to monitor the development of resistance‐associated substitutions (RAS) and re‐treatment outcomes if treatment failed. Methods: We performed an open‐label single‐centre randomized controlled trial, in which patients with chronic hepatitis C were randomized 1:1 to GLE/PIB ± ribavirin, stratified by genotype 3. The main inclusion criteria were treatment‐naive patients, aged 18‐49 with all genotypes accepted, and absence of liver fibrosis, determined by liver stiffness measurement less than 8 kPa. Viral genome sequences were determined by deep sequencing at baseline and at the time of relapse. Results: A total of 32 patients started treatment. Sustained virological response at week 12 (SVR12) was 59% (10/17) for GLE/PIB without ribavirin and 73% (11/15) for GLE/PIB with ribavirin. Drug target‐specific NS5A RAS were detected at baseline for 45% (5/11) of patients with treatment failure and for 14% (3/21) of patients who achieved SVR12. Ten failure patients were retreated 12 weeks with sofosbuvir‐based regimens; all have been cured. Conclusions: In this pilot study of 4‐week treatment with GLE/PIB with and without ribavirin, we found that baseline RAS were more frequent in patients with virological failure. Development of RAS did occur after short treatment but did not result in retreatment failure with a different regimen. EudraCT no: 2017‐005179‐21. [ABSTRACT FROM AUTHOR]

Abstract Background The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment. Methods We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis. Results The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≤ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin. Conclusions The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.

Direct‐acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance‐associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment‐failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral‐titre data were compared between the two patient groups, and HCV full‐length open reading frame deep‐sequencing was performed. The proportion of HCV NS5A‐RASs at baseline was higher in treatment‐failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment‐failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B‐substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3‐helicase and NS5A‐domain‐III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs. [ABSTRACT FROM AUTHOR]

Objectives: We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. Materials and Methods: In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. Results: In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). Conclusions: In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: The first standard of care in treatment of chronic HCV genotype 1 infection involving directly acting antivirals was protease inhibitors telaprevir or boceprevir combined with pegylated-interferon and ribavirin (triple therapy). Phase III studies include highly selected patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1 infection in a routine clinical setting. Methods: 80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis of the RT-PCR amplified NS3 protease were performed in patients without cure following triple therapy. Results: 38 (47%) of the patients achieved cure, 15 (19%) discontinued treatment due to adverse events and remained infected, and 27 (34%) experienced relapse or treatment failure of whom 15 of 21 analyzed patients had well-described protease inhibitor resistance variants detected. Most frequently detected protease variants were V36M and/or R155K, and V36M, in patients with genotype 1a and 1b infection, respectively. Conclusions: The cure rate after triple therapy in a routine clinical setting was 47%, which is substantially lower than in clinical trials. Resistance variants towards protease inhibitors were seen in 71% of patients failing therapy indicating that resistance could have an important role in treatment response. [ABSTRACT FROM AUTHOR]

Liver stiffness measurement (LSM) is widely used to evaluate liver fibrosis, but longitudinal studies are rare. The current study was aimed to monitor LSM during follow-up, and to evaluate the association of LSM data with mortality and liver-related outcomes. We included all patients with chronic viral hepatitis and valid LSM using Fibroscan. Information about liver biopsy, antiviral treatment, and clinical outcome was obtained from medical records and national registers. The study included 845 patients: 597 (71%) with hepatitis C virus (HCV), 235 (28%) with hepatitis B virus (HBV) and 13 (2%) with dual infection. The initial LSM distribution (<7/7–9.9/10–16.9/≥17 kPa) was 58%/16%/14%/12%. Among patients with initial LSM values of 7–9.9 kPa, 60% of HCV patients and 83% of HBV patients showed LSM values of <7 kPa at the latest follow-up. Progression rates (defined as >20% and >2 kPa increase, with one measure >7 kPa) were 3.4/100 person years (PY) for HCV and 1.5/100 PY for HBV infected patients. Patients with LSM values of ≥17 kPa had the same liver-related complication incidence as patients with biopsy-proven cirrhosis (11.1 versus 12.1/100 PY). Thirteen liver-related deaths occurred among HCV patients (0.6/100 PY), but none among HBV patients. Among patients who died of liver-related causes, all but one had baseline LSM values of ≥17 kPa. Overall, patients with LSM values <17 kPa were not associated with adverse outcomes. In contrast, LSM values ≥17 kPa were associated with significant risk of liver-related problems. The results of the current study suggest that clinical decisions should not be taken based on a single LSM measurement. [ABSTRACT FROM AUTHOR]

