Hepatitis C virus prevention and care for drug injectors: the French approach.

After France removed hepatitis C treatment reimbursement restrictions on 25 May 2016, an expert report presented recommendations, which focused on vulnerable groups including people who inject drugs (PWID). This commentary presents the key points of the chapter with a particular focus on policy. Thanks to the official lifting of restrictions based on disease stage and to the excellent efficacy and tolerance of the new DAA (Direct-Acting Antivirals) among PWID, the main issue is to improve the HCV care cascade. In France, many HCV-infected PWID, especially active/current PWID, remain undiagnosed and unlinked to care. Our challenge is to improve HCV screening by point of care testing (POCT), outreach methods with mobile teams, rapid tests, FibroScan, etc. and to provide PWID with appropriate services in all the settings they attend, such as drug treatment or harm reduction services, social services, prisons, etc. Another important issue is the prevention of reinfection through comprehensive and long-term follow-up. The report recommends a new national policy: testing and treating PWID as a priority, since this is the best way to eliminate HCV infection. It requires a global strategy consisting of combined and long-term interventions: prevention, outreach, screening, DAA, drug treatment programs including opiate substitution treatment (OST) and various harm reduction programs, including needle exchange programs (NEP). Ideally, these services should be delivered in the same place with an integrated approach. This should lead to meeting the national objective set by the government of eliminating hepatitis C by 2025.

Assessing the cost-effectiveness of hepatitis C screening strategies in France.

BACKGROUND & AIMS: In Europe, hepatitis C virus (HCV) screening still targets people at high risk of infection. We aim to determine the cost-effectiveness of expanded HCV screening in France. METHODS: A Markov model simulated chronic hepatitis C (CHC) prevalence, incidence of events, quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER) in the French general population, aged 18 to 80 years, undiagnosed for CHC for different strategies: S1 = current strategy targeting the at risk population; S2 = S1 and all men between 18 and 59 years; S3 = S1 and all individuals between 40 and 59 years; S4 = S1 and all individuals between 40 and 80 years; S5 = all individuals between 18 and 80 years (universal screening). Once CHC was diagnosed, treatment was initiated either to patients with fibrosis stage ≥F2 or regardless of fibrosis. Data were extracted from published literature, a national prevalence survey, and a previously published mathematical model. ICER were interpreted based on one or three times French GDP per capita (€32,800). RESULTS: Universal screening led to the lowest prevalence of CHC and incidence of events, regardless of treatment initiation. When considering treatment initiation to patients with fibrosis ≥F2, targeting all people aged 40-80 was the only cost-effective strategy at both thresholds (€26,100/QALY). When we considered treatment for all, although universal screening of all individuals aged 18-80 is associated with the highest costs, it is more effective than targeting all people aged 40-80, and cost-effective at both thresholds (€31,100/QALY). CONCLUSIONS: In France, universal screening is the most effective screening strategy for HCV. Universal screening is cost-effective when treatment is initiated regardless of fibrosis stage. From an individual and especially from a societal perspective of HCV eradication, this strategy should be implemented. LAY SUMMARY: In the context of highly effective and well tolerated therapies for hepatitis C virus that are now recommended for all patients, a reassessment of hepatitis C screening strategies is needed. An effectiveness and cost-effectiveness study of different strategies targeting either the at-risk population, specific ages or all individuals was performed. In France, universal screening is the most effective strategy and is cost-effective when treatment is initiated regardless of fibrosis stage. From an individual and especially from a societal perspective of hepatitis C virus eradication, this strategy should be implemented.

2014 French guidelines for hepatitis B and C screening: a combined targeted and mass testing strategy of chronic viruses namely HBV, HCV and HIV.

