PubMed Health⌕ Search

Biomedical subjects

F Zoulim

Publications and source records attributed to F Zoulim.

At least 55 records · Page 3Linked to original sources
PubMed1999

The SATE pronucleotide approach applied to acyclovir: part II. Effects of bis(SATE)phosphotriester derivatives of acyclovir on duck hepatitis B virus replication in vitro and in vivo.

The in vitro and in vivo antiviral activities of two mononucleoside phosphotriester derivatives of acyclovir (ACV) incorporating S-acyl-2-thioethyl (SATE) groups are reported using the duck model of hepatitis B (DHBV). In primary duck hepatocyte cultures, the described phosphotriesters significantly inhibited the replication of DHBV at submicromolar concentrations. They were found to be more potent than the parent nucleoside. This result was in agreement with our data concerning the anti-HBV activity of these pronucleotides in HepG2.2.15 cells (previous paper). In vivo, the studied SATE pronucleotide was also found to be more efficient than ACV in infected ducklings upon short-term oral therapy, while intraperitoneal treatment showed high anti-DHBV activity with both ACV and its SATE pronucleotide in this animal model. These findings demonstrate the potential of SATE pronucleotides of ACV as anti-HBV agents.

Acyclovir↗
PubMed1999

Therapy of chronic hepatitis B virus infection: inhibition of the viral polymerase and other antiviral strategies.

Chronic hepatitis B infection remains a major public health problem worldwide. The hepatitis B virus belongs to the family of hepadnaviruses that replicate their DNA genome via a reverse transcription pathway. The chronicity of infection in infected hepatocytes is maintained by the persistence of the viral covalently closed circular DNA. The main strategies to combat chronic HBV infection rely on the stimulation of the specific antiviral immune response and on the inhibition of viral replication. While the prolonged administration of reverse transcriptase inhibitors is most often associated with a control of viral replication rather than eradication, it may select for resistant mutants. The search for new viral targets is therefore mandatory to design combination strategies to prevent the emergence of resistant mutants and eventually clear viral infection.

Animals↗
PubMed1999

Hepatitis C virus infection in special groups.

Hepatitis C virus (HCV) infection is associated with a wide spectrum of clinical manifestations which may influence the choice of diagnostic assays, especially in haemodialysis patients, the clinical course of infection with possible multiple and sequential episodes of hepatitis in multiple transfused patients, and the severity of liver disease, especially in patients with HBV-HCV co-infection. The consequences of HCV infection in patients with organ graft are not completely understood due to the complexity of the clinical situations and the unavailability of long-term follow-up. Furthermore, current antiviral therapy is not very effective in these populations. Thus, it is especially important to protect patients at risk for HCV infection, using universal precautionary procedures.

Agammaglobulinemia↗
PubMed1999

[Hepatitis C virus infection and thyroid diseases].

INTRODUCTION: The combination of hepatitis C virus (HCV) infection and thyroid diseases raises several issues that are the prevalence of thyroid autoimmunity in patients with chronic hepatitis C, the prevalence of HCV infection in patients with autoimmune thyroid diseases, and the effects of interferon alpha treatment on thyroid function in chronic HCV hepatitis. CURRENT KNOWLEDGE AND KEY POINTS: The prevalence of anti-thyroid auto-antibodies ranges from 4.6 to 15% in HCV infection, which is considered as significant by various authors. Results have to be interpreted according to the following: the type of auto-antibodies detected, the age, sex, ethnic origin of the population studied, and characteristics of the control population. Recent data are suggestive of a high prevalence of anti-thyroid auto-antibodies in females with HCV infection. An increased prevalence of HCV infection in patients with Hashimoto's thyroiditis is not confirmed. During treatment of chronic hepatitis C, interferon alpha induces thyroid dysfunctions (3 to 15% of the cases) with various clinical presentations. Hypothyroidism is more common (two out of three cases) than hyperthyroidism (one out of three cases). Hyperthyroidism followed by hypothyroidism has also been described. Clinical symptoms vary, ranging from subclinical to severe manifestations. Thyroid dysfunction may be delayed after discontinuation of the interferon treatment. Hypothyroidism is easily cured by L-thyroxine replacement therapy when necessary, and regression may be observed following discontinuation of interferon treatment. Each case of hyperthyroidism has to be precisely evaluated. Development of anti-thyroid antibodies or an increase in anti-thyroid antibodies titers is often observed during interferon alpha treatment, thus suggesting the existence of immunological mechanisms at the origin of thyroid dysfunction. Furthermore, interferon would directly act on iodine. FUTURE PROSPECTS AND PROJECTS: Clinical studies are still necessary to better clarify the links between HCV infection and thyroid autoimmunity, and to determine risk factors for the development of thyroid dysfunction during interferon alpha therapy. The effects of HCV and interferon alpha on thyroid autoimmunity and function have to be investigated in basic research.

