HBV/HDV co-infection in the Western Brazilian Amazonia: an intriguing mutation among HDV genotype 3 carriers.

HDV infection still remains a serious public health problem in Amazonia. There are few data regarding the biomolecular aspects of HBV/HDV co-infection in this region. We studied 92 patients HBsAg(+) /anti-HDV IgG(+) followed at the Hepatitis Referral Centers of Porto Velho (RO), Rio Branco and Cruzeiro do Sul (AC), Brazil, from March 2006 to March 2007 for whom the HDV and/or the HBV genotype could be determined. The HDV genotype could be determined in 90 patients, while the HBV genotypes could be positively determined in 74. HBV subgenotype F2 is the most prevalent (40.2%), followed by the subgenotypes A1 (15.2%) and D3 (8.7%), while 16.4% were other subgenotypes or genotypes, 4.3% were discordant and 15.2% were unamplifiable. Surprisingly, HDV genotype 3 (HDV-3) was found in all of the HBV/HDV-infected patients that could be genotyped for HDV, confirming that HDV-3 can associate with non-F HBV genotypes. However, a HDV-3 mutant was found in 29.3% of patients and was more frequently associated with non-F HBV genotypes (P < 0.001) than were nonmutant strains, suggesting that the mutation may facilitate association of HDV-3 with non-F HBV genotypes.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Different patterns of decompensation in patients with alcoholic vs. non-alcoholic liver cirrhosis.

BACKGROUND: The histological pattern of fibrosis in liver cirrhosis varies in different chronic liver diseases, and hepatic decompensation may be differentiated in consequences of fibrosis (i.e. ascites, variceal bleeding) or in lack of function (i.e. jaundice) resulting in aetiology-specific variable morbidity and mortality. AIM: To evaluate patterns of hepatic decompensation in relation to the aetiology of liver cirrhosis. METHODS: Two different cohorts were retrospectively evaluated between 2002 and 2007. Cohort A was for hypothesis generation and consisted of 220 cirrhotic patients. To confirm the initial observations a second cohort B (n = 217) was analysed. The different patterns of hepatic decompensation evaluated were ascites, jaundice, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatorenal syndrome or hepatocellular carcinoma. Furthermore, we analysed survival in relation to pattern of decompensation in alcoholic vs. non-alcoholic liver disease. RESULTS: Alcoholics were more frequently hospitalised for ascites (cohort A: 81.4% vs. 65.4%, P = 0.016; cohort B 71.3% vs. 58.5%, P = 0.085). In contrast, non-alcoholics presented with higher rates of hepatocellular carcinoma (cohort A: 23.1% vs. 11.9%, P = 0.046; cohort B 38.6% vs. 22.5%, P = 0.018). There were no significant differences in jaundice, variceal bleeding, hepatorenal syndrome or encephalopathy. Survival was significantly impaired in non-alcoholic cirrhosis once ascites occurred (P = 0.003), whereas ascites did not predict higher mortality in patients with alcoholic cirrhosis. CONCLUSIONS: Ascites is the leading initial pattern of decompensation in alcoholic cirrhosis whereas hepatocellular carcinoma dominates in non-alcoholics. Non-alcoholics developing ascites show a poor survival.

Proficiency of transient elastography compared to liver biopsy for the assessment of fibrosis in HIV/HBV-coinfected patients.

Transient elastography (TE) is a noninvasive technique to evaluate liver fibrosis. We compared the performance of TE with liver biopsy (LB) in patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection. Patients prospectively underwent TE and LB. The diagnosis accuracy of TE was calculated using receiver operating characteristic (ROC) curves for different stages of fibrosis, and optimal cut-off values were defined. A sequential algorithm combining TE with biochemical score (Fibrotest) is proposed. Fifty-seven patients had both TE and LB (median time: 3 days) and two with proven cirrhosis, only TE. Forty-six (78%) were under antiretroviral therapy with anti-HBV drugs in 98%, and 19 (32%) had elevated alanine aminotransferase (ALT). A significant correlation was observed between liver stiffness measurement (LSM) and METAVIR fibrosis stages (P < 0.0001). Patients with elevated ALT tended to have higher LSM than those with normal ALT. The areas under the ROC curves were 0.85 for significant fibrosis (≥ F2), 0.92 for advanced fibrosis (≥ F3) and 0.96 for cirrhosis. Using a cut-off of 5.9 kPa for F ≥ 2 and 7.6 kPa for F ≥ 3, the diagnosis accuracy was 83% and 86%, respectively. With an algorithm combining TE and Fibrotest, 97% of patients were well classified for significant fibrosis. Using this algorithm, the need for LB can be reduced by 67%. In HIV/HBV-coinfected patients, most of them with normal ALT under antiretroviral treatment including HBV active drugs, TE was proficient in discriminating moderate to severe fibrosis from minimal liver disease.

