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.

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.

Depressive symptoms are frequent among drug users, but not associated with hepatitis C infection.

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.

Liver stiffness and 30-day mortality in a cohort of patients admitted to hospital.

BACKGROUND: Transient elastography (TE) is a new noninvasive method to assess the degree of liver fibrosis by measuring liver stiffness. The objective of this study was to determine whether increased liver stiffness in patients admitted to medical wards was associated with increased 30-day mortality. MATERIALS AND METHODS: A prospective cohort study at the medical admissions ward at Odense University Hospital, Denmark, covering a population of 300 000 inhabitants. Consecutive patients ≥ 18 years of age were examined by TE (Fibroscan) at admission. Outcome measure was 30-day mortality. RESULTS: Among 568 patients admitted during 24 days, 289 (50·8%) were included in the study, 212 (73·4%) with valid TE measurement. Increased liver stiffness (TE value > 8 kPa) was found in 22·6% (48/212). This was independently associated with cirrhosis of the liver (P < 0·001) and congestive heart failure (CHF) (P < 0·001). The estimated prevalence of cirrhosis was 7% (95% CI 4-11%). The 30-day mortality among patients with TE value > 8 kPa was 20·8% (10/48, 95%CI 10·5-35·0%) compared to patients with TE value ≤ 8 kPa 3·7% (6/164, 95%CI 1·3-7·8%) (P < 0·001), and TE value > 8 kPa was an independent predictor of death. CONCLUSIONS: Elevated TE value at admission is associated with increased mortality, cirrhosis of the liver and CHF. This information may potentially be used to improve the outcome of high-risk patients admitted to hospital.

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.

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.

Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study.

OBJECTIVE: New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly. PATIENTS AND METHODS: We randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period. RESULTS: A total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment. CONCLUSIONS: We found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment.

Dried blood spots, valid screening for viral hepatitis and human immunodeficiency virus in real-life.

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.

Microfibrillar-Associated Protein 4: A Potential Biomarker for Screening for Liver Fibrosis in a Mixed Patient Cohort.

BACKGROUND AND AIMS: A method for assessment of liver fibrosis and cirrhosis without the need for a liver biopsy is desirable. Microfibrillar-associated protein 4 (MFAP4) is a suggested biomarker for identification of high-risk patients with severe fibrosis stages. This study aimed to examine associations between plasma MFAP4 (pMFAP4) and transient elastography or chronic hepatitis C virus infection in drug users and in a mixed patient cohort with increased risk of liver disease. Moreover, the study aimed to identify comorbidities that significantly influence pMFAP4. METHODS: pMFAP4 was measured in samples from 351 drug users attending treatment centres and from 248 acutely hospitalized medical patients with mixed diagnoses. Linear and logistic multivariate regression analyses were performed and nonparametric receiver operating characteristic-curves for cirrhosis were used to estimate cut-off points for pMFAP4. Univariate and subgroup analyses were performed using non-parametric methods. RESULTS: pMFAP4 increased significantly with liver fibrosis score. pMFAP4 was significantly associated with chronic viral infection in the drug users and with transient elastography in both cohorts. In the mixed patient cohort, pMFAP4 was significantly increased among patients with a previous diagnosis of liver disease or congestive heart failure compared to patients with other diagnoses. CONCLUSIONS: pMFAP4 has the potential to be used as an outreach-screening tool for liver fibrosis in drug users and in mixed medical patients. pMFAP4 level is positively associated with transient elastography, but additional studies are warranted to validate the possible use of pMFAP4 in larger cohorts and in combination with transient elastography.

Liver stiffness measurement among patients with chronic hepatitis B and C: results from a 5-year prospective study.

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.

[Transient elastography for diagnosing liver fibrosis]. / Fibroskanning til diagnostik af leverfibrose.

Liver fibrosis is a known complication to chronic liver diseases. The reference method for diagnosing and assessing the progression of fibrosis or cirrhosis is histological examination of liver tissue. Since there is a slight but significant risk from every invasive procedure, a non-invasive method has been sought. Transient elastography is a new noninvasive method of assessing fibrosis by measuring liver stiffness. The method is described in the article, as well as its diagnostic sensitivity and specificity, and the reproducibility is briefly discussed by evaluating some studies.

Antibacterial properties of EMLA and lidocaine in wound tissue biopsies for culturing.

If a tissue biopsy from a chronic wound is sampled for culture, the antibacterial properties of local anesthetics may pose a problem in producing false-negative results. The purpose of this study was to investigate the effects of EMLA (AstraZeneca) and lidocaine on common wound pathogenic bacteria. An in vitro study of a total of 25 clinical isolates and ATCC reference strains of Staphylococcus aureus (including methicillin-resistant S. aureus), Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pyogenes was conducted. The isolates were exposed to the local anesthetic drugs (and some of their contents separately) at 35 degrees C over a 24-hour period and time-kill curves were recorded. No culture media were used and saline was used for controls. EMLA was found to have a rapid acting and powerful antibacterial effect and should not be used before culturing tissue samples. Lidocaine 1% was found not to inhibit the bacterial strains when exposure time was held below 2 hours. We conclude that culturing tissue from a wound biopsy is safe within 2 hours when a pure, preservative-free lidocaine 1% solution is used.