Adult↗
PubMed1999

Viral hepatitis.

Hepatitis A is still the most frequently reported vaccine preventable disease. A reduction in the incidence will only be achieved by routine childhood vaccination rather than by targeted vaccination of high-risk groups. A larger vaccine program is warranted. Hepatitis B remains a large public health problem. Vaccination targeted to high-risk adults failed to decrease the incidence of hepatitis B virus (HBV) infection. Sexual as well as nosocomial transmission remain serious problems. Vaccine escape variants have also been identified in newborns from infected mothers who had been vaccinated at birth. Clearance of HBV infection results from complex immune mechanisms including TH1 cytokines significantly associated with HLA class II alleles. Escape HBV mutants, especially precore mutants, influence the outcome. The sequences of the promoter and other critical regions were associated with severe activity. Lamivudine is a major advance in therapy of chronic hepatitis B which was recently approved in many countries. Although drug resistant mutants may be selected during therapy, additional nucleoside analogues including adefovir are promising. Optimal combination strategies of different active compounds need to be researched. Three per cent of the world population has been infected with hepatitis C virus (HCV). Epidemiology has shifted from transfusion to non-transfusion settings. Intravenous drug abuse is currently the main risk but nosocomial infection is also of concern. Three independent factors seem associated with fibrosis progression: age, daily alcohol consumption of 50 g or more and male gender. Median duration of progression to cirrhosis is about 30 years. At the cirrhotic stage, about 3-5% of patients per year develop hepatocellular carcinoma. There is little evidence that direct cytopathicity plays a significant role in liver cell injury. HCV also infects extrahepatic cells which seems critical in the pathogenesis of the many extrahepatic manifestations. The recent identification of CD81 protein as one of the HCV receptor candidates may help us to understand how chronic HCV infection may trigger a wide spectrum of clinical manifestations, autoimmune or even lymphoproliferative, through potent continuous B cell activation in the context of various host and/or environmental cofactors. Direct measurement of HCV RNA has clarified HCV replication kinetics and variability. Among patients with chronic hepatitis C, 48 weeks of treatment with interferon/ribavirin therapy produced a response rate of 28% among those with genotype 1 and 66% with other genotypes. Similar differences were found for combination therapy among patients who had relapsed following previous interferon (IFN) therapy. Viral load prior to treatment has been clearly shown to be predictive of response to interferon treatment, with increased viral load associated with decrease rates of response. In patients non-responsive to interferon, a second course of interferon alone has no beneficial effect whereas combination therapy may induce response in 25%. In conclusion, combination therapy should be given in all situations. Viral eradication should not be the only objective of the treatment since histological improvement may be obtained despite persisting viral replication with prolonged maintenance of antiviral therapy.

Journal Article↗
PubMed1999

New antiviral agents for the therapy of chronic hepatitis B virus infection.

The development of new antiviral strategies for the treatment of chronic hepatitis B remains a major goal since hepatitis virus (HBV) is resistant to interferon treatment as well as to new nucleoside analogs. HBV is a small DNA virus that replicates its genome via a reverse transcription step. The viral polymerase has been the main viral target that was studied to design new antiviral treatments. Active research has led to the discovery of new nucleoside analogs that are potent inhibitors of the viral reverse transcriptase. Among them, lamivudine has also proven antiviral efficacy in clinical trials with a sustained inhibition of viral replication. However, due to the kinetics of viral clearance, long-term antiviral therapy is necessary to eradicate viral infection. These prolonged regimens are associated with the emergence of drug-resistant strains that harbor mutations in the viral polymerase gene within the conserved B and C domains. New approaches using combinations of nucleoside analogs or other strategies, such as immune intervention (DNA vaccine, stimulation of the TH1 response ) or gene therapy (antisense oligonucleotides, dominant negative mutants), should therefore be evaluated in animal models to optimize the current antiviral protocols.

