Prospective Study on Lamivudine-Resistant Hepatitis B in Renal Allograft Recipients

The natural history of lamivudine-resistant hepatitis B virus (HBV) infection in renal transplant recipients (RTx) is unclear, despite its increasing incidence. Twenty-nine HBsAg-positive RTx with rising HBV DNA received lamivudine therapy. The course of lamivudine-resistant HBV infection was studied prospectively. During 68.7 +/- 12.5 months of follow-up, 14 (48.3%) patients developed lamivudine resistance, at 10-35 months (mean 16.9 +/- 7.0). All showed mutant sequences at codons 552 and 528 of the YMDD motif, while 13 patients demonstrated wild-type sequence at codon 555. Lamivudine resistance was unrelated to patient demographics, HBeAg status/sero-conversion, or genotype. Following resistance, HBV DNA and alanine aminotransferase showed an initial increase followed by spontaneous gradual reduction. The subsequent peak HBV DNA was lower (1.26 +/- 1.09 x 10(9) vs. 6.26 +/- 12.23 x 10(9) copies/mL, p = 0.011), while that of alanine aminotransferase was higher (196 +/- 117 vs. 77 +/- 47 imicro/l, p = 0.005), compared with pretreatment levels. Post-resistance hepatitic flare occurred in 11 (78.6%) patients. This was transient in four (36.4%), but became chronic in six (54.5%) patients. Decompensation was noted in one patient during this flare, but all survived. We conclude that drug resistance is prevalent in lamivudine-treated RTx. Despite a lower ensuing peak viremia compared with baseline, hepatitic flare is common. While most patients have spontaneous resolution, a minority may develop potentially fatal decompensation during the preceding exacerbation.     

拉米夫定对慢性乙型肝炎的疗效及肝脏组织病理学改变

目的:从血清生化,病毒学,肝纤维化指标以及肝脏组织病理学改变的角度分析拉米夫定(LMD)治疗慢性乙型肝炎的疗效.方法:慢性乙型肝炎患者21例,给予口服LMD100 mg/d,连用1 a,动态观察服药0,24和48 wk肝功能、乙肝五项、HBV-DNA定量、血清肝纤维化指标透明质酸(HA)、层黏蛋白(LN)、Ⅲ型前胶原(PⅢP)和Ⅳ型胶原(ⅣC)的变化,通过肝组织穿刺活检,观察用药前后肝脏组织病理学的改变.结果:LMD治疗48 wk,可显著抑制HBV-DNA(copy/L)复制(6.13×109±4.03×105 vs 9.01×105±4.89×103,P＜0.01),使大多数患者肝功能(nkat/L,ALT:1697±907 vs550±503;AST:1787±717 vs 498±430)恢复正常(P＜0.01),显著降低血清肝纤维化指标水平(P＜0.01).减轻肝细胞坏死,汇管区炎细胞浸润及纤维化.结论:LMD是治疗慢性乙型肝炎的一种较为切实有效的措施.     

肝移植后单一拉米夫定干预下HBV再感染及其相关因素分析

目的　探讨在单一拉米夫定 (LMV)干预下乙型肝炎相关性肝病肝移植后HBV再感染的发生 ,并分析其发生的易感因素。方法　随访 1999～ 2 0 0 3年接受肝移植并采用单一LMV防治HBV再感染的 6 3例乙肝相关性肝病患者 ,术后定期进行乙肝标志物、肝功能及HBVDNA定量检测 ,调查HBV再感染发生率并采用Logistic回归分析方法就术前诊断、病毒学资料及抗病毒治疗等分析其可能的易感因素。结果　在不同时期共出现HBV再感染 17例 ;各时间段HBV再感染率分别是 :6个月内9.5 % (6 / 6 3,其中 5例术后HBV标志物一直未阴转 ) ,6个月～ 1年 13.2 % (7/ 5 3) ,1～ 2年 2 7.8% (10 /36 ) ,2～ 3年 4 1.2 % (7/ 17) ,3年以上 6 0 .0 % (3/ 5 ) ;患者术前HBVDNA阳性及长期服用LMV与术后再感染呈正相关 (P <0 .0 5 ) ,而术前诊断、性别、年龄及血清HBsAg和HBeAg状态与HBV再感染则未发现显著相关性。结论　单一LMV预防HBV再感染对大多数肝移植者仍有效 ,但随术后存活时间的延长HBV再感染率呈现上升 ;术前使HBVDNA阴转及建立针对LMV耐药性变异的监测对防治再感染是必要的。     

