恩替卡韦联合替诺福韦与恩替卡韦联合阿德福韦治疗拉米夫定耐药性慢性乙型肝炎患者疗效比较

目的探讨恩替卡韦(ETV)联合替诺福韦(TDF)与ETV联合阿德福韦(ADV)治疗拉米夫定(LMD)耐药性慢性乙型肝炎患者疗效,并对主要预后影响因素进行分析。方法选取在本院治疗的拉米夫定耐药的成年慢性乙型肝炎患者103例作为研究对象,其中ETV联合ADV组51例,ETV联合TDF组52例。回顾性分析患者的病历资料,包括年龄、性别、身高、体质量、体质量指数(BMI)、血小板、丙氨酸氨基转移酶(ALT)、总胆红素、清蛋白、国际标准化比值INR(IQR)、Child-Pugh评分、乙型肝炎e抗原(HBeAg)阳性数、乙肝病毒(HBV)的DNA水平、HBV的ADV耐药突变数、rtA181V/T变异、rtA181V/T+rtN236T变异、HBV的ETV耐药突变数、rtS202G变异、rtT184I/L/S变异、rtM250V/L变异及HBV的LAM、ADV及ETV耐药突变数、3~12个月患者HBV的DNA减少量及病毒学反应等信息,并进行统计分析。结果 ETV联合TDF组患者9个月HBV的DNA减少量(3.14±1.58)log10IU/mL高于ETV联合ADV组(2.31±1.84)log10IU/mL,差异具有统计学意义(P0.05);ETV联合TDF组患者12个月HBV的DNA减少量(3.28±1.62)log10IU/mL高于ETV联合ADV组(2.85±1.73)log10IU/mL,差异具有统计学意义(P0.05)。ETV联合TDF组患者6个月、9个月及12个月病毒学反应正常数均高于ETV联合ADV组患者,差异具有统计学意义(P0.05)。ETV联合TDF患者HBV的ADV耐药突变及rtA181V/T变异均低于ETV联合ADV组患者,差异具有统计学意义(均P0.05);而ETV联合TDF患者HBV的ETV耐药突变及rtS202G变异均高于ETV联合ADV组患者,差异具有统计学意义(P0.05)。ETV联合TDF组男性12个月HBV的DNA减少量高于女性(P0.05);男性患者6个月及9个月病毒学反应高于女性(P0.05)。根据多因素Logistic回归分析结果,HBV的DNA水平(OR=0.26,95%CI:0.03~0.64,P=0.015)是拉米夫定耐药性慢性乙型肝炎患者预后的危险因素,ETV联合TDF治疗(OR=98.54,95%CI:75.77~323.55,P=0.001)是拉米夫定耐药性慢性乙型肝炎患者预后的保护性因素。结论在慢性乙肝患者抗病毒疗效方面,TDF较ADV具有更强的抑制病毒活性。在对LAM和ADV应答下降的HBV感染者,TDF可能是高度有效的替代治疗药物。     

Efficacy of Adefovir-Based Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B Virus Infection

Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups (P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model (P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.     

Efficacy of Entecavir-Tenofovir Combination Therapy for Chronic Hepatitis B Patients with Multidrug-Resistant Strains

The emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P = 0.072 and P = 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.     

Adefovir dipivoxil for treatment of breakthrough hepatitis caused by lamivudine-resistant mutants of hepatitis B virus

