Hepatitis C virus-specific CTL responses in PBMC from chimpanzees with chronic hepatitis C: determination of CTL and CTL precursor frequencies using a recombinant canarypox virus (ALVAC).

The aim of this study was to evaluate HCV-cytotoxic T lymphocyte response from PBMC in bulk CTL assays and in CTL precursor analyses using in vitro stimulation with canarypox virus (ALVAC) expressing HCV-capsid/E1/E2/NS2/NS3 antigens. Canarypox virus is naturally host-range restricted and does not replicate or cause cytopathology on mammalian cells. PBMC were obtained from four chimpanzees with chronic hepatitis C infection and one uninfected chimpanzee. CTL from bulk culture of PBMC and CTL precursor frequencies were found in three of the four chronically infected chimpanzees using ALVAC in vitro stimulation. No CTL response was detected in PBMC from the uninfected chimpanzee. The precursor frequencies of CTL specific for capsid, NS2 and NS3 proteins ranged between 1/2663 and 1/27202. No correlation was observed between percent cytolysis in bulk culture and CTL precursor frequencies. This method may prove useful in assessing the correlation between HCV-CTL response and virological or histological status.

Quantitative detection of hepatitis B virus DNA in serum using chemiluminescence: comparison with radioactive solution hybridization assay.

A quantitative, non-radioactive hybrid capture HBV DNA assay (Digene Diagnostics), which uses an efficient solution hybridization procedure coupled to a sensitive chemiluminescent signal amplification system, was compared with the quantitative, radioactive solution hybridization assay (Genostics, Abbott Laboratories), in hepatitis B virus carriers, particularly in those undergoing antiviral therapy. The qualitative reproducibility of the chemiluminescent method, tested on 30 sera, was acceptable, with a reproducibility rate of 93.3%. A comparison of this hybrid capture HBV DNA assay with the radioactive test on 113 sera obtained from 48 patients (39 HBsAg-positive patients) gave a sensitivity of 87.2%, a specificity of 100% and an agreement between the two tests of 89.4% (101 sera including 82 HBV DNA positive and 19 negative samples). Changes in HBV DNA levels measured by the two assays showed a good correlation with each other during interferon therapy. However, the hybrid capture values were higher than the radioactive assay values, with the ratio of the two values being variable in the same patient during the course of treatment. The Genostics assay therefore seems to be a more accurate procedure for evaluating changes in viral replication, particularly at high HBV DNA levels. However, the hybrid capture method is faster and has the advantage of being a non-radioactive procedure. This chemiluminescent assay is easy to perform as a routine diagnostic procedure and may be a useful alternative to the radioactive solution hybridization method.

[Can early recurrent hemorrhage in gastroduodenal ulcer be predicted?]. / Peut-on prédire la récidive hémorragique précoce des ulcères gastroduodénaux?

OBJECTIVE: To evaluate clinical, biological and endoscopic predictive factors of early recurrent bleeding from gastric or duodenal ulcers. PATIENTS AND METHODS: Seventy six patients (26 females and 50 males) with a mean age of 65.9 years (SD = 17.2) were included in a prospective study. Among the 76 patients, there were 39 NSAIDs users (51.3%). An endoscopy was performed systematically until 12 hours after admission. Treatment modalities were identical for all patients. The predictive value of 11 factors was evaluated through an univariate and multivariate analysis. RESULTS: Three factors had independent significant predictive value: a) the number of blood units used to treat a shock and to increase the haemoglobin level up to 100 g/L (P < 0.05); b) "high endoscopic risk" of recurrent bleeding including Forrest Ia, IIa and IIb ulcers (P < 0.05); c) a non steroidal anti-inflammatory treatment was associated with no recurrent bleeding contrary to the other factors (P < 0.05). Based on a second multivariate analysis including clinical factors only, a predictive score was calculated: 5 + number of blood units -5 x (NSAID = 0/1). The cut off point with maximum discrimination was 6 (specificity = 79.6%; sensitivity = 77.2%). CONCLUSION: A combination of clinical and endoscopic factors is useful to predict ulcer recurrent bleeding. Our clinical predictive score is interesting because of its simplicity. Its predictive value is of interest but have to be evaluated in another sample of patients.

[Primary sclerosing cholangitis and autoimmune cochlear deafness: a new syndrome?]. / Cholangite sclérosante primitive et surdité endocochléaire auto-immune: nouveau syndrome?

