The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with Non-Hodgkin's lymphoma who receive cytotoxic chemotherapy

We investigated the effectiveness of lamivudine to prevent hepatitis flare up due to reactivation of hepatitis-B virus (HBV) in hepatitis-B surface antigen (HBsAg)-positive patients with Non-Hodgkin's lymphoma (NHL) during cytotoxic chemotherapy. HBsAg-positive patients with NHL were identified from the lymphoma database of the Asan Medical Center from January 1995 to August 2002, and their medical records were reviewed. We found that 31 patients were received cytotoxic chemotherapy among 41 NHL patients with HBsAg-positive during same period. We divided them into 2 groups of HBsAg patients with NHL as follows: Group A who received cytotoxic chemotherapy with lamivudine 100 mg daily; Group B without any prophylactic antiviral therapy. There were no significant differences between Group A and B in several clinical variables. Seventeen patients (85%) in group B and one patient (9%) in Group A had hepatitis due to reactivation of HBV (p<0.001), with one hepatic failure related death in Group B and none in group A. The mean dose intensity of adriamycin actually delivered was 13.3 mg/m2/week (80% Relative Dose intensity (RDI)) in Group A and 9.1 mg/m2/week (55% RDI) in Groups B (p<0.001). Our data suggest that the frequency of chemotherapy-related HBV reactivation may be significantly decreased by lamivudine prophylaxis with maintenance of the dosage of adriamycin.     

Factors associated with viral breakthrough in lamivudine monoprophylaxis of hepatitis B virus recurrence after liver transplantation

This study aimed to investigate the factors associated with viral breakthrough among liver transplant recipients who receive lamivudine monoprophylaxis. Consecutive patients receiving liver transplantation for HBV-related liver disease from June 1999 to October 2000 were studied. All patients received lamivudine 100 mg daily pre- and post-transplant. Serum samples were collected before lamivudine treatment, before liver transplantation, and then every 3-6 months after liver transplantation. Lamivudine-resistant mutations at the YMDD motif of HBV P gene were detected by direct sequencing and HBV DNA was quantified by real-time polymerase chain reaction (PCR). Ten patients, 7 males and 3 females, aged 50.5 +/- 7.9 years, were studied. Three patients had fulminant hepatitis and 7 patients had end-stage cirrhosis before liver transplantation. Lamivudine was started at 4.5 (range 0-40) weeks before liver transplantation. The median post-transplant follow-up was 16 (range 12-23) months. Four patients developed YMDD mutations 10.5 (0-16) months after transplantation with relapse of viraemia (median 1,294, range 51-3,135 MEq/ml). All patients who developed YMDD mutants had end-stage liver cirrhosis, and HBV DNA were detectable on the day of liver transplantation (median 0.62, range 0.086-1.63 MEq/ml). On the contrary, all 3 patients transplanted for fulminant hepatitis did not have YMDD mutation. Among the 3 end-stage cirrhotic patients who had negative HBV DNA before liver transplantation, none developed YMDD mutation. In conclusion, patients transplanted for fulminant hepatitis B and cirrhotic patients in whom HBV DNA could be rendered PCR negative before liver transplantation are unlikely to develop YMDD mutation on lamivudine monoprophylaxis.     

Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors

Hepatitis B virus (HBV) reactivation is a well-described complication in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. As chemotherapy is used increasingly in cancer patients, HBV reactivation during cytotoxic treatment may become a more common problem. In lymphoma patients, the incidence of chronic HBV infection has been reported to be 26%, of whom 47% developed HBV reactivation during chemotherapy. However, corresponding data for patients with other malignancies undergoing cytotoxic chemotherapy are not known. In this prospective study, hepatitis B surface antigen (HBsAg) was determined in 626 consecutive cancer patients who received cytotoxic chemotherapy over a 12-month period. Seventy-eight patients (12%) were found to be HBsAg positive. Thirty-four (44%) developed raised alanine transaminase during their course of chemotherapy. In these 34 patients, hepatitis was attributed to HBV reactivation in 15 patients (44%), chronic active HBV infection in 1 patient (3%), hepatitis C infection in 1 patient (3%), malignant hepatic infiltration in 2 patients (6%), and the use of hepatotoxic chemotherapeutic agents in 11 patients (32%). The causes of hepatitis were unknown in 4 patients (12%). HBV reactivation was more likely to develop in patients who were male, younger age, HBeAg seropositive, and those with lymphoma. Presence of malignant hepatic infiltration, baseline pre-treatment alanine transaminase, total bilirubin, and HBV DNA levels did not correlate with the development of HBV reactivation. Of the 15 patients who developed HBV reactivation, antiviral therapy with lamivudine was available and used in 9. There was no HBV-related mortality during chemotherapy. It is concluded that in patients with chronic HBV infection under chemotherapy, HBV reactivation occurs in nearly 20% of them and accounts for 44% of hepatitis cases. The risk factors identified include male sex, younger age, HBeAg seropositive, and the diagnosis of lymphoma. In HBV endemic areas, patients with risk factors for HBV reactivation should be identified prior to receiving cytotoxic treatment and monitored closely. The potential benefit of lamivudine requires further confirmation.     

乙肝病毒YMDD变异与乙型肝炎病毒大蛋白相关性的探讨

目的 通过检测乙型肝炎病毒YMDD变异患者血清中的乙型肝炎病毒大蛋白（Hepatitis B Virus Large Surface Protein,LHBs）,探讨乙型肝炎病毒大蛋白（LHBs）的检测与YMDD变异的关系.方法 选取经过拉米夫定治疗后的患者,进行YMDD变异检测,再对所有患者进行HBVDNA和乙型肝炎病毒大蛋白（LHBs）的检测;YMDD变异和HBV DNA检测采用荧光定量PCR法,LHBs检测采用酶联免疫法（ELISA）.结果 65例YMDD变异患者中,HBV DNA拷贝数对数值与LHBs吸光度（A值）呈良好的相关关系（r=0.961）;75例非变异患者中,HBV DNA拷贝数对数值与LHBs吸光度（A值）呈良好的相关关系（r=0.954）.结论 在YMDD变异患者和非变异患者中LHBs吸光度与HBV DNA拷贝数均具有良好的正相关性,表明患者体内LHBs与病毒复制程度密切相关,而且不受乙肝病毒YMDD变异的影响.     

Efficacy of lamivudine in HBeAg-negative chronic hepatitis B

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B results from infection with hepatitis B virus mutants unable to produce HBeAg. It accounts for 7-30% of patients with chronic hepatitis B virus (HBV) worldwide, with the highest rates reported for Mediterranean Europe and Asia. Interferon (IFN) is currently the only approved therapy for these patients, but it has an unfavorable tolerance profile and limited efficacy. Studies show that responses to IFN are lower in HBeAg-negative than in HBeAg-positive patients; joint HBV DNA loss/ALT normalization is obtained in 38-59% of HBeAg-negative patients treated for 4-24 months with a high rate of virological relapse (54-87%), at 6-24 months posttreatment. Lamivudine is a nucleoside analogue with potent antiviral properties against HBV. Studies show that response rates in HBeAg-negative and HBeAg-positive patients are equivalent. After 12 months of treatment, 65-96% of HBeAg-negative patients have joint HBV DNA loss/ALT normalization, although 48-74% of patients relapse within 1 year posttreatment. 60% of patients have histological improvement after 12 months of treatment. Lamivudine is well tolerated with a safety profile equivalent to that of placebo. The incidence of YMDD variants increases with extended lamivudine treatment, present in up to 57-64% of patients after 2 years. Their clinical impact is unclear; some studies show breakthrough infection associated with their emergence, whereas other studies show maintained response to lamivudine. Lamivudine has benefits over IFN in its safety and efficacy profile in this patient group. Extended lamivudine treatment beyond 2 years is an option, but further investigation is required to define stopping criteria and the impact of YMDD variants.     

Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy.

