Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study

Purpose To elucidate the long-term natural course following the onset of cirrhosis in patients with chronic hepatitis B. Methods Ninety-three patients with chronic hepatitis B who had developed cirrhosis during regular follow-up were included in this long-term follow-up study. At the time of cirrhosis detection, 30% of the patients were seropositive for hepatitis B e antigen (HBeAg) and 73% had a HBV-DNA level >10⁴ copies/ml. Follow-up studies included liver biochemistry, viral markers, α-fetoprotein and ultrasonography every 3–6 months. Results During a mean follow-up period of 102 ± 60 (12–246; median 97) months, 32 patients (34.4%) experienced 55 episodes of hepatitis flare (7.0%/year), 15 (53.6%) of 28 HBeAg-positive patients seroconverted to anti-HBe (6.3%/yr) and 12 (12.9%) lost HBsAg (1.5%/year). Overall disease progression was observed in 25 (26.9%, 3.2%/year) patients: 12 (12.9%, 1.5%/year) hepatic decompensation, 21 (22.6%, 2.7%/year) hepatocellular carcinoma and 11 (11.8%, 1.4%/year) died. Multivariate analysis showed that age at onset of cirrhosis (P = 0.015) and persistent HBeAg seropositivity (P = 0.019) were the independent factors for overall disease progression. Conclusions These results suggest that patients with older age at onset of cirrhosis and persistent HBeAg seropositivity following the onset of cirrhosis were independent factors for the disease progression in the first 10-year after the development of cirrhosis in patients with chronic hepatitis B. This work was supported by grants from National Science Council, Taiwan (NSC95-2314-B-182A-032) and the Prosperous Foundation, Taipei, Taiwan.     

Hepatitis B virus precore mutations and HBeAg negative reactivation of chronic hepatitis B after interferon therapy

The objective of this study was to look for HBV precore mutations in three patients with chronic active hepatitis B who developed HBV-DNA-positive/HBeAg-negative reactivation after HBe seroconversion induced by interferon therapy. Direct sequencing of polymerase chain reaction products was performed on serum collected before and after HBe seroconversion. In two patients precore sequence showed only wild-type HBV before and after interferon therapy. In one patient, precore sequence showed only wild-type HBV before interferon therapy and a mixed infection by wild-type HBV and precore mutant viruses (1858 and 1896 nucleotide mutations) after treatment. The presence of HBeAg/anti-HBe immune complexes was found after HBe seroconversion in all cases. Our results suggest that: 1) precore mutations are not always found in patients with chronic hepatitis B who develop HBV DNA-positive/HBeAg-negative reactivation; and 2) HBeAg negativity, despite the presence of wild-type HBV, might be due to HBeAg/anti-HBe immune complexes. We speculate that the production of these immune complexes may be favored by interferon therapy.     

恩替卡韦对不同病毒载量慢性乙型肝炎患者的长期疗效观察

目的探讨长期应用恩替卡韦（ETV）对不同HBV DNA载量的慢性乙型肝炎患者的疗效。方法77例患者参照GLOBE研究方案,对基线HBVDNA〉10^7拷贝／mL的50例与HBV DNA〈10^7拷贝／mL的27例进行ETV抗病毒疗效比较。分别于治疗前及治疗24、48、96和157周时检测ALT、HBV DNA、HBV血清学标志物等指标,并对治疗后的应答情况进行分析。结果ETV治疗157周时基线HBV DNA〉10^7拷贝／mL和〈10^7拷贝／mL者的完全病毒学应答率分别为80．0％和77．8％（X2=0．053,P〉0．05）,两组HBeAg阴转率和HBeAg血清转换率分别为46．0％、42．0％和63．0％、63．O％,差异没有统计学意义X^2=2．021和3．082,P均〉0．05）。两组ALT复常率分别为90．0％和85．2％,差异无统计学意义X^2=0．394,P〉0．05）。结论长疗程恩替卡韦治疗不同基线HBVDNA水平慢性乙型肝炎的疗效基本相同。     

乙型肝炎患者e抗原转换与外周血γδT和Tc17的关系

目的探讨乙型病毒性肝炎患者e抗原(HBeAg)转换与外周血γδT、白细胞介素(IL)-17、γ干扰素(IFN-γ)等的相关性及临床意义。方法随机选取2017年10月至2018年4月在该院就诊的乙型肝炎患者90例作为研究组,选取同期30例健康人作为对照组。然后在研究组内根据HBeAg表达与否进一步分为3个亚组:HBeAg+/Ab-组(n=30)、HBeAg+/Ab+组(n=30)、HBeAg-/Ab+组(n=30)。运用流式细胞仪检测受试者外周血中的γδT细胞、IL-17+γδT细胞、IFN-γ+γδT细胞、IL-17+CD8细胞在外周血单个核细胞(PBMCs)中的比例,对比上述指标在研究组及对照组间、以及乙型肝炎患者HBeAg/Ab不同表达组内的差异。进一步分析乙型肝炎患者HBeAg/Ab不同表达组及不同血清丙氨酸氨基转移酶(ALT)水平下,血清内HBV-DNA水平的差异。结果研究组IFN-γ+γδT细胞、γδT细胞水平、IL-17+CD8细胞要明显高于对照组(P<0.05)。研究组中,HBeAg+/Ab-组和HBeAg+/Ab+组患者PBMCs内总γδT细胞水平要显著高于HBeAg-/Ab+组(P<0.05);HBeAg+/Ab+组乙型肝炎患者IL-17+CD8细胞明显高于HBeAg+/Ab-组和HBeAg-/Ab b组(P<0.05)。HBeAg+/Ab-组慢性乙型肝炎患者血清内HBV-DNA水平要明显高于HBeAg+/Ab+组和HBeAg-/Ab+组(P<0.05)。结论γδT细胞在HBeAg/Ab血清转换中可能发挥一定作用。IL-17+CD8细胞在慢性乙型肝炎良性转归中起重要作用,对于抗病毒治疗的效果可能具有预测意义。     

