Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥ 0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥ 20 g/day for ≥ 5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.

T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO.

A new hepatitis B virus (HBV) protein, hepatitis B splice-generated protein (HBSP), has been detected in liver biopsy specimens from patients with chronic active hepatitis. The aim of this study was to characterize the phenotype and functions of peripheral HBSP-specific T cells and to determine whether these T-cell responses may be implicated in liver damage or viral control. Two groups of patients were studied: HBV-infected patients with chronic active hepatitis and HBV-infected patients who were inactive carriers of hepatitis B surface antigen. HBSP-specific T-cell responses were analysed ex vivo and after in vitro stimulation of peripheral blood mononuclear cells. Soluble cytokines and chemokines were analysed in sera and in cell culture supernatants. Few HBSP- or capsid-specific T-cell responses were detected in patients with chronic active hepatitis whereas frequency of HBV-specific T cells was significantly higher in inactive carrier patients. HBSP activated CD8+ and CD4+ T cells that recognized multiple epitopes and secreted inflammatory cytokines. The IL-12 level was significantly lower in sera from asymptomatic carrier patients compared to patients with chronic active hepatitis. IL-12 and IP-10 levels in the sera were significantly and independently correlated with both alanine amino transferase and HBV DNA levels. Our results show that the HBSP protein activates cellular immune responses in HBV-infected patients but has probably no prominent role in liver damage. The pattern of cytokines and chemokines in sera was linked to HBV viral load and was consistent with the level of inflammation during chronic hepatitis.

Intervention study to improve smoking cessation during hospitalization.

OBJECTIVES: In France, hospitals have been smoke free since February 2007. A period of hospitalization may be a good time to enhance a smoker's motivation to quit. This study aimed to assess whether training medical staff in smoking cessation management might improve the rate of smoking cessation during hospitalization. STUDY DESIGN: Non-randomized intervention study. METHODS: Staff of the participating care units either received (intervention group) or did not receive (control group) training in smoking cessation management. The dependent variable was the proportion of inpatients that continued to smoke before (Period 1) and after (Period 2) the training session. RESULTS: In total, 358 patients were included. In Period 1, 55.6% and 50% of the smokers from the intervention and control groups stopped smoking, respectively; the corresponding rates in Period 2 were 64.3% and 48.1%. In Period 2, 36.4% and 31.8% of the smokers from the intervention and control groups claimed that they had received motivational counselling. In the intervention group, the request rate for nicotine replacement therapy (NRT) was higher (41.7%) compared with the control group (11.1%). In both groups, patients asked for NRT more often (P < 0.001) when they had received motivational counselling. CONCLUSIONS: This study was not able to demonstrate that training medical staff in smoking cessation management has a significant impact on smoking cessation in hospitalized smokers. The delivery of medium-intensity support to all smokers appears to be out of reach of physician/nurse teams. New strategies are needed, including a team specifically dedicated to the problems of addiction.

[Alcohol problems in drinking drivers and clinical management methods]. / Typologie des contrevenants à l'alcoolémie routière et modalités des prises en charge.

BACKGROUND: In order to improve knowledge on the typology of drinking drivers, their clinical management and their outcome in terms of alcohol consumption following treatment, 1086 drinking drivers attending one of the 18 outpatient centres for the care of alcoholics participating to the study were studied; those requiring long-term therapy or those mandated to treatment were followed-up during one year. Most of them (95%) were men with a mean age of 38 years. The drinking-driving offence was recorded during an alcohol spot-check (62%), following a traffic accident (23%) or a traffic offence (15%). For 35%, it was the second offence and 19% have been mandated to treatment. Alcohol consumption before checking were based on spirits in 67% of cases and only wine or beer for the remaining 33%. Severe alcohol problems (i.e. abuse or dependence) were diagnosed in 38%, both in men and women. Mean blood alcohol level was 1.6 g/l, without any difference according to sex; it was significantly increased in those checked following a traffic accident, in those having drank spirits, wine and beer and in those having a severe alcohol problem. Follow-up was organized for those mandated to treatment and for a third of the others, including mainly those second-offenders and those with a severe alcohol problem. Observance to appointments were similar in both groups. At the end of follow-up (350 subjects were concerned), 75% were either non- or moderate drinkers while the 25% remaining were still abuser or dependent; the single parameter independently and significantly associated to an absence of alcohol behaviour improvement was "to be mandated to treatment" (RR=4.4 CI [2.03-9.69], p<0.001). Our results confirm the high prevalence of severe alcohol problems in drinking drivers and demonstrate that women are concerned as much as men. They assess that since increased blood alcohol levels in drivers are observed whatever the type of alcoholic beverages consumed, all these latter without any exception are dangerous when drank in excess before driving. Finally, our results suggest that mandating to treatment a drinking driver should be discussed and its efficacy revisited.

Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C.

To analyze the spontaneous pathologic progression of chronic hepatitis C, we analyzed the histopathologic semiquantitative scores (Metavir and Knodell) of sequential liver biopsies performed in untreated hepatitis C virus (HCV)-infected patients. Subjects included 35 men and 41 women, with a mean age of 41 +/- 12 years, a duration of HCV infection of 11 +/- 5 years, and an interval between liver biopsies of 3.7 +/- 2.5 years. Results obtained using the Knodell score and the Metavir score were similar. At the first biopsy, 78.9% of patients had a low activity score (A0-A1) and 82.9% had a low fibrosis score (F0-F2). At the second biopsy, the activity decreased in 9.2%, was unchanged in 72.4%, and increased in 18.5%. An increase in activity was more frequently observed in patients infected with genotype 1 (28.9%) than with others (7.7%; P =.04); the yearly progression of activity was significantly higher in patients with a low rather than high initial activity score (0.11 v -0.02; P <.01). An increase in fibrosis was noted in 13.3% of those with a low and 43.8% of those with a high initial activity score (P <.01), with a highest rate of yearly fibrosis progression (0.12 U). In multivariate analysis, only a high activity score was significantly associated with an increased risk of fibrosis progression (relative risk, 25.5; 95% confidence interval, 2.7 to 238; P =.004). Spontaneous chronic hepatitis C evolution is worsening in only 20% of patients. Fibrosis progression is significantly associated with the necroinflammatory activity suggesting that this factor should be regarded as a major clue for deciding therapy.

Interactions between alcohol and hepatitis viruses in the liver.

There is a high frequency of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among individuals with alcoholic liver disease (ALD) and alcohol-associated hepatocellular carcinoma (HCC), suggesting that these viruses are implicated in the pathogenesis of these diseases. Alcohol may act synergistically by promoting the development and progression of liver disease. The interactions of alcohol with infected hepatocytes and with antiviral immunity may result in altered patterns of virus gene expression and replication, making diagnosis difficult in some cases of ALD and HCC. The potential association of ALD and alcoholic HCC with serologically negative virus variants raises major difficulties in the epidemiologic assessment of cause and effect, providing major challenges for the future.

Gender, menstrual cycle, oral contraceptives and red blood cell deformability in healthy adult subjects.

Gender, menstrual cycle and oral contraceptives may have influence on mechanical properties of Red Blood Cell (RBC) and particularly on RBC deformability. So cell transit parameters have been assessed by filtration with the Cell Transit Analyser (CTA) for a large healthy adult population (seventy-nine males and one-hundred-fifteen females). The CTA provides the distribution of cell transit times of 5000 red blood cells, the mean transit time of the population and different percentiles such as p50, p75, p90 and p95. No effect of oral contraceptives was found. Nevertheless, influence of sex and menstrual cycle were demonstrated. A significant increase of the filtration parameters measured in the female population with respect to the male population and during menstruation, preovulation and post-ovulation periods was observed. During ovulation, the CTA parameters are comparable to the same parameters found in males.

[Occurrence of increased alpha-fetoprotein in non-neoplastic hepatopathies of alcoholic or non-alcoholic origin]. / Fréquence d'augmentation de l'alpha-foetoprotéine au cours des hépatopathies non néoplasiques d'origine alcoolique ou non.

In order to improve the evaluation of the frequency of alpha-fetoprotein reappearance in non-neoplastic liver disease, we assayed serum alpha-fetoprotein in 251 patients: 134 chronic alcoholics including 7 HBs Ag positive patients, 113 of whom had cirrhosis and 117 patients with chronic active hepatitis, 56 of whom were HBs Ag positive. None of these patients had any signs of hepatocellular carcinoma. Alpha-fetoprotein values above the upper normal limit (much greater than 20 ng/ml) were compared with the type of the liver disease, the serum aminotransferase activity, the usual hepatitis B-virus markers assayed by standard radioimmunology and, in 70 patients, with the results of the HBV-DNA hybridization in the liver. Abnormal alpha-fetoprotein levels were found in only 6.3 p. 100 of patients with HBs Ag negative alcoholic disease and in 17 p. 100 of patients with chronic active hepatitis, without any statistical difference concerning the presence of HBs Ag or not. Alpha-fetoprotein was more often abnormal in subjects who had hypertransaminasemia. For given values of transaminases no statistical relationship between serum alpha-fetoprotein levels and the presence of HBs Ag was observed.