Association of autoimmune cochlear hearing loss with primary sclerosing cholangitis is reported in two patients. Endocochlear sensorineural hearing loss was associated with the presence of anti-cochlear antibodies in the serum directed against the walls of vessels in the stria vascularis. The hearing loss appeared at the same time or shortly after the diagnosis of cholangitis. This association, which has never been described, may reinforce the theory of the role of immunologic factors in the pathogenesis of primary sclerosing cholangitis, possibly linked to or initiated by vasculitis.

[Hepatitis C]. / Hépatite C.

Hepatitis C is usually poorly symptomatic, particularly in the acute phase. After an incubation period ranging from 5 to 12 weeks, the symptoms are nonspecific and icterus is rarely present. Laboratory results are more suggestive, showing characteristic fluctuations in transaminases comprising periods with normal values. Chronic hepatitis is probable when elevation of transaminases persists for more than 6 months. Chronic virus C hepatitis is usually asymptomatic. Clinical manifestations are poorly specific and transaminase concentrations are generally little increased and variable in over 75% of the cases. Some histological lesions are more often observed in the chronic stage, particularly steatosis, presence of intraportal lymphoid nodules and bile duct involvement. The natural history is dominated by the risk of development to cirrhosis and hepatocellular carcinoma. A course to chronic hepatitis C is observed in 20 to 70% of cases, while the risk of developing cirrhosis is between 10 and 38% within approximately 20 years. Prognosis is then linked to decompensation of cirrhosis and especially to the development of hepatocellular carcinoma, within approximately 10 years after appearance of cirrhosis, with a prevalence of at least 20%. The association of other factors such a hepatitis B virus or alcohol can accelerate this course.

Prednisone-interferon combination in the treatment of chronic hepatitis B: direct and indirect metanalysis.

The aim of this study was to review all published randomized clinical trials evaluating the efficacy of a combination of prednisone and interferon in treatment of chronic hepatitis B and to subject these studies to metanalysis. Two types of metanalyses were carried out: direct metanalysis, comparing the prednisone-interferon combination with interferon on its own; and indirect metanalysis, comparing the treatment efficacy of prednisone-interferon and of interferon with control results. At the end of follow-up, four assessable end points were analyzed: HBeAg, hepatitis B virus DNA, HBsAg loss and serum ALT normalization rate. The direct metanalysis included seven trials comparing prednisone-interferon with interferon treatment. No significant differences were observed between the two types of therapy, for all the criteria given. However, in patients with low ALT levels, the prednisone-interferon combination gave significantly better results than interferon alone--HBeAg loss was 48% in the former group vs. 18.4% with interferon alone (p < 0.01). Fifteen trials compared interferon with control values; all end points were significantly improved. Seven trials compared prednisone-interferon with control results and showed all end points to be significantly improved by treatment. Indirect metanalysis showed that the differences in odds ratios for prednisone-interferon/control group and interferon/control group studies were negative for all assessable end points. In conclusion, the use of corticosteroids did not produce any significant increase in the efficacy of interferon treatment in adults with chronic hepatitis B and high initial ALT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of anti-HBe-positive and HBe-antigen-positive chronic hepatitis B in France. French Multicentre Group.

Two groups of patients with HBV DNA-positive chronic active hepatitis B, from 20 French hospitals, separated according to HBe status, were prospectively subjected to a comparative analysis of various epidemiological, clinical, biochemical, serologic and histologic features. There were 61 patients with anti-HBe and 215 patients with HBeAg. At diagnosis, 25 variables were compared between the two groups. Some of the patients were followed up for 1 year. Anti-HBe chronic hepatitis B occurred with a prevalence of 22.1%. In the anti-HBe-chronic hepatitis B group, the patients were older, and more often of Southern European origin; the source of infection was more frequently unknown, hepatitis B markers were more frequently observed within the family, and the estimated duration of liver disease was longer. Serum HBV DNA levels were lower in the anti-HBe-positive group. No difference was observed in ALT levels at diagnosis and during follow up in the patients studied. Cirrhosis was more frequent in the anti-HBe-positive group. There was no difference in histological activity score between the two groups. These results suggest that anti-HBe-positive, chronic active hepatitis B is not rare in France, and that the higher occurrence of cirrhosis in this group may be related to a longer duration of the disease.

A randomized, controlled trial of interferon alfa-2b alone and with simultaneous prednisone for the treatment of chronic hepatitis B. French Multicenter Group.