A randomized trial of viral hepatitis prevention among underprivileged people in the Lyon area of France.

BACKGROUND: We compared the efficacy of two viral hepatitis B and C (VHBC) screening strategies, relative to no intervention, among underprivileged people (UP) living in shelters in the Lyon area. METHODS: Eighteen of 37 shelters were randomly sampled after stratification based on the accommodation capacity and the screening centres/shelters distance. Through randomization, the S0 strategy (no intervention), the S1 strategy [group information (GI) and referral for screening] and the S2 strategy (GI and in situ screening) were each applied in six shelters. A standardized questionnaire was offered to each participant. Follow-up of positive cases was organized via the reference centre of VHBC of Lyon. RESULTS: The screening completion rate (SCR) among 1276 included subjects in S0, S1 and S2 was 1.5, 42.8 and 59.7%, respectively (P < 10(-6)). This rate was higher in S2 regardless of the sociodemographic variable considered. Odds ratios (OR) of screening completion (SC) was significantly higher in S1 versus S0, OR = 49.8 [95% confidence interval (CI): 26.1-102.1], in S2 versus S0, OR = 98.5 (95% CI: 51.9-200.8) and in S2 versus S1, OR = 2.0 (95% CI: 1.3-2.9). Age, country of birth and professional inactivity were independently associated with SC. CONCLUSIONS: Health authorities must ensure widespread screening of UP, which is more effective when conducted in shelters than in screening centres.

[Results of a satisfaction survey carried out among patients living with the virus of human immunodeficiency (HIV) following therapeutic education sessions]. / Résultats d'une enquête de satisfaction réalisée auprès des patients vivant avec le virus de l'immunodéficience humaine (VIH) suivis en consultation d'éducation thérapeutique.

INTRODUCTION: Within the framework of a quality initiative aiming to improve HIV patients' care in our therapeutic educational unit, and to meet the recommendations of the Haute Autorité de Santé (HAS) regarding the evaluation of educational programs, we carried out a satisfaction survey among patients. Our goal was to identify their needs thanks to the analysis of questionnaires in order to improve their care. PATIENTS AND METHOD: Anonymous questionnaires were proposed and collected for two months during a medical or educational consultation or during a renewal of prescription. All 21 questions related to the organization of our unit, the patients' expectations, the tools used and the quality of life. An appreciation scale at four levels was proposed. RESULTS: Twenty-eight questionnaires were returned out of 60 given out; 96.4% of the patients were satisfied and found the sessions to be beneficial and to answer their needs; 85.7% changed their opinion on HIV and 78.6% altered their behaviour; 89.3% were satisfied by the number of sessions; 96.4% thought that the place, duration and frequency of consultations were adapted, and 89.3% approved the educational tools; 67.8% thought that follow-up pad would be useful. DISCUSSION-CONCLUSION: Patients were satisfied with the educational sessions, which constituted a real place of exchange and support, allowing them to evoke all the difficulties they meet. Any improvements must concern information media given out to patients and the ease of access to educational teams in case of difficulties.

[Treatment of hepatitis B: new perspectives]. / Traitement de l'hépatite B: progrès attendus.

Despite the development of new anitiviral agents, the treatment of chronic hepatitis B remains a major clinical challenge. Major achievements have been made with the rationale use of antivirals exhibiting a complementary cross resistance profile to prevent antiviral drug resistance. The current concept of modern antiviral therapy of chronic hepatitis B relies on a precise virologic monitoring and early treatment adaptation to prevent drug resistance. The difficulty of achieving viral clearance and the risk of drug resistance development are major arguments to continue research in the field of antivirals and to identify new targets for therapy. The development of true combination therapy is highly desirable to fulfil the objective of long-term viral suppression, clearance of viral cccDNA and infected cells and ultimately cure of the disease.