Hepatitis B virus (HBV) reactivation has been described in cancer patients who received cytotoxic/immunosuppressive therapy and may result in liver damage of varying degrees of severity. There is no known effective treatment. Lamivudine, a nucleoside analogue, has been found to suppress HBV replication and to improve histology in chronic carriers of hepatitis B virus. The outcome of lamivudine therapy (at doses of 100 or 150 mg/day) in eight patients who developed HBV reactivation while receiving cytotoxic chemotherapy is described. Each of the eight patients had >98% suppression of the pretreatment HBV DNA levels. Three of the five patients who were initially HBeAg positive underwent seroconversion. Five patients had normalization of liver function tests and improvement in clinical condition. However, one patient died of hepatic failure due to HBV-related submassive liver necrosis, and two died of widespread metastases (including liver) from the primary malignancies. It is concluded that early commencement, i.e., at the onset of HBV reactivation before severe hepatic decompensation, of lamivudine may be effective in the control of HBV reactivation during chemotherapy. In Hong Kong, where hepatitis B infection is endemic, we propose to screen all cancer patients for hepatitis B surface antigen before immunosuppressive/cytotoxic therapy, and to closely monitor liver function of those who are found to be HBsAg seropositive.     

Severe acute exacerbation of liver disease may reduce or delay emergence of YMDD motif mutants in long-term lamivudine therapy for hepatitis B e antigen-positive chronic hepatitis B

The pretherapy factors that could influence the emergence of resistant hepatitis B virus (HBV) tyrosine-methionine-aspartate-aspartate (YMDD) motif mutants against lamivudine are not fully known in prolonged lamivudine therapy for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. We analyzed prospectively 116 consecutive lamivudine-naïve patients who received long-term lamivudine therapy (>1 year) by using multivariate regression analyses. The cumulative HBeAg loss rates were 29, 44, and 47% at 1, 2, and 3 years of treatment, respectively. Stepwise Cox's regression analyses indicated that pretherapy viral load was a significant factor associated with HBeAg loss (P = 0.0068). The cumulative emergence rates of YMDD mutants were 23% at 1 year, 45% at 2 year, and 47% at 3 year of treatment. Stepwise Cox's regression analyses indicated that patient age and presence or absence of severe acute exacerbation of liver disease were independent significant factors associated with emergence of YMDD mutants (P = 0.018 and 0.048, respectively). For the development of virological breakthrough, patient age, the presence or absence of severe acute exacerbation, and pretherapy viral load were independent significant factors (P = 0.028, 0.043, and 0.044, respectively). Severe acute exacerbation tended to reduce or delay development of biochemical breakthrough. The present study provides important information for the development of more effective and rational long-term lamivudine therapy for HBeAg-positive chronic hepatitis B patients infected exclusively with genotype C. J. Med. Virol. 73:7–12, 2004. © 2004 Wiley-Liss, Inc.     

Hepatitis b e antigen and antibody: detection by radioimmunoassay in chimpanzees during experimental hepatitis b

Hepatitis B e antigen (HBeAg) and its antibody (anti-HBe) were evaluated using a sensitive radioimmunoassay (RIA) in weekly serum samples obtained from nine chimpanzees experimentally infected with hepatitis B virus (HBV). In two chimpanzees with HBV infection with detectable hepatitis B surface antigen (HBsAg) for less than five weeks, and in one chimpanzee with documented HBV infection with no detectable HBsAg, HBeAg was not detected; in all three, anti-HBe became detectable early in the infection. In six chimpanzees in which HBsAg was detected for 16 weeks or longer, HBeAg was detected early in the infection; in five, anti-HBe became detectable and HBeAg unde-tectable prior to the clearance of HBsAg. The sixth remained HBsAg-positive and HBeAg-positive for more than two years and never developed anti-HBe. These results confirm the sensitivity of this RIA and its value in predicting the course of HBV infections.     

Should lamivudine monotherapy be stopped or continued in patients infected with hepatitis B with favorable responses after more than 5 years of treatment?

