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Hepatitis B E Antigen (hepatitis + b_e_antigen)
Terms modified by Hepatitis B E Antigen Selected AbstractsEffect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitroHEPATOLOGY, Issue 1 2003Robert Y. M. Chen Hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame that creates a stop codon, causing premature termination of the PC protein. During lamivudine treatment, drug resistance develops at a similar rate in HBeAg positive and HBeAg negative CHB. Lamivudine-resistant HBV mutants have been shown to replicate inefficiently in vitro in the absence of PC mutations, but it is unknown whether the presence of PC mutations affects replication efficiency or antiviral sensitivity. This study utilized the recombinant HBV baculovirus system to address these issues. HBV baculoviruses encoding the G1896A PC stop codon mutation were generated in wild-type (WT) and lamivudine-resistant (rtM204I and rtL180M + rtM204V) backgrounds, resulting in a panel of 6 related recombinant baculoviruses. In vitro assays were performed to compare the sensitivities of the PC mutant viruses with lamivudine and adefovir and to compare relative replication yields. The PC mutation did not significantly affect sensitivities to either adefovir or lamivudine. WT HBV and PC mutant HBV showed similar replication yields, whereas the replication yields of the lamivudine-resistant mutants were greatly reduced in HBeAg positive HBVs, confirming previous observations. However, the presence of the PC mutation was found to compensate for the replication deficiency in each of the lamivudine-resistant mutants, increasing the replication yields of each virus. In conclusion, the PC stop codon mutation appears to increase the replication efficacy of lamivudine-resistant virus but does not affect in vitro drug sensitivity. [source] Hepatitis B e antigen,negative chronic hepatitis BHEPATOLOGY, Issue 4 2001Stephanos J. Hadziyannis M.D. First page of article [source] Molecular epidemiological study of hepatitis B virus infection in two different ethnic populations from the Solomon IslandsJOURNAL OF MEDICAL VIROLOGY, Issue 3 2007Takako Utsumi Abstract The Solomon Islands is a multi-ethnic nation with a high rate of hepatitis B virus (HBV) infection. The prevalence relative to ethnicity was examined in relation to HBV infection, genotypes, and mutations. Asymptomatic populations (n,=,564, 308 Melanesian and 118 Micronesian) from the Western Province were enrolled. Positive samples for Hepatitis B surface antigen (HBsAg) were examined for serological status, genotyping, viral load, and mutations of the basic core promoter (BCP) and pre-core (Pre-C) regions. The positive rate for HBsAg was 21.5%. The major Melanesian genotype was C (HBV/C), whereas the major Micronesian genotype was D (HBV/D). The prevalence of Hepatitis B e antigen (HBeAg) in serum was lower in carriers of HBV/D than of HBV/C. While the prevalence of the BCP mutation (T1762A1764) tended to be higher in HBV/C, that of the Pre-C mutation (T1846) was significantly higher in HBV/D (P,<,0.0001). Genetic distance and phylogenetic analyses based on complete genome sequences were also carried out for two strains of HBV/C and two strains of HBV/D, and the findings were compared with those in the DDBJ/EMBL/GenBank database. The full-length sequence revealed that strains from the Solomon Islands were classified into subgenotype C3 (HBV/C3) and D4 (HBV/D4), and that the HBV/D strains were related closely to those from Papua New Guinea. HBV infection in the Solomon Islands is hyperendemic, and the genotype is ethnicity-specific. HBeAg appears to clear from the serum in young adulthood in HBV/D infection, which may be influenced by genotype-dependent features in relation to viral mutations. J. Med. Virol. 79:229,235, 2007. © 2007 Wiley-Liss, Inc. [source] Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B,,HEPATOLOGY, Issue 3 2010Ting-Tsung Chang One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ,2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (,2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ,1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010) [source] Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels,HEPATOLOGY, Issue 2 2010Vincent Rijckborst Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg),negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB. (HEPATOLOGY 2010) [source] Serum hepatitis B surface antigen and hepatitis B e antigen titers: Disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers,,HEPATOLOGY, Issue 6 2010Alexander J.V. Thompson Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. Conclusion: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker. (HEPATOLOGY 2010) [source] Endpoints of therapy in chronic hepatitis B,HEPATOLOGY, Issue S5 2009Jordan J. Feld Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly. At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96,S102.) [source] Benefits and risks of interferon therapy for hepatitis B,HEPATOLOGY, Issue S5 2009Robert Perrillo Alpha interferon is the only licensed drug for