OBJECTIVE: Adefovir dipivoxil (ADV) is a nucleoside analogue that inhibits wild-type hepatitis B virus (HBV) and lamivudine-resistant HBV mutants in vitro and in vivo. The aim of this study was to evaluate the efficacy of ADV against lamivudine-resistant mutants and of adefovir and interferon (IFN) add-on to lamivudine for patients with severe acute exacerbation of hepatitis caused by lamivudine-resistant mutants. METHODS: Fourteen patients with breakthrough hepatitis were treated with ADV. Four of the 14 patients also received IFN as combined treatment for severe acute exacerbation of hepatitis. RESULTS: At week 24, serum HBV DNA levels had significantly decreased by a median of over 4.8 log copies/ml in the ADV group and over 5.9 log copies/ml in the ADV + IFN group compared to baseline. The median decrease in alanine aminotransferase (ALT) levels from baseline to week 24 was -1.05 times the upper limit of normal (ULN) in the ADV group [significant at week 24 compared with baseline (p = 0.012)] and -22.3 times the ULN in the ADV + IFN group. CONCLUSIONS: Administration of ADV add-on to lamivudine for patients with breakthrough hepatitis reduced HBV DNA and ALT levels. ADV and IFN add-on to lamivudine could prevent a fatal course in patients with severe acute exacerbation of hepatitis.     

Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: a retrospective, multicenter, nonrandomized, open-label study

Objectives:The aim of this study was to assess the therapeutic effectiveness of adefovir dipivoxil (ADV), administered in combination with lamivudine (LAM) or as monotherapy, and the rate of resistance to ADV, in hepatitis B e antigen (HBeAg)-negative adult patients with chronic hepatitis B virus (HBV) infection and clinical or virologic resistance to LAM. Furthermore, we evaluated in these selected patients the clinical co-variates associated with a sustained virologic response. Methods:Data from adult outpatients aged >18 years with chronic HBV infection and clinical or virologic resistance to LAM were used in this retrospective, multicenter, nonrandomized, open-label study. Patients were selected if they received ADV 10 mg PO QD + LAM 100 mg QD PO or ADV 10 mg PO QD as monotherapy for 24 to 32 months between June 2003 and July 2006. End points were the proportions of patients who achieved virologic response (undetectable HBV-DNA [<3.3 log(10) copies/mL]) and biochemical response (normalization [<40 IU/L] of alanine aminotransferase [ALT]), and the proportions in whom resistance to ADV (rebound serum HBV-DNA >1 log(10) copies/mL compared with on-treatment nadir, as confirmed on molecular analysis) was found. HBV-DNA and ALT levels were checked every month during the first 3 months of treatment and every 3 months thereafter until 28 months. Data from each center were stored in a centralized database and analyzed by a blinded independent investigator. Results:Data from 70 patients were included (48 men, 22 women; median age, 51 years; ADV + LAM, 36 patients; ADV monotherapy, 34). The median duration of the pharmacologic treatment in the 2 groups of patients was 28 months (range, 24-32 months). By month 3, virologic response was achieved in 30 patients (83%) in the ADV + LAM group and in 26 patients (76%) in the ADV monotherapy group. At 12 months, virologic response was achieved in 5 additional patients in the ADV + LAM group and 2 additional patients in the ADV monotherapy group. Biochemical response was found to be time dependent: in the 2 groups, the rates of biochemical response were, respectively, 56% and 54% at month 3, 80% and 71% at month 6, and 96% and 79% at month 12, persisting up to the end of the study period. The rates of clinical resistance to ADV were 3% with ADV + LAM and 18% with ADV monotherapy (with a 6% rate of resistance due to rtA181 mutation in the monotherapy group). Logistic regression analysis found that pre-treatment levels of HBV-DNA <5 log(10) copies/mL, ALT levels >150 IU/L, an inflammation score >7, and a fibrosis score <2 were the strongest covariates independently associated with a sustained virologic response in both groups of patients. No adverse events were reported in any of the patients. Conclusion:ADV, administered in combination with LAM or as monotherapy, appeared to be effective in this small, selected group of HBeAg-negative patients with clinical or virologic resistance to LAM, especially in those with low pretreatment HBV-DNA levels, high ALT levels, and low fibrosis scores.     

Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients

A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P = 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (−2.8 log₁₀ IU/ml and −2.8 log₁₀ IU/ml, respectively; P = 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P = 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01023217","term_id":"NCT01023217"}}NCT01023217.)     

