The clinical implications of hepatitis B virus genotype: Recent advances

Outcomes of chronic hepatitis B virus (HBV) infection are heterogeneous. Estimates of annual incidence of cirrhosis and hepatocellular carcinoma (HCC) are 2-10% and 1-3%, respectively. Several viral factors, including HBV genotype, viral load and specific viral mutations, have been associated with disease progression. Among these, HBV genotype is not only predictive of clinical outcomes but has also been associated with response to interferon treatment. Currently, at least 10 HBV genotypes and several subtypes have been identified; they have distinct geographic distribution. Acute infection with genotypes A and D results in higher rates of chronicity than genotypes B and C. Compared to genotype A and B cases, patients with genotypes C and D have lower rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion; when this occurs, it tends to be delayed. HBV genotype C has a higher frequency of basal core promoter (BCP) A1762T/G1764A mutation, pre-S deletion and is associated with higher viral load than genotype B. Similarly, genotype D has a higher prevalence of BCP A1762T/G1764A mutation than genotype A. These observations suggest important pathogenic differences between HBV genotypes. These may contribute to more severe liver disease, including cirrhosis and HCC with genotypes C and D HBV infection. In addition, genotype A and B patients have better responses to interferon-based therapy than genotypes C and D, but there are few consistent differences for direct HBV antivirals. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.     

Is There Any Value to Hepatitis B Virus Genotype Analysis?

Hepatitis B may cause a varying spectrum of diseases ranging from an asymptomatic or mild anicteric acute illness, to severe or fulminant hepatitis. Similarly, the outcome of chronic hepatitis B is variable. Viral factors associated with outcome of chronic hepatitis B virus (HBV) infection include hepatitis B e antigen status, HBV DNA, genotype, and HBV variants. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. A total of ten hepatitis B virus genotypes have been defined with a distinct geographical distribution. Hitherto, genotypes A, B, C and D have been studied most extensively. The HBV genotype appears to influence not only the natural history of HBV related liver disease but also the response to HBV treatment. HBV genotypes are also linked with both core promoter and BCP mutations. Progression to chronic infection appears to occur more frequently following acute infection with genotypes A and D than with the other studied genotypes. Genotypes A and B appear to have higher rates of spontaneous HBeAg seroconversion. More advanced liver disease and progression to HCC is more often seen in chronic infection with genotypes C and D in contrast to genotypes A and B. More specifically, genotypes A1, C, B2–B5 and H appear to be associated with more serious complications than genotypes A2, B1 and B6. These observations suggest important pathogenic differences between HBV genotypes. Genotypes A and B have higher response rates to interferon based therapy than genotypes C and D. Knowledge of HBV genotype enables clinicians to identify those patients at increased risk of disease progression whilst aiding the selection of appropriate antiviral therapy. Genotyping and monoclonal subtyping can provide useful information for epidemiological studies. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.     

Hepatitis B viral genotypes: clinical relevance and molecular characteristics

Hepatitis B virus (HBV) infection is a global health problem and the clinical outcome of chronic HBV infection depends on the frequency and severity of hepatitis flares in the immune clearance phase. Currently, four subtypes and seven genotypes of HBV are identified and most have specific geographic distributions. The impact of HBV genotypes on the clinical outcome of chronic HBV infection has been partially clarified. In Taiwan, genotype C is associated with more severe liver disease and genotype B is associated with the development of hepatocellular carcinoma (HCC) in young non-cirrhotic patients. In contrast, genotype B has a relatively good prognosis in Japan and China and is rarely associated with the development of HCC. Similarly, genotype D is associated with more severe liver disease than genotype A in India and may predict occurrence of HCC in young patients. Although superinfection of HBV on top of hepatitis B carriers occurs in Taiwan, it is rarely associated with acute exacerbations. As to the response to antiviral treatment, genotypes C and D are associated with a lower response rate to interferon therapy compared with genotypes B and A. In addition, the subtype adw is reported to be associated with a higher risk of lamivudine resistance than ayw. In HBV subtype adw-infected HCC patients, genotype B responds better to embolization therapy and has a lower rate of HCC recurrence than genotype C. In summary, pathogenic and therapeutic differences do exist among HBV genotypes and determining the genotype in patients with chronic HBV infection would help gain further information for etiologic, clinical, virologic and anthropologic investigations. Further studies to clarify the molecular virological factors that contribute to these differences are awaited.     

