[Hepavir, the first observational study of one cohort of patients treated with alpha-2a interferon, monotherapy. Evaluation of asthenia and its social consequences]. / Hépavir, première étude observationnelle d'une cohorte de malades traités par interféron alpha-2a en monothérapie. Evaluation de l'asthénie et de ses répercussions sociales.

OBJECTIVES: The aim of this observational study in patients with chronic hepatitis C and treated with interferon alpha-2a was to assess 1) monitoring in everyday practice, 2) the acceptability of treatment and 3) the intensity of fatigue. METHODS: Three hundred and fifty four patients were enrolled by physicians in both teaching and general hospitals, or private practice. Before treatment, clinical, epidemiological, and virological data were collected as well as a self-evaluation of fatigue using a visual analogic scale. Clinical follow-up was assessed every 3 months during treatment and 6 months after the end of treatment and included an evaluation of fatigue and the number of workdays missed due to sickness. RESULTS: Two hundred and nineteen men and 135 women, mean age 45 +/- 13, were included. The epidemiological, histological and virological features of this group were similar to those patients usually treated for chronic hepatitis C. Before treatment, the mean measurement of fatigue was 41 on a scale from 0 (perfect form) to 100 (exhausted). Fatigue was unrelated to age, source of infection, biological activity, or histological score. It worsened in patients who stopped interferon after 3 or 6 months, but was stable in patients who continued treatment for 12 months. Fatigue decreased after the end of treatment and was unrelated to treatment response. The need to stop work was strongly related to the intensity of fatigue and the number of workdays missed due to sickness represented nearly two months out of three in 25% of active patients during the first quarter and in 15% of patients thereafter. 61% of patients self-injected interferon (mainly previous drug users) whereas 30% of patients used nurse care throughout treatment. CONCLUSION: This study not only provides a realistic evaluation of fatigue in patients with chronic hepatitis C, before, during and after treatment, but also highlights its social and economic consequences. It shows the need for further cost-effectiveness studies on new therapeutic strategies using combined treatments.

Does HIV-infection influence the response of chronic hepatitis C to interferon treatment? A French multicenter prospective study. French Multicenter Study Group.

BACKGROUND/AIM: The aim of this prospective study was to compare the response to alfa-interferon treatment of chronic hepatitis C in two groups of patients: coinfected with human immunodeficiency virus (HIV) (G I) or not (G II). METHODS: One hundred and fifty-three patients with chronic hepatitis C had been enrolled in 30 French liver units or infectious diseases units between May 1992 and January 1995 (G I: 76, G II: 77) to receive alfa-2a interferon: 3 MU thrice weekly for 6 months. RESULTS: One hundred and twenty-seven patients (G I: 63, G II: 64) fulfilled all criteria for analysis. The two groups were comparable for all demographic data, while significantly more severe biological and histological (p=0.001) parameters attested to more serious hepatitis among HIV-HCV coinfected patients. HCV viremia was higher among HIV-coinfected patients (p=0.0169), while genotype repartition was identical among the two groups (more than 52% of genotype 1, more than 31% of genotype 3). ALT normalization was, respectively, (G I/G II) obtained in 17.46%/26.56% (not significant) of patients at the end of treatment and in 11.11%/12.5% (not significant) of patients after 6 months of follow-up. In a multivariate analysis, GGT level before therapy (relative risk 2.1, confidence interval 1.1-5.8) and body surface area (relative risk 1.9, confidence interval 1.1-3.7) were the variables independently associated with the response to alfa-interferon treatment (higher GGT and more elevated body surface area were associated with a risk of non-response). CONCLUSION: In our study HIV infection did not affect the alfa-interferon treatment response of chronic hepatitis C, and response could be achieved among HIV-coinfected patients. Present therapeutic anti-HCV schedules need to be proposed to HIV-HCV coinfected patients before severe immunosuppression occurs. On the other hand, more severe biological and histological parameters were observed among HIV-HCV coinfected patients, which suggests a need to study whether HIV infection is associated with a worsening course of chronic hepatitis C.