hepatitis B with immunomodulatory as well as viral inhibitory properties. Potential advantages of interferon compared to nucleoside analogs include a lack of drug resistance, a finite and defined treatment course, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. Approximately 30% of hepatitis B e antigen (HBeAg)-positive and 40% of HBeAg-negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or hepatitis B virus (HBV) DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48-week course of peginterferon alfa-2a These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Recent studies have shown that changes in HBsAg and HBeAg concentration during treatment predict sustained virological response and serial monitoring of HBsAg is helpful in predicting HBsAg clearance. HBeAg-positive patients with genotype A have higher rates of HBeAg and HBsAg clearance, whereas HBeAg-negative patients with genotype D have the lowest rate of response to interferon therapy. Long-term follow-up of virological responders to either standard alpha interferon or peginterferon has demonstrated a progressive increase in the rate of HBsAg clearance, particularly in patients who were initially HBeAg-positive. Future studies need to address if specific virological benchmarks during therapy can be used to tailor treatment duration. Conclusion: Peginterferon alfa has a place as first-line therapy of hepatitis B in patients who are carefully selected on the basis of pretreatment serum HBV DNA and aminotransferase levels, safety considerations, and viral genotype. (HEPATOLOGY 2009;49:S103,S111.) [source] Treatment recommendations for chronic hepatitis B: An evaluation of current guidelines based on a natural history study in the United States,HEPATOLOGY, Issue 4 2008Myron John Tong Current guidelines for treatment of chronic hepatitis B include hepatitis B e antigen (HBeAg) status, levels of hepatitis B virus (HBV) DNA, and serum alanine aminotransferase (ALT) values in the setting of either chronic hepatitis or cirrhosis. Based on findings from a prospective study of hepatitis B surface antigen (HBsAg)-positive patients, we determined whether these guidelines included patients who developed hepatocellular carcinoma (HCC) and who died of non-HCC liver-related complications. The criteria for treatment from four published guidelines were matched to a cohort of 369 HBsAg-positive patients enrolled in the study. During a mean follow-up of 84 months, 30 patients developed HCC and 37 died of non-HCC liver-related deaths. Using criteria for antiviral therapy as stated by the four guidelines, only 20%-60% of the patients who developed HCC, and 27%-70% of patients who died of non-HCC liver-related deaths would have been identified for antiviral therapy according to current treatment recommendations. If baseline serum albumin levels of 3.5 mg/dL or less or platelet counts of 130,000 mm3 or less were added to criteria from the four treatment guidelines, then 89%-100% of patients who died of non-HCC liver-related complications, and 96%-100% of patients who developed HCC would have been identified for antiviral therapy. In addition, if basal core promoter T1762/A1764 mutants and precore A1896 mutants also were included, then 100% of patients who developed HCC would have been identified for treatment. Conclusion: This retrospective analysis showed that the current treatment guidelines for chronic hepatitis B excluded patients who developed serious liver-related complications. (HEPATOLOGY 2008.) [source] Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia,HEPATOLOGY, Issue 4 2008Maura Dandri Analysis of hepatitis B virus (HBV) kinetics with mathematical models may disclose new aspects of HBV infection and host response mechanisms. To determine the kinetics of virion decay from the blood of patients in different phases of chronic infection, we applied mathematical modeling to real-time polymerase chain reaction assays, which enable quantification of viremia and intrahepatic HBV productivity by measuring both copy number and activity of covalently closed circular DNA (relaxed circular DNA/covalently closed circular DNA) in the liver of 80 untreated chronically active HBV carriers (38 hepatitis B e antigen [HBeAg]-positive and 42 HBeAg-negative individuals). We found that the half-life of circulating virions is very fast (median 46 and 2.5 minutes in HBeAg-positive and HBeAg-negative individuals, respectively) and strongly related to viremia, with clearance rates significantly accelerating as viral loads decrease. To investigate whether immune components can influence the kinetics of virion decay, we analyzed viral dynamics in immunodeficient urokinase-type plasminogen activator chimera mice. Virion half-life in mice (range, 44 minutes to >4 hours) was comparable to estimates determined in high viremic carriers, implying that clearance rates in these patients are mostly determined by common nonspecific mechanisms. Notably, the lack of correlation between virion half-life and viremia in mice indicated that immune components significantly accelerate virion clearance rates in individuals with