Mutations of T-cell epitopes in the hepatitis B virus surface gene in children with chronic infection and hepatocellular carcinoma

BACKGROUND AND OBJECTIVES:  Hepatitis B virus (HBV) infection induces an interaction of host immune responses against virus antigen-presenting hepatocytes. The emergence of mutants is a strategy through which the virus can escape host attacks and produce chronic infection. In this study, we aimed to investigate mutations of the human leukocyte antigen-A2-restricted T-cell epitope (TCE) in chronic HBV-infected children.
METHODS:  In total, 441 chronic HBV-infected children were longitudinally followed-up every 6 months. They were divided into hepatitis B e antigen (HBeAg) (−) (N = 60) and HBeAg (+) (N = 381) groups according to this seromarker at their enrollment. The HBeAg (+) group was further divided into HBeAg (+/−) (N = 229) and HBeAg (+/+) (N = 152) groups, depending on the occurrence of spontaneous HBeAg seroconversion. Twenty-five children with HBV-related hepatocellular carcinoma (HCC) were also recruited. TCE mutations were examined using the latest serum samples, and serum samples at enrollment were used if TCE mutations were present in the latest serum samples in the seroconverters. HBV genotypes and liver enzymes were also analyzed.
RESULTS:  The HBeAg (+/+) group had a lower TCE mutation rate (7.9%) than that of the HBeAg (+/−) (29.2%), HBeAg (−) (26.7%), and HCC (28.0%) groups. In the HBeAg (+/−) group, TCE mutations were present before HBeAg seroconversion in 11.9% of the subjects. Those with TCE mutations showed HBeAg seroconversion at an older age (16.1 ± 5.3 yr vs 12.7 ± 5.7 yr, P < 0.001) and with higher peak alanine aminotransferase (ALT) levels (median 175 U/L vs 119 U/L, P = 0.03) than those without TCE mutations.
CONCLUSIONS:  TCE mutations tended to be positively associated with HBeAg seroconversion and higher ALT levels in chronic HBV-infected children.     

湖北地区乙型肝炎病毒基因型分布与临床的相关性

目的 了解湖北地区乙型肝炎病毒(HBV)基因型的分布及其与临床的相关性。 方法 选择湖北地区HBV DNA阳性的慢性HBV感染者190例,其中乙型肝炎表面抗原(HBsAg)携带者52例、慢性乙型肝炎56例、重型肝炎32例、肝硬化22例、原发性肝癌28例,应用多对型特异性引物-聚合酶链反应检测HBV的基因型。 结果 多对HBV型特异性引物法可快速准确鉴定HBV的基因型。190份HBV DNA阳性血清标本中,B基因型140例(73.7％),C基因型42例(22.1％),BC混合型8例(4.2％),未发现A、D和E基因型;B基因型在重型肝炎和肝癌患者中占绝对优势,分别为87.5％和89.3％,显著高于HBsAg携带者的67.3％;B基因型患者血清丙氨酸氨基转移酶水平(253.1±306.7)U／L高于C基因型患者的(154.1±192.9)U／L,差异有统计学意义(P<0.05);除HBsAg携带者外的慢性HBV感染者中,B基因型患者血清抗-HBe阳性率50.5％(53／105)显著高于C基因型的18.5％(5／27),P<0.01。 结论 多对型特异性引物同时进行聚合酶链反应的基因分型方法可用于HBV基因型的流行病学调查;湖北地区存在HBV的B、C和BC混合基因型,B型为本地区的优势基因型并在严重肝病和肝癌中的比例较高,基因型的分布可能有较大的地区差异。     

Prevalence of hepatitis B virus precore stop codon mutations in chronically infected children

AIM: To find out whether there is a significant difference in the prevalence of the precore stop codon mutation between HBeAg positive and anti-HBe positive children. METHODS: We investigated a large pediatric population of 155 European children (mean age 10.9 years) with chronic hepatitis B by PCR and direct sequencing. Ninety were HBeAg positive and 65 had seroconversion to anti-HBe. Additionally genotyping was performed. RESULTS: Seventy-four (48%) of the sequenced HBV strains were attributed to genotype D and 81 (52%) to genotype A. In the group of 90 HBeAg positive patients, 2 (2.2%) 1896-G-to-A transitions leading to precore stop codon mutation were found, and in the group of 65 anti-HBe positive children, 5 (7.7%) were identified harbouring HBeAg-minus mutants. The difference was not statistically significant (P=0.13). CONCLUSIONS: HBeAg minus variants as predominant viral HB strains play a minor role in the course of chronic hepatitis B in European children.     