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.

BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Quantitation of hepatitis C virus RNA in plasma and peripheral blood mononuclear cells of patients with chronic hepatitis treated with interferon-alpha.

We quantified hepatitis C virus (HCV) RNA at different times in plasma and peripheral blood mononuclear cells (PBMC) in 51 patients with chronic hepatitis C undergoing interferon-alpha2a (IFN-alpha2a) therapy. HCV RNA loads in plasma correlated with those in PBMC before and during the treatment (P<0.001). After treatment, a sustained response was observed in 19 patients (SR), a response followed by relapse in 9 (RR), and non response in 23 (NR). By univariate analysis PBMC HCV RNA load before treatment was lower in SR than in RR and NR (P = 0.003). In the 9 RR, HCV RNA disappeared in PBMC before or at the same time as in plasma and again became detectable in plasma and PBMC simultaneously or earlier in plasma. These results indicate that quantitation of HCV RNA in PBMC is not a useful parameter for the follow-up of treated patients.

[Do general practitioners want to manage chronic hepatitis C and take part in hepatitis C health networks? A national survey]. / Les médecins généralistes souhaitent-ils prendre en charge l'hépatite chronique virale C et participer aux réseaux ville-hôpital?

OBJECTIVES: To assess information that general practitioners had on hepatitis C and on the hepatitis C network in hospitals and private practice. METHODOLOGY: A national telephone survey of 604 general practitioners was conducted between March 18 and 23, 1998. RESULTS: Screening and management of hepatitis C was important for 89% and 97% of general practitioners. Screening was performed in relation to the relative risk (IV drug users 89%, blood transfusion before 1991 88%). General practitioners wanted more information on treatment (54%), patient counselling (42%) and the potential risks of the disease (42%). Of 604 general practitioners, 6% were involved in a hepatitis C network, while 21% were involved in another network (drug users 9%, AIDS 8%). Of the 94% general practitioners who were not part of the network, 33% were willing to join a hepatitis C network. Only 56% were aware of a hepatitis C network (press article 30%, mailing 17% or local meeting 12%). The difficulties for the involvement of general practitioners were: lack of time, topics not adapted to daily practice and geographic constraints (74%), too few patients in their practice (52%), no need (38%), the idea itself of a network and lack of information (28%). CONCLUSION: General practitioners screen patients at risk of hepatitis C. They want to be better informed about treatment, patient counselling, and the potential risks of hepatitis C. They are less involved in hepatitis C networks than in other networks (drug, AIDS). However, one third of general practitioners would like to be involved in a hepatitis C network. These results could be useful for implementing post-graduate courses and general practitioner training.

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.

Hepatitis C virus infection and allogeneic bone marrow transplantation.

Serum antibodies to hepatitis C virus (HCV) were tested for inpatients undergoing allogeneic BMT to determine the risk of acquiring HCV infection and the role of HCV in posttransplant liver complications. The HCV seroconversion rate was evaluated according to the date of BMT and blood donor screening at the time. Anti-HCV antibodies (anti-HCV) were detected with a second-generation ELISA and confirmed with a second-generation radioimmunoblot assay. All patients received leukocyte-depleted blood products and most received apheresis platelet concentrates. One hundred twenty of 181 consecutive patients transplanted from January 1987 to December 1991 were anti-HCV-negative before BMT, had at least 6 months of follow-up, and were thus evaluated for the seroconversion rate. Before screening for non-A, non-B hepatitis, 14% of the patients seroconverted to HCV (0.44% per unit transfused). After introduction of screening for alanine aminotransferase and antibodies to hepatitis B core antigen the risk of seroconversion was 4% per patient (0.26% per unit). When, in addition, blood was screened for anti-HCV the risk fell to 1.6% (0.03% per unit). Positive anti-HCV status before and after BMT was not predictive of veno-occlusive disease, liver graft-versus-host disease (GVHD), or death due to liver dysfunction. In contrast, the risk of chronic hepatitis was significantly increased.

