Hepatitis B virus (HBV) infection is contagious with transmissiobn vertically or horizontally by blood products and body secretions. Over 50% of Iranian carriers contracted the infection prenatally, making this the most likely route of transmission of HBV in Iran. To evaluate the resistance to adefovir (ADV) therapy in patients with chronic hepatitis B infection, a study was conducted on 70 patients (63 males and 7 females), who had received in first line lamivudine and second line adefovir. All were tested for the presence of hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), serum alanine amino transferase (ALT) level and HBV DNA load before and after treatment with ADV. In all samples, resistance to lamivudine and ADV was tested with real time PCR. Among seventy patients with chronic hepatitis B infection, 18 (25.7%) were resistant to LAM and 8 (11.4%) were resistant to ADV. Only one patient was negative for the presence of HBS-Ag (5.6%) and two were negative for HBe-Ag (11.1%). In this study we used a new method (ALLGIO probe assay) that has high sensitivity in detection of adefovir resistance mutants, which we recommend to other researchers. Mutant strains of the YMDD motif of HBV polymerase can be found in some patients under treatment with lamivudine and ADV. ADV has been demonstrated to be efficient in patients with lamivudine resistant HBV.
In this study, we investigated the correlation between the administration of various antiviral agents and the alternation of specific biomarkers induced by the hepatitis B virus (HBV). Eligible subjects diagnosed with chronic hepatitis B were prescribed with antiviral drugs at the Gastroenterology Internal Medicine Department of E University Hospital in Daejeon between May 2004 and September 2009. Lamivudine was prescribed to 66 out of 100 patients. Of the 12 patients, 6 (50.0%) showed a change from being HBe-antigen-positive to being HBe-antigen-negative. Of the 39 patients, 23 (59.0%) showed higher than 40 IU/L alanine aminotransferase (ALT). Of the 65 patients, 41 (63.1%) showed HBV DNA decrease of 1 log, and were prescribed with Lamivudine. Adefovir was prescribed to 3 out of 100 patients. Of the 12 patients, 1 (8.3%) showed a change from being HBe-antigen-positive to being HBe-antigen-negative, and was prescribed with Adefovir. Entecavir was prescribed to 19 (19.0%) out of 100 patients. Of the 12 patients, 3 (25.0%) showed a change from being HBe-antigen-positive to being HBe-antigen-negative. Of the 12 patients, 3 (125.8%) showed higher than 40 IU/L ALT. Of the 65 patients, 14 (21.5%) showed HBV DNA decrease of 1 log, and were prescribed with Entecavir. Clavudine was prescribed to 7 out of 100 patients. Of the 12 patients, 1 (8.3%) showed a change from positive HBe antigen to negative HBe antigen. Of the 39 patients, 5 (12.8%) showed higher than 40 IU/L ALT. Of the 65 patients, 6 (9.2%) showed HBV decrease of 1 log, and were prescribed with Clavudine. These results do not show a statistically significant correlation between drugs and biomarkers. Data on combination therapy using Lamivudine and Adefovir show no statistically significant difference between drugs and biomarkers. Medications for periodic inspection was not correlated to HBe-antigen-negative conversion, ALT, and HBV DNA. HBV DNA was significantly reduced in patients with high levels of AST(aspartic acid aminotransferase) and ALT before treatment. In addition, the decrease of HBV DNA after 12 months of treatment was less frequently observed in patients treated with Lamivudine compared with other drugs. This result is associated with Lamivudine resistance. Although the association of drugs with diagnostic markers and the correct choice of treatment is difficult to determine, these results may be useful for further research on diagnosis and treatment of the hepatitis B virus.
This study was aimed to examine the prescribing patterns of antivirals in outpatients with chronic hepatitis B (CHB), using National Health Insurance adjudicated claims data (total 1,426,065 claims) dated March 19, 2008 submitted from nationwide healthcare providers to Health Insurance Review and Assessment Service. From the data, there were 2,965 claims with CHB diagnosis (ICD-10 code B18.0 and B18.1), and 44.2% (1,311 claims) of the CHB related claims included antivirals such as lamivudine, clevudine, adefovir and entecavir. Lamivudine, adefovir, clevudine and entecavir shared 54.9%, 19.9%, 13.2% and 11.9%, respectively, among antiviral prescriptions. Adefovir and entecavir 1mg presumed as the 2nd line therapy for HBV resistant cases were shared 23.3% of overall antiviral prescriptions. There were statistically significant difference in prescription patterns according to age and institution type: Lamivudine usage was higher in younger (< 20 years old) and older age group (> 70 years old) than the others (p = 0.016), and adefovir and entecavir, which were relatively newer antivirals, had higher prescription rates in higher level of institutions such as tertiary hospitals than the others (p < 0.001). This study would be of help to make an appropriate drug therapy plan for patients with CHB.