Hepatitis B virus genotype has no impact on hepatitis B e antigen seroconversion after lamivudine treatment

AIM: To investigate the association of hepatitis B virus (HBV) genotype and HBeAg seroconversion after nucleotide analogue treatment.METHODS: Chronic hepatitis B patients receiving lamivudine followed up for at least 6 months post-treatment were studied. Consecutive treatment-naïve patients who were prospectively followed up in the clinic for at least 18 months were studied as controls. HBeAg seroconversion was defined as loss of HBeAg, appearance of anti-HBe and normalization of alanine aminotransferase for at least 6 months.RESULTS: Thirty-five patients on lamivudine and 96 control patients followed up for 39 (18-49) months were studied. Lamivudine was given for 12 (10-18) months, and patients were followed up for 15 (6-34) months after drug cessation. Genotype B and C HBV were found in 43 and 88 patients and HBeAg seroconversion occurred in 12 (28%) and 16 (18%) patients, respectively (P = 0.30). There was no difference in HBeAg seroconversion between patients infected by genotype B and C HBV in the control (35% vs 21%, P = 0.25) and lamivudine-treated (14% vs 10%, P = 1.00) groups.CONCLUSION: HBeAg seroconversion after treatment by lamivudine was not influenced by the HBV genotype.     

Comparative study of genotype B and C hepatitis B virus-induced chronic hepatitis in relation to the basic core promoter and precore mutations

BACKGROUND: The clinicopathological profiles and outcome of chronic hepatitis B can differ by hepatitis B virus (HBV) genotypes. In Japan, genotype B and C are two major HBV genotypes. The basic core promoter and precore mutations are other known viral factors for disease activity, although the relationship between HBV genotypes and these mutations is not fully understood. METHODS: The HBV genotypes in 90 patients with chronic hepatitis B were determined using an ELISA. Obtained data were correlated with clinicopathological parameters, basic core promoter, precore and the nucleotide 1858 mutations of the HBV genome. RESULTS: Among 90 cases, 20 (22.2%) had genotype B and 70 (77.8%) had genotype C HBV. Genotype B patients were older than genotype C patients (44.0 +/- 13.9 vs 34.7 +/- 11.0 P = 0.0022). The HBeAg was more prevalent in genotype C than B patients (P = 0.0008) while anti-HBe was more common in genotype B than C patients (P = 0.0002). Serum aspartate aspartate aminotransferase/alanine aminotransferase levels (B: 220.7 +/- 612.8/257.0 +/- 498.0 IU/L vs C: 111.3 +/- 122.8/201.6 +/- 229.4 IU/L, P = 0.16/0.48) and HBV viral loads in blood (B: 6.1 +/- 3.1 log genome equivalent [LGE]/mL vs C: 6.7 +/- 2.3 LGE/mL, P = 0.42) were equivalent. The seroconversion from HBeAg to anti-HBe occurred significantly earlier in genotype B than C patients (62 +/- 53 months vs 136 +/- 54 months, P = 0.0028) during the mean observation period of 149 +/- 82 months even under various therapeutic modalities. The categories III and IV of the histological activity index in genotype C were higher (III: P < 0.005, IV: P < 0.05, n = 68) than that in B patients whereas category II was higher in genotype B than C patients (P < 0.05). The double mutation (1762T/1764A) in the basic core promoter was more frequently found in genotype C than in B HBV (P = 0.0068), whereas the precore mutation (1896A) was more common in genotype B than C HBV (P = 0.0233). The incidence of 1858C that was complementary to the precore mutation site in the stem-loop structure in, was equally rare in both genotype B and C HBV. CONCLUSIONS: Genotype B patients were older, had earlier HBeAg seroconversion and exhibited more severe lobular necroinflammation, less portal inflammation and fibrosis than genotype C patients. This genotypic difference is related to the basic core promoter and precore mutations irrespective of 1858C. (c) 2004 Blackwell Publishing Asia Pty Ltd.     

