Combining cross-sectional survey and register data improved the estimate of hepatitis C prevalence among patients attending a psychiatric emergency department in Denmark.

BACKGROUND: The prevalence of hepatitis C (HCV) among psychiatric patients is elevated compared to the background population in many studies, but the prevalence among Danish psychiatric patients is unknown. The aim of the study was to determine the HCV prevalence and the proportion of the psychiatric patient population that remains to be diagnosed and treated in a Danish setting. METHODS: During a 5-month period, patients attending the psychiatric emergency room in Vejle, Denmark, were offered point-of-care anti-HCV testing. Previous hepatitis C tests for all patients attending the Psychiatric Department in the study period were extracted from the national laboratory database (DANVIR). We combined the survey and register data in a capture-recapture estimate of undiagnosed patients with HCV. RESULTS: During the study 24.9% (589 of 2364) patients seen at the psychiatric department attended the emergency room. The prevalence of anti-HCV among those tested in the emergency room was 1.6%. The laboratory register identified 595/2364 patients previously tested for anti-HCV with a positive prevalence of 6.1%. The undiagnosed anti-HCV positives among the 1483 never tested was estimated to 1.1%. Thus the total estimated prevalence of anti-HCV was 2.3% (54/2364, 95% CI 1.7%-3.0%) in the population, of whom 70.4% had been diagnosed, and 72.2% of diagnosed patients had received treatment or cleared HCV. CONCLUSION: Combining survey and register data showed that the WHO target of 90% diagnosed and 80% treated was not met. To eliminate HCV in the psychiatric population, both undiagnosed and untreated patients must be targeted.

Retrieval of patients with hepatitis C who were lost to follow-up in Southern Denmark.

BACKGROUND: The goal of the C-Free-South project is to eliminate hepatitis C (HCV) in the Region of Southern Denmark (1.2 million inhabitants). One target group consists of people with HCV who had received care but were lost to follow-up. The study aim was to evaluate program efficacy in locating these patients and getting them into care. METHODS: Patients were contacted if they were HCV-RNA positive and age 18+ years, registered in the clinical hepatitis database as of November 1, 2019, and had no scheduled HCV-related appointment. They were contacted at 2-month intervals by phone or letter. For patients who did not respond, we asked their general practitioner to refer them, if possible. RESULTS: We identified 69 (7%) patients in the database who were listed as untreated and not being followed up. We successfully contacted 54 (78%), and the remaining 15 (22%) did not respond to our contacts. To date, 45 (65%) had initiated treatment, one (1%) had rejected treatment, and eight (12%) did not show up to their appointments. Among those receiving treatment, 20 (44%) responded after the first contact, 18 (40%) after the second contact, and 7 (16%) after informing the general practitioner. CONCLUSION: An intensified and persistent effort made it possible to reach most HCV patients lost to follow-up. All new contact attempts increased the possibility that patients would receive treatment. Nevertheless, 22% of HCV patients lost to follow-up did not respond to repeated contact attempts.

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.

A multi-level intervention to eliminate hepatitis C from the Region of Southern Denmark: the C-Free-South project.

Denmark has signed the WHO strategy to eliminate hepatitis C virus (HCV). In the absence of a national strategy for elimination, a local action plan was developed in the Region of Southern Denmark (RSD). The aim of the strategy is to diagnose 90% of HCV-infected persons and treat 80% of those diagnosed by 2025. The strategy was developed by reviewing Danish data on HCV epidemiology and drug use to identify key populations for screening, linkage to care, and treatment. Based on available published data from 2016, an estimated 3028 persons in the RSD were HCV-RNA positive (population prevalence 0.21%). Of these, 1002 were attending clinical care, 1299 were diagnosed but not in clinical care, and 727 were undiagnosed. Three different interventions targeting the HCV-infected population and two interventions for HCV surveillance are planned to achieve elimination. The "C-Free-South" strategy aims to eliminate HCV in our region by identifying (90%) and treating (80%) of infected persons by the end of 2025, 5 years earlier than the WHO elimination target date.

