Sequential combination therapy leads to biochemical and histological improvement despite low ongoing intrahepatic hepatitis B virus replication

BACKGROUND: We previously reported that 48 weeks of combination therapy with pegylated interferon-alpha2b (PEG-IFN-alpha2b) and adefovir dipivoxil (ADV) in patients with chronic hepatitis B led to marked decreases of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) (-2.4 log10 copies/ml). Combination therapy was followed by 96 weeks of ADV monotherapy. METHODS: Here, we report on the final outcome after 144 weeks of sequential antiviral treatment. Twenty-four patients were analysed, triplet liver biopsies (taken at baseline, week 48 and week 144) were available from 16 patients. RESULTS: At week 144, 12/15 patients positive for hepatitis B virus e antigen (HBeAg) had lost HBeAg, alanine transaminase (ALT) levels were normal in 23 patients (96%), median serum HBV DNA had decreased by -4.9 log10 copies/ml and was undetectable (<100 copies/ml) in 11/24 individuals (46%). Median total intrahepatic HBV DNA had decreased by -2.2 log. Although no further significant cccDNA changes occurred between week 48 and week 144, two years of ADV monotherapy proved capable of controlling cccDNA levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that combination therapy with PEG-IFN-alpha2b and ADV inhibited viral productivity by 99% and subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability within the first 12 weeks of treatment was strongly associated with long-term virological response and HBeAg and hepatitis B virus surface antigen HBsAg seroconversion. Histological improvement was determined in 11/16 patients at week 144. Two patients developed ADV resistance during the third year of treatment. CONCLUSIONS: Reduction of intrahepatic viral load achieved after 48 weeks of combination therapy with PEG-IFN-alpha2b and ADV was maintained in the following 96 weeks of ADV monotherapy and translated into long-term clinical benefit for most of the treated patients.     

初诊慢肝患者血清中乙肝病毒DNA载量与血清标志物的关系

目的探讨初诊慢性乙型肝炎血清标志物与HBV DNA的关系。对象与方法采用酶联免疫方法和荧光定量聚合酶链反应分别对512例不同乙肝病人及202例HBeAg阴性、257例HBeAg阳性慢肝病人进行血清标志物、HBV DNA定量检测并分析结果。结果慢肝组有315例(68.9%)病毒颗粒浓度高于107,肝硬化组7例(13.2%)病毒颗粒浓度高于107;HBeAg阳性慢肝组245例(95.3%)患者病毒颗粒含量高浓度,HBeAg阴性慢肝组68例(33.7%)患者病毒颗粒含量在105-7copy/mL区段。结果慢肝组与肝硬化组相比,高浓度病毒以慢肝组中最明显,病情发展至肝硬化期病毒含量多数不高;慢肝病人中不同乙肝血清标志物模式其病毒含量分布特点不同,与HBeAg阳性慢肝组相比HBeAg阴性组体内病毒复制水平低(p<0.01),传染性较前者弱。最常见前C区突变,导致HBeAg阴性CHB病情加重和病毒复制增加。     

Long-term lamivudine treatment is associated with a good maintained response in severe acute exacerbation of chronic HBeAg-negative hepatitis B

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B is difficult to treat and there is little long-term data for lamivudine treatment of severe acute exacerbation. We report a prospective, consecutive cohort of severe acute exacerbation of HBeAg-negative chronic hepatitis B patients treated by lamivudine between 1999 and 2004. All patients had respectively increased alanine aminotransferase and serum bilirubin to at least 10 and 2 times the upper limit of laboratory normal. Thirty-two patients were treated with lamivudine for 130 +/- 58 (range 48-217) weeks. Five patients had evidence of virological breakthrough (HBV DNA >10,000 copies/ml) during lamivudine treatment. The cumulative probability of maintained response without any virological breakthrough was 94% (95% confidence interval [CI], 86-100%) at year 1, 94% (95% CI, 82-100%) at year 2 and 71% (95% CI, 41-100%) at year 3. At the last follow-up visit, 31 (97%) lamivudine patients had HBV DNA <10,000 copies/ml. The prevalence of lamivudine resistance mutation was 1 in 32 patients (3%; 95% CI, 0-9%) at year 1, 1 in 17 patients (6%; 95% CI, 0-17%) at year 2, 1 in 9 patients (11%, 95% CI, 0-32%) at year 3 and 1 in 4 patients (25%; 95% CI, 0-67%) at year 4 of lamivudine treatment. In conclusion, extended lamivudine treatment is associated with a high maintained virological response and a low rate of drug resistance in severe acute exacerbation of HBeAg-negative chronic hepatitis B.     

