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Biomedical subjects

G M Dusheiko

Publications and source records attributed to G M Dusheiko.

At least 19 recordsLinked to original sources
PubMed1998

Influence of HIV-1 infection on GBV-C infection in multiply infected haemophilic patients.

Two hundred thirteen haemophilic patients were studied for the presence of GBV-C RNA and anti-E2 antibodies soon after their first treatment with unsterilised factor concentrates and in their most recent sample. An assessment was made to determine whether coinfection with HIV had any effect on the progression of GBV-C infection. All of the patients were infected with HCV and 81 patients (37%) were also infected with HIV. GBV-C RNA was detected using the Abbott LCx(TM) assay and by RT-PCR. Anti-E2 antibodies were detected using the microPLATE Anti-HGenv assay and by Abbott Laboratories. The HIV-negative patients were more likely than the HIV-positive patients to lose GBV-C RNA between the two time points. A proportion of the patients lost their anti-E2 antibodies over the time period, however, the majority of these were HIV-positive. This study shows that infection with HIV does affect the progression of GBV-C infection, however, this effect is little understood as yet.

Disease Progression↗
PubMed1998

Biodistribution, stability, and antiviral efficacy of liposome-entrapped phosphorothioate antisense oligodeoxynucleotides in ducks for the treatment of chronic duck hepatitis B virus infection.

This study investigated the feasibility of using liposomes to increase the hepatic delivery and antiviral efficacy of phosphorothioate antisense oligodeoxynucleotides (PS-ODN) for the in vivo treatment of hepatitis B virus (HBV) infection. Ducks infected with duck hepatitis B virus (DHBV) were used as the model. We studied the stability of an antisense PS-ODN in duck plasma, its integrity during the process of liposome entrapment, its in vivo biodistribution, plasma clearance, and excretion. In addition, the intrahepatic distribution of a labeled free and liposome-entrapped ODN was also investigated. The results of our studies show that: 1) phosphorothioate ODN remain stable during the process of liposome entrapment; 2) are stable in duck plasma for many hours; 3) are rapidly cleared from the plasma when injected intravenously; 4) intravenous injection of antisense ODNs entrapped within liposomes enhances delivery of the ODN to the liver; and 5) inhibit DHBV replication. Serum DHBV DNA levels fell rapidly, with a corresponding decrease in intrahepatic viral replicative intermediates at the end of the 5-day study period. Although inhibition of viral replication and a fall in the target protein was observed, a marked inhibition of viral replication was also observed with high doses of a random-sequence ODN. Thus, it is not certain that inhibition of viral replication was entirely through an antisense mechanism. Therefore, liposomes may be effective vehicles to improve the delivery of antisense oligonucleotides to the liver for the therapy of hepatotropic viruses.

Animals↗
PubMed1998

Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions.

AIMS: The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone. METHODS: In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. RESULTS: The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. CONCLUSIONS: There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.

Adolescent↗
PubMed1998

Therapy for chronic hepatitis B and C infection in haemophilia.

Haemophiliacs, until recently, have been at risk of hepatitis B and C infection. Substantial numbers of patients remain persistently infected. Several lines of evidence suggest that these diseases will cause considerable morbidity unless therapy can successfully reduce viraemia and prevent disease progression. Cessation of viral replication may prevent progression to hepatic fibrosis.

Antiviral Agents↗
PubMed1998

The natural course of chronic hepatitis C: implications for clinical practice.

Hepatitis C is an important public health problem with high rates of chronic infection ensuing after viral acquisition. The spectrum of the disease ranges from mild to severe chronic hepatitis, cirrhosis and hepatocellular carcinoma. Extra-hepatic manifestations may occur. The disease is complex and predictions about long-term prognosis for individual patients remain difficult. It is generally accepted that 10-20% of patients with chronic hepatitis C will develop cirrhosis within 10 years of first infection: identifying the group of patients at greatest risk remains a primary challenge for clinicians. Older age of infection, duration of infection, degree of liver inflammation at first biopsy and cofactors such as alcohol abuse, all appear to be predictors of a poorer prognosis. The following paper aims to identify some of the features of the natural history of hepatitis C most relevant to the clinician.