low titers. Conclusion: Our analyses suggest that both host defense mechanisms and levels of circulating virions affect the kinetics of HBV decay assessed in the serum of chronic carriers. Identification of the factors affecting clearance rates will be important for future antiviral drug developments and it may give insights into the mechanisms involved in clearance of other chronic infections, such as human immunodeficiency virus and hepatitis C virus. (HEPATOLOGY 2008.) [source] Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen,positive chronic hepatitis B,HEPATOLOGY, Issue 3 2008Patrick Marcellin Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log10 copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 × upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log10 copies/mL and ,50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. Conclusion: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement. (HEPATOLOGY 2008;48:750,758.) [source] Serum hepatitis B virus-DNA cutoff levels in hepatitis B e antigen,negative chronic hepatitis B virus infection,HEPATOLOGY, Issue 2 2007George V. Papatheodoridis No abstract is available for this article. [source] Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection,,HEPATOLOGY, Issue 2 2006Atsushi Ozasa The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 ± 16.3 vs. 36.0 ± 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n = 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection. (HEPATOLOGY 2006;44:326,334.) [source] Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipientsHEPATOLOGY, Issue 5 2002Tak Mao Chan Hepatitis B surface antigen (HBsAg)-positive kidney transplant recipients have increased liver-related mortality. The impact of lamivudine treatment on patient survival, the optimal time to start treatment, and the feasibility of discontinuing treatment have not been determined. This study examined these issues with a novel management protocol. Serum hepatitis B virus (HBV) DNA levels were measured serially in HBsAg-positive kidney transplant recipients, and lamivudine was administered preemptively to patients with increasing HBV DNA levels with or without elevation of aminotransferase levels. Outcomes of patients who underwent transplantation before or after institution of this preemptive management strategy (in January 1996) were compared. Eleven de novo patients (91.7%) who underwent transplantation between 1996 and 2000 and 15 existing patients (39.5%) who underwent transplantation between 1983 and 1995 received preemptive lamivudine therapy for 32.6 ± 13.3 months. The treatment criteria were met by de novo patients at 8.4 ± 6.2 months (range, 1-18 months) after transplantation. Suppression of HBV DNA and normalization of aminotransferase levels were achieved in all treated patients, and 21.4% had hepatitis B e antigen (HBeAg) seroconversion. The survival of preemptively managed de novo transplant patients was similar to that of HBsAg-negative controls, whereas HBsAg-positive patients who underwent transplantation before January 1996 had inferior survival (relative risk of death, 9.7 [P < .001]; relative risk of liver-related mortality, 68.0 [P < .0001]). Eleven patients (40.7%) developed lamivudine resistance. Discontinuation of lamivudine was attempted in 12 low-risk patients after stabilization and was successful in 5 (41.7%). In conclusion, preemptive lamivudine therapy based on serial HBV DNA levels and clinical monitoring improved the survival of HBsAg-positive renal allograft recipients. Treatment can be discontinued safely in selected patients after stabilization to minimize the selection of drug-resistant HBV mutants. [source] Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: Is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?HEPATOLOGY, Issue 5 2001Satheesh Nair During interferon treatment of chronic hepatitis B, an alanine aminotransferase (ALT) flare may herald a sustained loss of viral replication, but the relationship between virologic response, the extent of a flare, and pretreatment hepatitis B virus (HBV) DNA level has not been defined. We retrospectively examined the impact of an ALT flare on sustained virologic response in 121 interferon-treated patients and 42 untreated controls with either low-level (<100 pg/mL) or high-level (,100 pg/mL) viremia. The degree of ALT flare was classified as mild (increase in ALT of 86-171 IU/L above baseline), moderate (increase of 172 to 343 IU/L above baseline), and severe (increase of ,344 IU/L above baseline). Undetectable serum HBV DNA and hepatitis B e antigen (HBeAg) loss were significantly more likely at the end of follow-up in patients having a flare (P = .0001 and .001, respectively). In the high viremia group, a proportionate increase in virologic response was observed as the degree of flare increased. By multivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predictor for a sustained loss of serum HBV DNA (odds ratio, 5.3; P = .004). Severe flare was predictive of a virologic response in the high but not low viremia group. We conclude that a virologic response in patients with