BACKGROUND/AIMS: To investigate the association between the baseline profiles and dynamics of hepatitis B virus (HBV) DNA polymerase gene mutations and the long-term virological response of lamivudine (LAM)-adefovir (ADV) combination therapy in patients with LAM-resistant chronic hepatitis B. METHODS: Seventy-five patients who received LAM-ADV combination therapy for more than 12 months were analyzed. Restriction fragment mass polymorphism assays were used to detect and monitor the dynamics of LAM- and ADV-resistant mutations. RESULTS: The median duration of LAM-ADV combination therapy was 26 months (range, 12 to 58 months). The baseline mutation profiles, rtM204I (p=0.992), rtM204I/V (p=0.177), and rtL180M (p=0.051), were not correlated with the cumulative virological response, and the baseline HBV DNA level (p=0.032) was the only independent predictive factor for cumulative virological response. Tests for LAM- and ADV-resistant mutations were performed in 12 suboptimal responders in weeks 48 and 96. The population of rtM204 mutants persisted or increased in 8 of 12 patients, and rtA181T mutants newly emerged as a minor population in four patients until 96 weeks. Nevertheless, the viral loads progressively decreased during rescue therapy, and these dynamics did not correlate with virological response. CONCLUSIONS: The baseline profile and dynamics of LAM-resistant mutations during LAM-ADV combination therapy are not associated with a virological response.
Adenine/administration & dosage/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Antiviral Agents/administration & dosage/*therapeutic use ; DNA-Directed DNA Polymerase/genetics ; Drug Resistance, Viral/genetics ; Drug Therapy, Combination ; Female ; Hepatitis B virus/*genetics ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Lamivudine/administration & dosage/*therapeutic use ; Male ; Middle Aged ; Organophosphonates/administration & dosage/*therapeutic use ; Treatment Outcome ; Viral Load/drug effects ; Young Adult

OBJECTIVETo evaluate the efficacy of nucleos(t)ide analogues (NA) treatment and to assess the long-term outcomes, including survival, liver function improvement and virologic response, in patients with decompensated cirrhosis due to hepatitis B virus (HBV) infection.

METHODSPatients with Child-Turcotte-Pugh (CTP) scores more than or equal to 7, who had been treated with either lamivudine or other agents, but who were free of co-infection with other hepatitis virus were enrolled between January 2005 and December 2009. The study participants were subgrouped according to the antiviral drugs received or model for endstage liver disease (MELD) score for comparative analyses.Additionally, the 19 patients who were treated with NA for more than 5 years were investigated for changes in biochemical and virological indices, before and after the antiviral treatment.

RESULTSA total of 166 patients (125 males; 89 e-negative) and 52 untreated healthy patients (as control) were analyzed.The cohort of patients receiving antiviral therapy had significantly better 5-year actuarial survival than the untreated patients (74.1% vs.34.9%, P less than 0.001). For patients with MELD score more than or equal to 18, actuarial survival was not significantly different between the two groups (P=0.073).

CONCLUSIONAntiviral therapy significantly increases survival and improves the clinical long-term outcome of patients with HBV-induced decompensated cirrhosis.Antiviral treatment should be initiated at an early stage to maximize benefit in the improvement of clinical status.

Administration, Oral ; Antiviral Agents ; administration & dosage ; therapeutic use ; Cohort Studies ; Coinfection ; Female ; Hepatitis B virus ; Hepatitis B, Chronic ; complications ; drug therapy ; Humans ; Lamivudine ; Liver Cirrhosis ; etiology ; Male ; Retrospective Studies ; Treatment Outcome

Antiviral Agents ; administration & dosage ; therapeutic use ; Child ; Drug Therapy, Combination ; Hepatitis B, Chronic ; drug therapy ; Hepatitis C, Chronic ; drug therapy ; Humans ; Interferon-alpha ; administration & dosage ; therapeutic use ; Lamivudine ; administration & dosage ; therapeutic use ; Nucleosides ; administration & dosage ; therapeutic use ; Polyethylene Glycols ; administration & dosage ; therapeutic use

