Notre association a vu le jour il y a 15 ans a l’instigation de nos amis Paul Mainguet, Francis Klotz, Mohamed Fadel Ndiaye, Naima Amrani, Fernand Vicari et quelques autres visionnaires qui se reconnaitront mais que nous ne pouvons tous enumerer ici. Leur idee geniale et genereuse de depart etait de realiser un organe de formation medicale continue en hepato-gastroenterologie en Afrique pour les Africains et de demontrer son utilite. L’historique de cette association a ete retrace dans un excellent article du JAHG (2007) 3-4:107-9 http://link.springer.com/article/10.1007/s12157-008-0033-1 Depuis sa creation 15 reunions ou congres ont eu lieu :

Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb] <10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had 1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P < 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. (HEPATOLOGY 2013)

BACKGROUND:Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.METHODS:We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.RESULTS:A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.CONCLUSIONS:The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

BACKGROUND:Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. AIM:To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. METHODS:Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. RESULTS:TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. CONCLUSION:Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy.

Conclusion:Patients with CHC with "easy genotypes" and relapsers to a previous 24 weeks antiviral treatment have a >80% probability to obtain a sustained virological response with a 48 week treatment with PEG-IFN alpha-2a plus Ribavirin.

accelerated in HCV patients with significant steatosis and/or insulin resistance (IR).There is little data regarding the impact of these factors on the accuracy of TE.Aim: To evaluate the influence of metabolic variables on the performance of TE for predicting fibrosis in HBV/HCV subjects.Methods: This study enrolled treatment-naïve subjects with positive HBsAg or detectable HCV RNA ≥6 months, submitted to liver biopsy (LB) and TE on the same day.METAVIR score was used for histological analysis.Steatosis ≥30% was considered significant.TE cut-offs: 7.2 (F ≥ 2) and 8.1 (F ≥ 3) kPa for HBV; 7.1 (F ≥ 2) and 9.5 (F ≥ 3) kPa for HCV.IR was defined by HOMA-IR ≥3 and obesity by a BMI ≥30 kg/m 2 .Results: After excluding 48 cases (7.8%) with unreliable/unsuccessful TE measurement, 565 patients were analyzed (HBV = 202; HCV = 363).Mean age was 46.1±11.2years, 67% male.Obesity and diabetes were identified in 6% and 5%, respectively.Significant steatosis was observed in 118 cases (21%) and 141 (25%) had IR.METAVIR F ≥ 2 was seen in 42% and 54% in HBV and HCV groups, respectively (P = 0.005).Higher TE values were observed in diabetics (P < 0.001), subjects with significant steatosis (P < 0.001), and in those with IR (P < 0.001).Obesity had no influence on TE values (P = 0.607).There was no correlation between TE and BMI (r = 0.108; P = 0.11) and positive but weak correlations were found between TE and HOMA-IR (r = 0.213; P = 0.001) and glucose (r = 0.217; P < 0.001).Discordant results between LB and TE were observed in 117/565 cases (21%).Discordant cases were comparable to concordant ones regarding age, etiology, gender, ALT, AST, GGT, A2/3 METAVIR grade, and all metabolic factors.TE overestimation of fibrosis was identified in 33/565 cases (6%).Among these, none had diabetes or obesity and no association was found between overestimation and metabolic factors.Conclusions: Higher TE values are observed in chronic viral hepatitis patients with metabolic disorders (IR, diabetes, significant steatosis).However, this seems not to exert a significant negative impact on the diagnostic performance of TE for predicting liver fibrosis.

