Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic liver disease due to hepatitis B virus (HBV) infection remains a significant cause of morbidity and mortality after renal transplantation. Administration of immunosuppressive drugs facilitates viral replication and may lead to increased frequency of progressive chronic hepatitis, cirrhosis and hepatocellular carcinoma. Chronic HBV infection adversely affects both patient and graft survival. Because of increased risk of death HBV-seropositive renal graft recipients require prophylaxis and treatment of hepatitis B. Interferon due to its immunomodulating effects, risk of activation of rejection is not recommended for transplant recipients. Lamivudine seems to be efficacious and useful for treating hepatitis B in renal transplant recipients. The main disadvantages of lamivudine are relapse after withdrawal of the agent and emergence of lamivudine resistant strains due to mutations in the YMDD locus of the HBV polymerase gene during prolonged lamivudine therapy. Optimal lamivudine treatment regimen for HBsAg-positive renal transplant recipients should be defined. It seems better to initiate lamivudine therapy before or immediately after transplantation to prevent viral replication. The clinical course of hepatitis in most patients with lamivudine resistant HBV mutants seems relatively benign and long-term resistance was well tolerated. Discontinuation of lamivudine in order to minimize the emergence of drug resistant HBV mutants is safe in selected groups of patients. Lamivudine therapy has become the treatment of choice in HBV positive renal transplant recipients and improves prognosis and outcome of infected patients.
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PMID:Lamivudine therapy for chronic hepatitis B in renal transplant recipients. 1561 47

We report the use of capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) for the determination of antiretroviral dideoxynucleosides (ddNs), their nucleotides, and a set of ribonucleosides and ribonucleotides. A CE system for separation of most commonly used antiretroviral ddNs has been developed based on a basic buffer with a volatile electrolyte suitable for ESI-MS detection in an untreated capillary column. Positive and negative ionization modes are investigated and compared for sensitive and stable electrospray performance. A 14-compound mixture of nucleosides and nucleotides is profiled in a single capillary zone electrophoresis separation with a distinct elution order: electroosmotic flow, ddNs, mononucleotides, dinucleotides, and trinucleotides in less than 18 min. The fragmentation pathways of the nucleosides and nucleotides in ESI-MS have been interpreted. Concentration limits of detection are 100 to 200 nM with an injection volume of approximately 10 nL. This technique has been used to detect naturally occurring nucleotides and to study the metabolism of lamivudine (3TC) in the human hepatoma cell line Hep G2. 3TC and its metabolites 3TC-monophosphate, 3TC-diphosphate, and 3TC-triphosphate were detected after 10 h of incubation of 3TC with the cells.
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PMID:Capillary electrophoresis-electrospray-mass spectrometry of nucleosides and nucleotides: application to phosphorylation studies of anti-human immunodeficiency virus nucleosides in a human hepatoma cell line. 1576 17

As a leading cause of liver cirrhosis and hepatocellular carcinoma, chronic hepatitis B poses a major health care problem. Currently approved therapeutic options include interferon-alpha, pegylated interferon-alpha, lamivudine and adefovir. Interferon-alpha can induce long-term suppression of viral replication in a proportion of patients. However, treatment is associated with considerable side effects. Lamivudine and adefovir effectively suppress viral replication and induce histological improvement in the majority of patients. However, recurrence rates are high after cessation of treatment. During long-term treatment about 20% lamivudine-resistant mutants emerge annually, while currently available studies suggest that this number is about 3% for adefovir after two years of therapy. Efficacy of the respective antivirals is affected by virological and clinical parameters, thus requiring individual treatment strategies.
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PMID:[Management of chronic hepatitis B]. 1590 Aug 29

