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。     

Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance

Lamivudine is effective in suppressing viral replication, normalizing alanine aminotransferase (ALT), and improving histological appearance in HBe positive and negative hepatitis. It is unclear whether hepatitis B virus (HBV) genotype influences the response to lamivudine. We report the long-term response of patients with chronic hepatitis B with and without cirrhosis at baseline treated with lamivudine according to HBV genotype. Retrospective review of charts of all patients treated with lamivudine monotherapy between 1993 and 2002. Response to therapy defined as ALT in the normal range, undetectable HBV DNA, and in the HBeAg positive group loss of HBeAg and/or the development of anti-HBe. HBV DNA measured by the Digene Hybrid capture assay (sensitivity 1.4 x 10(6) copies/mL). YMDD mutation at rtL180M and rtM204V/I measured by restriction digest of amplified products. Genotyping performed by sequencing and phylogenetic tree analysis of the preS region of the virus genome. Seventy-one patients treated with lamivudine for 6 months or more, 53 (75%) were male, average age 47 years, 38 (54%) were HBeAg+ and 33 (46%) HBeAg-. Mean baseline HBV DNA viral titre was 1280.2 copies/mL and 518 copies/mL respectively. Cirrhosis was present in 30 (42%). Sera were examined for YMDD mutations at last patient visit in 61 (86%), and were detected in 45 (74%), there being no association with a particular genotype. Data from up to 5 years on lamivudine indicated no difference in biochemical or virological response between genotypes. Cirrhosis was more prevalent with specific genotypes. We found no influence of HBV genotype on the development of resistance to lamivudine, however liver disease severity was influenced by genotype.     

A 7‐year study of lamivudine therapy for hepatitis B virus e antigen‐positive chronic hepatitis B patients in China

OBJECTIVE: To evaluate the long‐term efficacy and safety of lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepatitis B virus (HBV). METHODS: A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily or a placebo in a 3:1 ratio for the first 12 weeks. Thereafter, all patients were administered with lamivudine 100 mg/d for 5 years and followed up for 2 years. RESULTS: After 12 weeks of the lamivudine treatment, serum HBV DNA levels decreased rapidly and HBV DNA negativity (<1.6 pg/mL) was 92.2%, whereas it was only 14.1% (P < 0.01) in the placebo group. At the end of 5 years, serum HBV DNA continued to be substantially suppressed. The loss of HBeAg and seroconversion were significantly correlated with baseline alanine aminotransferase (ALT) levels, in patients with baseline ALT > 2 × upper limits of normal, the loss of HBeAg was 54% and seroconversion rate was 50%, respectively. YMDD mutation developed in 70.8% of the patients at years 5. In YMDD mutant patients, HBV DNA levels were increased moderately and with mild to moderate elevations of ALT. ALT flares (ALT > 5ULN) occurred in 22 patients, 16 with YMDD variants and six with non‐variants. One year durability of seroconversion after stopping lamivudine was 80%. CONCLUSION: Lamivudine is effective and tolerable for chronic hepatitis B.     

拉米夫定治疗乙型肝炎病毒B、C基因型疗效比较

目的 研究乙型肝炎病毒(HBV)基因型对拉米夫定抗病毒疗效的影响。 方法 回顾调查235例拉米夫定治疗组和对照组患者的临床资料。 结果 135例患者接受拉米夫定抗病毒治疗,对照组100例。HBV优势基因型是B型和C型,拉米夫定治疗组有效率分别为92.9％和75.9％(x2=6.628,P<0.05),对照组有效率分别为9.8％和8.5％(P>0.05);YMDD变异发生率治疗组为3.6％和16.5％(x2=5.508.P<0.01)。结果发现,B基因型、丙氨酸氨基转移酶升高、HBV DNA低水平是抗病毒应答预测因素。 结论B基因氆HBV对拉米夫定的应答率优于C型,YMDD变异发生率低于C型,基因型是影响拉米夫定疗效和决定变异的重要因素之一。     

慢性乙型肝炎拉米夫定耐药患者HBV基因型及ALT变化的观察

观察慢性乙型肝炎患者用拉米夫定治疗后HBVP基因变异与不同HBV基因型感染及HBV DNA复升水平和转氨酶变化.收集51例慢性乙型肝炎患者用拉米夫定治疗52-78周后发生YMDD变异的血清标本,对照组128例未用拉米夫定治疗的慢性乙型肝炎患者血清标本,应用聚合酶链反应方法,测定HBV DNA基因型;用限制性片段长度多态性分析方法(PCR RELP)测定HBV DNA YMDD变异;同时进行HBV DNA定量分析.结果显示51例拉米夫定治疗后HBV DNA基因变异患者以B型和C型为主,分别为10例(19.6%)和39例(76.47%),B C混和型2例(3.92%),未见其它基因型.拉米夫定治疗引起HBVDNAYMDD变异可以发生在不同HBV基因型感染的慢性乙型肝炎患者中,与对照组比较二者没有显著性差异.     

