Liver stiffness improvement in hepatitis C patients after successful treatment.

BACKGROUND: Successful treatment of chronic hepatitis C with direct-acting antiviral agents (DAAs) is expected to lead to improvement in liver fibrosis in most of the patients. However, limited data are available on the improvement of advanced liver fibrosis and cirrhosis, measured by transient elastography after treatment. This study assessed the change in liver stiffness measurements after successful treatment with DAAs in patients with pre-treatment advanced fibrosis or cirrhosis. METHODS: This observational retrospective cohort study included 514 mono-infected chronic hepatitis C patients, treated with all possible DAA-regimes in the Amsterdam region, the Netherlands. Liver stiffness was measured using FibroScan® at baseline and during follow-up. Cut-off values for staging liver fibrosis were ≥ 9.5 kPa for advanced fibrosis (F3) and ≥ 14.6 kPa for cirrhosis (F4). RESULTS: Liver stiffness decreased significantly from a median of 15.6 kPa (IQR 11.4-25.4) to 9.4 kPa (IQR 6.2-17.0) in 197 patients with pre-treated advanced fibrosis or cirrhosis. In 50.3% of these patients, liver stiffness improved to a value fitting with mild to moderate fibrosis (< 9.5 kPa, F0-F2) after successful treatment. Multivariate analysis demonstrated that a pre-treatment FibroScan® value of ≥ 20.0 kPa was associated with persisting advanced fibrosis or cirrhosis after treatment (OR 29.07, p < 0.001). CONCLUSION: Liver stiffness improves significantly after successful direct-acting antiviral agent treatment in chronic hepatitis C patients with advanced fibrosis or cirrhosis prior to DAA treatment. Long-term outcomes regarding occurrence of hepatocellular carcinoma (HCC) in these patients are required to determine whether they can be safely discharged from HCC surveillance.

Retrieval of chronic hepatitis C patients. A manifesto for action to eliminate hepatitis C in the Netherlands: the CELINE project.

Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).

Sofosbuvir plus simeprevir for the treatment of HCV genotype 4 patients with advanced fibrosis or compensated cirrhosis is highly efficacious in real life.

Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver-related death. Recently, multiple regimens of different direct-acting antiviral agents (DAAs) have been registered. Although treatment with sofosbuvir (SOF) and simeprevir (SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real-life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response (SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon-based treatment, and one was treatment naive. In this real-life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment-experienced patients as recommended in guidelines.

Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir.

INTRODUCTION: Interferon-y-inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients. PATIENTS AND METHODS: A total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression. RESULTS: CR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003). CONCLUSIONS: Baseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.

The estimated future disease burden of hepatitis C virus in the Netherlands with different treatment paradigms.

BACKGROUND & AIMS: Prevalence of hepatitis C virus (HCV) infection in the Netherlands is low (anti-HCV prevalence 0.22%). All-oral treatment with direct-acting antivirals (DAAs) is tolerable and effective but expensive. Our analysis projected the future HCV-related disease burden in the Netherlands by applying different treatment scenarios. METHODS: Using a modelling approach, the size of the HCV-viraemic population in the Netherlands in 2014 was estimated using available data and expert consensus. The base scenario (based on the current Dutch situation) and different treatment scenarios (with increased efficacy, treatment uptake, and diagnoses) were modelled and the future HCV disease burden was predicted for each scenario. RESULTS: The estimated number of individuals with viraemic HCV infection in the Netherlands in 2014 was 19,200 (prevalence 0.12%). By 2030, this number is projected to decrease by 4 5% in the base scenario and by 85% if the number of treated patients increases. Furthermore, the number of individuals with hepatocellular carcinoma and liver-related deaths is estimated to decrease by 19% and 27%, respectively, in the base scenario, but may both be further decreased by 68% when focusing on treatment of HCV patients with a fibrosis stage of ≥ F2. CONCLUSIONS: A substantial reduction in HCV-related disease burden is possible with increases in treatment uptake as the efficacy of current therapies is high. Further reduction of HCV-related disease burden may be achieved through increases in diagnosis and preventative measures. These results might inform the further development of effective disease management strategies in the Netherlands.

IP-10 in chronic hepatitis C patients treated with high-dose interferon.

INTRODUCTION: Interferon-g-inducible protein-10 (IP-10) serum levels are associated with IL28B genotype and may predict response to interferon÷ribavirin-based therapy in chronic hepatitis C patients. Our aim was to relate IP-10 levels before and during treatment to treatment outcome, viral HCV-RNA kinetics and IL28B genotype. PATIENTS AND METHODS: A cohort of chronic hepatitis C patients was treated with high-dose interferon for six weeks, followed by standard peginterferon÷ ribavirin for 24 or 48 weeks. IP-10 and HCV-RNA levels were frequently determined before, during and after treatment. RESULTS: IP-10 levels increased from log2.56 pg÷ml at baseline to log3.48 pg÷ml at Day 1 and gradually diminished thereafter. IP-10 levels at any time point were not statistically different between patients with or without sustained viral response (SVR). Patients with IL28B CC genotype had significantly lower baseline IP-10 levels (p = 0.019) and a higher increase of IP-10 levels from baseline to Day 1 than patients with IL28B non-CC genotypes (p = 0.015). Patients with HCV-RNA decline ≥ 2.28log10 at Day 1 had significantly lower baseline IP-10 levels (p = 0.016) and a higher increase of IP-10 levels from baseline to Day1 (p = 0.047) than patients with HCV-RNA decline of < 2.28log10 at Day 1. CONCLUSIONS: In patients treated with high induction dose interferon, IP-10 levels at any time point were not predictive for SVR. Low baseline IP-10 levels and a higher increase of IP-10 levels from baseline to Day 1 were associated with IL28B CC genotype and HCV-RNA decline ≥ 2.28log10 at Day 1. This suggests that, in our cohort, for prediction of SVR the added value of IP-10 to IL28B genotype and early viral kinetics is limited.