Regarding the limited evidence for determining the optimal duration of antiviral treatment for hepatitis B, the long‐term outcome of patients with favorable responses to over 5 years of lamivudine monotherapy was investigated. Two hundred seventy‐one patients who had received lamivudine for at least 5 years were enrolled. Ultimately, 72 patients without YMDD mutations and showing hepatitis B virus (HBV) DNA levels <2.5 pg/ml after 5 years of treatment were analyzed. Mean treatment duration with lamivudine was 9.1 ± 2.6 years. During the treatment, HBeAg and HBsAg loss/seroconversion rates were 95 and 6.9%, respectively. Decompensation and hepatocellular carcinoma (HCC) developed in 2.8 and 6.9% of patients, respectively. Old age and cirrhosis were risk factors for HCC development. Finally, 11.1% of patients developed YMDD mutations after 8.3 ± 2.4 years of treatment. There was no hepatic decompensation among the patients who developed delayed YMDD mutations. Sixteen patients who achieved a complete response stopped lamivudine and four patients showed relapses 10.3 ± 8.5 months after stopping lamivudine. Relapsed patients had more cirrhotic livers and higher rates of HBeAg positivity at 5 years than patients who maintained complete response. The present study suggests that patients who do not develop YMDD mutations over 5 years of treatment with lamivudine may continue lamivudine monotherapy until the loss of HBsAg. However, even for the patients showing favorable response over 5 years of treatment, those in older ages, with cirrhosis or who show poor HBeAg responses should be on careful monitoring to detect the development of viral mutations, relapse and even HCC. J. Med. Virol. 85:34–42, 2012. © 2012 Wiley Periodicals, Inc.     

拉米夫定治疗慢性乙型肝炎2年临床疗效

目的 研究拉米夫定治疗慢性乙型肝炎的临床疗效和安全性。方法 选取72例慢性乙型肝炎病人,第一阶段为随机、双盲、安慰剂对照的研究共12周,分为拉米夫定组（n=54）和安慰剂组（n=18）;第二阶段为开放研究,所有病人均服用拉米夫定100mg/d至104周。观察指标包括临床症状、肝功、乙型肝炎病毒（HBV）血清标志物、HBV DNA和病毒YMDD变异等。结果 拉米夫定治疗12周时,HBV DNA阴转率显著高于安慰剂组（61％对6％,P＜0.01）,ALT持续复常率也高于安慰剂组（65％对11％,P＜0.05）;治疗52周时,两组病人总的HBV DNA阴转率为785,ALT持续复常率为39％,HBeAg阴转率和血清转换率分别为8.2%和6.1%;治疗104周时,两组病人总的HBV DNA阴转率36％,ALT持续复常率为33％,HBeAg阴转率和血清转换率分别为12.2%和6.1%。两组病人总的YMDD变异率在52周时为13.7%,104周时为39.7%。第一阶段拉米夫定和安慰剂组不良瓜在的差异不显著（P＞0.05）,治疗期间未发生与药物有关的严重不良反应。结论 拉米夫定100mg/d可以迅速降低血清HBV DNA和ALT水平,安全性良好。但应严密监测以及时发现YMDD病毒变异引起的HBV DNA反跳。     

Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients.

Lamivudine has demonstrated efficacy in the treatment and prevention of hepatitis B virus (HBV) reactivation after hematopoietic stem cell transplantation (HSCT). However, most of these studies involved short durations of prophylaxis, so there is significant concern regarding lamivudine resistance in these patients. Between March 1984 and November 2002, 71 HBV surface antigen-positive HSCT recipients, including a subgroup of 16 who received pretransplantation lamivudine therapy, which was continued into the posttransplantation period to prevent reactivation hepatitis, were enrolled onto our study. The efficacy of lamivudine therapy was first evaluated for the subgroup of 16 patients in terms of treatment response, lamivudine resistance, and viral recurrence after discontinuation by using virologic assays. Efficacy was then evaluated for all patients in terms of the hazards of lamivudine therapy for reactivation hepatitis after transplantation. During a median lamivudine therapy period of 73 weeks (range, 19-153 weeks), the initial response showed a median reduction of 2.54 log10 in serum HBV DNA (-0.28 to 6.72 range). Lamivudine-resistant mutations were detected in 10 (63%) of 16 patients during therapy, and 1 (12%) of 16 patients finally developed a viral breakthrough. At a median follow-up of 30 months after discontinuation, 3 (27%) of 11 cases had recurrence of HBV infection. Despite the emergence of the mutations, no deaths were due to HBV reactivation or severe cases of hepatitis. In the Cox proportion regression model regarding reactivation hepatitis after transplantation of all enrolled patients, lamivudine therapy was found to be the only favorable factor for the event, with a hazard ratio of 0.122 (95% confidence interval, 0.016-0.908; P = .040). In conclusion, extended lamivudine therapy is safe and effective for the prevention of HBV reactivation in an HSCT setting and significantly decreases reactivation hepatitis after transplantation.     

