OBJECTIVETo study the factors influencing the long-term usage of lamivudine (LAM) in chronic hepatitis B (CHB) patients and the management after drug-resistance.

METHODS383 cases of naive CHB patients in our outpatient clinic were treated with lamivudine (100 mg/d) and followed up for at least over 1 year from 2001 to 2010. 129 cases encountered lamivudine-resistance and were then divided into two groups: patients in group A were switched to adefovir dipivoxil (ADV) alternative treatment and those patients in group B were added with ADV for continuous treatment. Efficacy assessment factors included serum HBV markers, HBV DNA, ALT, AFP and other biochemical indicators.

RESULTSAmong the 383 cases, patients with HBV DNA negative conversion (PCR below test line) at 3 months, 6 months, 1 year, 2 years, 3 years and > 3 years after initial treatment were respectively 156 cases (40.7%), 213 cases (55.6%), 228 cases (59.5% ), 217cases (56.7%), 214 cases (55.9%) and 213 cases (55.6%). HBeAg/HBeAb seroconversion occurred in 62 cases (22.6%). 12 cases were found with primary LAM resistance, 129 cases with HBV breakthrough and rebound, the cumulative resistance rate was 36.8% and the cumulative rebound rate was 34.8%. High baseline viral load, baseline ALT levels < 2 ULN, Lower virologic response rate at week 24 were associated with a higher rebound rate (chi2 is 35.716, 8.728, 43.534, respectively, all with P < 0.01).Viral breakthrough and rebound occurred in 112 patients (86.8%) within 1 year and a half, 123 patients (95.3%) occurred at the end of 2 years and no patient with viral breakthrough and rebound after 5 years. For the patients with viral rebound in group A and group B, the rates of HBV DNA loss were 22.7% (15/66) and 58.7% (37/63) respectively, and the viral response rates were 59.1% (39/66) and 87.3% (52/63) respectively, with chi2 values equaled 17.364 and 12.975 respectively (P < 0.01).

CONCLUSIONFor the chronic hepatitis B patients on initial treatment with lamivudine, the viral rebound occurred mainly within 2 years. LAM combined with ADV is more effective than ADV alone for lamivudine-resistant patients.

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

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Drug Resistance, Viral ; Guanine ; analogs & derivatives ; pharmacology ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Lamivudine ; pharmacology ; therapeutic use ; Nucleosides ; pharmacology ; therapeutic use ; Organophosphonates ; pharmacology ; therapeutic use ; Pyrimidinones ; pharmacology ; therapeutic use ; Reverse Transcriptase Inhibitors ; pharmacology ; therapeutic use ; Tenofovir ; Thymidine ; analogs & derivatives ; Treatment Outcome ; Virus Replication

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

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

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Adult ; Drug Resistance, Viral ; Female ; Genes, Viral ; Genotype ; Hepatitis B virus ; drug effects ; genetics ; Hepatitis B, Chronic ; drug therapy ; Humans ; Male ; Middle Aged ; Organophosphonates ; pharmacology ; therapeutic use

Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.
Adenine/analogs & derivatives/pharmacology/therapeutic use ; Antiviral Agents/pharmacology/*therapeutic use ; Drug Resistance, Viral/drug effects ; Drug Therapy, Combination ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy/prevention & control ; Humans ; Mutation ; Nucleosides/*chemistry/pharmacology/therapeutic use ; Organophosphonates/pharmacology/therapeutic use ; Virus Replication/drug effects

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Administration, Oral ; Alanine Transaminase ; blood ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Female ; Guanine ; analogs & derivatives ; pharmacology ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Male ; Organophosphonates ; pharmacology ; therapeutic use ; Polymerase Chain Reaction ; methods ; Prospective Studies ; Treatment Outcome ; Virus Replication ; drug effects

OBJECTIVETo investigate the resistance mutation patterns of hepatitis B virus(HBV) during adefovir dipivoxil (ADV) monotherapy or combination therapy after lamivudine(LAM) resistance.

METHODSSerum samples from fifteen patients with suboptimal viral response to ADV therapy after LAM resistance were collected. The RT region of HBV P gene was PCR-applied, cloned and sequenced, and the mutation patterns in relation to resistance were analyzed.