Immunogenicity of SARS-CoV-2 mRNA vaccine in solid organ transplant recipients.

BACKGROUND: It is currently not well described if a two-dose regimen of a Covid-19 vaccine is sufficient to elicit an immune response in solid organ transplant (SOT) recipients. RESULTS: A total of 80 SOT recipients completed a two-dose regimen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine. Only 35.0% (n = 28) were able to mount a positive IgG immune response 6 weeks after the second dose of vaccine. CONCLUSION: This emphasizes that SOT recipients need continued use of personal protective measures. Future studies need to closely examine the cellular immune response in patients with compromised antibody response to Covid-19 vaccination.

Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs.

BACKGROUND AND AIMS: To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs). METHODS: 773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa [reference], 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression. RESULTS: Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001. CONCLUSION: Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.

Hepatitis C prevalence in Denmark in 2016-An updated estimate using multiple national registers.

BACKGROUND: Chronic hepatitis C (CHC) can be eliminated as a public health threat by meeting the WHO targets: 90% of patients diagnosed and 80% treated by 2030. To achieve and monitor progress towards elimination, an updated estimate of the size of the CHC population is needed, but Denmark has no complete national CHC register. By combining existing registers in 2007, we estimated the population living with CHC to be 16,888 (0.38% of the adult population). AIM: To estimate the population living with diagnosed and undiagnosed CHC in Denmark on 31 December 2016. Among additional aims were to estimate the proportion of patients attending specialised clinical care. METHODS: People with diagnosed CHC were identified from four national registers. The total diagnosed population was estimated by capture-recapture analysis. The undiagnosed population was estimated by comparing the register data with data from two cross-sectional surveys. RESULTS: The population living with diagnosed CHC in Denmark was 7,581 persons (95%CI: 7,416-12,661) of which 6,116 (81%) were identified in the four registers. The estimated undiagnosed fraction was 24%, so the total CHC infected population was 9,975 corresponding to 0.21% of the adult population (95%CI: 9,758-16,659; 0.21%-0.36%). Only 48% of diagnosed patients had received specialised clinical care. CONCLUSION: CHC prevalence in Denmark is declining and 76% of patients have been diagnosed. Linking diagnosed patients to care and increasing efforts to test people with former or current drug use will be necessary to achieve CHC elimination.

Incidence, prevalence and risk factors for hepatitis C in Danish prisons.

Hepatitis C virus (HCV) infection is prevalent among people in prison and prisons could therefore represent a unique opportunity to test risk groups for HCV. The aim of this sero-epidemiological study was to determine the incidence and prevalence of HCV infection and the corresponding risk factors in Danish prisons. Participants, recruited from eight Danish prisons, were tested for HCV using dried blood spots and filled out a questionaire with demographic data and risk factors for HCV infection. In total, 76.9% (801/1041) of all eligible prisoners consented to participate. The prevalence of HCV RNA positive prisoners was 4.2% (34/801) and the in-prison incidence rate was 0.7-1.0 per 100PY overall and 18-24/100PY among PWIDs. Infected prisoners were older than the overall population with a mean age of 42 years and only 17.6% (6/34) were younger than 35 years. The prevalence of PWID was 8.5% (68/801) and only 3% (2/68) of PWID were younger than 25 years. Among the PWID, 85.3% (58/68) had ever received opioid substitution therapy (OST) and 47.1% (32/68) were currently receiving OST. Risk factors associated with HCV infection were intravenous drug use, age ≥ 40 years, and being incarcerated ≥ 10 years. In conclusion, the prevalence of PWID in Danish prisons is low, possibly reflecting a decrease in injecting among the younger generation. This together with OST coverage could explain the low prevalence of HCV infection. However among PWIDs in prison the incidence remains high, suggesting a need for improved HCV prevention in prison.

Combining liver stiffness with hyaluronic acid provides superior prognostic performance in chronic hepatitis C.