Aim: To compare the prevalence and severity of depressive symptoms among drug users with and without hepatitis C virus (HCV) infection. Methods: This was a cross-sectional survey study carried out at the 2 major drug treatment centres on the island of Funen, Denmark. Participants were drug users presenting to the 2 treatment centres. Individuals with chronic hepatitis B virus or HIV infection were excluded. Participants completed the Major Depression Inventory (MDI) questionnaire when presenting at the centres. Patients with MDI scores indicating severe depression (total MDI score ≥ 35) were referred for treatment evaluation. Hepatitis C status was classified by the presence of anti-HCV as a marker of HCV exposure and HCV-RNA as a marker of ongoing infection. Results: Two hundred and sixty-eight patients were included, of whom 235 (88%) had complete serological testing; 100 (43%, 95% confidence interval (CI) 36-49%) had chronic hepatitis C. The median MDI score was 22 (interquartile range 12-33); 32% (95% CI 26-39%) had a score compatible with depression and 14% (95% CI 10-19%) were rated as severe depression. Depression was not associated with hepatitis C (HCV-infected 29%, non-infected 35%; p = 0.25). Forty-one percent (11/27) of the evaluated participants started antidepressant treatment. Conclusions: Our study demonstrated a high prevalence of depressive symptoms among drug users, but this was not more frequent among HCV-infected patients. The high overall prevalence of depression underlines the relevance of screening for depression in patients who are drug users. [ABSTRACT FROM AUTHOR]

Background: The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment. Methods: We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis. Results: The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≥ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin. Conclusions: The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about regression of cirrhosis of the liver found by elastiometry that was published in 2008 issue.

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., Competing Interests: Signe Bollerup (SB) received financial support for conference participation from Abbvie, Gilead and MSD. Frederik Neess Engsig (FNE) reports lecture fee from MSD, not related to this study. Amanda Mocroft (AM) reports lecture fees, honoraria or consultancy fees from Gilead, ViiV, and Eiland and Bonnin, not related to this study. Peer B Christensen (PBC) reports grants from Abbvie, Gilead and MSD. None were related to this study. Alex Laursen (AL) received grants from Abbvie and Gilead, not related to this study. Nina Weis (NW) reports grands from Abbvie, Gilead and Novo Nordisk Foundation, not related to this study. Moreover, NW has been clinical investigator, lecturer or member of advisory boards for Abbvie, Gilead, GSK and MSD. The authors report no other conflicts of interest in this work., (© 2022 Bollerup et al.)

Limited information is available in relation to surveillance, genotyping, genome sequences, and treatment outcomes for rare hepatitis C virus variants. Here, we have characterized a novel subtype of major hepatitis C virus genotype 1, which was deep sequenced before and after treatment failure with 4 weeks of glecaprevir and pibrentasvir.