Mutations within the hepatitis B virus (HBV) polymerase gene conferring drug-resistance are selected during prolonged lamivudine (3TC) or adefovir dipivoxil (ADV) treatment. Because there is no other approved drug against HBV, treatments with 3TC or ADV are used either sequentially or in addition, depending on treatment response or failure. Considering the use of de novo or add-on 3TC+ADV bitherapy, we investigated the possibility of the emergence of an HBV strain harboring polymerase mutations conferring resistance to both 3TC (rtL180M+M204V) and ADV (rtN236T). We constructed the L180M+M204V+N236T mutant and determined its replication capacity and its susceptibility to different nucleos(t)ide analogs in transiently transfected hepatoma cell lines. The triple mutant replicates its genome in vitro, but less efficiently than either the wild-type (wt) HBV or L180M+M204V and N236T mutants. Phenotypic assays indicated that the L180M+M204V+N236T mutant is resistant to pyrimidine analogs (3TC, -FTC, beta-L-FD4C, L-FMAU). Compared with wt HBV, this mutant displays a 6-fold decreased susceptibility to ADV and entecavir and a 4-fold decreased susceptibility to tenofovir. Interferon alfa inhibited equally the replication of wt and L180M+M204V+N236T HBV. In conclusion, the combination of rtL180M+M204V and rtN236T mutations impairs HBV replication and confers resistance to both 3TC and ADV in vitro. These results suggest that the emergence of the triple mutant may be delayed and associated with viral resistance in patients treated with 3TC+ADV. However, other nucleos(t)ide analogs in development showed an antiviral activity against this multiresistant strain in vitro. This provides a rationale for the clinical evaluation of de novo combination therapies.
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PMID:Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. 1591 63

Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.
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PMID:Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis. 1598 9

Lamivudine is widely used to treat patients with hepatitis B. However, the outcomes in patients with hepatocellular carcinoma (HCC) treated with lamivudine have not been established. This study was conducted to evaluate the outcomes of lamivudine treatment for patients with HCC using an untreated, matched control group. Thirty patients with controlled HCC orally received lamivudine. As controls, 40 patients with HCC who were not treated with lamivudine and matched for clinical features were selected. The lamivudine-treated and untreated groups were compared with respect to changes in liver function, HCC recurrence, survival, and cause of death. In the lamivudine-treated group, there was significant improvement in the Child-Pugh score at 24 months after starting treatment, while no improvement was observed in the untreated group. There was no significant difference in the cumulative incidence of HCC recurrence and survival between the groups. However, there was a significant difference in the cumulative incidence of death due to liver failure (P= 0.043). A significant improvement in liver function was achieved by lamivudine treatment, even in patients with HCC. These results suggest that lamivudine treatment for patients with HCC may prevent death due to liver failure. Further prospective randomized studies using a larger number of patients are required.
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PMID:Lamivudine treatment in patients with HBV-related hepatocellular carcinoma--using an untreated, matched control cohort. 1628 55

The Hepatitis B virus (HBV) is a DNA virus that can cause both acute and chronic liver disease in humans. Approximately 350-400 million people are affected worldwide and up to one million deaths occur annually from cirrhosis and hepatocellular carcinoma. When cirrhosis and liver failure develop, the definitive treatment of choice remains orthotopic liver transplantation (OLT). In the past, an unacceptable HBV recurrence rate with a high rate of graft loss was noted. The use of Hepatitis B immunoglobulin (HBIG) has resulted in improved patient and graft survival rates. The addition of the nucleoside analog Lamivudine (LAM) to HBIG has improved these survival curves to an even greater degree. Prolonged use of LAM will almost invariably lead to the development of viral mutations resistant to the drug. There are now several other nucleoside and nucleotide analogs (Adefovir, Entecavir, Tenofovir, and Truvada) available for the clinician to utilize against these resistant strains. It should be possible to prevent recurrence in most, if not all, post-transplant patients and also to significantly reduce viral loads with normalization of transaminases in those who have developed recurrent infection. The antiviral regimen should be robust and minimize the risk of breakthrough mutations. A prudent approach may be the implication of combination antiviral therapy. This review summarizes the efficacy of previous regimens utilized to prevent and treat recurrent HBV following OLT. Particular attention will be paid to the newer nucleoside and nucleotide analogs and the direction for future strategies to treat HBV in the post transplant setting.
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PMID:Prevention and treatment of recurrent Hepatitis B after liver transplantation: the current role of nucleoside and nucleotide analogues. 1660 49

