Hepatitis: Fafi-Kremer S

Stoll-Keller F, Fafi-Kremer S, Wolf P, Doffoël M, Baumert T. · Institut de Virologie de la Faculté de Médecine et Unité INSERM 748, 3 rue Koeberlé, 67000 Strasbourg. · Bull Acad Natl Med. · Pubmed #19445379 No free full text.

Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver disease. About 170 million people worldwide are chronically infected. No preventive or therapeutic vaccine is available. Current antiviral combinations based on pegylated interferon alpha (IFN-alpha) and ribavirin have limited efficacy, poor tolerability and high cost. End-stage liver disease due to chronic HCV infection is a leading indication for liver transplantation (LT). However, re-infection of the liver graft is inevitable, with a high risk of cirrhosis within 5 years. To infect the graft, circulating virions need to attach to and enter hepatocytes, via viral envelope glycoproteins E1-E2. E1-E2 can react with cell receptors despite the presence of neutralizing antibodies. Using the HCV pseudoparticle model system, we found that viral strains selected after liver transplantation are characterized by high infectivity and that they are poorly neutralized by autologous post-transplant serum. A better understanding of the early steps of viral attachment and escape from neutralizing antibodies could lead to novel antiviral strategies.

Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF. · Inserm, U748 et Laboratoire de Virologie des Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé 67000 Strasbourg, France. · Expert Rev Vaccines. · Pubmed #19249975 No free full text.

Abstract: Development of an effective vaccine against the hepatitis C virus (HCV) has long been defined as a difficult challenge due to the considerable variability of this RNA virus and the observation that convalescent humans and chimpanzees could be re-infected after re-exposure. On the other hand, progress in the understanding of antiviral immune responses in patients with viral clearance has elucidated key mechanisms playing a role in the control of viral infection. Studies investigating prophylactic vaccine approaches in chimpanzees have confirmed that the induction and maintenance of strong helper and cytotoxic T-cell immune responses against multiple viral epitopes is necessary for protection against viral clearance and chronic infection. A multispecific B-cell response, resulting in rapid induction of cross-neutralizing antibodies may assist cellular responses. Therapeutic vaccine formulations currently being evaluated in clinical trials are facing the fact that the immune system of chronic carriers is impaired and needs the restoration of T-cell functions to enhance their efficacy.

Schramm F, Moenne-Loccoz R, Fafi-Kremer S, Soulier E, Royer C, Weitten T, Brignon N, Ellero B, Woehl-Jaegle ML, Meyer C, Wolf P, Doffoel M, Baumert TF, Gut JP, Stoll-Keller F, Schvoerer E. · Unité Inserm 748, 3, rue Koeberlé, 67000 Strasbourg, France. · Pathol Biol (Paris). · Pubmed #18842359 No free full text.

Abstract: Besides hepatocytes, representing the main replication site of hepatitis C virus, peripheral blood mononuclear cells also represent a crucial target for viral infection. Hepatitis C virus compartmentalization (i.e., non-random distribution) of viral variants between plasma and peripheral blood mononuclear cells, more frequently observed in liver transplant patients compared to non-transplanted patients, makes liver transplantation an interesting model for the analysis of hepatitis C leukotropism. This article aims to present, firstly, in clinical and biological features arguing favour of hepatitis C virus infection leukotropism and, secondly, to review current knowledge about compartmentalization between plasma and peripheral blood mononuclear cells, especially in the liver transplantation setting.

Fafi-Kremer S, Zeisel MB, Schvoerer E, Soulier E, Habersetzer F, Wolf P, Doffoel M, Baumert TF, Stoll-Keller F. · Laboratoire de virologie, Inserm U748, 3, rue Koeberlé, 67000 Strasbourg, France. · Gastroenterol Clin Biol. · Pubmed #18467058 No free full text.

Abstract: Hepatitis C virus (HCV) results in persistent infection in more than 70% of infected individuals despite the development of humoral and cellular immune responses. Following infection, although antibodies targeting epitopes of both structural and non structural proteins are elicited, the virus evades antibody-mediated neutralization. Studies of host neutralizing responses against HCV have been limited by the lack of a convenient tissue culture system for HCV infection. In the past five years in vitro models have been developed to characterize interaction of HCV glycoproteins with host cell entry factors and detect antibodies interfering with HCV entry and infection. These models have been used to characterize targets of neutralizing responses and better understand their impact on the pathogenesis of infection.

Zeisel MB, Fafi-Kremer S, Fofana I, Barth H, Stoll-Keller F, Doffoel M, Baumert TF. · Inserm Unite 748, Universite Louis Pasteur, 3 Rue Koeberle, Strasbourg F-67000, France. · World J Gastroenterol. · Pubmed #17828813 links to  free full text

Abstract: Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodies for control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.

Fafi-Kremer S, Zarski JP. · Laboratoire de Virologie, CHU de Grenoble, France. · Gastroenterol Clin Biol. · Pubmed #15864196 No free full text.

This publication has no abstract.