Hepatitis C virus eradication followed by HBeAg to anti-HBe seroconversion after pegylated interferon-alpha2b plus ribavirin treatment in a patient with hepatitis B and C coinfection

In hepatitis B or hepatitis C endemic areas, the number of patients with dual infections is substantial. In such patients, interferon-alpha plus ribavirin can achieve sustained hepatitis C virus (HCV) clearance and hepatitis B e antigen (HBeAg) seroconversion. Pegylated interferon (PegIFN), an established treatment for hepatitis C, is currently increasingly recognized as an efficient therapy for hepatitis B. No case of successful use of PegIFN plus ribavirin has yet been reported, however, in hepatitis B virus (HBV) and HCV coinfection.We report on a 32-year-old man, of Kampuchean origin, with chronic hepatitis B, as documented by the presence of hepatitis B surface antigen with HBeAg, who was coinfected with HCV genotype 1. On therapy with PegIFN-alpha2b plus ribavirin, HCV RNA became undetectable at week 17. At the end of the 48 weeks of treatment, HCV RNA was still undetectable, HBV DNA was reduced and HBeAg remained positive. Twelve weeks after the end of treatment, HBV DNA reduction was followed by HBeAg to anti-HBe seroconversion. Two years after the end of treatment, HCV RNA and HBV DNA were still undetectable, and HBeAg to anti-HBe seroconversion was maintained. We conclude that the combination of PegIFN plus ribavirin may induce suppression of both viral infections.     

Childhood hepatocellular carcinoma develops exclusively in hepatitis B surface antigen carriers in three decades in Taiwan: Report of 51 cases strongly associated with rapid development of liver cirrhosis

To elucidate the etiologic role of chronic hepatitis B virus (HBV) infection and the role of liver cirrhosis in hepatocellular carcinoma (HCC), pathologic and virologic features of the disease were studied in 51 children with HCC; these accounted for 4.3% of 1195 pathologically proven HCC patients examined in the last three decades. Males predominated (M/F = 3.3:1), and the mean age was 11 years (range: 4-15 years). Hepatitis B surface antigen (HBsAg) was detected in the liver and/or serum of 100% of 42 children by immunocytochemical and/or radioimmunoassay, in the serum of 90% of 10 siblings, and more importantly in 94.1% of 17 mothers, suggesting that infection from familial HBsAg carriers, particularly carrier mothers, may contribute to the high incidence. Liver cirrhosis was frequent (74%), especially in the unresectable cases (87%); in the 20 children under 9 years of age, 95% were cirrhotic, a significantly higher level than the 58% of the 26 older children, P less than 0.005. All but one had advanced HCC, with 1-year survival in only 10.5%. The advanced HCC coupled with young age suggests that HCC can develop rapidly. The low positive rates of serum hepatitis B e antigen (HBeAg, 18%) and liver hepatitis B core antigen (11%) coupled with high frequency of liver cirrhosis indicate that an early HBeAg seroconversion to anti-HBe, in association with severe liver injury, may play an important role in the rapid development of HCC in children.     

Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B

During the course of chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) often coincides with normalization of liver biochemical test and clinical remission, but data regarding long-term outcome after spontaneous seroconversion are still scarce. Excluding patients with other virus(es) concurrent infection, 283 patients with chronic HBV infection were followed up for at least 1 year after spontaneous HBeAg seroconversion to anti-HBe. Follow-up studies included clinical, biochemical, and virologic evaluation and hepatocellular carcinoma (HCC) screening with ultrasonography and alpha-fetoprotein assay. During a median follow-up period of 8.6 years (range, 1 to 18.4 years) after HBeAg seroconversion in 283 patients, 189 (66.8%) showed sustained remission, whereas the remaining 94 (33.2%) experienced alanine aminotransferase (ALT) elevation over twice the upper limit of normal: 12 (4.2%) associated with HBeAg reversion, 68 (24%) with detectable serum HBV DNA but HBeAg negative, and 14 (4.9%) of undetermined causes. Of the 269 patients without evidence of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed cirrhosis with a cumulative incidence and relative risk significantly higher in patients developing active hepatitis than in patients with sustained remission (P <.05). HCC developed in 6 (2.2%) of the 283 patients, also with a significantly higher cumulative incidence in patients developing active hepatitis after HBeAg seroconversion (P <.005). In conclusion, the results suggest that spontaneous HBeAg seroconversion confers favorable long-term outcomes. However, active hepatitis still may develop and lead to cirrhosis and HCC.     

