UMLS:C0019204 - FACTA Search

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)

Hepatitis B virus (HBV) is a major world health problem and a common cause of cirrhosis and hepatocellular carcinoma. The natural history of HBV varies with many factors, including age of acquisition. Persistent elevation of alanine aminotransferase (ALT) levels and presence of hepatitis B surface antigen for > 6 months after infection suggest chronic HBV. Presence of hepatitis B e antigen (HBeAg) and HBV DNA in serum indicate active disease. Treatment is indicated for chronic active HBV. The aim of treatment is to suppress viral replication and eliminate the virus. Endpoints of treatment are normalization of ALT levels and elimination of HBeAg and HBV DNA from the blood. Available treatments are interferon alfa and lamivudine. Interferon is effective in 25% to 40% of patients, but has serious side effects. Lamivudine is effective in a similar percentage of patients and has fewer side effects; however, it is associated with the emergence of viral mutations and drug-resistant strains.
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PMID:Treatment of hepatitis B. 1150 Nov 92

(1) Chronic hepatitis B is defined by the persistence of circulating HBs antigen for more than 6 months. Between 15 and 25% of chronic HBV carriers die prematurely of complications (mainly cirrhosis and hepatocellular carcinoma). (2) Patients with chronic hepatitis B rarely clear the virus spontaneously, but viral replication ceases in approximately 10% of patients annually, with disappearance of HBe and viral DNA, and emergence of anti-HBe antibodies. (3) Active viral replication and histologically proven liver necrosis are risk factors for progression to cirrhosis. (4) Antiviral treatments have been assessed only in patients with active viral replication. (5) Interferon alfa has been widely tested in the clinical setting. In one trial, in which patients were followed for 7 years, mortality was lower in the treatment group than in untreated controls. (6) Interferon alfa must be injected, and its administration may be followed by adverse effects such as a 'flu-like syndrome (frequently), psychiatric problems and potentially severe thyroid disorders. (7) Interferon alfa monotherapy for 4-6 months (possibly extended to 8-9 months) remains the first-line treatment for chronic hepatitis B. (8) Lamivudine has documented antiviral efficacy but its effect is only temporary in many patients. In the only trial comparing lamivudine with interferon alfa, lamivudine was no more effective than interferon in the short term (on the basis of serological and histological end points), despite a bias in its favour. Trials of lamivudine + interferon alfa in patients who fail to respond to interferon monotherapy have given unfavourable results. (9) Adverse effects are infrequent on lamivudine, but pharmacovigilance is required to assess potential hepatic and pancreatic effects at the dose used in this indication. (10) The long-term effects of lamivudine are unknown, especially on the risks of cirrhosis, hepatocarcinoma and the selection of resistant mutants. (11) Pending further data, lamivudine should be used only in clinical trials and cohort studies.
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PMID:Treatment of chronic hepatitis B: interferon alfa first. 1150 53

It has been established that several types of cancers have a strong association with viruses. Thus, a potent antiviral compound without toxicity upon long-term usage will be useful not only for the treatment of viral diseases but also for the prevention or the delayed onset of those cancers that have a strong association with viruses. These compounds, depending upon their mechanism of action, could also potentially be useful for the treatment of those viral-associated cancers. L(-)Deoxynucleoside analogues were discovered in my laboratory and by others as an important class of antiviral and anti-cancer chemical entities. L(-)SddC (3TC, lamivudine), L(-)FTC, L(-)Fd4C, and L(-)FMAU are compounds with potent activity against hepatitis B virus (HBV), but with different biological and pharmacological profiles. These compounds may be useful in the prevention or delayed onset of hepatocellular carcinoma associated with HBV. L(-)I-OddU is a potent anti-Epstein-Barr virus (EBV) compound without cytotoxicity and animal toxicity upon long-term dosing, which allows drug concentration in plasma that are much higher than those that are antivirally active. This compound may have the potential to prevent B-cell lymphoma associated with patients undergoing organ transplants in addition to its potential use for the treatment of EBV infection. Furthermore, it may also be useful for the treatment of EBV-associated cancers. In this manuscript, the metabolism, mechanism of action and the resistance, as well as the potential use of this class of compounds targetted against HBV, will be discussed.
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PMID:L-Nucleoside analogues against cancer-causing viruses have potential in the prevention, delayed onset and treatment of viral associated cancers. 1159 88

