R.J. de Knegt

Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122

As chronic hepatitis C patients with progressive disease can present themselves with normal ALT levels, more sensitive biomarkers are needed. MicroRNAs are newly discovered small noncoding RNAs that are stable and detectable in the circulation. We aimed to investigate the association between hepatocyte‐derived microRNAs in serum and liver injury in patients with chronic hepatitis C. The hepatocyte‐derived miR‐122 and miR‐192 were analysed in sera of 102 chronic HCV‐infected patients and 24 healthy controls. Serum levels of miR‐122 and miR‐192 correlated strongly with ALT (R = 0.67 and R = 0.65, respectively, P < 0.001 for both). Median levels of miR‐122 and miR‐192 in HCV‐infected patients were 23 times and 8 times higher as in healthy controls (P < 0.001 for both). Even within the HCV‐infected patients with a normal ALT (n = 38), the levels of miR‐122 and miR‐192 were 12 times and 4 times higher compared with healthy controls (P < 0.001 for both). Multivariate logistic regression analyses showed that only miR‐122 was a significant predictor of the presence of chronic HCV infection (P = 0.026). Importantly, miR‐122 was also superior in discriminating chronic HCV‐infected patients with a normal ALT from healthy controls compared with the ALT level (AUC = 0.97 vs AUC = 0.78, P = 0.007). In conclusion, our study confirmed that liver injury is associated with high levels of hepatocyte‐derived microRNAs in circulation and demonstrated that in particular miR‐122 is a sensitive marker to distinguish chronic hepatitis C patients from healthy controls. More sensitive blood markers would benefit especially those patients with minor levels of hepatocellular injury, who are not identified by current screening with ALT testing.

Reduced risk of relapse after long-term nucleos(t)ide analogue consolidation therapy for chronic hepatitis B

Before stopping nucleos(t)ide analogue (NA) treatment in chronic hepatitis B (CHB), 6–12 months of consolidation therapy is recommended.

Randomised clinical trial: Anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV

Aliment Pharmacol Ther 2011; 34: 443–453

Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C

Aliment Pharmacol Ther 2011; 34: 1306–1317

Significant liver damage in patients with bleeding disorders and chronic hepatitis C: non‐invasive assessment of liver fibrosis using transient elastography

Summary.  Background: Many patients with bleeding disorders have been infected with the hepatitis C virus (HCV), mainly with genotype 1. Antiviral treatment is only effective in 50% of these patients and is often accompanied by serious side effects. Consequently, careful selection of patients for treatment is warranted. Liver biopsies are generally not performed in these patients because of increased bleeding risk and high costs. We therefore assessed liver fibrosis and cirrhosis non‐invasively using liver stiffness measurement (LSM). Methods: We enrolled 124 patients with bleeding disorders and chronic hepatitis C. Liver fibrosis was assessed by LSM using Fibroscan®. In order to assess the validity of LSM in our hands, a separate group of 63 patients without bleeding disorders infected with HCV were evaluated with both LSM and biopsy. Results: In the validation study, liver elasticity was highly correlated with histological fibrosis stage (correlations coefficient 0.73, P < 0.001). Based on LSM, 18% of patients with bleeding disorders and chronic hepatitis C had severe fibrosis, and 17% had cirrhosis after 34 years of infection (range 14–40). However, the prevalence of cirrhosis based on laboratory and ultrasonographic findings was only 7%. Independent risk factors for an increase in LSM were older age at infection, higher body mass index, presence of viral co‐infection, and male gender. Fifteen out of 59 patients (25%) with an apparent indication for treatment (significant fibrosis by LSM) agreed to start antiviral therapy within 3 months. Conclusions: We found an unexpected high number of patients with significant fibrosis and cirrhosis in patients with bleeding disorders and hepatitis C detected by LSM, with considerable impact on the management of the disease.

The number needed to treat to prevent mortality and cirrhosis-related complications among patients with cirrhosis and HCV genotype 1 infection