Short-term lamivudine therapy in HBeAg-negative chronic active hepatitis B in Taiwan

Lamivudine treatment in hepatitis B e antigen (HBeAg)-negative and hepatitis B virus (HBV) DNA-positive chronic hepatitis B (CHB) patients is associated with poor sustained response. A previous study has shown that short-term lamivudine therapy in HBeAg-positive patients with alanine aminotransferase (ALT) > 5x upper limit of normal (ULN) could achieve a high HBeAg response rate and low lamivudine resistance rate. We, therefore, prospectively treated 85 HBeAg-negative CHB patients with ALT > 5x ULN by lamivudine for 6-12 months. The mean pretreatment levels were as follows: ALT (normal < 36 U/I) 533 U/I (range: 180-2,418 U/I); total bilirubin (normal < 1.3 mg/dl) 2.0 mg/dl (range: 0.2-29.6 mg/dl), HBV DNA (normal, undetectable) 1.6 x 10(8) copies/ml (range: 1.4 x 10(5)-1.7 x 10(9) copies/ml). After a mean of 7.4 months (6-12 months) treatment, 69 (81%) patients achieved complete response. In a follow-up, 12 months after stopping lamivudine therapy, 33 (39%) patients showed sustained complete response. Patients with sustained response were younger than the relapsed patients (39.7 +/- 11.9 years versus 47.0 +/- 10.3 years; P = 0.005). The emergence of lamivudine-resistant variant HBV was documented in two patients (2%). It is concluded that in HBeAg-negative chronic hepatitis B patients with ALT levels above 5x ULN, a 6-12 month course of lamivudine therapy may achieve sustained an off-treatment response in approximately one-third of patients.     

Long-term follow-up of lamivudine treatment in patients with severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B

BACKGROUND: The long-term efficacy of lamivudine treatment for patients suffering from severe acute exacerbation of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is unknown. METHODS: Consecutive patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B were prospectively recruited from 1999 to 2004 and treated with lamivudine. All patients had alanine aminotransferase (ALT) and serum bilirubin levels 10x and 3x above the upper limit of normal, respectively. HBeAg-positive patients without severe acute exacerbation served as controls. RESULTS: Forty-five patients with severe acute exacerbation and 31 controls were treated with lamivudine for a median of 2.8 (range 1.0-7.1) years and 3.8 (range 3.5-8.4) years, respectively. Compared with controls, patients with severe acute exacerbation had higher HBeAg seroconversion rates (78% versus 52%; P=0.02) and lower risk of virological breakthrough. However, 33% of patients with severe acute exacerbation still developed lamivudine resistance and virological breakthrough by year 5. HBV DNA levels at week 4 and prolonged baseline prothrombin time were independent factors associated with virological breakthrough. All patients with week 4 HBV DNA <3 log10 copies/ml had maintained virological response. Among 15 patients who stopped lamivudine after sustained HBeAg seroconversion for > or =6 months, 11 (73%) had virological relapse at a median of 1.4 (0.2-3.9) years. ALT increased beyond 10x the upper limit of normal in six (38%) patients who stopped lamivudine and two (7%) patients on maintained lamivudine treatment (P=0.02). CONCLUSION: Among patients with severe acute exacerbation of HBeAg-positive chronic hepatitis B treated with lamivudine, virological breakthrough and post-treatment relapse are common despite a high rate of HBeAg seroconversion. Severe hepatitis flare is also common particularly among patients developing virological relapse after discontinuation of lamivudine.     