恩替卡韦联合免疫制剂治疗免疫耐受期乙型肝炎病毒携带者疗效探讨

目的观察恩替卡韦联合免疫制剂治疗免疫耐受期乙型肝炎病毒（HBV）携带者的临床疗效。方法按就诊顺序编号将66例HBV携带者随机分为治疗组33例和对照组33例。给予治疗组恩替卡韦联合重组乙肝疫苗（CHO细胞）20 μg、重组人白细胞介素-II 20万单位和重组人粒细胞集落刺激因子75 μg三角肌皮下注射,1次/m,疗程为3年;对照组只接受单纯的恩替卡韦治疗,疗程也为3年。治疗前后常规检测血清丙氨酸氨基转移酶（ALT）、HBV DNA、血清HBV标记物的变化。结果在治疗结束时,治疗组患者血清HBeAg阴转率、HBeAg血清转换率和HBV DNA阴转率分别为33.3%、24.2％和75.7%,显著高于对照组的12.1%、6.0%和51.5% （P<0.05）;在治疗结束后6个月时,治疗组血清HBeAg阴转率、HBeAg血清转换率和HBV DNA阴转率分别为42.3%、27.2%和78.7%,也显著高于对照组的12.1%、6.0%和45.4% （P<0.05）;在治疗过程中两组部分患者ALT升高,其中治疗组为42.3%,显著高于对照组的9.0%（P<0.05）。结论核苷类药物联合免疫制剂治疗HBV携带者,在部分人群能打破免疫耐受,并获得病毒学清除。     

Demonstration of hepatitis B virus DNA by polymerase chain reaction in the serum and the liver after spontaneous or therapeutically induced HBeAg to anti-HBe or HBsAg to anti-HBs seroconversion in patients with chronic hepatitis B.

The objective was to determine the proportion of patients with chronic hepatitis B in whom hepatitis B virus DNA is demonstrated by polymerase chain reaction after HBeAg to anti-HBe or HBsAg to anti-HBs spontaneous or therapeutically induced seroconversion. Polymerase chain reaction was performed on serum 6 and 12 mo after HBeAg to anti-HBe seroconversion in 12 patients and 2, 6 and 12 mo after HBsAg to anti-HBs seroconversion in 13 patients. Polymerase chain reaction was performed on liver tissue after HBeAg to anti-HBe seroconversion in five patients and after HBsAg to anti-HBs seroconversion in one patient. Serum HBV DNA was demonstrated by polymerase chain reaction in 83% of patients 6 or 12 mo after HBeAg to anti-HBe seroconversion and in 58%, 31% and 15% of patients at 2, 6 and 12 mo, respectively, after HBsAg to anti-HBs seroconversion. Liver HBV DNA was demonstrated by polymerase chain reaction in all patients tested. Our results show that (a) a reduced level of hepatitis B virus replication persists in most of the patients after HBeAg to anti-HBe seroconversion and might be predictive of reactivation, and (b) in contrast, hepatitis B virus replication progressively disappears in most of the patients after HBsAg to anti-HBs seroconversion.     

Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection

To elucidate the biologic significance of hepatocyte hepatitis B core antigen (HBcAg) expression and its relation to the natural course of hepatitis B virus (HBV) infection, the patterns of HBcAg were correlated with HBV virus replication state and the disease activity in 598 needle liver biopsies performed on 569 hepatitis B surface antigen (HBsAg) carriers aged 1-81 years. A good correlation of liver HBcAg with serum HBeAg and HBV DNA status was demonstrated. HBcAg was present in the hepatocyte nuclei (nHBcAg) or cytoplasm (cHBcAg), or in both (mixed). Pure nHBcAg was seen mainly in children and young adults; 86% of the patients had non-aggressive disease, but rare cases of chronic active hepatitis (CAH) and HBeAg seroconversion were observed. In contrast, cHBcAg was predominantly associated with CAH (52%) and accompanied by a significantly higher HBeAg seroconversion rate (27%). The HBeAg-negative group, particularly the liver HBcAg-negative subgroup, had a lower frequency of CAH, but an increased incidence of non-aggressive disease as well as cirrhosis and/or hepatocellular carcinoma, indicating that HBeAg seroconversion to anti-HBe does not necessarily mean a favorable prognosis. The results suggest that expression of HBcAg correlates with the liver pathology and the three phases of chronic HBV infection: (1) the early immune tolerance phase is characterized by nHBcAg, mild disease and low HBeAg seroconversion rate; (2) the virus replication/elimination phase by cHBcAg or negative HBcAg, frequent CAH, and high HBeAg seroconversion rate; and (3) the inactive virus replication phase by negative HBcAg and a bipolar disease spectrum.     

Significance of hepatitis B genotype in acute exacerbation,HBeAg seroconversion,cirrhosis-related complications,and hepatocellular carcinoma

The pathologic role of hepatitis B virus (HBV) genotype in Chinese patients with HBV infection is largely unknown. We examined the relationship between HBV genotypes, and hepatitis B e antigen (HBeAg) seroconversion, acute exacerbation, cirrhosis-related complications, and precore/core promoter mutations. Three hundred forty-three HBV patients (288 were asymptomatic, 55 presented with cirrhosis-related complications) were recruited. HBV genotypes and precore/core promoter mutations were determined by line probe assays. Genotypes B and C were the 2 most common genotypes, contributing 28% and 60%, respectively. The median age of HBeAg seroconversion for patients with genotype B was 9 years earlier than patients with genotype C (P =.011). There were no differences in the liver biochemistry, HBV DNA level, and cumulative risk of acute exacerbation (defined as increased alanine aminotransferase level > or =1.5 x upper limit of normal) between patients with genotypes B and C. There was a trend for patients with genotype B to have a higher cumulative rate of HBeAg seroconversion compared with patients with genotype C at the initial follow-up of 6 years (P =.053), but this difference became insignificant during subsequent follow-up. The prevalence of both genotypes was the same in patients with and without cirrhosis-related complications and/or hepatocellular carcinoma. Genotype B was associated with precore mutations (P <.0001), whereas genotype C was associated with core promoter mutations (P <.0001). In conclusion, although patients with genotype B had earlier HBeAg seroconversion, there was no significant reduction in the risk of development of complications. Genotypes B and C are associated with high prevalence of precore and core promoter mutations, respectively.     

Hepatitis B virus genotypes and hepatocellular carcinoma in Thailand

AIM: The role of hepatitis B virus (HBV) genotypes on the clinical features and prognosis of patients with hepatocellular carcinoma (HCC) is currently unknown. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Thai patients. METHODS: HBV genotypes were determined by PCR-RFLP in stored sera of 93 asymptomatic carriers, 103 patients with chronic hepatitis, 60 patients with cirrhosis and 76 patients with HCC. The clinical data were analyzed in relation to the HBV genotype. RESULTS: HBV genotypes C and B were predominant in Thailand, accounting for 73% and 21%, respectively. The distributions of genotypes B and C were similar in HCC patients compared to the other groups. Genotype C was significantly more common in HCC patients who were under 40 years old than genotype B (18% vs 0%, P= 0.03), but was significantly less common in patients older than 60 years (26% vs 56.5%, P= 0.01). The positive rate of hepatitis B e antigen (HBeAg) in patients with genotype C was significantly higher than that in patients with genotype B (71.6% vs 44.4%, P= 0.03 in chronic hepatitis; 56.8% vs 11.1%, P= 0.01 in cirrhosis). There were no differences between HCC patients with genotypes B and C regarding tumor staging by CLIP criteria and the overall median survival. Multivariate analyses showed that HBV genotype was not an independent prognostic factor of survival in HCC patients. CONCLUSION: Patients with genotype C had a higher positive rate of HBeAg and exhibited earlier progression of cirrhosis and HCC than those with genotype B. However, there were no differences in the risk of developing HCC and its prognosis between patients with these genotypes.     

