BACKGROUND/AIMS: To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. METHODS: This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. RESULTS: During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). CONCLUSION: The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression.
Adenine/*analogs & derivatives/pharmacology/therapeutic use ; Adult ; Alanine Transaminase/blood ; Antibodies, Viral/blood ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Disease Progression ; Drug Resistance, Viral/drug effects ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Genotype ; Guanine/analogs & derivatives/pharmacology/therapeutic use ; Hepatitis B e Antigens/blood ; Hepatitis B virus/drug effects/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/pharmacology/therapeutic use ; Male ; Middle Aged ; Organophosphonates/pharmacology/*therapeutic use ; Treatment Outcome

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 ; 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

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 ; 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 explore the mechanism for adefovir dipivoxil (ADV) resistance occurred in chronic hepatitis B patients of a series of phase III clinical trails.

METHODS30 resistant HBV strains were selected out from 177 cases of ADV treated chronic hepatitis B patients. HBV polymerase RT region were amplified by nested PCR and analyzed with the standard nucleotide sequence of HBV strains deposited in GeneBank.

RESULTS21 out of 30 HBV strains were primary resistant strains, among them 5 HBV strains (23.8%, 5/21) had the polymorphism site of rtN118H. While the other 9 HBV strains showed secondary resistance, variations in conservative region C (rtM207V) and other non-conservative regions were found. The classic mutation sites such as rtN236T and rtA181V/T were not found.

CONCLUSIONSPolymorphism site of rtN118H might be responsible for HBV primary resistance to ADV therapy. rtM207V variation in HBV RT C domain and other variation sites might play a role in HBV secondary resistance to ADV treatment, and natural resistant quasispecies may be the basis for the ADV quick resistance. These conclusions await further confirmation by phenotype test.

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Adult ; Alanine Transaminase ; blood ; Amino Acid Sequence ; Antiviral Agents ; pharmacology ; therapeutic use ; Base Sequence ; DNA Primers ; DNA, Viral ; blood ; Drug Resistance, Viral ; Female ; Genotype ; Hepatitis B virus ; drug effects ; genetics ; Hepatitis B, Chronic ; drug therapy ; genetics ; virology ; Humans ; Male ; Molecular Sequence Data ; Organophosphonates ; pharmacology ; therapeutic use ; Polymorphism, Genetic ; genetics ; RNA-Directed DNA Polymerase ; drug effects ; genetics ; Reverse Transcriptase Inhibitors ; pharmacology ; therapeutic use ; Reverse Transcriptase Polymerase Chain Reaction ; methods ; Sequence Analysis, DNA

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 identify factors associated with response to lamivudine in chronic hepatitis B patients.

METHODSClinical data of 233 chronic hepatitis B patients treated with lamivudine 100mg daily (91 patients were switched to Adefovir 10mg daily or Adefovir 10mg in combination with lamivudine 100mg daily) were retrospective. HBV DNA level and serum HBV markers were detected by polymerase chain reaction and enzyme-linked immunosorbent assay. Kaplan-Meier, long-rank, t test were conducted to evaluate the data.

RESULTS(1) The rates of HBV DNA loss, ALT normalization, viral breakthrough(VB), HBeAg loss and seroconversion were 63.4% , 83.8%, 30.9%, 30.9%, and 14.3%, respectively, in HBeAg(+) patients; and these were 84.6%, 81.3%, 14.3%, respectively in HBeAg(-) patients.(2) The rates of HBV DNA loss, HBeAg loss, HBeAg seroconversion, viral breakthrough (VB) were 55% and 66.7% (P more than 0.05), 55.0%, and 66.7% (P less than 0.05), 17.5% and 33.3% (P less than 0.05), 50% and 34.3% (P less than 0.05) in HBeAg(+) patients with baseline ALT less than 2.5 ULN and HBeAg(+) patients with baseline ALT is more than or equal to 2.5 ULN, respectively. (3) For HBeAg(+) patients, viral breakthrough rate was significantly lower in patients with baseline HBV DNA less than 10(6) copies/ml than that in patients with baseline HBV DNA more than 10(6) copies/ml patients (23.4% VS 46.3%, P less than 0.05) among HBeAg(+) patients. (4) The rate of HBV DNA loss, HBeAg loss, HBeAg seroconversion and viral breakthrough for the patients with IVR at week 24 were 76.3%, 72.3%, 40.8% and 28.9% compared to 47.6% (P less than 0.01), 46% (P less than 0.01), 12.7% (P less than 0.01) and 47.6% (P less than 0.05) for those without IVR. (4) For the 44 patients with viral breakthrough, 32 were switched to Adefovir monotherapy or adefovir in combination with lamivudine therapy, and 12 continued to receive lamivudine monotherapy. HBV DNA loss, HBeAg seroconversion were 40.6%, 21.9% for those switch/add group compare to 16.7%, 16.7% for the lamivudine monotherapy group. There were no significant differences in the background factors (sex, diagnosis, antiviral period, pre-tx ALT, pre-tx HBV DNA) between these two groups.

CONCLUSIONBoth the baseline ALT and HBV DNA are associated with the efficacy of lamivudine in chronic hepatitis B patients. Patients with baseline ALT is more than or equal to 2.5*ULN and (or) HBV DNA level of less than 1*10(6) copies/ml have better efficacy and lower rate of breakthrough rate. IVR at week 24 is an important predictive factor of a favorable response to lamivudine therapy. For the patients with viral breakthrough, those switched to/added on Adefovir have a favorable result.

Adenine ; analogs & derivatives ; pharmacology ; therapeutic use ; Adolescent ; Adult ; Alanine Transaminase ; blood ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Drug Administration Schedule ; Enzyme-Linked Immunosorbent Assay ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Lamivudine ; pharmacology ; therapeutic use ; Male ; Middle Aged ; Organophosphonates ; pharmacology ; therapeutic use ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Treatment Outcome ; Young Adult

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