The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment

BACKGROUND/AIMS: Genotype-dependent development of lamivudine resistance in hepatitis B virus (HBV) has not been reported. METHODS: We determined the cumulative rate of emergence of YMDD motif mutant in 213 Japanese patients with chronic hepatitis B infected with genotype A, B, or C and treated with lamivudine for more than 1 year. RESULTS: The emergence rate of lamivudine resistance was independent of the genotype (A, B, and C). In contrast, the emergence rate was significantly higher in the Ba ("a" stands for Asia) subgroup of HBV than in Bj ("j" for Japan) subgroup (P<0.05). For genotype C (HBV/C), the emergence rate in hepatitis B e antigen (HBeAg)-positive was significantly higher than in HBV/C-HBeAg-negative (P<0.05), but the rate in HBV/B-HBeAg-positive was similar to HBV/B-HBeAg-negative. Only four patients with HBV/C developed severe acute exacerbation of hepatitis accompanied by emergence of YMDD mutant, but none of the patients with other genotypes developed such complication. CONCLUSIONS: Our results suggest that lamivudine resistance in HBV does not seem to depend on the genotype but rather on the subgroup of HBV/B. The results also suggest that lamivudine resistance according to HBeAg state might be different between HBV/B and HBV/C. Large-scale prospective studies of each genotype should be conducted in the future to confirm these findings.     

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.     

HBeAg阳性和阴性慢性乙型肝炎患者YMDD的变异

目的研究YMDD变异在HBeAg阳性和HBeAg阴性乙型肝炎病毒（HBV）感染者中发生的情况.方法对我科接受拉米夫定治疗的247例慢性乙型肝炎患者进行定期随访,检测肝功能和HBV病毒学指标,利用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）检测YMDD变异,利用实时定量PCR检测HBV DNA定量以及利用Abbott试剂检测HBV标志物,对比分析HBeAg阳性和HBeAg阴性患者中YMDD变异的发生情况.结果247例患者中共有42例出现YMDD变异,YMDD变异的累积发生率随着时间的延长逐年增加.与治疗前HBeAg阴性患者相比,治疗前HBeAg阳性患者YMDD变异的发生率明显高于治疗前HBeAg阴性患者.结论HBeAg阳性患者YMDD变异年累积发生率高于HBeAg阴性患者.     

Clinical characteristics and distribution of hepatitis B virus genotypes in Guangxi Zhuang population

AIM: To investigate the distribution of HBV genotypes and their YMDD mutations in Guangxi Zhuang population, China, and to study the relationship between HBV genotypes and clinical types of HB, ALT, HBV DNA, HBe system as well as the curative effect of Lamivudine (LAM) on hepatitis B. METHODS: A total of 156 cases were randomly chosen as study subjects from 317 patients with chronic hepatitis B (CHB). HBV genotypes were determined by PCR-microcosmic nucleic acid cross-ELISA. YMDD mutations were detected by microcosmic nucleic acid cross-nucleic acid quantitative determination. HBV DNA was detected by fluorescence ratio PCR analysis. LAM was given to 81 cases and its curative effect was observed by measuring ALT, HBV DNA load, HBeAg, and HBeAg/HBeAb conversion rate. RESULTS: HBV genotypes B, C, D, and non-classified genotypes were found in Guangxi Zhuang population, accounting for 25.6%, 47.4%, 58.3%, and 16.0%, respectively. Seventy-four cases were CD-, CB-, BD-mixed genotypes (47.7%). Forty-six (29.5%) cases had YMDD mutations. Genotype B was mostly found in mild and moderate CHB patients. Genotypes C, D and mixed genotype mostly occurred in severe CHB cases. Genotypes D and CD HBV-infected patients had higher ALT and HBV DNA than patients with other types of HBV infection. There was no significant difference among the genotypes in YMDD mutations, clinical types, ALT and HBV DNA level. Non-classified types geno had a significantly lower positive rate of HBeAg than other genotypes (X2=12.841,P<0.05). There was no significant difference in ALT recovery rate, HBV DNA load, HBeAg, and HBeAg/HBeAb conversion rate, 48 wk after LAM treatment between groups of genotypes D, CD, and non-classified type. CONCLUSION: Genotypes B, C, and D, non-classified and mixed genotype of HBV are identified in the Guangxi Zhuang population. Variations in genotypes are associated with clinical severity and serum ALT levels, but not with YMDD mutation or HBV DNA load. Therapeutic effects of LAM on clinical parameters are not influenced by differences in genotypes. Further studies are needed to gain an in-depth understanding of the relationship between HBV genotypes and serum HBeAb and HBeAg.     

