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Biomedical subjects

F Lunel

Publications and source records attributed to F Lunel.

At least 37 records · Page 2Linked to original sources
PubMed1999

Response to interferon alpha treatment and disappearance of cryoglobulinaemia in patients infected by hepatitis C virus.

BACKGROUND: Mixed cryoglobulinaemia is closely associated with hepatitis C virus (HCV) infection. AIM: To assess in a prospective open study the efficiency of interferon alpha treatment of cryoglobulinaemia, as reflected by the disappearance of cryoglobulins and clinical manifestations of the disease, and to analyse the factors predictive of a response to interferon. METHOD: Eighty seven consecutive patients with chronic hepatitis C treated for the first time with interferon at a dose of 3 x 10(6) international units three times a week for six months were studied. Forty three patients had cryoglobulins, which were responsible for clinical manifestations in 12. RESULTS: At the end of interferon treatment, cryoglobulins had disappeared in 39% of the patients. A clinical improvement (except for neuropathies) was observed in all patients. Six months after interferon treatment was stopped, the same rate of response (normal alanine aminotransferase values and undectable HCV RNA) was observed in patients with or without cryoglobulins. Only 14% of patients still had undetectable cryoglobulins, and all of them also had undetectable serum HCV RNA. The disappearance of cryoglobulins was found less frequently in patients with clinical symptoms than in asymptomatic ones, but the difference was not significant. Sustained responders were more often men, infected by genotype 2 or 3, with a lower pretreatment viral load. CONCLUSION: The presence of cryoglobulins does not seem to affect the response to interferon in HCV infected patients. The improvement in cryoglobulinaemia is strongly associated with a virological response, reinforcing the hypothesis of a direct role for HCV in the pathogenesis of this disease.

Adult↗
PubMed1998

Mutations in NS5A region of hepatitis C virus genome correlate with presence of NS5A antibodies and response to interferon therapy for most common European hepatitis C virus genotypes.

A part of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) amino acid sequence, designated as an interferon (IFN)-sensitive determining region (ISDR), has been shown to be correlated with a response to IFN in Japanese patients. We have shown previously that the presence of NS5A antibodies (Abs) detected by the INNOLIA test (IL-NS5A Ab) is also correlated with a response to IFN. The aim of this study was to investigate, in a wide range of patients, the possible relationship within the NS5A protein between the sequence of ISDR and that used in the INNOLIA test designated as IL3R. Serum samples from 52 patients infected by HCV genotypes 1, 2, and 3 were analyzed before and after treatment. The patients were classified as nonresponders (NRs), responder-relapsers (RRs), or long-term responders (LTRs). We amplified the NS5A region for 42 patients using polymerase chain reaction (PCR), and these amplicons were sequenced directly. The 10 remaining patients were analyzed using PCR with mutation-specific primers. No correlation was found between the IL3R sequence of the HCV strains and the presence of the IL-NS5A Ab for all genotypes. However, for the subtype 1b, only 2 of 11 NR patients tested had an arginin in position 2218 within the ISDR versus 3 of 3 LTR and 10 of 13 RR patients. All patients with R-2218 had IL-NS5A Ab. For the genotype 1a, 2 of 2 LTR and 1 of 3 RR were mutated in position 2216-2218 in comparison to three NR sequences. For the genotype 3, no mutations were found in the region homologous to 1b-ISDR, but 4 of 5 LTR and RR patients had a mutation T-2161 to A or V versus 0 of 3 NR patients. A close correlation was found between arginin in position 2218 in ISDR, the presence of IL-NS5A Ab, and the response to IFN therapy for genotype 1b, but this association did not predict a long-term response. For genotype 3, a potential ISD mutation could be located at the codon 2161.

Amino Acid Sequence↗
PubMed1998

Pattern of HCV antibodies with special reference to NS5A reactivity in HCV-infected patients: relation to viral genotype, cryoglobulinemia and response to interferon.