乙型肝炎病毒基因型检测及其临床应用

目的:探讨HBV基因型的检测及其在临床上的应用.方法:用微板核酸分子杂交-ELISA方法检测468例HBV DNA阳性的慢性乙型肝炎患者血清HBV基因型.分析HBV基因型与病毒复制、基本C基因启动子(BCP)变异、肝病病情轻重、干扰素疗效的关系.结果:深圳地区HBV基因型以B和C基因型为主,分别占25.0%和64.9%;C基因型的HBeAg阳性率(68.8%)高于B基因型的HBeAg阳性率(35.0%)(P＜0.01);C基因型的血清HBV DNA水平也明显高于B基因型(1g 6.74 copies/ml vs. 1g 5.44 copies/ml, P＜0.01);轻中度慢性肝炎以B基因型为主,而重度慢性肝炎以C基因型为主;B基因型对干扰素的有效应答率为47.2%,C基因型的有效应答率为28.9%,两组比较差异有显著性意义(P＜0.05).结论:HBV基因分型有助于临床判断病情、估计预后及抗病毒治疗疗效预测.     

Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D

BACKGROUND AN AIMS: Current interferon alfa (IFN) treatment of chronic hepatitis B has limited efficacy. The role of hepatitis B virus (HBV) genotypes for response to IFN was investigated. PATIENTS AND METHODS: HBV genotype was determined by direct sequencing of the HBV X gene in 165 consecutive patients with chronic replicative hepatitis B treated with standard IFN. HBV genotype A or D was found in 144 cases. RESULTS: Sustained response (six months after treatment) to standard IFN therapy was higher in HBV genotype A compared with HBV genotype D infected patients (49% v 26%; p<0.005). Sustained response to IFN was 46% versus 24% (p<0.03) in hepatitis B e antigen (HBeAg) positive hepatitis (n = 99) and 59% versus 29% (p<0.05) in HBeAg negative hepatitis (n = 45) for HBV genotype A compared with HBV genotype D. HBeAg status had no negative impact on IFN response. Multivariate logistic regression identified HBV genotype A and high pretreatment alanine aminotransferase levels (>2 x upper limit of normal) as independent positive predictive parameters of IFN response. CONCLUSIONS: The present study indicates that HBV genotypes A and D are important and independent predictors of IFN responsiveness in chronic hepatitis B. HBV genotype adapted treatment regimens may further improve treatment efficacy in chronic hepatitis B.     

延安地区乙型肝炎病毒基因型与干扰素抗病毒治疗的效果

目的 了解延安地区不同HBV基因型临床特征及其干扰素抗病毒治疗的效果.方法 用PCR鉴定延安地区130例慢性乙型肝炎患者的HBV基因型,并对患者应用干扰素α-2b抗病毒治疗12个月,随访12个月,对治疗及随访资料进行回顾性分析.统计学处理采用x2检验.结果 延安地区HBV基因型以B、C基因型为最常见;B基因型HBeAg阳性率明显低于C基因型,且B+C基因型HBeAg阳性率也明显低于C基因型;B基因型与B+C基因型、B基因型与D基因型、C基因型与D基因型、D基因型与B+C基因型的HBeAg阳性率比较,差异均无统计学意义.B基因型对干扰素的完全应答率、持续应答率明显高于C基因型,而无应答率低于C基因型;B+C基因型的干扰素应答率低于B、C基因型.结论 延安地区B、B+C基因型HBeAg阳性率明显低于C基因型;B基因型对干扰素的完全应答率高于C基因型,B+C基因型的干扰素应答率低于B、C基因.     

Therapeutic implications of hepatitis B virus genotypes.

