Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

During more than 104 weeks of treatment with lamivudine (3TC) in chronic woodchuck hepatitis virus (WHV) carrier woodchucks, viral recrudescence occurred. Analysis of WHV DNA polymerase from woodchuck serum samples by PCR followed by DNA sequencing demonstrated that all samples were wild type at the conserved YMDD motif in domain C. Four of the six 3TC-treated woodchucks showed a mixture of the wild-type Ala (GCT) and the mutant Thr (ACT) at the conserved amino acid residue 566 (FLLA) in domain B of the WHV polymerase region. The appearance of the A566T mutation was temporally associated with viral recrudescence. This change is analogous with the amino acid 181 (FLLA) in HBV where 3TC selects for a change from Ala to Thr in humans. In the woodchuck, the Ala to Thr change in the polymerase gene results in a mutation of the WHV surface protein (amino acid 377) from Trp (TGG) to an opal codon (TGA), which may prematurely terminates the polypeptide. Three WHV molecular infectious clones were constructed to study this mutation in greater detail in vitro: A566T, analogous to A181T in HBV; M589V, analogous to the M204V in HBV; and the double mutant A566T/M589V, analogous to A181T/M204V in HBV. These mutants exhibited drug-sensitivity and replication profiles that paralleled those reported for analogous HBV variants. In transfected Huh7 cells, WHV containing the M589V mutation conferred at least 100-fold increased resistance to 3TC, but replicated approximately 5-fold less efficiently than wild-type virus as judged by both extracellular virus production and intracellular DNA replicative forms. In contrast, A566T mutant was approximately 10-fold more resistant to 3TC, replicated intracellularly as well as wild type, but produced 10-fold lower levels of virions than wild type. These findings are consistent with the observation that the A566T mutation alters the overlapping WHV surface antigen reading frame. WHV carrying mutations in the conserved YMDD motif, while not directly selected during lamivudine therapy in WHV carrier woodchucks, are replication competent in cell culture indicating the potential for their emergence in treated animals. These results further illustrate the utility of the WHV/woodchuck model to studies of HBV-drug resistance.
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PMID:Mutations in the conserved woodchuck hepatitis virus polymerase FLLA and YMDD regions conferring resistance to lamivudine. 1207 58

Two male patients, aged 54 years and 17 years respectively, were treated with chemotherapy for non-Hodgkin lymphoma. Both patients were chronic hepatitis-B-virus (HBV) carriers prior to the chemotherapy. One patients died as a result of the virus exacerbating during chemotherapy; the other patient received the antiviral drug lamivudine prior to the chemotherapy and finished the cures without any problems. Exacerbations of HBV replication followed by an increase in serum transaminase activity levels ('flares') occur naturally during the course of the viral infection. However, there is an elevated risk when a patient receives high doses of corticosteroids for a short period, as is the case in chemotherapy for non-Hodgkin's lymphoma. Lamivudine is registered for the treatment of chronic hepatitis B and can be used as a prophylactic prior to chemotherapy or to treat an exacerbation of the hepatitis. It is advisable to systematically test all patients with lymphoma for the presence of the HBsAg. If this is positive, prophylactic administration of lamivudine 100 mg once daily is strongly recommended if chemotherapy is indicated.
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PMID:[Lamivudine for the prevention of chronic hepatitis B exacerbations during chemotherapy for non-Hodgkin's lymphoma]. 1209 7

Reactivation of hepatitis B virus (HBV) replication in hepatitis B surface antigen (HBsAg)-positive patients is associated with immunosuppressive therapy. However, the interactions between endogenous glucocorticoid in Cushing's syndrome and HBV-related hepatitis remain unclear. Here, we describe the management of a 32-year-old male HBV carrier with Cushing's syndrome caused by an adrenal cortical adenoma, who developed severe hepatitis B. Repeated episodes of septicemia resulting from hypercortisolemia-related immunosuppression further compromised his hepatic condition. Adrenalectomy could not be performed due to coagulopathy. Lamivudine was not available at that time in Taiwan, and this patient died of hepatic failure and sepsis. At autopsy, his liver showed submassive necrosis with small regenerative nodules. The hepatocytes were positive for HBsAg (membrane and cytoplasmic) and hepatitis B core antigen (nuclear and cytoplasmic). Screening for HBsAg is of crucial significance for immunocompromised individuals. Once positive HBsAg is detected in immunosuppressed patients, liver function and viral status should be closely monitored to enable earlier diagnosis and prompt treatment with the newer nucleoside analogues that actively fight HBV.
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PMID:Submassive liver necrosis in a hepatitis B carrier with Cushing's syndrome. 1209 9

