Outcome of lamivudine resistant hepatitis B virus mutant post-liver transplantation on lamivudine monoprophylaxis

BACKGROUND: We aimed to investigate the clinical outcome of patients who develop lamivudine resistant hepatitis B virus mutants (YMDD mutants) after liver transplantation. METHODS: Patients who received liver transplantation for hepatitis B-related liver diseases from 1999 to 2002 were studied. All patients received lamivudine monotherapy before and after liver transplantation. HBsAg and HBV DNA were regularly monitored, and YMDD mutation was detected by direct sequencing. RESULTS: Twenty patients were followed up for median 94 wk (range: 15-177 wk) post-liver transplantation. Six patients developed YMDD mutants, and the cumulative probability of developing YMDD mutations post-liver transplantation was 21% in 1 yr and 34% in 2 yr. One patient developed YMDD mutants before liver transplantation and died of hepatitis reactivation and liver failure 15 wk post-transplantation. The other five patients developed YMDD mutants 32-72 wk after liver transplantation. Two of them developed severe hepatitis which responded promptly to adefovir dipivoxil. The remaining three patients with YMDD mutants had minimal to mild hepatitis. The cumulative survival for patients with YMDD mutants was 83% and 28% at 1 and 2 yr, respectively. Only one patient who did not develop YMDD mutants died at week 119 due to chronic rejection. The post-transplant survival for patients with YMDD mutants was significantly poorer than those without YMDD mutants (log rank test p = 0.083). CONCLUSIONS: The emergence of YMDD mutants after liver transplantation on lamivudine monoprophylaxis had wide range of clinical presentations and was associated with increased mortality.     

Adefovir treatment in posttransplant hepatitis B virus infection resistant to lamivudine plus hepatitis B virus immunoglobulin

Failure of prophylaxis for hepatitis B virus (HBV) recurrence in liver transplant patients with HBV immunoglobulin (HBIG) or lamivudine or both can be associated with rapid development of liver failure. Some of these patients develop a devastating clinicopathological state characterized by jaundice and rapidly progressive liver failure or fibrosing cholestatic hepatitis. We present two liver transplant recipients who experienced HBV recurrence while they were under lamivudine and HBIG prophylaxis. One of them had finding of severe HBV infection; the other, fibrosing cholestatic hepatitis. After commencing adefovir dipivoxil both patients showed improvements in clinical status and laboratory data. At month 4 of treatment, HBV DNA values became negative and liver function tests almost normalized. In addition, in one case showed HBs ag/anti-HBs seroconversion. When failure of prophylaxis with lamivudine and HBIG occurs, adefovir dipivoxil should be considered to be a safe and effective choice for recurrent HBV infections in liver transplant patients.     

Genotypic resistance of hepatitis B virus to lamivudine in renal transplant recipients

Renal recipients with hepatitis B virus (HBV) should be treated with prolonged lamivudine. However, lamivudine resistance usually results after YMDD mutation within the HBV polymerase gene. Thereupon, the aim of this study was to investigate the genotypic resistance to lamivudine among renal transplant recipients to identify its effect on the clinical course of HBV in these patients. Between March 1997 and September 2003, eight of 17 renal transplant patients with hepatitis B virus were enrolled into this study and treated with 100 mg of lamivudine once each day. We amplified a selected region of the polymerase gene of HBV in order to confirm mutations in the YMDD motif. Mutations of YMDD region were observed in five of eight patients (62.5%). Out of five patients positive for HBV DNA, three (60%) showed genotypic resistance (YMDD mutation) with a normal ALT level. Two patients converted to HBV DNA negative. But, they were not associated with HBeAg seroconversion. Out of three patients who were pretransplant HBV DNA negative, genotypic resistance was observed in two patients (67%) revealing both positivity of HBe antibody and negativity of HBV DNA. In conclusion, although a normal ALT level and HBV DNA negative are maintained, the mutation of the YMDD locus may develop. Accordingly, we suggest that if the YMDD mutation is not involved in the progression of hepatitis B, lamivudine therapy should be continued despite genotypic resistance.     

Use of adefovir in the treatment of the chronic hepatitis B virus infection with resistance to lamivudine

Current therapies for the treatment of chronic hepatitis B virus (HBV) infection do not eliminate viral replication once therapy is stopped, resulting in a rapid rebound of viremia in a majority of patients. Prolonged therapy results in emergence of resistant virus, which is a major clinical concern. The appearance of resistant HBV is associated with decreased seroconversion rates as well as worse liver histology. Adefovir dipivoxil, a nucleotide analogue with potent antiviral activity against HBV and human immunodeficiency virus (HIV), has shown in vivo and in vitro to have activity against lamivudine-resistant HBV. We present a series of 6 patients with chronic HBV infection and lamivudine-resistant HBV treated with adefovir dipivoxil. The viremia decreased in all patients; in 4 of them, serum HBV DNA was negative by chain reaction (PCR) in a mean period of 10 months from beginning of treatment. Resistance to adefovir after 12 months of treatment has not been detected. Alanine aminotransferase (ALT) levels decreased in all patients and, at this moment, 5 of 6 patients present normal levels. There were no toxic side effects due to adefovir treatment. The data confirm that adefovir treatment has efficacy against HBV lamivudine-resistant forms.     

Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation

BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.     

Seroconversion after the addition of famciclovir therapy in a child with hepatitis B virus infection after liver transplantation who developed lamivudine resistance

There is very little information about hepatitis B virus (HBV) infection in children after liver transplantation. This is the first report of the addition of famciclovir in a child who developed lamivudine resistance.A 5-year-old boy who was serum HBsAg-negative and was not vaccinated against HBV underwent living-related liver transplantation for fulminant hepatitis A. The donor was his mother, who was serum HBcAb-positive. No immunoprophylaxis was administered. HBV infection developed after 18 months and was treated with 3 mg/kg daily of lamivudine. Serum alanine aminotransferase normalized and HBV DNA load decreased significantly. Sixteen months later, lamivudine resistance developed; a mutation (M552I) was confirmed by sequencing through the YMDD locus of the HBV polymerase gene. The addition of 750 mg daily of famciclovir led to seroconversion and the disappearance of serum HBV DNA.Lamivudine in combination with famciclovir might be a therapeutic option for HBV reinfection after liver transplantation, also in children. Suppression of viral replication to undetectable values is possible even in the lamivudine-resistant mutant.     

Efficacy of lamivudine for the treatment of hepatitis B virus infection after liver transplantation in children

BACKGROUND: There is at present very little information about hepatitis B virus (HBV) infection in children after liver transplantation. This is the first study to assess the safety and efficacy of lamivudine in this patient population. METHODS: We describe three children aged 5-14 years who underwent liver transplantation for fulminant hepatitis A, hyperoxaluria, and cystic fibrosis. Despite adequate immunoprophylaxis, two of the children who were serum hepatitis B surface antigen-positive before transplantation (HBV DNA-negative by hybridization) had a reactivation of the disease, and one had a de novo HBV infection, at 12-18 months after transplantation. Lamivudine 3 mg/kg was administered on a compassionate-use basis for 14-36 months. RESULTS: After 1 month of therapy, HBV DNA disappeared from the serum in all patients by hybridization and in two patients by polymerase chain reaction. In all three children, alanine transaminase levels normalized. One child developed lamivudine resistance after 22 months with no evidence of hepatic decompensation. Repeated liver histological studies revealed progression of hepatic fibrosis in one child. All children remained serum hepatitis B surface antigen- and hepatitis B e antigen-positive. No adverse effects of the drug were noted. CONCLUSION: Lamivudine is beneficial and well tolerated in children with HBV infection after liver transplantation.     

Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation

BACKGROUND: Orthotopic liver transplantation (OLT) for end-stage liver disease resulting from hepatitis B virus (HBV) infection is associated with a high rate of recurrence and reduced survival. Lamivudine is effective in inhibiting HBV replication in patients with chronic hepatitis. This study evaluated the impact of lamivudine on viral suppression, liver function, and disease severity in patients awaiting OLT with HBV e-minus strain infection. METHODS: Twenty-five patients received lamivudine (100 mg per day) from the day of listing for OLT. All patients were positive for serum HBV-DNA by polymerase chain reaction and all had a Child-Pugh score of 7 or higher. RESULTS: Patients were followed for 12+/-9 months (mean +/- SD). Eleven underwent OLT within 13 months of treatment initiation, one died after 10 months, and one dropped out after 3 months. After 3, 6, and 9 months, HBV-DNA by polymerase chain reaction was undetectable in 14 of 25, 14 of 20, and 13 of 15 patients, respectively. Two patients developed lamivudine resistance after 9 and 18 months of treatment, respectively, without liver decompensation. Comparing baseline to last visit data, a significant improvement in prothrombin activity (43+/-15% vs. 52+/-19%; P=0.0014), serum bilirubin (3.4+/-1.9 vs. 2.5+/-2.2 mg/dL; P=0.0007), serum albumin (3.3+/-0.3 vs. 3.6+/-0.5 g/dL; P=0.0278), presence of ascites (15/25 vs. 7/25; P=0.0047), and Child-Pugh score (9 vs. 8; P=0.0003) was observed. Because of liver function improvement, four patients were placed on low priority status for OLT (United Network of Organ Sharing 3) and 9 on inactive status (United Network of Organ Sharing 7). The overall probability of survival at 6 and 12 months was 100% and 90.9%, respectively. CONCLUSIONS: Lamivudine has an important role in patients with end-stage liver disease caused by HBV precore mutant strain. Not only does HBV-DNA suppression allow patients to be eligible for OLT, but the improvement of the patients' clinical status may delay the need for OLT in an era of organ shortage.     