To investigate the efficacy of 104 weeks of lamivudine (LAM) and adefovir (ADV) de novo combination therapy, as compared to optimized combination therapy administered after 48 weeks of treatment with lamivudine or adefovir mono-therapy, in chronic hepatitis B (CHB) patients. A total of 174 patients with CHB were equally divided among three treatment groups: LAM mono-therapy; ADV mono-therapy; and LAM + ADV combination therapy. The patients in the LAM + ADV group were treated with LAM plus ADV for 104 consecutive weeks. The patients in the LAM or the ADV groups were first treated for 48 weeks with LAM or ADV, respectively, after which the patient's virological response was assessed. According to the results, the patient was continued on mono-therapy or switched to combination therapy for the subsequent 56 weeks. Virological and biochemical examinations were carried out at weeks 48 and 104. The rates of undetectable HBV DNA in the LAM mono-therapy, ADV mono-therapy, and LAM-ADV combination therapy groups at week 48 were 68%, 50%, and 84%, and at week 104 were 80%, 72%, and 95%, respectively. For the same groups, the virus breakthrough rates at week 48 were 15%, 0%, and 0%, and at week 104 were 18%, 2%, and 0%, respectively. Statistical analysis showed significant differences for the rate of undetectable HBV DNA between LAM + ADV group and LAM group at week 48 (x2 = 4.473, P= 0.034) and at week 104 (x2 = 5.795, P = 0.016), LAM + ADV group and ADM group at week 48 (x2 = 14.802, P less than 0.001) and week 104 (x2 = 5.547, P = 0.001). The hepatitis B e antigen (HBeAg) seroconversion rates at week 48 were 15% (x2 = 4.543, P = 0.033), 13% (x2 = 4.035, P = 0.045) and 38%, and at week 104 were 21% (x2 = 4.438, P = 0.035), 17% (x2 = 4.223, P = 0.04) and 44%, respectively, among patients positive for HBeAg. Statistical analysis showed that the differences among the three groups for each of these parameters were statistically significant (all, P less than 0.05). When compared with LAM or ADV mono-therapy followed by LAM+ADV at week 48, the LAM plus ADV de novo combination therapy for 104 weeks provided CHB patients with better virological and serological responses and a lower drug resistance rate.
Adenine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Adult ; Drug Therapy, Combination ; Female ; Hepatitis B, Chronic ; drug therapy ; Humans ; Lamivudine ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Organophosphonates ; administration & dosage ; therapeutic use ; Prospective Studies ; Treatment Outcome

To evaluate the efficacy and safety of pegylated-interferon (Peg-IFN) treatment as monotherapy or in combination with nucleoside analogues (NAs) for treating chronic hepatis B (CHB) infection.Searches of PubMed, OVID, EMBASE, and the Chinese Medical (WanFang, CNKI, and VIP) databases were conducted to identify all relevant randomized controlled trials published since January 1990. Twelve studies comparing Peg-IFN monotherapy to NA combination therapy (lamivudine (LAM), n =8); adefovir (ADV), n = 4) met the inclusion criteria (treatment duration, range: 48-52 weeks; follow-up, range: 24 weeks to three years). Meta-analysis was performed with RevMan 5.0 using the fixed-effects and random-effects models. Patients who had received combination therapy had a higher biochemical response rate at the end of treatment than those who had received monotherapy (51.1% vs. 38.9%, odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.33-2.01, P less than 0.01). Subgroup analysis of Peg-IFN combination therapies with LAM or ADV indicated that neither NA type significantly enhanced the increased efficacy of combination therapy compared to monotherapy. The combination therapy subgroups also had higher virologic response rates at the end of treatment than the monotherapy subgroups (LAM: 65.9% vs. 34.9%, OR = 3.57, 95% CI: 1.83-6.95, P less than 0.01; ADV: 74.6% vs. 46.2%, OR = 3.66, 95% CI: 2.13-6.30, P less than 0.01). Moreover, the combination therapy group had a higher sustained biochemical response rate at the end of follow-up than the monotherapy group (47.6% vs. 42.1%, OR = 1.28, 95% CI: 1.05-1.55, P less than 0.05). The LAM combination therapy subgroup had a significantly higher biochemical response rate than the monotherapy subgroup, but there was no significant difference between the LAM and ADV combination therapy subgroups. At the end of follow-up, the ADV combination therapy subgroup had a significantly lower rate of hepatitis B e antigen (HBeAg) than the monotherapy subgroup, but there was no significant difference between the ADV and LAM combination therapy subgroups for HbeAg reduction. The combination therapy group and monotherapy group showed no statistically significant differences in HBsAg reduction or occurrence of severe adverse events. Peg-IFN/NA combination therapy produces a higher biochemical response rate in CHB patients than PEG-IFN monotherapy. Moreover, Peg-IFN/ADV combination therapy produces a greater reduction in HBeAg than Peg-IFN monotherapy.
Adenine ; administration & dosage ; analogs & derivatives ; Antiviral Agents ; administration & dosage ; adverse effects ; therapeutic use ; Drug Therapy, Combination ; Hepatitis B, Chronic ; drug therapy ; Humans ; Interferons ; administration & dosage ; adverse effects ; therapeutic use ; Lamivudine ; administration & dosage ; Nucleosides ; administration & dosage ; adverse effects ; therapeutic use ; Organophosphonates ; administration & dosage ; Polyethylene Glycols ; administration & dosage ; adverse effects ; therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