BACKGROUND & AIMS: Worldwide and, to a lesser extent, in France, a minority of individuals infected with hepatitis B (HBV) and C (HCV) is aware of its status. Given the current availability of highly effective anti-HBV and anti-HCV agents, the high rate of undiagnosed people, associated with individual and community prejudices (liver disease worsening, persistence of a hidden transmission reservoir and medicoeconomic burden of delayed care), is unacceptable. METHODS: On the occasion of the first French general report on viral hepatitis, new recommendations for HBV and HCV testing were issued. We aim to introduce the new French strategy for HBV and HCV screening, and to describe the underlying epidemiological data. RESULTS: These recommendations comprise various items. First, the screening of chronic viruses, namely HBV, HCV and HIV, should be quasi-systematically combined. Second, the targeted screening of groups at risk of viral exposure must be strengthened. Third, routine testing for each of these three viruses should be offered at least once to men of 18-60 years old who had never been tested. In parallel, in pregnant women, in addition to HIV-HBV screening, currently recommended HCV testing should be routinely performed during the first trimester of pregnancy. In order to best achieve the target populations, community initiatives that propose testing actions should be encouraged, particularly those including rapid point-of-care tests. CONCLUSIONS: Overall, these recommendations aim to define a comprehensive testing strategy for chronic viral infections, emphasizing both targeted screening and mass screening and considering jointly HBV, HCV and HIV.

Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.

Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler-Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin-Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.

Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141).

BACKGROUND & AIMS: In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). METHODS: A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. RESULTS: Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0-1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. CONCLUSIONS: Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Hereditary conjugated hyperbilirubinaemia: 37 years later.

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.

Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent.

BACKGROUND & AIMS: During chronic HCV infection, activation of fibrogenesis appears to be principally related to local inflammation. However, the direct role of hepatic HCV protein expression in fibrogenesis remains unknown. METHODS: We used transgenic mice expressing the full length HCV open reading frame exposed to a 'second hit' of the fibrogenic agent carbon tetrachloride (CCl(4)). Both acute and chronic liver injuries were induced in these mice by CCl(4) injections. Liver injury, expression of matrix re-modeling genes, reactive oxygen species (ROS), inflammation, hepatocyte proliferation, ductular reaction and hepatic progenitor cells (HPC) expansion were examined. RESULTS: After CCl(4) treatment, HCV transgenic mice exhibited enhanced liver fibrosis, significant changes in matrix re-modeling genes and increased ROS production compared to wild type littermates despite no differences in the degree of local inflammation. This increase was accompanied by a decrease in hepatocyte proliferation, which appeared to be due to delayed hepatocyte entry into the S phase. A prominent ductular reaction and hepatic progenitor cell compartment expansion were observed in transgenic animals. These observations closely mirror those previously made in HCV-infected individuals. CONCLUSIONS: Together, these results demonstrate that expression of the HCV proteins in hepatocytes contributes to the development of hepatic fibrosis in the presence of other fibrogenic agents. In the presence of CCl(4), HCV transgenic mice display an intra-hepatic re-organization of several key cellular actors in the fibrogenic process.

Impact of hepatitis C triple therapy availability upon the number of patients to be treated and associated costs in France: a model-based analysis.

OBJECTIVE: The combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor (PI) has been approved in summer 2011 for the treatment of genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially improved efficacy. The aim of this study was to estimate the number of G1 patients to be treated in France in 2012 and associated costs. METHODS: A published model of HCV and data on PEG-IFN sales were used to estimate patients needing treatment using three scenarios. (1) HCV screening rate unchanged versus 2010; proportion of treated F0-F1 patients unchanged, proportion of treated F2-F4 patients increased to the current proportion of treated F2-F4 G2/3 patients. (2) Scenario 1 but the proportion of treated F0-F1 patients increased to the current proportion of treated F0-F1 G2/3 patients. (3) Scenario 2 but a 5% increase in the HCV screening rate. To estimate cost, treatment duration was multiplied by drug unit cost. Probabilities corresponding to treatment duration were estimated based on liver fibrosis stage, treatment-naive or experienced status of the patient and virological response kinetics on treatment. RESULTS: Compared with the 5100 G1 patients treated in 2010, the number of G1 patients receiving treatment in 2012 would be 15,000 in scenario 1, 18,300 in scenario 2 and 19,400 in scenario 3, among whom 2.5-3.7% may receive PEG-IFN/RBV and 96.3-97.5% PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638 million Euros. CONCLUSION: These model-based estimates indicate that new anti-HCV treatments may result in a three- to fourfold increase in the number of G1 patients to be treated in France in 2012.

Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily.