拉米夫定预防肝移植术后乙型肝炎病毒再感染的研究

目的 探讨和评价拉米夫定预防原位肝移植术后乙型肝炎病毒（HBV）再感染的效果。方法 41例患者，术前诊断为肝炎后肝硬化（失代偿期）者22例，慢性重型肝炎并肝炎后肝硬化（失代偿期）者12例，慢性重型肝炎者7例，其中HBVDNA阳性16例。41例患者均采用背驮式原位肝移植，术前15例给予拉米夫定治疗，术后41例患者均服用拉米夫定。结果 10例患者术后出现HBV再感染，其中9例为YMDD变异毒株感染，术后1、2年的HBV再感染率分别为9．8％（4／41）、24．4％（10／41）。术前血清HBVDNA阴性者术后HBV再感染率（12．0％，3／25）明显低于HBVDNA阳性者（43．8％，7／16）。术前长期服用（超过6个月）拉米夫定者和未服用拉米夫定者术后HBV再感染率分别为66．7％、23．1％，均明显高于术前短期（未超过6个月）服用拉米夫定者（0，P〈0．05）。结论 术前服用拉米夫定可降低乙型肝炎患者肝移植后HBV再感染率，但服药时间不宜超过6个月；长期、单一的应用拉米夫定易导致病毒变异而出现耐药毒株感染。     

Role of lamivudine in the posttransplant prophylaxis of chronic hepatitis B virus and hepatitis delta virus coinfection

BACKGROUND: Posttransplant combined lamivudine (LAM) and immunoglobulin (HBIg) prophylaxis is the gold standard in the case of single hepatitis B virus (HBV), but is still not recommended in the case of patients coinfected with hepatitis delta virus (HDV). METHODS: We compared two consecutive groups of chronic HDV carriers who survived >6 months after liver transplantation of the risk of recurrence, survival and HBIg requirements: 21 received passive prophylaxis (HBIg group) and 25 were treated with combined prophylaxis (LAM+HBIg group). The immunoprophylaxis schedule was the same in both groups: intramuscular HBIg targeted to maintain anti-HBs levels of >500 IU/L during the first 6 posttransplant months and >200 IU/L thereafter. RESULTS: The mean length of follow-up in the two groups was significantly different (133 vs. 40 months; P<0.001). None of the patients in either group developed recurrent hepatitis, and the 3-year actuarial survival rate was 100% in both groups. During the first 6 months, HBIg requirement was 38% lower in the LAM+HBIg group although similar anti-HBs target levels were maintained, leading to significantly lower costs (5,000 Euros in the first year and 500 Euros in the second). CONCLUSIONS: This is the first study of large and homogeneous cohort of long-term HDV coinfected liver transplant survivors showing the absence of HBV recurrence under combined prophylaxis. Although retrospective, our results suggest that combined anti-HBV prophylaxis should also be preferred to single immunoprophylaxis in patients with HDV coinfection because it allows significant cost savings in the first two posttransplant years.     

Use of combined treatment of hepatitis B immune globulin and lamivudine as prevention of hepatitis B virus recurrence in liver allograft

Antiviral prophylaxis with lamivudine appears to reduce hepatitis B virus (HBV) infection after liver transplantation, although recurrence of infection occurs in at least 20% of the patients because of the development of drug resistance. Treatment for HBV reinfection with lamivudine pretransplantation and posttransplantation together with hepatitis B immunoglobulin could abolish recurrence of HBV infections following liver transplantation. We report the experience at our center in which lamivudine has been used in combination with low doses of immunoglobulin. Lamivudine (100 mg/d) was administered to liver transplant candidates for at least 4 weeks before transplantation and was continued posttransplantation indefinitely. Immunoglobulin was administered intramuscularly (10,000 IU at time of liver transplantation; 1,000 IU for 1 week; 1,000 IU weekly the first month; and 1,000 IU monthly thereafter). Lamivudine and low-dose immunoglobulin administration prevents posttransplantation recurrence of hepatitis B with 100% efficiency; it is well tolerated and is less cost-effective than high-dose immunoglobulin regimens.     