2-Aminopurine↗
PubMed1999

[Vaccination against hepatitis B virus: current data].

Infection by hepatitis B virus remains a major health problem in the world despite the availability of effective vaccines. Although vaccination programs targeting high risk groups have been pushed to their limits, high prevalence rates persist especially in endemic zones. More recently mass vaccination programs conducted on Taiwan have demonstrated the efficacy of this approach with a decrease in the number of chronic hepatitis B virus carriers in the general population in association with a decrease in the incidence of hepatocellular carcinoma, one of the most serious complications of chronic hepatitis B virus infection. Side effects have been reported including the risk of central nervous system demyelination. However studies have shown no evidence of a significant correlation between vaccination and this type of disease. Occurrence of hepatitis B in properly vaccinated subjects could result from selection of mutant viral strains able to escape detection by the immune system. The recently revised benefit-to-risk ratio remains highly favorable for vaccination. Current data indicates that the policy of mass vaccination of the population should be pursued.

Carcinoma, Hepatocellular↗
PubMed1998

Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients.

Ribavirin is a purine nucleoside that inhibits the replication of a variety of RNA viruses and was shown to have a transient efficacy in chronic hepatitis C during short-term therapy. We have analysed retrospectively its efficacy in 95 patients with liver biopsy-proven chronic hepatitis C. Patients received oral ribavirin (600-1200 mg daily) for a mean duration of 11 months. Alanine aminotransferase (ALT) levels returned to normal values in 38 patients (40%) and decreased by more than 50% in 20 other patients (21%). HCV RNA clearance from serum was observed in seven patients (8%). The biochemical response rate was higher in patients with chronic hepatitis (54%) than in those with cirrhosis (24%) (P = 0.003). Clearance of HCV RNA was observed in 10% of the patients with chronic hepatitis vs 4% of the patients with cirrhosis. In non-responders to interferon (IFN) therapy, ALT levels returned to normal values in 11 (26%) and HCV RNA became negative in one (2%), as compared to 48% and 3%, respectively, in those contraindicated for IFN. In 17 patients in whom paired liver biopsy specimens were available, the histology activity index (HAI) improved in 12. Therapy was generally well tolerated although 11 patients had to stop therapy because of side-effects, which were more common in cirrhotic patients. In conclusion, our results suggest that long-term administration of ribavirin is well tolerated and may be beneficial in controlling the progression of chronic hepatitis C. This may represent an alternative therapy in patients who have contraindications for interferon therapy or as a palliative approach in non-responders to IFN.

Adult↗
PubMed1998

Clinical evaluation of the branched DNA assay for hepatitis B virus DNA detection in patients with chronic hepatitis B lacking hepatitis B e antigen and treated with interferon-alpha.

The aim of this study was to evaluate the Chiron branched DNA (bDNA) assay for detection of serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis B lacking hepatitis B e antigen (HBeAg) and undergoing interferon (IFN) therapy. Results obtained with the bDNA assay were compared with those obtained using the Abbott liquid hybridization (LH) assay and the polymerase chain reaction (PCR). Serial samples (274) from 34 patients were analysed. Analysis of variance results indicated that bDNA values were more significantly correlated than LH values with both PCR positive/negative results (probability of artifact (Prob > F) = 0.7 and 0.09 for LH and bDNA assays, respectively) and presence/absence of precore mutations (Prob > F = 0.21 and 0.001 for LH and bDNA assays, respectively). Both bDNA and LH results correlated highly with alanine aminotransferase (ALT) values (both had Prob > F values of 0.0) while PCR was not correlated with ALT (Prob > F = 0.05). In 26 evaluable patients, a model based on a generalized Knodell score was used to predict response to IFN therapy, as defined by normalization of ALT values during therapy. This model discriminated well between non-responders and responders. The bDNA results correlated well with the generalized Knodell score, while the LH results did not (Prob > F = 0.04 and 0.19 for the bDNA and LH assays, respectively). In conclusion, the bDNA assay appears to be useful for quantification of HBV DNA levels in HBeAg-negative chronic hepatitis as it correlates with biochemical and histological indications of disease severity as well as with response to IFN therapy.