The aim of the study was to evaluate the safety and effectiveness of interferon alpha-2b with or without concomitant corticosteroid treatment in patients with chronic hepatitis B. Fifty-six patients were randomly allocated to two treatment groups. Group I (n = 25) received interferon alpha-2b (INTRON A, Schering-Plough Corporation) 5 million unit subcutaneously, three times a week for 24 weeks. Group II (n = 31) received interferon according to the same protocol and prednisolone in decreasing doses of 60, 40, 20 mg for 6 weeks. The two groups were well matched for demographic, biochemical, virological and histologic features. Both groups were followed up for 24 weeks after treatment. No statistical difference was observed between the two groups at the end of the follow-up in alanine aminotransferase values, HBV DNA negativation, HBeAg loss, anti-HBe seroconversion and the Knodell score. The greater proportion of HBsAg clearance in the combination group, particularly in patients with low alanine aminotransferase values, was, however, not significant. In patients with low alanine aminotransferase values, only the Knodell score was significantly decreased in patients treated with interferon and prednisolone. The only factor which was found to be a predictor of response was the assumed duration of hepatitis. These findings showed that a concomitant short administration of corticosteroids during the first weeks of interferon therapy did not improve results with interferon alone.

Treatment of chronic hepatitis C by interferon for longer duration than six months.

The efficacy of various regimens using interferon-alpha (IFN-alpha) in the treatment of hepatitis C virus (HCV) infection was analyzed in a meta-analysis of 33 randomized clinical trials (RCTs). The results of the meta-analysis showed increased complete and sustained ALT response rates in patients receiving IFN 3 MU three times a week for six months compared with patients receiving placebo or no treatment. The dose effect (6 MU three times a week versus 3 MU three times a week) on complete ALT response rate at the end of treatment was significant, with a mean 10% improvement at both six and 12 months. There also was a significant dose effect on sustained response for 12 months treatment, with a mean 17% improvement. There was a significant treatment duration effect on sustained response rate at 3 MU three times a week and 6 MU three times a week, with a mean improvement of 16% (> or = 12 months vs six months) with 3 MU three times a week. Due to adverse events, we conclude that the best efficacy-risk ratio favors IFN treatment with 3 MU three times a week for at least 12 months. The results of our RCT comparing three IFN regimens showed that patients receiving 3 MU three times a week for up to 18 months exhibited significant improvements in histological activity score, normalization of serum ALT concentrations, and sustained response compared with patients receiving a lower dose or shorter duration of treatment with IFN. Together, these results support the conduct of another RCT to evaluate the hypothesis that long-term, continuous IFN treatment may significantly reduce the incidence of cirrhosis in patients with HCV infection.

Role of upper esophageal reflex and belch reflex dysfunctions in noncardiac chest pain.

Fifty-four patients examined for noncardiac chest pain (NCCP), showing no esophageal motor disorder or gastroesophageal reflux disease compatible with NCCP, were subjected to an intraesophageal balloon distension test and a study of the belching reflex provoked by intraesophageal air injection. Thirty-three control subjects were also studied, allowing us to define high-threshold belchers (group I) as those who belched during two of three 40-ml distensions and low-threshold belchers (group II) as those who did not. The balloon distension test induced NCCP in 64% of the patients in group I, and in 14% of the patients in group II (P < 0.01). High-threshold belching was a factor favoring the positivity of the balloon distension test. This result supports the hypothesis that esophageal distension by air due to a belching disorder may be the mechanism responsible for NCCP in some patients with an abnormal sensitivity to balloon distension.

Low ileal interleukin 10 concentrations are predictive of endoscopic recurrence in patients with Crohn's disease.

BACKGROUND: Endoscopic recurrence after surgery in Crohn's disease is frequent and unpredictable. Abnormal intestinal production of pro- (interleukin (IL)-1 beta, tumour necrosis factor alpha (TNF-alpha)) and anti- (IL-10) inflammatory cytokines has been associated with severe outcome in experimental models of colitis. PATIENTS AND METHODS: We evaluated if ileal TNF-alpha, IL-1 beta, or IL-10 mRNA levels measured at the time of surgery predict endoscopic recurrence, and if ileal IL-10 levels are associated with particular IL-10 promoter alleles. Ileal biopsies were obtained peroperatively from the healthy neoileum of patients undergoing a right ileocolectomy for Crohn's disease. Mucosal TNF-alpha, IL-1 beta, and IL-10 mRNA levels were quantified by competitive polymerase chain reaction. A cut off value was determined using a receiver operating curve. IL-10.G promoter haplotypes were analysed using a polymorphic dinucleotide repeat in the IL-10 promoter region. RESULTS: Three months after surgery, 53% of patients had endoscopic recurrence while 47% remained free of disease. The risk of endoscopic recurrence correlated with ileal IL-10 mRNA concentrations (r(2)=0.81). Endoscopic recurrence occurred more frequently in patients classified as low IL-10 producers than in those that were high producers (80% v 40%) (p=0.02). Patients with at least one of the two alleles G7-8 or G10-13 produced, respectively, higher (p=0.006) and lower (p=0.029) ileal IL-10 mRNA. The distribution of IL-10.G microsatellite genotypes was similar in patients with or without endoscopic recurrence. CONCLUSION: Low ileal IL-10 mRNA concentration is a good marker of endoscopic recurrence in Crohn's disease but the distribution of IL-10.G haplotypes cannot predict the postoperative evolution of the disease.

Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography.

BACKGROUND & AIMS: Prophylactic administration of interleukin (IL)-10 decreases the severity of experimental pancreatitis. Prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in humans is a unique model to study the potential role of IL-10 in this setting. METHODS: In a single-center, double-blind, randomized, placebo-controlled study, the effect of a single injection of 4 microg/kg (group 1) or 20 microg/kg (group 2) IL-10 was compared with that of placebo (group 0), all administered 30 minutes before therapeutic ERCP. The primary endpoint was the effect of IL-10 on serum levels of amylases and lipases measured 4, 24, and 48 hours after ERCP. The secondary objective was to evaluate changes in plasma cytokines (IL-6, IL-8, tumor necrosis factor) at the same time points and the incidence of acute pancreatitis in the 3 groups. Subjects undergoing a first therapeutic ERCP were eligible for inclusion. RESULTS: A total of 144 patients were included. Seven were excluded based on intention to treat (n = 1) or per protocol (n = 6). Forty-five, 48, and 44 patients remained in groups 0, 1, and 2, respectively. The 3 groups were comparable for age, sex, underlying disease, indication for treatment, type of treatment, and plasma levels of C-reactive protein (CRP), cytokines, and hydrolases at baseline. No significant difference was observed in CRP, cytokine, and hydrolase plasma levels after ERCP. Forty-three patients developed hyperhydrolasemia (18 in group 0, 14 in group 1, and 11 in group 2; P = 0.297), and 19 patients developed acute clinical pancreatitis (11 in group 0, 5 in group 1, 3 in group 2; P = 0.038). Two severe cases were observed in the placebo group. No mortality related to ERCP was observed. Logistic regression identified 3 independent risk factors for post-therapeutic ERCP pancreatitis: IL-10 administration (odds ratio [OR], 0.46; 95% confidence interval [95% CI], 0.22-0.96; P = 0.039), pancreatic sphincterotomy (OR, 5.04; 95% CI, 1.53-16.61; P = 0.008), and acinarization (OR, 8.19; 95% CI, 1.83-36.57; P = 0.006). CONCLUSIONS: A single intravenous dose of IL-10, given 30 minutes before the start of the procedure, independently reduces the incidence of post-therapeutic ERCP pancreatitis.

Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration.

The aims of this study were to evaluate the benefits of higher doses or of longer duration in comparison with a standard interferon regimen (3 MU three times per week for 6 months) in chronic hepatitis C, and to assess the efficacy of interferon in acute hepatitis C. Meta-analysis made use of the Peto et al. and the Der Simonian and Laird methods, with heterogeneity and sensitivity analyses. In chronic hepatitis, a total of 17 trials versus controls and of 16 trials comparing different interferon regimens were included. Standard regimen, 3 MU three times per week for 6 months, was associated with an increase of the complete alanine transaminase (ALT) response rate and sustained (ALT) response rate by 45% (95% confidence interval: 35% to 55%; P < .001) and 21% (13% to 28%; P < .001), respectively, with the natural course being less than 2% of spontaneous responses. There was a significant dose effect (6 vs. 3 MU three times per week) upon the sustained response rate at 12 months, with a mean 17% increase (7% to 28%; P < .001), but not at 6 months. There was a significant duration effect (12 vs. 6 months) upon the sustained response rate both at the dose of 3 MU with a mean of 16% (9% to 23%; P < .001), and at the dose of 6 MU three times per week with a mean of 20% (7% to 33%; P = .003). In acute hepatitis C, 3 months of interferon treatment showed significant efficacy versus controls (4 trials), upon the complete ALT response (69% vs. 29%; P < .001), the sustained response rate during the 12 months following treatment (53% vs. 32%; P = .02), and hepatitis C virus (HCV)-RNA clearance (41% vs. 4%; P < .001). The best efficacy/risk ratio was in favor of 3 MU three times per week for at least 12 months in patients with chronic hepatitis C who had never been treated with interferon. Patients with acute hepatitis should be treated with at least 3 MU three times per week for 3 months.