Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy.

New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon α2a (peg-IFN-α2a: 180 µg/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-α2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 ± 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR= 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a.

A randomized trial of ribavirin and interferon-alpha vs. interferon-alpha alone in patients with chronic hepatitis C who were non-responders to a previous treatment. Multicenter Study Group under the coordination of the Necker Hospital, Paris, France.

BACKGROUND/AIM: Fifty percent of patients infected with hepatitis C virus (HCV) show no response to alpha-interferon, and no alternative therapy has thus far proven to be effective. Therapeutic combination with ribavirin and alpha-interferon has shown promising results in naive patients and in relapsers, but based on limited series, it was reported to be inefficient in non-responders. The aim of our study was therefore to explore and compare, in a randomized trial, the tolerance and potential efficacy of alpha-interferon alone with a sequential combination of ribavirin and the same alpha-interferon regimen in those patients. METHODS: Sixty-four non-responder patients were randomized in the alpha2b-interferon group (a 6-month course at a dosage of 6 MU followed by a 6-month course of 3 MU three times weekly subcutaneously) and 62 in the "combination" group (sequential combination of the same alpha2b-interferon therapy preceded by a 2-month course of ribavirin which was then associated for 2 months with alpha2b-interferon at a daily dosage of 1.0 or 1.2 g). RESULTS: Treatment withdrawal was necessary for six patients from the alpha-interferon and eight patients from the combination group. Normalization of aminotransferase activities was significantly more frequent after the 4-month course of ribavirin with 2 months of interferon than after 2 months of interferon alone (52.8 vs. 26.2%, p<0.01), but this difference was not maintained after ribavirin withdrawal. Disappearance of serum HCV RNA (PCR) was significantly more frequent at the end of treatment in the combination group (24.5 vs. 7.7%, p=0.02), but did not differ 6 months after the end of therapy (9.8 and 8.3%, respectively). The long-term response was not associated with liver status (cirrhosis vs. absence of cirrhosis) or genotype. Mean viremia was significantly lower in long-term responders than in non-responders or relapsers in both groups (p<0.001 for the interferon group and p<0.05 for the combination group), but the large extent of viral load precluded reliable prediction. The pre- and post-treatment hepatitis activity index did not differ between the two groups. While a crude histopathological improvement in the hepatitis activity index for a given patient was more frequently observed in the combination group (69.2 vs. 35.9%, p<0.01), improvement as defined by a decrease of at least 2 in the hepatitis activity index was significant only for lobular necrosis and degeneration. CONCLUSIONS: This study demonstrates the efficacy of the combination of ribavirin/alpha-interferon in non-responders. Indeed, (i) it is fairly tolerated; (ii) it increases the rate of the initial biological response, and of the virological response by decreasing breakthrough, though this benefit is not sustained; and (iii) it induces a significant histological improvement in necrosis. A simultaneous and prolonged combination of ribavirin/alpha-interferon should be further evaluated in non-responders.

Tenoxicam, a non-steroid anti-inflammatory drug, is unable to increase the response rate in patients with chronic hepatitis C treated by alpha interferon.

The purpose of this study is to compare a combination of interferon (IFN)-alpha2a (Roferon) + Tenoxicam with IFN-alpha2a alone in the treatment of chronic hepatitis C. This prospective, randomized double-blind study included 149 patients, all of whom were diagnosed with active chronic hepatitis C but non-cirrhotic (ALT > or = 1.5 upper limit of normal, anti-hepatitis C virus (HCV) positive by enzyme-linked immunosorbant assay2 and RIBA3). The patients were randomized in two groups, as follows: G1 (n = 76): IFNalpha2a 3 million units times per week during 6 months + placebo; and G2 (n = 73): IFNalpha2a 3 million units three times per week + Tenoxicam (20 mg/day) during 6 months. Alanine aminotransferase (ALT) and HCV RNA were determined before and at months 6 and 12 of treatment. 2'5' oligoadenylate synthetase activity (2'5' AS) was dosed in mononuclear cells before and at 3-month treatment intervals in 28 patients. Liver biopsy was performed before and 6 months after the end of therapy. Parameters were similar before therapy for both groups. Biochemical and virological responses were similar for both groups at month 6 (49.3% vs. 42.9% and 43.3% vs. 38.3%, respectively) and month 12 (28.3% vs. 23.8% and 17.2% vs. 17.5%, respectively). HCV RNA level significantly decreased in both groups at month 6, with no difference whatever the therapy; however, the HCV RNA level returned to initial values at month 12 and was the only significant prognostic factor of a sustained response. No peak of 2'5' AS activity was observed during treatment in patients with dual therapy. A histological improvement was also noted in both groups without difference, regardless of therapy. The percentage of adverse events was identical for both groups. Paracetamol intake, assessed in 80 patients, was 49.1 g per 6 months in the G1 group and 22.5 g per 6 months in the G2 group (not significant). In conclusion, the non-steroid anti-inflammatory drug, Tenoxicam, does not increase IFNalpha efficacy in the treatment of chronic hepatitis C. This combination is well tolerated and partially lowers Paracetamol intake, but not preexisting alpha-IFN adverse events.