联合方案治疗拉米夫定耐药HBeAg阳性慢性乙型肝炎患者的临床观察

[目的]观察拉米夫定（LAM）联合阿德福韦酯（ADV）与恩替卡韦（ETV）联合ADV治疗LAM耐药HBeAg阳性慢性乙型肝炎（CHB）的临床疗效.[方法]选择LAM耐药的HBeAg阳性CHB患者50例,随机分为LAM联合ADV组（A组）,ETV联合ADV组（B组）,每组各25例,观察两组在治疗前及治疗12、24、48周时HBV DNA载量、谷丙转氨酶（ALT）水平、HBV血清标志物变化.[结果]两组在治疗12、24、48周HBV DNA均较治疗前下降（P＜0.05）;治疗48周时A组与B组的HBV DNA阴转率和ALT复常率率分别为76.0％与88.0％、80.0％与92.0％,两组间差异无统计学意义（P＞0.05）;治疗24周HBV DNA阴转率B组高于A组（分别为84.0％,52.0％）,差异有统计学意义（P＜0.05）;治疗24周ALT复常率B组高于A组（分别为80.0％,52.0％）,差异有统计学意义（P＜0.05）;治疗过程中两组HBeAg阴转率比较差异无统计学意义（P＞0.05）;未出现严重不良反应及病毒学突破.[结论]LAM联合ADV与ETV联合ADV治疗LAM耐药HBeAg阳性CHB患者均能获得良好的临床疗效且安全性良好;ETV联合ADV能快速抑制HBV DNA及降低ALT,早期HBV DNA阴转率及ALT复常率高于LAM联合ADV.     

阿德福韦酯治疗YMDD变异的慢性乙型肝炎的临床研究

目的：阿德福韦酯（ADV）治疗LAM耐药慢性乙型肝炎（CHB）患者的疗效。方法：选择LAM治疗后出现YMDD变异的HBeAg阳性CHB患者89例,其中随机分为（A组）43例接受ADV和LAM联合治疗3个月后,单用ADV治疗1年,B组45例给予ADV联合LAM治疗1年。结果：A、B两组治疗12月后,患者ALT复常率分别是60．5％、88．9％;HBVDNA阴转率分别为41．9％、82．2％,HBeAg阴转率分别是10．3％、29．7％。结论：ADV联合LAM治疗LAM耐药CHB患者有效,长期联合LAM能提高HBVDNA阴转率,有显著的抗病毒效果。     

In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir

Emergence of lamivudine-resistant hepatitis B virus (HBV) is a major concern in human immunodeficiency virus (HIV) and HBV coinfected patients. Following selection of resistant mutants, hepatitis flare or rapid progression to cirrhosis may occur. Treatment of patients with new nucleotide analogues such as adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF) has shown good efficacy in controlling wild-type or lamivudine-resistant HBV replication. The purpose of this study was to assess the in vitro efficacy of new nucleotide analogues on HBV strains isolated from lamivudine-treated patients. After purification of HBV DNA from patient sera, the whole HBV genome was PCR-amplified and cloned. Drug sensitivity was measured after transfection of the isolated full genomes into HepG2 cells and measurement of HBeAg, HBsAg and viral replication in the culture media under increasing drug concentrations. A wild-type strain isolated from an untreated patient served as control. In a clinical study of ADV (Gilead 460i study), seven of the 35 patients carried HBV strains with the triple lamivudine resistance-associated amino-acid changes rtV173L/L180M/M204V at baseline. Although all patients responded to ADV in this clinical study, the serum HBV reduction was lower in the seven patients with the triple mutation (median -3.3 log copies/ml) compared to the patients who had only the rtL180M/M204V mutations (median -4.1 log copies/ml) at week 48 (P=0.04, Mann-Whitney test). In our in vitro system, lamivudine IC50 on lamivudine-resistant HBV carrying amino-acid substitutions rtL180M and rtM204V within the polymerase encoding region increased by more than 16,000-fold (from 6 nM to over 100 microM) when compared to wild-type HBV. For ADV and TDF, comparison of wild-type and lamivudine-resistant HBV IC50 (rtL180M-M204V) showed, respectively, 2.85-fold (from 0.07 to 0.2 microM) and 3.3-fold (from 0.06 to 0.2 microM) increases, indicating a mild decrease of both drug activities, in vitro. At the ADV concentration of 0.1 microM, presence of the V173L mutation reduced the inhibition of HBsAg production from 50 to 30% (P<0.01) and the viral replication from 45 to 32% (P<0.01, Mann-Whitney). Conversely, tenofovir had similar potency on both HBV mutation profiles with 60% inhibition of HBsAg production and 45% inhibition of viral replication at 0.1 microM. Our study supports the high efficacy of ADV and TDF seen in patients after lamivudine breakthrough. The excellent activity of TDF on lamivudine-resistant virus independently of the resistance mutation profile offers an interesting treatment alternative to HIV-HBV coinfected patients.     

阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的疗效和安全性研究

目的评价一种国产阿德福韦酯用于治疗HBeAg阳性慢性乙型肝炎患者的疗效和安全性。方法采用多中心、随机、双盲、安慰剂对照的临床试验,选择HBeAg阳性的慢性乙型肝炎患者211例,按1∶1的比例随机分为阿德福韦酯组和拉米夫定组。完成12周治疗后均进入阿德福韦酯开放治疗期。完成12周和48周治疗时,检测血清HBVDNA及ALT水平。结果治疗12周时阿德福韦酯组（107例）血清HBVDNA水平平均下降2.94log10拷贝/ml,77.6%的受试者血清HBVDNA水平下降≥2log10拷贝/ml或血清HBVDNA≤104拷贝/ml,ALT均值下降76.9IU/L;而安慰剂组（104例）血清HBVDNA水平平均下降0.57log10拷贝/ml,血清HBVDNA水平下降≥2log10拷贝/ml或血清HBVDNA≤104拷贝/ml的受试者比例仅为13.5%,ALT均值下降20.9IU/L。两组血清HBVDNA水平下降值和血清ALT下降值比较,差异均有统计学意义（P〈0.05）。治疗48周时,阿德福韦酯组血清HBVDNA水平平均下降3.54log10拷贝/ml,ALT均值下降100.6IU/L;安慰剂组血清HBVDNA水平平均下降3.28log10拷贝/ml,ALT均值下降92.7IU/L;两组血清HBVDNA水平下降值和血清ALT下降值比较,差异无统计学意义（P〉0.05）。阿德福韦酯组不良事件发生率与安慰剂组相比,差异无统计学意义（P〉0.05）。结论阿德福韦酯治疗HBeAg阳性慢性乙型肝炎可在病毒学及生化学方面取得较好疗效,且安全性良好。     

Virological response and incidence of adefovir resistance in lamivudine-resistant patients treated with adefovir dipivoxil

BACKGROUND AND AIMS: The incidence of adefovir dipivoxil (ADV) resistance in patients with lamivudine (3TC)-resistant mutants who received ADV therapy remains unclear. The aims of this study were to determine the virological response to ADV, the incidence and the risk factors of ADV resistance, and the associated factors of initial virological response (IVR) in lamivudine-resistant patients. PATIENTS AND METHODS: Forty-six consecutive lamivudine-resistant chronic hepatitis B patients treated with ADV for more than 12 months with or without 3TC overlapping were prospectively examined for virological response and adefovir resistance. RESULTS: IVR was documented in 24 (52.2%) of patients. Of the 46 patients, 11 had ADV resistance (5 rtN236T, 5 rtA181T, 1 rtA181T and rtN236T). The cumulative incidence of ADV resistance at month 6, 12, 18 and 24 was 0%, 6.5%, 24.6% and 38.3% respectively. Compared with those without ADV resistance, patients with ADV resistance had a significantly higher rate of liver cirrhosis. Based on Cox regression analysis, the significant risk factor of ADV resistance was younger age (OR=0.92, 95% CI=0.86-0.99, P=0.023) and liver cirrhosis (OR=5.3, 95% CI=1.12-25.09, P=0.036). In addition, patients with ADV resistance were associated with higher HBV DNA levels and lower HBV DNA reduction in first 6 months of ADV treatment than those without ADV resistance. CONCLUSION: Only half of our patients achieved IVR on ADV treatment. The incidence of ADV resistance was high in 3TC-resistant patients treated with ADV.     

