Hervé Desmorat

Severe portal hypertensive gastropathy and antral vascular ectasia are distinct entities in patients with cirrhosis

BACKGROUND/AIMS Whereas severe portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) have been separately defined in patients with cirrhosis, there is much confusion in the literature because they are both characterized by red spots at endoscopy. This prospective study compared clinical, biochemical, and pathological features of these syndromes. METHODS Three groups of patients with cirrhosis and either GAVE (n = 14), severe portal hypertensive gastropathy (n = 14), or no gastric features at endoscopy (controls; n = 10) were included. RESULTS No difference was found between patients with gastropathy and controls. Patients with GAVE presented with the following significant differences compared with other patients: a higher Child-Pugh score, a lower blood level of hemoglobin and gastrin, and a higher intestinal blood loss. At pathological examination, these patients more frequently had vascular ectasia (P = 0.04), spindle cell proliferation (P < 0.01), fibrohyalinosis (P = 0.004), and Gilliams score of > or = 2 (P < 0.05); thrombi were encountered only in patients with GAVE (P = 0.006). Using discriminant analysis, spindle cell proliferation and fibrohyalinosis were the only significant variables yielding a diagnostic accuracy of 85% for GAVE and gastropathy. CONCLUSIONS GAVE and severe portal hypertensive gastropathy are two distinct entities.

Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding.

Because several studies have suggested that beta blockers are effective in the prophylaxis of first variceal bleeding in cirrhosis, screening for oesophageal varices might be appropriate. We prospectively studied 84 cirrhotic patients without obvious evidence of large oesophageal varices and previous bleeding during a mean follow up of 16 months. At entry to the study 41 patients had no oesophageal varices and in 43 these were grade 1. The subsequent percentages of patients without large oesophageal varices were 74% at one year and 52% at two years. Univariate analysis showed that a longer duration of cirrhosis (p less than 0.05) and grade 1 oesophageal varices at entry (p less than 0.001) were predictive factors for the occurrence of large oesophageal varices, whereas, multivariate analysis showed that the initial size of the oesophageal varices (p less than 0.001), a high initial Child-Pugh score, and a smaller improvement in Child-Pugh score during the study were independent risk factors. Among patients with grades 0 and 1 oesophageal varices at the start of the study the proportions with large oesophageal varices at two years were 31% and 70% respectively. We have calculated that, accepting a maximum risk of first bleeding of 10% without prophylactic treatment, a patient without oesophageal varices should be screened endoscopically every other year, while a patient with grade 1 disease should benefit from one annual upper gastrointestinal endoscopy.

Maintenance therapy with gradual reduction of the interferon dose over one year improves histological response in patients with chronic hepatitis C with biochemical response: results of a randomized trial.

BACKGROUND/AIMS Our aim was to assess whether histological response was improved by continuing interferon-alpha (IFN) treatment in patients with chronic hepatitis C (HCV) with a biochemical response and no viral clearance after a usual IFN treatment. METHODS Fifty-seven patients with normal alanine aminotransferase (ALAT) levels and positive HCV RNA at the end of a 1 year IFN treatment were randomly assigned to either group 1 (n = 28) where IFN was stopped, or group 2 (n = 29) where IFN was continued for 1 more year with gradual reduction of the dose to keep serum ALAT activity below the upper limit of normal. Liver biopsies were obtained before, and then 6 months after the end of treatment. RESULTS Knodells index improved between paired biopsies in group 2 (8.2+/-2.4 vs. 5.5+/-2.1), but not in group 1 (8+/-2.3 vs. 6.5+/-2). In post-treatment biopsies, the METAVIR activity score was significantly lower in group 2 than in group 1 (0.7+/-0.2 vs. 1.1+/-0.3, P < 0.05). In group 2, an improvement of the METAVIR fibrosis score was observed (1.3+/-0.4 vs. 1.1+/-0.2), whereas fibrosis progressed in group 1 (1.3+/-0.4 vs. 1.6+/-0.4). CONCLUSIONS Maintenance therapy by the minimal dose of IFN able to maintain biochemical response prevents histological progression in the sub-group of patients without virological response.

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.