high-level viremia is dependent on the degree of ALT flare. Induction of a robust flare may enhance virologic response when high-level viremia is detected. [source] Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in KoreaHEPATOLOGY, Issue 4 2000Byung-Cheol Song It has been suggested that hepatitis B e antigen (HBeAg) seroconversion after lamivudine therapy is durable in Caucasians with chronic hepatitis B (CHB). However, little is known whether it is also durable in endemic areas of hepatitis B virus (HBV) infection. We evaluated the posttreatment durability of lamivudine-induced HBeAg seroconversion and the predictive factors for relapse in Korean patients with CHB. We retrospectively analyzed 98 HBeAg-positive patients with CHB who were treated with lamivudine between August 1996 and December 1997. Lamivudine was given at a dose of 150 mg per day. After HBeAg seroconversion, lamivudine was continued for an additional 2 to 4 months, and posttreatment monitoring continued for up to 24 months. HBeAg seroconversion was achieved in 34 of the 98 patients (34.7%). The mean duration of treatment in these seroconverters was 9.3 ± 3.0 months. During the follow-up period, the cumulative relapse rates at 1 year and 2 years posttreatment were 37.5% and 49.2%, respectively. Most relapses were accompanied by elevation of serum alanine transaminase (94%) and reappearance of HBeAg (81%). Pretreatment serum HBV DNA levels and the duration of additional lamivudine therapy after HBeAg seroconversion were 2 independent predictive factors for posttreatment relapse. In conclusion, lamivudine-induced HBeAg seroconversion was not durable in this endemic area. And the duration of additional lamivudine therapy after HBeAg seroconversion significantly affected the posttreatment relapse. Further studies are needed to determine the duration of lamivudine and to elucidate the cause of high relapse after HBeAg seroconversion in endemic areas of HBV. [source] Prednisolone Priming Enhances Th1 Response and Efficacy of Subsequent Lamivudine Therapy in Patients With Chronic Hepatitis BHEPATOLOGY, Issue 3 2000Yun-Fan Liaw M.D. Asian lamivudine trial has shown that hepatitis B e antigen (HBeAg) seroconversion rate during 1 year of lamivudine therapy was only 16% but was 64% in the subgroup of patients with a pretherapy serum alanine transaminase (ALT) level over 5 times the upper limit of normal (ULN). To test whether ALT rebound following corticosteroid priming enhances response to lamivudine therapy, a pilot study was conducted in 30 patients with ALT levels less than 5× ULN (43-169; N < 36 U/L). They received 30 mg of prednisolone daily for 3 weeks, 15 mg daily for 1 week, no treatment for 2 weeks, and then 150 mg of lamivudine daily for 9 months. Complete response (CR) was defined as ALT normalization with HBV-DNA seroclearance and HBeAg seroconversion. Peripheral blood mononuclear cell proliferation and cytokine secretion in response to recombinant HBV core antigen were serially assayed in 7 patients during priming and after withdrawal of prednisolone. Clinical rebound with an ALT over 5× ULN was observed in 20 patients (67%). Of these 20, 12 (60%) showed CR as compared with 1 (10%) of the 10 patients without significant ALT rebound (P < .002). The HBeAg seroconversion sustained in 70% of the patients 3 to 6 months after the end of lamivudine therapy. Immunological assays revealed that the responders showed Th1 dominant response and higher stimulation index to prednisolone priming. No serious side effect was encountered. These results suggest that corticosteroid priming induced immune/ALT rebound greatly enhances response to lamivudine therapy in chronic hepatitis B. Confirmation by randomized controlled trial is needed. [source] Combination therapy with lamivudine and famciclovir for chronic hepatitis B,infected Chinese patients: A viral dynamics studyHEPATOLOGY, Issue 2 2000George Ka Lau M.D. In vitro studies have shown that lamivudine and penciclovir (the active metabolite of famciclovir) act synergistically to inhibit hepatitis B virus (HBV) replication. We compared the effectiveness of HBV viral suppression by lamivudine monotherapy versus lamivudine plus famciclovir combination therapy in Chinese patients with chronic HBV infection. Twenty-one Chinese hepatitis B e antigen (HBeAg)-positive patients, with detectable HBV DNA (Digene Hybrid Capture II), were randomized to receive either lamivudine 150 mg/d orally (group 1, 9 patients) or lamivudine 150 mg/d plus famciclovir 500 mg 3 times a day orally (group 2, 12 patients) for 12 weeks, with a follow-up period of at least 16 weeks. Serial serum HBV-DNA levels were determined and a mathematical model with provision for incomplete inhibition of virus production during therapy was applied to analyze the dynamics of viral clearance. The mean antiviral efficacy was significantly greater in group 2 than in group 1 (0.988 ± 0.012 vs. 0.94 ± 0.03, P = .0012). HBV DNA returned to pretreatment level within 16 weeks after the end of initial treatment in 4 patients (66.7%) in group 1 and none in group 2 (P = .08), who remained HBeAg