BACKGROUND/AIMS: Hepatitis B virus (HBV) is a global health problem. In addition to the implementation of universal hepatitis B vaccination, effective and individualized treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma is still needed. HBV has been designated eight genotypes (A-H) based on genome sequence divergence. The epidemiology of HBV genotypes and their implications on the responses to antiviral therapy have become increasingly recognized in both Asian and Western countries. METHODS: Published data are thus reviewed. Results: Each genotype has its distinct geographical and ethnic distribution. Genotypes A and D occur frequently in Africa, Europe, and India, while genotypes B and C are prevalent in Asia. Genotype E is restricted to West Africa, and genotype F is found in Central and South America. The distribution of genotypes G and H is less clear. Accumulating evidence indicates a better sustained response to conventional interferon in patients with genotype B than those with C, and in patients with genotype A than those with D. In contrast, conflicting results exist regarding the response to pegylated interferon. On the other hand, the therapeutic responses to nucleoside/nucleotide analogues are comparable among patients with different HBV genotypes. The impact of HBV subgenotypes, mixed genotype infections, and recombinants of different genotypes on the response to antiviral treatments awaits further examinations. CONCLUSION: Remarkable clinical and pathogenic differences do exist among HBV genotypes; however, researches on molecular and virologic mechanisms underlying the clinical phenotypes of different HBV genotypes are urgently needed.     

Hepatitis B genotypes and the response to interferon therapy

BACKGROUND/AIMS: Possible pathogenic differences among hepatitis B virus (HBV) genotypes have been observed; however, the response to interferon therapy among HBV genotypes remains unknown. We therefore analyzed the efficacy of interferon alfa in the treatment of chronic hepatitis B patients with different HBV genotypes. METHODS: Fifty-eight genotype B or C infected chronic hepatitis B patients who had been treated with interferon alfa-2b were retrospectively studied. The response to interferon was defined as normalization of serum aminotransferase level, loss of hepatitis B e antigen and HBV DNA 48 weeks post-treatment. RESULTS: Baseline data of both groups of patients were comparable; however, genotype C patients had a higher serum aminotransferase level and a higher frequency of core promoter mutation. The response rate was 41% and 15% in genotype B and C patients, respectively (p=0.045). In those with higher serum aminotransferase levels, the response rate was 50% and 17%, respectively (p=0.025). Additionally, younger age and genotype B infection may predict a better response to interferon alfa. CONCLUSIONS: HBV genotype C, compared to genotype B, is associated with a higher frequency of core promoter mutation, and a lower response rate to interferon alfa therapy.     

乙型肝炎病毒基因型与干扰素α1b疗效关系的研究

目的　探讨乙型肝炎病毒 (HBV)基因型与干扰素α1b治疗慢性乙型肝炎疗效的关系。方法　采用PCR、核酸杂交和酶联显色技术对慢性乙型肝炎患者进行HBV基因分型 ,随机观察 10 5例 (B型 5 3例和C型 5 2例 )慢性乙型肝炎患者干扰素α1b治疗 6个月和随访半年后肝功能和病毒学指标的变化。结果　干扰素α1b治疗 6个月和随访半年后 ,B基因型患者的HBeAg阴转率、HBVDNA阴转率和HBeAg/抗 HBe的血清转换率均显著高于C基因型 (P <0 . 0 1) ,B基因型患者的有效应答率为 5 2 . 83 %,显著高于C基因型的 2 5 . 0 0 %(P <0 . 0 1)。B基因型的持续应答率高于C型 ,复发率低于C型 ,但两组差异无显著性 (P >0 . 0 5 )。结论　B基因型对干扰素α1b的抗病毒疗效显著高于C型 ,HBV基因型是影响干扰素α1b疗效的重要因素之一。     

Hepatitis B virus genotypes and clinical manifestation among hepatitis B carriers in Thailand