BACKGROUND/AIMS: Some patients receiving adefovir at the approved dose of 10 mg daily for chronic hepatitis B have a "suboptimal" virological response characterized by a slow and moderate decrease in viral replication. METHODS: We assessed the efficacy and safety of adefovir 20 mg daily in patients with hepatitis B e antigen-positive chronic hepatitis B resistant to lamivudine and a suboptimal virological response to adefovir 10 mg daily add-on. RESULTS: No amino acid substitutions known to confer adefovir resistance were found in these patients. In the five treated patients, the switch from 10 mg to 20 mg of adefovir daily significantly improved antiviral efficacy (-1.78+/-0.28 log international units/mL versus -3.73+/-0.51 log international units/mL, respectively, p=0.0039), and alanine aminotransferase levels normalized in all but one of the patients. No signs of renal dysfunction occurred. CONCLUSIONS: These results suggest: (i) that suboptimal responses to adefovir 10 mg daily are due to underdosing; and (ii) that increasing the adefovir dose to 20 mg daily is beneficial and safe in patients with lamivudine-resistant HBV and a suboptimal response to adefovir 10 mg daily, especially when alanine aminotransferase levels are elevated and/or the liver disease is severe or rapidly progressive. Careful monitoring of renal function is necessary.

The nonstructural 5A protein of hepatitis C virus genotype 1b does not contain an interferon sensitivity-determining region.

BACKGROUND: The nonstructural (NS) 5A protein of hepatitis C virus (HCV) has been suggested to contain an interferon (IFN) sensitivity-determining region (ISDR). METHODS: We studied whether the degree of viral decline on day 1 is associated with differences in NS5A amino acid sequences among patients receiving IFN- alpha. RESULTS: Phylogenetic analyses of the full-length protein and of functional domains showed no relationship between the baseline protein sequence and the antiviral response. NS5A quasispecies sequences showed no differences in the number of mutations in the putative ISDR relative to a prototype sequence between responders and nonresponders or according to IFN- alpha antiviral efficacy. No relationship was found between antiviral efficacy at 24 h and the baseline sequence of any NS5A region. Amino acid changes were observed in a few cases at 24 h in both responders and nonresponders, but no consistent pattern of amino acid shifts was observed, ruling out the possibility that IFN- alpha selected IFN-resistant variants. CONCLUSION: Our findings show that there is no ISDR in the HCV genotype 1 NS5A protein and that the NS5A sequence does not influence the capacity of IFN- alpha to block viral replication. The findings do not rule out a role for NS5A in subsequent viral clearance.

Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.

A proper diagnosis of cirrhosis is essential for the management of patients with chronic liver diseases. We assessed the accuracy of liver stiffness measurement by Fibroscan for the diagnosis of cirrhosis in 1,257 patients with chronic liver diseases of various causes enrolled in a prospective multicenter study as well as clarified causes of discrepancies between liver histology and Fibroscan. One hundred thirty-two patients had unsuitable biopsy specimens, and 118 had unreliable liver stiffness measurements. Because 232 patients overlapped with a previous study, analysis was performed in the 775 new patients then derived in the whole population (1,007; 165 cirrhosis). Diagnostic accuracy was assessed by receiver operator curve (ROC) analysis. Liver samples were re-analyzed in case of discrepancies. The area under the ROC (AUROC) was 0.95 (95% CI, 0.93-0.96) for the diagnosis of cirrhosis in either 775 or 1,007 patients. The cutoff value with optimal diagnosis accuracy was 14.6 kPa in 1,007 patients (positive and negative predictive values, 74% and 96%) with discrepancies among the etiological groups. Eighty patients were misclassified: (1) among 45 patients without cirrhosis with liver stiffness 14.6 kPa or greater, 27 (60%) had extensive fibrosis and 10 (22%) significant perisinusoidal fibrosis; and (2) among 35 patients with cirrhosis and liver stiffness less than 14.6 kPa, 10 (29%) had a macronodular pattern and 25 (71%) either none or mild activity. In conclusion, Fibroscan is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases, better at excluding than at predicting cirrhosis using a threshold of 14.6 kPa. False-negatives are mainly attributable to inactive or macronodular cirrhosis.

Molecular epidemiology of hepatitis C virus subtype 3a in injecting drug users.