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis.

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60 min after oral administration of 4 mg molsidomine then 15 min after intravenous administration of 15 mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (-7.9%, (P < 0.01), cardiac output (-7.3%, P < 0.01), pulmonary wedged pressure (-45.8%, (P < 0.05) and hepatic venous pressure gradient (-11.7%, P < 0.01). Propranolol decreased heart rate (-21%, P < 0.01), further decreased cardiac output (-20.6%, (P < 0.01) and hepatic venous pressure gradient (-10.5%, P < 0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (-8%, P < 0.01), heart rate (-19%, P < 0.01), cardiac output (-26.5%, P < 0.01) and hepatic venous pressure gradient (-21%, P < 0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.

[Enterovenous fistula. An unusual complication of Crohn disease]. / La fistule entéro-veineuse. Une complication exceptionnelle de la maladie de Crohn.

We report a case of enterovenous fistula in a young 22-year-old patient with Crohn's disease associated with jaundice. Ultrasound and computed tomography showed stationary gaz and barium in the liver. Pathological examination showed a fistula between the lumen of the inflamed segment of the ileum and the superior mesenteric venous system. This unusual finding in Crohn's disease may be a severe complication.

Propranolol reduces the rebleeding rate during endoscopic sclerotherapy before variceal obliteration.

In patients treated with sclerotherapy, most rebleeding episodes are observed before variceal obliteration. This prospective randomized study aimed to assess if propranolol together with sclerotherapy could reduce the rebleeding rate before variceal obliteration. Seventy-five patients (59 male, 16 female; mean age, 54 +/- 15 years) with cirrhosis (from alcohol abuse in 91%) admitted with upper gastrointestinal bleeding, which was endoscopically proven to originate from ruptured esophageal varices, were included. After initial control of bleeding, the patients were randomized into the following two groups: group 1 treated with sclerotherapy alone (36 patients) and group 2 treated with sclerotherapy plus propranolol (39 patients). They were followed up to variceal obliteration. In group 2, 7 patients rebled as compared with 14 patients treated with sclerotherapy alone (P less than 0.005). When considering only rebleedings from esophageal varices, 4 patients rebled in group 2 vs. 10 in group 1 (P less than 0.10). The total number of rebleeding episodes was lower in group 2 than in group 1 whether considering all causes (8 vs. 17; P less than 0.07) or variceal rebleedings alone (4 vs. 13; P less than 0.01). Mean total blood requirement per patient was lower in group 2 than in group 1 (1.4 +/- 3.4 vs. 2.79 +/- 6.4 units of blood, respectively; P less than 0.01). Mortality was similar in both groups of patients (14% vs. 13% in groups 1 and 2, respectively, NS). It is concluded that patients treated with sclerotherapy should be given propranolol before variceal obliteration.

Systemic and splanchnic hemodynamic effects of molsidomine in rats with carbon tetrachloride-induced cirrhosis.

Molsidomine, a long-acting vasodilator mainly used as an antianginal agent, was reported to decrease the portohepatic venous pressure gradient in patients with alcoholic cirrhosis. This study investigated the effects of linsidomine, the active metabolite of molsidomine, on systemic and splanchnic hemodynamics in rats with CCl4-induced cirrhosis using the microsphere technique. Compared with placebo-treated rats, linsidomine-treated animals were found to have a significant decrease in portal venous pressure (-18%, p less than 0.01) and in mean arterial pressure (-16%, p less than 0.01), smaller peripheral resistances (p less than 0.01), greater portal venous inflow (p less than 0.05), smaller splanchnic arteriolar resistances (p less than 0.01) and smaller protocol-lateral resistances (p less than 0.05). Cardiac output, hepatic arterial blood flow, portal blood flow and estimated hepatic blood flow were not significantly different between the two groups of animals. Linsidomine-treated rats exhibited a trend toward greater collateral blood flow compared with controls, but this difference was not significant. We conclude that linsidomine decreases portal venous pressure by reducing portocollateral resistances without affecting liver blood flow. These effects should be beneficial for patients with cirrhosis and portal hypertension.

Hemodynamic evaluation of molsidomine: a vasodilator with antianginal properties in patients with alcoholic cirrhosis.