Comparison of the Efficacy of Lamivudine Plus Adefovir Versus Entecavir in the Treatment of Lamivudine-Resistant Chronic Hepatitis B: A Systematic Review and Meta-Analysis

Background

Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients.

Objective

The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB.

Methods

A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1.

Results

Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group.

Conclusions

For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.     

Hepatitis B virus e antigen loss during adefovir dipivoxil therapy is associated with enhanced virus-specific CD4+ T-cell reactivity

Weak T-cell reactivity to hepatitis B virus (HBV) is thought to be the dominant cause for chronic HBV infection. Treatment with adefovir dipivoxil (ADV) increases the rate of HBV e antigen (HBeAg) loss; however, the immune mechanisms associated with this treatment response are not understood. Serial analysis of HBV-specific CD4+ T-cell reactivity was performed during 48 weeks of therapy with ADV and correlated with treatment outcome for 19 HBeAg-positive patients receiving ADV (n = 13) or the placebo (n = 6). We tested T-cell reactivity to HBV at seven protocol time points by proliferation, cytokine production, and enzyme-linked immunospot assays. A panel of serum cytokines was quantitated by cytokine bead array. ADV-treated patients showed increased CD4+ T-cell responses to HBV and lower serum levels of cytokines compared to those of placebo-treated patients. Enhanced CD4+ T-cell reactivity to HBV, which peaked at treatment week 16, was confined to a subgroup of ADV-treated patients who achieved greater viral suppression (5.3 +/- 0.3 log(10) copies/ml [mean +/- standard error of the mean {SEM}] serum HBV DNA reduction from baseline) and HBeAg loss, but not to ADV-treated patients with moderate (3.4 +/- 0.2 log(10) copies/ml [mean +/- SEM]) viremia reduction who remained HBeAg positive or to patients receiving the placebo. In conclusion, T-cell reactivity to HBV increases in a proportion of ADV-treated patients and is associated with greater suppression of HBV replication and HBeAg loss.     

阿德福韦治疗慢性乙型肝炎的多中心、随机、部分双盲和安慰剂对照研究

目的：评价阿德福韦治疗慢性乙型病毒性肝炎（慢乙肝）的疗效和安全性。方法：进行52周的多中心、随机、部分双盲及安慰利对照临床研究。试验组119例在0～52周予阿德福韦10mg／d，对照组118例在0～12周（双盲对照期）予安慰剂10mg／d，第13～52周（开放治疗期）接受阿德福韦10mg／d。分别于治疗0、2、4、8、12、16、28、40及52周复查，除16周和28周外，均检测HBV血清标志物及HBV DNA水平，观察2组治疗期间HBV血清标志物、HBV DNA及ALT水平的变化及不良反应的发生情况。结果：双盲对照期结束时，试验组和对照组HBV DNA水平分别较基线下降2.9和0．6log10 copy／mL（P〈0、01），HBV DNA阴转率分别为28.8％和3．4％（P〈0．01），ALT复常率分别为46．0％和27．0％（P〈0.01）。开放治疗期结束时试验组和对照组HBV DNA水平的平均对数值分别较基线下降3、9和3、8 log10copy／mL，HBV DNA阴转率、ALT复常率及HBeAg血清转换率比较差异无统计学意义（P〉0.05）。不良反应轻微，无发生明显肾损害的病例。结论：阿德福韦能明显抑制慢乙肝患者的HBV DNA复制，促进ALT复常，且有良好的耐受性。     