Two-year lamivudine treatment for hepatitis B e antigen-negative chronic hepatitis B: a double-blind, placebo-controlled trial

OBJECTIVE: We conducted a multicentre, double-blind, placebo-controlled, randomized study to investigate the efficacy of 2-year lamivudine treatment in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. METHODS: One-hundred-and-thirty-nine treatment-naive patients with HBeAg-negative chronic hepatitis B were randomized to receive either lamivudine (100 mg daily) or placebo in a 2:1 ratio for 24 months and were followed for an additional 6 months. The primary endpoint was complete response, defined as hepatitis B virus (HBV) DNA < 10,000 copies/ml and normalization of alanine aminotransferase (ALT) levels at month 24. RESULTS: On intent-to-treat analysis at month 24, significantly more patients in the lamivudine group than in the placebo group had complete response (56% and 11%, respectively; P < 0.001) or negative HBV DNA (26% and 6%, respectively; P = 0.006). After adjustment of baseline HBV DNA and ALT, the odds ratio for complete response of the lamivudine group versus the placebo group was 10.8 (95% confidence interval: 3.8-30.2; P < 0.001). The median log HBV DNA reduction was 3.21 copies/ml for the lamivudine group compared with 0.47 copies/ml for the placebo group (P < 0.001). Genotypic resistance was detected in 23% and 31% of patients in the lamivudine group at months 12 and 24, respectively. Negative HBV DNA at month 6 was associated with high complete response (84%) and low drug resistance (1%) at month 24. At month 30, there was no difference between lamivudine and placebo groups in the rates of complete response (26% vs 19%, respectively; P = 0.38) or negative HBV DNA (10% vs 2%, respectively; P = 0.09). CONCLUSIONS: Two-year lamivudine treatment is effective in HBeAg-negative chronic hepatitis B. However, the response is not sustained after treatment cessation.     

替比夫定治疗e抗原阳性慢性乙型肝炎的疗效预测因素研究

目的探讨替比夫定酯治疗HBeAg（＋）慢性乙型肝炎的疗效预测指标,为个体化治疗提供依据。方法选取广州医学院第一附属医院HBeAg阳性慢性乙型肝炎患者60例,均予替比夫定600 mg治疗48周,检测治疗前及治疗后24、48周的HBsAg、HBeAg、HBV DNA定量及丙氨酸氨基转移酶（ALT）水平。根据治疗24周时血清HBV DNA水平,将患者分为两组,聚合酶链反应（PCR）低于检测下限（〈300拷贝/m l）的A组和高于检测下限（≥300拷贝/m l）的B组。结果治疗24周时HBV DNA水平越低,HBsAg下降幅度越大,在48周HBV DNA达到PCR检测不到的水平、HBeAg血清转换率和ALT复常率越高。A组患者在48周时HBeAg血清转换率为44.1%,B组患者则为8.3%,两组比较差异有统计学意义（χ2=22.1,P〈0.01）。结论乙型肝炎患者应用替比夫定治疗24周时HBV DNA水平及HBsAg下降幅度可作为48周疗效的预测指标。     

Pegylated interferon Alfa-2b monotherapy and pegylated interferon Alfa-2b plus lamivudine combination therapy for patients with hepatitis B virus E antigen-negative chronic hepatitis B

Forty-eight hepatitis B virus (HBV) E antigen-negative chronic hepatitis B patients received pegylated interferon alfa-2b either alone or with lamivudine for 48 weeks and were followed for an additional 24 weeks. At the end of follow-up, virological response rates (HBV DNA levels of <400 copies/ml) were similar in the monotherapy (24%) and combination therapy (26%) groups.     