BACKGROUND: Non-invasive methods are the first choice for liver fibrosis evaluation in chronic liver diseases, but few studies investigate the ability of combined methods to predict outcomes. METHODS: 591 chronic hepatitis C patients with baseline liver stiffness (LSM) by FibroScan and hyaluronic acid measurements were identified retrospectively. The patients were grouped by baseline LSM: < 10kPa, 10-16.9kPa, and 17-75kPa. Primary outcomes were all-cause mortality and liver-related mortality, analyzed using cox regression and competing risk regression models, respectively. RESULTS: Median follow-up was 46.1 months. Prevalence of cirrhosis at baseline was 107/591 (18.1%). Median LSM was 6.8kPa (IQR 5.3-11.6) and divided into groups, 404/591 (68.4%) had a LSM < 10kPa, 100/591 (16.9%) had a LSM between 10-16.9kPa and 87/591 (14.7%) had a LSM between 17-75kPa. There were 69 deaths, 27 from liver-related disease. 26 patients developed cirrhosis and 30 developed complications of cirrhosis. The mortality rate in the 17-75kPa group was 9.7/100 person-years, compared to 2.2/100 person-years and 1.1/100 person-years in the 10-16.9kPa and <10kPa groups (p<0.005). Liver-related mortality increased 10-fold for each group (p<0.005). Cirrhotic complications occurred almost exclusively in the 17-75kPa group, with an incidence of 10.3/100 person-years, compared to 1.8/100 person-years and 0.2/100 person-years in the 10-16.9kPa and <10kPa groups (p<0.005). Median hyaluronic acid in the 17-75kPa group was approximately 200ng/mL. Patients with a LSM 17-75kPa had significantly higher risks of death, liver-related death, and complications to cirrhosis if their hyaluronic acid measurement was more than or equal to 200ng/mL at baseline, with hazard ratios of 3.25 (95% CI 1.48-7.25), 7.7 (95% CI 2.32-28), and 3.2 (95% CI 1.35-7.39), respectively. CONCLUSIONS: The combination of LSM and circulating hyaluronic acid measurements significantly improved prognostic ability, relative to LSM alone. Combined static and dynamic markers of liver fibrosis could provide superior risk prediction.

Test uptake and hepatitis C prevalence in 5483 Danish people in drug use treatment from 1996 to 2015: a registry-based cohort study.

BACKGROUND AND AIMS: The aims of this study were, in people in treatment for drug use in Funen, Denmark, to: (1) assess prevalence of hepatitis C virus (HCV) test uptake and prevalence of HCV; (2) identify predictors of test update and HCV infection; and (3) characterize changes between 1996 and 2015 in test uptake, HCV prevalence and drug use. DESIGN: Cohort study linking the Danish National Registry on Drug Users in Treatment to the regional hepatitis test registry and the Danish Death Certificate Registry, thus combining longitudinal data on drug use with data on HCV testing and results. SETTING AND PARTICIPANTS: People recorded as having received treatment for drug use between 1996 and 2015 (n = 5483) in Funen, Denmark. In the cohort, 24.8% were female, median age 23 years [interquartile range (IQR) = 20-32] at entry and 50% had self-reported injecting or had received opiate substitution therapy (OST). MEASUREMENTS: The main outcomes were the test for HCV ever and latest HCV-RNA being positive. The main predictors were for test and infection investigated; ever receiving OST, self-reported injecting, age at entry and connection to treatment centre offering outreach hepatitis care. FINDINGS: HCV test uptake was 52% and prevalence of current HCV-RNA+ was 21% in people alive at the end of follow-up. Positive predictors of having undergone HCV testing were: receiving OST [odds ratio (OR) = 3.7; 95% confidence interval (CI) = 3.2-4.5], self-reported injecting (OR = 2.3; 95% CI = 2.0-2.7), female gender (OR = 1.7; 95% CI = 1.4-1.9) and having been connected to centres with outreach hepatitis care (OR = 1.4; 95% CI = 1.2-1.7). In people alive, HCV-RNA+ prevalence was 31% if ever on OST or self-reported injecting. Among HCV-infected people, 69% were in drug use treatment at end of follow-up. For participants entering the cohort after 2010, only 5% reported opiates as main drug of use and 17% had experience of injecting. CONCLUSION: Among Danish people in treatment for drug use from 1996 to 2015, receiving opiate substitution therapy had the largest associating to being tested for hepatitis C virus. As opiate use is declining, adapting test strategies will be necessary.