positive and received no further treatment after week 12. Hence, in Chinese chronic HBeAg-positive patients, combination therapy using lamivudine and famciclovir was superior to lamivudine monotherapy in inhibiting HBV replication. Further studies of longer duration are needed to define whether combination therapy will increase the HBeAg seroconversion rate and decrease the rate of emergence of lamivudine-resistant variants. [source] Effect of nucleoside analog-interferon sequential therapy on patients with acute exacerbation of chronic hepatitis BHEPATOLOGY RESEARCH, Issue 5 2010Chiaki Okuse Aim:, Nucleoside analog (NA)-interferon (IFN) sequential therapy may enable the long-term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA-IFN sequential therapy for acute exacerbation of CHB. Methods:, A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN-, 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN-, alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results:, Four out of nine (44.4%) HBeAg-positive and all three HBeAg-negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core-related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion:, NA-IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment. [source] Adefovir dipivoxil: review of a novel acyclic nucleoside analogueINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 9 2004M. Danta Summary Adefovir dipivoxil (ADF) is a novel acyclic nucleoside analogue that has recently been approved for the treatment of chronic hepatitis B virus (HBV). Adefovir was initially assessed at higher doses for the treatment of human immunodeficiency virus (HIV) infection. However, in these studies, nephrotoxicity proved a dose-limiting side effect. Large randomised controlled studies have recently shown that ADF results in histological, virological and biochemical improvement in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic HBV. While the rate of HBeAg seroconversion at 1 year (12%) was lower than both lamivudine and interferon, this increases with prolonged treatment. The clinical improvements occurred without serious side effects or the development of resistance at the dose of 10 mg daily, in treatment trials of up to 2 years, although resistance has now been observed. In addition, the drug is efficacious in HBV/HIV co-infection and hepatitis B-infected liver transplant recipients, particularly in those who have developed lamivudine resistance. ADF can be added as a treatment option to existing treatment options (interferon-alpha and lamivudine) and assumes a role in the ongoing management of chronic HBV. The optimal use of ADF as either a monotherapy or as part of combination therapy requires further assessment. [source] Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infectionJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2008Jun-ping Shi Abstract Background and Aims:, The clinical significance of hepatic steatosis in chronic hepatitis B infection (CHB) is unclear. The aims of this study were thus to investigate the prevalence and risk factors for hepatic steatosis in patients with CHB and its relationship with liver injury. Methods:, Consecutive patients with biopsy-proven CHB at Hangzhou Sixth People's Hospital between January 2005 and June 2007 were included. Patients co-infected with other viruses or suffering from liver disease of any other cause were excluded. Liver steatosis, necroinflammation and fibrosis were assessed by both Brunt and Scheuer classifications. Results:, A total of 1915 patients (1497 men) with a mean age of 31 ± 9.5 years were analyzed. Hepatic steatosis was present in 260 (14%) patients. The steatosis involved < 33% of hepatocytes in 90% of cases, and was more frequent among men than women (15% vs 8%, P < 0.001). Two-thirds (178 of 260) of patients with steatosis were hepatitis B e antigen (HBeAg)-positive, but there was no correlation with either serum HBeAg status or hepatitis B virus DNA titer. Degree of inflammation and fibrosis were more mild among those with steatosis than those without. Multivariate analysis showed that steatosis was independently associated with body mass index, serum triglyceride, apolipoprotein B, uric acid, and fasting blood glucose. However, fibrosis was only independently associated with age and inflammatory grade, and the latter associated with viral load and fibrosis stage. Conclusions:, Hepatic steatosis is common in CHB, it is associated with metabolic factors not viral ones, and does not appear to affect the severity of liver disease. [source] Combination therapy of thymosin alpha-1 and lamivudine for HBeAg positive chronic hepatitis B: A prospective randomized, comparative pilot studyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2008Hyun Woong Lee Abstract Background and Aim:, Monotherapy of lamivudine, interferon-alpha (IFN-,), and thymosin alpha-1 (T,1) is unlikely to be sufficient for the eradication of a chronic hepatitis B virus (HBV) infection. The aim of our study is to elucidate whether the combination of T,1 and lamivudine is superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naïve