Age Factors↗
PubMed1997

Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation.

BACKGROUND: Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS: We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

Adult↗
PubMed1997

Long-term evolution of the 5'UTR and a region of NS4 containing a CTL epitope of hepatitis C virus in two haemophilic patients.

Haemophilic patients exposed to unsterilized clotting factor concentrates prior to 1985 have become infected with hepatitis C virus (HCV). We have studied the sequence evolution of the 5'UTR and a region of NS4 over 12 years in one human immunodeficiency virus (HIV) positive haemophilic patient and 14 years for one HIV negative haemophilic patient. One sample each year from the date of HCV infection to 1994 was analysed for genotype, virus load and nucleotide sequence of the two genetic loci. Both patients were infected with HCV genotype 1 throughout the study period. The virus load profiles were similar except that the profile for the HIV infected patient was displaced 4 years earlier relative to the other patient. Mean divergence of the quasispecies at both the 5'UTR and NS4 loci was higher in the HIV coinfected patient. Phylogenetic analysis indicated that evolution of the 5'UTR was host independent, whereas the NS4 region containing a CD8 restricted CTL epitope evolved in a host specific fashion.

Amino Acid Sequence↗
PubMed1997

Hepatitis B virus and liver transplantation: concepts in antiviral prophylaxis.

Liver transplantation remains problematic in patients with end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection. Recurrent hepatitis is almost universal in those patients who are HBV DNA-positive prior to transplantation. Prophylactic hepatitis B immune globulin can be given to reduce the rate of hepatitis B recurrence in patients who are HBV DNA-negative prior to transplantation. More recently novel antiviral drugs such as lamivudine or famciclovir have been used specifically to inhibit hepatitis B viral replication. However, the development of drug-resistant viral mutants have been observed. Further studies are needed to investigate these drugs more extensively, particularly to assess whether combination therapy may be a more effective means of controlling viral recurrence in patients transplanted for chronic HBV infection.

Antiviral Agents↗
PubMed1997

Antigenic variation of core, NS3, and NS5 proteins among genotypes of hepatitis C virus.

Assays that detect antibody to hepatitis C virus (HCV) are used to screen blood donors and patients with hepatitis. Current enzyme-linked immunosorbent assay (ELISA)-based methods are invariably based upon antigens from expressed recombinant proteins or oligopeptides from HCV type 1. Some HCV antigens used in screening assays are coded by regions of the HCV genome that show extensive variability; therefore, HCV type 1-based assays may be less effective for the detection of antibody elicited by infection with other genotypes. In this study, we have measured antibody reactivity of sera from 110 hepatitis C patients infected with type 1b, 3a, or 4a to genotype-specific and cross-reactive epitopes present in recombinant proteins from HCV genotypes 1b (core, NS3, and NS5), 3a (NS3, NS5), and 4a (core, NS3), corresponding to those used in current third-generation screening ELISAs. By comparing the serological reactivities of sera to type-homologous and type-heterologous antigens, we detected a significant type-specific component to the reactivity to NS3 (61 to 77% of the total reactivity) and NS5 (60% of the total reactivity). Furthermore, despite the similarities in the amino acid sequences of the core antigens of type 1b and type 4a, we also found significantly greater reactivity to type-homologous antigens, with approximately 25% of reactivity being type specific. These findings are consistent with previous findings of fivefold weaker reactivity of sera from HCV type 2- and HCV type 3-infected blood donors in the currently used third-generation ELISAs and suggest that these assays are suboptimal for screening populations in which the predominant genotype is not type 1.

Amino Acid Sequence↗
PubMed1997

Lymphocyte and macrophage phenotypes in chronic hepatitis C infection. Correlation with disease activity.

