High pretransplant HBV level predicts HBV reactivation after kidney transplantation in HBV infected recipients

PURPOSE: HBsAg-positive kidney recipients are at increased risk for mortality and graft failure. The aims of this study were to identify the outcomes of HBsAg-positive recipients who received preemptive antiviral agents after successful kidney transplantation and to analyze risk factors for HBV reactivation. METHODS: We retrospectively reviewed the medical records of 944 patients performed kidney transplantation between 1999 and 2010. RESULTS: HBsAg-negative recipients were 902 patients and HBsAg-positive recipients, 42. Among HBsAg-positive recipients, HBV reactivation was detected in 7 patients and well controlled by switch or combination therapy. Graft failure developed in only one patient due to chronic rejection regardless of HBV reactivation but no deaths occurred. All patients were alive at the end of follow-up and none developed end-stage liver disease or hepatocellular carcinoma. There was statistically significant difference in graft survival between HBsAg-positive recipients and HBsAg-negative. Multivariate analysis identified increased HBV DNA levels (>5 x 10(4) IU/mL) in the HBsAg-positive kidney transplant recipients as a risk factor for HBV reactivation (P = 0.007). CONCLUSION: Effective viral suppression with antiviral agents in HBsAg-positive renal transplant recipients improves patient outcome and allograft survival. Antiviral therapy may be especially beneficial in patients with high HBV DNA levels prior to transplantation.

YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study

OBJECTIVE: This study aimed to determine the natural prevalence of variants of tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels. METHODS: A total of 1,042 antiviral treatment naïve CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real-time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA. RESULTS: YMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild-type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level. CONCLUSION: Mutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level.

Analysis of the poor answer situation in chronic hepatitis B with lamivudine treatment / 中国基层医药

Objective To explore the use of lamivudine alone induced the poor response,especially the related factors of the occurrence of YMDD.Methods Retrospective analysis of 160 cases of the poor answering cases after lamivudine treatment,the baseline parameter values,the time appearing to the poor answering and the HBVDNA load in treatment were analyzed,to study their relationship with poor response.Results The lamivudine prolonged,the poor response to the probability gradually increase.The mutation rate in the 12nd month was 19.67％ and in the 36th month was 49.18％ ( P ＜ 0.05 ).Response to the many reasons,the YMDD mutation is the more common one.The relationship among HBVDNA load,ALT level on baseline and the rate of poor response emergence,the YMDD mutation rate was clear.By comparison in groups,the difference was significant (P＜0.05).Conclusion The lower baselins of ALT level,the higher of HBVDNA load,the greater probability of the poor response and the YMDD mutation.

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo / Genotipagem do vírus da hepatite B de pacientes crônicos com resistência ao tratamento com lamivudina na Cidade de Ribeirão Preto, Estado de São Paulo

INTRODUCTION: Lamivudine is a nucleoside analogue that is used clinically for treating chronic hepatitis B infection. However, the main problem with prolonged use of lamivudine is the development of viral resistance to the treatment. Mutations in the YMDD motif of the hepatitis B virus DNA polymerase gene have been associated with resistance to drug therapy. So far, there have not been many studies in Brazil reporting on genotype-dependent development of resistance to lamivudine. Thus, the aim of the present study was to determine the possible correlation between a certain genotype and increased development of resistance to lamivudine among chronic hepatitis B patients. METHODS: HBV DNA in samples from 50 patients under lamivudine treatment was amplified by means of conventional PCR. Samples were collected at Hospital das Clínicas, FMRP-USP. The products were then sequenced and phylogenetic analysis was performed. RESULTS: Phylogenetic analysis revealed that 29 (58 percent) patients were infected with genotype D, 20 (40 percent) with genotype A and one (2 percent) with genotype F. Mutations in the YMDD motif occurred in 20 percent of the patients with genotype A and 27.6 percent of the patients with genotype D. CONCLUSIONS: Despite the small number of samples, our results indicated that mutations in the YMDD motif were 1.38 times more frequent in genotype D than in genotype A.

INTRODUÇÃO: Lamivudina é um análogo de nucleosídeo clinicamente utilizado para o tratamento da infecção crônica pela hepatite B. Entretanto, o principal problema do uso prolongado da lamivudina é o desenvolvimento de resistência viral ao tratamento. Mutações no motivo YMDD no gene da DNA polimerase do vírus da hepatite B estão associados com a resistência a terapia medicamentosa. Até o presente momento, não há muitos estudos no Brasil que descrevem o desenvolvimento genótipo-dependente da resistência à lamivudina. Assim, o intuito do trabalho aqui descrito foi determinar a possível correlação entre um determinado genótipo e o desenvolvimento aumentado da resistência à lamivudina em pacientes com hepatite B crônica. MÉTODOS: O HBV DNA foi amplificado por PCR convencional a partir de 50 amostras coletadas de pacientes submetidos ao tratamento com lamivudina no Hospital das Clínicas- FMRP- USP. Posteriormente, os produtos foram seqüenciados e a análise filogenética foi realizada. RESULTADOS: A análise filogenética mostrou que 29 (58 por cento) pacientes foram infectados com o genótipo D, 20 (40 por cento) com o genótipo A e 1 (2 por cento) com o genótipo F. Mutações no motivo YMDD ocorreu em 20 por cento dos pacientes com genótipo A e 27,6 por cento em pacientes do genótipo D. CONCLUSÕES: Apesar do baixo número de amostras, nossos resultados indicaram que mutações no motivo YMDD são 1,38 X mais frequentes no genótipo D em relação ao genótipo A.