Choe, Byung-Ho;Jang, You Cheol;Jang, Chang Hwan;Oh, Ki Won;Lee, Jun Hwa;Ko, Cheol Woo
Clinical and Experimental Pediatrics
/
v.48
no.1
/
pp.55-62
/
2005
Purpose : We compared the therapeutic efficacy of lamivudine and alpha-interferon in children with chronic hepatitis B two years after the initiation of treatment, so that we could verify the safety and long term efficacy of lamivudine in children. Methods : We prospectively studied 44 children(32 male and 12 female; age, 1-18 years, mean, 9 years) treated for chronic hepatitis B from September 1996 to June 2004 in Kyungpook National University Hospital in Korea. Twenty three children were treated with interferon, and 21 with lamivudine. Treatment efficacy was defined as the normalization of ALT and hepatitis B virus(HBV) DNA levels, loss of HBsAg and HBeAg seroconversion at two years after the initiation of treatment. Results : Among the 23 children treated with interferon, the ALT level normalized in 10 children(43 %) and HBV DNA was undetectable in 12 children(52%). HBsAg was undetectable in one child (4 %) and HBeAg seroconversion occurred in nine children(39%) two years after the initiation of treatment. In comparison, among the 21 children treated with lamivudine, ALT normalized in 20 children (95%), HBV DNA in 19(90%), HBsAg in 5(24%), and HBeAg seroconversion occurred in 13(62%). Above all, in the lamivudine treated group under the age of seven, HBeAg and HBsAg seroconversion occurred in six(75%) and five(63%) out of the eight children respectively, which showed superior HBsAg seroconversion rate if treated in preschool aged children. Conclusion : We believe that the therapeutic efficacy of lamivudine in children with chronic hepatitis B could be better than interferon with fewer side effects, especially in preschool aged children.
Purpose: Lamivudine is known to be effective for the treatment of chronic hepatitis B in adults. However, data on lamivudine therapy in pediatrics is limited. The aim of this study was to evaluate the efficacy and durability of lamivudine therapy for chronic hepatitis B in Korean children. Methods: A total of 44 children (27 males and 17 females, ages 6 months to 14.8 years, mean age 6.7 years) with chronic hepatitis B who received lamivudine (3 mg/kg/day, max 100 mg) for at least 12 months were enrolled. We evaluated the serum AST, ALT and serological HBV markers (HBsAg and anti-HBs, HBeAg and anti HBe, and HBV DNA) periodically. Predictive three year cumulative seroconversion rates were obtained using the Kaplan-Meier method. Results: Twenty one (48%) of 44 children achieved seroconversion of HBeAg by three years, while 23 (42%) children did not. HBV DNA was cleared in 34 (77%) children and the serum ALT levels were normalized in 41 children (93%). The three year cumulative seroconversion rates were 60% for HBeAg, and the clearance rates were 76% for HBV DNA. Eighteen children who discontinued lamivudine after HBeAg seroconversion maintained the therapeutic response for three years (treatment duration 13~58 months mean 24 months). Viral breakthrough developed in 12 children (27%) during the therapy and the YMDD mutation was documented in 11 children (25%). The mean duration for the development of a mutation was 22.7 months. Loss of HBsAg occurred in 6 children (14%). The pretreatment ALT levels were higher in responders; however, the differences were not statistically significant (p>0.05). Conclusion: The results of this study showed that lamivudine treatment had a favorable effect and durable therapeutic response in children with chronic hepatitis B. Long term follow-up and alternative therapy are warranted for those patients who do not respond to this treatment.
Purpose: Interferon is a widely used treatment for chronic hepatitis B in children. However, additional treatment options are needed because more than 50% of hepatitis B patients are unresponsive to interferon. Although lamivudine is widely used to treat hepatitis B, there are few studies on the effect of lamivudine in hepatitis B patients unresponsive to interferon. Methods: Eight interferon unresponsive patients (6 males and 2 females) were treated with lamivudine (3 mg/kg/day, maximum 100 mg/day) from 6~12 months after interferon treatment was discontinued among 33 children with chronic hepatitis B. They were treated with interferon (interferon ${\alpha}$-2b, 10 MU/$m^2$ or pegylated interferon $1.5{\mu}g/kg$) for 6 months from January 2000 to December 2007 at the Pusan National University Hospital. The medical records were analyzed retrospectively. Results: The age at treatment with interferon and lamivudine was 4.9${\pm}$3.1 and 6.1${\pm}$3.2 years, respectively. The serum ALT level before treatment with interferon was 148.1${\pm}$105.8 IU/L and the log HBV-DNA PCR mean value was 6.95${\pm}$0.70 copies/mL. The serum ALT level after treatment with interferon was 143.1${\pm}$90.4 IU/L and the log HBV-DNA mean PCR value was 6.46${\pm}$2.08. HBeAg negativization occurred in 2 patients. For all patients, normalization of the serum ALT levels and HBeAg seroconversion (except 2 patients with HBeAg negativization) occurred at 7.4${\pm}$2.1 and 7.9${\pm}$2.1 months respectively after lamivudine treatment. The HBV-DNA PCR became negative in 7 patients (87.5%) at 2.4${\pm}$2.8 months. Complete response was achieved in 7 patients and no recurrence was observed in 2 patients for 3 years after the completion of treatment. Five patients are still under treatment for a mean treatment duration of 24.4${\pm}$9.1 months. In one patient, viral breakthrough occurred and the treatment was stopped. Conclusion: The number of patients was small, however, lamivudine treatment in patients with chronic hepatitis B who were unresponsive to interferon was highly effective.