Cirrhotic patients with chronic hepatitis C virus (HCV) infection remain at risk for complications following sustained virological response (SVR). Therefore, we aimed to evaluate treatment efficacy with the number needed to treat (NNT) to prevent clinical endpoints. Mortality and cirrhosis‐related morbidity were assessed in an international multicentre cohort of consecutively treated patients with HCV genotype 1 infection and cirrhosis. The NNT to prevent death or clinical disease progression (any cirrhosis‐related event or death) in one patient was determined with the adjusted (event‐free) survival among patients without SVR and adjusted hazard ratio of SVR. Overall, 248 patients were followed for a median of 8.3 (IQR 6.2–11.1) years. Fifty‐nine (24%) patients attained SVR. Among patients without SVR, the adjusted 5‐year survival and event‐free survival were 94.4% and 80.0%, respectively. SVR was associated with reduced all‐cause mortality (HR 0.15, 95% CI 0.05–0.48, P = 0.002) and clinical disease progression (HR 0.16, 95% CI 0.07–0.36, P < 0.001). The NNT to prevent one death in 5 years declined from 1052 (95% CI 937–1755) at 2% SVR (interferon monotherapy) to 61 (95% CI 54–101) at 35% SVR (peginterferon and ribavirin). At 50% SVR, which might be expected with triple therapy, the estimated NNT was 43 (95% CI 38–71). The NNT to prevent clinical disease progression in one patient in 5 years was 302 (95% CI 271–407), 18 (95% CI 16–24) and 13 (95% CI 11–17) at 2%, 35% and 50% SVR, respectively. In conclusion, the NNT to prevent clinical endpoints among cirrhotic patients with HCV genotype 1 has declined enormously with the improvement of antiviral therapy.

Sustained virologic response after therapy with the HCV protease inhibitor narlaprevir in combination with peginterferon and ribavirin is durable through long‐term follow‐up

Achievement of a sustained virologic response (SVR) after peginterferon (PEG‐IFN) and ribavirin (RBV) treatment is considered to be a marker for the cure of chronic hepatitis C virus (HCV) infection. Long‐term follow‐up of patients with SVR after treatment with a direct acting antiviral has not yet been described. We used a randomized placebo‐controlled, double‐blind, two‐period phase 1b trial that was conducted in 40 HCV genotype 1 (treatment‐naïve and treatment‐experienced)‐infected patients. Nineteen patients achieved SVR after treatment with the HCV protease inhibitor narlaprevir followed by PEG‐IFN/RBV. In these patients, HCV‐RNA tests were scheduled at 3, 6, 12 and 24 months after end of treatment. Patients were followed for a median of 27 months (range 15–32) after end of treatment with a median number of follow‐up visits of 4 (range 3–8). All patients remained HCV‐RNA negative over time. SVR achieved following narlaprevir and PEG‐IFN/RBV‐therapy was durable up to 32 months after the end of treatment.

Binding of the Ligand (3H)MK-801 to the MK-801 Binding Site of the N-Methyl-D-Aspartate Receptor During Experimental Encephalopathy from Acute Liver Failure and from Acute Hyperammonemia in the Rabbit.

Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were prepared from brain cortex, hippocampus and striatum. Hepatic encephalopathy was induced by a two-stage liver devascularization procedure and acute hyperammonemia by a prolonged ammonium-acetate infusion; rabbits receiving a sodium-potassium-acetate infusion served as controls. In these animal models extracellular brain glutamate levels are known to be elevated. However no significant alterations in the number nor the affinity of the MK-801 binding sites of the NMDA receptors were found during acute liver failure and acute hyperammonemia. These findings suggest that the NMDA receptor population remains unaltered in experimental encephalopathy from acute liver failure and acute hyperammonemia, despite alterations in extracellular brain glutamate levels.

Psychiatric Side Effects and Fluctuations in Serotonergic Parameters in the Treatment of Chronic Hepatitis C Infection

Introduction: Treatment of hepatitis C with peginterferon induces psychiatric side effects. These might include changes in serotonergic function. Methods: Twenty-two hepatitis C patients were treated with peginterferon. At different time points, psychometric assessment was performed using the Profile of Mood States. Plasma samples were taken to study serotonergic parameters. Results: Anger and depression increased compared to baseline, starting with anger (from week 3 onwards), followed by depression (from week 7 onwards). Other scores did not show consistent changes. No consistent changes were observed in tryptophan, tryptophan/large neutral amino acids ratio, biopterin and 5-hydroxyindoleacetic acid. The tyrosine/large neutral amino acids ratio, neopterin, phenylalanine/tyrosine ratio, and prolactin concentrations increased compared to baseline. Prolactin levels were associated with the occurrence of depression and anger. Discussion: Particularly anger and depression increased during treatment. Neither a decrease in tryptophan and tryptophan availability was seen, nor a relationship between these parameters and the development of psychopathology. Therefore, other mechanisms in the induction of psychopathology should be considered. The observed increases in neopterin and phenylalanine/tyrosine ratio are indicative of changes in tetrahydrobiopterin, which is involved in the metabolism of serotonin, noradrenaline and dopamine, and possibly mediating the increase in prolactin. The increase in prolactin levels and its relationship with depression and anger needs further exploration.

Liver stiffness measurements to assess progression of fibrosis in HCV‐infected patients with inherited bleeding disorders

Summary.  Hepatitis C is a major co‐morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non‐invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM.