Dismal prognosis for cirrhotic patients with hepatitis C after initial failure of direct acting anti-virals, but salvage therapy may be life-saving.

BACKGROUND: Effective direct-acting antiviral treatment against hepatitis C virus infection is available in many countries worldwide. Despite good treatment results, a proportion of patients does not respond to treatment. The aim of this study was to investigate the long-term prognosis and the outcome of salvage therapy, after an initial treatment failure, in a nation-wide real-life setting. METHOD: Data from all adult patients registered in the national Swedish hepatitis C treatment register who did not achieve sustained virological response after initial antiviral treatment, was retrieved from 2014 through 2018. RESULTS: In total, 288 patients with primary treatment failure were included, of whom 236 underwent a second treatment course as salvage therapy after a median delay of 353 (IQR: 215-650) days. Fifteen patients received a third treatment course as second salvage treatment after a further median delay of 193 (IQR: 160-378) days. One-hundred-eleven out of 124 (90%) non-cirrhotic and 62/79 (78%) cirrhotic patients achieved sustained virological response following the first salvage treatment. Sustained virological response was achieved by 108/112 (96%) patients who received a triple antiviral regimen. In total 69 patients were lost to follow-up or died waiting for salvage treatment. Baseline cirrhosis was associated with poor long-term survival. CONCLUSION: Our study indicates that salvage therapy was effective in most patients with primary treatment failure, in particular when a triple direct acting antiviral regimen was given. To avoid the risk of death or complications, patients with primary treatment failure should be offered salvage therapy with a triple regimen, as soon as possible.

Linkage to hepatitis C treatment in two opioid substitution treatment units in Gothenburg, Sweden: a retrospective cohort study.

BACKGROUND: Chronic infection with the hepatitis C virus (HCV) is common in people with former or current injection drug use. Among the patients in the opioid substitution treatment (OST) program in Gothenburg, Sweden, more than 50% had been infected with HCV. However, many patients did not have any follow-up for their infection and the linkage to treatment could be improved. METHODS: A model of care for HCV was introduced at an OST unit in Gothenburg, Sweden, in 2017. The aim was to increase testing and linkage to HCV treatment. A nurse and a medical doctor, both specialized in infectious diseases, performed on-site testing at the OST unit with transient liver elastography (Fibroscan) to evaluate the fibrosis stage and initiated HCV treatment. This study retrospectively reviewed the patients' medical records to assess information regarding participation in the model of care, hepatitis C status, linkage to treatment and treatment outcome. RESULTS: Among the 225 patients enrolled in OST at baseline, 181 were still in the OST program at the end of study (December 31st, 2018). In total, 29 patients, most of whom did not attend the Clinic of Infectious Diseases, were referred to the model of care. By the end of study, 17 patients (100% of those treated) reached sustained virologic response. In parallel, an additional 19 patients got treatment directly at the Clinic of Infectious Diseases. CONCLUSION: Integrating HCV screening and examination in an OST unit successfully linked patients to treatment. However, not all patients received treatment. To reach the goal of eliminating HCV, different models of care are needed.

The relation of 25-hydroxy vitamin D concentrations to liver histopathology, seasonality and baseline characteristics in chronic hepatitis C virus genotype 2 or 3 infection.

BACKGROUND AND OBJECTIVES: The hydroxylation to 25-hydroxy vitamin D (25(OH)D) occurs in the liver and the impact of liver disease on vitamin D is unclear. This study evaluated the relationship between vitamin D concentrations and hepatic histopathology, seasonality and patient characteristics in well-characterized patients having undergone a liver biopsy. METHOD: 25(OH)D was measured post-hoc in pre-treatment serum from 331 North European patients with chronic HCV genotype 2 or 3 infection (NORDynamIC study). Liver biopsies were scored for fibrosis and inflammation according to the Ishak protocol, and graded for steatosis. Non-invasive markers of hepatic fibrosis as well as baseline viral and host characteristics, including genetic polymorphisms rs2228570, rs7975232, and rs10877012 were also evaluated. RESULTS: Mean 25(OH)D concentration was 59 ±23 nmol/L, with 41% having values <50 nmol/L and 6% were <30 nmol/L. 25(OH)D correlated with fibrosis (r = -0.10, p ≤0.05) in univariate but not in multivariate analyses. No association was observed between 25(OH)D and hepatic inflammation, but with steatosis in HCV genotype 2 infected patients. None of the genetic polymorphisms impacted on 25(OH)D levels or fibrosis. 25(OH)D levels were significantly inversely correlated to BMI (r = -0.19, p = 0.001), and was also associated with season and non-Caucasian ethnicity. CONCLUSION: Fibrosis was not independently associated with 25(OH)D concentration and no association was seen with hepatic inflammation, but HCV genotype 2 infected patients with moderate-to-severe steatosis had lower 25(OH)D levels compared to those without steatosis. A high percentage had potential risk of 25(OH)D deficiency, and BMI, seasonality and ethnicity were independently associated with 25(OH)D as previously reported.