BACKGROUND/AIMS: We aimed to compare the anti-hepatitis C virus reactivity in confirmatory assays (RIBA 3.0 Ortho Diagnostic and INNO-LIA HCV Ab III Innogenetics) among patients infected with different hepatitis C virus genotypes, with or without cryoglobulinemia, and in patients treated with interferon. METHODS: One hundred and three patients followed in our hepatogastroenterology unit were included in the study and compared to 320 consecutive patients tested using RIBA 3.0. Seventy-nine of the 103 patients were treated with interferon. Long-term responders to interferon were defined as having normal alanine aminotransferase levels and being HCV RNA negative 6 months after the end of treatment. Initial responders were defined as having normal alanine aminotransferase levels at the end of interferon therapy but abnormal alanine aminotransferase levels and/or detectable HCV RNA during the following 6 months. Non-responders were defined as still having elevated alanine aminotransferase during and after interferon. Serological tests (RIBA and INNO-LIA) were performed according to the manufacturers' instructions. HCV RNA was detected by nested polymerase chain reaction. Hepatitis C virus genotype was determined by using a Line Probe Assay (Innogenetics). RESULTS: There was no significant difference in the pattern of hepatitis C virus reactivity according to the hepatitis C virus genotype or presence of cryoglobulinemia. Twenty-three patients were classified as non-responders, 35 as initial responders, 21 as long-term responders. NS5 reactivity was significantly different (p<0.01) between these three groups: 34% of non-responders (8/23) had RIBA 3.0 NS5 reactivity and 13% (3/23) were reactive in the INNO-LIA III. Almost all long-term responders (95%) had NS5 reactivity by both RIBA 3.0 and INNO-LIA III. CONCLUSION: We conclude that patients who respond to interferon have stronger reactivity against NS5 antigens than non-responders. Molecular changes in the NS5A region may be responsible for such differences, as recently suggested.

Antiviral Agents↗
PubMed1998

[Update on hepatitis C virus: its variability and the implications].

Hepatitis C virus (HCV) is the main etiologic factor of post-transfusional and sporadic hepatitis, called non-A non-B in the past. These infections are characterized by a very high number of chronic carriers always with a persistent viral increase, but often at a slow pace. The seriousness of liver disease differs from one individual to another, varying from an asymptomatic form with minor or no liver injuries, to cirrhosis and hepatocellular carcinoma. Physiopathological mechanisms involved in liver injuries are still poorly understood. The direct role of immune response and of possible genetic factors is still under study. This review aims at summing up the discovery of HCV, its structure, and its variability in the various genome regions in the same individual and from one individual to another. The different methods and techniques to analyze this variability are also reviewed, as well as the various suggested ways of classifying the different types. The geographical distribution and both clinical and biological consequences of this variability are also discussed.

Antibody Specificity↗
PubMed1998

Sequence analysis of the NS5A protein of European hepatitis C virus 1b isolates and relation to interferon sensitivity.

Japanese studies have defined the discrete 2209-2248 amino acid region of the non-structural 5A protein (NS5A(2209-2248)) of hepatitis C virus genotype 1b (HCV 1b) isolates as the interferon sensitivity determining region (ISDR). European studies did not confirm these results since most of the ISDR sequences harboured an intermediate profile. Recently, a direct interaction between the NS5A protein, involving the ISDR, and the interferon-induced protein kinase (PKR) has been reported and presented as a possible explanation of HCV interferon resistance. In the present study, the entire NS5A amino acid sequence from 11 resistant and eight sensitive strains from European HCV 1b isolates was inferred from direct sequencing. The previously described important amino acid stretches and positions in NS5A were compared between the resistant and sensitive groups. Although some variations were observed, no clear differences could be directly correlated with the interferon sensitivity. However, sensitive strains were different, owing to more amino acid changes when compared to a consensus sequence from all strains. The carboxy-terminal region and especially the previously reported NS5A/V3 region showed most of the variations. Moreover, the conformational analysis of NS5A by secondary structure prediction allowed the differentiation of most sensitive strains from resistant ones. It was concluded that other regions different from ISDR were involved in resistance to interferon maybe via the interaction between NS5A and PKR.