[Reduction of the post-transfusion hepatitis C risk in patients undergoing bone marrow allograft]. / Diminution du risque d'hépatite C post-transfusionnelle chez les patients soumis à une allogreffe de moelle osseuse.

Post-transfusion hepatitis C incidence was studied in a series of patients with bone marrow allograft. The risk of HCV seroconversion was evaluated according to the date of grafting and the screening tests carried out in blood donors at this time. Anti-HCV antibodies were screened using Elisa tests of 2d generation and confirmed by Riba tests of 2d generation. Results were analysed. Out of 181 allografted patients from January 1987 to December 1991, 120 patients found anti-HCV negative prior to grafting, with at least six month post-transfusion follow-up were considered as evaluable in terms of HCV seroconversion. All these patients had received leucodepleted blood products and the most of them platelet unit concentrates. Prior to implementation of screening tests for non-A, non-B hepatitis, 14% of patients had seroconverted (0.44% per transfused product); after introduction of the screening for indirect markers (ALAT) and for antibodies directed against the antigen of hepatitis B virus core (anti-HBc), the seroconversion incidence was 4% (0.26% per product). At the present time, since the implementation of anti-HCV screening tests, the risk has reached 1.6% (0.03% per transfused product). 6 patients out of 7 having seroconverted have been developing chronic hepatitis.

Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations.

The effect on steatorrhoea of a pH-sensitive enteric-coated pancreatic preparation (Eurobiol 25,000) was compared with a conventional pancreatic enzyme preparation (Eurobiol) in six adult patients with exocrine pancreatic insufficiency. In addition, the fate of orally ingested pancreatic enzymes in the upper digestive tract was evaluated by measuring gastric and duodenal pH, amount of enzymes in the stomach, duodenal enzyme output, and fat absorption at the angle of Treitz for the 4 hours following a standard meal. When compared with placebo, Eurobiol and Eurobiol 25,000 reduced daily faecal fat excretion by 24% (not significant) and 43% (P less than 0.05), respectively. With the conventional preparation, enzyme output and fat absorption at the duodeno-jejunal flexure were significantly improved (P less than 0.05). Marked inter-individual differences in duodenal enzyme recovery (lipase 3% to 80%; chymotrypsin 26% to 100%) and, consequently, in the reduction of steatorrhoea (0% to 67%) were observed, with the gastric emptying rate emerging as a key determinant factor. With the enteric-coated preparation, enzyme output and fat absorption at the duodenojejunal flexure were not significantly improved. Discrepancy between the marked reduction of faecal fat excretion and the low duodenal enzyme recovery could indicate that enzyme delivery from microtablets occurs further down in the small bowel. Efficacy of enteric-coated preparations could be enhanced by adding unprotected enzymes, especially in patients with rapid gastric emptying.

[Comparison of fungal lipase and pancreatic lipase in exocrine pancreatic insufficiency in man. Study of their in vitro properties and intraduodenal bioavailability]. / Comparaison d'une lipase fungique et d'une lipase pancréatique au cours de l'insuffisance pancréatique exocrine chez l'homme. Etude de leur propriété in vitro et leur biodisponibilité intraduodénale.