In patients with compensated hepatitis B virus (HBV) cirrhosis, active viral replication correlates significantly with the risk of hepatic flare, decompensation, and the development of hepatocellular carcinoma (HCC). The 5-year survival of patients with compensated cirrhosis was reported to be 80 to 85%, and is significantly lower in patients with replicative HBV. Both interferon and maintenance lamivudine therapy have been shown to reduce the risk of decompensation or HCC and prolong survival in responders. A finite course of interferon is recommended as the first-line agent. For patients who had a contraindication for or who have failed interferon therapy, direct antiviral(s) can be considered for long-term treatment. Once decompensation occurs, mortality increases remarkably. Early treatment with nucleoside analogues should be instituted. Lamivudine therapy is associated with rapid viral suppression, improvement in Child-Pugh scores, and improved survival, but drug resistance is a major problem and is associated directly with a poor clinical outcome. Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance.
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PMID:Hepatitis B virus-related cirrhosis: natural history and treatment. 1667 92

Chronic hepatitis B is a common disease and approximately 20% of infected patients with compensated cirrhosis will decompensate over 5 years. If untreated, the survival of decompensated cirrhosis is poor (15% at 5 years). The extent of hepatitis B virus (HBV) replication, as assessed by serum HBV-DNA level, is a strong predictor of the risk of disease progression and hepatocellular carcinoma. This provides a rationale for antiviral therapy to arrest progression of liver disease. Lamivudine is a pyrimidine analogue that inhibits HBV-DNA reverse transcriptase. It decreases HBV replication, normalises alanine aminotransferase levels and reduces hepatic inflammation and fibrosis in patients with chronic hepatitis B. This article will focus on the use of lamivudine in patients with HBV-cirrhosis. In patients with compensated HBV-cirrhosis, a randomised, placebo-controlled trial has shown that lamivudine significantly reduced the rate of disease progression and hepatocellular carcinoma development over a 3-year period. In patients with decompensated cirrhosis, treatment with lamivudine can produce spectacular improvements of liver function, but the improvement is slow and a clinical benefit is usually not observed until after at least 3-6 months of treatment. A major drawback of lamivudine treatment is the development of resistance, observed in 15-20% of patients after 1 year and up to 70% after 5 years of continued treatment. Thus, patients with HBV-cirrhosis treated with lamivudine should have regular monitoring of serum HBV-DNA levels and prompt institution of additional antiviral therapy if viral breakthrough is observed. Adefovir, tenofovir and entecavir have demonstrated efficacy in patients with lamivudine resistance. In patients with decompensated cirrhosis, in whom the development of resistance can be fatal, combination therapy (such as lamivudine plus adefovir) may prove more effective than monotherapy and this issue needs further study.
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PMID:Lamivudine treatment in patients with chronic hepatitis B and cirrhosis. 1692 9

Hepatitis B virus (HBV) is one of the major causes of liver disease worldwide, and chronic HBV infection may progress to cirrhosis and hepatocellular carcinoma. Mutations at the active site of DNA polymerase of HBV, tyrosine-methionine-aspartate-aspartate (YMDD) motif, render infected patients resistant to antiviral drug (Lamivudine) therapy. Hence, sensitive and specific methods aimed at detecting the mutants are essential. The purpose of this study was to develop methods for detecting the mutations at YMDD by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR using locked nucleic acid (LNA)-mediated TaqMan probes. The results obtained by these methods were compared with those examined by conventional direct sequencing on serum samples of 77 patients treated with lamivudine. Our results show that both PCR-RFLP and real-time PCR could detect wild type, YMDD, and its mutants, tyrosine-isoleucine-aspartate-aspartate and tyrosine-valine-aspartate-aspartate. In addition, the mixtures of the wild-type virus and its mutants in the serum sample were detected. Importantly, real-time PCR is less time-consuming, and more sensitive for the detection of mixed populations than PCR-RFLP. The real-time PCR with LNA-mediated TaqMan probes is a sensitive, specific and rapid detection method for mutations at the YMDD motif, which will be essential for monitoring patients undergoing lamivudine antiviral therapy.
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PMID:Rapid detection of lamivudine-resistant hepatitis B virus mutations by PCR-based methods. 1696 Mar 47


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