扶正祛邪饮与替比夫定联合治疗对慢性乙型肝炎HBeAg血清转换作用的非随机对照研究临床观察

目的:探讨扶正祛邪饮与替比夫定联合治疗慢性乙型肝炎的疗效,重点观察HBeAg血清转换指标。方法:96例患者按意愿分为联合组50例和对照组46例,联合组患者口服替比夫定片,1次/d,600mg/次,疗程12个月。另加服扶正祛邪饮,2次/d,150ml/次,疗程6个月;对照组患者单用替比夫定,用法和疗程与联合组相同。观察两组患者治疗前后的临床症状改善、肝功能好转、HBV DNA下降、HBeAg转阴及HBeAg/抗-HBe血清转换的效果。结果:两组患者治疗后的ALT、AST、TBil、HBeAg转阴率、HBeAg/抗-HBe血清转换率、HBV DNA转阴率,与治疗前比较差异有显著性意义(P<0.01或P<0.05);两组患者治疗后的比较,联合组在ALT水平、HBeAg转阴率、HBeAg/抗-HBe血清转换率等早期应答方面优于对照组(P<0.05),联合组HBeAg转阴率、HBeAg/抗-HBe血清转换率在治疗12月时高于对照组,但差异无统计学意义(P>0.05)。结论:扶正祛邪饮联合替比夫定片治疗慢性乙型肝炎早期疗效明显,肝功能恢复较快,且能促进HBeAg转阴和HBeAg/抗-HBe血清转换提前应答,可作为慢性乙型肝炎治疗的辅助药物。     

Hepatitis B virus genotype A is more often associated with severe liver disease in northern India than is genotype D.

BACKGROUND: The clinical outcome of chronic hepatitis B may depend on hepatitis B virus (HBV) genotype. Data from India on this aspect are limited and contradictory. We studied the frequency of HBV genotypes and their clinical significance. METHODS: Stored sera from patients with chronic HBV infection were tested for HBV genotype using PCR-RFLP. Clinical data, and biochemical and serological parameters were retrieved from medical records; patients were classified as having chronic hepatitis or cirrhosis. RESULTS: Of 70 patients studied (mean age [SD] 38.4 [17.0] years; 63 men; ALT 140 [177] U/L), 32 had chronic hepatitis and 38 had cirrhosis. HBeAg was positive in 50/67 (75%), and anti-HBe in 12/66 (18%). Genotype A was the commonest (37; 53%), followed by D (32; 46%) and C (1; 1%). Patients with genotype A more often had ALT elevation exceeding 1.5 times normal (30/37 [81%] than those with genotype D (18/31 [58%]; p< 0.05). They also more often had positive HBeAg (32/37; 86%) and negative anti-HBe (33/36; 92%) than those with genotype D (18/29 [62%] and 21/29 [72%], respectively; p< 0.05 each). Of 37 patients with genotype A, 23 (62%) had cirrhosis and 14 (38%) had chronic hepatitis; of 32 patients with genotype D, 15 (47%) had cirrhosis and 17 (53%) had chronic hepatitis (p=ns). In the subgroup aged> 25 years, genotype A patients more often had cirrhosis than those with genotype D (23/28 [82%] vs 13/23 [57%]; p < 0.05). CONCLUSION: HBV genotypes A and D were the commonest in our population. Genotype A was more often associated with ALT elevation, HBeAg positivity, absence of anti-HBe and, among those aged 25 years and above, cirrhosis of liver, than was genotype D.     