BACKGROUND: Hepatitis B virus (HBV) genotypes have distinct geographic distributions. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Thailand. METHODS: Hepatitis B virus genotypes among 107 hepatitis B carriers residing in Thailand were evaluated using serologic and genetic methods. They were clinically classified into asymptomatic carriers with normal serum alanine transaminase (ALT) levels and patients with chronic liver disease, such as those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). RESULTS: Hepatitis B virus genotype distribution among the 107 patients was 25.2% for genotype B, 72.0% for genotype C and 2.8% for genotype D. The serum ALT levels, HBV-DNA and hepatitis B e antigen positivity were significantly higher in carriers infected with genotype C HBV than in those infected with genotype B (P < 0.05). The proportion of genotype B HBV was higher in asymptomatic carriers than in patients with CH and those who developed liver disease, such as LC and HCC (45.5, 16.9 and 25.0%, respectively; P < 0.05). In contrast, the proportion of genotype C HBV was higher in patients who developed liver disease and CH than in asymptomatic carriers (68.7, 83.0 and 50.0%, respectively; P < 0.05). Phylogenetic analysis based on entire genome sequences revealed three HBV isolates, which were classified into a subgroup of genotype C in isolates from South-East Asian countries. CONCLUSIONS: Genotypes B and C are the predominant types among hepatitis B carriers residing in Thailand and those genotypes influence the clinical manifestation in carriers with chronic hepatitis B infection.     

HBV基因分型的研究进展

乙型肝炎病毒(HBV)感染是一个影响全球的健康问题.HBV有8种基因型,呈地域性分布.研究表明HBV基因型对慢性HBV感染的自然病程、临床结局、抗病毒治疗等具有影响.A基因型与C基因型与严重的肝损害相关;A基因型与B基因型对干扰素的应答率分别较D基因型与C基因型均更高;有研究发现HBV的基因型可能影响HBV的传播途径.然而,目前大多数临床资料来自亚洲及对B、C基因型的相关研究,基于基因型的地域性分布,对HBV基因型的全面认识,还有待进一步的国际化合作.     

Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam

Eight genotypes (A-H) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in in vitro viral replication. In Asian patients, seven genotypes (A-G) were detected, with A, C, and D predominating. In European and African patients, only genotypes A, C, D, and G were identified. Genotype mixtures were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06). In Asian patients, the predominant genotype mixtures included A/C and C/D, compared to C/D in European and A/D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P < .0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P = .02). Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002). Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype (P = .019). Genotype mixtures were also associated with increased in vitro HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa, and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome.     

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.     

乙型肝炎病毒基因型与病毒复制的关系

检测慢性乙型肝炎患者血清乙型肝炎病毒(HBV)基因型和病毒载量(HBV-DNA定量),探讨它们之间的关系。用微板核酸杂交-ELISA方法对HBV进行基因分型,用PCR荧光定量检测血清HBV-DNA水平,共318例。检测到HBV B型111例(35％);C型128(40％);混合型(B+C,C+D,B+C+D)45例(14％);D型2例;F型2例;未分型30例(9.4％);没有发现A、E型。结果发现,C型和混合型HBV的血清DNA水平高于B型(1.14×107vs2.2×107vsl.60×106拷贝/ml,P<0.05);而混合型HBV的血清DNA水平与C型无差别(P=0.127)。研究提示,我国HBV以B,C两基因型为主,HBV基因型可能是影响HBV复制的重要因素之一。     

Prevalence and clinical implications of hepatitis B virus genotypes in southern Taiwan

BACKGROUND: Hepatitis B virus (HBV) infection is a major health problem. HBV genotypes may be associated with progression of liver disease. The distribution and clinical implications of HBV genotypes in southern Taiwan are evaluated. METHODS: We used a polymerase chain reaction-restriction fragment length polymorphism genotyping method to determine HBV genotypes. RESULTS: The genotype distribution for 265 patients with chronic HBV infection was as follows: A, 3 (1%); B, 158 (60%); C, 90 (34%); D, 7 (2.5%); E, 0: F, 0; and unclassified, 7 (2.5%). Compared with genotype B patients, genotype C patients had a higher hepatitis B e antigen positive rate and higher fibrosis score. There was no significant difference in the mean age between genotype B and genotype C patients with hepatocellular carcinoma (HCC). However, when patients were stratified by age, the prevalence of genotype C was significantly higher in young HCC patients (<50 years of age) than in age-matched asymptomatic carriers (40% versus 10%, P < 0.001). Using multivariate analysis, the significant risk factors for advanced liver disease (cirrhosis or HCC) for patients with chronic HBV infection were old age, male gender and genotype C. CONCLUSIONS: These results suggest that genotype C is associated with more severe liver diseases than the B variant.     

