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D Mutimer

Publications and source records attributed to D Mutimer.

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

Hepatitis C virus recurrence after liver transplantation.

Cirrhosis due to hepatitis C virus (HCV) is now the most common indication of liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent HCV infection is almost inevitable. Though the natural history and intermediate term outcome of recurrent HCV are now better documented, those factors which may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon (IFN) as a sole agent for the treatment of recurrent infection has proved unsatisfactory. Early intervention with a combination of IFN and ribavirin seems promising, and this approach may prevent or delay progression of HCV related graft disease after liver transplantation.

Hepatitis C↗
PubMed1999

Analysis of hepatitis B virus quasispecies changes during emergence and reversion of lamivudine resistance in liver transplantation.

This report describes nucleotide sequence analysis of part of the polymerase gene of hepatitis B virus (HBV) during the development of lamivudine-resistant HBV in five patients who received lamivudine treatment in conjunction with liver transplantation. Samples from patients were analysed before, during and after drug treatment in conjunction with serum HBV quantification by PCR. Lamivudine resistance was found to be associated with L526M and M550V changes in two patients and M550I change in three patients. Other changes associated with lamivudine resistance in some patients were V509I, A546V, S565A and A568T. The effects on HBV surface antigen are also described. Some patients were subsequently treated with famciclovir and/or ganciclovir with variable outcomes. In two out of three patients who stopped lamivudine treatment, reversion (partial or complete) to wild-type virus was observed after about 5 months. In contrast, a complex mixture of mutant viruses emerged in a third patient who stopped lamivudine treatment.

Antiviral Agents↗
PubMed1998

Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant chronic hepatitis B infection: results of a pilot study.

BACKGROUND/AIMS: Alpha-interferon achieves seroconversion in about one third of naive patients. Attempts to achieve seroconversion in patients who have previously failed alpha-interferon have proved disappointing. Combination chemotherapy (alpha-interferon with a nucleoside analogue) might provide a treatment alternative for these patients. We have undertaken a phase 2 study in 20 patients who had previously failed at least one course of alpha-interferon. The study was designed to assess the safety, tolerability and efficacy of the combination. METHODS: All patients were treated for 16 weeks with alpha-interferon in combination with 12 or 16 weeks of Lamivudine (3'TC). Patients were followed for 16 weeks post-treatment. Pharmacokinetic studies were performed to identify/exclude significant pharmacokinetic drug interaction. RESULTS: The combination was well tolerated, and side-effects of the combination were indistinguishable from the recognised side-effects of alpha-interferon. Pharmacokinetic studies performed on days 1 and 29 did not show any significant interaction. All patients achieved HBV DNA clearance during treatment, but 19 relapsed at the end of treatment. HBeAg/anti-HBe seroconversion was observed for four patients, but was sustained for a single patient (who also had sustained DNA clearance). CONCLUSIONS: Combination therapy with alpha-interferon and lamivudine given for 16 weeks appears safe and is well tolerated. However, for this group of patients who had previously failed interferon monotherapy, the efficacy of combination interferon/lamivudine therapy appears disappointing, and other treatment strategies should be investigated.

Adult↗
PubMed1998

Hepatitis B virus antiviral drug resistance: from the laboratory to the patient.

The development and application of nucleoside (and nucleotide) analogues for the treatment of chronic hepatitis B infection will transform the management of this condition. For instance, treatment with lamivudine effects a dramatic and measurable reduction of serum virus titre. This is associated with biochemical and histological improvements. Unfortunately, for the majority, replication resumes when treatment is withdrawn. Prolonged lamividine treatment may be associated with the emergence of drug-resistant species with specific polymerase mutations. Compared with the observed rate for the development of drug resistance observed during monotherapy of HIV infection, resistance is slow to emerge during treatment of hepatitis B. The rate of emergence might be dependent on the rate of infected hepatocyte turnover, which is extremely variable in chronic HBV infection (and significantly slower than infected lymphocyte turnover during HIV infection). Preliminary data suggest that pretreatment serum virus titre may be an important predictor of the development of drug resistance, an observation consistent with preexistance of the resistant virus in the hepatitis B virus quasispecies. Akin to developments in antiviral treatment of HIV infection, further progress in the treatment of chronic hepatitis B will depend on the development of drugs for use in combination therapy.