Assuming that acidic degradation of lipase was the major cause of failure for the correction of steatorrhea by pancreatic extracts, we compared the in vitro and in vivo activities of a fungal lipase (FL) (Rhizopus arrhizus) with classical porcine pancreatic extract (Eurobiol). The choice of FL was determined by its two optimum pH (3.5 and 7.4). Five factors known to modify lipase activity were tested: pH, biliary acids colipase, trypsin and albumin. Bioavailability was measured by using a double intubation method in 13 patients with severe pancreatic insufficiency. Each enzymatic preparation was given during a test meal in a randomized and cross-over fashion. Results of the in vitro study showed that FL differed from pancreatic lipase by the following properties: better resistance in acidic solution, inhibition by biliary salts, absence of effect of colipase and rapid degradation by trypsin. In vivo the percentage of lipase activity recovered was 14.2 +/- 10.6 p. 100 for FL and 56 +/- 50 p. 100 for the classical pancreatic preparation. Compared with placebo significant differences in the recovery rate of lipolytic activity were observed with the pancreatic preparation only and started at the 40th min after the end of the test meal. These results showed that lack of degradation in acidic milieu is not the only valuable criterion for the choice of an efficient lipase preparation. The role of other potential factors such as gastric emptying as well as proteolytic degradation of the enzyme should be considered as well.

Venocclusive disease of the liver after allogeneic bone marrow transplantation in man.

One hundred and fifty-one consecutive patients underwent allogeneic bone marrow transplantation (B.M.T.) following high-dose chemotherapy and single dose total body irradiation (T.B.I.) for hematologic malignancies between September 1980 and December 1985. All patients included in this study were treated using a 60 Co beam to deliver a prescribed dose of 10 Gy to the mid-plane of the abdomen. Total body irradiation was performed the day before B.M.T. The mean instantaneous dose-rate was 3.5 cGy/min (range: 2.6 to 4.7). The real dose received was measured using thermoluminescent dosimeters (lithium borate). The difference between the doses delivered to the liver and to the mid-plane of the abdomen did not exceed 5%. The mean real dose delivered to the reference point was 10 Gy (range 8.3 to 11.7). Ninety five per cent of the patients received a dose ranging from 9.1 Gy to 10.9 Gy. High-dose cyclophosphamide was given to 126 patients with a "standard-risk" of relapse (60 mg/kg on day 5 and 4 before B.M.T.). Chemotherapy was intensified by the addition of other drugs in 25 patients with "higher-risk" of relapse. We analyzed the effect of the following pretransplant characteristics on the subsequent posttransplant development of V.O.D.: age, sex, ASAT and/or ALAT before conditioning regimen, diagnosis and status of malignant disease, history of liver disease, interval between diagnosis of hematologic malignancy and B.M.T., conditioning regimen (i.e., classical or intensified) and dose delivered to the liver during T.B.I. Seventeen patients were classified as having clinical V.O.D. giving a prevalence of 11.2%. In the first 2 months following B.M.T., death occurred respectively in 9 of 17 (53%) and 23 of 134 (17%) patients with and without clinical V.O.D. Univariate analysis showed that four characteristics were significantly related to an increased prevalence of V.O.D.: sex (11/62 females vs 6/89 males; p less than 0.05); history of liver disease (7/28 vs 10/117 patients without antecedent; p less than 0.01); ASAT and/or ALAT levels greater than 1.5 upper normal limit (11/49 vs 6/102 patients with levels less than 1.5; p less than 0.01) and intensified conditioning regimen (6/25 vs 11/126 patients with classical regimen; p less than 0.05). The conditioning regimen and history of liver disease were highly correlated to transaminases levels. Only two factors, transaminases levels and female sex, remained significantly associated with V.O.D. after multivariate analysis.

Fracture of biliary endoprosthesis after endoscopic drainage for malignant biliary obstruction. Report of two cases.

The authors report two cases of fracture of a biliary endoprosthesis inserted endoscopically to treat malignant biliary obstruction. To their knowledge, such a complication has never been reported. In both cases, the fracture was revealed by cholangitis which occurred three and eight months after insertion. Successful treatment was achieved by replacement of the biliary stent.

Chronic liver disease after low daily doses of amiodarone. Report of three cases.