The pathogenesis of chronic hepatitis C and the mechanisms underlying progressive liver disease in patients with chronic hepatitis C infection are poorly understood. To demonstrate which inflammatory cells might be responsible for the necroinflammatory damage in chronic hepatitis C infection, we have correlated the phenotype of the intrahepatic lymphocytes and macrophages with histological activity in liver biopsy and explant specimens from 19 patients with chronic hepatitis C infection. In all stages of disease, more CD8+ than CD4+ lymphocytes were found. However, histologically active versus histologically mild hepatitis was associated with a trend toward greater parenchymal concentrations of CD4+ lymphocytes (0.71 +/- 0.27 per 10(4) microns 2 versus 0.35 +/- 0.15; not significant), significantly less parenchymal CD8+ lymphocytes (0.90 +/- 0.1 versus 1.70 +/- 0.3; t = 2.32, P = 0.03) and a greater parenchymal CD4/CD8 ratio (4.1 +/- 2.8 versus 0.91 +/- 0.3; t = 1.65, P = 0.07). No difference was found in the number of cells containing cytotoxic granules between the two groups. Greater numbers of CD4+ lymphocytes were found in liver biopsy specimens with little or no staining for hepatitis C virus antigen (1.47 +/- 0.88 versus 0.27 +/- 0.27; t = 2.28, P < 0.05). No significant differences were found in the macrophage subsets between the three stages of disease. Our data suggest that active histological disease in chronic hepatitis C infection may be associated with an increase in CD4+ lymphocytes and suggest that CD4+ T cells may play an important role in the hepatic injury in these patients.

CD4-CD8 Ratio↗
PubMed1996

A clinical evaluation of a new method for HBV DNA quantitation in patients with chronic hepatitis B.

Selection of HBsAg-positive patients for antiviral therapy requires an estimation of disease activity and viral replication. Serum transaminases and histological analysis are commonly used to assess disease activity, and viral replication is assessed by serological testing of HBeAg and serum hepatitis B virus (HBV) DNA. Dot blot hybridisation may be insufficiently sensitive to corroborate low-grade replication in patients with active hepatitis, and polymerase chain reaction (PCR) may be testing too sensitive for this role. Theoretically an assay of intermediate sensitivity is therefore required. Our aim was to evaluate whether the branched chain DNA (bDNA) assay would fulfil this function. Seventy-one HBsAg-positive patients were tested for HBV DNA by the bDNA assay; 64 were also tested by dot blot hybridisation and, when appropriate, also by PCR. Thirty-seven (52%) patients were positive for HBV DNA by the bDNA assay. HBV DNA was detected in the majority (21/28; 75%) of HBeAg-positive patients but also in 14 of 36 (39%) anti-HBe-positive patients. HBV DNA was detected by the bDNA assay in 20 of 48 (42%) patients negative for HBV DNA by dot blot hybridisation assay. All patients positive for HBV DNA by dot blot hybridisation were also positive by the bDNA assay. Sixteen of twenty-five (64%) patients negative for HBV DNA by the bDNA assay were positive for HBV DNA by PCR. The bDNA assay is a sensitive and reliable method for the detection of HBV DNA. As nucleoside analogue therapy becomes more widely available, the assay should provide a useful tool for the selection for and monitoring of patients on antiviral therapy.

Adult↗
PubMed1996

Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine.

We describe mutations in the hepatitis B virus (HBV) polymerase gene in viruses which reactivated in two patients during therapy with -2'-deoxy-3'-thiacytidine, or lamivudine (3TC), and following orthotopic liver transplantation for chronic hepatitis B. Virus resistance to 3TC is associated with mutations which lead to amino acid substitutions in the highly conserved tyr-met-asp-asp (YMDD) motif, part of the active site of the polymerase, and which parallel those seen in resistant human immunodeficiency virus (HIV). Substitutions of valine and isoleucine for methionine were found in the two cases. The significance of single secondary mutations, which differ between viruses from the two patients, remains to be determined. Thus, viral resistance to lamivudine of hepatitis B virus mimics that of HIV and can occur in the setting of immunosuppression after liver transplantations.

Adult↗
PubMed1996

Etiology, screening, and treatment of hepatocellular carcinoma.

The prognosis with large hepatocellular carcinomas is poor, and only palliative treatment is available. Small tumors are amenable to several modes of treatment, including liver transplantation, resection, or alcohol injection, with acceptable 5-year survival rates. Although the value of screening for hepatocellular carcinoma has yet to be shown, these data, coupled with the recognition of at-risk groups and useful diagnostic techniques, might encourage the clinician to screen at-risk patients in the clinic. New imaging techniques such as ultrasonographic angiography enhanced with CO2 microbubbles, or color Doppler ultrasound, may clarify the intratumoral blood flow of small tumors.