L'effet de la consommation de vin rouge sur l'insulinorésistance est controversé : actions de l'éthanol (EtOH) et/ou de constituants/resvératrol (RSV) ? Le métabolisme énergétique est impliqué dans les effets différentiels EtOH et RSV : l'activité SIRT1, activée par RSV et inhibée par EtOH (You AmJPhysiol294,2008), est régulée par le ratio NAD +/NADH. L'ATP glycolytique correspond à 20–30 % de l'ATP cellulaire total, et l'EtOH est connu pour inhiber cette voie métabolique. Nous étudions par RMN dans le foie entier les effets de l'EtOH et/ou du RSV sur le contenu en ATP d'origine glycolytique. Les foies de rat mâle Wistar (100 g) nourri ad libitum sont isolés et perfusés (5 ml/min/g, isotonie, 37 °C, O2 : CO2 95 : 5, glucose 30 mM, insuline 120 mUI/l) avec 0 ; 1,4 ; 14 ou 70 mM EtOH, avec ou sans trans-RSV (20 μM) (n = 5/groupe). L'ATP est suivi ex vivo par 31P RMN (DPX400, 9,4T). La glycolyse est inhibée (i) avant ou (ii) après l'addition d'EtOH et/ou RSV par ajout de l'inhibiteur irréversible de la glycéraldéhyde 3 phospho deshydrogénase, l'iodacétate (IAA, 0,5 mM, 2 min). L'ATP mesuré reflète l'équilibre (état stationnaire) entre les processus de synthèse (glycolyse et phosphorylation oxydative) et de consommation. L'EtOH induit une chute d'ATP par (i) inhibition partielle de la glycolyse et (ii) des mécanismes consommateurs d'ATP liés à sa détoxication. Si RSV est ajouté à l'EtOH avant l'inhibition de la glycolyse, le nouvel état stationnaire est supérieur en EtOH + RSV qu'en EtOH seul (t-test, 14 mM p = 0,01, 70 mM p = 0,0001). Si la glycolyse est préalablement inhibée, le nouvel état stationnaire est similaire, qu'il y ait ou non du RSV avec l'EtOH. RSV ajouté à EtOH améliore le niveau d'ATP seulement s'il est présent avant l'inhibition de la glycolyse. Si cette dernière est d'abord inhibée par IAA, le RSV n'améliore plus l'ATP, ce qui souligne clairement son effet direct en cours de perfusion sur la glycolyse, en amont ou au niveau de la cible de l'inhibiteur (glycéraldéhyde 3 phospho deshydrogénase). Au niveau hépatique, l'éthanol voit son effet d'inhibition partielle de la glycolyse contrebalancé par une action du RSV qui va dans le sens de l'insulinosensibilité.

We prospectively assessed contrast-enhanced sonography for evaluating the degree of liver fibrosis as diagnosed via biopsy in 99 patients. The transit time of microbubbles between the portal and hepatic veins was calculated from the difference between the arrival time of the microbubbles in each vein. Liver biopsy was obtained for each patient within 6 months of the contrast-enhanced sonography. Histological fibrosis was categorized into two classes: (1) no or moderate fibrosis (F0, F1, and F2 according to the METAVIR staging) or (2) severe fibrosis (F3 and F4). At a cutoff of 13 s for the transit time, the diagnosis of severe fibrosis was made with a specificity of 78.57%, a sensitivity of 78.95%, a positive predictive value of 78.33%, a negative predictive value of 83.33%, and a performance accuracy of 78.79%. Therefore, contrast-enhanced ultrasound can help with differentiation between moderate and severe fibrosis.

SummaryBackground The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.Aim To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG‐IFN) and ribavirin.Patients and methods Patients treated with PEG‐IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.Results At week 4, a strong correlation was found between HCV‐RNA and Cmin of ribavirin plasma level (r = −0.376, P = 0.002) and AUC0→12h of ribavirin plasma level (r = −0.277, P = 0.018). At week 12, a strong correlation was found between HCV‐RNA and Cmin of ribavirin plasma level (r = −0.384, P < 0.0001) and AUC0→12h of ribavirin plasma level (r = −0.257, P = 0.002). In genotype 1 patients, AUC0→12h ribavirin and Cmin were significantly correlated with negative HCV‐RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV‐RNA at week 12.Conclusion Cmin of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.