Telbivudine for the management of chronic hepatitis B virus infection

BACKGROUND: Telbivudine (LdT) is an L-nucleoside that is structurally related to lamivudine. It is highly selective for hepatitis B virus (HBV) and inhibits viral DNA synthesis. LdT was approved by the US Food and Drug Administration on October 25, 2006, for the treatment of chronic HBV infection in adults who have active viral replication and either elevations in liver transaminases or signs of active liver disease on histologic examination. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and therapeutic efficacy of LdT. Potential drug interactions and adverse events associated with the use of LdT are also reviewed. METHODS: Relevant publications were identified from searches of MEDLINE (1996-June 2007), the Cochrane Library, and BIOSIS (1993-June 2007). Search terms included, but were not limited to, telbivudine, beta-L-thymidine, LdT, pharmacology, pharmacokinetics, adverse events, resistance, drug interactions, hepatitis B, and therapeutic use. Additional publications were identified from the reference lists of the identified papers, meeting abstracts, and correspondence with the manufacturer of LdT. RESULTS: After 52 weeks of therapy in the Phase III GLOBE study, HBV resistance (breakthrough and resistance mutations) to LdT occurred in 3% of patients who were hepatitis B e antigen (HBeAg) positive and 2% of patients who were HBeAg negative. After 104 weeks of therapy, 17.8% to 21.6% of HBeAg-positive and 7.3% to 8.6% of HBeAg-negative LdT-treated patients had a rebound in HBV DNA associated with breakthrough and resistance mutations. After 24 weeks of treatment, the risk of resistance was greater in patients with HBV DNA titers >3 log(10) copies/mL than in those with lower numbers of copies. LdT is not active against lamivudine-resistant HBV. The proportion of HBeAg-positive patients with undetectable HBV DNA (by polymerase chain reaction assay) after 104 weeks of therapy in the GLOBE study was significantly greater with LdT compared with lamivudine (56% vs 39%, respectively; P < 0.05). After 104 weeks of therapy, the corresponding proportions of HBeAg-negative patients with undetectable HBV DNA were 82% and 57% (P < 0.05). Patients who failed lamivudine therapy in the GLOBE study showed cross-resistance to LdT. The most common adverse events associated with LdT are upper respiratory tract infection (14%-17%), fatigue and malaise (12%-14%), nasopharyngitis (11%-15%), headache (11%-12%), and abdominal pain (6%-12%). Grade 3/4 adverse events included elevations in serum creatine kinase, which were more common in patients receiving LdT than in those receiving lamivudine (9% vs 3%, respectively). Elevations in creatine kinase are typically asymptomatic; however, myopathy has been reported in 3 of 680 patients receiving LdT. CONCLUSIONS: LdT joins the increasing number of antiviral agents for the management of chronic HBV infection. Questions concerning the optimal length of therapy and long-term efficacy await the results of on-going clinical trials. Concerns about increasing resistance over time may relegate LdT to second-line status in the management of chronic HBV infection. The role of LdT in combination therapy is under investigation.     