拉米夫定治疗前后乙型肝炎病毒YMDD变异的相关因素分析

目的 了解遵义地区HBV基因型以及拉米夫定治疗前后发生YMDD变异的相关因素,及早进行拉米夫定疗效及耐药的预测. 方法 53例慢性乙型肝炎患者分别在口服拉米夫定前及治疗后3、6、12、18、24个月进行血清HBV DNA定量、乙型肝炎标志物、ALT、AST、总胆红素,白蛋白的检测.同时在接受拉米夫定治疗前采用基因测序法检测HBV基因型及YMDD变异株,治疗后HBV DNA定量下降又反弹升高,且血清HBV DNA＞1×104拷贝/ml时,再次进行YMDD变异株检测.率的比较用卡方检验及确切概率法,两组均数之间比较采用独立样本t检验,有序变量之间的比较采用秩和检验.结果 遵义地区的HBV基因型由B、C及B+C基因型构成.拉米夫定治疗后18例检出YMDD变异株,用药1年和2年的变异率分别为15.1%和34.0%.HBV突变类型有rtL180M/M204V、rtL180M/M204I、rtM204I和rtL180M四种,其中C区rtM204V全部合并rtL180M突变(100%),C基因型中rtL180M/M204V联合突变及rtL180M/M204I联合突变明显高于B基因型(77.8%比25.0%及22.2%比12.5%);C基因型中未见点突变,而rtM204I、rtL180M的点突变仅见于B基因型.YMDD变异与未变异组性别、民族、乙型肝炎家族史及HBeAg情况差异无统计学意义(P＞0.05),病程≥2年组和年龄＜35岁组变异率明显升高(X2值分别为4.707和5.853,P值均＜0.05).不同HBV DNA滴度患者YMDD变异率差异无统计学意义(X2=0.801,P＞0.05),但HBV DNA＜105拷贝/ml者未发现YMDD变异.结论 拉米夫定治疗后YMDD变异可能与HBV基因型及P基因突变类型有关,并随治疗时间的延长而增加.为了减少YMDD变异的发生,应选用病程短、HBV DNA水平较低、肝损害较重的患者进行拉米夫定治疗,有条件的应检测HBV基因型.     

135例乙型肝炎病毒感染者基因分型及其临床分布

目的研究乙型肝炎病毒（HBV）感染者中HBV基因分型及其临床分布情况。方法应用基因型和亚型特异性引物聚合酶链反应（PCR）法，对鲁西地区135例HBV感染者血清进行HBV基因型及亚型分型。结果未分型11例，已分型124例。其中C型111例（C2基因亚型87例、非C1／C2亚型24例）；B型11例，其中Ba型8例、Bj型3例；B／C混合型2例均为BaC2亚型混和感染。在肝硬化和重度慢性乙型肝炎中C型所占比例较高，分别为100％、88％；无症状携带者中B型所占比例较高为8．51％；HBV基因型分型与性别无关。结论鲁西地区HBV感染者以C基因型为主，其中C2亚型占优势。     

拉米夫定对湖北地区乙型肝炎病毒基因型的影响

目的研究拉米夫定对湖北地区乙型肝炎病毒基因型的影响及其临床意义。方法采用多对型特异性引物-聚合酶链反应检测160例慢性乙型肝炎患者血清HBV基因型;采用基因芯片技术对86例拉米夫定治疗18个月的慢性乙型肝炎患者进行酪氨酸—蛋氨酸—天冬氨酸—天冬氨酸(YMDD)基序、G1896A、A1814C、A1792T和G1764A单碱基变异检测。结果160例慢性乙型肝炎患者,B基因型127例(79%),C基因型24例(15%),BC混合型9例(6%),未发现A、D和E基因型。拉米夫定治疗的86例患者中,17例(19.7%)发生YMDD变异,B型14例,C型2例,BC混合基因型1例,其中6例发生多重变异,包括B型4例,C型2例;HBeAg/HBeAb血清转换率B型41例(68.3%)高于C型8例(40%)(P<0.05)。另外17例患者,经拉米夫定治疗后,HBVDNA仍阳性,亦未发现YMDD变异株。结论湖北地区HBV存在B、C和BC混合基因型,B型为本地区优势基因型,B型在拉米夫定治疗中更易发生YMDD变异;未变异者,血清HBeAg/HBeAb转换率高。     