High frequency of hepatitis B virus DNA in anti-HBe positive sera on longitudinal follow-up of patients with renal transplants and chronic hepatitis B

Hepatitis B virus (HBV) markers were determined in 821 patients receiving renal allografts and undergoing immunosuppressive therapy during 1970-1986. Twenty-four of the patients with a renal transplant functioning for longer than 1 year originally were or became chronic carriers of hepatitis B surface antigen (HBsAg). These patients remained carriers during the follow-up period, which lasted until death or until the end of 1986. Follow-up time was 1.2-15.3 years (mean 9.1 years). A total of 301 samples from the HBsAg-positive patients were tested for HBV DNA and HBeAg/DNA and HBeAg/anti-HBe. Nine patients who were constantly positive for HBeAg also remained positive for HBV DNA. Reactivation of HBV replication occurred in 11 patients. Among these, HBV DNA and HBeAg varied in parallel in six patients, three patients developed anti-HBe, and two patients were constantly positive for anti-HBe. Another four of the 24 patients seroconverted to anti-HBe, and two of these also lost HBV DNA. Three of 12 deceased patients died from liver failure during follow-up. None of these three had been constantly positive for HBeAg or HBV DNA, but they had had reactivations of HBV; two were also positive for HBV DNA in serum specimens available from their terminal month. HBV DNA was demonstrated in 99% of HBeAg-positive and 53% of anti-HBe-positive sera and in at least two samples from each of the 24 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Longitudinal study of hepatitis activity and viral replication before and after HBeAg seroconversion in chronic hepatitis B patients infected with genotypes B and C

The aims of this study were to compare chronic hepatitis B (CHB) patients with genotypes B and C for the probability of HBeAg seroconversion, hepatitis activity, and viral replication before and after HBeAg seroconversion and to compare the prevalence of core promoter and precore mutations. A total of 180 asymptomatic Chinese patients with CHB were monitored for a median of 53.8 months, and 38 patients with cirrhosis-related complications were studied. Hepatitis B virus (HBV) DNA levels were measured in 16 patients with HBeAg seroconversion at 3 months before, during, and 3 months after HBeAg seroconversion and in all patients at the last follow-up. Hepatitis B genotypes and core promoter and precore mutations were determined. Compared to patients with genotype C (n = 109), patients with subtype Ba (n = 69) had a higher rate of anti-HBe positivity on presentation (P = 0.05). HBeAg-positive patients with subtype Ba had a higher cumulative rate of HBeAg seroconversion than patients with genotype C (P = 0.02). However, there were no differences between the two groups with regard to the median HBV DNA levels before, during, and after HBeAg seroconversion; the probability of having persistently normal or elevated aminotransferase levels; and the median HBV DNA levels and liver biochemistry at the last follow-up. There was no difference in the prevalence of genotypes and core promoter and precore mutations between patients with and without cirrhosis-related complications. Though patients with subtype Ba had earlier HBeAg seroconversion, the liver biochemistry, HBV DNA levels in different phases of the disease, and the probability of development of cirrhosis-related complications were the same with genotypes Ba and C.     

Management of hepatitis B in China

A randomised, multicentre, double-blind, placebo controlled trial was conducted in Chinese patients with chronic hepatitis B to compare the efficacy of once-daily lamivudine and placebo on serum HBV DNA, and to assess the long-term efficacy and safety of lamivudine. Patients received lamivudine 100 mg (n = 322) or placebo (n = 107) once daily for 12 weeks, and were then offered open-label lamivudine treatment for 2 years. Lamivudine therapy resulted in increased hepatitis B e antigen (HBeAg) loss and seroconversion (loss of HBeAg plus the development of antibodies to HBeAg) in patients with high baseline serum alanine aminotransferase (ALT) concentrations. At 2 years, loss of HBeAg was achieved by 27% (38/140), 38% (25/66) and 60% (9/15), and seroconversion was achieved by 17% (24/140), 24% (16/66) and 33% (5/15) of patients with baseline serum alanine aminotransferase (ALT) concentrations of >1 x upper limit of normal (ULN), >2 x ULN and >5 x ULN, respectively. With lamivudine treatment, serum HBV DNA decreased rapidly to very low concentrations and remained low throughout the 2 years of the study. At 1 year, 15% (43/295) of patients in the lamivudine group had developed YMDD (tyrosine-methionine-aspartate-aspartate amino acid motif of HBV polymerase) variant HBV. These patients derived clinical benefit with continued lamivudine therapy, demonstrated by serum HBV DNA and ALT concentrations below baseline, or normal serum ALT concentrations. Lamivudine was well tolerated and an effective once-daily oral therapy for Chinese patients with chronic hepatitis B with viral replication and liver disease.     