Pastor R, Habersetzer F, Fafi-Kremer S, Doffoel M, Baumert TF, Gut JP, Stoll-Keller F, Schvoerer E. · Institut de Virologie, 3 Rue Koeberle, 67000 Strasbourg, France. · World J Gastroenterol. · Pubmed #19222103 links to  free full text

Abstract: Anti-hepatitis B virus (HBV) therapy leads to the emergence of mutant viral strains during the treatment of chronic hepatitis B with nucleos(t)ides analogues. The existence of HBV variants with primary antiviral resistance may be important for treatment choice. We studied two patients with chronic HBV infection by sequencing the HBV polymerase gene. They had adefovir- and tenofovir-related mutations in the viral polymerase, although they had never been treated. These mutations were rtV214A/rtN238T in one patient and rtA194T in the other. Thus, mutations in untreated patients deserve cautious surveillance. These data indicate that mutations that can theoretically confer adefovir or tenofovir resistance may emerge in treatment-naive patients.

Schramm F, Soulier E, Royer C, Weitten T, Fafi-Kremer S, Brignon N, Meyer N, Ellero B, Woehl-Jaegle ML, Meyer C, Wolf P, Doffoël M, Baumert TF, Stoll-Keller F, Schvoerer E. · Institut National de la Santé et de la Recherche Médicale Unité 748, Faculté de Médecine, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France. · J Infect Dis. · Pubmed #18925843 No free full text.

Abstract: BACKGROUND: Nonrandom distribution of hepatitis C virus (HCV) quasispecies (compartmentalization between blood plasma and leukocytes) suggests the presence of HCV leukotropic variants. HCV compartmentalization in the setting of liver transplantation (LT) is poorly understood. To study HCV leukotropic variants, we investigated the evolution of HCV compartmentalization after immunosuppression in liver transplant recipients. METHODS: Plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 5 liver transplant recipients before and after LT. We used clone sequencing to analyze the hypervariable region 1 (HVR1)-E2(384-419) region, which plays a key role in HCV entry and the induction of neutralizing responses, and assessed compartmentalization through phylogenetic analyses and Mantel's test. RESULTS: Compartmentalization was frequent in the LT setting. HCV quasispecies were more homogeneous after LT in both the plasma and PBMC compartments, with a significant decrease in quasispecies complexity (P = .003) and genetic distances (P = .004) after transplantation. Our analysis identified 8 PBMC-related amino acid residues in HVR1. CONCLUSIONS: HCV compartmentalization between plasma and PBMCs and the emergence of leukotropic variants could be potentiated by immunosuppression in liver transplant recipients. The identification of defined leukotropic variants may contribute to the understanding of virus-host interactions after transplantation.

Fafi-Kremer S, Stoll-Keller F, Baumert TF. · Institut National de la Santé et de la Recherche Médicale,Unit 748 Strasbourg, France. · Hepatology. · Pubmed #18366112 No free full text.

This publication has no abstract.

Dumortier J, Mekki Y, Rimmelé T, Ber C, Maillard E, Fafi-Kremer S, Lina B, Scoazec JY, Delafosse B, Boillot O. · Unité de Transplantation Hépatique, Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Lyon. · Gastroenterol Clin Biol. · Pubmed #17925776 No free full text.

Abstract: Viral hepatitis are the leading cause of fulminant hepatitis. Epstein Barr virus is the viral agent involved in infectious mononucleosis, associated with a frequent and usually benign hepatitis, except in case of immunodeficiency, congenital or acquired. We report the case of an immunocompetent young woman who presented an EBV induced fulminant hepatic failure, requiring liver transplantation that was successful. This observation emphasizes that EBV must be known as a possible cause of fulminant hepatitis and that liver transplantation is probably the unique therapeutic option to avoid a usually fatal course.

Schvoerer E, Soulier E, Royer C, Renaudin AC, Thumann C, Fafi-Kremer S, Brignon N, Doridot S, Meyer N, Pinson P, Ellero B, Woehl-Jaegle ML, Meyer C, Wolf P, Zachary P, Baumert T, Stoll-Keller F. · Laboratoire de Virologie, Hopital Civil, Strasbourg, France. · J Infect Dis. · Pubmed #17624837 No free full text.

Abstract: BACKGROUND: End-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period. METHODS: For 17 patients who received an LT for HCV disease, plasma viral quasispecies evolution was determined by sequence analysis of hypervariable region 1 of the E2 envelope gene before transplant (BT), after 7 days (D7), and after 1 month (M1). T helper (Th)1/Th2 cytokine levels were determined concomitantly. RESULTS: HCV quasispecies showed a significant decrease in amino acid diversity at D7 and M1, compared with BT (P<.05). A correlation was observed between low plasma tumor necrosis factor-alpha levels at D7 and decreased quasispecies amino acid complexity at the same date. Nucleic acid diversity was lower for genotype 1 than for genotype 3 infection (P<.05). The complexity and diversity of amino acids were lower in patients with hepatocellular carcinoma (HCC) BT than in those without HCC (P<.05). Conserved amino acid residues within quasispecies were shared by the whole cohort before and after LT. CONCLUSION: Viral structural and/or host immunological features could favor the emergence of fitter HCV strains after LT.