line that constitutively expresses HBV(HepG2215).These were co-cultured either directly or indirectly (separated by a membrane, allowing the passage of soluble factors only), in the presence/absence of blocking antibodies to PD-1/IFNg/TNFa.HBV-DNA was quantified with qRT-PCR.We also cultured HepG2215 cells with candidate cytokines.PD-1/PDL1/PDL2 expression was assessed by FACS and qRT-PCR.Cytolytic T-cell function was assessed by flow cytometry.A panel of 17 cytokines were quantified by CBA.We also transfected hepatoma cell lines with plasmids containing full HBV genome and assessed changes in HBV-DNA/PDL1/PDL2.Results: PDL1 was upregulated on hepatocytes in the presence of HBVspecific T-cells in direct and indirect co-cultures.The presence of blocking antibodies to IFNg abrogated this effect.Significant correlations were observed between PDL1 and IFNg (r = 0.80, p < 0.05) and TNFa (r = 0.99, p < 0.01).Blocking of PD1 increased target-cell lysis in the direct cell coculture.HepG2215 cells incubated with IFNg resulted in a dose-dependent increase in PDL1 expression which was augmented by TNFa.PDL2 was expressed on the hepatocytes in direct/indirect co-cultures which was not abrogated by blocking antibodies.Following transfection of hepatoma cells with HBV, PDL1 expression increased and correlated with HBV-DNA levels (r = 0.98, p < 0.01).Conclusions: Control of HBV replication depends upon a balance between the destructive and curative effector functions of virus-specific CD8+T-cells.These results demonstrate that CD8+T-cells upregulate PDL1 on target hepatocytes through IFNg production, and blockade of the PD1/PDL1 pathway results in increased cytolysis of infected cells.Thus PD1/PDL1 plays a central role in determining the balance between cytolytic and non-cytolytic viral clearance.

The recent advent of non-invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non-invasive methods, in a large cohort of HCV-infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV-infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow-up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non-invasive methods with liver biopsy. These non-invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.

L'effet de la consommation de vin sur l'insulinorésistance (IR) est controversé : effets de l'éthanol (EtOH) et/ou de constituants : resvératrol (RSV) ? La phosphorylation oxydative (PO) est altérée dans l'IR. La perfusion d'EtOH 10 mM, en post-prandial (PP), s'oppose à la stimulation par l'insuline de la PO hépatique. RSV aurait des effets "insulin-like" chez le rat diabétique, son action sur l'énergétique est donc étudiée dans le foie selon la dose d'EtOH. Le foie de rat mâle Wistar (100 g) nourri ad libitum est isolé et perfusé (5 mL/min/g, isotonie, 37 °C, O2 : CO2 95 : 5, glucose 30 mM, insuline 120 mUI/L) avec 1,4, 14 ou 70 mM EtOH, avec ou sans RSV (20 μM). L'ATP est suivi ex vivo par 31P RMN (DPX400, 9,4T) ; l'ajout d'inhibiteurs spécifiques de sa synthèse, glycolytique (IAA 0,5 mM) et mitochondriale (KCN 2,5 mM), permet le calcul in situ de la vitesse de PO (turn-over : R [t0] = –A.k selon la cinétique ATP = A exp-kt) (2). Dans le contrôle (G30mM + insuline = situation portale «þPPþ»), le contenu d'ATP est stable. EtOH entraîne une chute d'ATP, maximale dès 14 mM EtOH, réduite par RSV (t-test versus EtOH, *p = 0,04, **p = 0,0001). Le turn-over (contrôle = 3,61 ± 0,69 μmol/min.g−1) chute avec EtOH sans effet-dose. RSV tend à le normaliser. Les effets d'EtOH seul reflètent la consommation cellulaire d'ATP liée à la ré-équilibration de la chute du potentiel d'oxydo-réduction hépatique, existant dès une consommation modérée (10 mM∼alcoolémie après 2 verres de vin). RSV, proposé comme insulinosensibilisant, stimule l'énergétique hépatique probablement via la phosphorylation oxydative.

