Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion

Mutations in the core promoter and precore regions are frequently found in hepatitis B e antigen (HBeAg)-negative patients, but precore stop codon mutation is restricted to hepatitis B virus (HBV) genotypes that have T at nucleotide 1858. The aims of this study were to determine the role of core promoter and/or precore mutations in HBeAg seroconversion and their impact on the subsequent course of liver disease, and to determine if core promoter mutations are more frequently selected in patients with HBV genotypes that preclude the development of precore stop codon mutation. Serial sera from 45 patients with chronic HBV infection were polymerase chain reaction (PCR)-amplified, and the HBV core promoter and precore regions were sequenced. Ninety-two percent of patients had core promoter or precore mutations after HBeAg seroconversion: 42% had core promoter changes only, 38% had precore stop codon mutations only, and 12% had changes in both regions. Seventy-three percent of the patients had persistently normal aminotransferases, and only 8% had multiple flares in aminotransferases after HBeAg seroconversion. Core promoter changes were significantly more common in patients infected with HBV who have C at nucleotide 1858 (91% vs. 27%; P <.01), while precore stop codon changes were exclusively found in patients infected with HBV who have T at nucleotide 1858 (87% vs. 0; P <.01). The vast majority of our patients had core promoter and/or precore mutations after HBeAg seroconversion. Nevertheless, most patients had sustained remission of liver disease. Our data suggest that core promoter changes are preferentially selected in patients infected with HBV genotypes that preclude the development of precore stop codon mutation.     

Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong

BACKGROUND/AIMS: We conducted a population study to document the prevalence of hepatitis B virus (HBV) genotypes in Hong Kong. METHODS: HBV genotypes, core promoter (CP) and precore mutations were determined in 776 asymptomatic patients. RESULTS: 92.6% patients had single genotype [B (32.5%), C (62.5%)]. 99.1% of genotype B was subtype Ba. Patients with age <50 years had a lower prevalence of genotype B than patients with age >51 years (32.5% vs. 41%, respectively, P=0.028). Compared to patients with genotype C, patients with genotype B had a higher cumulative rate (P=0.018) and younger age (40.1 vs. 34.2 years, respectively, P=0.018) of HBeAg seroconversion. There were no differences in the HBV DNA levels between patients with genotypes B and C, and with wild-type and mutants of CP and precore regions. By multivariate analysis, patients with genotype C and with CP mutations had higher alanine aminotransferase (ALT) levels. CONCLUSIONS: B and C were the two most common HBV genotypes in Hong Kong. The former had a higher chance of earlier HBeAg seroconversion and lower ALT levels. The prevalence of genotype B was lower in patients with age <50, probably related to influx of immigrants from China since 1949.     

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.     

Association of core promoter/precore mutations and viral load in e antigen-negative chronic hepatitis B patients

Apart from core promoter A1762T/G1764A and precore G1896A mutations, other hepatitis B virus (HBV) mutants are detected in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). The aim of this study was to determine the effects of those mutants on clinical manifestation and viral loads of genotypes B and C HBV. Seventy-nine HBeAg-negative CHB patients with hepatitis flare were enrolled in this study and their HBV precore/core region were sequenced. Serial biochemical profiles and viral loads were assessed and compared. Fifty-three patients (67%) were infected by genotype B HBV and 26 (33%) were infected by genotype C HBV. The clinical manifestation and HBV viral loads were comparable between the two groups. However, genotype B was significantly associated with precore G1896A mutation (92.5%), and more mutations within nucleotide 1809-1817 were detected in patients infected by genotype B as compared with those infected by genotype C (18.9%vs 3.8%). Most of the cases had mutations at the -2, -3 or -5 position from the precore AUG initiation codon. Triple core promoter mutations T1753C/A1762T/G1764A [corrected] appeared to be linked to genotype C rather than genotype B HBV (19.2%vs 1.9%; P = 0.013). In multivariate analysis, the presence of either triple core promoter 1753/1762/1764 mutation or nucleotide 1809-1817 mutation was the only factor associated with lower HBV viral load (<70 Meq/mL) (odds ratio = 9.01; 95% CI 1.11-71.43; P = 0.04). In conclusion, minor HBV variants with mutations in the core promoter and precore region were detectable in genotypes B and C. Such HBV variants are genotype specific and related to viraemia levels.     

Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion

The underlying mechanisms for earlier hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) genotype B when compared with genotype C are unknown. We aimed to determine whether there were any differences in the T helper (Th) responses during hepatitis flares in HBeAg-positive patients with genotypes B and C. Proliferative response measured by (3)H-thymidine uptake and Th responses measured by Enzyme-Linked Immunosorbent Spot assays for interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-4, IL-5 and IL-10 were performed in 10 patients with genotype B and 10 with genotype C with hepatitis flares. HBV genotypes, core promoter, precore mutations, sequence of HBV core region and HBV DNA levels were determined. There was no difference in the HBV DNA levels during hepatitis flares between patients with genotypes B and C. Patients with genotype B had a significantly higher number of IFN-gamma producing cells [with hepatitis B core antigen (HBcAg) stimulation] and lower number of IL-10 producing cells (with HBcAg and HBeAg stimulation) compared with patients with genotype C (P = 0.011, =0.043, <0.001 respectively). There was a trend (P = 0.058) that patients with genotype B had a higher cumulative rate of HBeAg seroconversion. Patients with precore mutants also had a significantly higher number of IFN-gamma producing cells (with HBcAg stimulation) and lower number of IL-10 producing cells (with HBeAg stimulation) compared to patients without precore mutant (P = 0.038, =0.016 respectively). HBV genotype B induces a greater Th1 and lesser Th2 response than genotype C. This provides immunologic evidence for the higher chance of HBeAg seroconversion in patients with genotype B.     

Clinical significance and evolution of core promoter and precore mutations in HBeAg-positive patients with HBV genotype B and C: a longitudinal study.

BACKGROUND/AIMS: The aims of this longitudinal study were to investigate whether the clinical outcome and evolution of core promoter and precore mutations were different during hepatitis B e antigen (HBeAg) seroconversion between hepatitis B virus (HBV) genotypes B and C in HBeAg-positive patients with chronic hepatitis B. PATIENTS AND METHODS: The core promoter and precore sequences were determined from serial sera of 156 HBeAg-positive patients with chronic HBV infection. RESULTS: In HBV genotype C, the T1762/A1764 mutant was detected earlier than the A1896 mutant, and the frequency was significantly higher than in HBV genotype Ba over the entire follow-up period. In HBV genotype Ba, A1896 was found earlier than the T1762/A1764 mutant, and the frequency was significantly higher than in genotype C only before HBeAg seroconversion, and the A1896 mutant played an important role in HBeAg seroconversion in HBV genotype Ba. In addition, the T1846 variant was an independent factor associated with HBeAg seroconversion. Furthermore, HBV genotype C was associated with the development of G or C1753 and T1766/A1768 mutations, and the reactivation of hepatitis after HBeAg seroconversion. Based on Cox's regression analysis, the significant risk factors of liver cirrhosis were older age at entry [hazard ratio (HR)=1.085, 95% confidence interval (CI)=1.036-1.136, P=0.001], alanine transaminase (ALT) >80 U/l (HR=3.48, 95% CI=1.37-8.86, P=0.009), and the T1762/A1764 mutant (HR=5.54, 95% CI=2.18-14.08, P<0.001). CONCLUSIONS: Our study showed that different HBV genotypes were associated with various mutations in the core promoter and precore regions during HBeAg seroconversion. T1762/A1764 mutation could be useful in predicting clinical outcomes in HBeAg-positive patients with HBV infection.     