拉米夫定治疗慢性乙肝的疗效及乙肝病毒YMDD变异的研究

目的评价拉米夫定治疗慢性乙肝病人的1年疗效、乙肝病毒YMDD变异率、变异与治疗前HBV-DNA、ALT水平的联系。方法治疗组按入选标准随机选择32例慢性乙型肝炎患者给予拉米夫定100 mg/d并随访1年,并于治疗开始后3、6、9、12个月检测肝功能、HBV-M、HBV-DNA、YMDD变异。对照组随机选择36例从未接受抗病毒治疗的HBV-DNA阳性、ALT异常的慢性乙型肝炎患者,检测YMDD变异株。结果①拉米夫定治疗一年,HBV-DNA转阴率71.88%(23/32),HBeAg/HBeAb血清转换率18.52%(5/27),ALT复常率62.5%(20/32);治疗前及治疗12个月后ALT水平分别为132.59±66.07、49.78±27.94,治疗前后差别有统计学意义(P<0.001)。②治疗组在治疗前未发现YMDD变异,治疗6个月发现2例YMDD变异,变异率6.25%,治疗12个月发现5例YMDD变异,变异率15.63%;对照组36例从未接受抗病毒治疗的慢性乙型肝炎病人中检测出2例YVDD变异株与野生株共存。③治疗前ALT<3×ULN组及≥3×ULN组YMDD变异率分别为11.76%、20.00%,两组差别无统计学意义(P=0.645);治疗前HBV-DNA<106copies/mL组及≥106copies/mL组YMDD变异率分别为5.88%、26.67%,两组差别无统计学意义(P=0.161)。结论拉米夫定能迅速抑制乙肝病毒复制、改善肝功能;治疗前HBV-DNA水平及ALT水平不足以预见YMDD变异的发生;乙肝病毒YMDD变异株存在于未使用拉米夫定的慢性乙肝患者中,建议在抗病毒治疗前对YMDD变异进行常规检测。     

Prevention of hepatitis B virus recurrence after liver transplantation

Abstract:  Liver transplantation for hepatitis B virus (HBV)-related liver disease has changed from a contraindication to outcomes comparable with non-HBV-related liver transplantations during the last two decades. Mainly the implementation of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the use of nucleoside analogs such as lamivudine and adefovir account for this dramatic change. The standard of care in most centers today consists of lamivudine treatment in replicating hepatitis B pre-orthotopic liver transplantation (OLT) and a combination regimen of lamivudine and HBIG post-OLT. With adefovir, a potent antiviral drug became available in recent years that allows for the treatment of patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD)-mutant HBV. In the transplantation setting, first studies indicate that a triple prophylactic therapy consisting of lamivudine, adefovir, and HBIG will become the standard of care for YMDD-mutant-related hepatitis B. With new drugs emerging for the treatment of chronic HBV, there is optimism for new options also in the transplant setting.     

慢性乙型肝炎患者外周血来源的树突状细胞功能的研究

目的:研究慢性乙型肝炎患者外周血来源的树突状细胞(Dendritic cells, DCs)与慢性乙型肝炎的病程发展以及不同抗病毒治疗的关系.方法:采集71例慢性乙肝患者外周静脉血,抗凝,分离外周血单个核细胞(PBMCs).进行体外诱导培养,使之发育成DC,流式细胞仪检测其表面共刺激分子的表达.其中57例HBV-DNA阳性患者,分别采用拉米夫定或α-干扰素治疗,1个疗程后,再次检测DC表面分子的表达,并分析、比较治疗前后的表达水平.结果:与正常对照比较,慢性肝炎和慢性病毒携带者DC上CD1a(13.97±5.22和11.28±5.70 vs 27.25±4.32)%以及CD86(57.27±12.57和32.94±11.37 vs 82.12±13.54)%的表达,均明显降低(P＜0.05或0.01).比较血清HBV-DNA载量与DC表面分子的表达,发现DNA阴性组DC上CD1a、CD40、CD80和CD86的表达均比DNA阳性组高,但只有CD86的表达量有明显差别(P＜0.05).此外,57例抗病毒治疗后,拉米夫定治疗组CD40的表达(66.40±7.85 vs 43.48±7.93)%明显高于治疗前水平;而α-干扰素治疗组,CD40的表达(78.71±6.31)%高于治疗前水平外,CD86的表达(87.47±16.07 vs 44.18±10.07)%也明显高于治疗前水平(P＜0.05).结论:慢性乙型肝炎病毒感染与DC功能缺陷密切相关,血清中HBV-DNA载量越高,DC功能的缺陷越明显.拉米夫定和α-干扰素抗病毒治疗均能使患者外周血来源的DC表面的共刺激分子有不同程度的升高,促使DC成熟和功能的恢复.     