Conclusions: Among HCV genotype 1-infected pts treated with Peg/RBV, the magnitude of Hb decline is strongly associated with the likelihood of SVR.The effect of EPO varied by time to anemia; no benefit was observed for pts who became anemic after treatment week 8.These data suggest that Hb decline may be a pharmacodynamic marker of treatment effectiveness and that the primary effect of EPO was to prevent treatment discontinuation in pts with early anemia.

The great majority of patients with chronic viral hepatitis C are treated with pegylated interferon-ribavirin therapy. The aim of this study was to demonstrate that these patients were able to have some form of physical exercise, and that this activity can lead to an improvement in their quality-of-life. Twelve volunteer patients with hepatitis C, who were either sedentary or had become sedentary and who had been treated by combination therapy for the past few weeks, were recruited at hepatology clinics in the Midi-Pyrénées region of France early in 2006. All patients attended a sports medicine consultation for an initial evaluation: maximal aerobic power and maximal oxygen consumption tests, maximum heart rate (MHR), search for contraindications for participation in the proposed program of physical exercise. The patients were given a heart rate monitor so they could measure their heart rate during physical exercise and check that they exercised under safe conditions and remained within the so-called "endurance" zone. The patients came to a sports facility daily for 5 days for the exercise program. The activities were divided into four sessions each day: an individual physical exercise selected by the patient, team physical exercise, recreational physical exercise, lectures on the different types of hepatitis and their treatment, on nutrition and on sports medicine assessments. Data on hepatitis, results of the cardiorespiratory examination and personal history and record of past physical activity were collected for each patient. Quality-of-life (SF36) was assessed at enrollment in the study and one month after the training sessions. At the initial sports medicine consultation, all patients reached their MHR and were found capable of participating in the proposed physical exercise program. One enrolled patient was excluded from the analysis because of the presence of sinusitis on arrival. Seven men and four women, mean age of 46 years completed the full course of the study protocol. All participated in the three types of proposed physical activity with no problem. The score of the general perception item of the SF36 questionnaire increased from 63 on day 0 to 71 at one month (p=0.07). In conclusion, patients with hepatitis C receiving pegylated interferon plus ribavirin may safely participate in a program of suitably supervised physical exercise. Taking part in physical exercise leads to clear changes in the way patients perceive their bodies and its capacities. Participating in sports activities could improve self-confidence and lead to far-reaching changes in the way patients perceive their disease and the constraints of treatment.

Background and aim. Numerous non-invasive markers of liver fibrosis have been described but their clinical implementation is still a matter of controversy. Recent studies indicate that their performance may improve when combined. Two algorithms have been proposed to stage liver fibrosis in hepatitis C, combining either fibroscan and fibrotest (Castera's algorithm, gastroenterology 2005) or fibrotest and AST-to-platelet ratio (APRI) (sequential algorithm for fibrosis evaluation, SAFE biopsy, J Hepatol 2006). This study was aimed to compare prospectively these two algorithms in the same population for diagnostic performance to identify significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4).

The objective of this prospective, multicenter, observational study was to evaluate healthcare for hepatitis C virus (HCV)-infected drug abusers in France and to determine predictors of successful therapeutic intervention. A total of 170 drug users were recruited from 40 French centers. Three centers recruited 66 participants (38.8%), and one to eight patients each were enrolled from 37 other centers (n=104). A sustained viral response (SVR) was seen in 65 (38.2%) patients. SVR rates were significantly higher in compliant than in non-compliant patients (43.5% versus 23.9%; P=0.019), in patients from high- rather than low-recruiting centers (54.5% versus 27.9%; P<0.001) and in patients receiving Buprenorphine rather than methadone (48.1% versus 21.8%; P=0.001). In patients, who completed both the treatment and follow-up (n=94), SVR rate was 57.4%. Buprenorphine substitution therapy and genotypes 2 or 3 HCV infection were associated with significantly higher rates of SVR (P<0.01, for both comparisons). In conclusion, successful care of hepatitis requires an active treatment policy of every center toward drug addicts. Additional studies are needed to explore the difference in SVR with methadone versus Buprenorphine therapy.