OBJECTIVE: To evaluate the efficacy of combination therapy of lamivudine (LAM) and adefovir dipivoxyl (ADV) for patients with hepatitis B-induced decompensated cirrhosis. METHODS: A total of 81 patients were randomly divided into a combination group and an ADV group over 48 week treatment course. The combination group were treated with LAM (100 mg/d) plus ADV (10 mg/d), and the ADV group with ADV (10 mg/d ) for 48 weeks. All patients received hepatic function support and symptomatic treatment. The levels of HBV DNA, liver function, Child-Pugh scores and HBV DNA indicators were observed before and after the treatment. RESULTS: At week 4, the mean reduction of HBV DNA was 1.83 lgIU/mL, 17.9% of the patients achieved undetectable HBV DNA and 28.2% showed normal ALT in the combination group. The counterpart in the ADV group was 0.96 lgIU/mL, 5.3% and 10.5%. At week 4, 12, 24 and 48, the differences in the mean reduction of HBV DNA, undetectable HBV DNA and ALT normalization were statistically significant between the 2 groups. The difference in HBeAg negative conversion rates and HBeAg seroconversion at week 24 and 48 was not significant. CONCLUSION The combination therapy results in HBV suppression and improved liver function and Child-Pugh score. The combination treatment has an advantage over ADV due to low drug resistance rate and good tolerance.
Adenine ; administration & dosage ; analogs & derivatives ; Adult ; Antiviral Agents ; therapeutic use ; Drug Therapy, Combination ; End Stage Liver Disease ; drug therapy ; etiology ; Female ; Hepatitis B, Chronic ; complications ; Humans ; Lamivudine ; administration & dosage ; Liver Cirrhosis ; drug therapy ; etiology ; physiopathology ; Male ; Middle Aged ; Organophosphonates ; administration & dosage

OBJECTIVETo evaluate the efficacy of entecavir (ETV) 1.0 mg/d or ETV plus adefovir dipivoxil (ADV) in adults with chronic hepatitis B virus (HBV) infection who had previously resisted lamivudine (LAM) and failed with rescue treatment of LAM + ADV.

METHODS40 patients were enrolled. 14 patients were treated with ETV 1.0 mg/d monotherapy while 26 patients were treated with ETV 1.0 mg/d + ADV 10 mg/d. The HBV DNA level, liver function, HBV serology and renal function were observed.

RESULTSThere was no statistically significant difference with baseline situation between group ETV 1.0 mg and group ETV + ADV. HBV DNA level in group ETV 1.0 mg was (5.768 ± 0.709) log10 copies/ml on baseline, and it declined to (4.712 ± 0.846) log10 copies/ml, (3.914 ± 0.996) log10 copies/ml, (3.702 ± 0.934) log10 copies/ml, (3.879 ± 0.913) log10 copies/ml and (3.855 ± 1.070) log10 copies/ml at 4, 8, 12, 24 and 48 weeks. HBV DNA level in group ETV + ADV was (5.703 ± 0.845) log10 copies/ml on baseline, and it declined to (4.476 ± 0.905) log10 copies/ml, (3.590 ± 0.884) log10 copies/ml, (2.987 ± 0.673) log10 copies/ml and (2.933 ± 0.535) log10 copies/ml at 4, 8, 12 and 24 weeks. At 24 weeks, there were 28.6% patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but there were 80.8% patients in group ETV + ADV achieved this level. Statistically significant difference existed between (x(2) = 8.469, P = 0.004 ). At 48 weeks, there were still 4 patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but patients in group ETV + ADV all achieved it. At 24 weeks, ALT levels of 42.9% patients in group ETV 1.0 mg were back to normal, but there were 92.3% patients' ALT levels back to normal in group ETV + ADV. There was statistically significant difference (x(2) = 9.337, P = 0.002). At 48 weeks, ALT levels of 57.1% patients in group ETV 1.0 mg were back to normal, but all patients' ALT levels were back to normal in group ETV + ADV. At 48 weeks, there was 1 patient with HBeAg seroconversion in group ETV 1.0 mg while there were 4 patients in group ETV + ADV.