Amino Acid Sequence↗
PubMed1998

A comparative evaluation of the sensitivity of five anti-hepatitis C virus immunoblot assays.

BACKGROUND AND OBJECTIVES: In order to compare sensitivity, five anti-hepatitis C virus (HCV) immunoblot assays were tested (Deciscan plus, Inno-Lia III, Matrix, Murex Western blot and RIBA-3). MATERIALS AND METHODS: The test panel (50 samples for each assay) included 6 anti-HCV-negative samples and 44 samples from 36 HCV-infected subjects. RESULTS: There were minor differences in core reactivity among the assays. The smallest number of NS3-reactive results occurred with the Murex and Matrix assays, and the smallest number of NS4 reactives with RIBA-3 and Matrix. Among the 20 discrepant results for NS5 there was one clear false-negative with Inno-Lia. Only 28 of the 50 samples of the panel gave the same results in all the assays: 5 negatives and 23 positives. One of the 6 negative samples were indeterminate in 3 assays. Eighteen of the 21 other divergent results were interpreted as either indeterminate or positive, a common reactivity being exhibited by all 5 assays. The most important discrepancies occurred on 3 HCV-RNA-positive samples which came up negative in some assays: 2 samples with isolated NS3 reactivity were negative by Matrix and Murex Western blot, 1 of them being also negative by Inno-Lia III; another sample was negative by RIBA-3 and Matrix due to weak signals (< 1) on core and NS3 proteins, which did not exceed 1+ with the other assays. CONCLUSIONS: With more uniform criteria for interpretation, the results would have been less divergent. Some assays should improve their sensitivity to the NS3 protein.

Evaluation Studies as Topic↗
PubMed1997

Variations of serum IgG subclass levels in hepatitis C virus infection during interferon-alpha therapy.

Serum IgG1 levels are selectively increased in patients with chronic hepatitis C virus (HCV) infection. In 15 patients who received interferon (IFN)-alpha therapy, serum levels of immunoglobulin classes and IgG subclasses were measured during treatment and after it was discontinued. In spite of important individual variations, mean IgG, IgG1, IgA and IgM levels decreased during therapy and tended to return to pre-treatment levels afterwards, with no detectable correlation with clinical and biological parameters. These results suggest an effect of IFN-alpha on in vivo immunoglobulin production, in HCV carriers.

Adult↗
PubMed1997

Human cytomegalovirus DNA kinetics using a novel HCMV DNA quantitative assay in white blood cells of immunocompromised patients under Ganciclovir therapy.

The clearance of human cytomegalovirus (HCMV) was evaluated in infected patients under Ganciclovir (GCV) treatment, using a novel HCMV DNA quantitation assay (HCMV DNA hybrid capture system, Murex Diagnostics). Peripheral white blood cells (WBC) from whole blood specimens of seven AIDS patients, three kidney and two allogeneic bone marrow transplant (BMT) recipients suffering from HCMV disease, were assessed by this method. HCMV DNA 50 and 90% mean clearances were observed at 2.11 +/- 1.97 and 6.22 +/- 4.31 days, respectively, after initial GCV treatment. The viral DNA kinetics were correlated with positive and negative pp65 antigenaemia and viral blood culture. Two-fold higher clearances and initial DNA levels were observed in the AIDS group compared to the transplant group. Neither clinical nor virological relapses were observed under GCV treatment. HCMV DNA quantitation in WBC appears well adapted for a therapeutic follow up of patients with HCMV disease.

Antigens, Viral↗
PubMed1997

Mutations of hepatitis C virus 1b NS5A 2209-2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients.