[Sero-epidemiology of hepatitis A: alcoholic patients are a group at risk]. / Séro-épidémiologie de l'hépatite A: les alcooliques sont un groupe à risque.

OBJECTIVES: The possibility of "community-acquired" viral infection has been suggested in alcoholics. In order to assess this hypothesis, we evaluated the prevalence of antibodies against hepatitis A virus, a oro-fecally transmitted virus, in heavy drinkers. PATIENTS AND METHODS: We retrospectively studied 258 heavy drinkers, 188 males and 70 females, divided into sub-groups of increasing age, and compared them to 277 similarly classified blood donors. RESULTS: The prevalence of serum anti-hepatitis A antibodies was significantly higher in alcoholics than in controls (64.7 vs 52.3%, P < 0.01). The difference was particularly marked in patients younger than 45 years old (56.2 vs 39.1%, P < 0.01). In the alcoholics, there was no correlation between the prevalence of anti-hepatitis A antibodies and the socioeconomic level, the quantity of alcohol ingested, or the severity of the underlying liver disease. CONCLUSION: These results suggest that alcoholism is, per se, a risk factor for viral infections.

[Significance of isolated anti-HBs antibodies in subjects not vaccinated against hepatitis B viruses]. / Signification des anticorps anti-HBs isolés chez des sujets non vaccinés contre le virus de l'hépatite B.

The significance of isolated anti-HBs antibodies in subjects not vaccinated against the hepatitis B virus (HBV) was investigated in 13 healthy blood donors. All were European and none had any risk factor for hepatitis B infection. Serological assays included HBV-DNA and anti-preS 2 antibody determinations which were all negative. After injection with hepatitis B vaccine (Hevac B), only one out of the 13 subjects exhibited an anamnestic response in favor of secondary immunization. Neutralization tests for serum anti-HBs antibody were positive in only 6 subjects. Our data suggest that in most cases isolated anti-HBs positivity does not correspond to true antibody; booster injection of HBV vaccine seems to be the best way of verifying that antibodies are really protective.

[Prevalence of infection by hepatitis viruses in a rural area. Analysis according to risk factors and alcohol consumption]. / Prévalence des infections par les virus hépatotropes en milieu rural. Analyse en fonction des facteurs de risque viraux et de la consommation d'alcool.

OBJECTIVES: To evaluate the prevalence of serum markers of hepatitis A, B and C viruses in a rural area according to risk factors and alcohol consumption. METHODS: Transversal study of unselected subjects living and working in a rural area. Each subject included was asked to fill out an anonymous self-administered questionnaire dealing with his own risk factors, sexual behaviour and alcohol consumption. A blood sample was collected for detection of HBsAg, anti-HBc, anti-HBs, anti-HAV and anti-HCV antibodies. RESULTS: Three hundred three subjects with a mean age of 48 years were included. Main risk factors for viral infection were: blood transfusion (9.4%), intravenous drug addiction (0.73%), acupuncture (17.5%), tattoos (5. 8%), past hospitalizations (71.5%), homosexuality (1.1%), conjugal unfaithfulness (11%), sexual partners >5 (21.3%). Most subjects with at risk sexual behaviour had sexual relations without protection. Anti-HAV prevalence was 87.2% (95% confidence interval 83.4-91.0%). None of the subjects was HBsAg positive and 6.0% (confidence interval 4.7-8.7%) had anti-HBV antibodies. HBV prevalence was correlated to homosexuality only. Two subjects (0.67%, confidence interval 0-1.6%) without any identified risk factor had anti-HCV antibodies. There was no correlation between serum viral marker positivity and an excess alcohol consumption (>80 g of ethanol/d) which was present in 46 subjects. However HBV prevalence was 28.6% in the seven subjects who had been treated for alcoholism; these 7 subjects had a highly at risk sexual behaviour. CONCLUSION: In a rural area, infection by HAV is very frequent. The prevalence of HBV and HCV did not greatly differ from that observed in the general and urban population. The frequent failure to use protection in subjects with at risk sexual behaviour reinforces the need of prevention programs in rural areas.

[Cost-benefit analysis of vaccinal prevention of hepatitis B policy]. / Analyse coût-avantage d'une politique de prévention vaccinale de l'hépatite virale B.