High risk of non-alcoholic liver disease mortality in patients with chronic hepatitis C with illicit substance use disorder.

Aims: Hepatitis C virus (HCV) is a slowly progressive disease, often transmitted among people who inject drugs (PWID). Mortality in PWID is high, with an overrepresentation of drug-related causes. This study investigated the risk of death in patients with chronic hepatitis C virus (HCV) infection with or without illicit substance use disorder (ISUD).Methods: Patients with HCV were identified using the Swedish National Patient Registry according to the International Classification of Diseases-10 (ICD-10) code B18.2, with ≤5 matched comparators from the general population. Patients with ≥2 physician visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have ISUD. The underlying cause of death was analyzed for alcoholic liver disease, non-alcoholic liver disease, liver cancer, drug-related and external causes, non-liver cancers, or other causes. Mortality risks were assessed using the standardized mortality ratio (SMR) with 95% CIs and Cox regression analyses for cause-specific hazard ratios.Results: In total, 38,186 patients with HCV were included, with 31% meeting the ISUD definition. Non-alcoholic liver disease SMRs in patients with and without ISUD were 123.2 (95% CI, 103.7-145.2) and 69.4 (95% CI, 63.8-75.3), respectively. The significant independent factors associated with non-alcoholic liver disease mortality were older age, being unmarried, male sex, and having ISUD.Conclusions: The relative risks for non-alcoholic liver disease mortality were elevated for patients with ISUD. Having ISUD was a significant independent factor for non-alcoholic liver disease. Thus, patients with HCV with ISUD should be given HCV treatment to reduce the risk for liver disease.

A novel fibrosis index comprising a non-cholesterol sterol accurately predicts HCV-related liver cirrhosis.

Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = -12.17+ (age × 0.11) + (BMI (kg/m(2)) × 0.23) + (D7-lathosterol (µg/100 mg cholesterol)×(-0.013)) + (Platelet count (x10(9)/L) × (-0.018)) + (Prothrombin-INR × 3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86-0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82-0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.

Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection.

BACKGROUND AND AIMS: Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of hepatitis C virus (HCV) infection as well as outcome following pegylated interferon and ribavirin therapy among genotype 1 infected patients. Additionally the presence of the otherwise favorable IL28B genetic variants in the context of HCV genotype 3 infection reportedly entail more pronounced liver fibrosis and steatosis. The present study aimed to evaluate the impact of IL28B SNP variability on liver stiffness as accessed by transient elastography. METHODS: Seven hundred and seventy-one Swedish HCV infected patients sequentially undergoing liver stiffness measurement by means of Fibroscan® in the context of a real-life trial had samples available for IL28B genotyping (rs12979860) and HCV genotyping. RESULTS: CC(rs12979860) was more common among HCV genotype 2 or 3 infected treatment-naïve patients than among those infected with genotype 1 (P<0.0001). Additionally CC(rs12979860) among HCV genotype 3 infected patients was associated with higher liver stiffness values (P = 0.004), and higher AST to platelet ratio index (APRI; p = 0.02) as compared to carriers of the T allele. Among HCV genotype 1 infected patients, CC(rs12979860) was significantly associated with higher viral load (P = 0.001), with a similar non-significant trend noted among HCV genotype 3 infected patients. CONCLUSION: This study confirms previous reports that the CC(rs12979860) SNP is associated with more pronounced liver pathology in patients chronically infected with HCV genotype 3 as compared to genotype 1, suggesting that IL28B genetic variants differently regulates the course of HCV infection across HCV genotypes.