As documented in the recent literature, there are more than 50 million people infected with HIV worldwide to date since the emergence of HIV and AIDS in the Western world in 1981. More importantly, about 7000 people die of AIDS daily with 2.5 and 2.6 millions total deaths in 1998 and 1999, respectively. On the other hand, human hepatitis B virus (HBV) is the leading cause of chronic hepatitis in the world. According to WHO executive summary, over 350 millions (approximately 5% of the world s population) people are chronically infected with HBV. There are about 1 million chronic HBV carriers in the United States. Although safe and effective vaccination for HBV is available for developing countries, there is still no effective treatment for the millions of chronically infected individuals. Consequently, long term infection with chronic HBV could lead to cirrhosis, and hepatocellular carcinoma. In light of these facts, it is evident that the discovery and development of novel antiviral agents for the treatment of HIV and HBV is an extremely important undertaking.The interest in L-nucleosides was spurred in recent years by the findings that L-nucleosides are generally endowed with lower host toxicity while maintaining good antiviral activity in comparison to their respective D-nucleosides. The recent FDA approval of Lamivudine [L-BCH 189 (3TC)] for the treatment of HIV and HBV further supports these notions. Since the discovery of Lamivudine, a large number of 2 ,3 -dideoxy (dd)- and 2 ,3 -didehydro-2 ,3 -dideoxy (D4)-L-nucleoside analogs have been synthesized and evaluated in hopes of identifying even better antiviral agents. As a result, 2 ,3 -Dideoxy-2 ,3 -didehydro-beta-L-fluorocytidine (beta-L-Fd4C) was found to be a promising new lead. The first synthesis and antiviral activity assessment of L-Fd4C were reported by Lin and Cheng et al. in 1996. Recent disclosures from several laboratories clearly demonstrated that L-Fd4C was the most potent anti-HBV agent reported to date (vs. 3TC, L-FddC, L-FMAU, etc.). In fact, L-Fd4C proved to be at least 10 times more potent than Lamivudine on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15. Compared with L-Fd4C, D-Fd4C showed similar anti-HIV activity yet reduced anti-HBV activity. 2 F-L-Fd4C exhibited excellent acid stability but reduced antiviral activity and cytotoxicity. Although L-Fd4C is converted intracellularly by cytoplasmic deoxycytidine kinase to its mono-, di- and triphosphate metabolites,43 the newly prepared bis(SATE)-L-Fd4CMP proved to be more potent against HBV yet less cytotoxic than L-Fd4C itself. The chemically synthesized L-Fd4CTP was found to be a poor substrate for human polymerase gamma. A recent report from Zhu and Cheng et al. indicated that L-Fd4C had no inhibitory effect on mitochondrial DNA synthesis at concentrations up to 10 microM. An in vivo study involving HBV-infected ducks showed that longer administration of L-Fd4C induced a sustained suppression of viremia (>95%) and of viral DNA synthesis in the liver. The same study also demonstrated that L-Fd4C is more potent than 3TC in vivo. In summary, on the basis of the data presented in this chapter, it is evident that L-Fd4C is endowed with exceptional anti-HBV activity (both in vitro and in vivo) as well as an acceptable toxicity profile, thus rendering it a very promising development candidate.
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PMID:Comparative evaluation of L-Fd4C and related nucleoside analogs as promising antiviral agents. 1196 52