YMDD motif mutants of the hepatitis B virus(HBV) emerge in chronic hepatitis B patients after prolonged lamivudine treatment. HBV DNA breakthrough may be accompained by the emergence of YMDD mutants. We compared the performance of the sequencing method with that of RFMP method in chronic hepatitis B patients who had suffered the HBV DNA breakthrough after lamivudine treatment. Both sequencing and RFMP methods were used to detect YMDD variants in 20 chronic hepatitis B patients. YMDD mutants were detected in 17 samples (85.0%) by both methods. Among them, no mutants were detected in two samples(10.0%), while they were detected in the other sample(5.0%) with the RFMP method. The concordance rate between both methods was 95.0%. There was inconsistency in one sample showing mutants detected by the RFMP method, but not by sequencing method. In the sequencing method, the mutants was detected in the major type virus, but not in the minor type virus. However, both sequencing and RFMP methods were highly concordant except in one sample, so it is suggested that both methods are useful to detect YMDD mutants of chronic hepatitis B patients.
Purpose: To estimate the viral suppressive effect of entecavir monotherapy in Korean children and adolescents with lamivudine-resistant chronic hepatitis B (CHB). Methods: One milligram of entecavir was administered once daily to 6 patients (4 boys; mean age, 17.5 years; range, 15.10~24.6 years) with lamivudine-resistant CHB for a mean duration of therapy of 13.4 months (range, 1~21.1 months). The therapeutic results were compared with 11 patients who received adefovir (0.3 mg/kg/day [maximal dose 10 mg]) for at least 12 months (mean, 33.4 months; range, 12.4~58.3 months). The serum HBV DNA level and serologic markers were measured every 2 months. Results: The interval to a HBV DNA titer decrement (>1 $log_{10}$) was 1.2${\pm}$0.2 and 4.4${\pm}$5.2 months (p=0.185) for the entecavir and adefovir groups, respectively. The interval to a HBV DNA titer decrement (>2 $log_{10}$) was 2.4${\pm}$2.3 and 9.2${\pm}$7.3 months (p=0.025), for the entecavir and adefovir groups, respectively. Conclusion: The therapeutic efficacy of entecavir was favorable in children and adolescents, especially in shortening the interval to a >2 $log_{10}$ decrement in the HBV DNA titer. Long-term follow up is needed to determine the therapeutic efficacy of entecavir for lamivudine-resistant CHB in children and adolescents.
Purpose: To evaluate the long-term therapeutic efficacy and durability of lamivudine in Korean children with chronic hepatitis B. Methods: A total of 48 children (31 male and 17 female; age, 1~18 years, mean, 8 years) with chronic hepatitis B who received lamivudine for at least six months from March 1999 to September 2004 were followed for a mean period of 29 months (8~66 months) at Department of Pediatrics, Kyungpook National University Hospital in Korea. Response to treatment was defined as the normalization of ALT and HBV DNA levels, and HBeAg seroconversion after the initiation of treatment. Results: Twenty nine (60%) among the 48 children treated with lamivudine responded and nine (19%) children lost HBsAg during therapy. ALT and HBV DNA level had normalized in 94% one year after the initiation of treatment. Kaplan-Meier estimates of cumulative HBeAg seroconversion rates over the years were 13% (0.5 year), 34% (1 year), 50% (1.5 years), 68% (2 years), 79% (2.5 years) and 90% at 3 years respectively. Above all, among the 22 children treated before the age of seven, loss of HBsAg occurred in eight (36%), which showed superior rate of HBsAg loss (p=0.002 vs age >7). Conclusion: Long-term treatment of lamivudine improved the rate of HBeAg seroconversion in Korean children with chronic hepatitis B. After three years' observation, most of treated children have sustained HBeAg clearance. We believe that lamivudine should be tried as the first therapeutic option for children with chronic hepatitis B in immune clearance phase.
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