patients with chronic hepatitis B. Methods:, Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received T,1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously. Results:, The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201). Conclusions:, The combination treatment of T,1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of T,1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs. [source] Pre- and post-treatment predictors of the early achievement of HBeAg loss in lamivudine-resistant patients receiving adefovir therapyJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2007Jeong Won Jang Abstract Background and Aim:, This study investigated the clinical variables that predict hepatitis B e antigen (HBeAg) loss in lamivudine-resistant patients receiving adefovir therapy. Methods:, Fifty-six consecutive HBeAg-positive patients treated with adefovir for at least 12 months were enrolled in this study. All had serum alanine aminotransferase (ALT) levels over twice the upper limit of normal (ULN) as a result of lamivudine resistance. Predictors of HBeAg loss after switching from lamivudine to adefovir were examined. Results:, During the follow-up period, 18 (32.1%) of 56 patients showed a loss of HBeAg. The estimated rates of HBeAg loss at 6, 12, and 18 months were 11.5%, 26.8%, and 42.9%, respectively. Univariate analysis revealed that pretreatment ALT levels >10 × ULN (P = 0.029), a viral load at 3 months of therapy (P = 0.017), and viral decline by >3 log10 from baseline at 3 months (P < 0.001) were significantly associated with the loss of HBeAg within 12 months of therapy. With multivariate analysis using the stepwise logistic regression model, pretreatment ALT > 10 × ULN (odds ratio [OR], 4.22; 95% confidence interval [CI], 1.09,19.44; P = 0.044) and viral suppression >3 log10 at 3 months (OR, 10.39; 95% CI, 1.86,58.07; P = 0.008) were identified as the two independent predictors of HBeAg loss. Conclusions:, Pretreatment ALT levels and the initial pattern of post-treatment viral decline are the strongest predictors of the early achievement of HBeAg loss following treatment with adefovir in lamivudine-resistant patients. These results may provide useful information for the optimal timing of adefovir rescue as well as for better monitoring after treatment. [source] Four years of lamivudine treatment in Chinese patients with chronic hepatitis BJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2004TING-TSUNG CHANG Abstract Background and Aims:, This study assessed the efficacy and safety of up to 4 years of lamivudine treatment and the clinical relevance of the emergence of YMDD-variant hepatitis B virus (HBV). Methods:, Fifty-eight Chinese adult patients with chronic hepatitis B (CHB) were randomized to lamivudine 100 mg/day for up to 5 years and were monitored for YMDD-variant HBV, hepatitis B e antigen (HBeAg) seroconversion (loss of HBeAg and detectable antibody to HBeAg) and serum alanine aminotransferase (ALT) concentrations. Four-year data are reported here. Results:, The rate of HBeAg seroconversion increased with extended therapy and also with higher baseline ALT concentrations. YMDD-variant HBV was detected in 67% (39/58) of patients at some point during treatment. After 4 years, a total of 47% (27/58) of patients achieved HBeAg seroconversion. Thirty-three per cent (13/39) of patients with YMDD-variant HBV achieved HBeAg seroconversion; this increased to 57% (8/14) in patients with moderately elevated (>2,5 × upper limit of normal) pre-treatment ALT concentrations. The proportion of patients that achieved normal serum ALT increased from 29% (17/58) at baseline to 69% (31/45) following 4 years of treatment. That included 68% (23/34) of patients with YMDD-variant HBV and 73% (8/11) of those without the variant. All patients receiving lamivudine had reduced serum concentrations of HBV-DNA compared with baseline, despite the emergence of YMDD-variant HBV in 39 patients. Lamivudine was generally well tolerated; there was little change in the number or type of drug-related adverse events in the fourth year of the study. Conclusions:, Despite the emergence of YMDD-variant HBV, Chinese patients showed increased HBeAg seroconversion and improvement in ALT levels with an increased duration of treatment with lamivudine. [source] Effects of interferon alpha therapy on the catalytic domains of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virusJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2003ROBERT YUNG MING CHEN Aims: The aim of the present study was to examine the catalytic domains of the polymerase gene, the basal core promoter and the precore and core regions of the hepatitis B virus (HBV) genome for specific mutations. These may account for the response to interferon alpha (IFN-,) treatment, which may have prognostic value. Methods: Multiple serum samples were collected prospectively from 30 patients with chronic active hepatitis B who were treated with IFN-,. Patients were assigned to one of three groups: group A (n = 11) and group B (n = 10) individuals were hepatitis B e antigen (HBeAg)-positive prior