Innovative therapy for hepatocellular carcinoma: three-dimensional high-dose photon radiotherapy.

The development of three-dimensional conformal radiotherapy (3DCRT) has enabled high dose radiation to be directed to tumour with a frank sparing of the non-tumour surrounding liver parenchyma without restriction due to tumour topography and size, presence of peritumourous satellite nodules or associated segmental portal vein thrombosis. 3DCRT can be safely delivered alone or concomitantly with transarterial chemoembolization (TACE), giving very encouraging results. Efficacy is strongly related to a smaller tumor size and higher dose of radiation while toxicity closely correlates to the pre-radiotherapy liver functions and the dose delivered to the uninvolved liver. These data has led to integrate 3DCRT in the multimodal treatment of HCC as a possible curative-intent option as well as surgical resection or percutaneous procedures although phase-III controlled studies are warranted to clarify this point. This may represent a promising approach in patients who are inoperable or for whom other ablation therapies are not feasible. The next steps will be the optimization of delivery modes of this type of photon therapy, taking account that other radiation modalities such as proton beam therapy for instance might be shown as of great interest within the next few years.

Discordance between biochemical markers of liver activity and fibrosis (Actitest-Fibrotest) and liver biopsy in patients with chronic hepatitis C.

INTRODUCTION: The purpose of this clinical trial was to determine in routine practice and in comparison with liver biopsy the limitations of two blood tests, Actitest and Fibrotest, for the evaluation of hepatic activity and fibrosis in patients with chronic hepatitis C. METHODS: Routine blood tests, Actitest and Fibrotest, and liver biopsy were performed in 96 patients with chronic hepatitis C attending routine outpatient clinics. Receiver operating characteristics (ROC) curves were used to assess the diagnostic value of the biochemical tests in comparison with the METAVIR classification. RESULTS: The study population was predominantly male (63.5%) with a mean age of 48 years; 83.3% of the patients had genotype 1 hepatitis C virus infection. Treatment status was naive (62.5%), nonresponders (17.7%), relapsers (7.3%), or unknown (12.5%). The comparison of F0-F2 versus F3-F4 estimated the negative predictive value at 92% and the positive predictive value at 52% for a cut-off of 0.455. Discrepancies in activity score were more frequently due to a higher score of the biochemical test compared to biopsy (18 cases out of 19). Discrepancies for fibrosis were observed in 18 patients with a higher score for biochemical test in eight and a higher score for liver biopsy in 10 cases. A significant increase of gamma-glutamyl-transferase (GGT) (p=0.0001) and alanine aminotransferase (ALT) (p<0.0001) was observed in case of biochemical test overestimation of activity, and a significant increase of alpha2-macroglobulin (p=0.006) and GGT (p=0.018) in case of biochemical test overestimation of fibrosis. CONCLUSION: This prospective study confirms the good diagnostic value of biochemical tests for necrotico-inflammatory activity and fibrosis as compared with the histological analysis of liver biopsy. Clinicians must interpret Actitest and Fibrotest results with caution in patients with a significant elevation of ALT, and/or GGT and/or alpha2-macroglobulin which could overestimate hepatic injury.

A French prospective observational study of the treatment of chronic hepatitis C in drug abusers.

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.

[Hepatitis C: which strategy in case of treatment failure ?]. / Hépatite C : quelle stratégie en cas d'échec thérapeutique ?

After a treatment by peginterferon alpha and ribavirin, the percentages of non response and relapse are approximatively 33 and 18 % respectively. These treatment failures may be due either to viral resistance or to an insufficient treatment. The prevention of treatment failure is based on a good knowledge of the predictive factors of failure before and during the treatment. Among the patients who did not respond to interferon alpha and ribavirin, a new treatment with peginterferon alpha-2b and ribavirin makes it possible to obtain 45 % of sustained virological response (SVR) among the relapsers and 17 % of SVR among the non responders. Among the patients who did not respond to peginterferon alpha and ribavirin, a new treatment with peginterferon alpha-2b and ribavirin makes it possible to obtain 36 % of SVR among the relapsers and only 4 % of SVR among the non responders. New therapeutic strategies are necessary for the non responders. Until now no new therapeutic strategy allowed a significant benefit in term of SVR. Protease inhibitors are currently tested in non responders but there are some concerns about the risk of selection of multi-resistant strains.