CONCLUSIONAs rescue treatment for patients with chronic hepatitis B who had previously resisted LAM and failed with treatment of LAM + ADV, ETV + ADV was more efficient than ETV 1.0 mg monotherapy, and it can achieve better virological and biochemical response.

Adenine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Adult ; Antiviral Agents ; administration & dosage ; therapeutic use ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Guanine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Hepatitis B, Chronic ; drug therapy ; Humans ; Lamivudine ; therapeutic use ; Male ; Middle Aged ; Organophosphonates ; administration & dosage ; therapeutic use ; Treatment Outcome

To compare the efficacy and safety of interferon a-1b and interferon a-1b combined with lamivudine in the treatment of HBeAg positive chronic hepatitis B (CHB), to analyze the impact of variable factors on the efficacy, and to investigate the individualized anti-viral regimen for CHB patients. 111 CHB patients were enrolled and randomly divided into two groups. Group A: patients received interferon a-1b (49 patients, 50mug I. M. , qod. ) , Group B: interferon a-1b (idem) combined with lamivudine for 6-12 months or longer(62 patients, 100 mg, P.O. , q.d. ). (1) The HBeAg seroconversion rates of treatment by 12 and 18 months were 28.6% and 36.7% in group A, 29.0% and 38.7% in group B, respectively, no significant difference found between the two groups at the end of treatment (x2=0.003, P value is more than 0.05; x2=1.500, P value is more than 0.05). (2) The HBV DNA undetectable rates of treatment by 6 months, 12 months and 18 months were 8.2%, 53.1% and 57.1% in group A, 66.1%, 83.9% and 88.7% in group B, respectively, still no significant difference existed between the two groups (x2=38.150, P value is less than 0.05; x2=12.073, P value is less than 0.05, x2=14.459, P value is less than 0.05). (3) In group A, the HBeAg seroconversion rates for male and female patients were 34.5% and 40.0% respectively, no significant difference found between. As regard ages the rates were 34.9% and 50.0% for patients younger or more than 40 years of age, no significant difference existed between. The HBeAg seroconversion rate was higher in patients with lower baseline serum HBV DNA loads ( less than 6 log10 copies/ml) . (4) The rates of patients with fever and blood abnormality were 36.7% and 34.7% in group A, 32.3% and 27.4% in group B, respectively. The total incidences of adverse events were similar between group A and B (x2=0.244, P value is more than 0.05; x2=0.682, P value is more than 0.05). (5) The ratio of drug resistance in group B was only 1.6%. The adverse events of interferon a-1b treatment for CHB are low and mild. The HBeAg seroconversion rate persistently raises with the extension of interferon a-1b treatment course. The HBV DNA undetectable rate of interferon a-1b combined with lamivudine is significantly higher than that of interferon a-1b and the drug resistance of lamivudine can be reduced obviously by combination therapy.
Adult ; Antiviral Agents ; therapeutic use ; Drug Therapy, Combination ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Interferon-alpha ; administration & dosage ; therapeutic use ; Lamivudine ; therapeutic use ; Male ; Middle Aged ; Young Adult