to treatment. Group A patients underwent HBeAg seroconversion after treatment while group B patients did not. Group C (n = 9) patients were HBeAg-negative prior to treatment. The HBV DNA was extracted from the sera collected before, during and after treatment and the various genomic regions were amplified, sequenced and examined for mutations. Results: During IFN-, therapy, multiple changes were found in the catalytic domains of the HBV polymerase gene in all groups. The frequency of mutations and associated amino acid changes were highest in virus from group C patients and lowest in group A patients. The interdomain regions of the viral polymerase were the most affected. Multiple mutations were also found in the precore, core and core promoter regions. However, no specific mutations were associated with clinical response or outcome. Conclusions: During IFN-, treatment, multiple mutations occurred in the HBV genome, including the catalytic domains of the polymerase gene. Changes that did occur could not be correlated to the clinical response or treatment outcome. However, no mutations were found that have been linked to lamivudine escape, indicating that lamivudine therapy would be effective in IFN-, non-responder patients. [source] Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2002RAJKUMAR C GUPTAN AbstractBackground and Aims : Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B infection. The efficacy of combination therapy to enhance the immunomodulatory effect of IFN by combining granulocyte-macrophage colony-stimulating factor (GMCSF) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. Methods : Twenty-four patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. The end-of-treatment response was assessed by hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg) determination. Results : All patients successfully completed both the treatment schedules. The mean age, alanine aminotransferase (ALT) levels, liver histology, HBV-DNA levels and distribution of HBV genotypes were comparable between the two groups. At the end of treatment there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60%) patients in group A and in seven of 14 (50%) patients in group B. During a mean follow-up of 15 ± 3 months, two of six (33%) patients in group A and three of seven (43%) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40% and 28%, respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. There was a trend in patients with genotype A compared with genotype D towards non-response to therapy, although the difference was not significant. Conclusions : The combination of IFN plus GMCSF or lamivudine was effective in non-responders to IFN monotherapy. Larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B. © 2002 Blackwell Publishing Asia Pty Ltd [source] Change of hepatitis B virus genotypes in acute and chronic infections in JapanJOURNAL OF MEDICAL VIROLOGY, Issue 11 2008Mariko Kobayashi Abstract During 35 years from 1971 to 2005, 153 patients with acute and 4,277 with chronic HBV infection visited the Toranomon Hospital in Tokyo, Japan. They were grouped into seven 5-year periods, and HBV genotypes/subgenotypes were determined. Patients with acute HBV infection were younger (P,=,0.046), predominantly male (P,=,0.004), possessed higher alanine aminotransferase levels (P,<,0.001), positive more frequently for HBeAg (P,<,0.001), and had lower HBV DNA loads (P,=,0.014) than those with chronic infection. Sexual transmission was more frequent in patients with acute than chronic HBV infection (67% vs. 3%, P,<,0.001). The number of patients with acute infection increased throughout 1971,2005. Patients with chronic infection increased since 1971, peaked in 1986,1990 and then decreased. The number of patients increased since 1990,2000 again, however, reflecting recent boost of acute HBV infection. The distribution of HBV genotypes was considerably different between patients with acute and chronic infections (A, B, and C: 28.6%, 10.3%, and 59.5% vs. 3.0%, 12.3%, and 84.5%, respectively, P,<,0.001). Since 1991, genotype A foreign to Japan started to increase sharply in patients with acute infection, and gradually in those with chronic infection. There was a trend for the foreign subgenotype B2/Ba to increase recently (P,<,0.05). Despite immunoprophylaxis of high-risk babies born to carrier mothers with hepatitis B e antigen, implemented nationally since 1986, acute and chronic infections with HBV have been increasing in Japan. Based on genotypes/subgenotypes changing with time, the resurgence of hepatitis B could be attributed to infections, with foreign HBV genotypes/subgenotypes, spreading swiftly by sexual contact. J. Med. Virol. 