Effect of early initiation of highly active antiretroviral therapy on CD4 cell count and HIV-RNA viral load trends within 24 months of the onset of acute retroviral syndrome.

OBJECTIVES: The effect of starting highly active antiretroviral therapy (HAART) early after the onset of acute retroviral syndrome (ARS) on CD4 and HIV-RNA trends was studied over a 2-year follow-up period. METHODS: Four groups of HIV-infected patients stratified according to the time interval from ARS onset to HAART initiation and a control group of untreated patients were compared. RESULTS: The results indicated that the earlier the start of HAART, the faster was the rate of CD4 increase and HIV-RNA decrease. However, this difference did not seem to persist at 24 months. CONCLUSIONS: The optimal treatment strategy for HIV-infected patients needs to be explored further.

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma.

Dysregulation of growth factors and their receptors is central to human hepatocellular carcinoma (HCC). We previously demonstrated that the Frizzled-7 membrane receptor mediating the Wnt signalling can activate the beta-catenin pathway and promotes malignancy in human hepatitis B virus-related HCCs. Expression patterns of all the 10 Frizzled receptors, and their extracellular soluble autoparacrine regulators (19 Wnt activators and 4 sFRP inhibitors) were assessed by real-time RT-PCR in 62 human HCC of different etiologies and their matched peritumorous areas. Immunostaining was performed to localise Frizzled on cell types in liver tissues. Regulation of three known Frizzled-dependent pathways (beta-catenin, protein kinase C, and C-Jun NH(2)-terminal kinase) was measured in tissues by western blot. We found that eight Frizzled-potentially activating events were pleiotropically dysregulated in 95% HCC and 68% peritumours as compared to normal livers (upregulations of Frizzled-3/6/7 and Wnt3/4/5a, or downregulation of sFRP1/5), accumulating gradually with severity of fibrosis in peritumours and loss of differentiation status in tumours. The hepatocytes supported the Wnt/Frizzled signalling since specifically overexpressing Frizzled receptors in liver tissues. Dysregulation of the eight Frizzled-potentially activating events was associated with differential activation of the three known Frizzled-dependent pathways. This study provides an extensive analysis of the Wnt/Frizzled receptor elements and reveals that the dysregulation may be one of the most common and earliest events described thus far during hepatocarcinogenesis.

Long-term results of liver transplantation for Wilson's disease.

UNLABELLED: Wilson's disease is a hereditary defect in hepatic copper metabolism, causing hepatic, neurological and/or psychiatric manifestations. For patients with severe disease, liver transplantation is the treatment of choice. The aim of this study was to report the long-term outcome of patients who underwent liver transplantation for Wilson's disease. PATIENTS AND METHODS: Thirteen patients with Wilson's disease, transplanted in Lyon France between January 1987 and May 2006, were including in this study: eight women and five men, aged eight to 53 years (median 20 years, seven children and six adults). The diagnosis of Wilson's disease was established before liver transplantation. RESULTS: The indication for liver transplantation was chronic (69%) or fulminant liver failure (31%). The median follow-up after liver transplantation was 10 years with 100% patient survival. Copper metabolism returned to normal in all patients. None of the patients with exclusive liver disease required chelation treatment after liver transplantation and none developed neurological symptoms of Wilson's disease. CONCLUSION: Liver transplantation totally reverses the abnormalities of copper metabolism and subsequent hepatic failure, but the course of neurological symptoms remains unpredictable. Long-term patient survival can be excellent without occurrence of neurological complications.

Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B.

BACKGROUND: Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics. AIM: To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor. METHODS: A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method. RESULTS: A total of 31 patients were enrolled into the 10 mg (n = 10), 30 mg (n = 11) and 50 mg (n = 10) groups, respectively. At week 12, the median VL change was -3.2, -3.7 and -4.2 log(10) copies/mL (-0.64, -0.74 and -0.84 log(10) IU/mL) in the 10, 30 and 50 mg groups, respectively (P = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound. CONCLUSION: Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.