BACKGROUND/AIMS: Studies of HCV quasispecies during interferon treatment have shown the selection of resistant clones. Enomoto et al. have defined the interferon sensitivity-determining region in an amino acid stretch of the HCV-1b NS5A region. Patients with a mutant strain before treatment were complete responders, whereas those with wild-type HCV-J strain were resistant to interferon. The same region was studied in HCV isolates of French patients. METHODS: Forty-three HCV-1b chronically infected patients, consisting of 26 non-responders and 17 complete responders to interferon-alfa treatment (3 MUI tiw for 6 months), were included retrospectively. We directly sequenced the NS5A(2209-2248) HCV region of these patients before treatment. The viral load could be obtained from six complete responders and 15 non-responders. RESULTS: We detected wild-type and intermediate strains, but only two mutant strains were present. One of them was found in a non-responder. In three complete responders, we found a wild-type strain. The distribution of the various strains was rather different from that found in Japan. Before treatment, the viral load was lower in complete responders (p=0.01). CONCLUSIONS: Only two mutant strains were detected in our study. This could partially explain the low response rate to interferon treatment of French HCV-1b-infected patients, although the dose regimen was lower than in Japanese studies. Also, wild-type strains were found in some complete responders, and no correlation was determined between the mutation number in the NS5A(2209-2248) region and response to alfa interferon therapy. This may be related to epidemiological differences between HCV-1b strains present in France and those in Japan. Searching for the mutant NS5A pattern before treatment does not appear to be useful in French patients as it is too uncommon.

Adult↗
PubMed1997

Anticardiolipin, anti-beta2-glycoprotein I, and antinucleosome antibodies in hepatitis C virus infection and mixed cryoglobulinemia. Multivirc Group.

OBJECTIVE: To investigate anticardiolipin antibodies (aCL), anti-beta2-glycoprotein I (anti-beta2GPI), and antinucleosome antibodies in patients with hepatitis C virus (HCV) with or without mixed cryoglobulinemia. aCL can appear in infectious diseases, but are not then associated with thrombotic events. Antibodies directed to beta2GPI, a co-factor of aCL, have been said to be associated with the presence of "autoimmune" aCL. About 50% of cases of essential mixed cryoglobulinemia are associated with HCV infection. High prevalence of autoantibodies directed to nuclear antigens has been found in HCV infection but the prevalence of antibody to nucleosome has not yet been reported. METHODS: Group 1: 29 patients with chronic HCV infection and mixed cryoglobulinemia. Group 2: 17 patients with chronic HCV infection but without mixed cryoglobulinemia. To analyze the possible effect of mixed cryoglobulinemia itself on aCL production, we also studied 22 patients with essential mixed cryoglobulinemia and no HCV infection (Group 3). In addition, 96 healthy blood donors were used as a control group (Group 4). Mixed cryoglobulinemia was detected by immunofixation. Anti-HCV antibodies were detected by 3rd generation tests, aCL, anti-beta2GPI, and antinucleosorne antibodies were detected by ELISA. In patients with mixed cryoglobulinemia, we also looked for aCL separately in cryoprecipitate and in serum after extraction of mixed cryoglobulins to investigate a possible "capture" of aCL in the cryoprecipitate. RESULTS: IgG aCL were more frequently found in patients with HCV than in controls [9/46 (20%) vs 2/96 (2%); p < 0.001]. The prevalence of aCL was similar in patients with HCV with or without mixed cryoglobulinemia (6/29 vs 3/17; p = NS). No patient with positive aCL had anti-beta2GPI, antinucleosome antibodies, thrombotic events, or thrombocytopenia. IgG aCL were more frequent in patients with mixed cryoglobulinemia, whatever their status for HCV infection, than in subjects without mixed cryoglobulinemia [8/51 (16%) vs 5/113 (4%); p < 0.02]. The prevalence of aCL was similar in patients with type II or type III mixed cryoglobulinemia. When we looked for aCL separately in serum and in cryoprecipitate, we did not find aCL in cryoprecipitate. In patients with HCV, the prevalence of aCL was not different whether patients were treated or not with interferon alpha. CONCLUSION: IgG aCL are frequently found in patients with HCV regardless of status for mixed cryoglobulinemia. These aCL have the characteristics of infection related aCL: low titer, absence of thrombotic events, and absence of anti-beta2GPI. The high proportion of aCL in patients with mixed cryoglobulinemia compared to those without, and the absence of antinucleosome antibodies, suggest that these aCL may be secondary to endothelial damage induced by mixed cryoglobulinemia or HCV itself, rather than to nonspecific polyclonal lymphocyte activation.