Study on YMDD mutation during Lamivudine therapy of chronic hepatitis B / 临床肝胆病杂志

Objective To investigate the clinical significance of YMDD mutation during Lamivudine therapy on chronic hepatitis B.Methods Fluorometric analysis PCR, ELISA were used to estimate the YMDD mutation, HBVDNA quantative level and HBeAg for HBV of 72 cases with chronic hepatitis B before therapy (0 month), and after Lamivudine therapy for 9,12,18 months.Results The YMDD mutation was not observed in these cases before Lamivudine therapy. The mutation was found in 8 cases (11.1%), 17 cases (23.6%) and 28 cases (38.9%) at 9, 12, 18 month for therapy. The YMDD mutation rate rose with the therapy time lasting (P＜0.05). Moreover, the YmDD mutation rate in the patients with HBVDNA quantity higher than 108 copies/ml was significantly higher than that in the patients with HBVDNA quantity lower than 108 copies/ml (P＜0.005). The YMDD variation rate in patients with HBeAg positive and in patients with HBeAg negative showed no significant difference (P＞0.05). The HBeAg negative conversion rate was significantly higher in non-mutation group than that in mutation group (P＜0.05).Conclusion The serum virus quantity may be regard as an early estimate indication of the development of YMDD mutation during Lamivudine therapy.

Bicycolol tablets in treatment of patients with YMDD mutations of HBV / 中华临床感染病杂志

Objective To evaluate the clinical efficacy and safety of bicyelol tablets in treatment of hepatitis B patients infected with YMDD mutation of HBV. Methods Sixty-eight chronic hepatitis patients infected with HBV YMDD mutants and 100 patients with non-mutants HBV were enrolled in the study. All patients received bicyclol tablets orally 150 mg/d, t. i. d, for 24 weeks. Clinical symptoms, signs and adverse effects were observed, and the blood routine, liver function tests, serum HBV markers and HBV DNA loads were examined at 12th and 24th week of the study, Results After treatment for 24 weeks, the normalization rates of ALT and AST in mutant group were 79.4% ( 54/68 ) and 70. 6% (48/68) ; 11 ( 16. 2% ) patients were markedly effective and 14 (20. 6% ) were effective. Clearance rates of HBeAg and HBV DNA were 27.9% ( 17/61 ) and 17.6% ( 12/68 ), while the seroconversion rate of HBeAg was 14. 7% (9/61). The differences of the above indexes were not statistically significant between mutant group and non-mutant group. Conclusion Bicyciol can both protect liver functions and inhibit virus replication in patients infected with HBV YMDD mutants.

Efficacy of Lamivudine Therapy for Chronic Hepatitis B in Children / 대한소아소화기영양학회지

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.

A case report of treatment with pegylated interferon alpha for lamivudine-resistant chronic hepatitis B virus infection / 대한간학회지

The wide use of lamivudine in chronic hepatitis B has produced a monotonic increase in patients with lamivudine resistance. Therefore, treating lamivudine resistance in chronic hepatitis B is a major concern in clinical practice for the treatment of hepatitis B virus (HBV). There is conflicting evidence on the outcome of pegylated interferon alpha (PEG-IFN alpha) therapy against lamivudine-resistant HBV, which is due to mutations in the YMDD motif. We experienced a patient with chronic hepatitis B who was successfully treated with PEG-IFN alpha-2a after the development of virologic and biochemical breakthrough during lamivudine therapy. Virologic breakthrough was associated with the emergence of YMDD mutants 48 months after starting lamivudine therapy. Treatment with PEG-IFN alpha-2a for 12 months resulted in an undetectable serum level of HBV DNA and the resolution of hepatitis, and the virologic response was maintained over 16 months after cessation of PEG-IFN alpha-2a.