拉米夫定治疗HBeAg阳性慢性乙型肝炎患者血清转换持久性的研究

目的观察拉米夫定长期治疗慢性乙型肝炎(CHB)3年以上患者的血清转换率和停药后持久率,及影响疗效的有关因素.方法167例CHB患者,每天服用拉米夫定100mg,持续3年以上,连续2次以上出现血清转换(间隔3个月),即HBeAg转阴和抗HBe转阳,继续服药6～12个月后,停药并随访1年以上.服药第1年每月,以后第3个月观察临床症状和血清病毒学标志、丙氨酸转氨酶(ALT)、HBV DNA定量及YMDD变异等项目.HBV基因分型应用型特异性PCR方法.结果共有45例患者出现血清转换(27.0%),继续服药6～12个月后停药并随访1年以上,9例出现血清学重新激活,血清转换持久率为80.0%.经单因素统计和Logistic多元回归分析,得出血清转换率和停药后持久率与基线ALT水平呈正相关,与基线HBV DNA水平和治疗后YMDD变异呈负相关.结论CHB患者出现血清转换后继续应用拉米夫定治疗6个月以上,大多数患者可达到持续转换.对血清转换率和持久率有显著影响意义的因子为基线ALT、治疗后YMDD变异.     

乙型肝炎病毒PreS1抗原与HBV感染和复制的相关性研究

目的研究血清前S1抗原（PreS1）与乙型肝炎病毒（HBV）感染和复制的相关性。方法同时测定458例乙型肝炎患者和35例健康对照者血清HBV—DNA载量、PreS1和HBeAg。以HBV-DNA载量为标准,进行PreS1和HBeAg比较。结果HBV-DNA载量小于10^3拷贝／ml的223例中PreS1阳性102例（45．74％）,HBeAg阳性16例（7．17％）;PreS1和HBeAg与HBV-DNA载量等级的线性相关系数分别为0．9329和0．9718;PreS1和HBeAg诊断乙型肝炎病毒感染的敏感性分别为72．77％、52．34％,特异性分别为54．26％、92．82％,阳性预测值分别为62．64％、88．49％,阴性预测值分别为65．41％、64．89％,准确率分别为63．76％、72．05％。结论随HBV—DNA载量的升高,HBeAg的检出率显著提高,PreS1的检出率次之;PreS1与HBV-DNA有一定相关性,但其相关程度不及HBeAg。     

血清HBV DNA反跳发生时间与YMDD变异的关系

目的:研究拉米夫定治疗HBeAg阳性慢性乙型肝炎(CHB),血清HBVDNA反跳发生时间与YMDD变异的关系。方法:采用聚合酶链反应(PCR)方法,分别检测拉米夫定治疗前的血清样本和治疗后不同时间发生HBVDNA反跳时的血清样本中是否存在YMDD变异株。结果:40例发生血清HBVDNA反跳的HBeAg阳性CHB病人,拉米夫定治疗前的血清中均未检出YMDD变异株。拉米夫定治疗6个月时发生HBVDNA反跳的6例病人,血清中也未检出YMDD变异(0/6);于治疗9个月时发生HBVDNA反跳的13例病人中有3例病人的血清检出YMDD变异(23·08%);于治疗12个月时发生HBVDNA反跳的21例病人中有18例病人的血清检出YMDD变异(85·71%);P<0·01。结论:拉米夫定治疗HBeAg阳性慢性乙型肝炎,血清HBVDNA反跳发生时间与YMDD变异呈正相关,治疗9个月以后发生的血清HBVDNA反跳主要是由YMDD变异所致。     

HBsAg阳性者前S1抗原和HBV DNA检测的相关性探讨

目的 探讨HBsAg阳性者血清中HBV DNA及乙型肝炎病毒前S1抗原(PreS1Ag)和乙型肝炎e抗原(HBeAg)的关系及其临床应用价值.方法 对368例临床血清标本采用ELISA方法检测HBeAg和PreS1Ag,荧光定量PCR法检测HBV DNA.结果 HBeAg阳性组PreS1Ag阳性率为87.2%,HBV DNA阳性率为91.0%;HBeAg阴性组PreS1Ag阳性率为54.7%,HBV DNA阳性率为55.7%.患者血清PreS1Ag与HBV DNA结果无明显差异(P>0.05).结论 PreS1Ag与HBV DNA符合率较高,比HBeAg更能反映病毒复制情况,可作为一项新的病毒复制指标.