乙型肝炎病毒基因型与拉米夫定疗效关系的研究

探讨乙型肝炎病毒(HBV)基因型与拉米夫定治疗慢性乙型肝炎(CHB)疗效的关系。采用PCR、核酸杂交和酶联显色技术对CHB进行HBV基因分型,观察123例(B型93例和C型30例)CHB患者拉米夫定治疗1年后肝功能、病毒学指标和YMDD变异的变化。ALT复常率为92.47%,HBeAg阴转率为27.96%,HBVDNA阴转率为82.80%,有效应答率为89.25%,与C基因型相比差异有显著性(P<0.05或P<0.005)。B型YMDD变异的发生率为9.68%,显著低于C型的26.67%(P<0.05)。B型对拉米夫定的抗病毒疗效高于C型,YMDD变异的发生率则低于C型。HBV基因型是影响拉米夫定疗效和变异的重要因素之一。     

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.     

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.     

lnfluence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B

AIM: To investigate the influence of HLA-DRB(1) alleles and HBV genotypes on interferon-alpha therapy for chronic hepatitis B. METHODS: HLA-DRB1*03, *07, *09, *12, *15 alleles were determined using polymerase chain reaction/sequence specific primer (PCR/SSP) technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients. RESULTS: The positivity of HLA-DRB1*07 allele in chronic hepatitis B group was significantly higher than that in normal control group (chi(2) = 6.33, P<0.025, RR = 2.37). Among the 126 patients, genotype B was found in 38 (30.2%), genotype C in 69 (54.8%), and mixed genotype (B+C) in 19 (15.0%), genotypes D-F were not found. Among the 46 DRB1*07(+) patients, 7 were responders and 39 were non-responders among them (chi(2) = 6.71, P<0.05). The positivity of HLA-DRB1*07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders. CONCLUSION: High positivities of HLA-DRB1 *07 allele and HBV genotype C are closely associated with the lower response to interferon-alpha therapy for chronic hepatitis B.     

拉米夫定治疗无良好应答患者乙型肝炎病毒P区突变与基因型的关系

目的 观察拉米夫定治疗后无良好应答的慢性乙型肝炎患者HBV P区变异情况与基因型的关系.方法 对631例拉米夫定治疗后无良好应答的慢性乙型肝炎患者进行研究.通过荧光定量PCR或核酸测序确定HBV基因型,直接测序观察P区突变,实时荧光定量PCR方法检测患者病毒载量,比较不同基因型患者的HBV DNA水平及HBV P区变异情况.计量资料采用成组设计资料t检验,计数资料采用x~2检验或Fisher精确检验.结果 631例慢性乙型肝炎患者中,B基因型HBV感染者272例,C基因型感染者359例,C基因型感染者患者年龄为(39.1±11.4)岁,明显大于B基因型感染患者的(33.7±9.7)岁(t=-6.55,P<0.01).C基因患者病毒载量为(5.96±1.22)log_(10)拷贝/ml,高于B基因型患者的(5.58±1.21)log_(10)拷贝/ml,t=-2.01,P<0.05.A181V/T变异在C基因型的发生率高于B基因型(0.4%比5.3%,χ~2=12.23,P<0.01),M204I/V,L180M、T184A/G/I/S、S202G/I和V173L变异发生率在B、C基因型之间差异无统计学意义(P值均>0.05).M204I在B基因型的发生率为20.6%,高于C基因型的13.9%(χ~2=4.91,P<0.05);M204V和M201Ⅳ变异在B、C基因型中的发生率差异无统计学意义(χ~2值分别为1.70和2.21,P值均>0.05).拉米夫定耐药发生率在B、C基因型间差异无统计学意义(χ~2=0.00,P>0.05).结论 拉米夫定常见耐药位点在B、C基因型之间无明显差异,但是C基因HBV感染患者病毒载量高于B基因型HBV感染患者;M204I变异在B基因型中出现频率高于C基因型,拉米夫定加用或改用阿德福韦酯后可能会使A181V/T变异在C基因型出现的概率高于B基因型;年龄、免疫因素和非常见位点的变异或许是影响拉米夫定疗效的重要因素.