BACKGROUND/AIMS: Clevudine is a potent antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. This study compared the efficacy of clevudine (C), entecavir (E) and lamivudine (L) in treatment-naive patient with HBeAg-positive chronic hepatitis B. METHODS: A total of 146 treatment-naive patients with HBeAg-positive chronic hepatitis B received clevudine, entecavir or lamivudine. C group (n=39) received 30 mg of clevudine, E group (n=39) received 0.5 mg of entecavir and L group (n=68) received 100 mg of lamivudine once a day for more than 48 weeks. The efficacy analysis estimated the mean changes of the HBV DNA levels as a virologic response, the normalization of the ALT levels (less than 35 IU/L) as a biochemical response and loss of HBeAg or seroconversion as a serologic response. The serum HBV DNA level was quantified by hybrid capture and real-time PCR assay. RESULTS: Before the administration of clevudine, entecavir and lamivudine, the mean HBV DNA and ALT levels and the gender and age were well balanced among the three groups (p>0.05). For the virologic response at 48 weeks, the mean changes of the HBV DNA levels from baseline of the C, E and L groups were -3.8+/-2.2, -4.5+/-1.9 and -2.5+/-2.1 log copies/mL. C and E group showed superior antiviral activity compared to that of L group (p<0.0001), but no significant differences in antiviral response were noted between C and E groups. For the biochemical response at 48 weeks, the normalization of the ALT levels (less than 35 IU/L) among the C, E and L groups was 82%, 74% and 71%, respectively (p=0.46). The rates of undetectable serum HBV DNA (less than 300 copies/mL) of the C, E and L groups were 39%, 69% and 27%, respectively (p<0.0001). For the serologic response at 48 weeks, the loss of HBeAg was 13%, 31% and 24% and the seroconversion was 10%, 23% and 17%, respectively. There was no difference of efficacy among the three groups regarding ALT normalization or serologic response (p>0.05). Viral breakthrough in C group was noted at 24 weeks (5%) and 48 weeks (21%), but no biochemical breakthrough was noted. The elevation of the serum CK level was noted in only 1 patient of group C at 48 weeks (2.56%) after therapy. For the patients without or with liver cirrhosis (LC), C and E group showed superior antiviral activity compared to that of the L group, but the antiviral activity was more effective in non- LC group than LC group (p<0.0001 vs p=0.036). CONCLUSIONS: Clevudine therapy compared with lamivudine for 48 weeks showed significantly potent antiviral efficacy in treatment-naive patients with HBeAg-positive chronic hepatitis B, and especially in the non-LC patients. However, the antiviral efficacy of clevudine was similar to that of entecavir even though taking into account relatively short follow up period and retrospective study.
Adult ; Alanine Transaminase/blood ; Antiviral Agents/*administration & dosage ; Arabinofuranosyluracil/administration & dosage/*analogs & derivatives ; DNA, Viral/blood ; Drug Administration Schedule ; Drug Resistance, Viral ; Female ; Guanine/administration & dosage/*analogs & derivatives ; Hepatitis B e Antigens/*blood ; Hepatitis B, Chronic/*drug therapy ; Humans ; Lamivudine/*administration & dosage ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome

The authors assessed the efficacy and antiviral resistance of 48-week clevudine therapy versus lamivudine in treatment of naive patients with HBeAg positive chronic hepatitis B. In this retrospective study, a total of 116 HBeAg positive patients, who received 30 mg of clevudine once daily (n=53) or 100 mg of lamivudine once daily (n=63) for 48 weeks, were included. At week 48, clevudine therapy produced a significantly greater mean reductions in serum HBV DNA levels from baseline than lamivudine therapy (-5.2 vs. -4.2 log(10)IU/mL; P=0.005). Furthermore, a significantly higher proportion of patients on clevudine achieved negative serum HBV DNA by PCR (<13 IU/mL) at week 48 (60.4% vs. 38.1%; P=0.025). The incidence of virologic breakthrough in the clevudine group was significantly lower than in the lamivudine group (9.4% vs. 25.4%; P=0.031). However, rates of alanine aminotransferase normalization and HBeAg loss or seroconversion were similar in the two groups (83.0% vs. 81.0%, 11.3% vs. 11.1%; P=0.813, 1.000, respectively). In conclusion, clevudine is more potent for viral suppression and lower for antiviral resistance at week 48 than lamivudine in treatment of naive patients with HBeAg positive chronic hepatitis B.
Adult ; Antiviral Agents/administration & dosage ; Arabinofuranosyluracil/administration & dosage/*analogs & derivatives ; Drug Resistance, Viral ; Female ; Hepatitis B e Antigens/*blood ; Hepatitis B, Chronic/diagnosis/*drug therapy/*immunology ; Humans ; Lamivudine/*administration & dosage ; Male ; Treatment Outcome