Adenine ; analogs & derivatives ; pharmacology ; Drug Resistance, Viral ; Hepatitis B virus ; drug effects ; Humans ; Organophosphonates ; pharmacology

Objective To establish a convenient,accurate and practical method for detection of adefovir dipivoxil resistance-as- sociated mutation in hepatitis B virus:rtA181V/T/S and rtN236T mutations.Methods According to HBV complete sequences in GenBank,two pairs of primers were designed to amplify the region of HBV reverse transcriptase in order to introduce a BglI restriction site upon PCR product of wild type (wt) and a BseDI restriction site upon PCR product of rt236 mutant type.After amplification,the PCR products were digested with BglI and BseDI separately.We used this method to detect wild,rt181 mu- tant,rt236 mutant plasmids and 3 chronic hepatitis B patients' serum with obvious ADV resistance-associated mutations.We also tested the sensitivity of this method by mixing the wild and mutant plasmids in different proportions.Results The method could detect rt181 and rt236 mutations simultaneously.The result of RFLP analysis was in accordance with that of DNA se- quencing and cloning analysis.This method could detect the mutants even when they comprised only 10% of the total virus population.Conclusions The PCR-RFLP method with high sensitivity can detect rt181 and rt236 mutations simultaneously.It can be used for early detection of ADV resistance-associated mutation in hepatitis B virus.

OBJECTIVETo study the resistant rate of hepatitis B virus (HBV) to ADV and the dynamic evolution of HBV in lamivudine (Lam)-resistant chronic hepatitis B (CHB) patients.

METHODSTwenty-three Lam-resistant CHB patients were assigned to a 10mg/d ADV monotherapy for 68-116 weeks. The baseline and different time point blood samples after ADV monotherapy were analyzed for ADV-resistant mutations using direct sequencing of PCR products; the evolution of HBV mutations was examined by clonal analysis of serial samples from one patient infected with ADV-associated resistant HBV strains.

RESULTSThe cumulative incidence of genotypic ADV resistance at weeks 48 and 96 was 4.3% and 10.5% respectively respectively. The evolution analysis of HBV mutant strains in an ADV-resistant CHB patient showed that the proportion of YMDD mutants gradually decreased with rtA181S mutants increasing over time after ADV monotherapy, and that rtA181S+N236T mutants became the predominant strains during prolonged ADV monotherapy. The addition of Lam to the ongoing ADV treatment had poorer antiviral response in the patient with rtA181S or rtA181S+N236T mutant infection; one clone with multi-drug resistant mutations was selected during Lam and ADV combination therapy.

CONCLUSIONIncreased risk of adefovir resistance and selection of multi-drug resistant mutations are associated with long-term ADV monotherapy in patients with Lam-resistant chronic hepatitis B.

Adenine ; analogs & derivatives ; therapeutic use ; Adult ; Antiviral Agents ; therapeutic use ; Drug Resistance, Viral ; Evolution, Molecular ; Female ; Hepatitis B virus ; classification ; drug effects ; genetics ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Lamivudine ; pharmacology ; Male ; Middle Aged ; Organophosphonates ; therapeutic use

Adolescent ; Anemia, Hemolytic ; etiology ; Female ; Hemolysis ; Hepatic Encephalopathy ; etiology ; Hepatolenticular Degeneration ; complications ; Humans

OBJECTIVETo investigate the efficacy and safety of adefovir dipivoxil (ADV, DAIDING) for Chinese chronic hepatitis B patients with lamivudine (LAM) resistance.

METHODSThis study was a multicenter, double-blind clinical trial. 209 chronic hepatitis B patients with LAM resistance were randomly put in an ADV, DAIDING or a LAM group. After 24 and 48-weeks of treatment, serum HBV DNA levels were measured by quantitative PCR and liver function tests; HBV serology and safety assessments were also conducted.

RESULTSThe mean reduction of HBV DNA from baseline at 24 and 48 weeks was significantly greater in the ADV group compared with that in the LAM group (2.40 log10 vs 0.94 log10, P < 0.01; 2.71 log10 vs 1.07 log10, P < 0.01). In the ADV group, the virological response and ALT normalization at 24 and 48 weeks were significantly higher than those in the LAM group. There was no significant difference between the two groups in the portion of HBeAg reduction, HBeAg seroconversion and incidence of adverse events. There was no severe adverse event related to the investigational product, DAIDING, in this trial.

CONCLUSIONDAIDING (ADV) is effective and safe for the treatment of chronic hepatitis B patients with LAM resistance.

Adenine ; analogs & derivatives ; therapeutic use ; Adolescent ; Adult ; Aged ; Antiviral Agents ; therapeutic use ; Double-Blind Method ; Drug Resistance, Viral ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Lamivudine ; pharmacology ; Male ; Middle Aged ; Organophosphonates ; therapeutic use ; Young Adult

OBJECTIVESTo investigate the possibilities of an association between the degrees of HBV suppression with nucleoside treatments at week 24 and week 52 in hepatitis B patients and to find a useful predictor for treatment efficacy.

METHODSIn this phase III, double-blind, multicenter trial, we compared the efficacy of telbivudine treatment with lamivudine treatment in 332 Chinese compensated chronic hepatitis B patients. The patients were randomly assigned to a daily 600 mg telbivudine treatment group or daily 100 mg lamivudine group for 24 weeks. They were then categorized into 4 groups according to their serum HBV DNA levels (copies/ml) at week 24: a PCR-undetectable group (< 300 copies/ml); a QL- < 10(3) copies/ml group; a 10(3)-<10(4) copies/ml group; and a > or = 10(4) copies/ml group. The treatments were continued as they previously had been for another 28 weeks and the patients serum HBV DNA levels were examined again.

RESULTSAt week 52, mean reductions of serum HBV DNA were significantly greater in the telbivudine-treated patients than in the lamivudine-treated group (6.2 log10 vs 5.4 log10, t = 3.6, P < 0.01). Viral resistance was twice as common in lamivudine-treated patients compared to those receiving telbivudine. Telbivudine was well-tolerated with an adverse event profile similar to that of lamivudine. The lower the HBV DNA level achieved at week 24, the higher HBV DNA non-detectable by PCR. ALT normalization and HBeAg seroconversion achieved at week 52, and viral resistance at week 48 decreased parallel to the degree of HBV DNA inhibition.

CONCLUSIONHBV DNA PCR-undetectable at week 24 in nucleoside-treated hepatitis B patients suggests a better efficacy at week 52 and lower viral resistance at week 48. The degree of suppression of HBV at week 24 may be used as a predictor of 1-year outcome.

Adolescent ; Adult ; Aged ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; Double-Blind Method ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Lamivudine ; therapeutic use ; Male ; Middle Aged ; Nucleosides ; therapeutic use ; Pyrimidinones ; therapeutic use ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Young Adult