Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fialuridine (FIAU) is a thymidine nucleoside analog with activity against various herpesviruses and hepatitis B virus (HBV) in vitro and in vivo. In a clinical evaluation for its use as a treatment for chronic HBV infection, long term (HBV) in vitro and in vivo. In a clinical evaluation for its term oral administration of FIAU resulted in severe multi-organ toxicity characterized by a delayed onset and refractory lactic acidosis. These clinical manifestations led to the hypothesis that the toxicity of FIAU was mediated through mitochondrial dysfunction, possibly as a result of the inhibition of mitochondrial DNA polymerase gamma and/or incorporation of FIAU into mitochondrial DNA. In addition to describing the anti-HBV activity of FIAU, this review discusses results from in vitro experiments carried out by various laboratories in an effort to evaluate and understand more fully the mitochondrial toxicity of FIAU.
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PMID:Mechanisms for the anti-hepatitis B virus activity and mitochondrial toxicity of fialuridine (FIAU). 873 93

Fialuridine (FIAU) is a thymidine analog effective against hepatitis B virus. Toxicity associated with FIAU treatment included clinical signs consistent with mitochondrial dysfunction, including severe lactic acidosis. To understand further the mechanism of FIAU toxicity, we examined the effect of FIAU on DNA synthesis in mitochondria. Mitochondria isolated from livers of naive rats were treated in vitro with concentrations of FIAU or FIAU triphosphate (FIAU-TP) ranging from 0.1 to 200 microM. A 14 or 32% decrease in mitochondrial DNA synthesis compared to controls was observed when isolated mitochondria were treated with 25 microM FIAU or FIAU-TP, respectively. Since it is thought that nucleosides must be phosphorylated to inhibit DNA polymerase, studies were conducted to determine whether isolated rat mitochondria could phosphorylate FIAU. Results using lanthanum chloride precipitation and HPLC analysis showed that enzymes present in a mitochondrial lysate were capable of phosphorylating FIAU to form FIAU monophosphate.
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PMID:Fialuridine is phosphorylated and inhibits DNA synthesis in isolated rat hepatic mitochondria. 910 87

Fialuridine is an antiviral agent with potent activity against hepatitis B virus replication in vitro and in vivo. In a phase II study, 7 of 15 patients experienced severe toxicity due to the drug after 9 to 13 weeks of treatment. Adverse effects included nausea, vomiting and painful paraesthesia; subsequently, hepatic failure, pancreatitis, neuropathy, myopathy and lactic acidosis developed, probably due to multisystem mitochondrial toxicity. Possible mechanisms of fialuridine toxicity include mitochondrial injury and pyruvate oxidation inhibition. While other nucleoside analogues have shown evidence of inducing mitochondrial injury (zidovudine, didanosine, zalcitabine), others to date have not (lamivudine, famciclovir). Specific recommendations for future study of existing and new nucleoside analogues include testing for toxicity after prolonged incubation, specific investigations to measure mitochondrial function, toxicological tests and well designed clinical trials with appropriate testing to monitor for any adverse effects on mitochondrial integrity and function.
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PMID:Mitochondrial injury. Lessons from the fialuridine trial. 925 27

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.
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PMID:Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? 1114 57

Steatosis or fatty liver in individuals with human immunodeficiency virus (HIV) may result from HIV itself, the use of nucleoside analogues, concurrent infection with hepatitis B or C, alcohol use, diabetes mellitus, obesity, or combinations of these factors. Nucleoside analogues have been the focus of increasing concern, because several fatal cases of severe macrosteatosis, lactic acidosis, and hepatomegaly have been linked to the use of nucleoside analogues. Other classes of antiretroviral drugs, as well as opportunistic infections, can also cause hepatic injury without steatosis. The additive effect of these different risk factors, especially in the presence of underlying hepatic steatosis, likely contributes to the increased prevalence of hepatic abnormalities among HIV-infected individuals. The conditions under which some patients rapidly progress to hepatic failure and/or cirrhosis need to be defined. This is a US government work. There are no restrictions on its use.
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PMID:The fatty liver in AIDS. 1194 34

In the pre-HAART era, sustained response to single therapy with interferon in patients infected with HCV and HIV without sever immunodeficiency was low (10-23%). The figures were similar to those in HIV-negative people. Results of combination therapy with pegylated interferon (PEG-IFN) and ribavirin in the group of patients infected with HIV and HCV are similar to those observed in the HIV-negative group. The response is > 50%, and the patients who are most benefited are the carriers of genotype 1. Nevertheless, lactic acidosis is reported as a severe side effect, especially in the group who received HAART with nucleosides inhibitors of reverse transcriptase. Several HAART programs include lamivudin for patients infected with HIV and HCV. Molecular hybridation techniques and chain reaction polymerase assays eliminate the hepatitis B virus DNA in 50% of the cases studied. Serological conversion for AgeHB was observed in 35% and AgsHB was eliminated only in 5%. Average period of serological conversion for AgsHB was 8 months; these patients presented high CD4 cell counts and low HIV load. So far, this is the therapy with better results; however, more combinations of lamivudin with tenofovir and adefovir are being studied for patients with resistant viral mutations.
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PMID:[Treatment of chronic hepatitis C in patients coinfected with HIV-HCV/HBV]. 1271 59