Twelve months of lamivudine treatment for chronic hepatitis B virus infection in renal transplant recipients

BACKGROUND: Chronic hepatitis B virus (HBV) infection increases morbidity and mortality in renal transplant recipients (RTR). Lamivudine has shown promising results in patients with chronic hepatitis B, but experience with its use in RTR is limited. METHODS: In a prospective, open labeled, uncontrolled trial, 19 HBsAg(+) RTR were treated with lamivudine for 12 months. HBV-serologic analysis, HBV-DNA quantitation, and HBV genome sequence analysis were performed every 3 months. RESULTS: At baseline 16 patients were HBV DNA(+), 12 patients were HBeAg(+)/Ab (-). After 3 months HBV DNA was negative in 80% of patients. In the 3 patients with elevated liver enzymes, normal values were achieved within 12 weeks. At 12 months 4 of 8 HBeAg(+)/Ab(-) patients on treatment showed HBeAb, two of them with loss of HBeAg. Three patients developed mutations of the HBV polymerase gene associated with lamivudine resistance. CONCLUSIONS: Lamivudine is safe and effective in HB-sAg(+) RTR, the rate of HBe-seroconversion and of lamivudine-resistance is comparable to that of nonimmunosuppressed patients.     

Successful treatment of hepatitis B virus-associated membranous nephropathy with lamivudine

We present a case of chronic hepatitis B with membranous nephropathy, that was improved by lamivudine treatment. A 37-year-old man was admitted to our hospital for the evaluation of proteinuria. He was diagnosed as having chronic glomerulonephritis associated with chronic hepatitis B. Histopathological findings of the renal biopsy specimen indicated membranous nephropathy. He suffered from nephrotic syndrome associated with leg edema, which was parallel to the exacerbation of hepatitis. Lamivudine was started for the treatment of hepatitis, which caused the disappearance of serum hepatitis B virus DNA and the normalization of ALT level in 4 weeks. Additionally, proteinuria disappeared 120 weeks after the treatment was started. Lamivudine treatment may remit HBV-associated nephropathy.     

阿德福韦酯治疗拉米夫定耐药的乙型肝炎失代偿期肝硬化临床观察

目的观察阿德福韦酯对拉米夫定治疗过程中出现YMDD变异的乙型肝炎失代偿期肝硬化的疗效和安全性。方法将60例在拉米夫定治疗过程中出现YMDD变异的乙型肝炎失代偿期肝硬化患者随机分为治疗组（30例）和对照组（30例）,两组均在保肝、利胆等常规内科综合治疗基础上继续接受拉米夫定100mg／d口服治疗,治疗组在上述基础上联合阿德福韦酯10mg／d口服,疗程为15个月。结果对照组1例出现肝细胞癌死亡,3例因并发上消化道大出血死亡,1例因并发肺部真菌感染而给予抗真菌治疗后导致肝功能衰竭死亡,1例因合并腹腔感染未能很好控制导致肝功能衰竭死亡。治疗15个月时结果显示,治疗组肝功能恢复情况及HBVDNA低于检测下限的比率均优于对照组（P〈0．01）,治疗组病死率为O％,对照组为23．3％。结论阿德福韦酯治疗YMDD变异的乙型肝炎失代偿期肝硬化患者有良好的疗效和安全性,能提高患者生存质量,改善预后。     

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis.

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low-dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV-related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post-liver transplantation (LT) with a mean follow-up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1- and 2-yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1- and 2-yr recurrence rate of 13.5% and 15.2% (P = 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low-dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post-LT reinfection of the graft, but the safety and efficacy as a substitution for high-dose intravenous HBIG with LAM needs to be investigated further.     

Association of lamivudine resistance in recurrent hepatitis B after liver transplantation with advanced hepatic fibrosis.

BACKGROUND: Orthotopic liver transplantation (OLT) in patients with hepatitis B virus (HBV) infection is known to be associated with a high recurrence rate and poor prognosis. Lamivudine, a nucleoside analogue, is a potent inhibitor of HBV replication, but it is associated with a 14-39% rate of resistance. METHODS: We report on four patients who underwent OLT for HBV infection. In all cases, the HBV infection recurred in the grafted liver and was treated with lamivudine (100 mg daily) on a compassionate-use basis. The patients were monitored closely for serum liver enzymes, hepatitis B surface antigen and HBV DNA (by hybridization). Liver biopsy was performed before and after lamivudine therapy. HBV DNA was amplified from serum for each patient and sequenced through a conserved polymerase domain, the tyrosine-methionine-aspartate-aspartate (YMDD) locus. RESULTS: All four patients exhibited lamivudine resistance 9-20 months after initiation of the drug. In all patients with a clinically mild disease, liver histology findings (12-24 months after lamivudine therapy) showed progressive fibrosis as compared to biopsies performed before lamivudine therapy, with a significant increase (> or =2 points) in the Knodell score in three patients. Moreover, two patients exhibited worsening of the necroinflammatory process. A mutation at the YMDD motif of the HBV polymerase gene was detected in all cases. CONCLUSIONS: Lamivudine resistance frequently occurs in patients with recurrent HBV infection after OLT and is associated with advanced hepatic fibrosis and necroinflammatory process. A combination of antiviral therapies may be necessary.