Genotype and phylogenetic characterization of hepatitis B virus among multi-ethnic cohort in Hawaii

AIM: Hepatitis B virus (HBV) genomes in carriers from Hawaii have not been evaluated previously. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Hawaii. METHODS: Genotyping of HBV among 61 multi-ethnic carriers in Hawaii was performed by genetic methods. Three complete genomes and 61 core promoter/precore regions of HBV were sequenced directly. RESULTS: HBV genotype distribution among the 61 carriers was 23.0% for genotype A, 14.7% for genotype B and 62.3% for genotype C. Genotypes A, B and C were obtained from the carriers whose ethnicities were Filipino and Caucasian, Southeast Asian, and various Asian and Micronesian, respectively. All cases of genotype B were composed of recombinant strains with genotype C in the precore plus core region named genotype Ba. HBeAg was detected more frequently in genotype C than in genotype B (68.4% vs 33.3%, P<0.05) and basal core promoter (BCP) mutation (T1762/A1764) was more frequently found in genotype C than in genotype B. Twelve of the 38 genotype C strains possessed C at nucleotide (nt) position 1858 (C-1858). However there was no significant difference in clinical characteristics between C-1858 and T-1858 variants. Based on complete genome sequences, phylogenetic analysis revealed one patient of Micronesian ethnicity as having C-1858 clustered with two isolates from Polynesia with T-1858. In addition, two strains from Asian ethnicities were clustered with known isolates in carriers from Southeast Asia. CONCLUSION: Genotypes A, B and C are predominant types among multi-ethnic HBV carriers in Hawaii, and distribution of HBV genotypes is dependent on the ethnic background of the carriers in Hawaii.     

Hepatitis B post-partum e antigen clearance in hepatitis B carrier mothers: Correlation with viral characteristics

BACKGROUND: The purpose of the present paper was to correlate hepatitis B virus (HBV) genotype, e antigen titer, HBV-DNA level and precore/basal core promoter mutations with post-partum e antigen clearance in hepatitis B e antigen (HBeAg)-positive carrier mothers. METHODS: A total of 40 consecutive HBeAg-positive carrier mothers were studied from January 2002 to January 2003. The blood samples were taken at delivery, 3-4 months and at 1 year after delivery, and the follow-up period was until 1 year after delivery. All sera were assayed for HBeAg, HBV-DNA level, HBV genotype and precore/basal core promoter mutations. The correlation between HBV characteristics and post-partum e antigen clearance was analyzed by Mann-Whitney, Pearson chi2 and multiple logistic regression tests. RESULTS: The mean age of the 40 HBeAg-positive carrier mothers was 29.9 +/- 5.3 years with a mean parity of 1.4 +/- 0.7. Five of them (group I) had post-partum e antigen clearance, which persisted thereafter, whereas the remaining 35 carrier mothers (group II) had persistent positivity of HBeAg during the follow-up period. The prepartum comparisons of HBV characteristics between groups I and II were comparable in terms of demographics and distributions of HBV genotype and precore/basal core promoter mutations. In contrast, group I carrier mothers had lower HBeAg titer and HBV-DNA level than group II carrier mothers (1:80 vs 1:4000, P = 0.02, and 3.75 x 10(5) vs 3 x 10(8) copies/mL, P = 0.028, respectively). CONCLUSIONS: Post-partum e antigen clearance in HBeAg-positive carrier mothers is closely associated with prepartum low HBeAg titer or HBV-DNA level.     

Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection

OBJECTIVES: We aimed to study the relationship between the hepatitis B virus (HBV) genotypes, core promoter/precore stop codon mutations, and histological liver damage among hepatitis B e antigen (HBeAg)-negative patients. METHODS: Liver biopsy specimens of 55 HBeAg-negative chronic HBV-infected patients were studied. A histological activity index was scored for degree of necroinflammation (HAI-NI) and fibrosis (HAI-F) as described by Knodell et al. HBV DNA was determined by a cross-linking assay and polymerase chain reaction (PCR) at the core promoter/precore region and the S region. PCR-positive samples were directly sequenced for core promoter and precore mutations and examined by restriction fragment length polymorphism for genotyping. RESULTS: Forty-one males and 14 females at a median age of 43 were studied. HBV DNA was detectable in 32 (58%) and 37 (67%) patients by the cross-linking assay and PCR, respectively, at the time of liver biopsy. The median (range) HAI-NI and HAI-F scores were 5 (1-10) and 2 (0-4), respectively. HBV DNA detectable by either the cross-linking assay or PCR was associated with a higher HAI-NI score. Eleven and 31 patients had genotypes B and C HBV, respectively. Genotype C HBV was associated with higher HAI-NI than genotype B HBV. Core promoter mutations and precore stop codon mutation were detected in 74% and 40% patients, respectively, but they were not associated with higher HAI-NI or HAI-F scores. CONCLUSIONS: Detectable HBV DNA and genotype C HBV, but not core promoter or precore stop codon mutations, are associated with more severe liver damage in HBeAg-negative patients.     