慢性乙型肝炎病毒基因型与拉米夫定疗效关系的研究

目的：研究乙型肝炎病毒(HBV)基因型对拉米夫定抗病毒疗效的影响。方法：回顾性调查286例拉米夫定治疗组和对照组患者的临床资料。结果：HBV优势基因型是B(34％)和C(48％)型，共235例。135例患者接受拉米夫定抗病毒治疗，对照组100例。拉米夫定有效率在B、C两基因型中分别为92．9％和75．9％(P=0．02)，而对照组分别为9．8％和8．5％(P=0．59)；YMDD变异发生率为8．9％和22．8％(P=0．028)。Multivariate分析发现，B基因型、ALT升高、HBV DNA低水平是影响抗病毒应答的预测因素。在ALT升高患者中，B、C基因型拉米夫定有效率分别为93％和77％(P=0．01)，对照组为13％和8％(P=0．45)。Multivariate分析发现，B基因型、HBV DNA低水平是预测较好疗效的独立因素。结论：B基因型HBV对拉米夫定的应答率高于C型，而变异YMDD发生率低于C型，基因型是影响拉米夫定疗效和诱导变异的重要因素之一。     

Hepatitis B virus genotype B results in better immediate, late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients

Background and Aims: This study investigated outcome predictors in hepatitis‐B‐e‐antigen (HBeAg)‐positive chronic hepatitis B patients treated with peginterferon alfa‐2a. Methods: A total of 88 HBeAg‐positive patients receiving peginterferon alfa‐2a for 6 months and followed up for at least 24 weeks were prospectively analyzed. Precore and core promoter genes of hepatitis B virus (HBV) were sequenced from the serial serum samples of 88 patients. Results: After 24 weeks of follow up, 38.6% and 28.4% of patients achieved HBeAg clearance and combined response, respectively. Multivariate analysis disclosed that pretreatment HBeAg sample to cut‐off (S/Co) ratio ≤ 200, alanine aminotransferase > 200 IU/mL, HBV genotype B and T1846 were independent factors for HBeAg clearance, and HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for combined response. HBeAg S/Co ratio ≤ 10 at week 12 of therapy was the useful factor for treatment response and had a greater power (P = 0.012) to predict HBeAg clearance than HBV DNA. Patients with HBeAg clearance had a higher frequency of A1896 mutation at baseline and during therapy than those without HBeAg clearance, and the frequency of A1896 decreased during treatment. During follow up, delayed HBeAg seroconversion and reactivation of HBV after HBeAg clearance were observed in eight non‐responders and 20 patients with HBeAg clearance, respectively. HBV genotype B was a significant factor to predict both responses. Conclusions: Pretreatment HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for treatment response to peginterferon. Genotype‐B‐infected patients had higher probability of delayed HBeAg clearance and sustained response. Rapid decrease of HBeAg titer was useful on treatment predictor.     

Appropriate use of interferon for treatment of chronic hepatitis B

Hepatitis B is not only a preventable but now treatable disease. Five drugs have been approved for the treatment of chronic hepatitis B virus (HBV) infection: standard interferon-α (IFN), pegylated IFN, lamivudine, adefovir dipivoxil and entecavir. Among these agents, the responses to interferon therapy are invariably influenced by both host and viral factors. Therefore, understanding these factors is important for practicing hepatologists, and it may help design individualized medicine for the treatment of chronic hepatitis B. HBV genotypes affect the disease progression and outcomes of HBV-related chronic liver disease, as well as the response to antiviral treatments. Existing data indicate a better sustained response to standard IFN-α in HBeAg positive genotype B patients than genotype C patients, and in genotype A patients than genotype D patients. Nevertheless, conflicting results exist regarding the response to pegylated IFN, and more studies are needed. As to HBV genetic polymorphisms, a recent study showed that an IFN sensitivity-determiningregion may not exist within the whole genome of HBV subgenotype Ba, and host factors as well as virus–host interactions may be more important than viral factors alone in determining the treatment outcomes with IFN. Regarding host genetic polymorphisms, single nucleotide polymorphisms within eukaryotic translation initiation factor 2 and MxA promoter regions may be associated with the responsiveness to standard IFN-α treatment in patients with HBeAg positive chronic hepatitis B. In the foreseeable future, individualized chronic hepatitis B treatment algorithms should be tailored to host (immune status, ALT level and genomic polymorphisms), virus (HBeAg status, HBV DNA level, genotype, precore/basal core promoter mutants and pre-S deletion mutant) as well as liver disease status (hepatitis activity and fibrosis stage).     

