Switch to tenofovir-based therapy or to continue adefovir-based therapy in CHB patients with suboptimal response to adefovir-based combination?

No abstract available.

Long-Term Outcomes and Dynamics of Mutants Associated with Lamivudine-Adefovir Rescue Therapy in Patients with Lamivudine-Resistant Chronic Hepatitis B

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.

Entecavir plus tenofovir versus entecavir plus adefovir in chronic hepatitis B patients with a suboptimal response to lamivudine and adefovir combination therapy

BACKGROUND/AIMS: We compared the efficacies of entecavir (ETV) plus tenofovir (TDF) and ETV plus adefovir (ADV) in chronic hepatitis B (CHB) patients with genotypic resistance to lamivudine (LAM) who showed a suboptimal response to LAM and ADV combination therapy. METHODS: We reviewed 63 CHB patients with genotypic resistance to LAM who showed a suboptimal response to LAM and ADV combination therapy. Among these patients, 30 were treated with ETV + ADV and 33 were treated with ETV + TDF for 12 months. RESULTS: The only baseline characteristic that differed significantly between the two groups was the ETV resistance profile. The rate of a virologic response [serum hepatitis B virus (HBV) DNA level of <20 IU/mL] was significant higher for ETV+TDF than for ETV+ADV over 12 months (57.6% vs. 23.3%, P=0.006, at 6 months; 84.8% vs. 26.7%, P<0.001, at 12 months). The probability of a virologic response was significantly increased in ETV+TDF (P<0.001, OR=54.78, 95% CI=7.15-419.54) and decreased in patients with higher baseline viral loads (P=0.001, OR=0.18, 95% CI=0.07-0.50) in multivariate analysis. No serious adverse event occurred during the study period. CONCLUSIONS: In patients with CHB who showed a suboptimal response to LAM and ADV combination therapy, ETV+TDF was superior to ETV+ADV in achieving a virologic response regardless of the HBV resistance profile. Further large-scale and long-term follow-up prospective studies are needed to explain these results.

Entecavir 1 mg therapy for lamivudine-refractory chronic hepatitis B / 대한간학회지

No abstract available.

YVDD Mutation of Hepatitis B Virus, a Dominant Lamivudine-Resistant Type in Guangzhou, South China / 中国病毒学·英文版

The epidemiological effects of native and mutated YMDD motif in the HBV genome under the selective pressure of lamivudine were investigated. YMDD wild and mutation motif in HBV genome were detected by flow through reverse dot blots (FT-RDB) with KaiPuTM DNA HybriMax Rapid Hybridization Machine based on the principle of "Flow-through hybridization" and by the traditional Reverse Dot Blot assay. Sera from 1021 suspected lamivudine-resistant chronic HBV carders after more than 8 months of lamivudine therapy and the corresponding archived sera were collected and assayed. We found 35.94% were single type infections with 8.03% YMDD, 7.93% YIDD and 19.98% YVDD. It was also found that 64.06% were mixed infections including 1.96% YMDD and YIDD, 51.62% YMDD and YVDD, 1.96% YIDD and YVDD, 8.52% YMDD, YIDD and YVDD. The levels of infections containing YVDD motif reached 82.08%. The pretreatment infectious status were: YMDD single infection was 36.93%; YIDD single infection was 6.07%; YVDD single infection was 17.04%; YMDD and YIDD mixed infection was 0.97%; YMDD and YVDD mixed infection was33.99%; YIDD and YVDD mixed infection was 0.98%; YMDD, YIDD and YVDD mixed infection was 4.02%. Infections containing YVDD motif were only 56.03%. The 34.32% mutation rate of YMDD motif to YVDD was significantly higher than the 10.97% of YMDD to YIDD (U=10.98, P<0.05), as estimated by Mann-Whitney U-test for non-parametric data. HBV containing YVDD motif might have an evolutionary ascendancy and become the dominant type under the selective pressure of lamivudine.

The Comparison of Restriction Fragment Mass Polymorphism Method with Sequecing Method for the Detection of HBV YMDD Mutants / 대한진단검사의학회지