Accuracy of the Enhanced Liver Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in Patients With Alcoholic Liver Disease.

BACKGROUND & AIMS: Alcohol is the leading cause of cirrhosis and liver-related mortality, but we lack serum markers to detect compensated disease. We compared the accuracy of the Enhanced Liver Fibrosis test (ELF), the FibroTest, liver stiffness measurements (made by transient elastography and 2-dimensional shear-wave elastography), and 6 indirect marker tests in detection of advanced liver fibrosis (Kleiner stage ≥F3). METHODS: We performed a prospective study of 10 liver fibrosis markers (patented and not), all performed on the same day. Patients were recruited from primary centers (municipal alcohol rehabilitation, n = 128; 6% with advanced fibrosis) and secondary health care centers (hospital outpatient clinics, n = 161; 36% with advanced fibrosis) in the Region of Southern Denmark from 2013 through 2016. Biopsy-verified fibrosis stage was used as the reference standard. The primary aim was to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease recruited from primary and secondary health care centers, using the literature-based cutoff value of 10.5. Secondary aims were to assess the diagnostic accuracy of ELF for significant fibrosis and cirrhosis and to determine whether combinations of fibrosis markers increase diagnostic yield. RESULTS: The ELF identified patients with advanced liver fibrosis with an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% confidence interval 0.89-0.96); findings did not differ significantly between patients from primary vs secondary care (P = .917). ELF more accurately identified patients with advanced liver fibrosis than indirect marker tests, but ELF and FibroTest had comparable diagnostic accuracies (AUROC of FibroTest, 0.90) (P = .209 for comparison with ELF). Results from the ELF and FibroTest did not differ significantly from those of liver stiffness measurement in intention-to-diagnose analyses (AUROC for transient elastography, 0.90), but did differ in the per-protocol analysis (AUROC for transient elastography, 0.97) (P = .521 and .004 for comparison with ELF). Adding a serum marker to transient elastography analysis did not increase accuracy. For patients in primary care, ELF values below 10.5 and FibroTest values below 0.58 had negative predictive values for advanced liver fibrosis of 98% and 94%, respectively. CONCLUSION: In a prospective, direct comparison of tests, ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference). Advanced fibrosis can be ruled out in primary health care patients based on an ELF value below 10.5 or a FibroTest value below 0.58.

Late Presentation for Care Among Patients With Chronic Hepatitis C: Prevalence and Risk Factors.

Patients with chronic hepatitis C may have advanced fibrosis at first evaluation. Using the European Association for the Study of the Liver (EASL) definition (FibroScan® >9.5 kPa) for "late presenter for care" (LP), we found that 32% (169 of 527) of patients were LP. Being a LP was associated with increasing age and a history of alcohol overuse.

PRO-C3: a new and more precise collagen marker for liver fibrosis in patients with chronic hepatitis C.

OBJECTIVE: Detecting significant fibrosis and cirrhosis remains important in treatment and follow-up of patients with chronic hepatitis C Infection (CHC). The aim of this study was to assess the ability of PRO-C3 to identify significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) both as a single test and as a part of algorithms. MATERIALS AND METHODS: PRO-C3 was assessed in baseline samples from the NORDynamIC trial. 270 patients were stratified into groups according to baseline biopsy. Baseline APRI, FIB-4 and GUCI scores were available for comparison in 232 patients. RESULTS: PRO-C3 increased with Ishak scores (p = .001). Area under the curve (AUC) for significant fibrosis was 0.75 (95% CI 0.68-0.81) and 0.76 (95% CI 0.68-0.84) for cirrhosis. FIB-4, APRI and GUCI had similar AUCs. In a PRO-C3 algorithm including age, platelet count, body mass index (BMI) and international normalised ratio (INR), the diagnostic efficacy improved to 0.85 (CI 0.80-0.89) and 0.90 (IQR 0.84-0.96) for significant fibrosis and cirrhosis, respectively. CONCLUSIONS: In our study, PRO-C3 was an independent predictor of fibrosis stage, and may play an important role in managing CHC patients.

