Baseline HBsAg and HBcrAg titres allow peginterferon-based 'precision medicine' in HBeAg-negative chronic hepatitis B patients.

Quantitative hepatitis B core-related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon-alpha-2a (PegIFN)-based therapy. Sixty-two HBeAg-negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut-offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log10 IU/mL and 3.450 log10 U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post-treatment follow-up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI [0.578, 0.855]) for HBsAg and 0.668 (95% CI [0.524, 0.811]) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590-0.947), 0.714(0.533-1.000) and 0.800(0.611-1.000), and NPVs for AUCs(95%CI) were 0.756(0.660-0.899), 0.718(0.630-0.857) and 0.765(0.675-0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log10 IU/mL and qHBcrAg 3.450 log10 U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN-based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN-based 'precision therapy'. Our results emphasize that the combination of PegIFN alpha-2a plus TDF with 53% of SR might be an alternative to finite therapy.

Accurate model predicting sustained response at week 4 of therapy with pegylated interferon with ribavirin in patients with chronic hepatitis C.

Current models used to predict response to peginterferon plus ribavirin treatment, based on viral decline during the first 12 weeks of therapy, have focused on creating an early stopping rule to avoid unnecessary prolongation of therapy. We developed a multivariate model that predicted sustained virological response and nonresponse at baseline and during the first 12 weeks of therapy using collected data from 186 unselected patients with chronic hepatitis C treated with peginterferon plus ribavirin. This model employed ordinal regression with similarity least squares technology to assign the probability of a given outcome. Model variables include sex, age, prior treatment status, genotype, baseline serum alanine aminotransferase levels, histologic necroinflammation and fibrosis scores and serum hepatitis C virus RNA concentration at baseline and weeks, 4, 8, and 12. A multivariate model demonstrated high performance values at all time points. At baseline, the model demonstrated a negative predictive value (NPV) and a positive predictive value (PPV) of 91% and 95%, respectively. At week 4, these values improved to 97% and 100%, respectively, with 95% sensitivity, 89% specificity and 93% accuracy. At week 4, the model was equally efficient for naïve or previously treated patients. Internal validation demonstrated 90% PPV, 94% NPV, 95% sensitivity, 88% specificity and 92% accuracy. A week 4 stopping rule for patients with chronic hepatitis C treated with peginterferon with ribavirin might be proposed by using the model developed in our study.

Aquaretic effects of niravoline, a kappa-opioid agonist, in patients with cirrhosis.

BACKGROUND/AIMS: In patients with cirrhosis, decreased renal water excretion is a common complication. Niravoline (RU51599), a kappa-opioid receptor agonist, has been shown to induce an aquaretic response. The aim of this study was to evaluate the aquaretic effect and tolerance of niravoline in patients with cirrhosis. METHODS: Biochemical tests and hemodynamic values were determined before and 1, 2, 3 and 24 h after niravoline administration at doses ranging from 0.5 to 2 mg iv in 18 patients with cirrhosis. RESULTS: Diuresis significantly increased in the first hour from 64+/-9 to 146+/-31 ml/h, and returned to basal values after 3 h. Free water clearance also significantly increased, reaching the positive range at 1 h. Plasma osmolality significantly decreased at 2 h (from 290+/-4 to 286+/-4 mOsm/kg). Plasma sodium concentrations increased significantly at 3 h (from 133+/-1 to 134+/-1 mEq/l). Heart rate and arterial pressure did not change. The highest doses (1.5 mg or 2 mg) induced personality disorders and mild confusion within 2 h. These effects reversed completely within 8 h. CONCLUSION: This study shows that niravoline administration induces an aquaretic response and is well tolerated, at moderate doses, in patients with cirrhosis. Thus, moderate doses of niravoline may be useful for treating patients with cirrhosis and water retention.

Predictors of sustained response to alpha interferon therapy in chronic hepatitis C.

BACKGROUND/AIMS: The aim of this study was to determine the predictors for sustained response to alpha interferon therapy in a large population of patients with chronic hepatitis C, using multivariate analysis. METHODS: Two hundred and ninety-six patients were included in four controlled trials of alpha interferon. Pretreatment serum HCV RNA levels were assessed by the branched DNA version 2.0 assay and HCV genotypes by the reverse hybridization assay (LiPA). RESULTS: Sustained responses were observed in 37%, 14% and 6% of the patients with low, medium and high pretreatment serum HCV RNA levels, respectively (p<10(-4)). Sustained responses were observed in 5%, 4%, 32% and 27% of the patients with genotype 1a, 1b, 2a and 3a, respectively (p<10(-4)). The multivariate analysis showed that a non-transfusional source of HCV infection, low serum HCV RNA levels and HCV genotypes non-1 (2a or 3a) were independent factors associated with sustained response to interferon therapy. CONCLUSION: Virological factors (low pretreatment serum HCV RNA level and HCV genotype non-1a and non-1b), when adjusted in a large population of patients, using improved technology, are the main independent predictors of sustained response to alpha interferon therapy.