Morbidity and mortality related to hepatitis B (VHB) induce heavy costs even in low endemia countries as France. Recent changes in patterns of virus transmission (increasing heterosexual contamination) lead to discuss the opportunity of re-evaluation of current VHB vaccine policies aiming primarily at most exposed populations (patients under dialysis, hospital workers, infants born to VHB+ mothers). Using cost-benefit methodology, in a context where epidemiological and economical pertinent data are quite rare, this article evaluates different strategies ("no vaccination", "universal vaccination" and "vaccination after screening") for four different populations with contrasted exposure (French general population, young men adults, homosexual men and intravenous drug users). The cost-benefit ratios indicate that thresholds are, for low-risk populations, very far from usually accepted values attributed to epidemiological and economical parameters. If vaccine is administrated to young men adults, the cost-per-hepatitis saved relative to "no vaccination" is 36,000 F. For high-risk exposure groups, vaccination may be considered cost-benefit for attack rates near (homosexual men) or greater (drug users) than that observed; optimal strategy could be obtained if drug users are screened and vaccined. This is the result of combination of relatively low incidence of VHB and variability of medical course and chronic sequalae. Consequently, if universal vaccination has to be chosen, it would mean that the implicit value attributed to the prevention of one hepatitis is very high.

[Protein assay by immunoprecipitation with Centrifichem centrifugal analyser]. / Dosage des protéines par immunoprécipitation sur analyseur centrifuge Centrifichem.

The authors present an automatic technic of estimation of ten serum proteins (albumin, alpha-antitrypsin, orosomucoid, alpha-1-macroglobulin, haptoglobin, C'3 complement, transferrin, IgM, IgG, IgA) by immunoopacimetry on a Centrifichem centrifugal analyser. This technic is derived from an immunonephelometric method, with the following differences: --the use of two concentrations of polyethylene glycol permitting one to obtain for all proteins, a constant levelling-out of the reaction within 3 minutes; --by a first reading at 3 seconds avoiding the prior determination of blank reagents and sera; --by the use of two dilutions of serum permitting calculation of all concentrations. The results are reproducible and are satisfactory: 95% of the coefficients of variation are less than +/- 5% in the case of all the proteins. The correlation with IDR is good. The coefficients vary from 0.91 to 0.99.

[Acamprosate. From pharmacology to therapeutics]. / L'acamprosate. De la pharmacologie à la clinique.

Acamprosate is an homotaurine derivative, structural analogue of Gamma amino butyric acid and upper homologue of taurine. Its crossing through the blood brain barrier is facilitated by acetylation and calcium salification. Acamprosate has a very weak toxicity attributable to the ingested dose of calcium. Acamprosate is a GABAagonist showing pharmacological activity on direct and indirect tests of GABA activity and a high binding capacity with GABA receptors. Acamprosate also shows beta-adrenergic and serotoninergic activity, probably due to its GABAergic activity. Acamprosate is neither and antidepressant, nor a neuroleptic or a tranquillizer. In experimental alcohology, on different animal models (alcohol preferring or alcohol dependent) acamprosate induces a very clear and highly significant reduction of alcohol consumption. This effect is progressive and dose dependent, antagonized by bicuculine which is a GABA agonist. Besides, acamprosate reduces the intensity of the alcohol withdrawal syndrome. Clinical alcohology is a very difficult field for strict methodology in therapeutic trials: determination of inclusion characters, choice of judgment criteria, reduction of the number of drop out and lost subjects, length of evaluation... Different clinical controlled studies, most in double blind against placebo, on patients suffering from signs of physical or psychical alcohol addiction as well as biological modifications due to their ethylic consumption showed beneficial effects of acamprosate (in weaned alcoholics after withdrawal) according to clinical criteria (the number of abstinents after 3 months was doubled: 60% with active drug--30% with placebo) and for biological criteria (Normalization of Gamma Glutamyl Transpeptidase level in blood). The tolerance is good.(ABSTRACT TRUNCATED AT 250 WORDS)

[Alcohol dependence. Financial aspect and socio-occupational consequences]. / La dépendance à l'alcool. Aspect financier et conséquences socio-professionnelles.

The financial cost of alcohol dependence was evaluated in 133 alcoholic patients. The main amount of money spent daily on alcoholic beverages was 94 French francs, a figure that was unrelated to the patients' monthly incomes and highest in those living alone and in those drinking exclusively out of home. These results suggest that the economic cost of alcohol dependence plays a key role in the socio-professional degradation of alcoholics.