Antiviral Agents↗
PubMed1997

Enhanced (cytomegalovirus) viral replication associated with septic bacterial complications in liver transplant recipients.

BACKGROUND: Complications of the biliary anastomosis are the principal cause of clinically serious bacterial sepsis in liver transplant recipients. Reported series suggest an association of bacterial and fungal infection with cytomegalovirus (CMV) infection, although the mechanism of this association is unclear. METHODS: We examined the association of serious bacterial sepsis with CMV replication in a cohort of 106 consecutive liver transplant recipients. Sequentially collected buffy coats were examined with a polymerase chain reaction (PCR) assay that has been shown to have good predictive value for the development of CMV infection. For selected patients, CMV-specific IgM response and serum tumor necrosis factor-alpha (TNF-alpha) were also measured. RESULTS: Ten of 13 patients with serious bacterial sepsis developed buffy coat PCR positivity, compared with 26 of 93 patients without bacterial sepsis (chi-square, P<0.001). Ten of 10 septic recipients with a seropositive liver donor developed PCR positivity. For 9 of 10 recipients, bacterial sepsis developed before PCR positivity. Bacterial sepsis was associated with high serum levels of TNF-alpha. Immune response to CMV (reflected by the appearance CMV-specific IgM) was apparently affected by bacterial sepsis, and IgM response was not observed for the three septic patients who died during the study period. CONCLUSIONS: We conclude that CMV replication is encouraged by serious bacterial sepsis. Replication may be promoted by high antecedent levels of TNF-alpha, and/or by poor immune response to CMV in the context of serious bacterial infection.

Antibodies, Viral↗
PubMed1997

Patterns of viremia in liver transplant recipients with symptomatic cytomegalovirus infection.

Cytomegalovirus (CMV) titer in blood seems to be the principal determinant of clinical symptoms in immunosuppressed patients. We have developed an assay for quantitation of CMV DNA in serum. The assay requires the coamplification by polymerase chain reaction (PCR) of extracted serum DNA with 1000 molecules of mutated internal standard DNA, and then an ELISA detection system. We examined 133 paired buffy coats and sera from 15 patients with symptomatic infection. Sera were examined by quantitative PCR, and buffy coats were examined by qualitative PCR (with a detection threshold of approximately 40 copies per 150,000 cells). Serum viral titers peaked during the seventh week after transplant (median day 40, range 26-58) at about the time of symptom onset. Mean viral titer measured during the seventh week was 1.2 x 10(5) copies per milliliter of serum (standard error 6.5 x 10(4). Buffy-coat PCR results were generally concordant with results of serum PCR (overall concordance 103/133=77.4%). Serum CMV titer fell, as symptoms resolved with reduction of immunosuppression and specific antiviral therapy. High titers and poor response to antiviral therapy were observed in the context of excessive immunosuppression and bacterial sepsis. Measurement of serum CMV titer may be useful for the management of immunosuppressed transplant recipients, and provides a tool for the better understanding of factors that enhance or inhibit viral replication.

Antibodies, Viral↗
PubMed1997

Hepatitis G virus infection in patients with bleeding disorders.