Treatment of severe alcoholic hepatitis by infusion of insulin and glucagon. A multicentre sequential trial

Severe alcoholic hepatitis is still a therapeutic challenge. It has been recently advocated that a 3-wk infusion with insulin and glucagon reduces its short-term mortality rate. A multicenter, randomized, single-blind, sequential trial was designed to compare this treatment with placebo. The triangular boundary was defined with alpha = 0.05, beta = 0.10 and estimated survival at 4 wk of 50% with placebo, 75% with treatment. Patients with biopsy-proven severe alcoholic hepatitis (presence of one or more of three criteria: encephalopathy, prothrombin activity less than or equal to 50%, bilirubinemia greater than or equal to 100 mumol/L) were randomized into two groups; one treatment group received an infusion (12 hr/day) of an association of insulin (30 IU) and glucagon (3 mg), and a control group received an infusion of glucose. Treatments were administered during a 3-wk period, and the mortality rate was noted at 4 wk. The decision to discontinue the trial was reached on the basis of results from the first 44 patients. Overall results were assessed in the 72 patients included at the time of this decision (treatment group: n = 37; control group: n = 35). Fifty-three patients had cirrhosis. No significant differences were noted between the two groups at inclusion on the basis of clinical, laboratory and histological criteria. The mortality rate was not significantly different in the two groups; 10 patients (27%) in the treatment group and 5 patients (14%) in the control group died. Causes of death were similar in the two groups and consisted primarily of gastrointestinal hemorrhage, hepatic failure and infectious events.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of the association between major histocompatibility complex class II genes and the response to interferon alpha in patients with chronic hepatitis C infection

OBJECTIVE The aim of the study was to determine the influence of HLA class II genes on the response to interferon-alpha (IFN-alpha) in patients with chronic hepatitis C. METHODS The distribution of HLA DRB1 and DQB1 alleles was assessed in 170 caucasoïd patients treated with IFN-alpha for chronic hepatitis C. 50 patients had a long term sustained response to treatment whereas 120 patients were nonresponders. RESULTS Female sex, non-1 HCV genotype particularly genotype 2 and pretreatment low serum HCV RNA level were associated with long-term sustained response to IFN-alpha. A trend towards a higher prevalence of DRB1*07 allele in non responders than in patients with sustained response (45% vs. 28%, odds ratio 2.1; P < 0.05) on the one hand and of DQB1*06 allele in HCV genotype 1 patients with sustained response than in HCV genotype 1 nonresponders (75% vs 27.3%, odds ration 7.9; P < 0.02) on the other hand, were observed. However, none of these two differences remained significant after Bonferronis correction. CONCLUSION Accordingly, we conclude that the response to IFN-alpha therapy is more tightly related to virus factors than to hosts HLA class II genes.

Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C☆

BACKGROUND/AIMS Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. METHODS We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). RESULTS The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) (P=0.0001 and P=0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. CONCLUSIONS Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.

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. J. Med. Virol. 83:437–444, 2011.

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients.

AIM To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null-responders or relapsers with severe liver fibrosis. METHODS One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon (peg-INF) α2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study. RESULTS The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 × 10(3)/ mm(3) [OR = 5.3 (2.3, 12.4), P ≤ 0.001]. CONCLUSION More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness.

Safety and efficacy of combination therapy with peginterferon alfa-2a (40kD) and ribavirin in the outpatient setting: prospective analysis of 197 patients with chronic hepatitis C viral infection.

OBJECTIVES Combination therapy using peginterferon alfa-2a (40 kD) plus ribavirin achieves viral eradication in nearly 60% of patients with chronic hepatitis C viral infection. However, because of the numerous side effects, use of the combination regimen might be restricted for patients consulting private practitioners specialized in hepatogastroenterology. PATIENTS AND METHOD Conducted in this specific context, this prospective clinical trial investigated the safety and efficacy of combination therapy in 197 patients. Therapy was given in compliance with the recommendations of the French consensus conference on hepatitis C treatment. RESULTS Commonly reported adverse effects were noted in 90% of patients, most occurring during the first three months, with a stable prevalence thereafter and resolution after treatment end. The most frequent adverse events were asthenia (35 to 37.5% according to the treatment group pruritus (25 to 26.3%) and flu-like syndrome (19 to 21.7%). A depressive syndrome was reported in 20 to 21% of patients. Grade 4 neutropenia was exceptional and never led to severe infections. At intent-to-treat analysis, the rate of sustained virological response was 54.8% for the entire population. It was 71.1% for patients with genotypes 2 or 3 (mainly treated for 24 weeks) and 44.6% for patients with genotype 1 (all treated 48 weeks). CONCLUSION The characteristic features of combination therapy observed in the context of private hepatogastroenterology consultations are similar to those observed in randomized clinical trials.