A few cases of alcohol-like chronic liver disease have recently been described in patients on high daily doses of amiodarone (400-600 mg) for 5-24 months. We report here 3 cases in which similar lesions were observed after low daily doses of amiodarone. Daily dosage was 200 mg in 2 cases, 400 mg then 200 mg in the third one, and duration of therapy ranged between 36 and 60 months. Symptomatology was limited to hepatomegaly and/or mild elevation of serum aminotransferases. Liver biopsy showed alcohol-like lesions with fibrosis in 2 cases and cirrhosis in 1 case. Electron microscopy disclosed hepatic phospholipidosis. These cases indicate that chronic liver disease may be observed even when amiodarone is prescribed at low daily dosage, provided that duration of treatment is long. They also suggest that rather than the daily dosage, the cumulative dose of amiodarone is a major factor in the development of hepatic injury.

Computer-aided selection of diagnostic tests in jaundiced patients.

A model has been developed for ordering diagnostic tests in jaundiced patients. The system proceeds in two steps: (i) diagnostic hypotheses are calculated for each patient from the results of physical examination and routine biological investigations; (ii) given these hypotheses, the most efficient test (out of 22) for reaching the final diagnosis is selected using four criteria: diagnostic value, risk, financial cost, and time in obtaining the result. This model was tested in 62 patients. In 43 of them (69%), the selected test was sufficient for reaching a diagnostic accuracy of 100%. In this group of patients, a mean of 3.7 (range 1-6) tests per patient was ordered by physicians. In the 19 remaining patients, the selected test was not sufficient for the final diagnosis, thus requiring a multiple choice process. It is suggested that such a system could help physicians to improve the care of patients by more efficient ordering of diagnostic tests.

Hepatic vein obstruction in idiopathic hypereosinophilic syndrome.

We report an association between idiopathic hypereosinophilic syndrome and obstruction of the hepatic veins (Budd-Chiari syndrome). Budd-Chiari syndrome was assessed by liver biopsy and hepatic phlebography and documented by computed tomography. Postmortem examination revealed fibrous occlusion of the hepatic venous tree, as well as fibrosis of the endocardium and of myocardial and pulmonary vessels. To our knowledge, the association between idiopathic hypereosinophilic syndrome and Budd-Chiari syndrome has never previously been reported. Since it has been suggested that hypereosinophilia might cause endothelium damage, a link between these two entities is postulated.

[Chronic active hepatitis associated with anti-native DNA antibodies: incidence of drug etiology]. / Hépatites chroniques actives associées à des anticorps anti-ADN natif: fréquence de l'étiologie médicamenteuse.

Of 75 patients with HBsAg negative chronic active hepatitis (CAH), 28 had antinuclear antibodies in their serum. We have tested these patients' sera for serum antibodies against double stranded (native) DNA (anti-ds-DNA), by immunofluorescence with Crithidia luciliae as substrate. They were found in 14 patients (50 p. 100). Thirteen of the patients with anti-ds-DNA and 11 of those without were female; the mean ages were 64 +/- 16 and 56 +/- 19 years, respectively. The clinical and biological signs seemed to be more severe in patients with anti-ds-DNA than in those without. Liver histological activity and frequency of cirrhosis (about 50 p. 100) were similar in patients with or without anti-ds-DNA. Ten of the 14 patients with anti-ds-DNA had been given hepatotoxic drugs whereas only 2 patients lacking these antibodies had taken a hepatotoxic drug (p less than 0.01). In subjects with anti-ds-DNA, clometacin was the most common hepatotoxic drug, taken alone in 5 patients or together with other hepatotoxic drugs in 3 subjects. Only 4 of the patients with anti-ds-DNA displayed symptoms of systemic lupus erythematosus and two of these subjects took a hepatotoxic drug. In our experience, serum anti-ds-DNA were frequently found in patients with CAH and antinuclear antibodies; in this group CAH was often associated with hepatotoxic drugs, especially clometacin. Thus, the presence of anti-ds-DNA in sera of patients with HBsAg negative CAH may be an indication of drug-induced liver damage.