阿德福韦酯与苦参素联合治疗HBeAg阳性慢性乙型肝炎的疗效观察

目的:观察和比较单用阿德福韦酯与阿德福韦酯联合苦参素治疗HBeAg阳性慢性乙型肝炎的疗效。方法:将2005年12月至2007年3月收治的63例HBeAg阳性慢性乙型肝炎患者分成联合组和单用组。联合组31例,同时使用阿德福韦酯及苦参素26周,随后继续单用阿德福韦酯26周。单用组32例,单用阿德福韦酯10mg/d,疗程52周。定期检测丙氨酸氨基转氨酶(ALT)复常率,HBVDNA转阴率,HBeAg/抗HBe血清转换率,两组在治疗结束时进行疗效评价。结果:两组ALT复常率在12、26、52周差异无显著性(P>0.05)。联合组HBVDNA阴转率在12周时为19.4%,单用组为12.5%,两组比较差异无显著性(P>0.05),但在第26周(54.8%vs28.1%),52周(64.5%vs46.9%)时,两组比较差异有显著性(P<0.05)。联合组与单用组HBeAg/抗HBe血清转换率12周时无明显差异,在第26周(25.8%vs9.4%),52周(38.7%vs18.8%)时,两组比较差异有显著性(P<0.05)。两组治疗过程中,未发现明显副作用。结论:阿德福韦酯和苦参素联合治疗HBeAg阳性慢性乙型肝炎,安全性与...     

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。     

深圳地区乙型肝炎病毒基因型分布与核苷类药物治疗后相应突变位点筛查的研究

目的了解深圳地区乙肝病毒基因型分布特点以及拉米夫定（LMV）和阿德福韦（ADV）两种药物治疗后相关指标变化情况。方法276例HBeAg阳性患者采用实时荧光定量PCR法检测HBV DNA的含姑,免疫化学发光法检测HBeAg的相对含量．DNA反向斑点杂交芯片技术检测HBV DNA基因型与LMV常见耐药位点、ADV常见耐药位点,全自动生化测定谷丙转氦酶。随机选取未发牛以上突变位点慢性病例各96例,分别以LMV和ADV两种药物进行治疗,于治疗前和治疗3、12个月检测HBV DNA、HBeAg及ALT的含量,并在治疗12个月时筛查2组耐药突变位点。结果276例HBeAg阳性标本有270例可以进行分型,其中B型138例（50．0％）、C型96例（34．8％）、D型10例（3．6％）、B＋C混合型26例（9．4％）、末分碰6例（2．2％）。在治疗3个月时LMV组HBV DNA与HBeAg含量下降速度和阴转率以及ALT下降明显高于ADV组（P〈0．05）;但在治疗第12个月时LMV组HBV DNA含节下降速度和阴转率反而低于ADV组。LMV组有20例发生耐药他点,而ADV组无一例发生位点突变。结论深圳地区乙肝分型主要以B、C两型为主．B型略占优势,B＋C混合型也占有一定比例,核苷类药物LAM及ADV单药治疗慢性乙肝患者均有较好的疗效,但两种药物比较,短期效果LAM优于ADV,随着用药时间延长,耐药突变基因的逐渐出现,ADV长期治疗效果反而要优于LAM。     

拉米夫定联合阿德福韦酯治疗活动性乙型病毒性肝炎肝硬化临床观察

目的比较拉米夫定联合阿德福韦酯治疗乙型病毒性肝炎肝硬化的临床效果。方法 120例乙型病毒性肝炎肝硬化患者,依据治疗方法分为拉米夫定治疗组（拉米夫定组）、阿德福韦酯治疗组（阿德福韦酯组）、拉米夫定联合阿德福韦酯治疗组（联合组）各40例,3组均连续治疗12个月以上。比较3组治疗6、9、12个月后HBeAg、HBV-DNA转阴率及治疗12个月后肝功能Child-pugh分级情况。结果联合组治疗6个月后HBV-DNA转阴率、治疗12个月后HBeAg转阴率及肝功能Child-pugh分级A级比率高于拉米夫定组和阿德福韦酯组（P〈0.05）。结论拉米夫定联合阿德福韦酯在提高乙型病毒性肝炎肝硬化患者HBeAg及HBV DNA转阴率上明显优于单用拉米夫定、阿德福韦酯。