Prolonged interferon-alpha therapy of hepatitis B virus-related decompensated cirrhosis.

Interferon alpha therapy of hepatitis B virus-related decompensated cirrhosis with the dose and the duration generally used is frequently associated with severe side-effects and reactivations. Between 1989 and 1996, 15 patients with hepatitis B virus-related decompensated cirrhosis received prolonged (3-48 months) low-dose (3 million units) IFN-alpha therapy. Ten patients (66%) had a sustained loss of serum hepatitis B virus DNA and hepatitis Be antigen (if present initially) associated with a decrease of aminotransferase levels into the normal range. During follow-up of these 10 patients, seven had a marked clinical improvement and are alive and fully active. One has an hepatocellular carcinoma, and two died without reactivation. Among the five other patients, two had a transient loss of serum HBV DNA followed by reactivation and three did not respond to therapy. During follow-up, one of these five patients died and one underwent liver transplantation. Severe complications, possibly related to interferon were uncommon and included bacterial infection in one case and variceal bleeding in two cases. Eleven of the 15 patients treated are alive after 1.5-7 years of follow-up. Hence, in patients with hepatitis B-related cirrhosis, prolonged low-dose IFN-alpha therapy is relatively well tolerated and may induce a sustained inhibition of hepatitis B virus replication with marked clinical improvement.

Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. French Group of Clinicians and a Group of Biologists.

BACKGROUND/AIMS: Transjugular intrahepatic portosystemic shunts reduce portal pressure and can control ascites in patients with cirrhosis. We carried out a controlled study to evaluate this procedure for the management of refractory ascites in patients with cirrhosis and to clarify its mechanism of action. METHODS: Twenty-five patients with refractory ascites were included in the trial; 13 were randomly assigned to shunts and 12 to paracentesis. Four patients in each group were Child-Pugh class C and the others were class B. Follow-up ranged from 9 to 34 months. Hemodynamic values, liver and renal tests and neurohumoral factors were measured before and at 4 months after inclusion. RESULTS: Shunts were successfully placed in 10 out of 13 patients. At 4 months, ascites had improved in all class B patients in the shunt group and in none of the patients in the paracentesis group (p < 0.05); ascites did not improve in any of the class C patients in either of the groups. At 2 years, the overall survival rate was 29 +/- 13% (mean +/- SE) in the shunt group and 56 +/- 17% in the paracentesis group (p < 0.05). In class B patients, there was no significant difference in mortality. At 4 months, portal pressure was significantly lower than before the shunt, while plasma levels of atrial natriuretic peptide were significantly higher and plasma levels of renin and norepinephrine significantly lower. CONCLUSIONS: In this trial, intrahepatic shunts were effective on refractory ascites in patients with cirrhosis. However, the overall survival rate was lower in shunted patients than in those treated with paracentesis. The efficacy of intrahepatic shunts on ascites was only observed in class B patients. Survival did not improve in class B patients, and decreased in class C patients compared to paracentesis. The efficacy of shunts on ascites might be due to neurohumoral factors which control natriuresis and depend on hepatic sinusoidal pressure.

Heterogeneous lobular distribution of hepatocytes expressing acute-phase genes during the acute inflammatory reaction.

Functional heterogeneity in the lobule with regard to plasma protein synthesis is still debated. Therefore, we have localized in liver sections from normal rats and from rats with turpentine-induced AIR the mRNA and protein products of three genes with different alterations in their hepatic expression during an AIR: alpha 2M and alpha 1PI, two positively reacting acute-phase genes, and alpha 1I3, a negative acute-phase reactant. In normal liver, all hepatocytes expressed alpha 2M and alpha 1I3 mRNA, but a preferential expression of alpha 2M and alpha 1I3 mRNA and protein in the PP and ML zones was observed. During an AIR, the level of alpha 2M mRNA increased fourfold in the cytoplasm of PP and ML hepatocytes, while the level of cytoplasmic alpha 1I3 mRNA was decreased about fourfold in the same zones, with parallel variations in the expression of the corresponding proteins. In contrast, no significant modulation of the RNA and protein concentrations of both genes was detected in PV areas. alpha 1PI mRNA was expressed at the same levels in the three lobular zones in normal liver, but staining for the alpha 1PI protein was more intense in the PV zones. During the acute-phase response alpha 1PI mRNA levels were increased twofold in all three lobular zones, and alpha 1PI staining became homogeneous within the lobule. These results demonstrate that the location of a hepatocyte with the liver lobule can influence the expression of the three genes under study both at pre- and post-translational levels, in basal conditions, as well as during modulation of their expression during the inflammatory reaction.