基线HBeAg水平对HBeAg阳性慢性乙型肝炎阿德福韦酯治疗52周疗效的预测价值

目的评价HBeAg阳性慢性乙型肝炎患者的HBeAg基线水平对阿德福韦酯治疗1年疗效的预测价值。方法 98例HBeAg阳性、年龄18～60岁的慢性乙型肝炎患者进入研究。筛选时血浆HBV DNA定量≥1×106拷贝/ml,血清ALT水平1.5～10倍正常参考值上限,无其他原因引起的肝病。患者接受阿德福韦酯胶囊10mg/d治疗,共52周。定期随访,统一由专人检测HBV血清标志及HBV DNA。HBV血清标志物用Abbott试剂检测。HBeAg半定量采用样本值与截止值之比（s/co）表示,HBV DNA用实时荧光定量PCR方法检测,灵敏度为1×103拷贝/ml（3log10拷贝/ml）。结果阿德福韦酯治疗52周,HBV DNA水平较基线下降（3.63±1.26）log10拷贝/ml,HBV DNA检测不到率48.0%（47/98）,ALT复常率为83.7%（82/98）,HBeAg血清转换率为23.5%（23/98）。52周HBeAg血清转换组与无转换组患者的基线HBeAg水平分别为（251.9±117.3）s/co和（339.6±137.3）s/co（P=0.002）,基线HBeAg水平≤350s/co者分别占78.3%（18/23）和36%（27/75,P〈0.001）,而两组基线HBV DNA水平和ALT水平无统计学意义。基线HBeAg≤350s/co（n=45）组和〉350s/co（n=53）组比较,治疗12周两组HBV DNA检测不到率分别为35.6%和13.2%（P=0.009）,HBeAg阴转率为22.2%和0（P〈0.001）,ALT复常率为55.6%和17.0%（P〈0.001）;治疗52周HBV DNA检测不到率为64.4%和34.0%（P=0.003）,HBeAg血清转换率为42.2%和7.5%（P〈0.001）,ALT复常率为84.4%和83.0%。结论基线HBeAg水平对阿德福韦酯治疗HBeAg阳性慢性乙型肝炎患者的12周及52周疗效预测有一定的价值。基线HBeAg水平较低者能获得更好的早期病毒学应答和HBeAg血清转换率。     

Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B

Emtricitabine (FTC) is approved for the treatment of human immunodeficiency virus. FTC and clevudine (CLV) have activity against hepatitis B virus (HBV). This report summarizes the results of a double-blind, multicenter study of patients with chronic hepatitis B who had completed a phase 3 study of FTC and were randomized 1:1 to 200 mg FTC once daily (QD) plus 10 mg CLV QD or 200 mg FTC QD plus placebo for 24 weeks with 24 weeks of follow-up. One hundred sixty-three patients were treated (82 with FTC plus CLV [FTC+CLV] and 81 with FTC); 72% were men, 53% were Asian, 47% were Caucasian, and 52% were hepatitis B e antigen positive, and the median baseline HBV DNA level was 6 log(10) copies/ml. After 24 weeks of treatment, 74% (FTC+CLV) versus 65% (FTC alone) had serum HBV DNA levels of <4,700 copies/ml (P = 0.114) (Digene HBV Hybrid Capture II assay). Twenty-four weeks posttreatment, the mean change in serum HBV DNA levels from baseline was -1.25 log(10) copies/ml (FTC+CLV), 40% had undetectable viremia (versus 23% for FTC alone), and 63% had normal alanine aminotransferase levels (versus 42% for FTC alone) (P < or = 0.025 for all endpoints). The safety profile was similar between arms during treatment, with less posttreatment exacerbation of hepatitis B in the combination arm. In summary, after 24 weeks of treatment, no significant difference between arms was observed, but there was a significantly greater virologic and biochemical response 24 weeks posttreatment in the FTC+CLV arm.     

Effectiveness of entecavir in chronic hepatitis B NUC‐naive patients in routine clinical practice

Introduction: Registration studies showed entecavir (ETV) to be effective and safe in NUC‐naïve patients with chronic hepatitis B virus (HBV), but its effectiveness in routine clinical practice is unknown. Materials and methods: Sixty‐nine HBeAg positive and negative NUC naïve chronic HBV patients were treated with ETV for 110 weeks. 63% were HBeAg positive, 16% were cirrhotics, mean HBV‐DNA was 7.09 log IU/ml and mean ALT was 157 IU/ml. Results: Sixty‐one (88%) patients achieved undetectable DNA, with 46%, 77% and 100% virological response rates at week 24, 48 and 96 of treatment, respectively. Thirty‐seven (84%) patients in the HBeAg‐positive population achieved undetectable DNA, with 67% and 100% virological response rates at week 48 and 96 of treatment, respectively. Twenty‐four (96%) patients in the HBeAg‐negative population achieved undetectable DNA, with 91% and 100% virological response rates at week 48 and 96 of treatment, respectively. Twenty‐three (53%) patients cleared HBeAg and 19 (44%) patients seroconverted to antiHBe positive status; seven (10%) patients cleared hepatitis B surface antigen and five (7%) patients developed antiHBs. At the end of the study, 10 patients successfully stopped therapy: nine HBeAg positive (four developed antiHBs positive) and one HBeAg negative. None of the patients had primary non‐response. ETV resistance was not tested. None of the patients developed hepatocellular carcinoma, underwent liver transplantation or died because of liver‐related events. No serious adverse events were reported. Conclusion: The ETV monotherapy showed high virological response rates, a favourable safety profile for NUC‐naive HBeAg‐positive and negative patients treated in routine clinical practice.     