Pneumococcal pneumonia in HIV-infected patients by antiretroviral therapy periods.

OBJECTIVE: To ascertain the relationship between periods of various antiretroviral therapies and the incidence of first community-acquired pneumococcal pneumonia (CAPP) among HIV-1 infected patients. METHODS: We analysed 4075 patients enrolled prospectively in the Lyon section of the French Hospital Database on HIV between 1993 and 2004, stratified into three groups. The first group (G1) included patients for whom enrolment and last follow-up were before the highly active antiretroviral therapy (HAART) period (beginning 1 July 1996); the second group (G2) comprised patients who were enrolled before HAART but had last follow-up in the HAART period; the third group (G3) included patients for whom both enrolment and last follow-up took place in the HAART period. RESULTS: Fifty-five CAPP episodes were identified. The incidence of CAPP per 1000 patient-years declined over time, from 10.6 to 1.5 and 2.5 in calendar periods G1, G2 and G3, respectively (P=0.004 for linear trend). Factors associated with a decreased risk of CAPP were lower age, baseline CD4 count >or=200 cells/microL and more recent years of enrolment, when HAART use became extensive (P<0.001). The use of intravenous drugs increased the risk of CAPP (P<0.001). CONCLUSIONS: There has been a significant reduction in the incidence of CAPP in HIV-1 infected patients since the advent of HAART.

Characteristics and survival of HIV-infected patients not screened for hepatitis C virus infection in a hospital-based cohort.

The rate of human immunodeficiency virus (HIV) disease progression or death of individuals coinfected with hepatitis C virus (HCV) is conflicting. The complete-case analysis systematically used, excludes patients unscreened for HCV. Our objective was to assess if rate of survival differed between HIV-infected patients screened and unscreened for HCV in a hospital-based prospective cohort study. Patients were enrolled in the Lyon section of the French Hospital Database on HIV between 1 July 1992 and 31 May 2005. A multivariate Cox regression model was used to analyse the association of HCV screening with survival. Of 3244 patients, 299 (9.2%) were not screened for HCV. The populations screened and unscreened differed by the proportion of acquired immune deficiency syndrome at baseline, presumed route of infection, CD4 cell count category at baseline, mean duration of follow-up, mean number of visits per year, type of antiretroviral therapy and survival. The rate of progression to death was higher for non-HCV-screened vs HCV-screened patients: the incidence rate among HCV-screened patients was 22.9/1000 patient-years; the incidence rate among HCV-unscreened patients was 52.4/1000 patient-years. The adjusted hazards ratio of death was 2.48 [95% confidence interval (1.83-3.35); P < 0.001] for patients with unknown HCV status compared with others. In conclusion, unscreened or unknown HCV status was associated with an increased risk of death in our hospital cohort. Important prognostic factors are related to, or confounded by the practice of HCV screening.

Long-term follow-up of the hepatitis C HENCORE cohort: response to therapy and occurrence of liver-related complications.

The aims of the study were to verify the long-term effect of time on viral clearance in hepatitis C virus (HCV) patients and to find out factors possibly associated with disease progression. A total of 1641 patients recruited from eight European centres in 1996-1997 were re-analysed 5-7 years after inclusion. The occurrence of decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation was analysed in relation to different host and viral factors. Ninety-three per cent of the HCV patients who had cleared the virus (spontaneously or after antiviral therapy) remained HCV-RNA-negative during follow up and may be considered as 'cured'. Among patients who were sustained responders at inclusion, 2.3% developed liver complications during follow up, and 31% of non-responders did. Advanced age at infection and presence of the human leucocyte antigen (HLA) DRB1*1201-3 allele were possibly associated with a higher rate of progression to decompensated cirrhosis or HCC. Decompensated cirrhosis might be further associated with male gender, non-response to previous therapy, and lack of HLA DRB1*1301 allele, whereas HCC seems to be associated with the presence of the HLA DQ02 allele. Long-term follow up of HCV patients indicates that virological response persists over time and is associated with a very low incidence of liver complications. Advanced age at inclusion, advanced age at infection, viral genotype 1, non-response to previous therapy and possibly some specific HLA alleles are factors independently associated with a faster rate of progression towards liver complications. The large proportion of patients lost to follow up stresses the need for a strengthened and optimized management of HCV patients.