Hepatitis C virus subtype 3a (HCV-3a) originates from Asia and has spread widely among injecting drug users as well as other patient groups in industrialized countries. HCV subtype 3a infection remains highly prevalent and frequently transmitted in the population of intravenous drug users. The objective of this study was to understand better the mechanisms of the worldwide HCV-3a epidemics in drug users. Ninety-three sera from HCV-3a-infected IDUs from France, the United States, Brazil, Argentina, and Australia were studied. Phylogenetic analyses of the non-structural 5B region showed no specific clustering according to the continent of the patient's origin. Non-exclusive clusters of viral sequences from South America, Australia, and California were observed, but topologies were not supported by strong bootstrap values. The results suggest that HCV-3a has been transmitted from a common origin through a unique worldwide epidemic that rapidly spread among drug users. Regional transmission occurred in the recent past, leading to an embryonic genetic diversification of HCV-3a among local injecting drug user population.

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P < .0001) and histological (0.79, P < .0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F) > or =2, 0.95 for F > or =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F > or =2, F > or =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

Laparoscopic liver resection for peripheral hepatocellular carcinoma in patients with chronic liver disease: midterm results and perspectives.

OBJECTIVE: Report the midterm results of laparoscopic resection for hepatocellular in chronic liver disease (CLD). SUMMARY BACKGROUND DATA: Surgical resection for hepatocellular carcinoma (HCC) in chronic liver disease (CLD) remains controversial because of high morbidity and recurrence rates. Laparoscopic resection of liver tumors has recently been developed and could reduce morbidity. METHODS: From 1998 to 2003, patients with HCC and CLD were considered for laparoscopic liver resection. Inclusion criteria were chronic hepatitis or Child's A cirrhosis, solitary tumor < or =5 cm in size, and location in peripheral segments of the liver. Mortality, morbidity, recurrence rates, and survival were analyzed. RESULTS: A total of 27 patients were included. Liver resections included anatomic resection in 17 cases and non anatomic resection in 10. Seven conversions to laparotomy (26%) occurred for moderate hemorrhage in 5 cases and technical difficulties in 2 cases. Mortality and morbidity rates were 0% and 33%, respectively. Postoperative ascites and encephalopathy occurred in 2 patients (7%) who both had undergone conversion to laparotomy. Mean surgical margin was 11 mm (range, 1-47 mm). After a mean follow-up of 2 years (range, 1.1-4.7), 8 patients (30%) developed intrahepatic tumor recurrence of which one died. Treatment of recurrence was possible in 4 patients (50%), including orthotopic liver transplantation, right hepatectomy, radiofrequency ablation, and chemoembolization in 1 case each. There were no adhesions in the 2 reoperated patients. Overall and disease-free 3-year survival rates were 93% and 64%, respectively. CONCLUSION: Our study shows that laparoscopic liver resection for HCC in selected patients is a safe procedure with very good midterm results. This approach could have an impact on the therapeutic strategy of HCC complicating CLD as a treatment with curative intent or as a bridge to liver transplantation.

Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients.

BACKGROUND: Chronic hepatitis C in HIV-infected patients is an increasing cause of death dependent on the development of liver fibrosis, which is currently assessed by liver biopsy despite its limitations. Liver stiffness measurement, a new noninvasive method, allows the evaluation of liver fibrosis. The aim of this prospective study was to assess the accuracy of liver stiffness measurement for the detection of fibrosis and cirrhosis in HIV/hepatitis C virus (HCV)-coinfected patients and to compare its accuracy with other noninvasive methods. METHODS: We studied 72 consecutive HIV patients with chronic hepatitis C who had a simultaneous liver biopsy and liver stiffness measurement by transient elastography (FibroScan; Echosens, Paris, France) for the assessment of liver fibrosis. RESULTS: Liver stiffness values ranged from 3.0 to 46.4 kilopascal. Liver stiffness was significantly correlated to fibrosis stage (Kendall tau-b = 0.48; P < 0.0001). The area under the receiver operating characteristic (AUROC) curve of liver stiffness measurement was 0.72 for F > or = 2 and 0.97 for F = 4. For the diagnosis of cirrhosis, AUROC curves of liver stiffness measurement were significantly higher than those for platelet count (P = 0.02), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (P = 0.0001), Aspartate aminotransferase-to-Platelet Ratio Index (APRI) (P = 0.01), and FIB-4 (P = 0.004). CONCLUSION: Liver stiffness measurement is a promising noninvasive method for the assessment of fibrosis in HIV-infected patients with chronic HCV infection. Its use for the follow-up of these patients should be further evaluated.