Aim: To detect chronic hepatitis B (CHB), chronic hepatitis C (CHC) and human immunodeficiency virus (HIV) infections in dried blood spot (DBS) and compare these samples to venous blood sampling in real-life., Methods: We included prospective patients with known viral infections from drug treatment centers, a prison and outpatient clinics and included blood donors as negative controls. Five drops of finger capillary blood were spotted on filter paper, and a venous blood sample was obtained. The samples were analyzed for HBsAg, anti-HBc, anti-HBs, anti-HCV, and anti-HIV levels as well as subjected to a combined nucleic acid test (NAT) for HBV DNA, HCV RNA and HIV RNA., Results: Samples from 404 subjects were screened (85 CHB, 116 CHC, 114 HIV and 99 blood donors). DBS had a sensitivity of > 96% and a specificity of > 98% for the detection of all three infections. NAT testing did not improve sensitivity, but correctly classified 95% of the anti-HCV-positive patients with chronic and past infections. Anti-HBc and anti-HBS showed low sensitivity in DBS (68% and 42%)., Conclusion: DBS sampling, combined with an automated analysis system, is a feasible screening method to diagnose chronic viral hepatitis and HIV infections outside of the health care system., Competing Interests: Conflict-of-interest statement: Peer Brehm Christensen has received research grants from Abbvie and Gilead; no other authors have any conflicts of interest to disclose.

With the demonstration of an effect of GBV-C infection on the outcome of HIV infection, it has become important to understand the epidemiology of GBV-C. The purpose of this study was to determine the prevalence in high- and low-risk populations. The following populations were tested: school children, 9 and 15 years of age (n = 901), blood donors (n = 5,203), hospital employees (n = 1,432), and prisoners and injecting drug users (n = 447). In-house RT-PCR for GBV-CRNA was used together with a commercial ELISA for anti-E2 (Boehringer, Germany). In addition, questionnaires for risk factors for transmission and serological tests for HIV and hepatitis were applied. The overall prevalence of GBV-CRNA was 1.4% among children, 2.2% among blood donors, 2.2% among hospital employees, 12.5% among non-injecting prisoners, and 34.9% among drug injectors. Correspondingly anti-E2 was found in 0.3%, 12.3%, 25.0%, and 42.7%. Among hospital employees, independent risk factors for GBV-C were professions with blood exposure and sexual risk partners. Among prisoners and drug users, injecting and a sexual risk index were associated independently with GBV-C. Based on these results, the following hypothesis is suggested: GBV-C is transmitted frequently at birth or early childhood and this leads to chronic infection in most cases. Sexual transmission is the most important route of transmission in the adult population but this infection is usually transient. Blood borne transmission plays a role among health care workers and injecting drug users and GBV-C should be further evaluated as a surrogate marker for professional blood exposure., (Copyright 2003 Wiley-Liss, Inc.)

Injecting drug users and prisoners have high prevalences of antibodies to hepatitis A-C. The aim of this study was to determine the prevalence of antibodies to hepatitis E virus (anti-HEV) in two Danish high-risk populations and correlate anti-HEV with risk factors for transmission. Three hundred thirty male prisoners and 137 patients at a drug treatment center were tested for anti-HEV with an in-house enzyme-linked immunoassay (EIA) utilizing antigens derived from open reading frame 2 (ORF2). This was compared with a commercial test with antigens derived from ORF2 and ORF3 (Abbott HEV EIA). In addition the samples were tested for antibodies against hepatitis A-C viruses, human immunodeficiency virus (HIV) 1 and 2, human T lymphotropic virus (HTLV) I and II and herpes simplex virus type 2 (HSV2). The participants were interviewed about risk factors for transmission. The anti-HEV prevalence was 16.9% (95% CI 14-21) for the in-house assay compared to 4.1% (95% CI 2.5-6.3) with the commercial assay. The correlation between the two assays was low (87% overall agreement; kappa value 0.32). One sample was strongly anti-HEV IgM positive, suggesting recent HEV infection inside Denmark. The presence of anti-HEV was associated significantly with anti-HAV among prisoners and increased with age in both groups. In contrast, associations were not found with injecting drug use or sexual risk factors. With the commercial assay an increased prevalence of anti-HEV was found among participants who had spent more than 5 years outside Northern Europe. In conclusion, anti-HEV was highly prevalent among Danish prisoners and drug users but not related to risk factors for blood-borne or sexual transmission., (Copyright 2002 Wiley-Liss, Inc.)