Organic nitrates were reported to reduce portohepatic venous pressure gradient in patients with cirrhosis. However, these drugs lower arterial pressure and are well known to induce tolerance. The aim of the present study was to assess the hemodynamic effects of molsidomine, an antianginal agent, which does not induce tolerance and has little effect on arterial pressure in patients with normal liver, in 13 patients with alcoholic cirrhosis. Wedged hepatic vein pressure (-11%, p less than 0.01), portohepatic venous pressure gradient (-15%, p less than 0.005), hepatic blood flow (-17.4%, p less than 0.005), mean arterial pressure (-13.5%, p less than 0.01) and cardiac output (-17%, p less than 0.001) were significantly reduced by molsidomine. Free hepatic vein pressure, intrinsic hepatic clearance indocyanine green, heart rate and systemic vascular resistances were not significantly modified. There was no correlation between the decrease in portohepatic venous pressure gradient and the reduction in mean arterial pressure on one hand and the decrease in cardiac output on the other hand. We therefore conclude that in patients with cirrhosis, molsidomine has effects similar to nitrates on systemic and splanchnic hemodynamics.

[Obstructive intramural hematoma of the esophagus. A rare complication of endoscopic sclerotherapy of esophageal varices]. / Hématome intramural obstructif de l'oesophage. Une complication rare de la sclérose endoscopique des varices oesophagiennes.

Obstructive intramural hematoma of the esophagus is an unusual complication of endoscopic sclerotherapy. We report three patients with liver cirrhosis who experienced such a complication. In our series, the frequency was 1.6 percent. A few hours after sclerotherapy, all three patients complained of low retrosternal pain, dysphagia and hypersialorrhea. Endoscopy was performed in two patients and showed a typical bluish submucosal mass occupying the esophageal lumen. Outcome was favorable in all patients within one week of conservative treatment. We hypothesized that hematoma could be ascribed to variceal puncture. The extension of the hematoma with dissection of the esophageal wall which had been fragilized by previous sclerotherapy sessions could have been facilitated by impaired coagulation.

1-naphthyl N-methyl carbamate effect on intra- and extracellular concentrations of arachidonic acid metabolites, and on the chemiluminescence generation by mouse peritoneal macrophages.

1-Naphthyl N-methyl carbamate (carbaryl), potent carbamate insecticide with anticholinesterase activity, was tested for its ability to affect mouse peritoneal macrophages in particular arachidonic acid (AA) metabolism and oxidative burst. Carbaryl inhibited in a dose-related manner the reactive oxygen intermediate dependent chemiluminescence (CL) induced by opsonized zymosan (OZ), 12-O-tetradecanoyl phorbol-13-acetate (TPA) and calcium ionophore (A23187); this carbamate did not affect CL-mediated by AA. The intracellular and extracellular concentrations of prostaglandins (PGs) and 5-hydroxyeicosatetraenoic (5-HETE) generated in macrophages stimulated with OZ has been investigated for various periods. Carbaryl effect displayed two successive phases on AA metabolism stimulation. In a first phase (up to 2-15 min), carbaryl did not alter the rapid AA metabolite synthesis (total amount of intra- and extracellular metabolites) but it increased intracellular concentration of PGE2, PGA2, PGF2 alpha and decreased 5-HETE intracellular concentration. In a second phase (after 2-15 min), carbaryl inhibited AA metabolite synthesis. The release of cyclooxygenase (CO) and lipoxygenase (LO) metabolites decreased, in particular PGF2 alpha and PGD2 which in addition seemed to be submit to a cellular retention; the inhibition of other metabolite release appeared essentially related to the inhibition of their synthesis since the intracellular amount did not augment. The inhibition by carbaryl of the NADPH-oxidase dependent CL induced by OZ may be related to the alteration of the intra- and extracellular concentrations of AA metabolites.

Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis.

This study aimed to assess the effects of verapamil, a calcium-channel blocker, on porto-hepatic pressure gradient and on hepatic function as measured by the intrinsic hepatic clearance of indocyanine green (ICG) in patients with biopsy proven alcoholic cirrhosis. Hepatic venous pressures and hepatic extraction of ICG were measured before and 60 min after intravenous injection of 10 mg of verapamil in 19 consecutive patients. Hepatic blood flow and intrinsic hepatic clearance of ICG were calculated in the 10 patients whose hepatic extraction fraction was higher than 10%. No significant difference was observed when comparing porto-hepatic pressure gradient (17.72 +/- 4.79 vs. 17.77 +/- 4.43 mmHg), hepatic blood flow (13.47 +/- 4.75 vs. 16.13 +/- 7.88 ml.min-1.kg-1) and intrinsic hepatic clearance of ICG (1.99 +/- 0.54 vs. 1.97 +/- 0.45 ml.min-1.kg-1) before and after verapamil injection. We conclude that verapamil has no beneficial effect in patients with alcoholic cirrhosis.