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D Mutimer

Publications and source records attributed to D Mutimer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir.

BACKGROUND: Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure. CASE REPORT: A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the development of graft failure. OUTCOME: A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved. CONCLUSION: The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.

Acute Disease↗
PubMed2001

Epstein-Barr virus infection in paediatric liver transplant recipients: detection of the virus in post-transplant tonsillectomy specimens.

AIMS: Post-transplant lymphoproliferative disease (PTLD) is an important and serious complication in transplant patients. Recent studies have suggested that quantitative assessment of Epstein-Barr virus (EBV) infection in transplant patients might help to identify those at risk of developing PTLD. Therefore, tonsils from paediatric liver transplant recipients were studied for evidence of EBV infection. METHODS: Tonsils were studied by in situ hybridisation for the detection of the small EBV encoded nuclear RNAs (EBERs). The phenotype of EBV infected cells was determined by double labelling in situ hybridisation and immunohistochemistry. The expression of viral latent and lytic antigens was determined by immunohistochemistry. Tonsils from patients without known immune defects were studied as controls. RESULTS: Tonsils from transplant patients showed pronounced follicular hyperplasia and minor paracortical hyperplasia. In situ hybridisation revealed variable numbers of EBV infected B cells in the tonsils from transplant patients (range, 2-1000/0.5 cm(2); mean, 434/0.5 cm(2); median, 105/0.5 cm(2)). Lower numbers were detected in the control tonsils (range, 1-200/0.5 cm(2); mean, 47/0.5 cm(2); median, 9/0.5 cm(2)). The latent membrane protein 1 (LMP1) of EBV was not detected and there were only rare cells in two cases showing expression of the EBV encoded nuclear antigen 2 (EBNA2). There was no evidence of lytic infection. None of the patients developed PTLD within a follow up period of up to five years. CONCLUSIONS: These data indicate that tonsillar enlargement in paediatric liver transplant patients does not necessarily imply a diagnosis of PTLD. Furthermore, the presence of increased numbers of EBV infected cells in tonsils from liver transplant recipients by itself does not indicate an increased risk of developing PTLD.

Antigens, Viral↗
PubMed2000

Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up.

BACKGROUND: This open, multicenter study was conducted to evaluate the efficacy and safety of lamivudine prophylaxis given to chronic hepatitis B virus-(HBV) infected patients before and after orthotopic liver transplantation (OLT). We now present long-term data that follow our previous short-term report. METHODS: Twenty-three patients were treated with lamivudine (100 mg orally, daily); 13 (57%), were serum HBV DNA positive (Abbott Genostics, Abbott Laboratories, Chicago, IL) at study entry. Patients received lamivudine for at least 4 weeks before OLT, and for up to 50 months (median 25 months) after OLT. RESULTS: Of the 23 treated patients, 17 survived to undergo OLT. Eleven patients (65%) survived up to 4 years (median 36 months) after OLT. One of the survivors stopped lamivudine because of a possible adverse reaction 9 months post-OLT, and prophylaxis with HBV immune globulin was then established. Ten survivors continue lamivudine. Eight long-term survivors have normal liver function without evidence of HBV reinfection. Of the 17 transplanted patients, 6 died. Four patients died (3 days to 5 months post-OLT) without evidence of graft reinfection. Two further patients died at 19 and 23 months post-OLT from graft failure. Both patients had YMDD variant detected at 12 months post-OLT. Two other patients with YMDD-variant HBV remain alive on lamivudine, 9 and 15 months after development of the variant. CONCLUSIONS: Lamivudine, given before and after OLT, prevents significant graft reinfection for the majority of treated patients. The study has also shown that lamivudine is extremely well tolerated by liver failure patients and for a prolonged period after transplantation.

Biopsy↗
PubMed2000

Quantitation of Epstein-Barr virus DNA in the blood of adult liver transplant recipients.