Detection of hepatitis B virus polymerase variations resistant to lamivudine therapy

Objective To investigate variations in hepatitis B virus (HBV) polymerase gene in chronic HBV infected patients resistant to lamivudine therapy. Methods Specimens were obtained from nine patients with chronic HBV infection, who were resistant to lamivudine therapy. Partial segments of the HBV DNA polymerase gene we re amplified by polymerase chain reaction (PCR). Nucleotide sequence was performed using an applied 373 automated sequencer. Titre of HBV DNA was measured by branched DNA assay (Chiron). Results Of nine patients with HBV DNA positive after 64 weeks of treatment, five (56%) had variations in the highly conserved YMDD motif in domain C of the HBV polymerase, three of those were substitutions of isoleucine for methionine(M), and two were substitutions of valine(V) for methionine. Additionally, in two patients with variations characterized by substitutions of V for M, one had a simultaneous amino acid change from the first aspartic acid to glycine and this pattern of variation was not reported in other literatures. With respect to viremia, in two subjects with low titre of HBV DNA (&lt;100 MEq/ml), no variation was found in the YMDD motif, whereas in seven patients with high titre of HBV DBA (&gt;300 MEq/ml), five (71%) had variations in the YMDD motif. Conclusions Lamivudine is a potent anti-viral agent for treatment of chronic HBV infection. Resistance to lamivudine is likely caused by the variations in the YMDD motif of the HBV polymerase gene.     

拉米夫定治疗慢性乙型肝炎及乙型肝炎病毒携带者的疗效评价

目的：观察拉米夫定对慢性乙型病毒性肝炎和病毒携带的疗效。方法：将92例病人分为治疗组50例，对照组42例，治疗组用拉米夫定100mg.d^-1。疗程52wk。治疗前后作肝功能。HBV－二对半HBV－DNA的测定。结果：治疗12wk时，治疗组与对照组ALT复常率的差异无的统计学意义（P＞0．05），但对于HBV－DNA阴转率，治疗组显高于对照组（P＜0．01）。治疗52wk时，治疗组ALT复常率和HBV－DNA阴转率分别为79．4％，74．0％，而对照组为46．9％和7．1％（P＜0．05），结论：拉米夫定能有效地抑制乙肝病毒的复制，是治疗慢性乙型肝炎的安全有效药物。     

Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin's lymphoma

Chronic carriers of Hepatitis B virus (HBV) infection, who are treated for malignant lymphoma, are at high risk of mortality from reactivated HBV infection. We report a case of a 29-year-old male chronic HBV carrier who developed fulminant reactivated HBV infection following intensive chemotherapy for stage IV^B large cell B-cell non-Hodgkin's lymphoma associated with extensive central nervous system and bone marrow involvement. Prior to chemotherapy the patient had normal liver function tests and was negative for HBV DNA by semi-quantitative PCR assay. Fulminant HBV reactivation was confirmed following clinical deterioration, massive rises in hepatic transaminases (peak alanine aminotransferase = 2,850 U/l), liver biopsy and rising levels of serum HBV DNA. Following treatment with lamivudine 150 mg bd for 18 weeks dramatic and sustained recovery ensued. Symptoms and liver function tests improved within days and HBV DNA became negative within 12 weeks. Our patient later died from relapsed lymphoma but without evidence of reactivated HBV infection. We advise that lamivudine should be considered during intensive chemotherapy treatment of chronic carriers of HBV.