Antibodies, Anticardiolipin↗
PubMed1996

Effects of lamivudine on replication of hepatitis B virus in HIV-infected men.

BACKGROUND: Therapy for hepatitis B virus (HBV) infection is still unsatisfactory, particularly in patients who are co-infected with the human immunodeficiency virus (HIV). Lamivudine, a retroviral inhibitor, has been shown to have activity against HBV replication in vitro, in animal models, and in studies of immunocompetent persons. OBJECTIVE: To assess the efficacy of lamivudine in inhibiting HBV replication during a 12-month period in patients with both HBV and HIV infection. DESIGN: Prospective, open study. SETTING: University hospital. PATIENTS: 40 consecutive patients (39 men and 1 woman) infected with both HIV and HBV. All had progressive HIV disease; were refractory to or unable to tolerate therapies other than lamivudine; and received lamlvudine, 600 mg/d or 600 mg/d followed by 300 mg/d, as therapy for HIV disease. MEASUREMENTS: Serum concentrations of HBV DNA were assessed every 2 months by using molecular hybridization. Polymerase chain reaction (PCR) for HBV DNA was done at baseline and was done at months 2, 6, and 12 only if the HBV DNA concentration was less than 5 pg/mL. RESULTS: Two groups were retrospectively identified at baseline: patients with high HBV replication (serum HBV DNA concentrations > 5 pg/mL) (n = 30) and patients with low HBV replication (serum HBV DNA concentrations < 5 pg/mL) (n = 10). After 12 months of treatment, 26 of 27 patients (96.3% [95% Cl, 81% to 99.9%]) who had had high HBV replication at baseline had serum HBV DNA concentrations less than 5 pg/mL. However, PCR could still detect HBV DNA in serum in 11.5% (Cl, 2% to 30%) of these patients. Among patients who had had low HBV replication at baseline, the results of PCR for serum HBV DNA became negative in the 6 patients who had had a positive result on PCR at baseline. No serious adverse events occurred during treatment. CONCLUSION: Although this study was not a randomized, blinded trial, it suggests that lamivudine is active against.

AIDS-Related Opportunistic Infections↗
PubMed1996

[Mixed cryoglobulinemia in hepatitis C virus infection].

Mixed cryoglobulinemia occurs in about half of all patients with chronic hepatitis C. Mixed cryoglobulinemia results from a lymphoproliferative disorder caused by polyclonal lymphocyte B proliferation (type III) or expansion of a B-cell clone producing monoclonal Ig with anti-immunoglobulin activity (type II). Among the different viral infections studied to date (hepatitis A or B, cytomegalovirus, Epstein-Barr or herpes simplex virus) none except hepatitis C has been formally linked to cryoglobulinemia. The mechanisms involved with the hepatitis C virus and persistant cryoglobulinemia are unknown. Several studies have shown that the hepatitis C virus plays a distinct role in the pathogenesis of cryoglobulinemia. The high content of anti-HVC antibodies and viral RNA in the cryoprecipitates suggests that entire viral particles or encapsidized viral RNA may be involved. Viral variability over time and within the same individual might be responsible for repeated antigenic stimulation of the immune system leading to proliferation or expansion of the B-cell clone.

Cryoglobulinemia↗