Hepatitis B virus genotype-associated variability in antiviral response to adefovir dipivoxil therapy in Chinese Han population

It is well known that different genotypes of hepatitis B virus (HBV) have a different sensitivity to interferon-alpha or lamivudine (nucleoside analogue) antiviral therapy. However, for adefovir dipivoxil (ADV, a nucleotide analogue), the antiviral response of the different genotypes remains to be clarified. In order to evaluate the response of HBV genotypes to ADV therapy and to identify factors that might affect initial virological response, we performed a retrospective analysis on patients with chronic hepatitis B (CHB) in Chinese Han population. The study included 183 patients, who had been tested positive for hepatitis B e antigen (HBeAg) and had been treated with ADV (10 mg/day) for 48 weeks. The numbers of patients infected with HBV genotype B and genotype C were 98 and 75 cases, respectively, and the remaining 10 patients were mixture infection of genotypes B plus C or genotypes B plus D. The mean HBV-DNA reduction and HBV-DNA seroclearance of genotypes B and C at 48 weeks were 3.6 log(10) and 3.1 log(10) copies/ml (p < 0.05) and 41.8% and 34.6% (p < 0.05), respectively. There were no statistically significant differences between genotypes B and C in terms of HBeAg loss, anti-HBe seroconversion and normalization of serum alanine aminotransferase (ALT). Multivariate analysis showed that young age, low pretreatment HBV-DNA and/or elevated ALT level might be independent predictive factors associated with initial virological response. Thus, in Han CHB patients who are HBeAg-positive, HBV genotype B shows a better virological response to ADV therapy than does genotype C.     

Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response

The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146; P = 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997; P = 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (P = 0.018). None of the PVR patients with HBV DNA at ≥5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009; P = 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at ≥5,000 copies/ml at year 1).     

肝硬化病原学分析和乙肝肝硬化中HBeAg阳性与阴性患者的临床特点比较

目的 通过大样本横断面回顾性调查，了解临床肝硬化患者病原组成及临床所见HBeAg(－)和HBeAg(＋)两类肝硬化患者临床相关因素的异同。 方法 对599例肝硬化患者的住院病历进行回顾性调查，分析肝硬化患者病因构成及占主要病因的乙肝肝硬化中的HBeAg(－)和HBeAg(＋)肝硬化组年龄、ALT、HBV DNA定量、CTP评分、PLT等指标的组内和组间差异。 结果 在肝硬化病因中以病毒性肝炎后肝硬化常见，有557例，占93.0％，其中又以乙肝肝硬化居多。在乙肝肝硬化中HBeAg (－)乙肝肝硬化306例，占62.3％；HBeAg(＋)肝硬化185例，占37.7％。HBeAg(＋)组ALT、HBV DNA总体上均高于HBeAg(－)组。HBeAg(－)组患者年龄明显高于HBeAg(＋)组。两组之间Child-Pugh，（CTP）积分无明显差异。 结论 目前我国临床所见肝硬化病例以病毒性肝炎感染后所致占绝大多数，乙肝肝硬化中又以HBeAg(－)者占多数。HBeAg(－) 与HBeAg(＋)肝硬化患者在病情轻重方面无明显差异，无论HBeAg是否阳性，病毒载量高时，抗病毒治疗及控制肝脏炎症能减轻病情恶化。     