BACKGROUND: YMDD motif mutants of the hepatitis B virus (HBV) emerged in some chronic hepatitis B patients after prolonged lamivudine treatment. Recently a novel genotyping assay, the restriction fragment mass polymorphism (RFMP) method, was introduced for the detection of YMDD mutations. We compared the performance of the RFMP method with that of sequencing method in chronic hepatitis B patients who had suffered the HBV DNA breakthrough after lamivudine treatment. METHODS: Enrolled in this study were 18 chronic hepatitis B patients who experienced the DNA breakthrough after a period during which HBV DNA was undetectable by Hybrid capture II HBV DNA test (Digene Inc., Gaithersburg, MD, USA). Both sequencing and RFMP methods were used to detect YMDD variants in three phases such as before treatment, before breakthrough and after breakthrough. RESULTS: YMDD mutants were detected in 13 samples (72.2%) by both methods after DNA breakthrough. Among them were two samples with a mixed HBV population detected by RFMP. Before breakthrough, the mutants were detected in three samples (16.7%) by sequencing and four (22.2%) by RFMP, showing discrepant results for two samples. The concordance rate between both methods was 92.6%. CONCLUSIONS: Both sequencing and RFMP methods were highly concordant except in a few cases, so it is suggested that both methods are appropriate in detecting YMDD mutants.

Efficacy of adefovir dipivoxil in treating patients with hepatitis B resistant to lamivudine / 中国临床药理学与治疗学

AIM:To evaluate the efficacy and safety of adefovir dipivoxil in treating patients with hepatitis B resistant to lamivudine. METHODS: 68 patients with hepatitis B resistant to lamivudine were administered 10 mg adefovir dipivoxil orally daily for over 1 years.The serum HBV-DNA levels were measured by quantitative PCR and liver function test,HBeAg/anti-HBe and safety assessments were also performed at 0,12,24,52 weeks after treatment. RESULTS: After 12,24,52 weeks of treatment, the mean HBV-DNA levels were reduced by 1.6 lg copies/mL (t=10.10,P

Detection of HBV YMDD Mutation by Sequencing Method / 대한진단검사의학회지

BACKGROUND: YMDD motif variants of the hepatitis B virus (HBV) emerge in some chronic hepatitis B patients after prolonged lamivudine treatment. HBV DNA breakthrough may be accompanied by the emergence of YMDD variants. The detection of YMDD motif variants will be necessary since Adefovir dipivoxil was recently approved to be an effective treatment for lamivudine-resistant patients. METHODS: Samples were chosen from twenty-one patients who experienced the DNA breakthrough after an undetectable HBV DNA period by HBV DNA hybrid-capture assay. We tested the samples of each stage for detection of YMDD motif variants by a sequencing method using Accu-Typer(TM) HBV YMDD typing Kit (DNA Link, Seoul, Korea) and ABI PRISM 3700 DNA Analyzer. RESULTS: All 17 samples that were collected before treatment had the wild-type YMDD motif. Of 20 samples amplified, which were from the undetectable HBV DNA period, three (15%) samples showed YMDD mutation. After DNA breakthrough, YMDD mutants were detected in 13 (63%) of 21 samples (YIDD 8 cases, YVDD 5 cases). CONCLUSION: We could reconfirmed that YMDD motif variants were remarkably related to the lamivudin resistance. YMDD motif variants; however, were not detected in one-third of the lamivudine resistance. The sequencing method of our study would be useful in providing the neighboring nucleotide information other than the YMDD motif in patients experiencing DNA breakthrough.

Clinical and Virologic Characteristics of Lamivudine Resistance in HBV-associated Chronic Liver Disease / 대한간학회지

BACKGROUND/AIMS: Lamivudine therapy in chronic hepatitis B has been shown to be effective in inhibiting HBV replication. However, lamivudine resistance has been developed with prolonged use. We studied to determine the prevalence, predictive factors, and clinical outcomes of lamivudine resistance. Mutations in YMDD motif of HBV polymerase, which have been associated with lamivudine resistance, were also assessed. METHODS: 170 patients with HBV-associated chronic liver disease who have received lamivudine for at least one year, were studied. The clinical, biochemical, and virologic characteristics were analyzed and compared according to presence (resistance group) or absence (non-resistance group) of DNA breakthrough. Their clinical outcomes were regularly followed. Stored sera before treatment and after DNA breakthrough were examined for detection of HBV polymerase mutation by direct sequencing and/or RFLP. RESULTS: Cumulative rates of lamivudine resistance after one and two years of treatment were 11% and 34%, respectively. In the resistance group, as compared to the non-resistance group, age, the presence of HBeAg before treatment, and disappearance of HBeAg during treatment, were significantly different. The predictive factors associated with lamivudine resistance were not found. ALT and HBV-DNA level after lamivudine resistance was variable, but jaundice or hepatic failure was absent. Mutation in YMDD motif was detected in 73% and other variable mutations were detected before treatment and after DNA breakthrough. CONCLUSIONS: Lamivudine resistance increases the longer the duration of treatment and clinical outcomes are variable. The mutation in YMDD motif was found in about 2/3 of cases. Other causes for lamivudine resistance may be considered.