The emergence of YMDD mutants precedes biochemical flare by 19 weeks in lamivudine-treated chronic hepatitis B patients: an opportunity for therapy reevaluation

Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine (LMV) and the availability of new alternative treatments for chronic hepatitis B patients, early detection of viral genotypic resistance could allow the clinician to consider therapy modification before viral breakthrough and biochemical relapse occur. To this end, 28 LMV-treated patients (44 ± 12 years; 24 men), on their first therapy schedule, were monitored monthly at four Brazilian centers for the emergence of drug resistance using the reverse hybridization-based INNO-LiPA HBV DR assay and occasionally sequencing (two cases). Positive viral responses (HBV DNA clearance) after 6, 12, and 18 months of therapy were achieved by 57, 68, and 53 percent of patients, while biochemical responses (serum alanine aminotransferase normalization) were observed in 82, 82, and 53 percent of cases. All viral breakthrough cases (N = 8) were related to the emergence of YMDD variants observed in 7, 21, and 35 percent of patients at 6, 12, and 18 months, respectively. The emergence of these variants was not associated with viral genotype, HBeAg expression status, or pretreatment serum alanine aminotransferase levels. The detection of resistance-associated mutations was observed before the corresponding biochemical flare (41 ± 14 and 60 ± 15 weeks) in the same individuals. Then, if highly sensitive LMV drug resistance testing is carried out at frequent and regular intervals, the relatively long period (19 ± 2 weeks) between the emergence of viral resistance and the onset of biochemical relapse can provide clinicians with ample time to re-evaluate drug therapy.

Clinical study on YMDD mutation and pre-core C region and core promotor region mutation of the patients with chronic hepatitis B virus receiving lamivudine therapy / 中国基层医药

Objective To mvesugate the Tate of YMDD mutation accompamed with pre-core(region and core promotor region mutation and the clinical significance.Methods YMDD mutation and pre-core(at 1896 nu- cleotide)region and core promotor region(at 1762.1764 nucleotide)mutation were detected from the 122 patients with chronic hepatitis B virus after receiving lamivudine treatment above 6 months.Results 40 cases were tested for YMDI)mutations in 122 HBV patients with lamivudine treatment,and the positive rate of YMDD mutation was 32.8 %.After YMDD mutation,ALT,AST and HBV DNA of the patients significantly increased(P0.05).Conclusion The patients with YMDD mutation had higher rate of pre-core region(at 1896 nucleotide)and basal core promotor region(at 1762, 1764 nucleotide)mutation than those without YMDD mutation,but there was no correlation between the mutation and the deterioration of disease condition and the bad prognosis.

YMDD Mutation and Genotype of HBV / 中华医院感染学杂志

0.05).Genotype B with YMDD mutations in 10 samples were found,including 2 YIDD(M+I) mutations and 8 YVDD(M+V) mutations.Genotype C with YMDD mutations in 68 samples were found,including 44 mutations I(M+I) and 24 mutations V(M+V).There was significant difference in YMDD mutation types between genotypes B and C(?2=5.5,P

Relationship Between Variation and Distribution of Differential Gene Sites of Hepatitis B Virus and Enzymatic Activity of Liver Function / 中华医院感染学杂志

0.05).CONCLUSIONS G1896A Variation principally distributes in HBeAg(-) group that expressed low level HBV DNA.A1762T Variation and HBeAg(+) haven′t obvious correlation.YMDD variation principally distributes in HBeAg(+) group that expressed high lever HBV DNA.YMDD variation initiates acute damage of liver cell.The variation of G1896A or A1762T may contribute to progressive damage of chronic liver disease.

Therapeutic Strategy for YMDD Mutants of Hepatitis B Virus / 대한간학회지

No abstract available.

Detection of YMDD Motif Mutants by Oligonucleotide Chips in Lamivudine-Untreated Patients with Chronic Hepatitis B Virus Infection

Lamivudine, a nucleoside analogue, has been used widely as an effective antiviral agent for the treatment of patients with chronic hepatitis B virus (HBV) infection. However, the YMDD motif mutation of HBV polymerase resistant to lamivudine occurs very frequently after long term therapy. We developed an oligonucleotide chip for the detection of YMDD motif mutants resistant to lamivudine and investigated the prevalence of the mutants in patients with chronic HBV infection who had not been treated by lamivudine before. Forty patients who had not been treated with lamivudine were included in this study. Serum samples were tested by the oligonucleotide chips designed for detection of wild-type YMDD motif, M552V and M552I. Samples were confirmed by restriction fragment length polymorphism (RFLP) and direct sequencing. M552I mutants were detected by the oligonucleotide chips in 7.5% (3/40) of chronic HBV infected patients (2 chronic hepatitis and 1 cirrhosis). The results were in accordance with those of RFLP. YMDD motif mutants occur as natural genome variabilities in patients with chronic HBV infection who had not been treated with lamivudine before. Oligonucleotide chip technology is a reliable and useful diagnostic tool for the detection of mutants resistant to antiviral therapy in chronic HBV infection.

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.