Payan C, Pivert A, Morand P, Fafi-Kremer S, Carrat F, Pol S, Cacoub P, Perronne C, Lunel F, Anonymous00133. · Départment de Microbiologie-EA3882, CHU-Hôpital Morvan, Brest, France. · Gut. · Pubmed #17363475 No free full text.

Abstract: BACKGROUND AND AIMS: An algorithm based on a 2 log(10) decline in hepatitis C virus (HCV) RNA at week (W) 12 has been proposed in US and European recommendations for the management of patients with chronic hepatitis C treated with pegylated-interferon and ribavirin. METHODS: We examined rapid virological response (RVR; at W2 and W4 after the initiation of therapy) in HIV/HCV co-infected patients. Using HCV RNA measurements (Versant HCV RNA 3.0, Cobas Amplicor HCV 2.0), RVR was studied in 323 patients from the ANRS HC02 RIBAVIC trial, comparing interferon alpha2b 3 MU x3/week with pegylated interferon alpha2b 1.5 microg/kg/week, each combined with ribavirin 800 mg/day over 48 weeks. RESULTS: The best positive and negative predictive values of sustained virological response (SVR) were obtained with an undetectable HCV RNA at W4 (97%) and with more than a 2 log(10) decrease at W12 (99%), respectively. Prediction of non-SVR was obtained in all patients by using HCV RNA cut-off levels above 460,000 IU/ml at W4 and above 39,000 UI/ml at W12 irrespective of the HCV genotype and arm of treatment. CONCLUSION: We propose a new algorithm based on RVR thresholds using HCV RNA that allows for excellent prediction of non-SVR as early as W4.

Schvoerer E, Thumann C, Soulier E, Royer C, Fafi-Kremer S, Brignon N, Ellero B, Woehl-Jaegle ML, Meyer C, Wolf P, Jaeck D, Stoll-Keller F. · Institut de virologie et unité Inserm 748, CHRU de Strasbourg, 3, rue Koeberlé, 67000 Strasbourg, France. · Pathol Biol (Paris). · Pubmed #17027191 No free full text.

Abstract: Cirrhosis due to chronic infection by hepatitis C virus (HCV), associated or not to a primary hepatocarcinoma, has become the first indication of liver transplantation. Graft reinfection by HCV is considered to be systematic while its prognosis is variable from one patient to another. A better knowledge of factors implicated in the occurrence and severity of hepatitis C recurrence is crucial in order to make optimal patients' monitoring. This article aims to present available data in this field, clarifying the role of viral factors (viral load, genotype, evolution of viral quasispecies) and host-related factors (immune response) which could take part in the development of hepatitis C recurrence.

Pivert A, Payan C, Morand P, Fafi-Kremer S, Deshayes J, Carrat F, Pol S, Cacoub P, Perronne C, Lunel F. · Laboratoire de Bactériologie-Virologie-Hygiène Hospitalière, CHU Angers, 4 rue Larrey, 49933 ANGERS Cedex, France. · J Clin Microbiol. · Pubmed #16455894 links to  free full text

Abstract: Trak-C (Ortho-Clinical Diagnostics) is an enzyme-linked immunosorbent assay-based method capable of quantifying hepatitis C virus (HCV) core antigen (CA) in serum and could be an alternative to molecular detection and quantification of HCV RNA. We have evaluated the Trak-C assay in comparison with an HCV RNA quantitative assay (Versant HCV v3.0; Bayer Diagnostics) in the follow-up of 348 treated, human immunodeficiency virus (HIV)/HCV-coinfected patients included in the ANRS HC02 RIBAVIC trial. ANRS HC02 RIBAVIC is a therapeutic, multicenter, randomized protocol comparing the efficacy of alpha interferon 2b (IFN-alpha2b) (3 million units three times a week)-ribavirin (800 mg/day) to that of pegylated IFN-alpha2b (1.5 mug/kg of body weight/week)-ribavirin (800 mg/day) during 48 weeks of treatment of HIV/HCV-coinfected patients naïve to HCV treatment. Patients were assessed for virological analysis at day 0 and weeks 4, 12, 24, 48, and 72. Correlation of HCV RNA and HCV CA at the initiation of treatment was excellent (r = 0.92). HCV RNA and CA kinetics were similar during follow-up of HCV treatment from day 0 to week 72 whatever the group of response and genotype. The positive and negative predictive values of response to the treatment at week 4 were 59 and 94%, respectively, for HCV RNA load reduction of >2 log and 54 and 94%, respectively, for HCV CA below the threshold value (4.18 log(10) pg/ml . 10(4)). Trak-C, a new assay able to quantify CA in HIV/HCV-coinfected patients, correlates well with quantitative HCV RNA assays and is cheaper and easier to perform than molecular technology. HCV CA could be a valuable alternative test for therapeutic follow-up of coinfected patients treated with IFN plus ribavirin in developing countries.