A novel hepatitis B virus mutant coexisting with wild type virus in a carrier with negative HBsAg yet positive HBeAg and anti-HBs

BackgroundOccult infection of hepatitis B virus (HBV) has important impacts on both public health and clinical medicine.ObjectivesTo characterize the sequences of HBV S region in a chronic carrier with occult HBV infection.Study designSerological markers for HBV were tested by commercial kits. Western blotting was performed to detect HBsAg. PCR was used to amplify HBV S region; the resultant products were sequenced directly and cloned and then sequenced.ResultsTests with commercial kits showed that the carrier was HBsAg negative yet HBeAg positive. HBsAg was positive in Western blotting analysis. Although anti-HBs titers were as high as 5356–11,578 mIU/ml, serum HBV DNA was positive, ranging from 370 to 491 copies/ml. Wild type and mutant HBV coexisted in circulation. The mutant virus had mutations in both preS2 and S genes: the preS2 ATG mutated to ATA, and the S gene had a 15-nucleotide repeat insertion in the a determinant. By Blast search in the GenBank, the mutant virus had not been identified before. Nevertheless, the carrier had no signs of liver dysfunction during follow-up period.ConclusionWe identified a novel mutant HBV coexisted with wild type virus in a carrier with negative HBsAg and positive HBeAg and high level of anti-HBs.     

Mutations in hepatitis B virus DNA from patients with coexisting HBsAg and anti-HBs

Background

The serological markers with coexistence of hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) of hepatitis B virus (HBV) infection were rare pattern. The virological significance, immune response and clinical outcome of these patients remain largely unknown.

Objectives

This research explores the relationship between this serological profile and HBV genome variants.

Study design

We studied 35 patients both carrying HBsAg and anti-HBs (group I), and 70 patients with HBsAg positive but anti-HBs negative (group II, served as control). The HBV genome sequences were obtained by direct sequencing of polymerase chain reaction (PCR) products.

Results

The amino acid (aa) variation within major hydrophilic region (MHR), especially in the first loop (aa124-137) of “a” determinant in group I is significantly higher than those in group II. The aa variation of cytotoxic lymphocyte (CTL) epitope in HBsAg (aa87–aa95) in group I is also significantly higher than that in group II. Interestingly, the basal core promoter (BCP) double mutations (A1762T/G1764A) in group I is significantly higher than those in group II as well.

Conclusions

In patients with HBV infection, the coexistence of HBsAg and anti-HBs is associated with an increased aa variability in several key areas of HBV genome. The molecular characteristic of HBV in HBsAg and anti-HBs positive patients is distinct and worth further studies.     

Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient.

BACKGROUND: Hepatitis B virus (HBV) often persists after resolution, but its replication is suppressed by antiviral T cells. Immunosuppressive treatment may lead to viral reactivation and severe hepatitis. Early antiviral therapy prevents reactivation but some occult HBV infections are not easily detectable. RESULTS: Here we describe a patient with a progressive non-Hodgkin lymphoma who had probably not been vaccinated against HBV and, before immunosuppression, showed antibodies (anti-HBs) against the viral surface antigen (HBsAg) as the only possible marker of occult HBV infection. Under immunosuppression he developed viremia (>10(8)copies/mL). The virus exhibited three S gene mutations (L109R, C137W, G145R) which led to false negative HBsAg results and diminished binding of vaccine-induced anti-HBs. CONCLUSIONS: Reliable screening and monitoring of severely immunosuppressed patients for HBV should include, in addition to anti-HBc and HBsAg, anti-HBs and sensitive HBV DNA assays. Furthermore, active vaccination or hepatitis B immune globulin may not protect against such mutants.     

Acute hepatitis B virus infection with simultaneous high HBsAg and high anti-HBs signals in a previously HBV vaccinated HIV-1 positive patient

We present a case of a clinical manifest hepatitis B virus infection and a potentially misleading HBV serological profile in an HIV-1 positive patient despite previous HBV vaccination. The patient presented with an acute hepatitis B and there was no indication of chronic HBV infection or the presence of a mutation in the ‘a’ determinant. Remarkably, simultaneously with high HBV surface antigen and HBV viral load, high anti-HBs antibodies were present. If, due to previous HBV vaccination only anti-HBs was tested in this patient, the result of the high anti-HBs antibodies could be very misleading and offering a false sense of security. Our findings contribute to the ongoing discussion on how to assess HBV specific immunological memory and determining the role of HBV booster vaccinations in immunocompromised individuals.     

竞争性聚合酶链反应法定量检测慢性乙型肝炎患者血清中乙型肝炎病毒前C区野毒株及变异株

设计了以内参照为基础的竞争性聚合酶链反应（ＰＣＲ）方法，同时定量检测ＨＢｅＡｇ阴性的慢性乙型肝炎患者血清中乙型肝炎病毒（ＨＢＶ）基因前Ｃ区野毒株及变异株，并观察了在应用α干扰素（ＩＦＮ）治疗以后的变化。结果发现干扰素治疗有效者中，病毒核酸量迅速下降至转阴；而干扰素治疗无效者中，病毒核酸量也可有所下降，但仍高于检测水平甚至反跳；另外，野毒株对ＩＦＮ的反应似乎优于突变株。该方法可用于研究乙型肝炎病毒感染过程及考核抗病毒药物疗效。     