80:1880,1884, 2008. © 2008 Wiley-Liss, Inc. [source] Characterization of viral kinetics in patients with hepatitis B e antigen-positive chronic hepatitis BJOURNAL OF MEDICAL VIROLOGY, Issue 6 2007I-Chin Wu Abstract A study was conducted during a 1 year follow-up to characterize the viral kinetics in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and to develop a model of predicting the probability of spontaneous HBeAg seroconversion. Fifty-seven patients with HBeAg-positive chronic hepatitis B were enrolled with monthly follow-ups from three Phase III clinical trial placebo groups. According to serial viral loads, 30 patients (52.6%) with the stationary pattern maintained stable HBV DNA levels with fluctuations of less than 1.5 log copies/ml. Twenty patients (35.1%) with the declining pattern exhibited a spontaneous decline of more than 1.5 log copies/ml without a following rebound of at least 1.5 log copies/ml. The remaining seven patients (12.3%) had the wavering pattern. Both declining and wavering patterns, when compared with the stationary pattern, had significantly higher hepatic necroinflammation in terms of ALT and Knodell scores at the baseline and peak ALT levels during the follow-up period. The declining pattern had a significantly better clinical outcome in terms of the lowest final HBV DNA and a reduction in the necroinflammatory score after 1 year. Furthermore, the declining pattern had a favorable HBeAg seroconversion rate (40%) compared with the wavering (14.3%) and stationary patterns (0%). A regression equation, incorporating simultaneous serum bilirubin, ALT, and HBV DNA levels, predicted the probability of HBeAg seroconversion with a sensitivity of 76.8% and a specificity of 74.7%. In conclusion, different viral kinetic patterns in patients with chronic hepatitis B implicate distinct clinical significance and immunologic perspective. J. Med. Virol. 79: 663,669, 2007. © 2007 Wiley-Liss, Inc. [source] Serological markers of hepatitis B, C, and E viruses and human immunodeficiency virus type-1 infections in pregnant women in Bali, IndonesiaJOURNAL OF MEDICAL VIROLOGY, Issue 4 2005I Gede Putu Surya Abstract Except for hepatitis B virus (HBV), there have been few data on serological markers of hepatitis viruses such as hepatitis C virus (HCV) and E virus (HEV), and human immunodeficiency virus type-1 (HIV) in Bali, Indonesia. During 5 months from April to August 2003, sera were collected from 2,450 pregnant women at eight jurisdictions in Bali, and they were tested for markers of these viruses. Only one (0.04%) was positive for antibody to HCV, but none for antibody to HIV. Hepatitis B surface antigen (HBsAg) was detected in 46 (1.9%) at a prevalence significantly lower than that in 271 of the 10,526 (2.6%) pregnant women in Bali surveyed 10 years previously (P,<,0.045). The prevalence of hepatitis B e antigen in pregnant women with HBsAg decreased, also, from 50% to 28% during the 10 years (P,<,0.011). Antibody to HEV (anti-HEV) was examined in 819 pregnant women who had been randomly selected from the 2,450. The overall prevalence of anti-HEV was 18%, and there were substantial regional differences spanning from 5% at Tabanan district to 32% at Gianyar district. Furthermore, the prevalence of anti-HEV differed substantially by their religions. In the Sanglah area of Denpasar City, for instance, anti-HEV was detected in 20 of the 102 (20%) Hindus, significantly more frequently than in only 2 of the 101 (2.0%) Muslims (P,<,0.001). Swine that are prohibited to Muslims, therefore, is likely to serve as a reservoir of HEV in Bali. In conclusion, HBV is decreasing, HCV and HIV have not prevailed, as yet, while HEV is endemic probably through zoonotic infection in Bali. J. Med. Virol. 75:499,503, 2005. © 2005 Wiley-Liss, Inc. [source] Clinical and virological characteristics of lamivudine resistance in chronic hepatitis B patients: A single center experienceJOURNAL OF MEDICAL VIROLOGY, Issue 3 2005Jian Sun Abstract We have investigated the characteristics of lamivudine-resistant strains in patients with chronic hepatitis B in Guangdong, China, where the predominant genotypes are B and C. Two hundred forty-seven patients treated with lamivudine in Nanfang Hospital were followed-up. Patients with hepatitis B e antigen (HBeAg) positive and hepatitis B virus (HBV)-DNA levels over 7.5,×,106 copies/ml at baseline had a shorter time to the selection of YMDD mutant (P,=,0.02 and 0.00, respectively). The detection of YMDD mutant precedes HBV-DNA breakthrough and alanine transaminase (ALT) flare in about 2 and 3 months, respectively. The ALT flare after the appearance of YMDD mutants was more evident in HBeAg positive patients than HBeAg negative patients (P,=,0.02). After emergence of YMDD mutant, the HBV-DNA level was significantly higher in genotype C patients compared with genotype B patients (P,=,0.02). No significant difference of YMDD mutant pattern was found between patients with genotype B and C. Four kinds of new mutants were found in over two patients including rtL80I, rtG172E, rtG174C, and rtG172E/rtG174C. In vitro transfection and real-time analysis showed that rtG172E, rtG174C, and rtG172E/rtG174C mutants had a decreased replication competence compared with wild type (33%, 27%, and 15% of the wild type HBV, respectively). Our result suggest that genotypic monitoring of YMDD mutant is important for the management of patients treated with lamivudine. J. Med. Virol. 75:391,398, 2005. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||