Biomarkers, Tumor↗
PubMed1996

Quantitative assessment of hepatitis C virus RNA and IgM antibodies to hepatitis C core in chronic hepatitis C.

BACKGROUND/AIMS: IgM antibodies to hepatitis C virus have been found in a variable proportion of patients with chronic hepatitis C. We have evaluated whether IgM anti-core antibodies correlate with viraemia or hepatic injury in chronic hepatitis C. METHODS: Serum from 106 patients with chronic hepatitis C with varying stages of disease were tested for IgM anti-core hepatitis C virus by immunoassay. All patients were seropositive for IgG antibody to hepatitis C virus by second-generation ELISA; 25 had histologic cirrhosis and 57 chronic hepatitis. IgM anti-core was detected in 84/106 (79.2%) patients. HCV-RNA was tested by branched (bDNA) signal amplification assay or by polymerase chain reaction in 92 patients. RESULTS: All IgM-anti-HCV positive patients had detectable HCV-RNA. Seventy of 87 (80.5%) HCV-RNA-positive patients were IgM anti-core positive. Levels of IgM anti-HCV were significantly higher in patients with HCV-RNA detected by bDNA than in those who were bDNA negative, but there was no correlation between HCV-RNA concentrations and IgM anti-HCV levels. Of the 84 patients with positive results for IgM anti-core hepatitis C virus, 59 (70.2%) had abnormal alanine aminotransferase levels. The levels of IgM anti-core hepatitis C virus were likewise significantly higher in those with abnormal alanine aminotransferase levels. There was no difference in the percentage of patients with a positive IgM anti-HCV, or in levels of IgM anti-core hepatitis C virus in those with chronic hepatitis versus cirrhosis. CONCLUSIONS: These data suggest that the majority of patients with chronic hepatitis C virus infection are IgM anti-core hepatitis C virus positive, and the detection seems to be associated with viral replication and biochemical evidence of hepatic necrosis. IgM anti-core hepatitis testing may prove useful as an adjunct in the clinical assessment of patients with chronic hepatitis C.

Adolescent↗
PubMed1995

Epirubicin-Lipiodol chemotherapy versus 131iodine-Lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma.

BACKGROUND: Arterially administered iodized oil (Lipiodol) is selectively retained by hepatocellular carcinomas (HCCs), and has been used as a vehicle for delivery of therapeutic agents to these tumors. This study compared the efficacy of Lipiodol-targeted epirubicin chemotherapy with Lipiodol-131I radiotherapy. METHODS: Ninety-five patients with unresectable HCC confined to the liver were administered either Lipiodol-epirubicin emulsion (n = 69; 61 cirrhotics; Okuda tumor Stage I, 14; II, 37; III, 18; epirubicin dose, 75 mg/m2) or Lipiodol-131I (131I) (n = 26; 18 cirrhotics; Okuda tumor Stage I, 6; II, 19; III, 1; dose 750-1050 MBq). The last 28 patients (17 epirubicin, 11 131I) were treated within a prospective randomized trial. Bolus drug or isotope was injected into the hepatic artery by transfemoral cannulation. Lipiodol and 131I uptake were gauged by 10th day computed tomography and 48-hour scintiscan. Treatments were repeated two-monthly when indicated. RESULTS: Tumor size at 2 months remained static or diminished partially in 21 of 38 epirubicin recipients (55%) and 15/22 131I recipients (68%). Actuarial survival at 6, 12, and 24 months was 40%, 25%, and 6% with epirubicin, and 58%, 25%, and 0% with 131I; 30-day mortality was 11% and 15%, respectively. Comparison with historic controls indicated survival benefit in Stages I and II. Similar findings were recorded in the 28 patients in the randomized trial. CONCLUSIONS: Patients with unresectable HCC receiving Lipiodol-epirubicin or Lipiodol-131I show good tumor localization, acceptable toxicity, and comparable survival benefit at 6 and 12 months with either modality.

Actuarial Analysis↗