Impact of donor histology on survival following liver transplantation for chronic hepatitis C virus infection: a Scandinavian single-center experience.

OBJECTIVE: Survival following liver transplantation for hepatitis C virus (HCV) infection is affected by several factors. The aims of this single-center study were to evaluate survival from 1992 to 2006 in HCV-infected liver transplant recipients and to identify factors influencing patient and graft survival, with particular focus on donor liver histopathology. MATERIAL AND METHODS: Survival among 84 patients transplanted for HCV-related liver disease at the Sahlgrenska University Hospital during the above period was evaluated. Median follow-up time was 57 months (range 28-87). A perioperative liver biopsy from the donor liver graft was available in 68 cases. Biopsies were assessed for fibrosis, necroinflammatory activity, and degree of steatosis. Patient and graft survival according to relevant factors including donor histopathology were analyzed by Kaplan-Meier analysis. RESULTS: We found an association between donor liver fibrosis and patient survival (p = 0.016) as well as between graft survival and portal inflammation in the donor liver (p = 0.026). Both these associations remained significant in multivariate analysis (p = 0.007 and 0.017 respectively). Moreover, recipient age over 60 was found predictive of patient survival and repeated steroid boluses or steroid-resistant rejection of graft survival. Donor age was high throughout the study period. CONCLUSION: Histopathological features, especially portal inflammation and stage of fibrosis, in the donor liver may deleteriously affect graft and patient survival following HCV-related liver transplantation. Thus, pretransplant evaluation of donor histopathology may be of value in the selection of donors for transplantation of HCV-positive individuals, especially among donors older than 60 years.

Look-back screening for the identification of transfusion-induced hepatitis C virus infection in Sweden.

BACKGROUND: Following the discovery of the hepatitis C virus (HCV) in 1989, screening of all blood donors for antibodies became mandatory in Sweden as of 1 January 1992. METHODS: Serum samples were collected from patients who had received a blood transfusion in the period prior to 1992 in western Sweden. The prevalence of HCV infection was assessed by antibody screening. RESULTS: Of 13,573 screening serologies, 124 patients (0.9%) had antibodies against HCV; 113 (0.8%) had detectable HCV RNA indicating an ongoing infection. Ninety-one (73%) were female, of whom 32 had been transfused in conjunction with childbirth. A review of the 32 liver biopsy reports available showed that 2 patients had cirrhosis and an additional 9 patients had periportal or septal fibrosis. CONCLUSION: A considerable portion of screened patients had an ongoing HCV infection and were eligible for antiviral treatment. Look-back screening for HCV among recipients of blood transfusions prior to 1992 is meaningful and should include women transfused in childbirth.

A non-invasive fibrosis score predicts treatment outcome in chronic hepatitis C virus infection.

OBJECTIVE: The results of a previous study suggest that an index calculated according to the formula (normalized ASAT x PK-INR) x 100/thrombocyte count (x 10(9)/L; GUCI) may reflect liver fibrosis in patients with chronic hepatitis C virus (HCV) infection. The aims of the present study were (i) to validate the association between the Göteborg University Cirrhosis Index (GUCI) score and liver fibrosis and (ii) to evaluate the utility of this index in predicting the outcome of antiviral treatment. MATERIAL AND METHODS: A total of 269 patients with chronic HCV infection, stratified according to HCV genotype (1/4 versus 2/3) participated in a phase III trial using pegylated interferon alpha-2a and ribavirin (DITTO study). Retrospective analyses of the baseline GUCI scores and assessments of pretreatment liver biopsies using the Ishak protocol were performed. Cut-off GUCI scores were calculated to distinguish patients with a high or low probability of sustained viral response (SVR). RESULTS: Striking associations between GUCI and Ishak fibrosis stages (stages 0-2 versus stages 3-4, p = 0.0002, stages 3-4 versus stages 5-6, p = 0.002) were observed. In patients with genotype 1 or 4, a GUCI score below 0.33 was associated with a rapid viral response to antiviral treatment and an SVR rate of 80%. Ninety-two percent of patients (92/101) with a SVR had a pretreatment GUCI score below 1.11. CONCLUSIONS: Our results suggest that the GUCI score appropriately reflects the stage of liver fibrosis in HCV-infected patients, and predicts initial viral kinetics as well as treatment outcome in patients infected with HCV genotype 1 or 4.