Reliability Criteria for Liver Stiffness Measurements with Real-Time 2D Shear Wave Elastography in Different Clinical Scenarios of Chronic Liver Disease.

PURPOSE: Liver stiffness measurement by real-time 2-dimensional shear wave elastography (2D-SWE) lacks universal reliability criteria. We sought to assess whether previously published 2D-SWE reliability criteria for portal hypertension were applicable for the evaluation of liver fibrosis and cirrhosis, and to look for criteria that minimize the risk of misclassification in this setting. MATERIALS AND METHODS: In a biopsy-controlled diagnostic study, we obtained five 2D-SWE measurements of optimal image quality. Correctly classified cases of fibrosis and cirrhosis were compared to misclassified cases. We compared reliability predictors (standard deviation (SD), SD/mean, size of region of interest (ROI) and difference between a single measurement and the patient's median) with those obtained in a prior study on clinically significant portal hypertension. RESULTS: We obtained 678 2D-SWE measurements from 142 patients. Overall, the variability in liver stiffness within single 2D-SWE measurements was low (SD = 1.1 ±â€Š1.5kPa; SD/mean = 12 ±â€Š9 %). Intra-observer analysis showed almost perfect concordance (intraclass correlation coefficient = 0.95; 95 % CI 0.94 - 0.96; average difference from median = 0.4 ±â€Š0.9kPa). For the diagnosis of cirrhosis, a smaller SD (optimally ≤ 1.75 kPa) and larger ROI size (optimally ≥ 18 mm) were associated with higher accuracy. Similarly, within the published cohort of patients assessed for portal hypertension, a low variability of measurements was associated with high reliability. CONCLUSION: A high quality 2D-SWE elastogram ensures low variability and high reliability, regardless of indication. We recommend aiming for a combination of low standard deviation and large ROI.

Feasibility of transient elastography versus real-time two-dimensional shear wave elastography in difficult-to-scan patients.

BACKGROUND AND AIMS: Transient elastography (TE) is hampered in some patients by failures and unreliable results. We hypothesized that real time two-dimensional shear wave elastography (2D-SWE), the FibroScan XL probe, and repeated TE exams, could be used to obtain reliable liver stiffness measurements in patients with an invalid TE examination. METHODS: We reviewed 1975 patients with 5764 TE exams performed between 2007 and 2014, to identify failures and unreliable exams. Fifty-four patients with an invalid TE at their latest appointment entered a comparative feasibility study of TE vs. 2D-SWE. RESULTS: The initial TE exam was successful in 93% (1835/1975) of patients. Success rate increased from 89% to 96% when the XL probe became available (OR: 1.07, 95% CI 1.06-1.09). Likewise, re-examining those with a failed or unreliable TE led to a reliable TE in 96% of patients. Combining availability of the XL probe with TE re-examination resulted in a 99.5% success rate on a per-patient level. When comparing the feasibility of TE vs. 2D-SWE, 96% (52/54) of patients obtained a reliable TE, while 2D-SWE was reliable in 63% (34/54, p < 0.001). The odds of a successful 2D-SWE exam decreased with higher skin-capsule distance (OR = 0.77, 95% CI 0.67-0.98). CONCLUSIONS: Transient elastography can be accomplished in nearly all patients by use of the FibroScan XL probe and repeated examinations. In difficult-to-scan patients, the feasibility of TE is superior to 2D-SWE.