BACKGROUND: Posttransplant lymphoproliferation is most often observed in pediatric transplant recipients who experience primary Epstein-Barr virus (EBV) infection at the time of or after transplantation. Lymphoproliferation is believed to be caused by impaired control of EBV-infected cells, which may be of recipient or donor origin. Most studies of EBV infection and lymphoproliferation have focused on the pediatric age group. METHODS: We have undertaken a prospective study of EBV infection in adult liver transplant recipients. Sequentially collected peripheral blood lymphocytes were examined with a recently developed quantitative polymerase chain reaction assay. The assay quantitates EBV DNA genomic titre over a 5 log10 range. RESULTS: Compared with healthy EBV seropositive people not undergoing immunosuppressive therapy, blood EBV DNA titre is elevated in patients with liver disease before transplantation. Overall, highest titres were observed during the first posttransplant month, and in the context of antilymphocyte therapy. In one patient, lymphoproliferation was associated with high titres which fell during reduction of immunosuppressive therapy. In another patient with lymphoproliferation of donor lymphocyte origin, blood EBV DNA titre was not as high. CONCLUSIONS: EBV proliferation is seen in the context of advanced liver disease and after liver transplantation. EBV DNA quantitation is a useful tool to examine the effects of immunosuppression on EBV-associated lymphoproliferation, and may be an essential technique for programs exploring the merits of EBV adoptive immunotherapy.

Adult↗
PubMed2000

Selection of multiresistant hepatitis B virus during sequential nucleoside-analogue therapy.

Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.

2-Aminopurine↗
PubMed2000

Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.

BACKGROUND: In many transplant centres lamivudine is an important component of prophylaxis against, and treatment of, hepatitis B virus (HBV) graft infection. Drug resistant HBV species with specific polymerase mutations may emerge during lamivudine treatment. AIMS: To examine the clinical consequences of graft infection by lamivudine resistant virus. METHODS: The clinical course of four liver transplant patients who developed graft infection with lamivudine resistant virus was reviewed. The response of HBV infection to reduction of immunosuppression and to manipulation of antiviral therapy was assessed. For each patient, serum viral titre was measured and the viral polymerase gene was sequenced at multiple time points. RESULTS: High serum titres were observed following emergence of the lamivudine resistant species. Wild type HBV re-emerged as the dominant serum species after lamivudine withdrawal. All patients developed liver failure, and onset of liver dysfunction was observed when resistant virus was the dominant serum species. In three patients, liver recovery was observed when immunosuppression was stopped and when alternative antivirals were given. Wild type virus appeared to respond to ganciclovir, and to reintroduction of lamivudine. For one patient, introduction of famciclovir was associated with clinical, virological, and histological response. CONCLUSIONS: Failure of lamivudine prophylaxis may identify patients at special risk for the development of severe graft infection. Treatment of graft reinfection should include reduction of immunosuppression, and systematic exposure to alternative antivirals. Viral quantitation and genetic sequencing are essential components of therapeutic monitoring.

Adult↗
PubMed2000

Additive antiviral effects of lamivudine and alpha-interferon in chronic hepatitis B infection.

alpha-Interferon has limited efficacy against chronic hepatitis B virus (HBV) infection. Nucleoside analogues may confer greater benefits, however, it is likely that combination therapies will be required for effective control of this infection. We investigated the antiviral effect of lamivudine and interferon therapy in eight patients with high HBV-DNA levels. Six patients received lamivudine/interferon combination therapy followed, after a 6-month drug-free period, with lamivudine monotherapy. Mean HBV viral load (copies/ml) reduction was significantly greater after 4 months of combination therapy (4.3 x 10(3)) compared to an equivalent period of lamivudine monotherapy (2.9 x 10(2)) (P=0.03). Two patients were given 6 months of lamivudine/interferon combination therapy followed immediately by lamivudine monotherapy. Cessation of interferon in these patients led to a rapid 1-2 log10 increase in HBV viral load. These findings suggest that alpha-interferon has a direct antiviral effect on chronic HBV infection, which may be additive to, or synergistic with lamivudine.

Antiviral Agents↗
PubMed1999

Significance testing of clinical data using virus dynamics models with a Markov chain Monte Carlo method: application to emergence of lamivudine-resistant hepatitis B virus.