竞争性聚合酶链反应法定量检测慢性乙型肝炎患者血…

设计了以内参照为基础的竞争性聚合酶链反应方法，同时定量检测ＨＢｅＡｇ阴性的慢性乙型肝炎患者血清中乙型肝炎病毒基因前Ｃ区野毒株及变异株，并观察了在应用α干扰素治疗以后的变化。结果发现干扰素治疗有效者中，病毒核酸量迅速下降至转阴；而干扰素治疗无效者中，病毒核酸量也可有所下降，但仍高于检测水平甚至反跳。     

Efficacy of alpha-interferon therapy of chronic hepatitis patients infected with wild type hepatitis B virus and HBEAG-minus mutant

The aim of this study was to evaluate the efficacy of alpha-interferon (alpha-IFN) treatment of 56 chronic hepatitis B (HB) patients positive for HB e antigen (HBeAg), which were previously not treated with alpha-IFN (group A). Seven of them, which did not respond to initial alpha-IFN treatment, were subjected to additional treatment with alpha-IFN (group B). Another 7 patients with chronic HB caused apparently by an HBeAg-minus HB virus (HBV) mutant represented group C. In the alpha-IFN treatment, 5 megaunits (MU) of alpha-IFN were administered subcutaneously three times a week for six months. A trend of improvement of important markers of the disease in the treated patients could be seen with increasing time after completion of the treatment even though it was not statistically significant. In group A, the absence of serum HBV DNA was found in 43% of the patients at the end of the treatment, in 41% 6 months later, and in 46% 12 months later. At the same time intervals group A showed negative HBeAg in 36%, 39% and 46%, positive anti-HBeAg in 36%, 38%, and 46%, negative HBsAg in 9%, 11%, and 14%, and normal level of alanine transaminase (ALT) in 23%, 39%, and 44%, respectively. A trend toward better results of alpha-interferon therapy for the group A patients displaying lower baseline viremia and higher ALT activity could be seen; however, this relationship was not statistically significant. Groups B and C were too small for statistical analysis. Nevertheless, 4 of 7 patients of group B were negative for HBV DNA 12 months after the treatment and HBV DNA was eliminated during the treatment in all patients of group C; however, 3 patients relapsed after the treatment.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

Low level wild-type and pre-core mutant hepatitis B viruses and HBeAg negative reactivation of chronic hepatitis B.

A qualitative and a quantitative mutation-site specific polymerase chain reaction assay (MSSA) was used to detect low level wild-type and pre-core mutant hepatitis B virus (HBV)-DNA. Serum samples from 11 anti-hepatitis B e (anti-HBe)-positive asymptomatic HBV carriers (Group A) and 10 anti-HBe-positive chronic hepatitis B patients who achieved alanine transaminase (ALT) normalization after antiviral therapy (Group B) were tested. Eleven patients had both wild-type and pre-core mutant HBV-DNA (52%, 4 from Group A and 7 from Group B), whereas 3 patients had only pre-core mutant HBV-DNA (14%, 2 from Group A and 1 from Group B) by qualitative MSSA assay. During a 3-year follow-up period, relapses were observed in 3 patients from Group B and intermittent ALT elevation was observed in 4 patients from Group A and 3 patients from Group B. The wild-type HBV-DNA concentration in the patients with reactivation was 10(2.06+/-2.62) copies/ml, whereas that in all patients without reactivation was below 10(2) copies/ml (P < .05). The pre-core mutant HBV-DNA concentration in the patients with reactivation was also significantly higher than that in the patients without reactivation (10(3.94+/-2.25) vs. 10(0.65+/-1.45) copies/ml, P < .001). All patients with both HBV-DNA concentrations below 10(2) copies/ml did not exhibit reactivation. Our result suggest that a high prevalence of coexistence of low level wild-type and pre-core mutant HBV-DNA has the potential for reactivation in anti-HBe-positive patients. Furthermore, quantification of wild-type and pre-core mutant HBV-DNA was useful to predict the prognosis of anti-HBe-positive infection and evaluate the efficacy of antiviral therapy.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.     

HBeAg阴性与阳性慢性乙肝患者的临床对比分析

目的 探讨HBeAg阳性和HBeAg阴性慢性乙肝患者的临床特征异同.方法 随机选取慢性乙肝患者354例,其中HBeAg阳性组124例,HBeAg阴性组230例,对两组的人口学、生化学、病毒学及诊断分型进行分析比较.结果 ①与HBeAg阳性组比较,HBeAg阴性组患者年龄较大(P=0.000),中度和重度慢性肝炎比例较低(P:0.007和0.014),重型肝炎发生率较高(P=0.008).②HBeAg阴性组的ALT、ALB、PTA及HBV DNA载量对数值低于HBeAg阳性组(P=0.035,0.002,0.000和0.000),但TBil水平高于HBeAg阳性组(P=0.003);两组AST水平差异无统计学意义(P=0.222).③HSeAs阴性组在高病毒载量组(HBV DNA105拷贝/m1)的比例低于HBeAg阳性组(37.4%VS55.6%,P=0.001).结论 HBeAg阴性患者与HBeAg阳性患者相比存在年龄偏大和HBV DNA水平较低等特征,HBeAg阴性乙肝患者的病情有时反而可能较重.