Eighty-two patients with bleeding, disorders registered with our centre were screened for infection with hepatitis G virus (HGV). 80 patients were positive for hepatitis C (HCV) antibodies, 66 of whom (83%) were HCV PCR positive. 11 patients (13%) were HGV RNA-positive, a similar prevalence rate to that of other studies of patients with bleeding disorders who received factor concentrates prior to the introduction of viral inactivation procedures. There was no significant difference in histological activity index (HAI) between the 10 HGV RNA-positive and the 31 HGV RNA-negative patients who underwent liver biopsy for assessment of HCV infection (median HAI scores 5.5, range 2-10 and four, range 0-10 respectively, P = 0.07). One patient in each group had established cirrhosis. In patients who underwent HCV quantitation there was no significant difference in HCV viral titre between HGV RNA-positive and negative patients (median HCV titre in HGV RNA-positive patients 2.10 x 10(5) DNA copies/ml (n = 8) range 4.17 x 10(2) to 4.17 x 10(6), median HCV titre in HGV RNA-negative patients 3.33 x 10(5) (n = 31) range 1.00 x 10(3) to 6.67 x 10(6), P = 0.68). In this study there was no evidence that individuals co-infected with HGV and HCV have more severe liver disease than those infected with HCV alone.

Adult↗
PubMed1996

Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.

BACKGROUND: Orthotopic liver transplantation in patients positive for hepatitis B virus (HBV) DNA is associated with a high reinfection rate, even with hepatitis B immunoglobulin (HBIG) prophylaxis. Nucleoside analogues that inhibit hepatitis B replication in patients with chronic hepatitis B could prevent reinfection after transplantation. The aim of this study was to analyse the efficacy and safety of prophylaxis both before and after transplantation with the nucleoside analogue lamivudine, without HBIG, in patients undergoing liver transplantation. METHODS: 17 HBsAg-positive patients with decompensated cirrhosis and previous evidence of viral replication were enrolled. 12 were HBV-DNA-positive by a signal amplification assay. Patients were treated with oral lamivudine (100 mg daily) for at least 4 weeks before transplantation and followed up for 18-90 weeks after transplantation. FINDINGS: HBV DNA became undetectable in serum before transplantation in all HBV-DNA-positive patients. Four died before transplantation from complications of cirrhosis; one patient was withdrawn from the study because of a cerebrovascular accident. The remaining 12 patients underwent transplantation. Two patients died after transplantation (one at 3 days and one [suicide] at 20 weeks). HBV DNA reappeared in one patient with histological evidence of recurrent hepatitis (72 weeks). By week 24 the nine remaining patients had lost HBsAg and remained negative for HBV DNA. INTERPRETATION: Lamivudine treatment may prove useful in preventing recurrence of hepatitis B after liver transplantation. The effect on survival of patients after transplantation remains to be assessed.

DNA, Viral↗
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↗
PubMed1995

Quantitation of cytomegalovirus in the blood of liver transplant recipients.

An assay for quantitation of cytomegalovirus (CMV) has been developed. The assay combines DNA amplification and enzyme-linked immunosorbent assay (ELISA) detection. In this study, the assay has been used to examine sequential buffy-coats from 32 consecutive liver transplant recipients. In a febrile patient, CMV titres in excess of 10(4) copies per 150,000 cells strongly suggest a diagnosis of symptomatic CMV infection. Antiviral therapy causes a rapid decline in viral titre. Viral titres are seen to rise presymptomatically in some patients. Median peak viral titres differ significantly between symptomatic patients (1.1 x 10(5)), asymptomatic CMV IgM-positive patients (1.7 x 10(3)), and asymptomatic CMV immunoglobulin (Ig)M-negative patients (2.9 x 10(2)). CMV quantitation can be used for diagnosis and surveillance and can also be used to monitor antiviral treatment.

Adult↗
PubMed1995

Failure to incriminate hepatitis B, hepatitis C, and hepatitis E viruses in the aetiology of fulminant non-A non-B hepatitis.

Sporadic non-A, non-B hepatitis is the most common indication for liver transplantation in patients presenting with fulminant and subacute liver failure. This study used serological, histological, and molecular biological techniques to examine specimens from 23 consecutive patients transplanted for sporadic non-A, non-B hepatitis. No evidence was found of hepatitis C virus, hepatitis E virus, or 'cryptic' hepatitis B virus infection.

Adolescent↗