Analysis of Variance↗
PubMed1998

Inhibitory effect of 2'-fluoro-5-methyl-beta-L-arabinofuranosyl-uracil on duck hepatitis B virus replication.

The antiviral activity of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), a novel L-nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) of L-FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the L-FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals. L-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that L-FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that L-FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of L-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.

Administration, Oral↗
PubMed1998

Design, synthesis and structure relationships of new N,N',N",N"'-tetrakis (omega-amino alkyl) tetraazamacrocycles.

A number of N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles and related compounds were synthesized and evaluated for their inhibitory effects on human immunodeficiency virus type 1 (HIV-1) and duck hepatitis B virus (DHBV) replication. The activity of these compounds was found to be highly dependent upon structural features: (i) the length of the alkyl linker connecting the nitrogen atoms of the macrocyclic ring to the exocyclic nitrogen atoms of the terminal amino groups (five methylenes favoured antiviral activity); (ii) substitution of the terminal amino groups of the linker reduced antiviral activity; and (iii) the size of the tetraazamacrocyclic ring (14 or 15 atoms) did not markedly affect the antiviral activity. Some analogues were potent inhibitors of HIV-1 replication, with anti-HIV activity similar to that of biscyclam (JM 2763). In contrast, other analogues were found to be highly toxic in duck hepatocyte primary culture, the 2.2.15 cell line and to a lesser extent in MT-4 cells. Structural parameters, macrocyclic ring size and metal-chelating ability have been used to develop a structure-activity relationship model in order to aid the design of antiviral molecules derived from N,N',N",N"'-tetrakis (omega-aminoalkyl) tetraazamacrocycles.

Animals↗
PubMed1997

Woodchuck hepatitis virus-induced carcinoma as a relevant natural model for therapy of human hepatoma.

BACKGROUND: Eastern American woodchuck (Marmota monax), naturally infected with woodchuck hepatitis virus, a virus similar to human hepatitis B virus, develops liver cancer with a high prevalence. AIMS: The aim of this work was to assess Marmota monax as a model of human hepatocellular carcinoma, especially to assess new potential adjuvant therapies after surgical resection. METHODS: Forty-four woodchuck hepatitis virus-infected animals were regularly screened by ultrasound examination from the age of 18 months and for a 30-month period. One or more liver tumors were diagnosed in 31 animals (70%). Five of them with multifocal tumor or poor general status were considered unsuitable for surgery. The other 26 were operated on. At laparotomy no tumor was found in three. RESULTS: The 18 liver tumors studied were hepatocellular carcinomas, grossly and microscopically similar to human hepatocellular carcinoma. Peritumoral parenchyma studied in 13 specimens was always non-cirrhotic but adequate staining demonstrated patterns of fibrosis in four cases. Clear evidence of chronic active hepatitis, periportal hepatitis and steatosis were demonstrated in five, seven and one of the 13 specimens, respectively. Tumors were treated by tumorectomy in eight animals, by alcoholization in seven and by laser photocoagulation in one. A simple tumor biopsy was performed in the other seven. Ten animals died postoperatively. All the survivors in the tumorectomy group died from tumor recurrence within 10-18 months after surgery. CONCLUSIONS: It is concluded that woodchuck hepatitis virus-induced liver carcinoma is a natural model of human hepatocellular carcinoma with similar pathology and natural history, including early ultrasonic detection and tumor recurrence after resection. Tumor excision is feasible in this animal model, which now provides the basis for assessment of new potential adjuvant therapies for human hepatocellular carcinoma in an attempt to reduce the high recurrence rate after surgical resection in humans.

Animals↗
PubMed1997

Selective inhibition of the duck hepatitis B virus by a new class of tetraazamacrocycles.