Effects of hepatitis B virus precore and basal core promoter mutations on the expression of viral antigens: genotype B vs C

Hepatitis B virus (HBV) genotypes/mutants are known to affect natural outcomes. The virologic differences among HBV genotype, precore and basal core promoter (BCP) mutations were investigated. HBV strains were isolated from 18 hepatitis B e antigen (HBeAg)-positive patients (nine genotype B and nine genotype C). All had precore and BCP wild-type sequences. After cloning of full-length HBV genome, the effects of viral genotype, precore and BCP mutations singly or additively on the expression of viral DNA and antigens were investigated by mutagenesis and transfection assays in Huh7 cells. Significant findings included the following: (i) expression of intracellular core protein increased when precore or BCP mutation was introduced in genotype C strains; (ii) expression of intracellular surface protein was lower in genotype C precore wild-type strain compared with genotype B; (iii) precore mutation was associated with a lower extracellular expression level of HBV DNA; (iv) secretion of hepatitis B surface antigen in genotype C was lower than that in genotype B; and (v) secretion of HBeAg in genotype B was lower than that in genotype C. No additive effect was observed by combining precore and BCP mutations. Hence, HBV genotype and precore/BCP mutations correlate with intrahepatic expression of viral antigens in vitro.     

乙型肝炎病毒前C区和BCP区突变及基因型对HBeAg表达的影响

研究乙型肝炎病毒前C区和BCP区突变及基因型对HBeAg表达的影响。分别用基因芯片和基因测序的方法检验HBV DNA阳性的乙型肝炎病毒前C区和BCP区突变及基因型,应用时间分辨免疫荧光法检测HBeAg含量,按照有无HBV前C区1896、BCP区1762、1764双突变、基因型等指标进行分组分析。无前C区1896和BCP区1762/1764双突变组、单纯1762、1764双突变和1896突变组以及1896、1762、1764联合突变组之间相互比较,HBeAg含量相差显著,F=6.47,P〈0.01;B、C基因型间HBeAg含量相比,相差无显著性,t=0.1394,P〉0.05。乙型肝炎病毒前C区和BCP区突变能显著影响HBeAg量的表达,从而导致乙型肝炎病毒致病能力的变化。     

Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B

Background. Mutations in the precore stop codon (G1896A) and the basal core promoter (A1762T and G1764A) are frequently found in hepatitis B envelope antigen (HBeAg)-negative chronic hepatitis B. However, the clinical significance of these mutations remains controversial. We therefore investigated the influence of hepatitis B virus (HBV) genotypes, as well as precore/basal core promoter mutants, on the clinical and virological features of patients with HBeAg-negative chronic hepatitis B. Methods. Serum samples from 37 patients with HBeAg-negative chronic hepatitis B were collected for serological and molecular assays. The precore and basal core promoter regions were amplified by polymerase chain reaction and the amplicons were directly sequenced and analyzed. HBV geno-type was determined by polymerase chain reaction-restriction fragment length polymorphism. Results. Most of the patients had detectable serum HBV DNA, and genotypes B and C were the predominant strains. The overall prevalence of the precore stop codon mutant and basal core promoter mutant was 67% and 60%, respectively. The baseline clinical and virological features of patients with genotype B and genotype C infection were comparable. However, in the patients with precore/basal core promoter dual mutations there was a significantly lower proportion of individuals with a high detectable serum HBV DNA level (>100 pg/ml) than in the patients with either the precore stop codon mutation alone or the basal core promoter mutation alone (P = 0.04 by the logistic regression test for the trend). Conclusions. Our data suggest a high prevalence of precore stop codon and basal core promoter mutation in Taiwanese patients with HBeAg-negative chronic hepatitis B, and the influence of the basal core promoter mutation on HBV replication is modulated by the emergence of the precore stop codon mutation. Received: May 14, 2001 / Accepted: September 14, 2001     

HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C

Hepatitis B virus (HBV) genotype and precore/core promoter mutations have been implicated in spontaneous and interferon alfa (IFN-alpha)-related hepatitis B e antigen (HBeAg) seroconversion. We performed a retrospective analysis of a previously reported randomized controlled trial to determine the effects of HBV genotype and precore/core promoter mutations on IFN-alpha response in patients with HBeAg-positive chronic hepatitis. Clinical data and stored sera from 109 (95%) patients in the original trial were analyzed. Seventy-three patients received IFN-alpha and 34 received no treatment (controls). Almost all patients had HBV genotypes B (38%) and C (60%). Antiviral response was achieved in 39% and 17% of IFN-alpha-treated patients (P =.03) and in 10% and 8% of untreated controls (P =.88) with HBV genotype B and C, respectively. Multivariate analysis identified HBV genotype B, elevated pretreatment alanine aminotransferase (ALT) levels, and low pretreatment HBV-DNA levels but not IFN-alpha treatment as independent factors associated with antiviral response. Among the 66 patients with elevated pretreatment ALT level, antiviral response was achieved in 57% and 21% of IFN-alpha-treated patients (P =.019), and in 25% and 8% of untreated controls (P =.45) with HBV genotype B and C, respectively. Multivariate analysis showed that genotype B and low pretreatment HBV-DNA levels were independent predictors of antiviral response. In conclusion, our data showed that HBV genotype B was associated with a higher rate of IFN-induced HBeAg clearance compared with genotype C. Stratification for HBV genotypes should be considered in future clinical trials of antiviral therapy of chronic hepatitis B.     

乙型肝炎病毒基因型对乙型肝炎病毒变异的影响

目的探讨乙型肝炎病毒(HBV)基因型对病毒前核心区(前C区,nt1896)及基本核心启动子(BCP,nt1762/1764)变异的影响.方法416例血清HBsAg阳性、HBV DNA定量大于1.0×104拷贝/ml的患者,采用微流基因芯片检测HBV基因型、前C区及BCP变异.结果416例HBV感染者中406例有基因分型结果:B型20.9%、C型65.9%、BC混合型10.8%,10例患者未分出基因型.302例为HBeAg(-)且HBV DNA( )患者,其中248例(82.12%)有前C区或BCP变异,41.06%为前C区变异,31.12?P变异,2种同时变异为9.94%.B型患者前C区变异率为22.9%(20/87),与C型患者前C区变异率39.4%(108/274)及B、C混合型变异率40.0%相比均有显著差异(P＜0.01).在BCP变异及双变异,C型患者变异率均大于B型患者,但差异无统计学意义(P＞0.05).B、C混合型患者前C区及BCP变异率与C型相似.结论HBV基因型可影响病毒前C区及BCP变异,以C型为著.     

Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea

BACKGROUND/AIMS: The aims of this study were to determine the frequency of precore/core promoter mutations and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Korea. METHODS: Patients with chronic hepatitis B virus (HBV) infection were tested for HBeAg, anti-HBe, liver profile and HBV-DNA by a branched DNA (bDNA) assay. Serum HBV-DNA was amplified by a polymerase chain reaction and the precore/core promoter sequence was determined. RESULTS: Among the 413 consecutive HBeAg-negative patients, 19.6% were bDNA-positive. Evidence of liver disease was found in 90.1% of bDNA-positive and 41.7% of bDNA-negative patients. Overall, 17.7% of HBeAg-negative patients had e-CHB. Precore mutation (A1896) was detected in 93.7% of HBeAg-negative bDNA-positive and 93.9% of HBeAg-negative bDNA-negative patients. In 59 HBeAg-positive patients, 78% had wild-type and 22% had a mixture of wild-type and A1896 mutant. Core promoter TA mutation was detected in 89.9% of HBeAg-negative bDNA-positive patients, 89.8% of HBeAg-negative bDNA-negative patients, and 74.6% of HBeAg-positive patients. No correlation was found between the presence of precore/core promoter mutations and HBV-DNA levels or disease severity. CONCLUSIONS: In Korean patients infected with HBV genotype C, precore mutation occurred almost invariably along with HBeAg seroconversion and core promoter TA mutation was frequent irrespective of viral replication levels or disease severity.     