Hepatotoxicity is a relevant adverse effect derived from the use of antiretrovirals that may increase the morbidity and mortality among treated HIV-infected patients and challenges the treatment of HIV infection. Although several antiretrovirals have been reported to cause fatal acute hepatitis, they most often cause an asymptomatic elevation of transaminase levels. In addition to ruling out a variety of processes not related to the use of antiretrovirals or to the HIV infection, for appropriate management of the complication it is necessary to deduce the possible pathogenic mechanisms of the hepatotoxicity. Among these mechanisms, direct drug toxicity, immune reconstitution in the presence of hepatitis C virus (HCV) and/or hepatitis B virus (HBV) co-infections, hypersensitivity reactions with liver involvement and mitochondrial toxicity play a major role, although several other pathogenic pathways may be involved. Liver toxicity is more frequent among subjects with chronic HCV and/or HCB co-infections and alcohol users. Complex immune changes that alter the response against hepatitis virus antigens might be involved in the elevation of transaminase levels after suppression of the HIV replication by highly active antiretroviral therapy (HAART) in patients co-infected with HCV/HBV. The contribution of each particular drug to the development of hepatotoxicity in a HAART regimen is difficult to determine. The incidence of liver toxicity is not well known for most of the antiretrovirals. Although it is most often mild, fatal cases of acute hepatitis linked to the use of HAART have been reported across all families of antiretrovirals. Acute hepatitis is related to hypersensitivity reactions in the case of non-nucleosides and to mitochondrial toxicity in the case of nucleoside analogues. Alcohol intake and use of other drugs are other co-factors that increase the incidence of transaminase level elevation among HIV-infected patients. The management of liver toxicity is based mainly on its clinical impact, severity and pathogenic mechanism. Although low-grade HAART-related hepatotoxicity most often spontaneously resolves, severe grades may require discontinuation of the antiretrovirals, for example when there is liver decompensation, hypersensitivity reaction or lactic acidosis.
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PMID:Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. 1564 5

Adefovir is classified as a nucleotide reverse transcriptase inhibitor because it acts by inhibiting hepatitis B virus DNA polymerase (reverse transcriptase) and causing DNA chain termination after its incorporation into the viral DNA. Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine [ALT] or aspartate [AST]) or histologically active disease. It is useful in the treatment of patients with either hepatitis B e antigen-positive or -negative chronic hepatitis B. The recommended adefovir dipivoxil dose in the treatment of chronic hepatitis B in patients with adequate renal function is 10 mg once daily. Adefovir dipivoxil therapy can reduce viral load, improve ALT, and produce histologic improvement in patients with chronic hepatitis B. Improvements are generally seen within the first few weeks of therapy and have shown persistence up to at least 3 years with continued therapy. Therapy with adefovir dipivoxil is generally well tolerated. However, nephrotoxicity is a risk with adefovir therapy, especially in patients receiving higher doses (30-120 mg/d). Patients should have their renal function monitored closely throughout therapy and may require an adjustment in dose relative to changes in the creatinine clearance. Lactic acidosis and severe hepatomegaly with steatosis may also occur during therapy.
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PMID:Adefovir dipivoxil: focus on its use in the treatment of chronic hepatitis B. 1597 40

Lactic acidosis, a rare but life-threatening condition is fairly common in HIV-infected individuals. The cause of lactic acidosis appears to stem from the use of HAART, causing mitochondrial dysfunction and the depletion of flavoprotein cofactors necessary for electron transport. Deficiencies of riboflavin or thiamin can contribute to the development of hyperlactic acidemia. Further, the high incidence of liver disease (hepatitis B or C and alcoholic liver disease) in this population predisposes HIV patients to metabolic abnormalities. Supplementation with thiamin or riboflavin, depending on the individual patient's condition, can reduce elevated lactic acid levels.
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PMID:Treatment of HAART-induced lactic acidosis with B vitamin supplements. 1621 28

Cirrhosis is a serious complication of viral hepatitis, and its incidence is increasing in HIV patients coinfected with HCV or HBV as they live longer, thanks to effective antiretroviral treatment (Haart). HIV coinfection accelerates the progression of fibrosis in hepatitis. To implement preventive measures, prompt diagnosis of cirrhosis is important, either by liver biopsy or the noninvasive tests for fibrosis now under wide study (FibroTest, FibroScan, etc.). Afterwards, assessment of the severity of cirrhosis and screening for complications are both necessary: testing for liver failure (Child-Pugh and MELD scores), portal hypertension (upper gastrointestinal endoscopy), and hepatocellular carcinoma (ultrasound and alpha fetoprotein assay). Careful consideration of drug prescriptions and possible interactions is essential. Specific treatment for hepatitis B or C virus is possible at this stage of cirrhosis, although more difficult, especially for HCV (results influenced by genotype, additional risk of complications by lactic acidosis or hepatic decompensation). Management of the complications of portal hypertension must be planned, as for those without HIV infection. Treatment of hepatocellular carcinoma is still disappointing, and liver transplantation, although possible in these patients, must be evaluated.
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PMID:[Management of cirrhosis complications in HIV patients coinfected with hepatitis B or C virus]. 1631 17


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