This study aimed to investigate the factors associated with viral breakthrough among liver transplant recipients who receive lamivudine monoprophylaxis. Consecutive patients receiving liver transplantation for HBV-related liver disease from June 1999 to October 2000 were studied. All patients received lamivudine 100 mg daily pre- and post-transplant. Serum samples were collected before lamivudine treatment, before liver transplantation, and then every 3-6 months after liver transplantation. Lamivudine-resistant mutations at the YMDD motif of HBV P gene were detected by direct sequencing and HBV DNA was quantified by real-time polymerase chain reaction (PCR). Ten patients, 7 males and 3 females, aged 50.5 +/- 7.9 years, were studied. Three patients had fulminant hepatitis and 7 patients had end-stage cirrhosis before liver transplantation. Lamivudine was started at 4.5 (range 0-40) weeks before liver transplantation. The median post-transplant follow-up was 16 (range 12-23) months. Four patients developed YMDD mutations 10.5 (0-16) months after transplantation with relapse of viraemia (median 1,294, range 51-3,135 MEq/ml). All patients who developed YMDD mutants had end-stage liver cirrhosis, and HBV DNA were detectable on the day of liver transplantation (median 0.62, range 0.086-1.63 MEq/ml). On the contrary, all 3 patients transplanted for fulminant hepatitis did not have YMDD mutation. Among the 3 end-stage cirrhotic patients who had negative HBV DNA before liver transplantation, none developed YMDD mutation. In conclusion, patients transplanted for fulminant hepatitis B and cirrhotic patients in whom HBV DNA could be rendered PCR negative before liver transplantation are unlikely to develop YMDD mutation on lamivudine monoprophylaxis.
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PMID:Factors associated with viral breakthrough in lamivudine monoprophylaxis of hepatitis B virus recurrence after liver transplantation. 1221 Apr 6

Hepatitis C virus (HCV) infection is present in 2-50% of renal transplant recipients and patients receiving hemodialysis. Renal transplantation confers an overall survival benefit in HCV positive (HCV+) hemodialysis patients, with similar 5-year patient and graft survival to those without HCV infection. However, longer-term studies have reported increased liver-related mortality in HCV-infected recipients. Unfortunately, attempts to eradicate HCV infection before transplant have been disappointing. Interferon is poorly tolerated in-patients with end-stage renal disease and ribavirin is contraindicated because reduced renal clearance results in severe hemolysis. Antiviral therapy following renal transplantation is also poorly tolerated, because of interferon-induced rejection and graft loss. Although the prevalence of hepatitis B virus (HBV) infection has declined in hemodialysis patients and renal transplant recipients since the introduction of routine vaccination and other infection control measures, it remains high within countries with endemic HBV infection (especially Asia-Pacific and Africa). Renal transplantation is associated with reduced survival in HBsAg+ hemodialysis patients. Unlike interferon, lamivudine is a safe and effective antiviral HBV treatment both before and after renal transplantation. Lamivudine therapy commenced at transplantation should prevent early posttransplant reactivation and subsequent progression to cirrhosis and late liver failure. This preemptive therapy should also eradicate early liver failure from fibrosing cholestatic hepatitis. Because cessation of treatment may lead to severe lamivudine-withdrawal hepatitis, most patients require long-term therapy. The development of lamivudine-resistance will be accelerated by immunosuppression and may result in severe hepatitis flares with decompensation. Regular monitoring with liver function tests and HBV DNA measurements should enable early detection and rescue with adefovir. Chronic HCV and HBV infections are important causes of morbidity and mortality in renal transplant recipients. The best predictor for liver mortality is advanced liver disease at the time of transplant, and liver biopsy should be considered in all potential HBsAg+ or HCV+ renal transplant candidates without clinical or radiologic evidence of cirrhosis. Established cirrhosis with active viral infection should be considered a relative contraindication to isolated renal transplantation.
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PMID:Management of chronic viral hepatitis before and after renal transplantation. 1235 99

1. Patients undergoing orthotopic liver transplantation (OLT) for hepatitis B without effective prophylaxis have a high risk for recurrent infection and severe graft damage, leading to death or re-OLT. 2. Long-term prophylaxis with hepatitis B immune globulin (HBIg) significantly reduces the risk for hepatitis B virus (HBV) recurrence and increases survival. Patients with detectable HBV DNA at the time of OLT have a high risk for recurrence despite HBIg prophylaxis. 3. Lamivudine (LAM) therapy for patients with decompensated HBV cirrhosis before OLT results in inhibition of viral replication and clinical improvement. Its efficacy is limited by the frequent emergence of LAM-resistant YMDD mutations. The ideal length of therapy with LAM pre-OLT has not yet been defined. 4. Prophylaxis of HBV recurrence with LAM monotherapy is not recommended because of the reappearance of hepatitis B surface antigen after OLT in approximately 50% of patients. 5. LAM is the best available treatment for patients with established recurrent hepatitis B. Long-term therapy is associated with the emergence of drug-resistant mutants in up to 60% of patients. Severe hepatitis and liver failure have been described among liver transplant recipients with YMDD mutations. 6. Combination therapy with HBIg and LAM prevents HBV recurrence in 90% to 100% of patients who undergo OLT for hepatitis B. The optimal HBIg protocol in the LAM era is yet to be defined. 7. Preliminary studies suggest that adefovir dipivoxil inhibits HBV replication in patients infected with LAM-resistant HBV strains. 8. Fifteen years ago, hepatitis B was regarded as a relative or absolute contraindication for OLT. Today, hepatitis B is a universally accepted indication for OLT.
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PMID:Hepatitis B: progress in the last 15 years. 1236 1

