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Muito obrigado pelo seu voto! Ferner bestätige ich Ihnen und wiederhole, was ich [ Wie ich bereits eingangs sagte, werden [ Juni, al s o nächsten Dienstag N a ch mittag, zu einer [ Penso que, como o [ Martin Bangemann, das für Gewerbliche Wirtschaft, Informations- und Telekommunikations-Technologien zuständige Mitglied der Kommission, hat die nachstehend genannten [ DE Senhor [ Apresentarei estes detalhes - as bases daquilo que iremos propor a muito [ Ist der Dispositionstermin ein Montag, geht das der Rechnung zugrundeliegende [ Die europäische Lotterie wird den Jackpot-Höchstbetrag von Millionen [ August, [ Wenn Sie unser Recht auf Demokratie gegen den neuen Verfassungsentwurf verteidigen [ Por favor, lembrem-se que [ Ich hoffe, dass es möglich [ Espero que [ Ein Beispiel: Wenn Sie den Antrag [ Por exemplo: Se [ Ich hoffe, dass Herr Miller [ Insofern ist es unmöglich, etwas zu ändern, denn wir haben in den [ In der neuen Mitteilung wird eine spürbare zweistufige Senkung [ Was zum Beispiel die IUU angeht, [ Erstaunlicherweise ist das BSE-Thema noch immer nicht offiziell in die [ Die konstituierende Tagung für die zwölfte vierjährige Mandatsperiode des Europäischen [ Ist dieser Zustand bereits erreicht, [ These findings are supported by a recent histologic analysis, in which both necroinflammatory activity and fibrosis were improved in most patients who harbored YMDD variants after 2 years of lamivudine therapy [ 29 ].

Compared with baseline, liver histologic findings were improved in 5 of 9 patients who harbored YMDD variants after 3 years of lamivudine therapy, but histologic findings had deteriorated compared with the findings of the year 1 biopsy in 6 of these 9 patients.

Thus, after the emergence of YMDD variants, histologic responses to lamivudine may diminish, even though they do not generally disappear.

Although, in our experience, YMDD variants were generally benign, other reports document that, in cohorts of liver allograft recipients, YMDD variants with enhanced replication and more-severe clinical consequences occur [ 28 , 31 ].

Throughout 4 years of lamivudine therapy, the rate of HBeAg seroconversion in patients who harbored YMDD variants remained lower than in patients without variants, probably a reflection of less substantial reduction in HBV replication in the variant group [ 19 ].

The similarity of adverse events in patients with or without YMDD variants, even with extended lamivudine therapy, suggests that YMDD variants have no unique pathogenic effects.

Predominantly asymptomatic ALT elevations during treatment were somewhat more common among patients with YMDD variants; however, these generally coincided with the return of detectable viremia and were often associated with HBeAg seroconversion [ 33 ].

Baseline virus level, disease severity, and body size were associated with the emergence of YMDD variants during the first year of lamivudine therapy.

Baseline virus level, reflecting the rate of HBV replication and, therefore, mutational frequency, is a logical predictor of YMDD variants.

Similarly, recent data suggest that initial virologic response after 3 or 6 months of lamivudine therapy predicts whether YMDD variants will emerge subsequently [ 34 , 35 ].

In the same vein, the association between the level of HBV replication and liver injury may explain the higher frequency of YMDD variants in patients with high baseline necroinflammatory activity.

Increased body size might enhance YMDD variant frequency as a result of reduced drug concentration; however, YMDD incidence was unaffected by lamivudine dose in study B Although some have suggested that YMDD variants are more likely in certain HBV genotypes [ 37 ], others have failed to corroborate this association [ 38 , 39 ].

When this study was conducted, routine clinical assays for YMDD variants were not available. Therefore, we sought to identify an algorithm based on routine laboratory tests to suggest the presence of phenotypically relevant i.

Most patients with YMDD variants retain at least partial clinical response for several years, but approaches to lamivudine resistance will change as new antiviral agents are introduced.

The urgency with which new therapies are needed is greatest in patients with end-stage liver disease and after liver transplantation, in which additional clinical deterioration has a potentially fatal outcome [ 40 , 41 ].

Recently approved adefovir dipivoxil, which has potent activity against YMDD-variant hepatitis B, will simplify management of infection due to such variants in the future [ 42—44 ].

In summary, in compensated chronic hepatitis B, YMDD variants increased with the duration of lamivudine treatment.

Despite the emergence of variants, many patients maintained improvements in markers of HBV infection and liver injury, although there was not necessarily histologic benefit, after several years of YMDD-variant HBV infection.

Google Scholar. Google Preview. Hepatology ; A. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

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Volume Article Contents Abstract. Patients and Methods. Reprints or correspondence: Dr. Lai, University Dept.

Oxford Academic. Jules Dienstag. Eugene Schiff. Nancy W. Mark Atkins. Christine Hunt. Nathaniel Brown. Mary Woessner.

Richard Boehme. Lynn Condreay. Select Format Select format. Permissions Icon Permissions. Open in new tab Download slide. Google Scholar Crossref.

Search ADS. Antiviral resistance: mechanisms, clinical significance, and future implications. A short-term clinical evaluation of L,, a non-nucleoside inhibitor of HIV-1 reverse transcriptase.

Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir. A ganciclovir-resistant clinical isolate of human cytomegalovirus exhibiting cross-resistance to other DNA polymerase inhibitors.

Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine.

Therapy of chronic hepatitis B virus infection: inhibition of the viral polymerase and other antiviral strategies.

Naturally occurring hepatitis B virus genomes bearing the hallmarks of retroviral G to A hypermutation. Variants of hepatitis B, C, and D viruses: molecular biology and clinical significance.

Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation.

Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Functional analysis of mutations conferring lamivudine resistance on hepatitis B virus.

Hepatitis B mutants induced by 3TC and famciclovir are replication defective. Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy.

Lamivudine as initial treatment for chronic hepatitis B in the United States. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial.

A placebo controlled study of lamivudine and interferon alpha-2b in patients with chronic hepatitis B who previously failed interferon therapy [abstract ].

Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after three years of therapy.

Two sensitive PCR-based methods for detection of hepatitis B virus variants associated with reduced susceptibility to lamivudine.

Google Scholar PubMed. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine 3TC.

Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Improvements in liver histology and cirrhosis with extended lamivudine therapy [abstract ].

The effect of longer duration of harbouring lamivudine-resistant hepatitis B virus YMDD mutants on liver histology during 3 years lamivudine in Chinese patients [abstract ].

Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.

Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.

Quantitative hepatitis B virus DNA testing for the early prediction of the maintenance of response during lamivudine therapy in patients with chronic hepatitis B.

Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.

Three years of lamivudine in anti-HBe positive patients decreased virological and biochemical response [abstract ]. Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation.

A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.

Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants.

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