B和C基因型乙型肝炎病毒对阿德福韦酯治疗的病毒学应答比较

目的 阐明不同基因型HBV对阿德福韦酯治疗反应是否存在差异.方法 首先利用型特异引物PCR法结合型特异核苷酸分析法检测HBV基因型,然后根据基因型对阿德福韦酯Ⅲ期临床资料进行分析及统计学处理(计量资料用t检验,计数资料用卡方检验).结果 177例临床标本检出B基因型HBV感染者102例,C基因型感染者65例,B+C混合型感染者6例,B+D混合型感染者4例.治疗第12、24周时,B基因型组和C基因型组血清HBV DNA下降均值分别为2.2log10>拷贝/ml、2.1log10拷贝/ml和2.7log10拷贝/ml、2.4log10拷贝/ml,两组差异均无统计学意义(P>0.05),第48周时两组HBV DNA分别下降3.6log10拷贝/ml和3.1log10拷贝/ml,差异有统计学意义(P<0.05).治疗结束时(48周)B基因型组和c基因型组分别有43例(42.2%)和22例(33.8%)出现血清HBV DNA转阴,差异有统计学意义(P<0.05);两组患者HBeAg阴转率抗-Hbe血清转换率分别为30.4%、29.2%和21.6%、20.0%,差异无统计学意义(P>0.05).两组患者血清ALT复常率在治疗第12、24、36周和48周时分别为35.3%、33.9%,51.0%、53.9%,63.4%、61.5%和83.3%、81.5%,各时间段两组ALT复常率差异均无统计学意义(P>0.05).结论 阿德福韦酯治疗慢性乙型肝炎48周时,部分病毒学指标(如血清HBV DNA下降均值和HBV DNA阴转率)B基因型优于C基因型HBV感染者.但由于阿德福韦酯起效较慢,抑制病毒作用相对较弱,有必要延长治疗时间进一步证实这一现象.     

Hepatitis B virus genotypes and the response to lamivudine therapy

Hepatitis B virus (HBV) can be classified into eight major genotypes (A-H) that have mainly a geographic distribution. The HBV genotype may influence disease progression, HBeAg seroconversion rates, response to antiviral treatment. The aim of study was to analyze the distribution and frequency of genotypes in patients with chronic hepatitis B. Response to lamivudine 100 mg daily therapy was examined in respect to genotype. Sixty six patients (45 (68,2%) male, 21 (31,8%) female) with chronic hepatits B were enrolled. HBV genotypes were assigned before treatment with INNO-LiPA HBV Genotyping, Innogenetics, N. V., Ghent assay, which is a line probe test based on the reverse hybridization principle. In baseline and after 12 months of treatment serological markers of HBV infection, alanine aminotransferase (ALT) activities and HBV DNA serum levels were tested. Patients with chronic hepatitis B were infected predominantly with genotype A. HBV genotype distribution was: 78,8% for genotype A, 13,6% for genotype D, 1,5% for mixed infection with genotypes A and D. Distribution of genotypes A and D was asymmetrically regardless of sex, HBeAg status, ALT and HBV DNA levels. Four (6,1%) specimens had indeterminate A results by LiPA. There were no significant differences between patients with genotypes A and D regarding age and sex. There were also no significant differences between these two groups regarding rates of HBeAg and anti-HBe positivity, ALT activity and viral load. Twenty months of lamivudine (100 mg daily) therapy resulted in significant decreases in serum HBV DNA and ALT activities in patients with genotype A as well as with genotype D. After 12 months of treatment there were no statistical differences in HBeAg seroconversion rates, ALT activities, viral loads, frequency of HBeAg and anti-HBe between genotypes A and D.     