Dynamics of hepatitis B virus resistance to lamivudine.

Lamivudine was the first approved inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT). Lamivudine resistance develops in 53% to 76% of patients after 3 years of treatment. We extensively characterized the dynamics of HBV quasispecies variant populations in four HBV-infected patients who developed lamivudine resistance. Virological breakthrough was preceded by 2 to 4 months by the emergence of quasispecies variants bearing amino acid substitutions at RT position 204, i.e., within the YMDD catalytic motif (rtM204V/I). Three patients had a gradual switch from a YMDD variant population at baseline to a 100% lamivudine-resistant variant population, whereas the remaining patient had a fluctuating pattern of resistance variant dynamics. Careful analysis of amino acid substitutions located outside domain C of HBV RT, including those known to partially restore replication capacities in vitro, showed that the in vivo replication of HBV variants is driven by multiple forces, including intrinsic replicative advantages conferred by mutations accumulating outside domain C and the changing environment in which these variants replicate. Our findings also suggest that individual treatment optimization will require sensitive methods capable of detecting the emergence of viral resistance before the relevant variants acquire optimal replicative capacities.

[Congenital cystic diseases of the intra and extrahepatic bile ducts]. / Lésions kystiques congénitales des voies biliaires intra et extra-hépatiques.

Congenital cystic lesions of bile ducts may affect intra or extrahepatic bile ducts. Intrahepatic lesions include five entities: congenital hepatic fibrosis, Caroli's syndrome, von Meyenburg complexes, simple cyst of the liver and polycystic liver disease. Congenital hepatic fibrosis and von Meyenburg complexes are secondary to ductal plate malformation affecting the smallest intrahepatic bile ducts. Cystic dilatations are of small size and only detected at histological examination of the liver. They have few clinical consequences. In congenital hepatic fibrosis, the main manifestations result from portal hypertension. Caroli's syndrome is secondary to ductal plate malformation affecting the largest intrahepatic bile ducts. Cystic dilatations are macroscopic and responsible for cholangitis and may lead to biliary stones and carcinoma which develop within cystic dilatations. Caroli's syndrome may be or not associated with congenital hepatic fibrosis. In case of associated congenital hepatic fibrosis, portal hypertension is present. Simple cyst of the liver and polycystic liver disease are characterized by cystic dilatations which, by contrast to the preceding entities, do not communicate with the rest of biliary tree. As a result, they have only few clinical consequences. In congenital hepatic fibrosis and polycystic liver disease, renal abnormalities are frequently observed. They correspond to renal malformations associated with biliary malformations. In congenital hepatic fibrosis, renal lesions are characterized by ectatic collecting tubules which are present in two thirds of the cases and transmitted as an autosomal recessive trait. In polycystic liver disease, renal lesions are characterized by polycystic disease which is present in half of the cases and transmitted as an autosomal dominant trait. Congenital cystic lesions of extrahepatic bile ducts consist of choledochal cyst, which is secondary to malformation of the pancreato-biliary ductal junction. The major risk of choledochal cyst is the development of intracystic cancer, the prevention of which is total surgical resection of the cyst.

Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.

BACKGROUND/AIMS: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. METHODS: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 microg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. RESULTS: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or > or = 2 log10 decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximately 20% lower in those who received <80% compared with patients who received > or = 80% of the planned ribavirin dose. CONCLUSIONS: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a > or = 2 log10 reduction in HCV RNA after 12 weeks.

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case-control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no-TACE group). Patients and controls were matched for the pre-LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre- and posttransplantation treatments. Kaplan-Meier estimates were calculated 5 years after LT and were compared with the log-rank test. The mean waiting time before LT was 4.2 +/- 3.2 months in the TACE group and 4.3 +/- 4.4 months in the no-TACE group. The median number of TACE procedures was 1 (range: 1-12). Demographic data, median alpha-fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre- and post-LT morphologic characteristics of the tumors did not differ in the TACE and no-TACE groups. Overall 5-year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis > or =80% on the liver explant with a 5-year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre-LT TACE does not influence post-LT overall survival and disease-free survival.