慢性乙型肝炎基因分型与阿德福韦酯疗效相关性研究

目的 调查本地区乙型肝炎病毒(HBV)基因分型的分布情况,观察乙型肝炎基因分型对阿德福韦酯抗病毒疗效的影响.方法 对285例慢性乙型肝炎(其中HBV基因型B型219例,C型66例)用阿德福韦酯治疗的慢性乙型肝炎的患者进行分析,观察治疗12周、24周、48周及96周丙氨酸转氨酶(ALT)、HBV DNA定量、乙型肝炎病毒e抗原(HBeAg)乙型肝炎病毒e抗体定量.结果 阿德福韦酯治疗12周时B组以及C组HBV DNA转阴率为30.6%及36.4%,HBV DNA下降均值为(1.36±0.98)eopies/ml及(1.31±1.40)copies/ml(P>0.05);治疗24周两组HBV DNA转阴率分别为33.8%及42.4%,HBV DNA下降均值为(2.19±1.18)copies/ml及(2.22±1.10)copies/ml(P>0.05).治疗48周两组HBV DNA转阴率分别为38.8%及45.5%,HBV DNA下降均值为(2.98±1.24)copies/ml及(2.97±0.92)copies/ml(P>0.05).治疗96周两组HBV DNA转阴率分别为44.8%及48.5%,HBV DNA下降均值为(3.41±1.68)copies/ml及(3.50±1.72)copies/ml(P>0.05).治疗12周后B、C两组HBeAg转阴HBeAb出现分别为10.6%vs 8.6%及11.6%vs 9.3%,24周后B、C两组HBeAg转阴/HBeAb出现分别为14.6%vs 11.3%及16.3%vs 11.6%,48周后B、C两组HBeAg转阴/HBeAb出现分别为27.8%vs 21.2%及25.6%vs 20.9%,96周后B、C两组HBeAg转阴/HBeAb出现分剐为36.4%vs 25.2%及39.5%vs 25.6%,两组差异均无统计学意义(P>0.05).两组ALT复常率12周为59.8%vs 47.0%(P<0.05),24周为60.3%vs 63.6%,48周为76.3%vs 77.3%,96周为80.0%vs 80.3%,两组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B型及C型,病毒应答、生化应答及血清学应答相当,阿德福韦酯时HBV基因B型及C型疗效无明显影响.本地区HBV基因型以B型为主,C型次之,未发现A、D型.     

拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效预测分析

目的分析拉米夫定治疗HBeAg阳性慢性乙型肝炎52周疗效与24周抑制HBVDNA程度的相关性,探讨临床疗效预测指标。方法回顾性分析拉米夫定治疗HBeAg阳性慢性乙型肝炎患者96例,根据治疗24周时HBVDNA是否阴转（HBVDNA〈10^3拷贝／ml）分为病毒学转阴组和未转阴组,比较两组治疗52周时HBVDNA、HBeAg、ALT和YMDD病毒变异。结果治疗52周时,转阴组和未转阴组HBVDNA、HBeAg转阴率、ALT复常率和YMDD变异率分别为87．7％、59．6％、93．0％、3．5％和48．7％、30．8％、2．6％、74．4％、28．2％,有统计学意义（P〈0．01）。结论拉米夫定治疗24周时,若HBVDNA〈10^3拷贝／ml,52周可获得较好疗效;若HBVDNA〉10^3拷贝／ml,则52周时疗效不佳且发生耐药的可能性增加。24周拉米夫定对HBVDNA的抑制程度可作为1年疗效的预测指标。     

520例慢性乙型肝炎HBeAg阴性与阳性患者临床和HBV-DNA比较分析

目的:了解HBeAg(-)慢性乙型肝炎(CHB)患者临床特点和血清HBV-DNA检测的意义。方法:对520例CHB患者的住院病历进行回顾性调查,分析HBeAg(-)和HBeAg( )CHB患者HBV-DNA定量组内和组间差异。结果:HBeAg(-)CHB 166例,占31.92%;HBeAg( )CHB 354例,占68.08%。HBeAg( )组HBV-DNA总体上高于HBeAg(-)组;不同病程HBeAg(-)CHB比例轻度组为12.8%,中度组为13.2%,重度组为19.2%,重型组为31.4%,肝硬化组为47.5%。结论:目前我国CHB病例以HBeAg( )者占多数,HBeAg( )组HBV-DNA总体上高于HBeAg(-)组,随着病程进展HBeAg(-)CHB比例上升。     