Chronic hepatitis virus infection in children

Hepatitis B and C viruses (HBV and HCV) are the two main hepatitis viruses causing chronic liver diseases in children. In hyperendemic areas, nearly half of the primary infection in chronic HBV carriers occurs during the perinatal period through the transmission from hepatitis B e antigen (HBeAg)-positive mothers. The other half are from horizontal transmission mainly through intrafamilial spread or injection using unsterilized needles. During the natural course of chronic HBV infection, spontaneous HBeAg/anti-HBe seroconversion occurs very rarely (2% annually) before 3 years of age. After 3 years of age, the HBeAg seroconversion rate increases gradually to 5% per year. Those with mothers who are hepatitis B carriers tend to clear HBeAg slower than those whose mothers are non-carriers. Transplacental HBeAg may cause T cell tolerance in infected children. Universal HBV immunization programmes have been effective in reducing the hepatitis B carrier rate more than 10-fold, and the incidence of hepatocellular carcinoma in children has also been decreased significantly. Hepatitis C virus infection occurs mainly in high-risk children, such as those who received blood products (blood diseases, malignancies, post-open heart surgery etc.), children of HCV-infected mothers, and in hyperendemic areas, from injection using unsterile needles. Mother-to-infant transmission occurs on average in 5% of infants of viraemic mothers. The maternal HCV-RNA titre is the most important factor determining the infectivity. Chronicity developed in 60–80% of HCV-infected children. Although transient or persistent elevation of aminotransferases occurs frequently in chronically HCV-infected children, liver histology showed minimal or mild changes only. The most prevalent genotype of HCV in children is Ib. Screening of the blood products for HCV antibody has markedly reduced the rate of HCV infection in children at risk. However, vaccine development is needed to prevent mother-to-infant transmission and other routes of infections.     

Hepatitis B virus infection in 6,130 unvaccinated Korean-Americans surveyed between 1988 and 1990

OBJECTIVES: During the past decades, the influx of immigrants from hepatitis B virus (HBV) endemic regions has brought significant changes in the prevalence of HBV-associated liver diseases and hepatocellular carcinoma (HCC) in the United States. Our program, which was intended to identify those in need of hepatitis B vaccination, helped us to learn of the natural history of HBV infection in Korean Americans. METHODS: Between November of 1988 and May 1990, we screened 6,130 Korean Americans in the eastern United States for HBV infection. RESULTS: The overall hepatitis B surface antigen (HBsAg) (+) rate was 6.1%, with 8.0% for males and 4.4% for females. The carrier rate peaked in subjects between the ages of 21 and 40 yr. The HBsAg (+) rate for 452 U.S.-born children was lower (2.7%) than that of 623 Korean-born (5.5%). None received hepatitis B immune-globulin or HBV vaccination. The vertical transmission rate was 30.3% in children born to HBsAg (+) mothers and 100% in those born to hepatitis B e antigen (HBeAg) positive mothers. In contrast, the paternal transmission rate was low; 10.3% in children with HBsAg (+) fathers and 19.2% in those with HBeAg (+) fathers. Another significant observation was the unexpected finding of ongoing liver diseases in incidentally identified carriers. Evaluation of 139 asymptomatic adult carriers revealed that 42% had elevated liver enzymes and 11% had already developed liver cirrhosis. CONCLUSION: These findings strongly suggest the need for active HBV screening of immigrants from endemic regions and, most importantly, the need for careful monitoring of the carriers.     

Mutations of pre-core and basal core promoter before and after hepatitis B e antigen seroconversion

AIM: To investigate the role of pre-core and basal core promoter(BCP) mutations before and after hepatitis Be antigen(HBe Ag) seroconversion.METHODS: The proportion of pre-core(G1896A) and basal core promoter(A1762T and G1764A) mutant viruses and serum levels of hepatitis B virus(HBV) DNA, hepatitis B surface antigen(HBs Ag), and HB core-related antigen were analyzed in chronic hepatitis B patients before and after HBe Ag seroconversion(n = 25), in those who were persistently HBe Ag positive(n = 18), and in those who were persistently anti-HBe positive(n = 43). All patients were infected with HBV genotype C and were followed for a median of 9 years.RESULTS: Although the pre-core mutant became predominant(24% to 65%, P = 0.022) in the HBe Ag seroconversion group during follow-up, the proportion of the basal core promoter mutation did not change. Median HBV viral markers were significantly higher in patients without the mutations in an HBe Ag positive status(HBV DNA: P = 0.003; HBs Ag: P < 0.001; HB core-related antigen: P = 0.001). In contrast, HBV DNA(P = 0.012) and HBs Ag(P = 0.041) levels were significantly higher in patients with the pre-core mutation in an anti-HBe positive status.CONCLUSION: There is an opposite association of the pre-core mutation with viral load before and after HBe Ag seroconversion in patients with HBV infection.