Bayesian analysis using a virus dynamics model is demonstrated to facilitate hypothesis testing of patterns in clinical time-series. Our Markov chain Monte Carlo implementation demonstrates that the viraemia time-series observed in two sets of hepatitis B patients on antiviral (lamivudine) therapy, chronic carriers and liver transplant patients, are significantly different, overcoming clinical trial design differences that question the validity of non-parametric tests. We show that lamivudine-resistant mutants grow faster in transplant patients than in chronic carriers, which probably explains the differences in emergence times and failure rates between these two sets of patients. Incorporation of dynamic models into Bayesian parameter analysis is of general applicability in medical statistics.

Antiviral Agents↗
PubMed1999

High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation.

BACKGROUND/AIMS: Orthotopic liver transplantation has an established role for the treatment of patients with chronic liver failure secondary to hepatitis B virus (HBV) infection. Unfortunately, recurrent infection of the graft can be associated with aggressive disease, and with diminished graft and patient survival. Currently, the role of nucleoside analogues for prevention of graft re-infection is being evaluated. Preliminary results are encouraging, but treatment failure has been associated with emergence of drug-resistant virus. METHODS: We have studied ten consecutive patients who received lamivudine prophylaxis for prevention of HBV graft reinfection. Sequential sera, collected prelamivudine then during treatment before and after liver transplantation, were examined. Conventional serological markers were measured, as were serum viral DNA levels with a sensitive quantitative polymerase chain reaction assay. RESULTS: Lamivudine treatment effected a reduction in serum HBV levels, but six patients still had measurable viral DNA at the time of transplantation. Five patients developed graft re-infection with lamivudine-resistant virus. Resistant virus emerged 8 to 15 months post-transplant. The likelihood of emergence of resistant virus was related to the pre-treatment serum HBV titre. Persistent serum viral DNA positivity and evidence of graft re-infection during the early post-transplant period did not predict the subsequent emergence of resistant virus. CONCLUSIONS: Our observations suggest that the resistant species may be present in the viral quasispecies in the serum and liver of patients with high-level replication prior to lamivudine exposure. The resistant species can persist during lamivudine treatment prior to transplantation, and emerge following transplantation. These observations suggest strategies which might prevent the emergence of drug-resistant species, and imply that graft re-infection may be a preventable phenomenon.

Antiviral Agents↗
PubMed1999

Histological progression during short-term follow-up of patients with chronic hepatitis C virus infection.

Assessment of prognosis from hepatitis requires liver histology. When the fibrosis stage is known, and if the fibrosis progression rate can be established, time to development of cirrhosis can be calculated. The fibrosis progression rate can be calculated from a single biopsy when duration of infection prior to biopsy is known. Sequential biopsies can also be examined. In this work, we studied histological activity and fibrosis stage in liver biopsies of 157 hepatitis C virus (HCV)-infected patients, including 92 for whom the approximate duration of infection was known. The mean fibrosis progression rate was 0.09 units per year, and was not influenced by mode of infection or viral genotype. Forty-six patients who had very mild histological changes in the initial biopsy underwent repeat biopsy 2 years later (with no intervening anti-viral treatment). Comparison of paired biopsies confirmed a tendency to histological progression and increasing hepatic fibrosis (mean, 0.15 fibrosis units per year). A normal baseline alanine aminotransferase (ALT) value was associated with slow fibrosis progression before baseline biopsy and between biopsies. These data do not differ from published cross-sectional and longitudinal studies, and suggest that histological progression will be observed during follow-up of most patients, including those with mild histological changes at time of initial assessment.

Adult↗
PubMed1999

Autoimmune liver disease in patients with neoplastic diseases.