The antiviral activity of a new class of N,N,N',N",NA'''-pentakis (omega-aminoalkyl) tetraazamacrocycles was evaluated in primary duck hepatocyte cultures infected with the duck hepatitis B virus (DHBV). Three of the four tested compounds were able to selectively inhibit DHBV replication by acting at an early step of the hepadnavirus infection but were associated with significant toxicity.

Antiviral Agents↗
PubMed1997

[Favorable course of hepatitis B virus reactivation with hepatocellular insufficiency by a treatment combining corticoids, foscarnet and ganciclovir].

Reactivation of hepatitis B virus replication is a rare event during the natural history of chronic hepatitis B. However, the clinical presentation may be severe and an effective therapeutic protocol must be established. We report a case of spontaneous reactivation of hepatitis B virus infection with liver failure. For the moment, no medical treatment has been defined in this situation. A combination of corticosteroids and antiviral drugs (foscarnet and ganciclovir) resulted in clinical and biological recovery, and HBV elimination. If the efficacy of this combined treatment is confirmed in a larger population, this new physiopathological approach should be considered whenever life threatening liver failure occurs.

Adult↗
PubMed1996

Analysis of hepatitis B virus genotypes and pre-core region variability during interferon treatment of HBe antigen negative chronic hepatitis B.

The clinical importance of hepatitis B virus (HBV) genome variability has been reported recently. One example is the occurrence of hepatitis B virus pre-core mutants, which arise during spontaneous or interferon-induced seroconversion from HBeAg to anti-HBe and are thought to be selected by immune pressure. A survey of HBV pre-core mutants and viral genotypes in 35 HBeAg negative patients during interferon therapy was carried out to understand viral pathogenesis in this form of chronic hepatitis B. Seventeen patients responded to interferon therapy as assessed by the sustained normalization of serum ALT levels and the significant decrease of viremia levels. The response rate to interferon was independent of both initial serum viral DNA level and interferon doses. During interferon therapy, a significant decrease of M0 (wild-type pre-core sequence at pos. 1887-1908), M1 (TGG to TAG at pos. 1896) or M2 (TGG to TAG at pos. 1896, and GGC to GAC at pos. 1899) positive viral genomes was found in 48%, 42%, and 33% of patients, respectively. A higher response rate to interferon therapy was observed in patients infected with HBV genotype A (70%) or M0 positive strains (75%) as compared to patients infected with genotype D/E (40%) or M1/M2 positive strains (44%). The data support the hypothesis that pre-core defective HBV represent viral mutants with an increased capacity to resist exogenous alpha interferon. These findings emphasize that characterization of HBV genome variability prior to interferon therapy may help to predict antiviral response in HBeAg negative patients.

Adult↗
PubMed1996

Heterogeneity of hepatitis B virus (HBV) core gene in a patient with HBV-associated cirrhosis and serum negativity for anti-HBc.

AIMS: We describe here the case of a patient suffering from severe chronic hepatitis B associated with an unusual hepatitis B virus serology: HBsAg and HBeAg were both positive while anti-HBc was negative by radioimmunoassay. METHODS: A very sensitive anti-HBc ELISA (IMx CORE) was performed and was able to detect anti-HBc sporadically throughout the clinical course. Molecular characterization of hepatitis B virus strains in this patient enabled us to explain this particular serological and clinical pattern of hepatitis B virus infection. RESULTS: Hepatitis B virus genotype determined by size polymorphism of the core gene and the pre-S region was found to be D/E and consistent with the results of serological subtyping (HBV ayw2-4). DNA sequence analysis of the pre-C/C region showed the presence of significant nucleotide changes. In association with a wild type hepatitis B virus strain, we could detect at least four hepatitis B virus variants with nucleotide deletions leading to a frameshift in the core gene. According to the position of the mutations, these hepatitis B virus core variants are expected to be defective for B-cell epitopes and TH-cell epitopes. CONCLUSIONS: These mutations explain the low level production of anti-HBc antibody. It is noteworthy that the absence of detectable anti-HBc in serum was associated with severe liver damage, suggesting that the deficient humoral response to HBcAg was not accompanied by a cellular immune tolerance to HBc/eAg, the supposed target for cytotoxic T-cell lysis.

Adult↗