Lamivudine (3TC) is a nucleoside analogue which inhibits replication of HIV and HBV and which is used in the treatment of chronic hepatitis B-infected patients with safety and efficacy. The activity of lamivudine was evaluated by the measurement of DNA-HBV concentration in plasma using a very sensitive assay (1,000 copies/mL) (Amplicor VHB Monitor. Roche). Ten patients chronically infected with hepatitis B (group A) and 24 patients with HIV-1 co-infection (group B) were enrolled. In 9 patients of group A, HBVDNA load was undetectable a median of 3.5 months after the beginning of treatment and remained negative for 2 years with hepatitis Be antigen disappearing and normal alanine aminotransferase concentration. In the last immunodeficient patient, the virus which had been resistant to three interferon treatments, was also resistant to lamivudine. In five patients of group B, HBV DNA load remained undetectable after 18 months with HBe antigen disappearing and baseline concentration of alanine aminotransferase. In the remaining 19 patients after a transient decrease of HBV DNA concentration for one year, HBV DNA load increased again without disappearing of HBe antigen and without decrease of alanine aminotransferase concentration showing lamivudine resistant hepatitis B virus. Mutations in the YMDD motif of the DNA polymerase gene were identified in 11 patients (3 with M550V/I mutation; 7 with M550V/I and L256M mutations; 1 with M550V/I, L526M and V519L mutations). In 6 of these patients, was found a M184V mutation in the VIH polymerase. No correlation could be observed between the mutations detected in the two viruses. Using a sensitive HBV-DNA assay, efficacy of lamivudine for a long time in HBV infected patients was proved. However, the prevalence of lamivudine resistance is related to duration of treatment and it may be necessary to use a multitherapy.
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PMID:[Evaluation of a quantitative HBV-DNA PCR assay in lamivudine treated hepatitis B-infected patients]. 1236 44

Better understanding of hepatitis B virus (HBV) replication, natural history and the immunopathogenesis of chronic hepatitis B, together with the introduction of effective agents with different mechanisms of action are the basis for better therapeutic strategies against chronic hepatitis B. Among currently available drugs, interferon-alpha and thymosin-alpha1 have only modest efficacy (approximately 40% vs 9-20% in controls). In the past decade, lamivudine has dominated in the treatment of chronic HBV infection because it is easy to use, safe, and is effective in terms of hepatitis B e antigen and/or HBV-DNA loss, ALT normalization, and improvement in histology. The response rate increases with increasing pretherapy alanine aminotransferase (ALT) levels, suggesting that patients with stronger endogenous immune response against HBV have a better response to direct antiviral agents. Lamivudine is also beneficial in decompensated cirrhotics with HBV replication. Hepatitic flares may occur after stopping lamivudine therapy in nonresponders and also in responders. Therefore, prolonged therapy is usually required. However, tyrosine-methionine-aspartate-aspartate (YMDD) mutations conferring resistance to lamivudine start to emerge after 6-9 months of therapy, and hepatitis flare, even decompensation, may develop after viral breakthrough. Thus the benefits of long-term lamivudine therapy must be balanced against the concern about YMDD mutations and the durability of treatment response. Adefovir dipivoxil, entecavir, emtricitabine, clevudine and other nucleoside/ nucleotide analogues have shown encouraging results and some agents appear effective in patients with YMDD mutants. Further development of new drugs and new strategies may help to improve treatment in the new century.
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PMID:Therapy of chronic hepatitis B: current challenges and opportunities. 1243 Dec

Lamivudine, an oral nucleoside analogue, has demonstrated efficacy against the hepatitis B virus (HBV) in both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B. Treatment with lamivudine is safe and well tolerated and induces a virological and biochemical response in most patients within a short time. Significant histological improvement was seen in clinical trials after 52 weeks of lamivudine treatment. However, durable posttreatment remission of chronic hepatitis B has not been shown to occur in a significant number of lamivudine-treated patients. To maintain the response to treatment, therefore, long-term therapy is required. Prolongation of therapy, however, is associated with the emergence of HBV resistance to lamivudine in most patients. This is accompanied by virological rebound and reversal of the initial therapeutic response, and sometimes by exacerbation of hepatitis. The need remains for effective, safe, and tolerable oral agents with durable activity against HBV.
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PMID:Clinical experience with lamivudine. 1244 25


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