BACKGROUND: Development of de novo autoimmune liver disease has not been well documented in patients with malignant diseases. METHODS/RESULTS: In this paper we report on a series of six patients with neoplastic disorders who acquired liver disease with autoimmune features. Five patients had suffered from haematological neoplasms and one from colonic cancer. In two patients, liver disease was detected at the time of presentation with malignancy. In the remaining four, all of whom were successfully treated for malignancies, features of liver disease presented at intervals 24-72 months after the cancer diagnosis. Twelve liver specimens (11 biopsies and one hepatectomy specimen) were obtained at time intervals of 1-76 months after initial presentation of neoplastic disease. Biopsies from three patients showed features of hepatitis (one acute, one sub-acute, one chronic). Two patients had histological features suggestive of an overlap syndrome (one autoimmune hepatitis/primary biliary cirrhosis, one autoimmune hepatitis/primary sclerosing cholangitis). The sixth patient had features of autoimmune cholangiopathy. All but one responded well to steroid therapy with complete clinical and biochemical remission obtained 4 weeks to 8 months after steroid introduction. We discuss briefly possible aetiologies of autoimmune liver disease in these patients. CONCLUSIONS: Autoimmune liver disease may be precipitated by therapy for neoplastic disease or malignant disease itself. The unusually heterogeneous clinicopathological findings in this group as well as the response to treatment support the concept of a wide spectrum of manifestations of autoimmune liver disease. The results may also suggest that autoimmune liver disease may be possibly added to the list of paraneoplastic syndromes. Further prospective studies are required to confirm a causal association and to determine whether the mechanisms involved are disease- or treatment-related.

Adult↗
PubMed1999

Successful treatment of acquired perforating dermatosis with rifampicin in an Asian patient with sclerosing cholangitis.

Acquired perforating dermatosis (APD) is a very rare disorder which has been described in association with systemic diseases such as diabetes mellitus, HIV infection or lymphoma. In this report we describe a patient with APD associated with sclerosing cholangitis and diabetes mellitus who was successfully treated with rifampicin. A 33-year-old Indian woman with a history of extensive pancreatic surgery, sclerosing cholangitis and insulin dependent diabetes mellitus was referred to our unit with intractable pruritus. She was treated with cholestyramine, ursodeoxycholic acid, several analgesics, UVB therapy, topical steroids, sedative antihistamines and plasmapheresis without significant improvement. Increasingly severe itching was associated with papular skin changes limited initially to the lower limbs but which later involved her entire body. Biopsy of a representative lesion showed the changes of APD. She was subsequently treated with rifampicin which produced a dramatic resolution of pruritus within 3 weeks and the skin changes progressively resolved over subsequent months. In this newly described association of APD with sclerosing cholangitis, rifampicin treatment appeared to be efficient in ameliorating pruritus and the papular skin changes typical of APD.

Adult↗
PubMed1999

Use of real-time PCR and fluorimetry to detect lamivudine resistance-associated mutations in hepatitis B virus.

Very rapid amplification of DNA by PCR in small volumes can be continuously monitored by the detection of the binding of probes with a rapid cycler with built-in fluorometric detection. Primers were designed to amplify approximately 100 bp of the polymerase gene of hepatitis B virus (HBV) spanning codon 550, where mutations associated with resistance to lamivudine invariably occur. Four hybridization probes were synthesized: one was 3' labelled with fluorescein and hybridized upstream of codon 550. The others were 5' labelled with Cy5 and 3' labelled with biotin and spanned codon 550. The Cy5-labelled oligonucleotides contained either wild-type (ATG) or mutant (GTG or ATT) sequences. A Cy5-labelled probe and either the fluorescein-labelled probe or Sybr Green 1 (a compound that fluoresces when bound to double-stranded DNA) were included in each PCR. After completion of the amplification by using a LightCycler (Idaho Technology), the temperature at which the Cy5 probe melted from the product was determined in a melt program that took ca. 3 min. Pre- and posttreatment samples from eight patients (five chronic and three transplant) who failed lamivudine treatment were amplified, and the presence of mutations in codon 550 was determined by ABI sequencing and by using the LightCycler; in some cases PCR products were also cloned, and multiple clones were sequenced. Concordant results were obtained in all cases. We found the LightCycler to be better at resolving the sequences of genomic mixtures; for example, two samples showed a sequence at codon 550 of (A/G)T(G/T), which was found by fluorimetry to be mixtures of GTG and ATT but no ATG, and this finding was confirmed by the sequencing of clones. However, this approach was not more sensitive than population sequencing for the detection of the presence of mixtures. Overall, this pilot study has demonstrated an approach that could be an extremely rapid and economical method for the detection of lamivudine resistance-associated mutations in HBV.

Anti-HIV Agents↗