Children with chronic hepatitis B, face life long disease and complications of cirrhosis and hepatocarcinoma. Naturally, it is estimated that half to two third of the children will clear the hepatitis Be antigen during childhood. Treatments aim to increase the HBe Ag to Ab seroconversion rate, which may also favour the loss of HBs antigen, ultimate goal. Interferon alpha was the first approved treatment for pediatric chronic hepatitis B, and was shown to increase the HBe ag loss from 11% in control group to 26% in treated patients (5 MU/square meter body surface area for six months) at one year, and 33% at 18 months. Side effects include mainly fever, flu like symptoms, and growth impairment during the treatment phase. Nucleotide analogues have now emerged as a promising alternative to treat chronic hepatitis B. The optimal dose for children is established to 3 mg/kg once daily up to 12 years old. Efficacy trials show complete virologic response in 23% of all treated patients after one year, as compared to 13% in the placebo group, and in 34% of patients with basal transaminases above two times upper limit of normal; versus 16% in controls. Lamivudine inhibits viral DNA which favours cellular immune response. Lamivudine resistance due to variant viruses is observed in 19% of children after one year. Other nucleotide analogues, such as entecavir and adefovir will soon be tested in children, and combination with Lamivudine may improve results. Finally, vaccine technology is being tested in adults, to induce a cellular immune response towards hepatitis B antigens, but no clinical benefit has so far been established.
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PMID:[Hepatitis B in children: natural history and therapy]. 1199 83

Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. The natural history and clinical outcomes of chronic HBV infection are determined by the viral replication cycle and the host immune responses. Treatment of chronic hepatitis B is directed at interrupting the natural history by suppressing HBV replication before development of any significant irreversible liver cell damage. Effective antiviral therapies should be followed by sustained suppression of HBV-DNA, normalization of transaminases levels and a stable stage of HBeAg seroconversion with persistence of circulating anti-HBeAg antibodies. Two major classes of antiviral therapeutic agents that have been approved for treatment of chronic hepatitis B are immunomodulating agents (i.e. interferon) and the nucleoside analogs (i.e. lamivudine). A 4-6 month course of interferon-alpha has resulted in improvement of survival in 20%-30% of patients with chronic hepatitis B who had elevated serum ALT levels without hepatic decompensation. Interferon-alpha therapy is associated with HBeAg seroconversion; normalization of ALT levels, reduced hepatic inflammation, and possibly reduced disease progression to cirrhosis and hepatocellular carcinoma. Interferon can also be used with caution in patients with early compensated cirrhosis. A 12-month course of lamivudine has been shown to be well tolerated and effective. Lamivudine can be used in decompensated cirrhosis and immunosuppressed patients and for prevention of recurrent HBV infection after liver transplantation. The response rates after 3 years of lamivudine therapy account for 40-65%. A major problem of antiviral treatment is the emergence of drug resistance conferred by mutations in the YMDD motif of HBV reverse transcriptase. The prevalence of YMDD mutations increases with longer durations of antiviral therapies and this has been detected in 20% of immunocompetent patients receiving lamivudine per year. Contentious issues remain when to stop the treatment if HBeAg seroconversion does not occur. Many new immunomodulatory therapies and antiviral agents are in various stages of clinical development and have shown some promise. Among newer HBV antivirals, adefovir dipivoxil, entecavir, emtricitabine, DAPD and clevudine appear to be at least as potent as lamivudine in suppressing HBV replication. In vitro studies have shown that YMDD mutations confer cross-resistance between lamivudine and emtricitabine. However, adefovir, dipivoxil, lobucavir, DAPD and possibly clevudine suppress replications of both YMDD mutants and wild types of HBV. Immunomodulatory approaches for treatment of chronic hepatitis B are conceptually attractive, but newer agents used to date (thymosin-alpha, interleukin-12, therapeutic vaccines) have not demonstrated sufficient efficacy for widespread use. Combinations of an immunomodulatory agent and nucleoside analog may improve the therapeutic efficacy and reduce the emergence of drug resistance. Nevertheless, combinations of interferon and lamivudine therapies do not confer such additional benefits. The next challenge for HBV treatment is to use antivirals in combination and/or in cyclical therapy to minimize the emergence of drug resistance and increase efficacy, particularly to achieve sustainable post-treatment suppression of HBV. Randomized prospective control trials of combined antiviral therapies given simultaneously or sequentially are needed to establish safe and effective combined regimens that can be recommended for future treatment strategies.
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PMID:Management of viral hepatitis B. 1200 May 99