拉米夫定相关性HBV变异对乙型肝炎预后的影响

目的 进一步探讨拉米夫定相关性ＨＢＶ变异对患者临床经过的影响。方法 将接受拉米夫定治疗１００ｍｇ／ｄ的８２例患者在第１０４周按其发生变异程序分为完全变异、部分变异和无变异３组,分别进行肝功能和血清学指标比较。结果 在第１０４周,Ｆ和Ｍ组无１例ＨＢｃＡｇ阴国专,而Ｎ组有１８例ＨＢｅＡｇ阴转 ,１１例ｃＡｇ／抗－ＨＢｅ血清转换;拉米夫定相关性ＨＢＶ变异发生后ＡＬＴ可增高,完全变异组Ｈ ＢＶＤＮＡ水平明     

双环醇治疗慢性乙型肝炎的临床研究

初步探讨双环醇治疗慢性乙型肝炎的保肝、抗病毒效果 ,并比较双环醇对不同基因型的乙肝患者的疗效。选取 33例慢性乙型肝炎患者 ,口服双环醇 2 5mg每日 3次 ,6个月。治疗前测乙型肝炎病毒基因型 ,治疗结束后分析不同基因型乙肝患者ALT、AST、HBeAg、HBVDNA变化。复常率ALT2 1例 (6 3 6 % ) ,AST15例 (4 5 5 % ) ,转阴率HBeAg :11例 (33 3% ) ,HBVDNA :9例 (2 7 3% )。B型和C型抗病毒总有效率分别是 5例 (4 1 7% )、8例 (4 0 0 % )。双环醇治疗慢性乙型肝炎有较好的保护肝细胞抑制乙肝病毒的效果。基因型B型和C型患者对双环醇疗效比较无显著差异     

乙型肝炎病毒YMDD联合前C变异及其临床意义

目的：研究拉米夫定治疗过程中乙型肝炎病毒（HBV）前C区，P区YMDD基序变异及其对疗效的影响。方法：对5例拉米夫定（100mg/d)治疗过程中HBeAg血清转换而HBV DNA仍阳性的慢性乙型肝炎患者，采用聚合酶链反应（PCR）产物直接测序方法分析HBV前C、P区的基因序列，结果：5例患者前C区均发现有G1896A变异，其中3例HBeAg血清转换前未发现此变异，2例已有此变异，同时5例患者在拉米夫定治疗后检测出YMDD变异，变异类型均为M5521，其中有1例在出现M5521变异40周后变为M552V变异，有2例M5521联合L528M变异，5例患者中有1例治疗无反应，另4例在治疗过程中HBV DNA突发，结论：拉米夫定治疗过程中YMDD变异的出现可导致HBV DNA突发，而前C区G1896A变异可致HBeAgbe阴转，因此在治疗过程中出现HBeAg血清转换后需结合HBV DNA检测，排除前C区变异的可能。     

乙型肝炎病毒基因型、YMDD变异与拉米夫定治疗后HBV DNA反弹关系的研究

目的探讨HBV基因型、YMDD变异与拉米夫定抗病毒治疗后HBV DNA反弹的关系。方法应用多引物对巢式PCR法、PCR-序列分析法检测拉米夫定治疗的27例乙型肝炎患者和19例从未用过抗病毒治疗的患者HBV基因型和P区（YMDD）的突变位点。结果在27例HBV DNA反弹的患者中，13例（48．15％）检出YMDD变异，而对照人群无YMDD变异（P〈0．05）。YMDD变异的位点为rtM204V／I（C区）±rtL180M（B区）；在治疗组YMDD变异的患者中，B、C基因型构成比（46．15％和59．26％）与对照组（53．85％和68．42％）比较无显著性差异（P〉0．05）。结论YMDD变异是拉米夫定治疗后出现耐药导致HBV DNA反弹的主要原因；YMDD变异的常见位点依然为rtM204V／I（C区）±rtL180M（B区）；YMDD变异在B、C基因型病人中无差别。