Emergence of YMDD motif mutants of hepatitis B virus during lamivudine treatment of immunocompetent type B hepatitis patients

Lamivudine is an effective antiviral agent for the treatment of chronic type B hepatitis. Recent studies have shown the appearance of lamivudine resistant viruses with mutations at the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the viral polymerase in hepatitis B virus (HBV) infected patients who received orthotopic liver transplantation. In order to confirm the appearance of such mutant HBV in immunocompetent patients, the HBV sequences in and around the YMDD motif of HBV DNA polymerase were examined in the sera from 16 lamivudine treated and 10 untreated control patients. Approximately 200 bases including the YMDD motif of HBV DNA polymerase were amplified by polymerase chain reaction (PCR) and sequenced directly by an automated sequencer. Of the 16 patients receiving lamivudine, mutant viruses with mutations in the YMDD motif were found in 3 of 8 patients treated with lamivudine for 52 weeks. However, this mutation was not found in any of the 8 patients treated for 32 weeks or a shorter period. Mutant viruses appeared after 40 weeks of treatment and were undetectable within 12 weeks after the cessation of the treatment. Such mutant viruses were not detected in any of the 10 untreated patients. This study confirms the emergence of YMDD mutant viruses during long-term lamivudine treatment in immunocompetent type B hepatitis patients. The results from this study suggest the need for combination therapies to reduce the levels of such mutant viruses in some patients.     

Response to long-term lamivudine treatment in patients infected with hepatitis B virus genotypes A, B, and C

Response to lamivudine treatment longer than 1 year was compared in 15 patients persistently infected with hepatitis B virus (HBV) genotype A, 38 with genotype B, and 449 with genotype C. Patients with genotype A were younger (median age 37 [range 24-49] vs. 47 [24-67] or 44 [18-73], P = 0.015), possessed hepatitis B e antigen (HBeAg) more frequently (73% vs. 21% or 56%, P < 0.001) and HBV DNA in higher levels (8.6 [6.1-8.7] vs. 6.5 [<3.7-8.7] or 6.5 [<3.7-8.7] log genome equivalents (LGE)/ml, P = 0.024) than those with genotype B or C. During lamivudine, YMDD mutants (89% vs. 53% or 42%, P = 0.0001) and breakthrough hepatitis developed more often (47% vs. 21% or 29%, P = 0.023) in patients with genotype A than B or C. YMDD mutants elicited more frequently in patients with genotype A than B or C who were positive (82% [9/11] vs. 25% [2/8] or 48% [117/245], P = 0.037) or negative for HBeAg (75% [3/4] vs. 30% [9/30] or 33% [68/204], P = 0.003). HBeAg (hazard ratio 2.1 [95% confidence interval 1.53-2.92], P < 0.001) and genotype A (2.78 [1.08-7.12], P = 0.034) enhanced the emergence of YMDD mutants by the Cox proportional hazard model. The risk for breakthrough hepatitis was increased by the baseline alanine aminotransferase level <500 IU/L (2.56 [1.82-5.50], P = 0.018), HBeAg (2.11 [1.40-3.16], P < 0.001), cirrhosis (1.92 [1.24-2.97], P = 0.004) and HBV DNA > or =8.0 LGE/ml (1.57 [1.04-2.36], P = 0.03); it was influenced by genotypes only in patients with HBeAg. In conclusion, HBV genotypes help in predicting response to long-term lamivudine treatment and development of YMDD mutants in patients with chronic hepatitis B.