Geographic distribution, virologic and clinical characteristics of hepatitis B virus genotypes in China

The significance of hepatitis B virus (HBV) genotypes for the heterogeneity of chronic HBV infection and severity of liver disease is not well understood. The aim of this study was to determine the distribution and virologic characteristics of HBV genotypes in China and possible association with the diversity of liver disease. The study includes 1096 chronic HBV carriers from nine provinces in China. We collected clinical and laboratory data and analysed the HBV strains in sera by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and nucleotide sequencing techniques. The most common HBV genotypes were B (41%) and C (53%), while genotypes A and D were also found. A North-South divide was identified in genotype B and C distribution - genotype C was predominant in northern China, while genotype B was more prevalent in southern provinces. Patients with genotype B were younger than those with genotype C, and had a lower prevalence of HBeAg - 65%vs 72%, respectively (P = 0.03). However, the severity of liver disease did not differ significantly between patients infected with genotype B or C - neither when comparing liver function tests (1024 patients), nor hepatic inflammation and fibrosis (264 patients). Amongst 47 patients with genotype D (by PCR-RFLP), 37 (79%) were infected with a new subtype (designated Dc), having a recombination fragment from genotype C precore/core region. This is the first large-scale HBV genotype study from China and convincing documentation of the North-to-South gradient of genotypes C vs B in this country. HBV DNA recombination over the surface and precore/core genes increases the diversity of HBV strains and may have diagnostic and clinical implications.     

病毒学因素对ALT持续正常的e抗原阴性慢性乙型肝炎病毒感染者肝脏组织学改变的影响

目的 探讨ALT持续正常的HBeAg阴忡慢性HBV感染者病毒学因素与肝脏组织学改变的关系.方法 枪测52例研究对象的HBV DNA水平、基因型、基本核心启动了(BCP)与前C区变异,分析各病毒学因素对肝脏组织学改变的影响.止态分布数据两组间均数比较采用t检验,多组均数比较采用单因素方差分析;非正态分布数据比较采用Mann-Whitney I检验;两样本率的比较用χ2检验及Fisher精确概率法;HBV DNA与肝脏组织学的关系等非参数双变量相关分析采用Spearman相关系数方法;采用受试者T作特征曲线下而积评价HBV DNA水平对肝脏病理改变的诊断价值. 结果 BCP与前C区联合突变组的病毒载量高于非联合突变组[(4.9±1.4)10g10拷贝/ml比(4.1±1.1)log10拷贝/ml,t=2.308,P<0.05];联合突变组32.1%的患者HAI≥4分、14.3%的患者F≥3分.前C区或BCP野毒株的感染者中,HBV DNA与肝脏炎症呈正相关(r值分别为0.626和0.592,P值均<0.01)、与纤维化改变也呈正相关(r值分别为0.730和0.641,P值均<0.01).在尢联合突变的研究对象中,HBV DNA用于预测其F≥3分的肝脏病理改变有显著意义(受试者工作特征曲线下面积为0.905,95%可信区间为0.771～1.039,P<0.05),临界值为4.5 log10拷贝/ml(敏感度1.000,特异度0.778,阿I性预测值为42.9%,阴性预测值为100.0%).基因B型的HBV DNA高于C型[(5.1±1.5)log10拷贝/ml比(4.3±1.0)lOg10拷贝/ml],差异有统计学意义(t= 2.059,P<0.05);但两者在显著肝脏病理改变方面的差异尢统计学意义. 结论 HBV联合突变株的复制能力最强,行且部分联合突变株感染者出现显著肝组织学改变,此类患者有必要接受抗病毒治疗.在前C区或BCP变异野毒株感染者中,HBVDNA与肝脏的炎症、纤维化改变呈正相关,病毒载量用于预测这部分感染者F≥3分的肝脏病理改变有显著意义.