Children with chronic hepatitis B are at risk of developing long-term complications such as cirrhosis and hepatocarcinoma. It is estimated that half to two-thirds of affected children will clear the hepatitis B e antigen (HBeAg) naturally before reaching adulthood. As in adults, treatments in children accelerate the virological response (DNA negativity and HBeAg loss, with anti-HBe seroconversion), which is associated with normalization of transaminase levels. Treatments also favor subsequent loss of hepatitis B surface antigen (HbsAg), the ultimate goal for minimizing long-term consequences. Interferon-alpha was the first approved treatment for pediatric chronic hepatitis B, and was shown to promote DNA negativity and HBeAg loss in 26% of treated patients (6 MU/m(2) body surface area for 6 months) at 1 year and 33% at 18 months (versus 11% in controls). 10% of treated patients also lost HBsAg. Adverse effects mainly included fever, flu-like symptoms and growth impairment during the treatment phase. Nucleotide analogs have now emerged as promising alternatives for the treatment of chronic hepatitis B. Lamivudine dose-ranging studies showed a higher clearance in children, and the optimal dosage was established to be 3 mg/kg once daily in children up to 12 years of age. Efficacy trials showed complete virological response (HBeAg loss and DNA negativity) in 23% of all treated patients after 1 year, and in 34% of patients with initial transaminase levels >2 x the upper limit of normal. Lamivudine resistance due to mutant/variant viruses is observed in 19% of children after 1 year, a figure that may increase by an average of 20% per year. Other nucleotide analogs, such as adefovir, will soon be tested in children, and have shown promising results in adults without so far demonstrating viral resistance. Finally, therapeutic vaccines aiming to induce a cellular immune response towards hepatitis B antigens are being tested in adults, but no clinical benefit has so far been established.
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PMID:Drug treatment of pediatric chronic hepatitis B. 1203 72

The annual rate of progression to cirrhosis in patients with chronic HBV is 0.4 to 14.2% and that of death 4 to 10%. HCC risk increases in parallel with the severity and duration of infection, with an annual incidence less than 0.5% in carriers and 6% in patients with cirrhosis. The main aim of antiviral therapy for chronic "wild-type" HBV infection is to suppress viral replication before cirrhosis and HCC develop. Two drugs are approved: IFN alpha and lamivudine. IFN alpha is costly, has a narrow range of efficacy, safety, and tolerability. Lamivudine is active, cheaper, and better tolerated but has limited efficacy, being associated with increasing resistance and loss of clinical response in the long term. IFN may be the first choice treatment in HBeAg-positive patients with a favourable profile and compensated liver disease. Patients with HBeAg-negative active disease can benefit from 12-24 months IFN treatment if early response is observed. Lamivudine should be started only after considering the uncertainties about duration of therapy and risks of stopping it. In patients with slowly progressive liver disease, treatment is better postponed until effective combination regimens are available. Lamivudine is of paramount importance in end-stage chronic liver disease to suppress HBV replication and allow successful transplantation. The role of interferon in preventing HCC is controversial. In two studies comparing the incidence of HCC in patients with HBeAg-negative chronic hepatitis treated with IFN, HCC developed less frequently in sustained responders than in non-responders in Greece (2 vs. 10%, P = 0.045), but not in Milan (7 vs. 10%, P = ns).
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PMID:Recent progress and new trends in the treatment of hepatitis B. 1211 46

Patients with chronic renal failure on hemodialysis suffer from impaired immune defense mechanisms. A defect in costimulatory signalling from antigen-presenting cells (APCs) for the antigen-specific activation of T cells leads to immune incompetence, particularly toward viral infections. The epidemiologic situation of dialysis patients who are treated in centers together with other immunocompromised patients and who need blood access 3 times weekly places them at a high risk for viral hepatitis B. Clinically, the infection shows a mild and subclinical, often anicteric, course, leading to chronic infection in the majority of cases. Typical consequences such as cirrhosis and hepatocellular carcinoma may occur, however, seem to be less frequent than in hepatitis B-infected persons with normal renal function. Protection by vaccination is also hampered by the immune defect. Nevertheless, a high percentage of vaccinated patients is still desirable for infection control. Treatment of hepatitis B in dialysis patients is difficult because interferon-alfa is less effective and frequently leads to side effects. Lamivudine may become a future alternative, however, current experience is limited.
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PMID:Hepatitis B virus infection in hemodialysis patients. 1211 99

Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100- to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20- to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.
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PMID:Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. 1212 28

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