Natural YMDD Motif Mutations of HBV Polymerase in the Chronic Hepatitis B Virus Infected Patients / 대한간학회지

BACKGROUND/AIMS: Lamivudine, a nucleoside analogue has been widely used as an effective antiviral agent for the treatment of patients with chronic hepatitis B infection. However, the YMDD motif mutation of HBV polymerase resistant to lamivudine very frequently occurs after long-term use of lamivudine. It is well known that the mutation is selected by the lamivudine. We hypothesized that a few mutant strains of YMDD motif are present as quasispacies before the lamivudine treatment, are selected by the treatment, and breakthrough during treatment. We investigated the prevalence of the YMDD motif mutants in patients with chronic hepatitis B infection who had not been treated by antiviral agents before. METHODS: The study included the serums of 40 patients with chronic heptitis B infection, which stored at -70 degrees C. Thirty-four patients had chronic hepatitis and 6 patients had cirrhosis. Thirty-one patients were diagnosed by liver biopsy. The average age and range were 29 years and 13-57 years respectively. None had taken any antiviral agents before. To detect YMDD mutants, YVDD (M552V), and YIDD (M552I), we used direct sequencing and the restriction fragment length polymorphism (RFLP) method. RESULTS: The YMDD mutant was detected by RFLP method in 7.5% (3/40) of the patients with chronic hepatitis B infection, in two patients with chronic hepatitis and one with cirrhosis. All were YMDD+ YIDD mutants. CONCLUSIONS: The YMDD motif mutation occurs spontaneously without antiviral therapy in patients with chronic hepatitis B infection.

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.

Viral Breakthrough in HBeAg-Negative Chronic Hepatitis B Patients Receiving Lamivudine Therapy / 대한간학회지

BACKGROUND/AIMS: Long-term efficacy and the rate of viral breakthrough in patients with HBeAg- negative chronic hepatitis B receiving lamivudine therapy is uncertain. This study was conducted to determine the rate of viral breakthrough according to the HBeAg status and the relation of viral breakthrough with YMDD mutants. METHODS: Two hundred and five patients with HBeAg-positive and 49 patients with HBeAg-negative chronic hepatitis B, who had received lamivudine for at least 9 months, were included. The mean durations of the lamivudine treatment were 176 months and 155 months in HBeAg-positive and negative patients, respectively. Analysis of HBV genome for YMDD mutations was performed by restriction-fragment-length polymorphism assay and direct sequencing. RESULTS: While the cumulative rates of viral breakthrough at 12th and 24th months of the lamivudine therapy were 0% and 7% in the HBeAg-negative group, they were 12% and 39% in the HBeAg-positive group. The cumulative rate of viral breakthrough in the HBeAg-negative group was significantly lower than in the HBeAg-positive group (p<0.01). In multivariate analysis, the only significant factor related to viral breakthrough was the HBeAg status (p<0.05). The YMDD mutants were detected in all patients with viral breakthrough irrespective of HBeAg status. However, in patients without viral breakthrough, the rate of YMDD mutants was significantly higher in the HBeAg-negative group than in the HBeAg-positive group (13.3% vs 5.1%; p<0.01). CONCLUSIONS: Lamivudine is expected to be more persistently effective in HBeAg-negative chronic hepatitis B because of a lower viral breakthrough rate than in HBeAg-positive chronic hepatitis B in spite of the emergence of YMDD mutants.

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.

Emergence of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy / 대한내과학회지

BACKGROUND: The emergence of YIDD or YVDD mutant hepatitis B virus (HBV), with point mutation in the YMDD motif of DNA polymerase gene, has been reported in patients with lamivudine treatment group. The aims of this study was to investigate the emergence of mutant HBV during long-term lamivudine therapy using nested polymerase chain reaction (PCR) method and direct DNA sequencing. METHODS: Twenty-one chronic hepatitis B patients with HBeAg and HBV DNA positive were evaluated. During lamivudine therapy, there were reported breakthroughs of HBV DNA (over 50 pg/mL) when investigated the emergence of YMDD mutants by nested PCR method using restriction fragment length polymorphism (RFLP) in all patients. Direct DNA sequencing of HBV DNA polymerase gene including YMDD motif was also performed. RESULTS: There were 13 patients (61.9%) with YIDD mutant and 8 patients (38.1%) with YVDD mutant. The results of direct DNA sequencing were consistent with those of nested PCR data based on RFLP. The breakthrough was occurred at 15 to 106 weeks (57.9+/-23.6). At the point of breakthrough, the level of ALT was 74.8+/-117.7 (14-546) IU/L, and it was lower than the level of ALT before the therapy. CONCLUSION: In the long-term therapy of lamivudine, the emergence of YMDD motif mutant HBV was related to the breakthrough of HBV DNA and YIDD mutant was frequent. The nested PCR method using RFLP may be simple and sensitive to detect the YMDD motif mutant HBV.