RESULTSThe ADV resistance mutation patterns of A181T+N236T, A181V, A181T were selected in ADV monotherapy group. The LAM resistance mutation patterns of M204V+L180M, M204V+L180M+L229V, M204I+L80I, M204V+L180M+V207I were detected in the combination therapy group. 20% of clones from three serum samples were detected double resistance to LAM and entecavir (ETV) in the combination therapy group, the resistance patterns were M204I+L80I+T184I (2/10), M204V+L180M+T184S (2/10), and M204V+L180M+G173L+S202G (2/10) respectively. I269L clones were detected in two serum samples from both two groups and P109S clones also detected in the one from monotherapy group.

CONCLUSIONSIn the patients with suboptimal viral response to ADV therapy after LAM resistance, the ADV resistance mutation patterns of A181T+N236T, A181V and A181T could easily be selected during ADV monotherapy; while in the patients with combination therapy, the LAM resistance mutation patterns of M204V+L180M, M204V+L180M+L229V, M204I+L80I, and M204V+L180M+V207I were predominant, the ETV resistance mutation T184I/S and S202G could be selected. The mutation patterns of I269L and P109S may impact the responses to ADV therapy in some patients.

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

OBJECTIVETo observe the efficacy and safety of PEG-interferon alpha-2a (PEG-IFNalpha-2a) treatment on lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients.

METHODSEighty-one patients with lamivudine-resistant HBeAg (+) chronic hepatitis B patients were enrolled and divided into PEG-IFNalpha-2a treatment group (40 cases) and adefovir dipivoxil (ADV) control group (41 cases). Two groups were combined with LAM in the first 12 weeks(w). The ALT normalization rate, the HBV DNA and HBeAg negative rate, and the HBeAg seroconversion rate were observed in 12 W, 24 W, 48 W.

RESULTSThe ALT normalization rate in 12 W, 24 W of PEG-IFNalpha-2a group was 62.5% and 80.0%. And it was higher than that of ADV group. The HBeAg negative rate and HBeAg seroconversion rate in 48 W of PEG-IFNalpha-2a group were 60% and 57.5% , which were higher than that of ADV group. The difference was statistically significant (P < 0.05).

CONCLUSIONPEG-IFNalpha-2a treatment of lamivudine-resistant HBeAg (+) chronic hepatitis B is superior to ADV, and its security is well.

Adenine ; analogs & derivatives ; therapeutic use ; Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; analysis ; drug effects ; Drug Resistance, Viral ; drug effects ; genetics ; Female ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Interferons ; immunology ; pharmacology ; Lamivudine ; therapeutic use ; Male ; Middle Aged ; Mutation ; Organophosphonates ; therapeutic use ; Polyethylene Glycols ; therapeutic use ; Recombinant Proteins ; Treatment Outcome ; Watchful Waiting

OBJECTIVETo investigate the role of HBV genotypes on their response to adefovir dipivoxil (ADV) antiviral therapy.

METHODSHBV genotypes from 177 HBeAg-positive chronic hepatitis B (CHB) patients were identified and the patients were treated with ADV 10 mg per day for 48 weeks. The clinical data in terms of serum HBV DNA seroclearance, mean HBV DNA reduction (log value), HBeAg loss, anti-HBe seroconversion and serum ALT of those patients were analyzed against their HBV genotypes.

RESULTSGenotype B and genotype C were found in 102 and 65 cases, respectively. The mean HBV DNA reduction in patients with genotype B and genotype C at their treatment times of 12, 24 and 48 weeks was 2.2 log10copies/ml, 2.1 log10copies/ml (P more than 0.05), 2.7 log10copies/ml, 2.4 log10copies/ml (P more than 0.05) and 3.6 log10copies/ml, 3.1 log10copies/ml (P less than 0.05), respectively. At the end of the therapy (48 weeks), 43 (42.2%) patients with genotype B HBV infection and 22 (33.8%) patients with genotype C HBV infection had achieved HBV DNA seroclearance (P less than 0.05).

CONCLUSIONSOur results suggest that genotype B HBV has a better virological response to ADV therapy in HBeAg-positive chronic hepatitis B patients than that of genotype C. Longer terms of ADV treatment are needed to confirm this conclusion.

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Adolescent ; Adult ; Aged ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; Female ; Genotype ; Hepatitis B virus ; drug effects ; genetics ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Male ; Middle Aged ; Organophosphonates ; pharmacology ; therapeutic use ; Treatment Outcome ; Young Adult