替比夫定联合阿德福韦酯治疗阿德福韦酯应答不佳的乙型肝炎病毒e抗原阳性慢性乙型肝炎患者

目的评估替比夫定与阿德福韦酯联合治疗优化阿德福韦酯单药治疗应答不佳的阳性慢性乙型肝炎患者的疗效。方法选择2008年6月-2009年8月间共26例阿德福韦酯治疗至少12个月且病毒学应答不佳的乙型肝炎病毒e抗原(HBeAg),阳性的慢性乙型肝炎患者,在10 mg阿德福韦酯治疗的基础上,加用600 mg替比夫定。肝功能和乙型肝炎病毒(HBV)DNA每3个月评估1次,乙型肝炎两对半和腹部B型超声每半年评估1次。结果在第1年的治疗期间,所有患者血清HBV DNA水平均呈进行性下降,其中24例(92.3%)血清HBV DNA水平在联合治疗12个月时低于检测值下限,有25例(96.2%)患者丙氨酸转氨酶水平复常。治疗6个月时,分别有7例(26.9%)和2例(7.7%)患者发生HBeAg消失和血清学转换;治疗12个月时,分别有11例(42.3%)和8例(30.8%)患者发生HBeAg消失和血清学转换。整个治疗期间,26例患者均未出现病毒学突破。结论阿德福韦酯单药治疗应答不佳时,加用替比夫定可有效控制病毒,使患者获得较好的病毒学、生化学和免疫学应答。     

Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring

BACKGROUND/AIMS: Treatment of chronic delta hepatitis is long and difficult and better monitoring is needed. METHODS: In this study, hepatitis delta virus (HDV) RNA, hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA were retrospectively quantified in 53 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis delta. Twenty-one had received 28 courses of 3-5 MU interferon-alpha2b (IFN-alpha2b) thrice weekly for a median of 12.6 months (interquartile range [IQR]: 7.3-31.6), five had received eight courses of 100 mg lamivudine (LAM) daily for 23.6 months (IQR: 8.4-61.5) and 27 were untreated. The controls were 54 untreated, randomly selected, HBeAg-negative chronic hepatitis B patients without delta infection. Quantification of serum HDV RNA, HBsAg and HBV DNA were performed at baseline, during and at the end of treatment and end of follow up. RESULTS: Untreated patients had significantly higher median HBsAg levels than controls (5,872 vs 3,501 IU/ml; P = 0.046), but lower median HBV DNA levels (2.933 vs 6.459 log10 copies/ml; P < 0.001). Median baseline HDV RNA (6.374 log10 copies/ml) was similar in IFN-alpha2b-treated, LAM-treated and untreated patients. At the end of treatment, IFN-alpha2b significantly suppressed in paired measurements HDV RNA (P = 0.012) and HBsAg (P = 0.043), but LAM was inefficient. In IFN-alpha2b-treated patients, HDV RNA became undetectable in five patients within a median of 30 months (IQR: 8-90), followed by a slower decrease in HBsAg. CONCLUSIONS: In untreated chronic delta hepatitis, suppressed HBV replication is associated with significantly increased HBsAg serum levels. IFN-alpha2b significantly suppresses both HDV RNA and HBsAg, but LAM has no effect. Long-term IFN-alpha2b treatment (IQR: 1.5-5.0 years) appears necessary for undetectable serum HDV RNA and further treatment is required for HBsAg loss. Monitoring of HDV RNA and HBsAg serum levels in patients with chronic delta hepatitis provides insight during treatment.